Vol. 29 (2024)



No.  01DOI: 10.1186/s11658-023-00527-9 Volume 29 (2024) - 29:01
Title CORRECTION: ClC-2 KNOCKDOWN PREVENTS CEREBROVASCULAR REMODELING VIA INHIBITION OF THE Wnt/β-CATENIN SIGNALING PATHWAY
Authors Jingjing Lu1, Feng Xu2, Yingna Zhang3, Hong Lu4 & Jiewen Zhang1*
Abstract Correction: Cellular & Molecular Biology Letters (2018)
23:29 https://doi.org/10.1186/s11658-018-0095-z

Following publication of the original article [1], the authors informed us that there is in Fig. 3C. The pictures used in the AngII and AngII + Negative groups in Fig. 3C were repeated. Neither of these changes affects the results and conclusions of this study.

The original article can be found online at https://doi.org/10.1186/s11658-018-0095-z.
Keywords
Address and Contact Information 1 Department of Neurology, Henan People’s Hospital, No. 7 Wai-5 Road, Zhengzhou 450052, Henan, China
2 Department of Urology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
3 Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
4 Department of Neurology, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan, China
*Corresponding author: HZ_Sammy@163.com
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No.  02DOI: 10.1186/s11658-023-00523-z Volume 29 (2024) - 29:02
Title TRANSFER RNA-DERIVED SMALL RNA tRF-Glu-CTC ATTENUATES NEOINTIMAL FORMATION VIA INHIBITION OF FIBROMODULIN
Authors Qi‐Lan Jiang1, Jia‐Ying Xu2, Qing‐Ping Yao3, Rui Jiang4, Qin Xu2, Bo‐Tao Zhang2, Tao Li5* and Jun Jiang2*
Abstract Neointimal hyperplasia is a pathological vascular remodeling caused by abnormal proliferation and migration of subintimal vascular smooth muscle cells (VSMCs) following intimal injury. There is increasing evidence that tRNA-derived small RNA (tsRNA) plays an important role in vascular remodeling. The purpose of this study is to search for tsRNAs signature of neointima formation and to explore their potential functions. The balloon injury model of rat common carotid artery was replicated to induce intimal hyperplasia, and the differentially expressed tsRNAs (DE-tsRNAs) in arteries with intimal hyperplasia were screened by small RNA sequencing and tsRNA library. A total of 24 DE-tsRNAs were found in the vessels with intimal hyperplasia by small RNA sequencing. In vitro, tRF-Glu-CTC inhibited the expression of fibromodulin (FMOD) in VSMCs, which is a negative modulator of TGF-β1 activity. tRF-Glu-CTC also increased VSMC proliferation and migration. In vivo experiments showed that inhibition of tRF-Glu-CTC expression after balloon injury of rat carotid artery can reduce the neointimal area. In conclusion, tRF-Glu-CTC expression is increased after vascular injury and inhibits FMOD expression in VSMCs, which influences neointima formation. On the other hand, reducing the expression of tRF-Glu-CTC after vascular injury may be a potential approach to prevent vascular stenosis.
Keywords Transfer RNA (tRNA)-derived small RNAs (tsRNAs), Vascular smooth muscle cell, Vascular remodeling, Neointimal hyperplasia (NIH), Proliferation, Migration
Address and Contact Information 1 Department of Clinical Nutrition, Afliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
2 Department of General Surgery (Thyroid Surgery), The Afliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou 646000, Sichuan Province, China
3 Institute of Mechanobiology and Medical Engineering, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
4 Department of Urology, Afliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
5 Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, Sichuan Province, China
*Corresponding author: leta49@swmu.edu.cn; jiangjun@swmu.edu.cn
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No.  03DOI: 10.1186/s11658-023-00520-2 Volume 29 (2024) - 29:03
Title CIRCULAR RNA-circPan3 ATTENUATES CARDIAC HYPERTROPHY VIA miR-320-3p/HSP20 AXIS
Authors Xinyu Fang1, Xiang Ao1, Dandan Xiao1, Yu Wang1, Yi Jia1, Peiyan Wang1, Mengyang Li1* and Jianxun Wang1*
Abstract Background: Circular RNAs are enriched in cardiac tissue and play important roles in the pathogenesis of heart diseases. In this study, we aimed to investigate the regulatory mechanism of a conserved heart-enriched circRNA, circPan3, in cardiac hypertrophy.
Methods: Cardiac hypertrophy was induced by isoproterenol. The progression of cardiomyocyte hypertrophy was assessed by sarcomere organization staining, cell surface area measurement, and expression levels of cardiac hypertrophy markers. RNA interactions were detected by RNA pull-down assays, and methylated RNA immunoprecipitation was used to detect m6A level.
Results: The expression of circPan3 was downregulated in an isoproterenol-induced cardiac hypertrophy model. Forced expression of circPan3 attenuated cardiomyocyte hypertrophy, while inhibition of circPan3 aggravated cardiomyocyte hypertrophy. Mechanistically, circPan3 was an endogenous sponge of miR-320-3p without affecting miR-320-3p levels. It elevated the expression of HSP20 by endogenously interacting with miR-320-3p. In addition, circPan3 was N6-methylated. Stimulation by isoproterenol downregulated the m6A eraser ALKBH5, resulting in N6-methylation and destabilization of circPan3.
Conclusions: Our research is the first to report that circPan3 has an antihypertrophic effect in cardiomyocytes and revealed a novel circPan3-modulated signalling pathway involved in cardiac hypertrophy. CircPan3 inhibits cardiac hypertrophy by targeting the miR-320-3p/HSP20 axis and is regulated by ALKBH5-mediated N6-methylation. This pathway could provide potential therapeutic targets for cardiac hypertrophy.
Keywords Cardiac hypertrophy, m6A modifcation, Circular RNA, circPan3, miR- 320-3p, HSP20
Address and Contact Information 1 School of Basic Medicine, Qingdao University, Qingdao 266071, China
*Corresponding author: limengyang@qdu.edu.cn; wangjx@qdu.edu.cn
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No.  04DOI: 10.1186/s11658-023-00521-1 Volume 29 (2024) - 29:04
Title THE REGULATORY RELATIONSHIP BETWEEN TRANSCRIPTION FACTOR STAT3 AND NONCODING RNA
Authors Siyi Liu1,2, Wentao Li2, Lin Liang2, Yanhong Zhou2* and Yanling Li1*
Abstract Signal transducer and activator of transcription 3 (STAT3), as a key node in numerous carcinogenic signaling pathways, is activated in various tumor tissues and plays important roles in tumor formation, metastasis, and drug resistance. STAT3 is considered a potential subtarget for tumor therapy. Noncoding RNA (ncRNA) is a special type of RNA transcript. Transforming from “junk” transcripts into key molecules involved in cell apoptosis, growth, and functional regulation, ncRNA has been proven to be closely related to various epithelial–mesenchymal transition and drug resistance processes in tumor cells over the past few decades. Research on the relationship between transcription factor STAT3 and ncRNAs has attracted increased attention. To date, existing reviews have mainly focused on the regulation by ncRNAs on the transcription factor STAT3; there has been no review of the regulation by STAT3 on ncRNAs. However, understanding the regulation of ncRNAs by STAT3 and its mechanism is important to comprehensively understand the mutual regulatory relationship between STAT3 and ncRNAs. Therefore, in this review, we summarize the regulation by transcription factor STAT3 on long noncoding RNA, microRNA, and circular RNA and its possible mechanisms. In addition, we provide an update on research progress on the regulation of STAT3 by ncRNAs. This will provide a new perspective to comprehensively understand the regulatory relationship between transcription factor STAT3 and ncRNAs, as well as targeting STAT3 or ncRNAs to treat diseases such as tumors.
Keywords circRNA, LncRNA, microRNA, STAT3, Transcription factor
Address and Contact Information 1 Department of Nuclear Medicine, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
2 Cancer Research Institute, Basic School of Medicine, Central South University, Changsha 410011, Hunan, China
*Corresponding author: zhouyanhong@csu.edu.cn; liyanling@hnca.org.cn
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No.  05DOI: 10.1186/s11658-023-00522-0 Volume 29 (2024) - 29:05
Title MYCT1 INHIBITS HEMATOPOIESIS IN DIFFUSE LARGE B-CELL LYMPHOMA BY SUPPRESSING RUNX1 TRANSCRIPTION
Authors Ying Liang1,2, Xin Wei2, Peng‐Jie Yue2, He‐Cheng Zhang1, Zhen‐Ning Li3, Xiao‐Xue Wang2, Yuan‐Yuan Sun1* and Wei‐Neng Fu1*
Abstract Background: The abnormality of chromosomal karyotype is one factor causing poor prognosis of lymphoma. In the analysis of abnormal karyotype of lymphoma patients, three smallest overlap regions were found, in which MYCT1 was located. MYCT1 is the first tumor suppressor gene cloned by our research team, but its studies relating to the occurrence and development of lymphoma have not been reported.
Methods: R banding analyses were employed to screen the abnormality of chromosomal karyotype in clinical specimen and MYCT1 over-expression cell lines. FISH was to monitor MYCT1 copy number aberration. RT-PCR and Western blot were to detect the mRNA and protein levels of the MYCT1 and RUNX1 genes, respectively. The MYCT1 and RUNX1 protein levels in clinical specimen were evaluated by immunohistochemical DAB staining. The interaction between MYCT1 and MAX proteins was identified via Co-IP and IF. The binding of MAX on the promoter of the RUNX1 gene was detected by ChIP and Dual-luciferase reporter assay, respectively. Flow cytometry and CCK-8 assay were to explore the effects of MYCT1 and RUNX1 on the cell cycle and proliferation, respectively.
Results: MYCT1 was located in one of three smallest overlap regions of diffuse large B-cell lymphoma, it altered chromosomal instability of diffuse large B-cell lymphoma cells. MYCT1 negatively correlated with RUNX1 in lymphoma tissues of the patients. MAX directly promoted the RUNX1 gene transcription by binding to its promoter region. MYCT1 may represses RUNX1 transcription by binding MAX in diffuse large B-cell lymphoma cells. MYCT1 binding to MAX probably suppressed RUNX1 transcription, leading to the inhibition of proliferation and cell cycle of the diffuse large B-cell lymphoma cells.
Conclusion: This study finds that there is a MYCT1-MAX-RUNX1 signaling pathway in diffuse large B-cell lymphoma. And the study provides clues and basis for the in-depth studies of MYCT1 in the diagnosis, treatment and prognosis of lymphoma.
Keywords MYCT1, Difuse large B-cell lymphoma, Chromosomal karyotype
Address and Contact Information 1 Department of Medical Genetics, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, People’s Republic of China
2 Department of Hematology, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of China
3 Department of Oromaxillofacial‐Head and Neck Surgery, Liaoning Province Key Laboratory of Oral Disease, School and Hospital of Stomatology, China Medical University, Shenyang, People’s Republic of China
*Corresponding author: yysun@cmu.edu.cn; wnfu@cmu.edu.cn
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No.  06DOI: 10.1186/s11658-023-00519-9 Volume 29 (2024) - 29:06
Title ONCOGENIC ACTIVATION OF EEF1A2 EXPRESSION: A JOURNEY FROM A PUTATIVE TO AN ESTABLISHED ONCOGENE
Authors Saket Awadhesbhai Patel1,2, Md. Khurshidul Hassan1,2 and Manjusha Dixit1,2*
Abstract Protein synthesis via translation is a central process involving several essential proteins called translation factors. Although traditionally described as cellular “housekeepers,” multiple studies have now supported that protein initiation and elongation factors regulate cell growth, apoptosis, and tumorigenesis. One such translation factor is eukaryotic elongation factor 1 alpha 2 (EEF1A2), a member of the eukaryotic elongation factor family, which has a canonical role in the delivery of aminoacyl-tRNA to the A-site of the ribosome in a guanosine 5′-triphosphate (GTP)-dependent manner. EEF1A2 differs from its closely related isoform, EEF1A1, in tissue distribution. While EEF1A1 is present ubiquitously, EEF1A2 replaces it in specialized tissues. The reason why certain specialized tissues need to essentially switch EEF1A1 expression altogether with EEF1A2 remains to be answered. Abnormal “switch on” of the EEF1A2 gene in normal tissues is witnessed and is seen as a cause of oncogenic transformation in a wide variety of solid tumors. This review presents the journey of finding increased expression of EEF1A2 in multiple cancers, establishing molecular mechanism, and exploring it as a target for cancer therapy. More precisely, we have compiled studies in seven types of cancers that have reported EEF1A2 overexpression. We have discussed the effect of aberrant EEF1A2 expression on the oncogenic properties of cells, signaling pathways, and interacting partners of EEF1A2. More importantly, in the last part, we have discussed the unique potential of EEF1A2 as a therapeutic target. This review article gives an up-to-date account of EEF1A2 as an oncogene and can draw the attention of the scientific community, attracting more research.
Keywords Cancer, EEF1A1, EEF1A2, PI3K, AKT
Address and Contact Information 1 School of Biological Sciences, National Institute of Science Education and Research, Room No. 204, P.O. Jatni, Khurda, Bhubaneswar, Odisha 752050, India
2 Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai 400094, India
*Corresponding author: manjusha@niser.ac.in
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No.  07DOI: 10.1186/s11658-023-00516-y Volume 29 (2024) - 29:07
Title THE PYROPTOSIS MEDIATED BIOMARKER PATTERN: AN EMERGING DIAGNOSTIC APPROACH FOR PARKINSON’S DISEASE
Authors Junhan Liang1, Zhirong Wan2, Cheng Qian1, Madiha Rasheed1, Changling Cao1, Jingyan Sun3, Xuezhe Wang1, Zixuan Chen1* and Yulin Deng1*
Abstract Background: Parkinson’s disease (PD) affects 1% of people over 60, and long-term levodopa treatment can cause side effects. Early diagnosis is of great significance in slowing down the pathological process of PD. Multiple pieces of evidence showed that non-coding RNAs (ncRNAs) could participate in the progression of PD pathology. Pyroptosis is known to be regulated by ncRNAs as a key pathological feature of PD. Therefore, evaluating ncRNAs and pyroptosis-related proteins in serum could be worthy biomarkers for early diagnosis of PD.
Methods: NcRNAs and pyroptosis/inflammation mRNA levels were measured with reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Luciferase assays were performed to confirm GSDME as a target of miR-675-5p and HMGB1 as a target of miR-1247-5p. In the serum of healthy controls (n = 106) and PD patients (n = 104), RT-qPCR was utilized to assess miR-675-5p, miR-1247-5p, and two related ncRNAs (circSLC8A1and lncH19) levels. The enzyme-linked immunosorbent assay measured serum levels of pyroptosis-related proteins in controls (n = 54) and PD patients (n = 70).
Results: Our data demonstrated that miR-675-5p and miR-1247-5p significantly changed in PD neuron and animal models. Overexpressed miR-675-5p or downregulated miR-1247-5p could regulate pyroptosis and inflammation in PD neuron models. Using the random forest algorithm, we constructed a classifier based on PD neuron-pyroptosis pathology (four ncRNAs and six proteins) having better predictive power than single biomarkers (AUC = 92%). Additionally, we verified the performance of the classifier in early-stage PD patients (AUC ≥ 88%).
Conclusion: Serum pyroptosis-related ncRNAs and proteins could serve as reliable, inexpensive, and non-invasive diagnostic biomarkers for PD.
Keywords Parkinson’s disease, Biomarker patterns, Machine learning
Address and Contact Information 1 Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Zhongguancun South Street, Haidian District, Beijing 100081, People’s Republic of China
2 Department of Neurology, Aerospace Center Hospital, Beijing 100049, People’s Republic of China
3 School of Life Sciences, Beijing Institute of Technology, Beijing 100081, People’s Republic of China
*Corresponding author: zx-chen@bit.edu.cn; deng@bit.deu.cn
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No.  08DOI: 10.1186/s11658-023-00529-7 Volume 29 (2024) - 29:08
Title IDH1/MDH1 DEACETYLATION PROMOTES ACUTE LIVER FAILURE BY REGULATING NETosis
Authors Yukun Wang1, Chunxia Shi1, Jin Guo1, Danmei Zhang1, Yanqiong Zhang1, Long Zhang1 and Zuojiong Gong1*
Abstract Background: Acute liver failure (ALF) is a life-threatening disease, but its pathogenesis is not fully understood. NETosis is a novel mode of cell death. Although the formation of neutrophil extracellular traps (NETs) has been found in various liver diseases, the specific mechanism by which NETosis regulates the development of ALF is unclear. In this article, we explore the role and mechanism of NETosis in the pathogenesis of ALF.
Methods: Clinically, we evaluated NETs-related markers in the liver and peripheral neutrophils of patients with ALF. In in vitro experiments, HL-60 cells were first induced to differentiate into neutrophil-like cells (dHL-60 cells) with dimethyl sulfoxide (DMSO). NETs were formed by inducing dHL-60 cells with PMA. In in vivo experiments, the ALF model in mice was established with LPS/D-gal, and the release of NETs was detected by immunofluorescence staining and western blotting. Finally, the acetylation levels of IDH1 and MDH1 were detected in dHL-60 cells and liver samples by immunoprecipitation.
Results: Clinically, increased release of NETs in liver tissue was observed in patients with ALF, and NETs formation was detected in neutrophils from patients with liver failure. In dHL-60 cells, mutations at IDH1-K93 and MDH1-K118 deacetylate IDH1 and MDH1, which promotes the formation of NETs. In a mouse model of ALF, deacetylation of IDH1 and MDH1 resulted in NETosis and promoted the progression of acute liver failure.
Conclusions: Deacetylation of IDH1 and MDH1 reduces their activity and promotes the formation of NETs. This change aggravates the progression of acute liver failure.
Keywords Deacetylation, Acute liver failure, NETosis
Address and Contact Information 1 Department of Infectious Diseases, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, China
*Corresponding author: zjgong@163.com
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No.  09DOI: 10.1186/s11658-023-00525-x Volume 29 (2024) - 29:09
Title MYH1G-AS IS A CHROMATIN-ASSOCIATED lncRNA THAT REGULATES SKELETAL MUSCLE DEVELOPMENT IN CHICKEN
Authors Bolin Cai1,2, Manting Ma1,2, Rongshuai Yuan1,2, Zhen Zhou1,2, Jing Zhang3, Shaofen Kong1,2, Duo Lin1,2, Ling Lian4, Juan Li5, Xiquan Zhang1,2 and Qinghua Nie1,2*
Abstract Background Skeletal muscle development is pivotal for animal growth and health. Recently, long noncoding RNAs (lncRNAs) were found to interact with chromatin through diverse roles. However, little is known about how lncRNAs act as chromatin-associated RNAs to regulate skeletal muscle development. Here, we aim to investigate the regulation of chromatin-associated RNA (MYH1G-AS) during skeletal muscle development. Methods We provided comprehensive insight into the RNA profile and chromatin accessibility of different myofibers, combining RNA sequencing (RNA-seq) with an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). The dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to analyze the transcriptional regulation mechanism of MYH1G-AS. ALKBH5-mediated MYH1G-AS N6-methyladenosine (m6A) demethylation was assessed by a single-base elongation and ligation-based qPCR amplification method (SELECT) assay. Functions of MYH1G-AS were investigated through a primary myoblast and lentivirus/cholesterol-modified antisense oligonucleotide (ASO)-mediated animal model. To validate the interaction of MYH1G-AS with fibroblast growth factor 18 (FGF18) protein, RNA pull down and an RNA immunoprecipitation (RIP) assay were performed. Specifically, the interaction between FGF18 and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5) protein was analyzed by coimmunoprecipitation (Co-IP) and a yeast two-hybrid assay. Results A total of 45 differentially expressed (DE) lncRNAs, with DE ATAC-seq peaks in their promoter region, were classified as open chromatin-associated lncRNAs. A skeletal muscle-specific lncRNA (MSTRG.15576.9; MYH1G-AS), which is one of the open chromatin-associated lncRNA, was identified. MYH1G-AS transcription is coordinately regulated by transcription factors (TF) SMAD3 and SP2. Moreover, SP2 represses ALKBH5 transcription to weaken ALKBH5-mediated m6A demethylation of MYH1G-AS, thus destroying MYH1G-AS RNA stability. MYH1G-AS accelerates myoblast proliferation but restrains myoblast differentiation. Moreover, MYH1G-AS drives a switch from slow-twitch to fast-twitch fibers and causes muscle atrophy. Mechanistically, MYH1G-AS inhibits FGF18 protein stabilization to reduce the interaction of FGF18 to SMARCA5, thus repressing chromatin accessibility of the SMAD4 promoter to activate the SMAD4-dependent pathway. Conclusions Our results reveal a new pattern of the regulation of lncRNA expression at diverse levels and help expound the regulation of m6A methylation on chromatin status.
Keywords Chromatin accessibility, LncRNA MYH1G-AS, m6A methylation, Skeletal muscle development
Address and Contact Information 1 State Key Laboratory of Livestock and Poultry Breeding, Guangdong Laboratory for Lingnan Modern Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, China
2 Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, National-Local Joint Engineering Research Center for Livestock Breeding, Guangzhou, China
3 Randall Centre of Cell and Molecular Biophysics, Faculty of Life Sciences and Medicine, New Hunt’s House, King’s College London, Guy’s Campus, London, UK
4 National Engineering Laboratory for Animal Breeding and MOA Key Laboratory of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing,China
5 Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
*Corresponding author: nqinghua@scau.edu.cn
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No.  10DOI: 10.1186/s11658-023-00526-w Volume 29 (2024) - 29:10
Title THE EFFICACY OF ADIPOSE-DERIVED STEM CELLS IN BURN INJURIES: A SYSTEMATIC REVIEW
Authors Michael Kohlhauser1*, Alexandru Tuca1,2 and Lars‐Peter Kamolz1,3
Abstract Background: Burn injuries can be associated with prolonged healing, infection, a substantial inflammatory response, extensive scarring, and eventually death. In recent decades, both the mortality rates and long-term survival of severe burn victims have improved significantly, and burn care research has increasingly focused on a better quality of life post-trauma. However, delayed healing, infection, pain and extensive scar formation remain a major challenge in the treatment of burns. ADSCs, a distinct type of mesenchymal stem cells, have been shown to improve the healing process. The aim of this review is to evaluate the efficacy of ADSCs in the treatment of burn injuries.
Methods: A systematic review of the literature was conducted using the electronic databases PubMed, Web of Science and Embase. The basic research question was formulated with the PICO framework, whereby the usage of ADSCs in the treatment of burns in vivo was determined as the fundamental inclusion criterion. Additionally, pertinent journals focusing on burns and their treatment were screened manually for eligible studies. The review was registered in PROSPERO and reported according to the PRISMA statement.
Results: Of the 599 publications screened, 21 were considered relevant to the key question and were included in the present review. The included studies were almost all conducted on rodents, with one exception, where pigs were investigated. 13 of the studies examined the treatment of full-thickness and eight of deep partial-thickness burn injuries. 57,1 percent of the relevant studies have demonstrated that ADSCs exhibit immunomodulatory effects during the inflammatory response. 16 studies have shown improved neovascularisation with the use of ADSCs. 14 studies report positive influences of ADSCs on granulation tissue formation, while 11 studies highlight their efficacy in promoting re-epithelialisation. 11 trials demonstrated an improvement in outcomes during the remodelling phase.
Conclusion: In conclusion, it appears that adipose-derived stem cells demonstrate remarkable efficacy in the field of regenerative medicine. However, the usage of ADSCs in the treatment of burns is still at an early experimental stage, and further investigations are required in order to examine the potential usage of ADSCs in future clinical burn care.
Keywords Adipose-derived stem cells, Mesenchymal stem cells, Stem cell research, Burns, Burn injury, Burn care, Tissue engineering, Regenerative medicine, Wound healing
Address and Contact Information 1 Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
2 Department of Surgery, State Hospital Güssing, Güssing, Austria
3 COREMED‐Cooperative Centre for Regenerative Medicine, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Graz, Austria
*Corresponding author: michael.kohlhauser@medunigraz.at
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No.  11DOI: 10.1186/s11658-023-00524-y Volume 29 (2024) - 29:11
Title RETRACTION NOTE: INHIBITION OF INFLAMMATION USING DIACEREIN MARKEDLY IMPROVED RENAL FUNCTION IN ENDOTOXEMIC ACUTE KIDNEY INJURED MICE
Authors Guangzhe Yu1, Qian Liu2, Xuening Dong2, Kaihong Tang2, Bohui Li2, Chunmei Liu2, Wenzheng Zhang2, Yiduo Wang2 and Yingyu Jin2*
Abstract The Original Article was published on 16 August 2018

Retraction: Cellular & Molecular Biology Letters (2018) 23:38
https://doi.org/10.1186/s11658-018-0107-z

    The Editor-in-Chief has retracted this article due to concerns about several images, specifically:
  • In Fig. 1C the LPS panel is similar to Fig. 6C WKY/BCL6 OE in a previously-published paper by different authors [1].
  • In Figs. 2A,B there are multiple overlaps with panels in Figs. 8 and 3A in two previously-published papers by different authors [2, 3] respectively.


The authors stated that they used third-party services to obtain some of their data. The Editor-in-Chief, therefore, has lost confidence in the integrity of the article's findings. We contacted the authors on the emails they provided at submission. Yingyu Jin has stated on behalf of the authors that they agree to this retraction.
Keywords
Address and Contact Information 1 Department of Emergency Surgery, The 1st Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
2 Department of Laboratory Diagnosis, The 1st Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, People’s Republic of China
*Corresponding author: yingyu_jin@163.com
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No.  12DOI: 10.1186/s11658-023-00530-0 Volume 29 (2024) - 29:12
Title INCREASED SERUM EXTRACHROMOSOMAL CIRCULAR DNA SORBS1circle LEVEL IS ASSOCIATED WITH INSULIN RESISTANCE IN PATIENTS WITH NEWLY DIAGNOSED TYPE 2 DIABETES MELLITUS
Authors Xiang Kong1,2,3†, Shu‐jun Wan1,3†, Tian‐bing Chen1,3†, Lan Jiang1,3, Yu‐jie Xing1,2, Ya‐ping Bai1, Qiang Hua4, Xin‐ming Yao4, Yong‐li Zhao4, Hong‐mei Zhang5, De‐guo Wang2*, Qing Su5* and Kun Lv1,3*
Abstract Background: Extrachromosomal circular DNAs (eccDNAs) exist in human blood and somatic cells, and are essential for oncogene plasticity and drug resistance. However, the presence and impact of eccDNAs in type 2 diabetes mellitus (T2DM) remains inadequately understood.
Methods: We purified and sequenced the serum eccDNAs obtained from newly diagnosed T2DM patients and normal control (NC) subjects using Circle-sequencing. We validated the level of a novel circulating eccDNA named sorbin and SH3‐domain‐ containing‐1circle97206791–97208025 (SORBS1circle) in 106 newly diagnosed T2DM patients. The relationship between eccDNA SORBS1circle and clinical data was analyzed. Furthermore, we explored the source and expression level of eccDNA SORBS1circle in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model.
Results: A total of 22,543 and 19,195 eccDNAs were found in serum samples obtained from newly diagnosed T2DM patients and NC subjects, respectively. The T2DM patients had a greater distribution of eccDNA on chromosomes 1, 14, 16, 17, 18, 19, 20 and X. Additionally, 598 serum eccDNAs were found to be upregulated, while 856 eccDNAs were downregulated in T2DM patients compared with NC subjects. KEGG analysis demonstrated that the genes carried by eccDNAs were mainly associated with insulin resistance. Moreover, it was validated that the eccDNA SORBS1circle was significantly increased in serum of newly diagnosed T2DM patients (106 T2DM patients vs. 40 NC subjects). The serum eccDNA SORBS1circle content was positively correlated with the levels of glycosylated hemoglobin A1C (HbA1C) and homeostasis model assessment of insulin resistance (HOMA-IR) in T2DM patients. Intracellular eccDNA SORBS1circle expression was significantly enhanced in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. Moreover, the upregulation of eccDNA SORBS1circle in the HG/PA-treated HepG2 cells was dependent on generation of apoptotic DNA fragmentation.
Conclusions: These results provide a preliminary understanding of the circulating eccDNA patterns at the early stage of T2DM and suggest that eccDNA SORBS1circle may be involved in the development of insulin resistance.
Keywords Extrachromosomal circular DNAs, T2DM, SORBS1, Insulin resistance
Address and Contact Information 1 Anhui Provincial Key Laboratory of Non‐Coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu 241002, China
2 Geriatric Endocrinology Unit, Department of Gerontology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu 241001, China
3 Central Laboratory of Yijishan Hospital, Wuhu 241001, China
4 Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu 241001, China
5 Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
*Corresponding author: wangdeguo@medmail.com.cn; suqing@xinhuamed.com.cn; lvkun315@126.com
† Xiang Kong, Shu-jun Wan and Tian-bing Chen contributed equally to this work.
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No.  13DOI: 10.1186/s11658-023-00528-8 Volume 29 (2024) - 29:13
Title MULTIPRONGED REGULATION OF AUTOPHAGY AND APOPTOSIS: EMERGING ROLE OF TRIM PROTEINS
Authors Nuzhat Ahsan1*†, Mohd Shariq1†, Avadhesha Surolia2*, Reshmi Raj1, Mohammad Firoz Khan1 and Pramod Kumar1
Abstract TRIM proteins are characterized by their conserved N-terminal RING, B-box, and coiled-coil domains. These proteins are efficient regulators of autophagy, apoptosis, and innate immune responses and confer immunity against viruses and bacteria. TRIMs function as receptors or scaffold proteins that target substrates for autophagy-mediated degradation. Most TRIMs interact with the BECN1-ULK1 complex to form TRIMosomes, thereby efficiently targeting substrates to autophagosomes. They regulate the functions of ATG proteins through physical interactions or ubiquitination. TRIMs affect the lipidation of MAP1LC3B1 to form MAP1LC3B2, which is a prerequisite for phagophore and autophagosome formation. In addition, they regulate MTOR kinase and TFEB, thereby regulating the expression of ATG genes. TRIM proteins are efficient regulators of apoptosis and are crucial for regulating cell proliferation and tumor formation. Many TRIM proteins regulate intrinsic and extrinsic apoptosis via the cell surface receptors TGFBR2, TNFRSF1A, and FAS. Mitochondria modulate the anti- and proapoptotic functions of BCL2, BAX, BAK1, and CYCS. These proteins use a multipronged approach to regulate the intrinsic and extrinsic apoptotic pathways, culminating in coordinated activation or inhibition of the initiator and executor CASPs. Furthermore, TRIMs can have a dual effect in determining cell fate and are therefore crucial for cellular homeostasis. In this review, we discuss mechanistic insights into the role of TRIM proteins in regulating autophagy and apoptosis, which can be used to better understand cellular physiology. These findings can be used to develop therapeutic interventions to prevent or treat multiple genetic and infectious diseases.
Keywords TRIM proteins, E3-Ub ligase, Apoptosis, Autophagy, Ubiquitination, Autophagosome, BECN1, ULK1, TP53, Autophagy receptor
Address and Contact Information 1 Quantlase Lab LLC, Unit 1-8, Masdar City, Abu Dhabi, UAE
2 Molecular Biophysics Unit, Indian Institute of Science, Bangalore 460012, India
*Corresponding author: nuzhat.ahsan@quantlase. ae; nuzhatahsan@gmail.com; surolia@iisc.ac.in
† Nuzhat Ahsan and Mohd Shariq are contributed equally to this work.
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No.  14DOI: 10.1186/s11658-024-00531-7 Volume 29 (2024) - 29:14
Title MECHANISTIC ROLE OF QUERCETIN AS INHIBITOR FOR ADENOSINE DEAMINASE ENZYME IN RHEUMATOID ARTHRITIS: SYSTEMATIC REVIEW
Authors Amira Atta1, Maha M. Salem1*, Karim Samy El‐Said1 and Tarek M. Mohamed1
Abstract Rheumatoid arthritis (RA) is an autoimmune disease involving T and B lymphocytes. Autoantibodies contribute to joint deterioration and worsening symptoms. Adenosine deaminase (ADA), an enzyme in purine metabolism, influences adenosine levels and joint inflammation. Inhibiting ADA could impact RA progression. Intracellular ATP breakdown generates adenosine, which increases in hypoxic and inflammatory conditions. Lymphocytes with ADA play a role in RA. Inhibiting lymphocytic ADA activity has an immune-regulatory effect. Synovial fluid levels of ADA are closely associated with the disease’s systemic activity, making it a useful parameter for evaluating joint inflammation. Flavonoids, such as quercetin (QUE), are natural substances that can inhibit ADA activity. QUE demonstrates immune-regulatory effects and restores T-cell homeostasis, making it a promising candidate for RA therapy. In this review, we will explore the impact of QUE in suppressing ADA and reducing produced the inflammation in RA, including preclinical investigations and clinical trials.
Keywords Rheumatoid arthritis, Adenosine deaminase, Flavonoid, Quercetin, Synovial fuid
Address and Contact Information 1 Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Egypt
*Corresponding author: maha_salem@science.tanta.edu.eg
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No.  15DOI: 10.1186/s11658-024-00533-5 Volume 29 (2024) - 29:15
Title SUMOylation MODULATES eIF5A ACTIVITIES IN BOTH YEAST AND PANCREATIC DUCTAL ADENOCARCINOMA CELLS
Authors Rocío Seoane1,7, Tomás Lama‐Díaz1,2, Antonia María Romero3,15, Ahmed El Motiam1,16, Arantxa Martínez‐Férriz4, Santiago Vidal1,7, Yanis H. Bouzaher1, María Blanquer1, Rocío M. Tolosa1, Juan Castillo Mewa5, Manuel S. Rodríguez6, Adolfo García‐Sastre7,8,9,10, Dimitris Xirodimas11, James D. Sutherland12, Rosa Barrio12, Paula Alepuz3,13, Miguel G. Blanco1,2, Rosa Farràs4 and Carmen Rivas1,14*
Abstract Background: The eukaryotic translation initiation protein eIF5A is a highly conserved and essential factor that plays a critical role in different physiological and pathological processes including stress response and cancer. Different proteomic studies suggest that eIF5A may be a small ubiquitin-like modifier (SUMO) substrate, but whether eIF5A is indeed SUMOylated and how relevant is this modification for eIF5A activities are still unknown.
Methods: SUMOylation was evaluated using in vitro SUMOylation assays, Histidine-tagged proteins purification from His6–SUMO2 transfected cells, and isolation of endogenously SUMOylated proteins using SUMO-binding entities (SUBES). Mutants were engineered by site-directed mutagenesis. Protein stability was measured by a cycloheximide chase assay. Protein localization was determined using immunofluorescence and cellular fractionation assays. The ability of eIF5A1 constructs to complement the growth of Saccharomyces cerevisiae strains harboring thermosensitive mutants of a yeast EIF5A homolog gene (HYP2) was analyzed. The polysome profile and the formation of stress granules in cells expressing Pab1–GFP (a stress granule marker) by immunofluorescence were determined in yeast cells subjected to heat shock. Cell growth and migration of pancreatic ductal adenocarcinoma PANC-1 cells overexpressing different eIF5A1 constructs were evaluated using crystal violet staining and transwell inserts, respectively. Statistical analysis was performed with GraphPad Software, using unpaired Student’s t-test, or one-way or two-way analysis of variance (ANOVA).
Results: We found that eIF5A is modified by SUMO2 in vitro, in transfected cells and under endogenous conditions, revealing its physiological relevance. We identified several SUMO sites in eIF5A and found that SUMOylation modulates both the stability and the localization of eIF5A in mammalian cells. Interestingly, the SUMOylation of eIF5A responds to specific stresses, indicating that it is a regulated process. SUMOylation of eIF5A is conserved in yeast, the eIF5A SUMOylation mutants are unable to completely suppress the defects of HYP2 mutants, and SUMOylation of eIF5A is important for both stress granules formation and disassembly of polysomes induced by heat-shock. Moreover, mutation of the SUMOylation sites in eIF5A abolishes its promigratory and proproliferative activities in PANC-1 cells.
Conclusions: SUMO2 conjugation to eIF5A is a stress-induced response implicated in the adaptation of yeast cells to heat-shock stress and required to promote the growth and migration of pancreatic ductal adenocarcinoma cells.
Keywords eIF5A, Pancreatic ductal adenocarcinoma, Stress granules, Stress response, SUMO2
Address and Contact Information 1 Centro de Investigación en Medicina Molecular (CIMUS), IDIS, Universidade de Santiago de Compostela, Avda Barcelona, 15706 Santiago de Compostela, Spain.
2 Departamento de Bioquímica e Bioloxía Molecular, Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain.
3 Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas, Universitat de València, Burjassot, 46100 Valencia, Spain.
4 Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
5 Research Department in Genomics and Proteomics, Instituto Conmemorativo Gorgas de Estudios de la Salud, 0816‐02593 Panamá, Republic of Panama.
6 Laboratoire de Chimie de Coordination LCC-UPR 8241-CNRS, 31400 Toulouse, France.
7 Present Address: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8 Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9 Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
10 The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
11 Montpellier Cell Biology Research Center (CRBM), CNRS-UMR 5237 Université de Montpellier, Montpellier, France.
12 Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain.
13 Instituto Bio TecMed, Universitat de València, Burjassot, 46100 Valencia, Spain.
14 Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CNB), CSIC, Darwin 3, 28049 Madrid, Spain.
15 Present Address: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), C/ Américo Vespucio 24, Edificio Cabimer, 41092 Seville, Spain.
16 Present Address: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. *Corresponding author: mcarmen.rivas@usc.es
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No.  16DOI: 10.1186/s11658-024-00534-4 Volume 29 (2024) - 29:16
Title CORRECTION: ALKBH5 IN MOUSE TESTICULAR SERTOLI CELLS REGULATES Cdh2 mRNA TRANSLATION TO MAINTAIN BLOOD–TESTIS BARRIER INTEGRITY
Authors Zhonglin Cai1,2,3, Yao Zhang2, Lin Yang2, Chunhui Ma2, Yi Fei2, Jing Ding2, Wei Song4, Wei‐Min Tong2,5*, Yamei Niu2,5* and Hongjun Li1*
Abstract Correction: Cellular & Molecular Biology Letters (2022) 27:101
https://doi.org/10.1186/s11658-022-00404-x

Following publication of the original article [1], the authors corrected the Funding section.

The incorrect Funding is:
This work is supported by the Grant from National Natural Science Foundation of China (81871152, 82171588), National Key R&D Program of China (2019YFA080703), and Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (2021-I2M-1-002).

The correct Funding is:
This work is supported by the Grant from National Natural Science Foundation of China (81871152, 82171588), National Key R&D Program of China (2019YFA0801703), and Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (2021-I2M-1-002).
Keywords
Address and Contact Information 1 Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
2 Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
3 Department of Urology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
4 Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
5 Molecular Pathology Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
*Corresponding author: wmtong@ibms.pumc.edu.cn; niuym@ibms.pumc.edu.cn; lihongjun@pumch.cn
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No.  17DOI: 10.1186/s11658-024-00535-3 Volume 29 (2024) - 29:17
Title FFAR4 ACTIVATION INHIBITS LUNG ADENOCARCINOMA VIA BLOCKING RESPIRATORY CHAIN COMPLEX ASSEMBLY ASSOCIATED MITOCHONDRIAL METABOLISM
Authors Zhe Wang1†, Jinyou Li2†, LongFei Wang3†, Yaowei Liu4, Wei Wang1, JiaYao Chen1, HuiJun Liang1, Y. Q. Chen1 and ShengLong Zhu1*
Abstract Despite notable advancements in the investigation and management of lung adenocarcinoma (LUAD), the mortality rate for individuals afflicted with LUAD remains elevated, and attaining an accurate prognosis is challenging. LUAD exhibits intricate genetic and environmental components, and it is plausible that free fatty acid receptors (FFARs) may bridge the genetic and dietary aspects. The objective of this study is to ascertain whether a correlation exists between FFAR4, which functions as the primary receptor for dietary fatty acids, and various characteristics of LUAD, while also delving into the potential underlying mechanism. The findings of this study indicate a decrease in FFAR4 expression in LUAD, with a positive correlation (P < 0.01) between FFAR4 levels and overall patient survival (OS). Receiver operating characteristic (ROC) curve analysis demonstrated a significant diagnostic value [area under the curve (AUC) of 0.933] associated with FFAR4 expression. Functional investigations revealed that the FFAR4-specific agonist (TUG891) effectively suppressed cell proliferation and induced cell cycle arrest. Furthermore, FFAR4 activation resulted in significant metabolic shifts, including a decrease in oxygen consumption rate (OCR) and an increase in extracellular acidification rate (ECAR) in A549 cells. In detail, the activation of FFAR4 has been observed to impact the assembly process of the mitochondrial respiratory chain complex and the malate–aspartate shuttle process, resulting in a decrease in the transition of NAD+ to NADH and the inhibition of LUAD. These discoveries reveal a previously unrecognized function of FFAR4 in the negative regulation of mitochondrial metabolism and the inhibition of LUAD, indicating its potential as a promising therapeutic target for the treatment and diagnosis of LUAD.
Keywords FFAR4, LUAD, OXPHOS, Metabolism reprogramming
Address and Contact Information 1 Wuxi School of Medicine, Jiangnan University, Wuxi, China
2 Department of Thoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
3 The First Affiliated Hospital of Ningbo University, Ningbo, China
4 State Key Lab of Food Science and Resources, Jiangnan University, Wuxi, China
*Corresponding author: shenglongzhu@jiangnan.edu.cn
† Zhe Wang, Jinyou Li, and LongFei Wang contributed equally to this work.
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No.  18DOI: 10.1186/s11658-024-00537-1 Volume 29 (2024) - 29:18
Title PRO-INFLAMMATORY CYTOKINES STIMULATE CFTR-DEPENDENT ANION SECRETION IN PANCREATIC DUCTAL EPITHELIUM
Authors Dora Angyal1, Tessa A. Groeneweg1, Anny Leung1, Max Desain1, Kalyan Dulla2, Hugo R. de Jonge1^ and Marcel J. C. Bijvelds1*
Abstract Background: Loss of CFTR-dependent anion and fluid secretion in the ducts of the exocrine pancreas is thought to contribute to the development of pancreatitis, but little is known about the impact of inflammation on ductal CFTR function. Here we used adult stem cell-derived cell cultures (organoids) obtained from porcine pancreas to evaluate the effects of pro-inflammatory cytokines on CFTR function.
Methods: Organoids were cultured from porcine pancreas and used to prepare ductal epithelial monolayers. Monolayers were characterized by immunocytochemistry. Epithelial bicarbonate and chloride secretion, and the effect of IL-1β, IL-6, IFN-γ, and TNF-α on CFTR function was assessed by electrophysiology.
Results: Immunolocalization of ductal markers, including CFTR, keratin 7, and zonula occludens 1, demonstrated that organoid-derived cells formed a highly polarized epithelium. Stimulation by secretin or VIP triggered CFTR-dependent anion secretion across epithelial monolayers, whereas purinergic receptor stimulation by UTP, elicited CFTR-independent anion secretion. Most of the anion secretory response was attributable to bicarbonate transport. The combination of IL-1β, IL-6, IFN-γ, and TNF-α markedly enhanced CFTR expression and anion secretion across ductal epithelial monolayers, whereas these cytokines had little effect when tested separately. Although TNF-α triggered apoptotic signaling, epithelial barrier function was not significantly affected by cytokine exposure.
Conclusions: Pro-inflammatory cytokines enhance CFTR-dependent anion secretion across pancreatic ductal epithelium. We propose that up-regulation of CFTR in the early stages of the inflammatory response, may serve to promote the removal of pathogenic stimuli from the ductal tree, and limit tissue injury.
Keywords CFTR, Cystic fbrosis, Cytokines, Epithelial ion transport, Organoid, Pancreatitis
Address and Contact Information 1 Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, PO Box 2040, 3000CA Rotterdam, The Netherlands
2 Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Strasse 173, 55216 Ingelheim Am Rhein, Germany
*Correspondence: m.bijvelds@erasmusmc.nl
Hugo R. de Jonge: Deceased.
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No.  19DOI: 10.1186/s11658-024-00539-z Volume 29 (2024) - 29:19
Title REGULATION OF TUMOR METASTASIS AND CD8+ T CELLS INFILTRATION BY circRNF216/miR-576-5p/ZC3H12C AXIS IN COLORECTAL CANCER
Authors Wenqi Du1,3,4†, Xin Quan1†, Chaoqun Wang1†, Qiuya Song1, Jie Mou2* and Dongsheng Pei1,4*
Abstract Background: The tumor immune microenvironment (TIME) is an important regulator of tumor progression, growth and metastasis. In addition, tumor metastasis is one of the principal obstacles to the treatment of colorectal cancer (CRC). Circular RNAs (circRNAs) have been recognized as important regulators in the development of malignancies. However, their specific roles and mechanisms in both CRC metastasis and TIME have not been thoroughly investigated.
Methods: High-throughput next-generation sequencing technology and real-time fluorescence quantitative PCR technology were performed to identify differential circRNAs in CRC. Functional assays including transwell assay, wound healing assay, and metastasis models were conducted to assess the effect of circRNF216 on CRC metastasis. In addition, luciferase reporter, western blot, RNA immunoprecipitation (RIP), and fluorescent in situ hybridization (FISH) were performed to explore the underlying mechanism of circRNF216. The level of immune infiltration was assessed by bioinformatics analysis and flow cytometry in CRC model. Furthermore, rescue and mutation experiments were used for verification.
Results: circRNF216 was identified as a putative tumor suppressor that is downregulated in CRC tissues and cells. Overexpression of circRNF216 inhibits metastasis in vitro and vivo. Mechanistically, circRNF216 acts as a competitive endogenous RNA (ceRNA) for miR-576-5p, alleviating miR-576-5p repression on its target ZC3H12C, which in turn downregulated N-cadherin. Additionally, circRNF216 could enhance the infiltration level of CD8+ T cells by upregulating ZC3H12C, ultimately inhibiting the development of CRC, which suggests that circRNF216 is a potential biomarker for the treatment of CRC.
Conclusions: Here, we provide novel mechanistic insight revealing how circRNF216 functioned in CRC metastasis and TIME via the circRNF216/miR-576-5p/ZC3H12C pathway. Therefore, circRNF216 holds promise as a potential therapeutic target and novel diagnostic marker for CRC.
Keywords Tumor immune microenvironment, Metastasis, Colorectal cancer, CircRNF216, MiR-576-5p, ZC3H12C
Address and Contact Information 1 Department of Pathology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, People’s Republic of China
2 School of Pharmacy, Xuzhou Medical University, Xuzhou, China
3 Department of Human Anatomy, Xuzhou Medical University, Xuzhou, China
4 Cancer Institute, Xuzhou Medical University, Xuzhou, China
*Correspondence: mou.jie@xzhmu.edu.cn; dspei@xzhmu.edu.cn
† Wenqi Du, Xin Quan and Chaoqun Wang contributed equally to this work.
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No.  20DOI: 10.1186/s11658-024-00532-6 Volume 29 (2024) - 29:20
Title ROLE OF microRNA-4739 IN ENHANCING CISPLATIN CHEMOSENSITIVITY BY NEGATIVE REGULATION OF RHBDD2 IN HUMAN CERVICAL CANCER CELLS
Authors Yuling Li1, Zhengtong Zhou2, Jinfeng Qu1, Peiling Gong3, Yuyan Wei1 and Yaping Sun1*
Abstract Background: Cisplatin (DDP) is a widely used chemotherapy drug for advanced cervical cancer (CC), but resistance poses a significant challenge. While miR-4739 has been implicated in tumor development, its specific role in regulating DDP resistance in CC remains unclear.
Methods: We analyzed the expression levels of miR-4739 and RHBDD2 in DDP-resistant and DDP-sensitive CC tissues using quantitative real-time polymerase chain reaction (PCR) and assessed their correlation through Spearman’s correlation analysis. DDP-resistant CC cell lines (HeLa/DDP and SiHa/DDP) were established by gradually increasing DDP concentrations, followed by transfection with miR-4739 mimics, si-RHBDD2, or a RHBDD2 overexpression vector. A series of functional assays, including CCK-8 assay, colony formation, flow cytometry, and transwell assay were performed. The interaction between miR-4739 and RHBDD2 was confirmed by luciferase reporter assay. We examined the protein levels of RHBDD2, P-gP, MRP1, cleaved caspase-3, and E-cadherin through western blot analysis. Moreover, we generated xenograft tumors by injecting stably transfected HeLa/DDP cells into mice to compare their tumorigenesis capacity.
Results: We observed downregulation of miR-4739 and upregulation of RHBDD2 in DDP-resistant CC tissues and cell lines. MiR-4739 was shown to directly bind to RHBDD2 gene sequences to repress RHBDD2 expression in HeLa/DDP and SiHa/DDP cells. Our in vitro and in vivo experiments demonstrated that overexpressing miR-4739 overcame DDP resistance in CC cells by targeting RHBDD2. Furthermore, RHBDD2 overexpression reversed the effects of miR-4739 mimics on drug-resistance-related proteins (P-gP and MRP1) and the expression of cleaved caspase-3 and E-cadherin in HeLa/DDP cells.
Conclusions: In summary, our study revealed that miR-4739 can reverse DDP resistance by modulating RHBDD2 in CC cells.
Keywords Cervical cancer, miR-4739, Cisplatin, Drug resistance, RHBDD2
Address and Contact Information 1 Department of Gynecology, Central Hospital Affiliated to Shandong First Medical University, No.105, Jiefang Road, Lixia District, Jinan 250013, Shandong, China
2 Institute of Medical Genomics, Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
3 Yiyuan Maternal and Child Health Hospital, Zibo 256100, Shandong, China
*Corresponding author: sun_yapingS78@yeah.net
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No.  21DOI: 10.1186/s11658-024-00536-2 Volume 29 (2024) - 29:21
Title NEW INSIGHTS INTO THE ROLE OF MITOCHONDRIAL METABOLIC DYSREGULATION AND IMMUNE INFILTRATION IN SEPTIC CARDIOMYOPATHY BY INTEGRATED BIOINFORMATICS ANALYSIS AND EXPERIMENTAL VALIDATION
Authors Yukun Li1,2, Jiachi Yu3, Ruibing Li3, Hao Zhou1,3* and Xing Chang1,4*
Abstract Background: Septic cardiomyopathy (SCM), a common cardiovascular comorbidity of sepsis, has emerged among the leading causes of death in patients with sepsis. SCM’s pathogenesis is strongly affected by mitochondrial metabolic dysregulation and immune infiltration disorder. However, the specific mechanisms and their intricate interactions in SCM remain unclear. This study employed bioinformatics analysis and drug discovery approaches to identify the regulatory molecules, distinct functions, and underlying interactions of mitochondrial metabolism and immune microenvironment, along with potential interventional strategies in SCM.
Methods: GSE79962, GSE171546, and GSE167363 datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and module genes were identified using Limma and Weighted Correlation Network Analysis (WGCNA), followed by functional enrichment analysis. Machine learning algorithms, including support vector machine–recursive feature elimination (SVM–RFE), least absolute shrinkage and selection operator (LASSO) regression, and random forest, were used to screen mitochondria-related hub genes for early diagnosis of SCM. Subsequently, a nomogram was developed based on six hub genes. The immunological landscape was evaluated by single-sample gene set enrichment analysis (ssGSEA). We also explored the expression pattern of hub genes and distribution of mitochondria/inflammation-related pathways in UMAP plots of single-cell dataset. Potential drugs were explored using the Drug Signatures Database (DSigDB). In vivo and in vitro experiments were performed to validate the pathogenetic mechanism of SCM and the therapeutic efficacy of candidate drugs.
Results: Six hub mitochondria-related DEGs [MitoDEGs; translocase of inner mitochondrial membrane domain-containing 1 (TIMMDC1), mitochondrial ribosomal protein S31 (MRPS31), F-box only protein 7 (FBXO7), phosphatidylglycerophosphate synthase 1 (PGS1), LYR motif containing 7 (LYRM7), and mitochondrial chaperone BCS1 (BCS1L)] were identified. The diagnostic nomogram model based on the six hub genes demonstrated high reliability and validity in both the training and validation sets. The immunological microenvironment differed between SCM and control groups. The Spearman correlation analysis revealed that hub MitoDEGs were significantly associated with the infiltration of immune cells. Upregulated hub genes showed remarkably high expression in the naive/memory B cell, CD14+ monocyte, and plasma cell subgroup, evidenced by the feature plot. The distribution of mitochondria/inflammation-related pathways varied across subgroups among control and SCM individuals. Metformin was predicted to be the most promising drug with the highest combined score. Its efficacy in restoring mitochondrial function and suppressing inflammatory responses has also been validated.
Conclusions: This study presents a comprehensive mitochondrial metabolism and immune infiltration landscape in SCM, providing a potential novel direction for the pathogenesis and medical intervention of SCM.
Keywords Septic cardiomyopathy, Molecular mechanism, Drug discovery, Mitochondrial metabolism, Immune infltration
Address and Contact Information 1 Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
2 National Clinical Research Center for Cardiovascular Diseases, Beijing, China
3 Department of Cardiology, The Sixth Medical Center of People’s Liberation Army General Hospital, Beijing, China
4 Guanganmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
*Corresponding author: zhouhao@plagh.org; xingchang_tcm@outlook.com
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No.  22DOI: 10.1186/s11658-023-00509-x Volume 29 (2024) - 29:22
Title IP3R1-MEDIATED MAMs FORMATION CONTRIBUTES TO MECHANICAL TRAUMA-INDUCED HEPATIC INJURY AND THE PROTECTIVE EFFECT OF MELATONIN
Authors Rui Shi1,2,3†, Zhenhua Liu2†, Huan Yue2,4†, Man Li2,4, Simin Liu1, Dema De1,3, Runjing Li1,3, Yunan Chen1,3, Shuli Cheng5, Xiaoming Gu2, Min Jia2, Jun Li2, Juan Li2, Shumiao Zhang2, Na Feng2, Rong Fan2, Feng Fu2, Yali Liu2*, Mingge Ding1,5* and Jianming Pei2*
Abstract Introduction: There is a high morbidity and mortality rate in mechanical trauma (MT)-induced hepatic injury. Currently, the molecular mechanisms underlying liver MT are largely unclear. Exploring the underlying mechanisms and developing safe and effective medicines to alleviate MT-induced hepatic injury is an urgent requirement. The aim of this study was to reveal the role of mitochondria-associated ER membranes (MAMs) in post-traumatic liver injury, and ascertain whether melatonin protects against MT-induced hepatic injury by regulating MAMs.
Methods: Hepatic mechanical injury was established in Sprague–Dawley rats and primary hepatocytes. A variety of experimental methods were employed to assess the effects of melatonin on hepatic injury, apoptosis, MAMs formation, mitochondrial function and signaling pathways.
Results: Significant increase of IP3R1 expression and MAMs formation were observed in MT-induced hepatic injury. Melatonin treatment at the dose of 30 mg/kg inhibited IP3R1-mediated MAMs and attenuated MT-induced liver injury in vivo. In vitro, primary hepatocytes cultured in 20% trauma serum (TS) for 12 h showed upregulated IP3R1 expression, increased MAMs formation and cell injury, which were suppressed by melatonin (100 μmol/L) treatment. Consequently, melatonin suppressed mitochondrial calcium overload, increased mitochondrial membrane potential and improved mitochondrial function under traumatic condition. Melatonin’s inhibitory effects on MAMs formation and mitochondrial calcium overload were blunted when IP3R1 was overexpressed. Mechanistically, melatonin bound to its receptor (MR) and increased the expression of phosphorylated ERK1/2, which interacted with FoxO1 and inhibited the activation of FoxO1 that bound to the IP3R1 promoter to inhibit MAMs formation.
Conclusion: Melatonin prevents the formation of MAMs via the MR-ERK1/2-FoxO1-IP3R1 pathway, thereby alleviating the development of MT-induced liver injury. Melatonin-modulated MAMs may be a promising therapeutic therapy for traumatic hepatic injury.
Keywords Mechanical trauma, Melatonin, MAMs, ERK1/2, FoxO1, IP3R1
Address and Contact Information 1 Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
2 Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi’an, China
3 Key Laboratory of Surgical Critical Care and Life Support, Xi’an Jiaotong University, Ministry of Education, Xi’an, China
4 School of Life Science, Northwest University, Xi’an, China
5 The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Laboratory Center of Stomatology, Department of Orthodontics, College of Stomatology, Xi’an Jiaotong University, Xi’an, China
*Corresponding author: yaliliu@fmmu.edu.cn; dingmingge@xjtu.edu.cn; jmpei8@fmmu.edu.cn
† Rui Shi, Zhenhua Liu and Huan Yue contributed equally to this study.
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No.  23DOI: 10.1186/s11658-024-00541-5 Volume 29 (2024) - 29:23
Title UBIQUITOUS PROTEIN LACTYLATION IN HEALTH AND DISEASES
Authors Junyong Wang1,4†, Ziyi Wang1,4†, Qixu Wang1,4, Xiao Li3 and Yaping Guo1,2,4*
Abstract For decades, lactate has been considered a byproduct of glycolysis. The lactate shuttle hypothesis shifted the lactate paradigm, demonstrating that lactate not only plays important roles in cellular metabolism but also cellular communications, which can transcend compartment barriers and can occur within and among different cells, tissues and organs. Recently, the discovery that lactate can induce a novel post-translational modification, named lysine lactylation (Kla), brings forth a new avenue to study nonmetabolic functions for lactate, which has inspired a ‘gold rush’ of academic and commercial interest. Zhang et al. first showed that Kla is manifested in histones as epigenetic marks, and then mounting evidences demonstrated that Kla also occurs in diverse non-histone proteins. The widespread Kla faithfully orchestrates numerous biological processes, such as transcription, metabolism and inflammatory responses. Notably, dysregulation of Kla touches a myriad of pathological processes. In this review, we comprehensively reviewed and curated the existing literature to retrieve the new identified Kla sites on both histones and non-histone proteins and summarized recent major advances toward its regulatory mechanism. We also thoroughly investigated the function and underlying signaling pathway of Kla and comprehensively summarize how Kla regulates various biological processes in normal physiological states. In addition, we also further highlight the effects of Kla in the development of human diseases including inflammation response, tumorigenesis, cardiovascular and nervous system diseases and other complex diseases, which might potentially contribute to deeply understanding and interpreting the mechanism of its pathogenicity.
Keywords Glycolysis, Lactate, Lactylation, Pathological process
Address and Contact Information 1 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Science Avenue 100, Zhengzhou 450001, Henan, China
2 State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou 450001, Henan, China
3 Department of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou 450001, Henan, China
4 Center for Basic Medical Research, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
*Corresponding author: guoyaping@zzu.edu.cn
† Junyong Wang and Ziyi Wang equally contributed to this work.
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No.  24DOI: 10.1186/s11658-024-00542-4 Volume 29 (2024) - 29:24
Title THE DIRECT BINDING OF BIOACTIVE PEPTIDE ANDERSONIN-W1 TO TLR4 EXPEDITES THE HEALING OF DIABETIC SKIN WOUNDS
Authors Chao Li3†, Yuxin Xiong1,4†, Zhe Fu1†, Yuxin Ji1, Jiayi Yan1, Yan Kong1, Ying Peng1, Zeqiong Ru1, Yubing Huang3, Yilin Li1, Ying Yang4*, Li He5*, Jing Tang3*, Ying Wang2* and Xinwang Yang1*
Abstract Background: Chronic nonhealing wounds remain a considerable challenge in clinical treatment due to excessive inflammation and impeded reepithelialization and angiogenesis. Therefore, the discovery of novel prohealing agents for chronic skin wounds are urgent and important. Amphibian-derived prohealing peptides, especially immunomodulatory peptides, provide a promising strategy for the treatment of chronic skin trauma. However, the mechanism of immunomodulatory peptides accelerating the skin wound healing remains poorly understood.
Methods: The prohealing ability of peptide Andersonin-W1 (AW1) was assessed by cell scratch, cell proliferation, transwell, and tube formation. Next, full-thickness, deep second-degree burns and diabetic full-thickness skin wounds in mice were performed to detect the therapeutic effects of AW1. Moreover, the tissue regeneration and expression of inflammatory cytokines were evaluated by hematoxylin and eosin (H&E), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry staining. Molecular docking, colocalization, and western blotting were used to explore the mechanism of AW1 in promoting wound healing.
Results: We provide solid evidence to display excellent prohealing effects of AW1, identified as a short antimicrobial peptide in our previous report. At relative low concentration of nM, AW1 promoted the proliferation, migration, and scratch repair of keratinocyte, macrophage proliferation, and tube formation of HUVEC. AW1 also facilitated reepithelialization, granulation regeneration, and angiogenesis, thus significantly boosting the healing of full-thickness, deep second-degree burns and diabetic skin wounds in mice. Mechanistically, in macrophages, AW1 directly bound to Toll-like receptor 4 (TLR4) in the extracellular region and regulated the downstream nuclear factor‐κB (NF-κB) signaling pathway to facilitate the inflammatory factor secretion and suppress excessive inflammation induced by lipopolysaccharide (LPS). Moreover, AW1 regulated macrophage polarization to promote the transition from the inflammatory to the proliferative phase and then facilitated reepithelialization, granulation regeneration, and angiogenesis, thus exhibiting excellent therapeutic effects on diabetic skin wounds.
Conclusions: AW1 modulates inflammation and the wound healing process by the TLR4/NF-κB molecular axis, thus facilitating reepithelialization, granulation regeneration, and angiogenesis. These findings not only provided a promising multifunctional prohealing drug candidate for chronic nonhealing skin wounds but also highlighted the unique roles of “small” peptides in the elucidation of “big” human disease mechanisms.
Keywords Diabetic skin wound healing, TLR4/NF-κB, Infammation, Angiogenesis
Address and Contact Information 1 Department of Anatomy and Histology and Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, Yunnan, China
2 Key Laboratory of Chemistry in Ethnic Medicinal Resources and Key Laboratory of Natural Products Synthetic Biology of Ethnic Medicinal Endophytes, State Ethnic Affairs Commission and Ministry of Education, School of Ethnic Medicine, Yunnan Minzu University, Kunming 650504, Yunnan, China
3 Department of Biochemistry and Molecular Biology, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, Yunnan, China
4 Department of Endocrinology, Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan, China
5 Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
*Correspondence: yangying2072@126.com; drheli2662@126.com; gracett916@163.com; wangying_814@163.com; yangxinwanghp@163.com; yangxinwang@kmmu.edu.cn
† Chao Li, Yuxin Xiong, and Zhe Fu contributed equally to this manuscript.
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No.  25DOI: 10.1186/s11658-024-00540-6 Volume 29 (2024) - 29:25
Title CircMAST1 INHIBITS CERVICAL CANCER PROGRESSION BY HINDERING THE N4-ACETYLCYTIDINE MODIFICATION OF YAP mRNA
Authors Chunyu Zhang1,2†, Li Yuan1,2†, Qiaojian Zou1,2†, Caixia Shao1,2, Yan Jia1,2, Jiaying Li1,2, Yan Liao1,2, Xueyuan Zhao1,2, Weijia Wen1,2, Xu Jing3, Guofen Yang1,2, Wei Wang1,2*, Hongye Jiang1,2* and Shuzhong Yao1,2*
Abstract Background: Cervical cancer (CCa) is the fourth most common cancer among females, with high incidence and mortality rates. Circular RNAs (circRNAs) are key regulators of various biological processes in cancer. However, the biological role of circRNAs in cervical cancer (CCa) remains largely unknown. This study aimed to elucidate the role of circMAST1 in CCa.
Methods: CircRNAs related to CCa progression were identified via a circRNA microarray. The relationship between circMAST1 levels and clinicopathological features of CCa was evaluated using the clinical specimens and data of 131 patients with CCa. In vivo and in vitro experiments, including xenograft animal models, cell proliferation assay, transwell assay, RNA pull-down assay, whole-transcriptome sequencing, RIP assay, and RNA-FISH, were performed to investigate the effects of circMAST1 on the malignant behavior of CCa.
Results: CircMAST1 was significantly downregulated in CCa tissues, and low expression of CircMAST1 was correlated with a poor prognosis. Moreover, our results demonstrated that circMAST1 inhibited tumor growth and lymph node metastasis of CCa. Mechanistically, circMAST1 competitively sequestered N-acetyltransferase 10 (NAT10) and hindered Yes-associated protein (YAP) mRNA ac4C modification to promote its degradation and inhibit tumor progression in CCa.
Conclusions: CircMAST1 plays a major suppressive role in the tumor growth and metastasis of CCa. In particular, circMAST1 can serve as a potential biomarker and novel target for CCa.
Keywords Cervical cancer, Circular RNA circMAST1, N4-acetylcytidine, NAT10, YAP
Address and Contact Information 1 Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
2 Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, China
3 Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
*Corresponding author: wangw245@mail.sysu.edu.cn; jianghye@mail.sysu.edu.cn; yaoshuzh@mail.sysu.edu.cn
† Chunyu Zhang, Li Yuan and Qiaojian Zou have contributed equally to this work.
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No.  26DOI: 10.1186/s11658-024-00544-2 Volume 29 (2024) - 29:26
Title HIGH-CONTENT IMAGE SCREENING TO IDENTIFY CHEMICAL MODULATORS FOR PEROXISOME AND FERROPTOSIS
Authors Daheng Zheng1, Fei Li1, Shanshan Wang2, Pu‐Ste Liu3 and Xin Xie1*
Abstract Background: The peroxisome is a dynamic organelle with variety in number, size, shape, and activity in different cell types and physiological states. Recent studies have implicated peroxisomal homeostasis in ferroptosis susceptibility. Here, we developed a U-2OS cell line with a fluorescent peroxisomal tag and screened a target-selective chemical library through high-content imaging analysis.
Methods: U-2OS cells stably expressing the mOrange2-Peroxisomes2 tag were generated to screen a target-selective inhibitor library. The nuclear DNA was counterstained with Hoechst 33342 for cell cycle analysis. Cellular images were recorded and quantitatively analyzed through a high-content imaging platform. The effect of selected compounds on ferroptosis induction was analyzed in combination with ferroptosis inducers (RSL3 and erastin). Flow cytometry analysis was conducted to assess the level of reactive oxygen species (ROS) and cell death events.
Results: Through the quantification of DNA content and peroxisomal signals in single cells, we demonstrated that peroxisomal abundance was closely linked with cell cycle progression and that peroxisomal biogenesis mainly occurred in the G1/S phase. We further identified compounds that positively and negatively regulated peroxisomal abundance without significantly affecting the cell cycle distribution. Some compounds promoted peroxisomal signals by inducing oxidative stress, while others regulated peroxisomal abundance independent of redox status. Importantly, compounds with peroxisome-enhancing activity potentiated ferroptosis induction.
Conclusions: Our findings pinpoint novel cellular targets that might be involved in peroxisome homeostasis and indicate that compounds promoting peroxisomal abundance could be jointly applied with ferroptosis inducers to potentiate anticancer effect.
Keywords Peroxisome, Homeostasis, U-2OS, High-content screening, Ferroptosis, Oxidative stress, Target selective inhibitor
Address and Contact Information 1 School of Life and Environmental Sciences, Shaoxing University, Shaoxing City, Zhejiang, China
2 School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangdong, China
3 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
*Corresponding author: 2022000032@usx.edu.cn
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No.  27DOI: 10.1186/s11658-024-00546-0 Volume 29 (2024) - 29:27
Title THE ANCESTRAL TYPE OF THE R-RAS PROTEIN HAS ONCOGENIC POTENTIAL
Authors Antea Talajić1†, Kristina Dominko1†, Marija Lončarić2, Andreja Ambriović‐Ristov2 and Helena Ćetković1*
Abstract Background: The R-RAS2 is a small GTPase highly similar to classical RAS proteins at the regulatory and signaling levels. The high evolutionary conservation of R-RAS2, its links to basic cellular processes and its role in cancer, make R-RAS2 an interesting research topic. To elucidate the evolutionary history of R-RAS proteins, we investigated and compared structural and functional properties of ancestral type R-RAS protein with human R-RAS2.
Methods: Bioinformatics analysis were used to elucidate the evolution of R-RAS proteins. Intrinsic GTPase activity of purified human and sponge proteins was analyzed with GTPase-GloTM Assay kit. The cell model consisted of human breast cancer cell lines MCF-7 and MDA-MB-231 transiently transfected with EsuRRAS2-like or HsaRRAS2. Biological characterization of R-RAS2 proteins was performed by Western blot on whole cell lysates or cell adhesion protein isolates, immunofluorescence and confocal microscopy, MTT test, colony formation assay, wound healing and Boyden chamber migration assays.
Results: We found that the single sponge R-RAS2-like gene/protein probably reflects the properties of the ancestral R-RAS protein that existed prior to duplications during the transition to Bilateria, and to Vertebrata. Biochemical characterization of sponge and human R-RAS2 showed that they have the same intrinsic GTPase activity and RNA binding properties. By testing cell proliferation, migration and colony forming efficiency in MDA-MB-231 human breast cancer cells, we showed that the ancestral type of the R-RAS protein, sponge R-RAS2-like, enhances their oncogenic potential, similar to human R-RAS2. In addition, sponge and human R-RAS2 were not found in focal adhesions, but both homologs play a role in their regulation by increasing talin1 and vinculin.
Conclusions: This study suggests that the ancestor of all animals possessed an R-RAS2-like protein with oncogenic properties similar to evolutionarily more recent versions of the protein, even before the appearance of true tissue and the origin of tumors. Therefore, we have unraveled the evolutionary history of R-RAS2 in metazoans and improved our knowledge of R-RAS2 properties, including its structure, regulation and function.
Keywords Cancer, Cell migration, Cell proliferation, Evolution, Focal adhesion, Intracellular localization, Metazoa, R-RAS2, Small GTPase, Porifera
Address and Contact Information 1 Laboratory for Molecular Genetics, Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia
2 Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia
*Corresponding author: Helena.Cetkovic@irb.hr
† Antea Talajić and Kristina Dominko have contributed equally to this work.
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No.  28DOI: 10.1186/s11658-024-00543-3 Volume 29 (2024) - 29:28
Title N6-METHYLADENOSINE-MODIFIED circ_104797 SUSTAINS CISPLATIN RESISTANCE IN BLADDER CANCER THROUGH ACTING AS RNA SPONGES
Authors Congjie Xu1†, Jiaquan Zhou1†, Xiaoting Zhang2†, Xinli Kang1, Shuan Liu1, Mi Song1, Cheng Chang1, Youtu Lin3 and Yang Wang1*
Abstract Background: Bladder cancer (BCa) ranks among the predominant malignancies affecting the urinary system. Cisplatin (CDDP) remains a cornerstone therapeutic agent for BCa management. Recent insights suggest pivotal roles of circular RNA (circRNA) and N6-methyladenosine (m6A) in modulating CDDP resistance in BCa, emphasizing the importance of elucidating these pathways to optimize cisplatin-based treatments.
Methods: Comprehensive bioinformatics assessments were undertaken to discern circ_104797 expression patterns, its specific interaction domains, and m6A motifs. These findings were subsequently corroborated through experimental validations. To ascertain the functional implications of circ_104797 in BCa metastasis, in vivo assays employing CRISPR/dCas13b-ALKBH5 were conducted. Techniques, such as RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assays, and western blotting, were employed to delineate the underlying molecular intricacies.
Results: Our investigations revealed an elevated expression of circ_104797 in CDDP-resistant BCa cells, underscoring its pivotal role in sustaining cisplatin resistance. Remarkably, demethylation of circ_104797 markedly augmented the potency of cisplatin-mediated apoptosis. The amplification of circ_104797 in CDDP-resistant cells was attributed to enhanced RNA stability, stemming from an augmented m6A level at a distinct adenosine within circ_104797. Delving deeper, we discerned that circ_104797 functioned as a microRNA reservoir, specifically sequestering miR-103a and miR-660-3p, thereby potentiating cisplatin resistance.
Conclusions: Our findings unveil a previously uncharted mechanism underpinning cisplatin resistance and advocate the potential therapeutic targeting of circ_104797 in cisplatin-administered patients with BCa, offering a promising avenue for advanced BCa management.
Keywords Bladder cancer, Cisplatin resistance, circ_104797, miR-103a, N6-methyladenosine
Address and Contact Information 1 Department of Urology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan, People’s Republic of China
2 Shenzhen Baoan District Songgang People’s Hospital, Shenzhen, Guangdong, People’s Republic of China
3 Department of Urology, The Third People’s Hospital of Danzhou, Danzhou, Hainan, People’s Republic of China
*Corresponding author: Wysci2008@126.com
† Congjie Xu, Jiaquan Zhou, and Xiaoting Zhang contributed equally to this work.
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No. 29 DOI: 10.1186/s11658-024-00552-2 Volume 29 (2024) - 29:29
Title LOSS OF miR-101-3p iN MELANOMA STABILIZES GENOMIC INTEGRITY, LEADING TO CELL DEATH PREVENTION
Authors Lisa Lämmerhirt1, Melanie Kappelmann‐Fenzl2, Stefan Fischer2, Paula Meier1,3, Sebastian Staebler1, Silke Kuphal1 and Anja‐Katrin Bosserhof1*
Abstract Malignant melanoma remains the most lethal form of skin cancer, exhibiting poor prognosis after forming distant metastasis. Owing to their potential tumor-suppressive properties by regulating oncogenes and tumor suppressor genes, microRNAs are important player in melanoma development and progression. We defined the loss of miR-101-3p expression in melanoma cells compared with melanocytes and melanoblast-related cells as an early event in tumor development and aimed to understand the tumor suppressive role of miR-101-3p and its regulation of important cellular processes. Reexpression of miR-101-3p resulted in inhibition of proliferation, increase in DNA damage, and induction of apoptosis. We further determined the nuclear structure protein Lamin B1, which influences nuclear processes and heterochromatin structure, ATRX, CASP3, and PARP as an important direct target of miR-101-3p. RNA sequencing and differential gene expression analysis after miR-101-3p reexpression supported our findings and the importance of loss of mir-101-3p for melanoma progression. The validated functional effects are related to genomic instability, as recent studies suggest miRNAs plays a key role in mediating this cellular process. Therefore, we concluded that miR-101-3p reexpression increases the genomic instability, leading to irreversible DNA damage, which leads to apoptosis induction. Our findings suggest that the loss of miR-101-3p in melanoma serves as an early event in melanoma progression by influencing the genomic integrity to maintain the increased bioenergetic demand.
Keywords Melanoma, miRNA, DNA damage, Apoptosis, RNA-seq, Genomic integrity, miR-101-3p
Address and Contact Information 1 Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Fahrstraße 17, 91054 Erlangen, Germany
2 Faculty of Computer Science, Deggendorf Institute of Technology, Dieter‐Görlitz‐Platz 1, 94469 Deggendorf, Germany
3 Julius-Maximilians-University Würzburg (JMU), Sanderring 2, 97070 Würzburg, Germany
*Corresponding author: anja.bosserhof@fau.de
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No. 30 DOI: 10.1186/s11658-024-00551-3 Volume 29 (2024) - 29:30
Title Nrf2 ACTIVATION: A KEY MECHANISM IN STEM CELL EXOSOMES-MEDIATED THERAPIES
Authors Zeinab Vahidinia1* , Abolfazl Azami Tameh1, Shirin Barati2, Melika Izadpanah3 and Elahe Seyed Hosseini4
Abstract Exosomes are nano-sized membrane extracellular vesicles which can be released from various types of cells. Exosomes originating from inflammatory or injured cells can have detrimental effects on recipient cells, while exosomes derived from stem cells not only facilitate the repair and regeneration of damaged tissues but also inhibit inflammation and provide protective effects against various diseases, suggesting they may serve as an alternative strategy of stem cells transplantation. Exosomes have a fundamental role in communication between cells, through the transfer of proteins, bioactive lipids and nucleic acids (like miRNAs and mRNAs) between cells. This transfer significantly impacts both the physiological and pathological functions of recipient cells. Nuclear factor erythroid 2–related factor 2 (Nrf2), a transcription factor, is able to mitigate damage caused by oxidative stress and inflammation through various signaling pathways. The positive effects resulting from the activation of the Nrf2 signaling pathway in different disorders have been documented in various types of literature. Studies have confirmed that exosomes derived from stem cells could act as Nrf2 effective agonists. However, limited studies have explored the Nrf2 role in the therapeutic effects of stem cell-derived exosomes. This review provides a comprehensive overview of the existing knowledge concerning the role of Nrf2 signaling pathways in the impact exerted by stem cell exosomes in some common diseases.
Keywords Nrf2, Exosomes, Stem cells, MicroRNAs
Address and Contact Information 1 Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
2 Department of Anatomy, Saveh University of Medical Sciences, Saveh, Iran
3 Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
4 Gametogenesis Research Center, Institute for Basic Sciences, Kashan University of Medical Science, Kashan, Iran
*Corresponding author: vahidinia-z@kaums.ac.ir
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No. 31 DOI:10.1186/s11658-024-00553-1 Volume 29 (2024) - 29:31
Title INHIBITION OF Drp1- Fis1 INTERACTION ALLEVIATES ABERRANT MITOCHONDRIAL FRAGMENTATION AND ACUTE KIDNEY INJURY
Authors Zhixia Song1,2*†, Yao Xia1,2†, Lang Shi2,3†, Hongchu Zha1,2, Jing Huang3, Xiaohong Xiang4, Huiming Li1,2, Hua Huang1,2, Ruchi Yue1,2, Hongtao Wang1,2 and Jiefu Zhu2,5,6*
Abstract Background: Acute kidney injury (AKI) is a common clinical disorder with complex etiology and poor prognosis, and currently lacks specific and effective treatment options. Mitochondrial dynamics dysfunction is a prominent feature in AKI, and modulation of mitochondrial morphology may serve as a potential therapeutic approach for AKI.
Methods: We induced ischemia–reperfusion injury (IRI) in mice (bilateral) and Bama pigs (unilateral) by occluding the renal arteries. ATP depletion and recovery (ATP-DR) was performed on proximal renal tubular cells to simulate in vitro IRI. Renal function was evaluated using creatinine and urea nitrogen levels, while renal structural damage was assessed through histopathological staining. The role of Drp1 was investigated using immunoblotting, immunohistochemistry, immunofluorescence, and immunoprecipitation techniques. Mitochondrial morphology was evaluated using confocal microscopy.
Results: Renal IRI induced significant mitochondrial fragmentation, accompanied by Dynamin-related protein 1 (Drp1) translocation to the mitochondria and Drp1 phosphorylation at Ser616 in the early stages (30 min after reperfusion), when there was no apparent structural damage to the kidney. The use of the Drp1 inhibitor P110 significantly improved kidney function and structural damage. P110 reduced Drp1 mitochondrial translocation, disrupted the interaction between Drp1 and Fis1, without affecting the binding of Drp1 to other mitochondrial receptors such as MFF and Mid51. High-dose administration had no apparent toxic side effects. Furthermore, ATP-DR induced mitochondrial fission in renal tubular cells, accompanied by a decrease in mitochondrial membrane potential and an increase in the translocation of the pro-apoptotic protein Bax. This process facilitated the release of dsDNA, triggering the activation of the cGAS-STING pathway and promoting inflammation. P110 attenuated mitochondrial fission, suppressed Bax mitochondrial translocation, prevented dsDNA release, and reduced the activation of the cGAS-STING pathway. Furthermore, these protective effects of P110 were also observed renal IRI model in the Bama pig and folic acid-induced nephropathy in mice.
Conclusions: Dysfunction of mitochondrial dynamics mediated by Drp1 contributes to renal IRI. The specific inhibitor of Drp1, P110, demonstrated protective effects in both in vivo and in vitro models of AKI.
Keywords Acute kidney injury, Ischemia reperfusion injury, Mitochondria, Drp1, Fis1
Address and Contact Information 1 Department of Nephrology, Center People’s Hospital of Yichang, The First Clinical Medical College of Three Gorges University, Yichang 443000, Hubei, China
2 Kidney Disease Research Institute of Three Gorges University, Yichang 443000, Hubei, China
3 Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China
4 Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha 410000, China
5 Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China
6 Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan 430060, China
*Correspondence: songzhixia@ctgu.edu.cn; jiefuzhu@whu.edu.cn
† Zhixia Song, Yao Xia and Lang Shi contributed equally to this work.
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No. 32DOI: 10.1186/s11658-024-00556-y Volume 29 (2024) - 29:32
Title CURRICULUM VITAE OF CUG BINDING PROTEIN 1 (CELF1) IN HOMEOSTASIS AND DISEASES: A SYSTEMATIC REVIEW
Authors Wan‐Jia Qin1,2, Jin‐Jin Shi1,2, Ru‐Yi Chen1,2, Chang‐Yun Li1,2, Yan‐Jun Liu1,2, Jian‐Fei Lu1,2, Guan‐Jun Yang1,2*, Jia‐Feng Cao1,2* and Jiong Chen1,2*
Abstract RNA-binding proteins (RBPs) are kinds of proteins with either singular or multiple RNA-binding domains (RBDs), and they can assembly into ribonucleic acid–protein complexes, which mediate transportation, editing, splicing, stabilization, translational efficiency, or epigenetic modifications of their binding RNA partners, and thereby modulate various physiological and pathological processes. CUG-BP, Elav-like family 1 (CELF1) is a member of the CELF family of RBPs with high affinity to the GU-rich elements in mRNA, and thus exerting control over critical processes including mRNA splicing, translation, and decay. Mounting studies support that CELF1 is correlated with occurrence, genesis and development and represents a potential therapeutical target for these malignant diseases. Herein, we present the structure and function of CELF1, outline its role and regulatory mechanisms in varieties of homeostasis and diseases, summarize the identified CELF1 regulators and their structure–activity relationships, and prospect the current challenges and their solutions during studies on CELF1 functions and corresponding drug discovery, which will facilitate the establishment of a targeted regulatory network for CELF1 in diseases and advance CELF1 as a potential drug target for disease therapy.
Keywords CELF1, RNA-binding protein, Diseases, Cancer therapy, Inhibitor
Address and Contact Information 1 State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro‐Products, Ningbo University, Ningbo 315211, Zhejiang, China
2 Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China
*Corresponding author: champion2014@126.com; caojiafeng@nbu.edu.cn; chenjiong@nbu.edu.cn
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No. 33 DOI: 10.1186/s11658-024-00538-0 Volume 29 (2024) - 29:33
Title UNLOCKING THE SECRETS: EXPLORING THE INFLUENCE OF THE ARYL HYDROCARBON RECEPTOR AND MICROBIOME ON CANCER DEVELOPMENT
Authors Menatallah Rayan1,2, Tahseen S. Sayed1, Ola J. Hussein1, Lubna Therachiyil1,3, Zaid H. Maayah1, Cristina Maccalli4, Shahab Uddin3,5, Jochen H. M. Prehn2,6 and Hesham M. Korashy1*
Abstract Gut microbiota regulates various aspects of human physiology by producing metabolites, metabolizing enzymes, and toxins. Many studies have linked microbiota with human health and altered microbiome configurations with the occurrence of several diseases, including cancer. Accumulating evidence suggests that the microbiome can influence the initiation and progression of several cancers. Moreover, some microbiotas of the gut and oral cavity have been reported to infect tumors, initiate metastasis, and promote the spread of cancer to distant organs, thereby influencing the clinical outcome of cancer patients. The gut microbiome has recently been reported to interact with environmental factors such as diet and exposure to environmental toxicants. Exposure to environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) induces a shift in the gut microbiome metabolic pathways, favoring a proinflammatory microenvironment. In addition, other studies have also correlated cancer incidence with exposure to PAHs. PAHs are known to induce organ carcinogenesis through activating a ligand-activated transcriptional factor termed the aryl hydrocarbon receptor (AhR), which metabolizes PAHs to highly reactive carcinogenic intermediates. However, the crosstalk between AhR and the microbiome in mediating carcinogenesis is poorly reviewed. This review aims to discuss the role of exposure to environmental pollutants and activation of AhR on microbiome-associated cancer progression and explore the underlying molecular mechanisms involved in cancer development.
Keywords Microbiome, Aryl hydrocarbon receptor, Cancer, CYP1A1, Environmental pollutants
Address and Contact Information 1 Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P. O. Box 2713, Doha, Qatar
2 Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
3 Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
4 Research Branch, Sidra Medicine, Doha, Qatar
5 Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
6 RCSI Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland
*Corresponding author: hkorashy@qu.edu.qa
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No. 34 DOI: 10.1186/s11658-024-00548-y Volume 29 (2024) - 29:34
Title A MULTIPLEX RPA-CRISPR/Cas12a-BASED POCT TECHNIQUE AND ITS APPLICATION IN HUMAN PAPILLOMAVIRUS (HPV) TYPING ASSAY
Authors Yan Liu1†, Zhujun Chao2†, Wei Ding1†, Tanfeng Fang1†, Xinxian Gu3*†, Man Xue4, Wei Wang1, Rong Han1 and Wanping Sun1*†
Abstract Persistent infection with high-risk human papillomavirus (HR-HPV) is the primary and initiating factor for cervical cancer. With over 200 identified HPV types, including 14 high-risk types that integrate into the host cervical epithelial cell DNA, early determination of HPV infection type is crucial for effective risk stratification and management. Presently, on-site immediate testing during the HPV screening stage, known as Point of Care Testing (POCT), remains immature, severely limiting the scope and scenarios of HPV screening. This study, guided by the genomic sequence patterns of HPV, established a multiplex recombinase polymerase amplification (RPA) technology based on the concept of “universal primers.” This approach achieved the multiple amplification of RPA, coupled with the CRISPR/Cas12a system serving as a medium for signal amplification and conversion. The study successfully constructed a POCT combined detection system, denoted as H-MRC12a (HPV—Multiple RPA—CRISPR/Cas12a), and applied it to high-risk HPV typing detection. The system accomplished the typing detection of six high-risk HPV types (16, 18, 31, 33, 35, and 45) can be completed within 40 min, and the entire process, from sample loading to result interpretation, can be accomplished within 45 min, with a detection depth reaching 1 copy/μL for each high-risk type. Validation of the H-MRC12a detection system’s reproducibility and specificity was further conducted through QPCR on 34 clinical samples. Additionally, this study explored and optimized the multiplex RPA amplification system and CRISPR system at the molecular mechanism level. Furthermore, the primer design strategy developed in this study offers the potential to enhance the throughput of H-MRC12a detection while ensuring sensitivity, providing a novel research avenue for high-throughput detection in Point-of-Care molecular pathogen studies.
Keywords HR-HPV, Multiplex RPA, CRISPR/Cas12a, POCT
Address and Contact Information 1 Laboratory of Molecular Diagnostics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215000, Jiangsu, People’s Republic of China
2 Soochow University, Suzhou Medical College of Soochow University, Suzhou 215000, Jiangsu, People’s Republic of China
3 Dushu Lake Hospital, Affiliated to Soochow University, Dushu Lake Hospital Affiliated to Soochow University, Suzhou 215004, Jiangsu, People’s Republic of China
4 Biological Products and Biochemical Drugs, Suzhou Institute for Food and Drug Control, Suzhou 215101, Jiangsu, People’s Republic of China
*Corresponding author: guxinxian@suda.edu.cn; sunwanping@suda.edu.cn
† Yan Liu and Zhujun Chao have contributed equally as co-first authors.
† Yan Liu, Zhujun Chao, Wei Ding, Tanfeng Fang, Xinxian Gu and Wanping Sun have contributed equally to this work.
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No. 35 DOI: 10.1186/s11658-024-00557-x Volume 29 (2024) - 29:35
Title THE micro-743a-3p–GSTM1 PATHWAY IS AN ENDOGENOUS PROTECTIVE MECHANISM AGAINST ALCOHOL-RELATED LIVER DISEASE IN MICE
Authors Tiantian Xu1†, Yan Pan2†, Qinchao Ding1†, Feiwei Cao1 , Kaixin Chang2 , Jiannan Qiu2 , Hui Zhuge2 , Liuyi Hao1 , Haibin Wei2 , Caijuan Si3 , Xiaobing Dou2 and Songtao Li1,3*
Abstract Background and aims: Epidemiological evidence suggests that the phenotype of glutathione S-transferase mu 1 (GSTM1), a hepatic high-expressed phase II detoxification enzyme, is closely associated with the incidence of alcohol-related liver disease (ALD). However, whether and how hepatic GSTM1 determines the development of ALD is largely unclear. This study was designed to elucidate the role and potential mechanism(s) of hepatic GSTM1 in the pathological process of ALD.
Methods: GSTM1 was detected in the liver of various ALD mice models and cultured hepatocytes. Liver-specific GSTM1 or/and micro (miR)-743a-3p deficiency mice were generated by adenoassociated virus-8 delivered shRNA, respectively. The potential signal pathways involving in alcohol-regulated GSTM1 and GSTM1-associated ALD were explored via both genetic manipulation and pharmacological approaches.
Results: GSTM1 was significantly upregulated in both chronic alcohol-induced mice liver and ethanol-exposed murine primary hepatocytes. Alcohol-reduced miR-743a-3p directly contributed to the upregulation of GSTM1, since liver specific silencing miR-743a-3p enhanced GSTM1 and miR-743a-3p loss protected alcohol-induced liver dysfunctions, which was significantly blocked by GSTM1 knockdown. GSTM1 loss robustly aggravated alcohol-induced hepatic steatosis, oxidative stress, inflammation, and early fibrotic-like changes, which was associated with the activation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK), and p38. GSTM1 antagonized ASK1 phosphorylation and its downstream JNK/p38 signaling pathway upon chronic alcohol consumption via binding with ASK1. ASK1 blockage significantly rescued hepatic GSTM1 loss-enhanced disorders in alcohol-fed mice liver.
Conclusions: Chronic alcohol consumption-induced upregulation of GSTM1 in the liver provides a feedback protection against hepatic steatosis and liver injury by counteracting ASK1 activation. Down-regulation of miR-743a-3p improves alcohol intake-induced hepatic steatosis and liver injury via direct targeting on GSTM1. The miR-743a-3p–GSTM1 axis functions as an innate protective pathway to defend the early stage of ALD.
Keywords GSTM1, Alcohol-related liver disease, Hepatic steatosis, miR-743a-3p, ASK1
Address and Contact Information 1 School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
2 School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
3 Department of Clinical Nutrition, School of Medicine, Affiliated Zhejiang Hospital, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
*Corresponding author: lisongtao@zcmu.edu.cn
† Tiantian Xu, Yan Pan and Qinchao Ding contributed equally to this paper.
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No. 36 DOI: 10.1186/s11658-024-00558-w Volume 29 (2024) - 29:36
Title OBESITY-INDUCED DOWNREGULATION OF miR-192 EXACERBATES LIPOPOLYSACCHARIDE-INDUCED ACUTE LUNG INJURY BY PROMOTING MACROPHAGE ACTIVATION
Authors Siqi Wu1†, Wenjing Tang1†, Ling Liu1*, Ke Wei1*, Yin Tang1, Jingyue Ma1, Hongbin Li1 and Yichan Ao1
Abstract Background: Macrophage activation may play a crucial role in the increased susceptibility of obese individuals to acute lung injury (ALI). Dysregulation of miRNA, which is involved in various inflammatory diseases, is often observed in obesity. This study aimed to investigate the role of miR-192 in lipopolysaccharide (LPS)-induced ALI in obese mice and its mechanism of dysregulation in obesity.
Methods: Human lung tissues were obtained from obese patients (BMI ≥ 30.0 kg/m2) and control patients (BMI 18.5–24.9 kg/m2). An obese mouse model was established by feeding a high-fat diet (HFD), followed by intratracheal instillation of LPS to induce ALI. Pulmonary macrophages of obese mice were depleted through intratracheal instillation of clodronate liposomes. The expression of miR-192 was examined in lung tissues, primary alveolar macrophages (AMs), and the mouse alveolar macrophage cell line (MH-S) using RT-qPCR. m6A quantification and RIP assays helped determine the cause of miR-192 dysregulation. miR-192 agomir and antagomir were used to investigate its function in mice and MH-S cells. Bioinformatics and dual-luciferase reporter gene assays were used to explore the downstream targets of miR-192.
Results: In obese mice, depletion of macrophages significantly alleviated lung tissue inflammation and injury, regardless of LPS challenge. miR-192 expression in lung tissues and alveolar macrophages was diminished during obesity and further decreased with LPS stimulation. Obesity-induced overexpression of FTO decreased the m6A modification of pri-miR-192, inhibiting the generation of miR-192. In vitro, inhibition of miR-192 enhanced LPS-induced polarization of M1 macrophages and activation of the AKT/ NF-κB inflammatory pathway, while overexpression of miR-192 suppressed these reactions. BIG1 was confirmed as a target gene of miR-192, and its overexpression offset the protective effects of miR-192. In vivo, when miR-192 was overexpressed in obese mice, the activation of pulmonary macrophages and the extent of lung injury were significantly improved upon LPS challenge.
Conclusions: Our study indicates that obesity-induced downregulation of miR-192 expression exacerbates LPS-induced ALI by promoting macrophage activation. Targeting macrophages and miR-192 may provide new therapeutic avenues for obesity-associated ALI.
Keywords Obesity, Acute lung injury, microRNA, Macrophage activation, m6A, Metabolic stress
Address and Contact Information 1 Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, No 1. YouYi Road, Yuzhong District, Chongqing 400016, China
*Corresponding author: Lingsoasprenal@hospital.cqmu.edu.cn; 202448@hospital.cqmu.edu.cn; wk202448@hospital-cqmu.com
† Siqi Wu and Wenjing Tang contributed equally to this work.
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No. 37 DOI: 10.1186/s11658-024-00547-z Volume 29 (2024) - 29:37
Title MRE11A: A NOVEL NEGATIVE REGULATOR OF HUMAN DNA MISMATCH REPAIR
Authors Demin Du1†, Yueyan Yang2†, Yuanyuan Zhang1, Guanxiong Wang1, Liying Chen1, Xiaowei Guan1*, Lene Juel Rasmussen3* and Dekang Liu1*
Abstract Background: DNA mismatch repair (MMR) is a highly conserved pathway that corrects DNA replication errors, the loss of which is attributed to the development of various types of cancers. Although well characterized, MMR factors remain to be identified. As a 3′–5′ exonuclease and endonuclease, meiotic recombination 11 homolog A (MRE11A) is implicated in multiple DNA repair pathways. However, the role of MRE11A in MMR is unclear.
Methods: Initially, short-term and long-term survival assays were used to measure the cells’ sensitivity to N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). Meanwhile, the level of apoptosis was also determined by flow cytometry after MNNG treatment. Western blotting and immunofluorescence assays were used to evaluate the DNA damage within one cell cycle after MNNG treatment. Next, a GFP-heteroduplex repair assay and microsatellite stability test were used to measure the MMR activities in cells. To investigate the mechanisms, western blotting, the GFP-heteroduplex repair assay, and chromatin immunoprecipitation were used.
Results: We show that knockdown of MRE11A increased the sensitivity of HeLa cells to MNNG treatment, as well as the MNNG-induced DNA damage and apoptosis, implying a potential role of MRE11 in MMR. Moreover, we found that MRE11A was largely recruited to chromatin and negatively regulated the DNA damage signals within the first cell cycle after MNNG treatment. We also showed that knockdown of MRE11A increased, while overexpressing MRE11A decreased, MMR activity in HeLa cells, suggesting that MRE11A negatively regulates MMR activity. Furthermore, we show that recruitment of MRE11A to chromatin requires MLH1 and that MRE11A competes with PMS2 for binding to MLH1. This decreases PMS2 levels in whole cells and on chromatin, and consequently comprises MMR activity.
Conclusions: Our findings reveal that MRE11A is a negative regulator of human MMR.
Keywords Alkylating agents, DNA mismatch repair, DNA repair, MRE11A, PMS2
Address and Contact Information 1 Department of Human Anatomy and Histoembryology, Nanjing University of Chinese Medicine, Nanjing 210023, China
2 Afliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210023, China
3 Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
*Corresponding author: guanxw918@njucm.edu.cn; lenera@sund.ku.dk; dekang@njucm.edu.cn
† Demin Du and Yueyan Yang are joint frst authors.
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No. 38 DOI: 10.1186/s11658-024-00550-4 Volume 29 (2024) - 29:38
Title UREMIC TOXINS MEDIATE KIDNEY DISEASES: THE ROLE OF ARYL HYDROCARBON RECEPTOR
Authors Hongyan Xie1, Ninghao Yang2, Chen Yu1* and Limin Lu2*
Abstract Aryl hydrocarbon receptor (AhR) was originally identified as an environmental sensor that responds to pollutants. Subsequent research has revealed that AhR recognizes multiple exogenous and endogenous molecules, including uremic toxins retained in the body due to the decline in renal function. Therefore, AhR is also considered to be a uremic toxin receptor. As a ligand-activated transcriptional factor, the activation of AhR is involved in cell differentiation and senescence, lipid metabolism and fibrogenesis. The accumulation of uremic toxins in the body is hazardous to all tissues and organs. The identification of the endogenous uremic toxin receptor opens the door to investigating the precise role and molecular mechanism of tissue and organ damage induced by uremic toxins. This review focuses on summarizing recent findings on the role of AhR activation induced by uremic toxins in chronic kidney disease, diabetic nephropathy and acute kidney injury. Furthermore, potential clinical approaches to mitigate the effects of uremic toxins are explored herein, such as enhancing uremic toxin clearance through dialysis, reducing uremic toxin production through dietary interventions or microbial manipulation, and manipulating metabolic pathways induced by uremic toxins through controlling AhR signaling. This information may also shed light on the mechanism of uremic toxin-induced injury to other organs, and provide insights into clinical approaches to manipulate the accumulated uremic toxins.
Keywords Uremic toxins, Aryl hydrocarbon receptor, Acute kidney injury, Chronic kidney disease, Diabetic nephropathy
Address and Contact Information 1 Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, China
2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China
*Corresponding author: yuchen@tongji.edu.cn; lulimin@shmu.edu.cn
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No. 39 DOI: 10.1186/s11658-024-00545-1 Volume 29 (2024) - 29:39
Title IGF2BP3 PREVENT HMGB1 mRNA DECAY IN BLADDER CANCER AND DEVELOPMENT
Authors Lei Lv1†, Qinqin Wei2†, Jianxiao Zhang3†, Yitong Dong2, Zhenglei Shan4, Na Chang5, Ye Zhao2*, Po Bian2* and Qiyi Yi2*
Abstract Background: IGF2BP3 functions as an RNA-binding protein (RBP) and plays a role in the posttranscriptional control of mRNA localization, stability, and translation. Its dysregulation is frequently associated with tumorigenesis across various cancer types. Nonetheless, our understanding of how the expression of the IGF2BP3 gene is regulated remains limited. The specific functions and underlying mechanisms of IGF2BP3, as well as the potential benefits of targeting it for therapeutic purposes in bladder cancer, are not yet well comprehended.
Methods: The mRNA and protein expression were examined by RT-qPCR and western blotting, respectively. The methylation level of CpG sites was detected by Bisulfite sequencing PCR (BSP). The regulation of IGF2BP3 expression by miR-320a-3p was analyzed by luciferase reporter assay. The functional role of IGF2BP3 was determined through proliferation, colony formation, wound healing, invasion assays, and xenograft mouse model. The regulation of HMGB1 by IGF2BP3 was investigated by RNA immunoprecipitation (RIP) and mRNA stability assays.
Results: We observed a significant elevation in IGF2BP3 levels within bladder cancer samples, correlating with more advanced stages and grades, as well as an unfavorable prognosis. Subsequent investigations revealed that the upregulation of IGF2BP3 expression is triggered by copy number gain/amplification and promoter hypomethylation in various tumor types, including bladder cancer. Furthermore, miR-320a-3p was identified as another negative regulator in bladder cancer. Functionally, the upregulation of IGF2BP3 expression exacerbated bladder cancer progression, including the proliferation, migration, and invasion of bladder cancer. Conversely, IGF2BP3 silencing produced the opposite effects. Moreover, IGF2BP3 expression positively correlated with inflammation and immune infiltration in bladder cancer. Mechanistically, IGF2BP3 enhanced mRNA stability and promoted the expression of HMGB1 by binding to its mRNA, which is a factor that promotes inflammation and orchestrates tumorigenesis in many cancers. Importantly, pharmacological inhibition of HMGB1 with glycyrrhizin, a specific HMGB1 inhibitor, effectively reversed the cancer-promoting effects of IGF2BP3 overexpression in bladder cancer. Furthermore, the relationship between HMGB1 mRNA and IGF2PB3 is also observed in mammalian embryonic development, with the expression of both genes gradually decreasing as embryonic development progresses.
Conclusions: Our present study sheds light on the genetic and epigenetic mechanisms governing IGF2BP3 expression, underscoring the critical involvement of the IGF2BP3-HMGB1 axis in driving bladder cancer progression. Additionally, it advocates for the investigation of inhibiting IGF2BP3-HMGB1 as a viable therapeutic approach for treating bladder cancer.
Keywords IGF2BP3, HMGB1, m6A, Methylation, Copy number amplifcation, Glycyrrhizin
Address and Contact Information 1 Department of Cancer Epigenetics Program, Anhui Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230031, Anhui, China
2 Institute of Radiation Medicine, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
3 Medical Consulting Center, Hebei Children’s Hospital, Shijiazhuang 050030, Hebei, China
4 The Second Clinical College, Anhui Medical University, Hefei 230032, Anhui, China
5 Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230031, Anhui, People’s Republic of China
*Corresponding author: zhaoye@ahmu.edu.cn; bianpo@ahmu.edu.cn; yiqiyi@ahmu.edu.cn
† Lei Lv, Qinqin Wei and Jianxiao Zhang are contributed equally to this work.
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No. 40 DOI: 10.1186/s11658-024-00560-2 Volume 29 (2024) - 29:40
Title ROLE OF FERROPTOSIS AND FERROPTOSIS-RELATED LONG NON'CODING RNA IN BREAST CANCER
Authors Shasha Xiang1,2†, Wen Yan1†, Xing Ren2, Jianbo Feng1* and Xuyu Zu1*
Abstract Ferroptosis, a therapeutic strategy for tumours, is a regulated cell death characterised by the increased accumulation of iron-dependent lipid peroxides (LPO). Tumour-associated long non-coding RNAs (lncRNAs), when combined with traditional anti-cancer medicines or radiotherapy, can improve efficacy and decrease mortality in cancer. Investigating the role of ferroptosis-related lncRNAs may help strategise new therapeutic options for breast cancer (BC). Herein, we briefly discuss the genes and pathways of ferroptosis involved in iron and reactive oxygen species (ROS) metabolism, including the XC−/GSH/GPX4 system, ACSL4/LPCAT3/15-LOX and FSP1/CoQ10/NAD(P)H pathways, and investigate the correlation between ferroptosis and LncRNA in BC to determine possible biomarkers related to ferroptosis.
Keywords LncRNA, Breast cancer, Ferroptosis, Ferroptosis-related lncRNA, Biomarker
Address and Contact Information 1 Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
2 Department of Clinical Laboratory Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
*Corresponding author: fengjianbobody@126.com; zuxuyu0108@hotmail.com
† Shasha Xiang and Wen Yan have contributed equally to this work.
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No. 41 DOI: https://cmbl.biomedcentral.com/articles/10.1186/s11658-024-00554-0 Volume 29 (2024) - 29:41
Title EMERGING ROLES OF PROMININ-1 (CD133) IN THE DYNAMICS OF PLASMA MEMBRANE ARCHITECTURE AND CELL SIGNALING PATHWAYS IN HEALTH AND DISEASE
Authors Petr Pleskač1,2, Christine A. Fargeas3,4, Renata Veselska1,2, Denis Corbeil3,4* and Jan Skoda1,2*
Abstract Prominin-1 (CD133) is a cholesterol-binding membrane glycoprotein selectively associated with highly curved and prominent membrane structures. It is widely recognized as an antigenic marker of stem cells and cancer stem cells and is frequently used to isolate them from biological and clinical samples. Recent progress in understanding various aspects of CD133 biology in different cell types has revealed the involvement of CD133 in the architecture and dynamics of plasma membrane protrusions, such as microvilli and cilia, including the release of extracellular vesicles, as well as in various signaling pathways, which may be regulated in part by posttranslational modifications of CD133 and its interactions with a variety of proteins and lipids. Hence, CD133 appears to be a master regulator of cell signaling as its engagement in PI3K/Akt, Src-FAK, Wnt/β-catenin, TGF-β/Smad and MAPK/ERK pathways may explain its broad action in many cellular processes, including cell proliferation, differentiation, and migration or intercellular communication. Here, we summarize early studies on CD133, as they are essential to grasp its novel features, and describe recent evidence demonstrating that this unique molecule is involved in membrane dynamics and molecular signaling that affects various facets of tissue homeostasis and cancer development. We hope this review will provide an informative resource for future efforts to elucidate the details of CD133’s molecular function in health and disease.
Keywords Cancer, Cancer stem cell, Cell signaling, CD133, Cilium, Exosome, Lipid raft, Microvillus, Prominin-1, Stem cell
Address and Contact Information 1 Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
2 International Clinical Research Center, St. Anne’s University Hospital, Brno, Czech Republic
3 Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Tatzberg 47/49, 01307 Dresden, Germany
4 Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Dresden, Germany
*Corresponding author: denis.corbeil@tu-dresden.de; jan.skoda@sci.muni.cz
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No. 42 DOI: 10.1186/s11658-024-00564-y Volume 29 (2024) - 29:42
Title DECODING EPITRANSCRIPTOMIC REGULATION OF VIRAL INFECTION: MAPPING OF RNA N6-METHYLADENOSINE BY ADVANCED SEQUENCING TECHNOLOGIES
Authors Xiangdong Fan1†, Yitong Zhang1†, Ruiying Guo1†, Kuo Yue1 , Guy Smagghe2,3,4, Yongyue Lu1* and Luoluo Wang1*
Abstract Elucidating the intricate interactions between viral pathogens and host cellular machinery during infection is paramount for understanding pathogenic mechanisms and identifying potential therapeutic targets. The RNA modification N6-methyladenosine (mm6A) has emerged as a significant factor influencing the trajectory of viral infections. Hence, the precise and quantitative mapping of m6A modifications in both host and viral RNA is pivotal to understanding its role during viral infection. With the rapid advancement of sequencing technologies, scientists are able to detect m6A modifications with various quantitative, high-resolution, transcriptome approaches. These technological strides have reignited research interest in m6A, underscoring its significance and prompting a deeper investigation into its dynamics during viral infections. This review provides a comprehensive overview of the historical evolution of mm6A epitranscriptome sequencing technologies, highlights the latest developments in transcriptome-wide m6A mapping, and emphasizes the innovative technologies for detecting m6A modification. We further discuss the implications of these technologies for future research into the role of m6A in viral infections.
Keywords m6 A modifcation, Epitranscriptome sequencing technologies, Viral infection
Address and Contact Information 1 National Key Laboratory of Green Pesticide, College of Plant Protection, South China Agricultural University, Guangzhou 510642, China
2 Molecular and Cellular Life Sciences, Department of Biology, Vrije Universiteit Brussel (VUB), 1050 Brussels, Belgium
3 Institute of Entomology, Guizhou University, Guiyang 550025, China
4 Department of Plants and Crops, Faculty of Bioscience Engineering, Ghent University, 9000 Ghent, Belgium
*Corresponding author: luyongyue@scau.edu.cn; Luoluo.wang@scau.edu.cn
† Xiangdong Fan, Yitong Zhang and Ruiying Guo have contributed equally to this work.
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No. 43 DOI: 10.1186/s11658-024-00549-x Volume 29 (2024) - 29:43
Title ONCOGENIC circ-SLC16A1 PROMOTES PROGRESSION OF NON-SMALL CELL LUNG CANCER VIA REGULATION OF THE miR-1287-5p/profilin 2 AXIS
Authors Mingming Jin1†, Tailei Yuan1,2,3,4†, Kaisai Tian1,2,3†, Jingjing Li1†, Qingqing Huang1*, Yongbin Chi2,3* and Gang Huang1*
Abstract Background: Circular RNAs (circRNAs) are single-stranded RNAs with covalently closed structures that have been implicated in cancer progression. However, the regulatory mechanisms remain largely unclear. So, the aim of this study was to reveal the role and regulatory mechanisms of circ-SLC16A1.
Methods: In this study, next-generation sequencing was used to identify abnormally expressed circRNAs between cancerous and para-carcinoma tissues. Fluorescence in situ hybridization and quantitative reverse transcription polymerase chain reaction were performed to assess the expression patterns of circ-solute carrier family 16 member 1 (SLC16A1) in non-small cell lung cancer (NSCLC) cells and tissue specimens. The dual-luciferase reporter assay was utilized to identify downstream targets of circ-SLC16A1. Transwell migration, wound healing, 5-ethynyl-2′-deoxyuridine incorporation, cell counting, and colony formation assays were conducted to assess the proliferation and migration of NSCLC cells. A mouse tumor xenograft model was employed to determine the roles of circ-SLC16A1 in NSCLC progression and metastasis in vivo.
Results: The results found that circ-SLC16A1 was upregulated in NSCLC cells and tissues. Downregulation of circ-SLC16A1 inhibited tumor growth by reducing proliferation, lung metastasis, and lymphatic metastasis of NSCLC cells, and arrested the cell cycle in the G1 phase. Also, silencing of circ-SLC16A1 promoted apoptosis of NSCLC cells. The results of bioinformatics analysis and the dual-luciferase reporter assay confirmed that microRNA (miR)-1287-5p and profilin 2 (PFN2) are downstream targets of circ-SLC16A1. PFN2 overexpression or circ-SLC16A1 inhibition restored proliferation and migration of NSCLC cells after silencing of circ-SLC16A1. PFN2 overexpression restored migration and proliferation of NSCLC cells post miR-1287-5p overexpression.
Conclusions: Collectively, these findings show that miR-1287-5p/PFN2 signaling was associated with downregulation of circ-SLC16A1 and reduced invasion and proliferation of NSCLC cells. So, circ-SLC16A1 is identified as a mediator of multiple pro-oncogenic signaling pathways in NSCLC and can be targeted to suppress tumor progression.
Keywords Circular RNA SLC16A1, Non-small cell lung cancer, microRNA-1287-5p, Proflin 2, Lymphatic metastasis
Address and Contact Information 1 Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, People’s Republic of China
2 Postgraduate Training Base of Shanghai Gongli Hospital, Ningxia Medical University, Shanghai 200135, People’s Republic of China
3 Department of Clinical Lab, Shanghai Pudong New Area Gongli Hospital, Shanghai 200135, People’s Republic of China
4 Jiangbei Hospital Afliated to Xinglin College, Nantong University, Jiangsu 210048, People’s Republic of China
*Corresponding author: qingqinghuang80@163.com; chiyb1@hotmail.com; huanggang@sumhs.edu.cn
† Mingming Jin, Tailei Yuan, Kaisai Tian, and Jingjing Li contributed equally to this manuscript.
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No. 44 DOI: 10.1186/s11658-024-00563-z Volume 29 (2024) - 29:44
Title TRANSCRIPTIONAL AND METABOLIC EFFECTS OF ASPARTATE-GLUTAMATE CARRIER ISOFORM 1 (AGC1) DOWNREGULATION IN MOUSE OLIGODENDROCYTE PRECURSOR CELLS (OPCs)
Authors Nicola Balboni1†, Giorgia Babini1†, Eleonora Poeta1, Michele Protti1, Laura Mercolini1, Maria Chiara Magnifco2, Simona Nicole Barile2, Francesca Massenzio1, Antonella Pignataro2, Federico M. Giorgi1*, Francesco Massimo Lasorsa2* and Barbara Monti1*
Abstract Aspartate–glutamate carrier isoform 1 (AGC1) is a carrier responsible for the export of mitochondrial aspartate in exchange for cytosolic glutamate and is part of the malate–aspartate shuttle, essential for the balance of reducing equivalents in the cells. In the brain, mutations in SLC25A12 gene, encoding for AGC1, cause an ultra-rare genetic disease, reported as a neurodevelopmental encephalopathy, whose symptoms include global hypomyelination, arrested psychomotor development, hypotonia and seizures. Among the biological components most affected by AGC1 deficiency are oligodendrocytes, glial cells responsible for myelination processes, and their precursors [oligodendrocyte progenitor cells (OPCs)]. The AGC1 silencing in an in vitro model of OPCs was documented to cause defects of proliferation and differentiation, mediated by alterations of histone acetylation/deacetylation. Disrupting AGC1 activity could possibly reduce the availability of acetyl groups, leading to perturbation of many biological pathways, such as histone modifications and fatty acids formation for myelin production. Here, we explore the transcriptome of mouse OPCs partially silenced for AGC1, reporting results of canonical analyses (differential expression) and pathway enrichment analyses, which highlight a disruption in fatty acids synthesis from both a regulatory and enzymatic stand. We further investigate the cellular effects of AGC1 deficiency through the identification of most affected transcriptional networks and altered alternative splicing. Transcriptional data were integrated with differential metabolite abundance analysis, showing downregulation of several amino acids, including glutamine and aspartate. Taken together, our results provide a molecular foundation for the effects of AGC1 deficiency in OPCs, highlighting the molecular mechanisms affected and providing a list of actionable targets to mitigate the effects of this pathology.
Keywords White matter disorder, Mitochondria, Omics analysis, Oligodendrocytes, Neurodevelopment, SLC25A12/aralar1/AGC1 defciency
Address and Contact Information 1 Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
2 Department of Biosciences, Biotechnologies and Environment, University of Bari, Bari, Italy
*Corresponding author: federico.giorgi@unibo.it; francesco.lasorsa@uniba.it; b.monti@unibo.it
† Nicola Balboni and Giorgia Babini contributed equally to the work.
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No.  45DOI: 10.1186/s11658-024-00559-9 Volume 29 (2024) - 29:45
Title EFFECTS OF MIFEPRISTONE ON ADIPOCYTE DIFFERENTIATION IN MOUSE 3T3-L1 CELLS
Authors Takeshi Hashimoto1* and Katsuya Hirano1
Abstract Background: Both glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ) play a critical role in adipocyte differentiation. Mifepristone is not only an antagonist of the glucocorticoid receptor but also an agonist of PPARγ. Therefore, the present study investigated the effect of mifepristone on adipocyte differentiation.
Methods: Mouse 3T3-L1 cells were used as a model for adipocyte differentiation. The lipid droplet formation was evaluated with Bodipy493/503 staining and the expression of adipocyte markers [adiponectin and adipocyte fatty acid binding protein-4 (Fabp4)] was evaluated with quantitative PCR and immunoblot analyses for indication of adipocyte differentiation. siRNA and neutralizing antibodies were used to elucidate the molecular mechanism of mifepristone-induced adipocyte differentiation. Luciferase reporter assay was used to examine the effect of mifepristone on the promoter activity of PPAR-response element (PPRE). The DNA microarray analysis was used to characterize the transcriptome of the mifepristone-induced adipocytes. In vivo adipogenic effect of mifepristone was examined in mice.
Results: Mifepristone not only enhanced adipocyte differentiation induced by the conventional protocol consisting of insulin, dexamethasone and 3-isobutyl-1-methylxanthine but also induced adipocyte differentiation alone, as evidenced by lipid droplets formation and induction of the expression of adiponectin and Fabp4. These effects were inhibited by an adiponectin-neutralizing antibody and a PPARγ antagonist. Mifepristone activated the promoter activity of PPRE in a manner sensitive to PPARγ antagonist. A principal component analysis (PCA) of DNA microarray data revealed that the mifepristone-induced adipocytes represent some characteristics of the in situ adipocytes in normal adipose tissues to a greater extent than those induced by the conventional protocol. Mifepristone administration induced an increase in the weight of epididymal, perirenal and gluteofemoral adipose tissues.
Conclusions: Mifepristone alone is capable of inducing adipocyte differentiation in 3T3-L1 cells and adipogenesis in vivo. PPARγ plays a critical role in the mifepristone-induced adipocyte differentiation. Mifepristone-induced adipocytes are closer to the in situ adipocytes than those induced by the conventional protocol. The present study proposes a single treatment with mifepristone as a novel protocol to induce more physiologically relevant adipocytes in 3T3-L1 cells than the conventional protocol.
Keywords Mifepristone, Adipocyte diferentiation, PPARγ, siRNA, Neutralizing antibodies
Address and Contact Information 1 Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, 1750-1 Miki-Cho, Kita-Gun, Kagawa 761-0793, Japan
*Corresponding author: hashimoto.takeshi@kagawa-u.ac.jp
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No.  46DOI: 10.1186/s11658-024-00562-0 Volume 29 (2024) - 29:46
Title SIALYLATION ON VESICULAR INTEGRIN β1 DETERMINED ENDOCYTIC ENTRY OF SMALL EXTRACELLULAR VESICLES INTO RECIPIENT CELLS
Authors Meixuan Lin1, Xiaoqiang Xu1, Xiaoman Zhou1, Hui Feng1, Ruili Wang1, Yunyun Yang1, Jing Li1, Ning Fan1, Yazhuo Jiang2, Xiang Li3, Feng Guan1* and Zengqi Tan3*
Abstract Background: Small extracellular vesicles (sEV) are closely associated with the development and metastasis of many types of mammalian cancer. Glycoconjugates are highly expressed on sEV and play important roles in sEV biogenesis and their interaction with other cells. However, the study on vesicular glycoconjugates are far behind proteins and nucleic acids. Especially, the functions of sialic acids which are the terminal components of glycoconjugates, are poorly understood in sEV.
Methods: Sialic acid levels on sEV from plasma and bladder cancer cells were determined by ELISA and lectin blotting. Effects of sialylation on sEV uptake were determined by flow cytometry. Vesicular glycoproteins bearing sialic acids responsible for sEV uptake was identified by proteomics and density gradient centrifugation, and their site-specific sialylation functions were assayed by N-glycosylation site mutation. Effects of integrin β1 bearing sialic acids on the pro-metastatic function of sEV in vivo were explored using Balb/c nu/nu mice.
Results: (1) Increased sialic acid levels were observed in sEV from malignant bladder cancer cells. (2) Elimination of sialic acids on sEV impaired sEV uptake by recipient cells. (3) Vesicular integrin β1 bearing sialic acids was identified to play a key role in sEV uptake. (4) Desialylation of the hybrid domain of vesicular integrin β1 inhibited its binding to matrix fibronectin, and reduced sEV entry into recipient cells. (5) Sialylation on integrin β1 affected pro-metastatic function of sEV in Balb/c nu/nu mice.
Conclusions: Taken together, our findings indicate important functional roles of sialic acids in sEV uptake and reprogramming plasticity of surrounding normal epithelial cells.
Keywords Sialic acid, Small extracellular vesicles, Integrin β1, Bladder cancer, Matrix fibronectin
Address and Contact Information 1 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi’an, China
2 Department of Urology, Provincial People’s Hospital, Xi’an, China
3 Institute of Hematology, School of Medicine, Northwest University, Xi’an, China
*Corresponding author: guanfeng@nwu.edu.cn; zengqtan@nwu.edu.cn
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No.  47DOI: 10.1186/s11658-024-00566-w Volume 29 (2024) - 29:47
Title G6PD MAINTAINS THE VSMC SYNTHETIC PHENOTYPE AND ACCELERATES VASCULAR NEOINTIMAL HYPERPLASIA BY INHIBITING THE VDAC1–Bax-MEDIATED MITOCHONDRIAL APOPTOSIS PATHWAY
Authors Ting Zhang1,2, Rui‐Jie Cao1, Jiang‐Ling Niu1, Zhi‐Huan Chen1, Shi‐Qing Mu1, Tong Cao1, Jie‐Xin Pang1 and Li‐Hua Dong1*
Abstract Background: Glucose-6-phosphate dehydrogenase (G6PD) plays an important role in vascular smooth muscle cell (VSMC) phenotypic switching, which is an early pathogenic event in various vascular remodeling diseases (VRDs). However, the underlying mechanism is not fully understood.
Methods: An IP‒LC‒MS/MS assay was conducted to identify new binding partners of G6PD involved in the regulation of VSMC phenotypic switching under platelet-derived growth factor-BB (PDGF-BB) stimulation. Co-IP, GST pull-down, and immunofluorescence colocalization were employed to clarify the interaction between G6PD and voltage-dependent anion-selective channel protein 1 (VDAC1). The molecular mechanisms involved were elucidated by examining the interaction between VDAC1 and apoptosis-related biomarkers, as well as the oligomerization state of VDAC1.
Results: The G6PD level was significantly elevated and positively correlated with the synthetic characteristics of VSMCs induced by PDGF-BB. We identified VDAC1 as a novel G6PD-interacting molecule essential for apoptosis. Specifically, the G6PD-NTD region was found to predominantly contribute to this interaction. G6PD promotes VSMC survival and accelerates vascular neointimal hyperplasia by inhibiting VSMC apoptosis. Mechanistically, G6PD interacts with VDAC1 upon stimulation with PDGF-BB. By competing with Bax for VDAC1 binding, G6PD reduces VDAC1 oligomerization and counteracts VDAC1–Bax-mediated apoptosis, thereby accelerating neointimal hyperplasia.
Conclusion: Our study showed that the G6PD–VDAC1–Bax axis is a vital switch in VSMC apoptosis and is essential for VSMC phenotypic switching and neointimal hyperplasia, providing mechanistic insight into early VRDs.
Keywords Vascular smooth muscle cells, Apoptosis, G6PD, VDAC1, Bax
Address and Contact Information 1 Department of Biochemistry and Molecular Biology, College of Basic Medicine, Cardiovascular Medical Science Center, Key Laboratory of Vascular Biology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China
2 Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
*Corresponding author: donglihua@hebmu.edu.cn
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No.  48DOI: 10.1186/s11658-024-00565-x Volume 29 (2024) - 29:48
Title ESCAPING FROM CRISPR–Cas-MEDIATED KNOCKOUT: THE FACTS, MECHANISMS, AND APPLICATIONS
Authors Ying Wang1,2†, Yujing Zhai1,2†, Mingzhe Zhang1†, Chunlin Song1, Yuqing Zhang1 and Gang Zhang1*
Abstract Clustered regularly interspaced short palindromic repeats and associated Cas protein (CRISPR–Cas), a powerful genome editing tool, has revolutionized gene function investigation and exhibits huge potential for clinical applications. CRISPR–Cas-mediated gene knockout has already become a routine method in research laboratories. However, in the last few years, accumulating evidences have demonstrated that genes knocked out by CRISPR–Cas may not be truly silenced. Functional residual proteins could be generated in such knockout organisms to compensate the putative loss of function, termed herein knockout escaping. In line with this, several CRISPR–Cas-mediated knockout screenings have discovered much less abnormal phenotypes than expected. How does knockout escaping happen and how often does it happen have not been systematically reviewed yet. Without knowing this, knockout results could easily be misinterpreted. In this review, we summarize these evidences and propose two main mechanisms allowing knockout escaping. To avoid the confusion caused by knockout escaping, several strategies are discussed as well as their advantages and disadvantages. On the other hand, knockout escaping also provides convenient tools for studying essential genes and treating monogenic disorders such as Duchenne muscular dystrophy, which are discussed in the end.
Keywords CRISPR, Knockout escaping, Alternative splicing, Translation reinitiation
Address and Contact Information 1 The Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
2 School of Public Health, Qingdao University, Qingdao, China
*Corresponding author: zhanggang_sma@qdu.edu.cn
† Ying Wang, Yujing Zhai, and Mingzhe Zhang contributed equally to this work.
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No.  49DOI: 10.1186/s11658-024-00567-9 Volume 29 (2024) - 29:49
Title CORRECTION: A MULTIPLEX RPA-CRISPR/Cas12a-BASED POCT TECHNIQUE AND ITS APPLICATION IN HUMAN PAPILLOMAVIRUS (HPV) TYPING ASSAY
Authors Yan Liu1†, Zhujun Chao2†, Wei Ding1†, Tanfeng Fang1†, Xinxian Gu3*†, Man Xue4, Wei Wang1, Rong Han1 and Wanping Sun1*†
Abstract CORRECTION: Cellular & Molecular Biology Letters (2024) 29:34
https://doi.org/10.1186/s11658-024-00548-y Following publication of the original article [1], we have been informed that the Supple- mentary Information is incomplete.

The original article has been corrected.

Reference
1. Liu Y, Chao Z, Ding W, Fang T, Gu X, Xue M, Wang W, Han R, Sun W. A multiplex RPA-CRISPR/Cas12a-based POCT technique and its application in human papillomavirus (HPV) typing assay. Cell Mol Biol Lett. 2024;29:34. https://doi.org/10.1186/s11658-024-00548-y.
Keywords
Address and Contact Information 1 Laboratory of Molecular Diagnostics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215000, Jiangsu, People’s Republic of China
2 Soochow University, Suzhou Medical College of Soochow University, Suzhou 215000, Jiangsu, People’s Republic of China
3 Dushu Lake Hospital, Affiliated to Soochow University, Dushu Lake Hospital Affiliated to Soochow University, Suzhou 215004, Jiangsu, People’s Republic of China
4 Biological Products and Biochemical Drugs, Suzhou Institute for Food and Drug Control, Suzhou 215101, Jiangsu, People’s Republic of China
*Corresponding author: guxinxian@suda.edu.cn; sunwanping@suda.edu.cn
† Yan Liu, Zhujun Chao, Wei Ding, Tanfeng Fang, Xinxian Gu and Wanping Sun have contributed equally to this work.
† Yan Liu and Zhujun Chao have contributed equally as co-first authors.
The original article can be found online at https://doi.org/10.1186/s11658-024-00548-y.
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No.  50DOI: 10.1186/s11658-024-00555-z Volume 29 (2024) - 29:50
Title COMBINED THERAPY OF DABRAFENIB AND AN ANTI-HER2 ANTIBODY–DRUG CONJUGATE FOR ADVANCED BRAF-MUTANT MELANOMA
Authors Weisong Li1,2†, Chao Zheng2,3†, Xi Xu2,3†, Yujie Xia2,3, Kai Zhang2,3, Ao Huang4, Xinyu Zhang1,2, Yong Zheng2,3*, Guofang Chen4* and Shuyong Zhang2,3*
Abstract Background: Melanoma is the most lethal skin cancer characterized by its high metastatic potential. In the past decade, targeted and immunotherapy have brought revolutionary survival benefits to patients with advanced and metastatic melanoma, but these treatment responses are also heterogeneous and/or do not achieve durable responses. Therefore, novel therapeutic strategies for improving outcomes remain an unmet clinical need. The aim of this study was to evaluate the therapeutic potential and underlying molecular mechanisms of RC48, a novel HER2-target antibody drug conjugate, either alone or in combination with dabrafenib, a V600-mutant BRAF inhibitor, for the treatment of advanced BRAF-mutant cutaneous melanoma.
Methods: We evaluated the therapeutic efficacy of RC48, alone or in combination with dabrafenib, in BRAF-mutant cutaneous melanoma cell lines and cell-derived xenograft (CDX) models. We also conducted signaling pathways analysis and global mRNA sequencing to explore mechanisms underlying the synergistic effect of the combination therapy.
Results: Our results revealed the expression of membrane-localized HER2 in melanoma cells. RC48 effectively targeted and inhibited the growth of HER2-positive human melanoma cell lines and corresponding CDX models. When used RC48 and dabrafenib synergically induced tumor regression together in human BRAF-mutant melanoma cell lines and CDX models. Mechanically, our results demonstrated that the combination therapy induced apoptosis and cell cycle arrest while suppressing cell motility in vitro. Furthermore, global RNA sequencing analysis demonstrated that the combination treatment led to the downregulation of several key signaling pathways, including the PI3K-AKT pathway, MAPK pathway, AMPK pathway, and FOXO pathway.
Conclusion: These findings establish a preclinical foundation for the combined use of an anti-HER2 drug conjugate and a BRAF inhibitor in the treatment of BRAF-mutant cutaneous melanoma.
Keywords HER2, RC48, Antibody drug conjugate, Dabrafenib, Synergetic efect, Melanoma
Address and Contact Information 1 Department of General Surgery, First Affiliated Hospital, Gannan Medical University, Ganzhou 341000, China
2 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, 1 Hexie Road, Rongjiang New District, Ganzhou 341000, China
3 School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
4 Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
*Corresponding author: zy@ncpsb.org.cn; chenguofang@tongji.edu.cn; zsy206@163.com
† Weisong Li, Chao Zheng and Xi Xu are contributed equally to this work.
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No.  51DOI: 10.1186/s11658-024-00568-8 Volume 29 (2024) - 29:51
Title METHYLATED lncRNAs SUPPRESS APOPTOSIS OF GASTRIC CANCER STEM CELLS VIA THE lncRNA–miRNA/PROTEIN AXIS
Authors Yuan Ci1, Yuan Zhang1 and Xiaobo Zhang1*
Abstract Background: Long noncoding RNAs (lncRNAs) play essential roles in the tumorigenesis of gastric cancer. However, the influence of lncRNA methylation on gastric cancer stem cells (GCSCs) remains unclear.
Methods: The N6-methyladenosine (m6A) levels of lncRNAs in gastric cancer stem cells were detected by methylated RNA immunoprecipitation sequencing (MeRIP-seq), and the results were validated by MeRIP-quantitative polymerase chain reaction (qPCR). Specific sites of m6A modification on lncRNAs were detected by single-base elongation- and ligation-based qPCR amplification (SELECT). By constructing and transfecting the plasmid expressing methyltransferase-like 3 (METTL3) fused with catalytically inactivated Cas13 (dCas13b) and guide RNA targeting specific methylation sites of lncRNAs, we obtained gastric cancer stem cells with site-specific methylation of lncRNAs. Reverse transcription (RT)-qPCR and Western blot were used for detecting the stemness of treated gastric cancer stem cells.
Results: The site-specific methylation of PSMA3-AS1 and MIR22HG suppressed apoptosis and promoted stemness of GCSCs. LncRNA methylation enhanced the stability of PSMA3-AS1 and MIR22HG to suppress apoptosis of GCSCs via the PSMA3-AS1–miR-411-3p– or MIR22HG–miR-24-3p–SERTAD1 axis. Simultaneously, the methylated lncRNAs promoted the interaction between PSMA3-AS1 and the EEF1A1 protein or MIR22HG and the LRPPRC protein, stabilizing the proteins and leading to the suppression of apoptosis. The in vivo data revealed that the methylated PSMA3-AS1 and MIR22HG triggered tumorigenesis of GCSCs.
Conclusions: Our study revealed the requirement for site-specific methylation of lncRNAs in the tumorigenesis of GCSCs, contributing novel insights into cancer development.
Keywords Gastric cancer stem cells, LncRNA, Methylation, Apoptosis, Stemness
Address and Contact Information 1 College of Life Sciences, Laboratory for Marine Biology and Biotechnology of Pilot National Laboratory for Marine Science and Technology (Qingdao), Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhejiang University, Hangzhou 310058, People’s Republic of China
*Corresponding author: zxb0812@zju.edu.cn
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No.  52DOI: 10.1186/s11658-024-00561-1 Volume 29 (2024) - 29:52
Title CRISPR–Cas9 APPLICATIONS IN T CELLS AND ADOPTIVE T CELL THERAPIES
Authors Xiaoying Chen1 , Shuhan Zhong2 , Yonghao Zhan3* and Xuepei Zhang3*
Abstract T cell immunity is central to contemporary cancer and autoimmune therapies, encompassing immune checkpoint blockade and adoptive T cell therapies. Their diverse characteristics can be reprogrammed by different immune challenges dependent on antigen stimulation levels, metabolic conditions, and the degree of inflammation. T cell-based therapeutic strategies are gaining widespread adoption in oncology and treating inflammatory conditions. Emerging researches reveal that clustered regularly interspaced palindromic repeats–associated protein 9 (CRISPR–Cas9) genome editing has enabled T cells to be more adaptable to specific microenvironments, opening the door to advanced T cell therapies in preclinical and clinical trials. CRISPR–Cas9 can edit both primary T cells and engineered T cells, including CAR-T and TCR-T, in vivo and in vitro to regulate T cell differentiation and activation states. This review first provides a comprehensive summary of the role of CRISPR–Cas9 in T cells and its applications in preclinical and clinical studies for T cell-based therapies. We also explore the application of CRISPR screen high-throughput technology in editing T cells and anticipate the current limitations of CRISPR–Cas9, including off-target effects and delivery challenges, and envisioned improvements in related technologies for disease screening, diagnosis, and treatment.
Keywords CRISPR–Cas9, T cells, Adoptive T cell therapy, CAR-T, TCR-T, TIL
Address and Contact Information 1 Department of Cardiology, Cardiovascular Institute of Zhengzhou University, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, China
2 Department of Hematology, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310003, China
3 Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, China
*Corresponding author: yonghao_zhan@163.com; zhangxuepei@263.net
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No.  53DOI: 10.1186/s11658-024-00570-0 Volume 29 (2024) - 29:53
Title ROLE OF REACTIVE OXYGEN SPECIES IN MYELODYSPLASTIC SYNDROMES
Authors Qiangan Jing1,2†, Chaoting Zhou1†, Junyu Zhang3†, Ping Zhang1, Yunyi Wu1, Junyu Zhou1, Xiangmin Tong4, Yanchun Li4*, Jing Du1* and Ying Wang4*
Abstract Reactive oxygen species (ROS) serve as typical metabolic byproducts of aerobic life and play a pivotal role in redox reactions and signal transduction pathways. Contingent upon their concentration, ROS production not only initiates or stimulates tumorigenesis but also causes oxidative stress (OS) and triggers cellular apoptosis. Mounting literature supports the view that ROS are closely interwoven with the pathogenesis of a cluster of diseases, particularly those involving cell proliferation and differentiation, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML). OS caused by excessive ROS at physiological levels is likely to affect the functions of hematopoietic stem cells, such as cell growth and self-renewal, which may contribute to defective hematopoiesis. We review herein the eminent role of ROS in the hematological niche and their profound influence on the progress of MDS. We also highlight that targeting ROS is a practical and reliable tactic for MDS therapy.
Keywords Reactive oxygen species, Oxidative stress, Myelodysplastic syndromes, Hematological niche
Address and Contact Information 1 Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, Zhejiang, China
2 HEALTH BioMed Research & Development Center, Health BioMed Co., Ltd, Ningbo 315803, Zhejiang, China
3 Department of Hematology, Lishui Central Hospital, Lishui 323000, Zhejiang, China
4 Department of Central Laboratory, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, Zhejiang, China
*Corresponding author: lycmed@163.com; dujing1@hmc.edu.cn; nancywangying@163.com † Qiangan Jing, Chaoting Zhou, and Junyu Zhang contributed equally to this work.
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No.  54DOI: 10.1186/s11658-024-00574-w Volume 29 (2024) - 29:54
Title GOLGI-ASSOCIATED RETROGRADE PROTEIN (GARP) COMPLEX-DEPENDENT ENDOSOMES TO TRANS GOLGI NETWORK RETROGRADE TRAFFICKING IS CONTROLLED BY Rab4b
Authors Jérôme Gilleron1*, Abderrahman Chafik1, Sandra Lacas‐Gervais2, Jean‐François Tanti1 and Mireille Cormont1*
Abstract Background: The trafficking of cargoes from endosomes to the trans-Golgi network requires numerous sequential and coordinated steps. Cargoes are sorted into endosomal-derived carriers that are transported, tethered, and fused to the trans-Golgi network. The tethering step requires several complexes, including the Golgi-associated retrograde protein complex, whose localization at the trans-Golgi network is determined by the activity of small GTPases of the Arl and Rab family. However, how the Golgi-associated retrograde protein complex recognizes the endosome-derived carriers that will fuse with the trans-Golgi network is still unknown.
Methods: We studied the retrograde trafficking to the trans-Golgi network by using fluorescent cargoes in cells overexpressing Rab4b or after Rab4b knocked-down by small interfering RNA in combination with the downregulation of subunits of the Golgi-associated retrograde protein complex. We used immunofluorescence and image processing (Super Resolution Radial Fluctuation and 3D reconstruction) as well as biochemical approaches to characterize the consequences of these interventions on cargo carriers trafficking.
Results: We reported that the VPS52 subunit of the Golgi-associated retrograde protein complex is an effector of Rab4b. We found that overexpression of wild type or active Rab4b increased early endosomal to trans-Golgi network retrograde trafficking of the cation-independent mannose-6-phosphate receptor in a Golgi-associated retrograde protein complex-dependent manner. Conversely, overexpression of an inactive Rab4b or Rab4b knockdown attenuated this trafficking. In the absence of Rab4b, the internalized cation-independent mannose 6 phosphate receptor did not have access to VPS52-labeled structures that look like endosomal subdomains and/or endosome-derived carriers, and whose subcellular distribution is Rab4b-independent. Consequently, the cation-independent mannose-6-phosphate receptor was blocked in early endosomes and no longer had access to the trans-Golgi network.
Conclusion: Our results support that Rab4b, by controlling the sorting of the cation-independent mannose-6-phosphate receptor towards VPS52 microdomains, confers a directional specificity for cargo carriers en route to the trans-Golgi network. Given the importance of the endocytic recycling in cell homeostasis, disruption of the Rab4b/Golgi-associated retrograde protein complex-dependent step could have serious consequences in pathologies.
Keywords Endosome, Trans Golgi network, Cation-independent mannose-6-phosphate receptor, VPS52
Address and Contact Information 1 Université Côte d’Azur, INSERM, Mediterranean Center of Molecular Medicine (C3M), Team “Insulin Resistance in Obesity and Type 2 Diabetes”, Bâtiment Archimed, 151 Route de Saint Antoine de Ginestière, BP 2 3194, 06200 Nice Cedex 03, France
2 Université Côte d’Azur, CCMA, Centre Commun de Microscopie Appliquée (CCMA), Nice, France
*Corresponding author: jerome.gilleron@univ-cotedazur.fr; mireille.cormont@univ-cotedazur.fr
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No.  55DOI: 10.1186/s11658-024-00576-8 Volume 29 (2024) - 29:55
Title miR-29b-3p REGULATES CARDIOMYOCYTES PYROPTOSIS IN CVB3-INDUCED MYOCARDITIS THROUGH TARGETING DNMT3A
Authors Ya Wang1†, Zhengyang Zhang1†, Hui Li1, Min Wang1, Yuting Qiu1 and Lili Lu1*
Abstract Background: Viral myocarditis (VMC) is a disease resulting from viral infection, which manifests as inflammation of myocardial cells. Until now, the treatment of VMC is still a great challenge for clinicians. Increasing studies indicate the participation of miR-29b-3p in various diseases. According to the transcriptome sequencing analysis, miR-29b-3p was markedly upregulated in the viral myocarditis model. The purpose of this study was to investigate the role of miR-29b-3p in the progression of VMC.
Methods: We used CVB3 to induce primary cardiomyocytes and mice to establish a model of viral myocarditis. The purity of primary cardiomyocytes was identified by immunofluorescence. The cardiac function of mice was detected by Vevo770 imaging system. The area of inflammatory infiltration in heart tissue was shown by hematoxylin and eosin (H&E) staining. The expression of miR-29b-3p and DNMT3A was detected by quantitative real time polymerase chain reaction (qRT–PCR). The expression of a series of pyroptosis-related proteins was detected by western blot. The role of miR-29b-3p/DNMT3A in CVB3-induced pyroptosis of cardiomyocytes was studied in this research.
Results: Our data showed that the expression of miR-29b-3p was upregulated in CVB3-induced cardiomyocytes and heart tissues in mice. To explore the function of miR-29b-3p in CVB3-induced VMC, we conducted in vivo experiments by knocking down the expression of miR-29b-3p using antagomir. We then assessed the effects on mice body weight, histopathology changes, myocardial function, and cell pyroptosis in heart tissues. Additionally, we performed gain/loss-of-function experiments in vitro to measure the levels of pyroptosis in primary cardiomyocytes. Through bioinformatic analysis, we identified DNA methyltransferases 3A (DNMT3A) as a potential target gene of miR-29b-3p. Furthermore, we found that the expression of DNMT3A can be modulated by miR-29b-3p during CVB3 infection.
Conclusions: Our results demonstrate a correlation between the expression of DNMT3A and CVB3-induced pyroptosis in cardiomyocytes. These findings unveil a previously unidentified mechanism by which CVB3 induces cardiac injury through the regulation of miR-29b-3p/DNMT3A-mediated pyroptosis.
Keywords Viral myocarditis, miR-29b-3p, DNMT3A, CVB3, Pyroptosis
Address and Contact Information 1 Hubei Province Key Laboratory of Occupational Hazard Identifcation and Control, College of Medicine, Wuhan University of Science and Technology, Wuhan 430065, Hubei, People’s Republic of China
*Corresponding author: lulili@wust.edu.cn
† Ya Wang and Zhengyang Zhang contributed equally to this work.
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No.  56DOI: 10.1186/s11658-024-00573-x Volume 29 (2024) - 29:56
Title RECIPROCAL NEGATIVE FEEDBACK BETWEEN Prrx1 AND miR-140-3p REGULATES RAPID CHONDROGENESIS IN THE REGENERATING ANTLER
Authors Pengfei Hu1,2*, Guokun Zhang1, Hengxing Ba1, Jing Ren1, Jiping Li1, Zhen Wang1 and Chunyi Li1*
Abstract During growth phase, antlers exhibit a very rapid rate of chondrogenesis. The antler is formed from its growth center reserve mesenchyme (RM) cells, which have been found to be the derivatives of paired related homeobox 1 (Prrx1)-positive periosteal cells. However, the underlying mechanism that drives rapid chondrogenesis is not known. Herein, the miRNA expression profiles and chromatin states of three tissue layers (RM, precartilage, and cartilage) at different stages of differentiation within the antler growth center were analyzed by RNA-sequencing and ATAC-sequencing. We found that miR-140-3p was the miRNA that exhibited the greatest degree of upregulation in the rapidly growing antler, increasing from the RM to the cartilage layer. We also showed that Prrx1 was a key upstream regulator of miR-140-3p, which firmly confirmed by Prrx1 CUT&Tag sequencing of RM cells. Through multiple approaches (three-dimensional chondrogenic culture and xenogeneic antler model), we demonstrated that Prrx1 and miR-140-3p functioned as reciprocal negative feedback in the antler growth center, and downregulating PRRX1/upregulating miR-140-3p promoted rapid chondrogenesis of RM cells and xenogeneic antler. Thus, we conclude that the reciprocal negative feedback between Prrx1 and miR-140-3p is essential for balancing mesenchymal proliferation and chondrogenic differentiation in the regenerating antler. We further propose that the mechanism underlying chondrogenesis in the regenerating antler would provide a reference for helping understand the regulation of human cartilage regeneration and repair.
Keywords Chondrogenesis, Antler, miR-140-3p, Prrx1, Negative feedback
Address and Contact Information 1 Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
2 Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
*Corresponding author: pfhoo@hotmail.com; lichunyi1959@163.com
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No.  57DOI: 10.1186/s11658-024-00577-7 Volume 29 (2024) - 29:57
Title A TOMATO NAC TRANSCRIPTION FACTOR, SlNAP1, DIRECTLY REGULATES GIBBERELLIN-DEPENDENT FRUIT RIPENING
Authors Changxia Li1,2, Xuemei Hou1, Zongxi Zhao1, Huwei Liu1, Panpan Huang1, Meimei Shi1, Xuetong Wu1, Rong Gao1, Zhiya Liu1, Lijuan Wei3, Yihua Li1 and Weibiao Liao1*
Abstract In tomato (Solanum lycopersicum), the ripening of fruit is regulated by the selective expression of ripening-related genes, and this procedure is controlled by transcription factors (TFs). In the various plant-specific TF families, the no apical meristem (NAM), Arabidopsis thaliana activating factor 1/2 (ATAF1/2), and cup-shaped cotyledon 2 (CUC2; NAC) TF family stands out and plays a significant function in plant physiological activities, such as fruit ripening (FR). Despite the numerous genes of NAC found in the tomato genome, limited information is available on the effects of NAC members on FR, and there is also a lack of studies on their target genes. In this research, we focus on SlNAP1, which is a NAC TF that positively influences the FR of tomato. By employing CRISPR/Cas9 technology, compared with the wild type (WT), we generated slnap1 mutants and observed a delay in the ethylene production and color change of fruits. We employed the yeast one-hybrid (Y1H) and dual-luciferase reporter (DLR) assays to confirm that SlNAP1 directly binds to the promoters of two crucial genes involved in gibberellin (GA) degradation, namely SlGA2ox1 and SlGA2ox5, thus activating their expression. Furthermore, through a yeast two-hybrid (Y2H), bimolecular fluorescence complementation (BIFC) and luciferase (LUC) assays, we established an interaction between SlNAP1 and SlGID1. Hence, our findings suggest that SlNAP1 regulates FR positively by activating the GA degradation genes directly. Additionally, the interaction between SlNAP1 and SlGID1 may play a role in SlNAP1-induced FR. Overall, our study provides important insights into the molecular mechanisms through which NAC TFs regulate tomato FR via the GA pathway.
Keywords NAC, Gibberellin, Tomato, Transcription factor, Fruit ripening, Protein–protein interaction
Address and Contact Information 1 College of Horticulture, Gansu Agricultural University, 1 Yinmen Village, Anning District, Lanzhou 730070, China
2 College of Agriculture, Guangxi University, 100 East University Road, Xixiangtang District, Nanning 530004, China
3 Spice Crops Research Institute, College of Horticulture and Gardening, Yangtze University, Jingzhou 434025, China
*Corresponding author: liaowb@gsau.edu.cn
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No.  58DOI: 10.1186/s11658-024-00578-6 Volume 29 (2024) - 29:58
Title TARGETED INHIBITION OF THE PI3K/AKT/mTOR PATHWAY BY (+)-ANTHRABENZOXOCINONE INDUCES CELL CYCLE ARREST, APOPTOSIS, AND AUTOPHAGY IN NON-SMALL CELL LUNG CANCER
Authors Xiao‐Qian Li1, Xiao‐Ju Cheng1, Jie Wu1, Kai‐Feng Wu1* and Tie Liu1,2*
Abstract Non-small cell lung cancer (NSCLC), characterized by low survival rates and a high recurrence rate, is a major cause of cancer-related mortality. Aberrant activation of the PI3K/AKT/mTOR signaling pathway is a common driver of NSCLC. Within this study, the inhibitory activity of (+)-anthrabenzoxocinone ((+)-ABX), an oxygenated anthrabenzoxocinone compound derived from Streptomyces, against NSCLC is demonstrated for the first time both in vitro and in vivo. Mechanistically, it is confirmed that the PI3K/AKT/mTOR signaling pathway is targeted and suppressed by (+)-ABX, resulting in the induction of S and G2/M phase arrest, apoptosis, and autophagy in NSCLC cells. Additionally, the augmentation of intracellular ROS levels by (+)-ABX is revealed, further contributing to the inhibition of the signaling pathway and exerting inhibitory effects on tumor growth. The findings presented in this study suggest that (+)-ABX possesses the potential to serve as a lead compound for the treatment of NSCLC.
Keywords Anthrabenzoxocinones, Non-small cell lung cancer, Cell cycle arrest apoptosis, Autophagy, PI3K/AKT/mTOR pathway, ROS
Address and Contact Information 1 The Third Affiliated Hospital of Zunyi Medical University, The First People’s Hospital of Zunyi, Scientifc Research Center, Guizhou 563002, People’s Republic of China
2 Yunnan Characteristic Plant Extraction Laboratory, Key Laboratory of Medicinal Chemistry for Natural Resource, Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People’s Republic of China
*Corresponding author: kiphoonwu@126.com; liutiefes@outlook.com
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No.  59DOI: 10.1186/s11658-024-00572-y Volume 29 (2024) - 29:59
Title THE ROLE OF MITOCHONDRIAL DYNAMICS AND MITOPHAGY IN SKELETAL MUSCLE ATROPHY: FROM MOLECULAR MECHANISMS TO THERAPEUTIC INSIGHTS
Authors Yuhang Lei1,2†, Mailin Gan1,2†, Yanhao Qiu1,2, Qiuyang Chen1,2, Xingyu Wang1,2, Tianci Liao1,2, Mengying Zhao1,2, Lei Chen1,2, Shunhua Zhang1,2, Ye Zhao1,2, Lili Niu1,2, Yan Wang1,2, Li Zhu1,2* and Linyuan Shen1,2*
Abstract Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.
Keywords Mitochondrial dynamics, Mitophagy, Skeletal muscle atrophy, Intermodulation, Molecular mechanism, Prevention and treatment
Address and Contact Information 1 Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
2 Key Laboratory of Livestock and Poultry Multi‐Omics, Ministry of Agriculture and Rural Afairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
*Corresponding author: zhuli@sicau.edu.cn; shenlinyuan@sicau.edu.cn
† Yuhang Lei and Mailin Gan contributed equally to this work.
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No.  60DOI: 10.1186/s11658-024-00571-z Volume 29 (2024) - 29:60
Title DECIPHERING THE IMPACT OF circRNA-MEDIATED AUTOPHAGY ON TUMOR THERAPEUTIC RESISTANCE: A NOVEL PERSPECTIVE
Authors Ting Wang1, Mengjie He2, Xudong Zhang1, Zhixun Guo1, Pinghan Wang2* and Fangyi Long2*
Abstract Cancer therapeutic resistance remains a significant challenge in the pursuit of effective treatment strategies. Circular RNAs (circRNAs), a class of non-coding RNAs, have recently emerged as key regulators of various biological processes, including cancer progression and drug resistance. This review highlights the emerging role of circRNAs-mediated autophagy in cancer therapeutic resistance, a cellular process that plays a dual role in cancer by promoting both cell survival and death. Increasing evidence suggests that circRNAs can modulate autophagy pathways, thereby influencing the response of cancer cells to therapeutic agents. In this context, the intricate interplay between circRNAs, autophagy, and therapeutic resistance is explored. Various mechanisms are discussed through which circRNAs can impact autophagy, including direct interactions with autophagy-related genes, modulation of signaling pathways, and cross-talk with other non-coding RNAs. Furthermore, the review delves into specific examples of how circRNA-mediated autophagy regulation can contribute to resistance against chemotherapy and radiotherapy. Understanding these intricate molecular interactions provides valuable insights into potential strategies for overcoming therapeutic resistance in cancer. Exploiting circRNAs as therapeutic targets or utilizing them as diagnostic and predictive biomarkers opens new avenues for developing personalized treatment approaches. In summary, this review underscores the importance of circRNA-mediated autophagy in cancer therapeutic resistance and proposes future directions for research in this exciting and rapidly evolving field.
Keywords Cancer, Circular RNAs (circRNAs), Autophagy, Therapeutic resistance
Address and Contact Information 1 Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China
2 Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu 610041, China
*Corresponding author: zxcvbnm_345@126.com; 376722919@qq.com
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No.  61DOI: 10.1186/s11658-024-00575-9 Volume 29 (2024) - 29:61
Title MITOCHONDRIAL (mt)DNA–CYCLIC GMP–AMP SYNTHASE (cGAS)–STIMULATOR OF INTERFERON GENES (STING) SIGNALING PROMOTES PYROPTOSIS OF MACROPHAGES VIA INTERFERON REGULATORY FACTOR (IRF)7/IRF3 ACTIVATION TO AGGRAVATE LUNG INJURY DURING SEVERE ACUTE PANCREATITIS
Authors Yiqiu Peng1, Yuxi Yang1, Yingying Li1, Tingjuan Shi1, Ning Xu1, Ruixia Liu1, Yingyi Luan1*, Yongming Yao2* and Chenghong Yin1*
Abstract Background: Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate the cellular immune suppression during the process of SAP, where cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) plays an important role. However, the function and mechanism of cGAS–STING in SAP-induced lung injury (LI) remains unknown.
Methods: Lipopolysaccharide (LPS) was combined with caerulein-induced SAP in wild type, cGAS −/− and sting −/− mice. Primary macrophages were extracted via bronchoalveolar lavage and peritoneal lavage. Ana-1 cells were pretreated with LPS and stimulated with nigericin sodium salt to induce pyroptosis in vitro.
Results: SAP triggered NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis of alveolar and peritoneal macrophages in mouse model. Knockout of cGAS/STING could ameliorate NLRP3 activation and macrophage pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria further induced macrophage STING activation in a cGAS- and dose-dependent manner. Upregulated STING signal can promote NLRP3 inflammasome-mediated macrophage pyroptosis and increase serum interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α levels and, thus, exacerbate SAP-associated LI (SAP-ALI). Downstream molecules of STING, IRF7, and IRF3 connect the mtDNA–cGAS–STING axis and the NLRP3–pyroptosis axis.
Conclusions: Negative regulation of any molecule in the mtDNA–cGAS–STING–IRF7/IRF3 pathway can affect the activation of NLRP3 inflammasomes, thereby reducing macrophage pyroptosis and improving SAP-ALI in mouse model.
Keywords Severe acute pancreatitis, Macrophage, NLRP3, Pyroptosis, IRF7, IRF3
Address and Contact Information 1 Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, No. 251 Yaojiayuan Road, Chaoyang District, Beijing 100026, China
2 Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese People’s Liberation Army (PLA) General Hospital, Beijing 100048, China
*Corresponding author: luanyingyi@mail.ccmu.edu.cn; c_f@sina.com; yinchh@ccmu.edu.cn
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No.  62DOI: 10.1186/s11658-024-00579-5 Volume 29 (2024) - 29:62
Title NEAT1 INHIBITS THE ANGIOGENIC ACTIVITY OF CEREBRAL ARTERIAL ENDOTHELIAL CELLS BY INDUCING THE M1 POLARIZATION OF MICROGLIA THROUGH THE AMPK SIGNALING PATHWAY
Authors Ting Chen1 , Xin Huang1 , Yi‐Xuan Zhao1 , Zhi‐wen Zhou1* and Wen‐sheng Zhou1*
Abstract Background: Enhancing angiogenesis may be an effective strategy to promote functional recovery after ischemic stroke. Inflammation regulates angiogenesis. Microglia are crucial cells that initiate inflammatory responses after various brain injuries. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) plays a role in regulating brain injury. This study aimed to explore the effects of NEAT1-regulated microglial polarization on the neovascularization capacity of cerebrovascular endothelial cells and the underlying molecular regulatory mechanisms.
Methods: Mouse cerebral arterial endothelial cells (mCAECs) were co-cultured with BV-2 cells in different groups using a Transwell system. NEAT1 expression levels were measured by fluorescence quantitative reverse transcription PCR. Levels of IL-1β, IL-6, TNF-α, Arg-1, IL-4, and IL-10 were determined using ELISA. Expression levels of CD86 and CD163 were detected by immunofluorescence. The neovascularization capacity of mCAECs was assessed using CCK-8, Transwell, Transwell-matrigel, and tube formation assays. Label-free quantification proteomics was carried out to identify differentially expressed proteins. Protein levels were measured by Western blotting.
Results: NEAT1 overexpression induced M1 polarization in BV-2 cells, whereas NEAT1 knockdown blocked lipopolysaccharide-induced M1 polarization in microglia. NEAT1-overexpressing BV-2 cells suppressed the angiogenic ability of mCAECs, and NEAT1-knocking BV-2 cells promoted the angiogenic ability of mCAECs under lipopolysaccharide treatment. Label-free quantitative proteomic analysis identified 144 upregulated and 131 downregulated proteins that were induced by NEAT1 overexpression. The AMP-activated protein kinase (AMPK) signaling pathway was enriched in the Kyoto Encyclopedia of Genes and Genomes analysis of the differentially expressed proteins. Further verification showed that NEAT1 inactivated the AMPK signaling pathway. Moreover, the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide reversed the effect of NEAT1 on BV-2 polarization and the regulatory effect of NEAT1-overexpressing BV-2 cells on the angiogenic ability of mCAECs.
Conclusions: NEAT1 inhibits the angiogenic activity of mCAECs by inducing M1 polarization of BV-2 cells through the AMPK signaling pathway. This study further clarified the impact and mechanism of NEAT1 on microglia and the angiogenic ability of cerebrovascular endothelial cells.
Keywords NEAT1, Microglia, Cerebrovascular endothelial cells, Angiogenesis, AMPK
Address and Contact Information 1 Department of Neurology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha 410005, China
*Corresponding author: 15409979@qq.com; zhouwensheng2004@163.com
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No.  63DOI: 10.1186/s11658-024-00583-9 Volume 29 (2024) - 29:63
Title SESAMOLIN SERVES AS AN MYH14 INHIBITOR TO SENSITIZE ENDOMETRIAL CANCER TO CHEMOTHERAPY AND ENDOCRINE THERAPY VIA SUPPRESSING MYH9/GSK3β/β-CATENIN SIGNALING
Authors Yibin Lin1†, Xiao Chen2,3†, Linping Lin4 , Benhua Xu5*, Xiaofeng Zhu6,9* and Xian Lin7,8*
Abstract Background: Endometrial cancer (EC) is one of the most common gynecological cancers. Herein, we aimed to define the role of specific myosin family members in EC because this protein family is involved in the progression of various cancers.
Methods: Bioinformatics analyses were performed to reveal EC patients’ prognosis-associated genes in patients with EC. Furthermore, colony formation, immunofluorescence, cell counting kit 8, wound healing, and transwell assays as well as coimmunoprecipitation, cycloheximide chase, luciferase reporter, and cellular thermal shift assays were performed to functionally and mechanistically analyze human EC samples, cell lines, and a mouse model, respectively.
Results: Machine learning techniques identified MYH14, a member of the myosin family, as the prognosis-associated gene in patients with EC. Furthermore, bioinformatics analyses based on public databases showed that MYH14 was associated with EC chemoresistance. Moreover, immunohistochemistry validated MYH14 upregulation in EC cases compared with that in normal controls and confirmed that MYH14 was an independent and unfavorable prognostic indicator of EC. MYH14 impaired cell sensitivity to carboplatin, paclitaxel, and progesterone, and increased cell proliferation and metastasis in EC. The mechanistic study showed that MYH14 interacted with MYH9 and impaired GSK3β-mediated β-catenin ubiquitination and degradation, thus facilitating the Wnt/β-catenin signaling pathway and epithelial–mesenchymal transition. Sesamolin, a natural compound extracted from Sesamum indicum (L.), directly targeted MYH14 and attenuated EC progression. Additionally, the compound disrupted the interplay between MYH14 and MYH9 and repressed MYH9-regulated Wnt/β-catenin signaling. The in vivo study further verified sesamolin as a therapeutic drug without side effects.
Conclusions: Herein, we identified that EC prognosis-associated MYH14 was independently responsible for poor overall survival time of patients, and it augmented EC progression by activating Wnt/β-catenin signaling. Targeting MYH14 by sesamolin, a cytotoxicity-based approach, can be applied synergistically with chemotherapy and endocrine therapy to eventually mitigate EC development. This study emphasizes MYH14 as a potential target and sesamolin as a valuable natural drug for EC therapy.
Keywords Endometrial cancer, MYH14, Sesamolin, Chemotherapy, Endocrine therapy
Address and Contact Information 1 Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, Fujian, China.
2 Department of Intensive Care Unit, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian, China.
3 Department of Intensive Care Unit, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian, China.
4 Hunan Institute of Engineering, Xiangtan 411100, Hunan, China.
5 Department of Radiation Oncology, Fujian Medical University Union Hospital, Xinquan Road 29, Gulou District, Fuzhou 350001, Fujian, China.
6 Department of Oral Maxillo-Facial Surgery, The First Affiliated Hospital, Fujian Medical University, No. 20 Chazhong Road, Taijing District, Fuzhou 350005, Fujian, China.
7 Shenzhen Key Laboratory of Infammatory and Immunology Diseases, No. 1120 Lianhua Road, Futian District, Shenzhen 518036, Guangdong, China.
8 Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong, China.
9 Department of Oral Maxillo-Facial Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China. *Corresponding author: benhuaxu@163.com; zhuxiaofengfmu@163.com; dentzxf@163.com; linxiangabriel@fmu.edu.cn † Yibin Lin and Xiao Chen contributed equally to this work.
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No.  64DOI: 10.1186/s11658-024-00581-x Volume 29 (2024) - 29:64
Title EMERGING TECHNOLOGY HAS A BRILLIANT FUTURE: THE CRISPR-Cas SYSTEM FOR SENESCENCE, INFLAMMATION, AND CARTILAGE REPAIR IN OSTEOARTHRITIS
Authors Shicheng Jia1,2†, Rongji Liang2†, Jiayou Chen1,2†, Shuai Liao3,4, Jianjing Lin1* and Wei Li1*
Abstract Osteoarthritis (OA), known as one of the most common types of aseptic inflammation of the musculoskeletal system, is characterized by chronic pain and whole-joint lesions. With cellular and molecular changes including senescence, inflammatory alterations, and subsequent cartilage defects, OA eventually leads to a series of adverse outcomes such as pain and disability. CRISPR-Cas-related technology has been proposed and explored as a gene therapy, offering potential gene-editing tools that are in the spotlight. Considering the genetic and multigene regulatory mechanisms of OA, we systematically review current studies on CRISPR-Cas technology for improving OA in terms of senescence, inflammation, and cartilage damage and summarize various strategies for delivering CRISPR products, hoping to provide a new perspective for the treatment of OA by taking advantage of CRISPR technology.
Keywords CRISPR-Cas system, Osteoarthritis, Cellular senescence, Infammation, Cartilage repair
Address and Contact Information 1 Department of Sports Medicine and Rehabilitation, Peking University Shenzhen Hospital, Shenzhen 518036, China
2 Shantou University Medical College, Shantou 515041, China
3 Department of Bone and Joint, Peking University Shenzhen Hospital, Shenzhen 518036, China
4 Shenzhen University School of Medicine, Shenzhen 518060, China
*Corresponding author: linjianjing@bjmu.edu.cn; lwjnu2003@126.com
† Shicheng Jia, Rongji Liang, and Jiayou Chen contributed equally to this work and share first authorship.
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No.  65DOI: 10.1186/s11658-024-00582-w Volume 29 (2024) - 29:65
Title FTH1 OVEREXPRESSION USING A dCasRx TRANSLATION ENHANCEMENT SYSTEM PROTECTS THE KIDNEY FROM CALCIUM OXALATE CRYSTAL-INDUCED INJURY
Authors Ziqi He1†, Caitao Dong1†, Tianbao Song1†, Jiawei Zhou1, Tao Xu3, Ruyuan He4* and Sheng Li2*
Abstract The engineered clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein (Cas) system is currently widely applied in genetic editing and transcriptional regulation. The catalytically inactivated CasRx (dCasRx) has the ability to selectively focus on the mRNA coding region without disrupting transcription and translation, opening up new avenues for research on RNA modification and protein translation control. This research utilized dCasRx to create a translation-enhancement system for mammals called dCasRx-eIF4GI, which combined eukaryotic translation initiation factor 4G (eIF4GI) to boost translation levels of the target gene by recruiting ribosomes, without affecting mRNA levels, ultimately increasing translation levels of different endogenous proteins. Due to the small size of dCasRx, the dCasRx-eIF4GI translation enhancement system was integrated into a single viral vector, thus optimizing the delivery and transfection efficiency in subsequent applications. Previous studies reported that ferroptosis, mediated by calcium oxalate (CaOx) crystals, significantly promotes stone formation. In order to further validate its developmental potential, it was applied to a kidney stone model in vitro and in vivo. The manipulation of the ferroptosis regulatory gene FTH1 through single-guide RNA (sgRNA) resulted in a notable increase in FTH1 protein levels without affecting its mRNA levels. This ultimately prevented intracellular ferroptosis and protected against cell damage and renal impairment caused by CaOx crystals. Taken together, this study preliminarily validated the effectiveness and application prospects of the dCasRx-eIF4GI translation enhancement system in mammalian cell-based disease models, providing novel insights and a universal tool platform for protein translation research and future therapeutic approaches for nephrolithiasis.
Keywords CRISPR–Cas system, dCasRx, eIF4GI, Gene regulation, Protein translation, Nephrolithiasis, FTH1, Ferroptosis
Address and Contact Information 1 Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, People’s Republic of China
2 Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, People’s Republic of China
3 Department of Urology, Huanggang Central Hospital of Yangtze University, Huanggang 438000, Hubei, People’s Republic of China
4 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, People’s Republic of China
*Corresponding author: hry_whu@163.com; lisheng-znyy@whu.edu.cn
† Ziqi He, Caitao Dong and Tianbao Song contributed equally to this work.
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No.  66DOI: 10.1186/s11658-024-00569-7 Volume 29 (2024) - 29:66
Title CRISPR-BASED GENE EXPRESSION PLATFORM FOR PRECISE REGULATION OF BLADDER CANCER
Authors Tianying Zhan1†, Xiao Li4†, Jiumin Liu2,3* and Chujin Ye2,3*
Abstract The development of compact CRISPR systems has facilitated delivery but has concurrently reduced gene editing efficiency, thereby limiting the further utilization of CRISPR systems. Enhancing the efficiency of CRISPR systems poses a challenging task and holds significant implications for the advancement of biotechnology. In our work, we report a synthetic dual-antibody system that can stably exist in the intracellular environment, specifically inhibiting the functions of NF-κB and β-catenin. This not only elevates the transgenic expression of the CRISPR system by suppressing the innate immune response within cells to enhance the gene editing efficiency but also demonstrates a notable tumor inhibitory effect. Based on the specific output expression regulation of CRISPR-CasΦ, we constructed a CRISPR-based gene expression platform, which includes sensor modules for detecting intracellular β-catenin and NF-κB, as well as an SDA module to enhance overall efficiency. In vitro experiments revealed that the CRISPR-based gene expression platform exhibited superior CDK5 expression inhibition efficiency and specific cytotoxicity towards tumor cells. In vitro experiments, we found that CRISPR-based gene expression platforms can selectively kill bladder cancer cells through T cell-mediated cytotoxicity. Our design holds significant assistant potential of transgene therapy and may offer the capability to treat other diseases requiring transgene therapy.
Keywords CRISPR system, Bladder cancer, Gene regulation tool, Transgene, Gene therapy
Address and Contact Information 1 Department of Clinical Laboratory, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
2 Department of Urology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
3 Guang Dong Medical Academic Exchange Center, Guangzhou, China
4 Department of Urology, Carson International Cancer Centre, Shenzhen University General Hospital, Shenzhen, China
*Corresponding author: jiumin8388@163.com; fengziwei@gdph.org.cn
† Tianying Zhan and Xiao Li contributed equally to this work .
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No.  67DOI: 10.1186/s11658-024-00584-8 Volume 29 (2024) - 29:67
Title LIVER SINUSOIDAL ENDOTHELIAL CELLS RELY ON OXIDATIVE PHOSPHORYLATION BUT AVOID PROCESSING LONG-CHAIN FATTY ACIDS IN THEIR MITOCHONDRIA
Authors Patrycja Kaczara1*, Izabela Czyzynska‐Cichon1, Edyta Kus1, Anna Kurpinska1, Mariola Olkowicz1, Kamila Wojnar‐Lason1,2, Marta Z. Pacia1, Olena Lytvynenko1, Myriam Baes3 and Stefan Chlopicki1,2
Abstract Background: It is generally accepted that endothelial cells (ECs), primarily rely on glycolysis for ATP production, despite having functional mitochondria. However, it is also known that ECs are heterogeneous, and their phenotypic features depend on the vascular bed. Emerging evidence suggests that liver sinusoidal ECs (LSECs), located in the metabolically rich environment of the liver, show high metabolic plasticity. However, the substrate preference for energy metabolism in LSECs remains unclear.
Methods: Investigations were conducted in primary murine LSECs in vitro using the Seahorse XF technique for functional bioenergetic assays, untargeted mass spectrometry-based proteomics to analyse the LSEC proteome involved in energy metabolism pathways, liquid chromatography-tandem mass spectrometry-based analysis of acyl-carnitine species and Raman spectroscopy imaging to track intracellular palmitic acid.
Results: This study comprehensively characterized the energy metabolism of LSECs, which were found to depend on oxidative phosphorylation, efficiently fuelled by glucose-derived pyruvate, short- and medium-chain fatty acids and glutamine. Furthermore, despite its high availability, palmitic acid was not directly oxidized in LSEC mitochondria, as evidenced by the acylcarnitine profile and etomoxir’s lack of effect on oxygen consumption. However, together with L-carnitine, palmitic acid supported mitochondrial respiration, which is compatible with the chain-shortening role of peroxisomal β-oxidation of long-chain fatty acids before further degradation and energy generation in mitochondria.
Conclusions: LSECs show a unique bioenergetic profile of highly metabolically plastic ECs adapted to the liver environment. The functional reliance of LSECs on oxidative phosphorylation, which is not a typical feature of ECs, remains to be determined.
Keywords LSEC, Mitochondrial respiration, Glycolysis, Peroxisomes, l-carnitine, Palmitic acid
Address and Contact Information 1 Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30‐348 Krakow, Poland
2 Jagiellonian University Medical College, Department of Pharmacology, Grzegorzecka 16, 31‐531 Krakow, Poland
3 KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Laboratory of Cell Metabolism, 3000 Leuven, Belgium
*Corresponding author: patrycja.kaczara@jcet.eu
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No.  68DOI: 10.1186/s11658-024-00580-y Volume 29 (2024) - 29:68
Title NLRP4E REGULATES ACTIN CAP FORMATION THROUGH SRC AND CDC42 DURING OOCYTE MEIOSIS
Authors Li‐Ya Shi1,2,5,6,7†, Yang Wang1,5,6,7†, Yan‐Jie Yang1,5,6,7†, Qian Li3†, Zhi‐Xia Yang1,5,6†, Li‐Hua Sun2†, Fu‐Qiang Luo1,5,6, Yu‐hao He1,5,6,7, Shu‐Ping Zhang1,5,6,7, Ning Su1,5,6,7, Jia‐Qi Liu1,5,6,7, Ye He1,5,6, Yi‐Chun Guan4*, Zhao‐Lian Wei1,5,6*, Yun‐Xia Cao1,5,6* and Dong Zhang1,5,6,7*
Abstract Background: Members of the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing (NLRP) family regulate various physiological and pathological processes. However, none have been shown to regulate actin cap formation or spindle translocation during the asymmetric division of oocyte meiosis I. NLRP4E has been reported as a candidate protein in female fertility, but its function is unknown.
Methods: Immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were employed to examine the localization and expression levels of NLRP4E and related proteins in mouse oocytes. small interfering RNA (siRNA) and antibody transfection were used to knock down NLRP4E and other proteins. Immunoprecipitation (IP)-mass spectrometry was used to identify the potential proteins interacting with NLRP4E. Coimmunoprecipitation (Co-IP) was used to verify the protein interactions. Wild type (WT) or mutant NLRP4E messenger RNA (mRNA) was injected into oocytes for rescue experiments. In vitro phosphorylation was employed to examine the activation of steroid receptor coactivator (SRC) by NLRP4E.
Results: NLRP4E was more predominant within oocytes compared with other NLRP4 members. NLRP4E knockdown significantly inhibited actin cap formation and spindle translocation toward the cap region, resulting in the failure of polar body extrusion at the end of meiosis I. Mechanistically, GRIN1, and GANO1 activated NLRP4E by phosphorylation at Ser429 and Thr430; p-NLRP4E is translocated and is accumulated in the actin cap region during spindle translocation. Next, we found that p-NLRP4E directly phosphorylated SRC at Tyr418, while p-SRC negatively regulated p-CDC42-S71, an inactive form of CDC42 that promotes actin cap formation and spindle translocation in the GTP-bound form.
Conclusions: NLRP4E activated by GRIN1 and GANO1 regulates actin cap formation and spindle translocation toward the cap region through upregulation of p-SRC-Tyr418 and downregulation of p-CDC42-S71 during meiosis I.
Keywords NLRP4E, CDC42, Meiosis, Actin cap, SRC
Address and Contact Information 1 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China.
2 Reproductive Medicine Center, Shanghai East Hospital, Tongji University School of Medicine, 551 Pudong South Road, Shanghai 200120, China.
3 Department of Gynecology, Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), 123 Tianfei Lane, Nanjing 210018, China.
4 Center for Reproductive Medicine, The Third Affiliated Hospital of Zhengzhou University, 7 Rehabilitation Front Street, Zhengzhou 450000, Henan, China.
5 NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei 230032, Anhui, China.
6 Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China.
7 State Key Lab of Reproductive Medicine, Nanjing Medical University, 101 Longmian Ave., Nanjing 211166, Jiangsu, China.
*Corresponding author: Lisamayguan@126.com; weizhaolian_1@126.com; caoyunxia6@126.com; dong.ray.zhang@ahmu.edu.cn
† Li-Ya Shi, Yang Wang, Yan-Jie Yang, Qian Li, Zhi-Xia Yang and Li-Hua Sun contributed equally to this work.
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No.  69DOI: 10.1186/s11658-024-00590-w Volume 29 (2024) - 29:69
Title N6-METHYLADENOSINE MODIFICATION OF KLF2 MAY CONTRIBUTE TO ENDOTHELIAL-TO-MESENCHYMAL TRANSITION IN PULMONARY HYPERTENSION
Authors Kang Kang1†, Jingjing Xiang1†, Xingshi Zhang1†, Yuting Xie1, Mengting Zhou1, Le Zeng2, Junhao Zhuang1, Jiahao Kuang1, Yuanyuan Lin1, Bozhe Hu1, Qianmin Xiong1, Qing Yin1, Qiang Su2, Xiaoyun Liao2, Jun Wang2, Yanqin Niu2, Cuilian Liu2, Jinglin Tian2 and Deming Gou2*
Abstract Background: Pulmonary hypertension (PH) is a progressive disease characterized by pulmonary vascular remodeling. Increasing evidence indicates that endothelial-to-mesenchymal transition (EndMT) in pulmonary artery endothelial cells (PAECs) is a pivotal trigger initiating this remodeling. However, the regulatory mechanisms underlying EndMT in PH are still not fully understood.
Methods: Cytokine-induced hPAECs were assessed using RNA methylation quantification, qRT-PCR, and western blotting to determine the involvement of N6-methyladenosine (m6A) methylation in EndMT. Lentivirus-mediated silencing, overexpression, tube formation, and wound healing assays were utilized to investigate the function of METTL3 in EndMT. Endothelial-specific gene knockout, hemodynamic measurement, and immunostaining were performed to explore the roles of METTL3 in pulmonary vascular remodeling and PH. RNA-seq, RNA Immunoprecipitation-based qPCR, mRNA stability assay, m6A mutation, and dual-luciferase assays were employed to elucidate the mechanisms of RNA methylation in EndMT.
Results: The global levels of m6A and METTL3 expression were found to decrease in TNF-α- and TGF-β1-induced EndMT in human PAECs (hPAECs). METTL3 inhibition led to reduced endothelial markers (CD31 and VE-cadherin) and increased mesenchymal markers (SM22 and N-cadherin) as well as EndMT-related transcription factors (Snail, Zeb1, Zeb2, and Slug). The endothelial-specific knockout of Mettl3 promoted EndMT and exacerbated pulmonary vascular remodeling and hypoxia-induced PH (HPH) in mice. Mechanistically, METTL3-mediated m6A modification of kruppel-like factor 2 (KLF2) plays a crucial role in the EndMT process. KLF2 overexpression increased CD31 and VE-cadherin levels while decreasing SM22, N-cadherin, and EndMT-related transcription factors, thereby mitigating EndMT in PH. Mutations in the m6A site of KLF2 mRNA compromise KLF2 expression, subsequently diminishing its protective effect against EndMT. Furthermore, KLF2 modulates SM22 expression through direct binding to its promoter.
Conclusions: Our findings unveil a novel METTL3/KLF2 pathway critical for protecting hPAECs against EndMT, highlighting a promising avenue for therapeutic investigation in PH.
Keywords Pulmonary arterial hypertension, Transcription factor, Methylation, Epigenetics, Epithelial-mesenchymal transition
Address and Contact Information 1 Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518060, Guangdong, People’s Republic of China
2 Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen 518060, China
*Corresponding author: dmgou@szu.edu.cn
† Kang Kang, Jingjing Xiang, and Xingshi Zhang contributed equally to this work.
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No.  70DOI: 10.1186/s11658-024-00585-7 Volume 29 (2024) - 29:70
Title ANALYSIS OF THE COMPONENTS OF Mycobacterium tuberculosis HEAT-RESISTANT ANTIGEN (Mtb-HAg) AND ITS REGULATION OF γδ T-CELL FUNCTION
Authors Jing Wei1,3, Fangzheng Guo1,3, Yamin Song1,3, Tong Feng1,3, Ying Wang3, Kun Xu3, Jianhan Song3, Eldana Kaysar2, Reyima Abdukayyum2, Feiyang Lin1,3, Kangsheng Li1,3, Baiqing Li1,3, Zhongqing Qian1,3, Xiaojing Wang4, Hongtao Wang1,2,3* and Tao Xu1,3*
Abstract Background: Mycobacterium tuberculosis heat-resistant antigen (Mtb-HAg) is a peptide antigen released from the mycobacterial cytoplasm into the supernatant of Mycobacterium tuberculosis (Mtb) attenuated H37Ra strain after autoclaving at 121 °C for 20 min. Mtb-HAg can specifically induce γδ T-cell proliferation in vitro. However, the exact composition of Mtb-HAg and the protein antigens that are responsible for its function are currently unknown.
Methods: Mtb-HAg extracted from the Mtb H37Ra strain was subjected to LC‒MS mass spectrometry. Twelve of the identified protein fractions were recombinantly expressed in Escherichia coli by genetic engineering technology using pET-28a as a plasmid and purified by Ni–NTA agarose resin to stimulate peripheral blood mononuclear cells (PBMCs) from different healthy individuals. The proliferation of γδ T cells and major γδ T-cell subset types as well as the production of TNF-α and IFN-γ were determined by flow cytometry. Their proliferating γδ T cells were isolated and purified using MACS separation columns, and Mtb H37Ra-infected THP-1 was co-cultured with isolated and purified γδ T cells to quantify Mycobacterium viability by counting CFUs.
Results: In this study, Mtb-HAg from the attenuated Mtb H37Ra strain was analysed by LC‒MS mass spectrometry, and a total of 564 proteins were identified. Analysis of the identified protein fractions revealed that the major protein components included heat shock proteins and Mtb-specific antigenic proteins. Recombinant expression of 10 of these proteins in by Escherichia coli genetic engineering technology was used to successfully stimulate PBMCs from different healthy individuals, but 2 of the proteins, EsxJ and EsxA, were not expressed. Flow cytometry results showed that, compared with the IL-2 control, HspX, GroEL1, and GroES specifically induced γδ T-cell expansion, with Vγ2δ2 T cells as the main subset, and the secretion of the antimicrobial cytokines TNF-α and IFN-γ. In contrast, HtpG, DnaK, GroEL2, HbhA, Mpt63, EsxB, and EsxN were unable to promote γδ T-cell proliferation and the secretion of TNF-α and IFN-γ. None of the above recombinant proteins were able to induce the secretion of TNF-α and IFN-γ by αβ T cells. In addition, TNF-α, IFN-γ-producing γδ T cells inhibit the growth of intracellular Mtb.
Conclusion: Activated γδ T cells induced by Mtb-HAg components HspX, GroES, GroEL1 to produce TNF-α, IFN-γ modulate macrophages to inhibit intracellular Mtb growth. These data lay the foundation for subsequent studies on the mechanism by which Mtb-HAg induces γδ T-cell proliferation in vitro, as well as the development of preventive and therapeutic vaccines and rapid diagnostic reagents.
Keywords Mycobacterium tuberculosis heat resistant antigen (Mtb-HAg), γδ T cell, TNF-α, IFN-γ
Address and Contact Information 1 Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical University, Bengbu 233000, China
2 Xinjiang Key Laboratory of Hotan Characteristic Chinese Traditional Medicine Research, College of Xinjiang Uyghur Medicine, Hotan, 848099, China
3 Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233000, China
4 Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Bengbu Medical University, Bengbu 233000, China
*Corresponding author: hongtaowang@bbmc.edu.cn; taoxu@bbmc.edu.cn
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No.  71DOI: 10.1186/s11658-024-00586-6 Volume 29 (2024) - 29:71
Title FGFR2-TRIGGERED AUTOPHAGY AND ACTIVATION OF Nrf-2 REDUCE BREAST CANCER CELL RESPONSE TO anti-ER DRUGS
Authors Monika Gorska‐Arcisz1, Marta Popeda2, Marcin Braun3, Dominika Piasecka1, Joanna I. Nowak4, Kamila Kitowska1, Grzegorz Stasilojc5, Marcin Okroj5, Hanna M. Romanska3* and Rafal Sadej1*
Abstract Background: Genetic abnormalities in the FGFR signalling occur in 40% of breast cancer (BCa) patients resistant to anti-ER therapy, which emphasizes the potential of FGFR-targeting strategies. Recent findings indicate that not only mutated FGFR is a driver of tumour progression but co-mutational landscapes and other markers should be also investigated. Autophagy has been recognized as one of the major mechanisms underlying the role of tumour microenvironment in promotion of cancer cell survival, and resistance to anti-ER drugs. The selective autophagy receptor p62/SQSTM1 promotes Nrf-2 activation by Keap1/Nrf-2 complex dissociation. Herein, we have analysed whether the negative effect of FGFR2 on BCa cell response to anti-ER treatment involves the autophagy process and/or p62/Keap1/Nrf-2 axis.
Methods: The activity of autophagy in ER-positive MCF7 and T47D BCa cell lines was determined by analysis of expression level of autophagy markers (p62 and LC3B) and monitoring of autophagosomes’ maturation. Western blot, qPCR and proximity ligation assay were used to determine the Keap1/Nrf-2 interaction and Nrf-2 activation. Analysis of 3D cell growth in Matrigel® was used to assess BCa cell response to applied treatments. In silico gene expression analysis was performed to determine FGFR2/Nrf-2 prognostic value.
Results: We have found that FGFR2 signalling induced autophagy in AMPKα/ULK1-dependent manner. FGFR2 activity promoted dissociation of Keap1/Nrf-2 complex and activation of Nrf-2. Both, FGFR2-dependent autophagy and activation of Nrf-2 were found to counteract the effect of anti-ER drugs on BCa cell growth. Moreover, in silico analysis showed that high expression of NFE2L2 (gene encoding Nrf-2) combined with high FGFR2 expression was associated with poor relapse-free survival (RFS) of ER+ BCa patients.
Conclusions: This study revealed the unknown role of FGFR2 signalling in activation of autophagy and regulation of the p62/Keap1/Nrf-2 interdependence, which has a negative impact on the response of ER+ BCa cells to anti-ER therapies. The data from in silico analyses suggest that expression of Nrf-2 could act as a marker indicating potential benefits of implementation of anti-FGFR therapy in patients with ER+ BCa, in particular, when used in combination with anti-ER drugs.
Keywords FGFR2, Autophagy, p62, Keap1, Nrf-2, Luminal breast cancer
Address and Contact Information 1 Laboratory of Enzymology and Molecular Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80‐211 Gdansk, Poland
2 Department of Pathomorphology, Medical University of Gdansk, Gdansk, Poland
3 Department of Pathology, Chair of Oncology, Medical University of Lodz, Pomorska 251, 92‐213 Lodz, Poland
4 Department of Histology, Medical University of Gdansk, Gdansk, Poland
5 Department of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland
*Corresponding author: hanna.romanska@gmail.com; rafal.sadej@gumed.edu.pl
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No.  72DOI: 10.1186/s11658-024-00588-4 Volume 29 (2024) - 29:72
Title lncRNA Oip5-as1 INHIBITS EXCESSIVE MITOCHONDRIAL FISSION IN MYOCARDIAL ISCHEMIA/REPERFUSION INJURY BY MODULATING DRP1 PHOSPHORYLATION
Authors Xiaowei Niu1,2,3,4, Jingjing Zhang5,6, Shuwen Hu1,2,3,4, Wenhui Dang2, Kaiwen Wang4 and Ming Bai1,2,3,4*
Abstract Background: Aberrant mitochondrial fission, a critical pathological event underlying myocardial ischemia/reperfusion (MI/R) injury, has emerged as a potential therapeutic target. The long non-coding RNA (lncRNA) Oip5-as1 is increasingly recognized for its regulatory roles, particularly in MI/R injury. However, its precise mechanistic role in modulating mitochondrial dynamics remains elusive. This study aims to elucidate the mechanistic role of Oip5-as1 in regulating mitochondrial fission and evaluate its therapeutic potential against MI/R injury.
Methods: To simulate in vitro MI/R injury, HL-1 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R). Lentiviral vectors were employed to achieve overexpression or knockdown of Oip5-as1 in HL-1 cells by expressing Oip5-as1 or shRNA targeting Oip5-as1, respectively. The impact of Oip5-as1 on mitochondrial dynamics in HL-1 cells was assessed using CCK-8 assay, flow cytometry, immunofluorescence staining, and biochemical assays. MI/R injury was induced in mice by ligating the left anterior descending coronary artery. Conditional knockout mice for Oip5-as1 were generated using the CRISPR/Cas9 genome editing technology, while overexpression of Oip5-as1 in mice was achieved via intramyocardial administration of AAV9 vectors. In mice, the role of Oip5-as1 was evaluated through echocardiographic assessment, histopathological staining, and transmission electron microscopy. Furthermore, Western blotting, RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation assays were conducted to investigate Oip5-as1’s underlying mechanisms.
Results: The expression levels of Oip5-as1 are significantly decreased in MI/R-injured HL-1 cells and myocardium. In HL-1 cells undergoing H/R injury, overexpression of Oip5-as1 attenuated excessive mitochondrial fission, preserved mitochondrial functionality, and reduced cellular apoptosis, while knockdown of Oip5-as1 exhibited the opposite effects. Furthermore, in a mouse model of MI/R injury, overexpression of Oip5-as1 diminished mitochondrial fission, myocardial infarct size and improved cardiac function. However, knockout of Oip5-as1 exacerbated myocardial injury and cardiac dysfunction, which were significantly reversed by treatment with a mitochondrial division inhibitor-1 (Mdivi-1). Mechanistically, Oip5-as1 selectively interacts with AKAP1 and CaN proteins, inhibiting CaN activation and subsequent DRP1 dephosphorylation at Ser637, thereby constraining DRP1’s translocation to the mitochondria and its involvement in mitochondrial fission.
Conclusions: Our study underscores the pivotal role of Oip5-as1 in mitigating excessive mitochondrial fission during MI/R injury. The findings not only enhance our comprehension of the molecular mechanisms underlying MI/R injury but also identify Oip5-as1 as a potential therapeutic target for ameliorating MI/R injury.
Keywords Long non-coding RNAs, Oip5-as1, Myocardial ischemia/reperfusion injury, Mitochondrial fssion, Calcineurin, AKAP1, DRP1
Address and Contact Information 1 Department of Cardiology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, China
2 Gansu Key Laboratory of Cardiovascular Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, China
3 Gansu Clinical Medical Research Center for Cardiovascular Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, China
4 The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu 730000, China
5 Medical Genetics Center, Gansu Provincial Central Hospital/Gansu Provincial Maternity and Child-Care Hospital, Lanzhou, Gansu 730000, China
6 Gansu Provincial Clinical Research Center for Birth Defects and Rare Diseases, Lanzhou, Gansu 730000, China
*Corresponding author: ldyy_baim@aliyun.com
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No.  73DOI: 10.1186/s11658-024-00591-9 Volume 29 (2024) - 29:73
Title THE ROLE OF PROINFLAMMATORY CYTOKINES AND CXC CHEMOKINES (CXCL1–CXCL16) IN THE PROGRESSION OF PROSTATE CANCER: INSIGHTS ON THEIR THERAPEUTIC MANAGEMENT
Authors Amin Ullah1†, Wang Jiao1† and Bairong Shen1*
Abstract Reproductive cancers are malignancies that develop in the reproductive organs. One of the leading cancers affecting the male reproductive system on a global scale is prostate cancer (PCa). The negative consequences of PCa metastases endure and are severe, significantly affecting mortality and life quality for those who are affected. The association between inflammation and PCa has captured interest for a while. Inflammatory cells, cytokines, CXC chemokines, signaling pathways, and other elements make up the tumor microenvironment (TME), which is characterized by inflammation. Inflammatory cytokines and CXC chemokines are especially crucial for PCa development and prognosis. Cytokines (interleukins) and CXC chemokines such as IL-1, IL-6, IL-7, IL-17, TGF-β, TNF-α, CXCL1–CXCL6, and CXCL8–CXCL16 are thought to be responsible for the pleiotropic effects of PCa, which include inflammation, progression, angiogenesis, leukocyte infiltration in advanced PCa, and therapeutic resistance. The inflammatory cytokine and CXC chemokines systems are also promising candidates for PCa suppression and immunotherapy. Therefore, the purpose of this work is to provide insight on how the spectra of inflammatory cytokines and CXC chemokines evolve as PCa develops and spreads. We also discussed recent developments in our awareness of the diverse molecular signaling pathways of these circulating cytokines and CXC chemokines, as well as their associated receptors, which may one day serve as PCa-targeted therapies. Moreover, the current status and potential of theranostic PCa therapies based on cytokines, CXC chemokines, and CXC receptors (CXCRs) are examined.
Keywords Prostate cancer (PCa), Cytokines, CXC chemokines, Infammation, Targeted therapies
Address and Contact Information 1 Joint Laboratory of Artifcial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
*Corresponding author: bairong.shen@scu.edu.cn
† Amin Ullah and Wang Jiao contributed equally to this work and should be considered first authors.
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No.  74DOI: 10.1186/s11658-024-00587-5 Volume 29 (2024) - 29:74
Title THE LACK OF TEX44 CAUSES SEVERE SUBFERTILITY WITH FLAGELLAR ABNORMALITIES IN MALE MICE
Authors Sophie Dupuis1, Marie‐Sophie Girault1, Morgane Le Beulze1, Côme Ialy‐Radio1, Luis Bermúdez‐Guzmán2, Ahmed Ziyyat1,3† and Sandrine Barbaux1*†
Abstract By analyzing a mouse Interspecific Recombinant Congenic Strain (IRCS), we previously identified a quantitative trait locus (QTL), called Mafq1 on mouse chromosome 1, that is associated with male hypofertility and ultrastructural sperm abnormalities. Within this locus, we identified a new candidate gene that could be implicated in a reproductive phenotype: Tex44 (Testis-expressed protein 44). We thus performed a CRISPR/Cas9-mediated complete deletion of this gene in mice in order to study its function. Tex44-KO males were severely hypofertile in vivo and in vitro due to a drastic reduction of sperm motility which itself resulted from important morphological sperm abnormalities. Namely, Tex44-KO sperm showed a disorganized junction between the midpiece and the principal piece of the flagellum, leading to a 180° flagellar bending in this region. In addition, the loss of some axonemal microtubule doublets and outer dense fibers in the flagellum’s principal piece has been observed. Our results suggest that, in mice, TEX44 is implicated in the correct set-up of the sperm flagellum during spermiogenesis and its absence leads to flagellar abnormalities and consequently to severe male hypofertility.
Keywords Spermatogenesis, Male infertility, Flagellar bending, Sperm, Mouse model
Address and Contact Information 1 Université de Paris, Institut Cochin, INSERM, CNRS, 75014 Paris, France
2 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
3 Service d’Histologie, d’Embryologie, Biologie de La Reproduction, AP-HP, Hôpital Cochin, 75014 Paris, France
*Corresponding author: sandrine.barbaux@inserm.fr
† Ahmed Ziyyat and Sandrine Barbaux have contributed equally to this work.
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No.  75DOI: 10.1186/s11658-024-00589-3 Volume 29 (2024) - 29:75
Title BLOCKADE OF THE ADAM8-Fra-1 COMPLEX ATTENUATES NEUROINFLAMMATION BY SUPPRESSING THE Map3k4/MAPKs AXIS AFTER SPINAL CORD INJURY
Authors Zhanyang Qian1,2† , Rulin Li1,3†, Tianyu Zhao1,3†, Kunxin Xie4 , PengFei Li1,5, Guangshen Li1 , Na Shen6 , Jiamin Gong6 , Xin Hong2 , Lei Yang1* and Haijun Li1*
Abstract Background: Mechanical spinal cord injury (SCI) is a deteriorative neurological disorder, causing secondary neuroinflammation and neuropathy. ADAM8 is thought to be an extracellular metalloproteinase, which regulates proteolysis and cell adherence, but whether its intracellular region is involved in regulating neuroinflammation in microglia after SCI is unclear.
Methods: Using animal tissue RNA-Seq and clinical blood sample examinations, we found that a specific up-regulation of ADAM8 in microglia was associated with inflammation after SCI. In vitro, microglia stimulated by HMGB1, the tail region of ADAM8, promoted microglial inflammation, migration and proliferation by directly interacting with ERKs and Fra-1 to promote activation, then further activated Map3k4/JNKs/p38. Using SCI mice, we used BK-1361, a specific inhibitor of ADAM8, to treat these mice.
Results: The results showed that administration of BK-1361 attenuated the level of neuroinflammation and reduced microglial activation and recruitment by inhibiting the ADAM8/Fra-1 axis. Furthermore, treatment with BK-1361 alleviated glial scar formation, and also preserved myelin and axonal structures. The locomotor recovery of SCI mice treated with BK-1361 was therefore better than those without treatment.
Conclusions: Taken together, the results showed that ADAM8 was a critical molecule, which positively regulated neuroinflammatory development and secondary pathogenesis by promoting microglial activation and migration. Mechanically, ADAM8 formed a complex with ERK and Fra-1 to further activate the Map3k4/JNK/p38 axis in microglia. Inhibition of ADAM8 by treatment with BK-1361 decreased the levels of neuroinflammation, glial formation, and neurohistological loss, leading to favorable improvement in locomotor functional recovery in SCI mice.
Keywords ADAM8, Fra-1, Spinal cord injury, Microglia, Neuroinfammation, Map3k4
Address and Contact Information 1 Department of Orthopedics, Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
2 Department of Orthopedics, Zhongda Hospital of Southeast University, Nanjing, China
3 School of Postgraduate, Dalian Medical University, Dalian, China
4 Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
5 School of Postgraduate, Nanjing University of Chinese Medicine, Nanjing, China
6 School of Basic Medicine, Nanjing Medical University, Nanjing, China
*Corresponding author: leiyang@njmu.edu.cn; 13901436563@139.com
† Zhanyang Qian, Rulin Li and Tianyu Zhao contributed equally.
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No.  76DOI: 10.1186/s11658-024-00593-7 Volume 29 (2024) - 29:76
Title UNVEILING THE HIDDEN ROLE OF THE INTERACTION BETWEEN CD36 AND FcγRIIb: IMPLICATIONS FOR AUTOIMMUNE DISORDERS
Authors Chenfei He1,4*, Guoying Hua1, Yong Liu5 and Shuijie Li2,3*
Abstract Background: The role of the scavenger receptor CD36 in cell metabolism and the immune response has been investigated mainly in macrophages, dendritic cells, and T cells. However, its involvement in B cells has not been comprehensively examined.
Methods: To investigate the function of CD36 in B cells, we exposed CD36
fl/flMB1
cre mice, which lack CD36 specifically in B cells, to apoptotic cells to trigger an autoimmune response. To validate the proteins that interact with CD36 in primary B cells, we conducted mass spectrometry analysis following anti-CD36 immunoprecipitation. Immunofluorescence and co-immunoprecipitation were used to confirm the protein interactions.
Results: The data revealed that mice lacking CD36 in B cells exhibited a reduction in germinal center B cells and anti-DNA antibodies in vivo. Mass spectrometry analysis identified 30 potential candidates that potentially interact with CD36. Furthermore, the interaction between CD36 and the inhibitory Fc receptor FcγRIIb was first discovered by mass spectrometry and confirmed through immunofluorescence and co-immunoprecipitation techniques. Finally, deletion of FcγRIIb in mice led to decreased expression of CD36 in marginal zone B cells, germinal center B cells, and plasma cells.
Conclusions: Our data indicate that CD36 in B cells is a critical regulator of autoimmunity. The interaction of CD36-FcγRIIb has the potential to serve as a therapeutic target for the treatment of autoimmune disorders.
Keywords Apoptotic cell, Autoreactive B cell, FcγRIIb, Germinal center, Scavenger receptor CD36
Address and Contact Information 1 Center for Research in Animal Genomics, Agricultural Genome Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China
2 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, China
3 Heilongjiang Province Key Laboratory of Research On Molecular Targeted Anti-Tumor Drugs, Harbin, China
4 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
5 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna Campus, Stockholm, Sweden
*Corresponding author: hechenfei@caas.cn; shuijie.li@hrbmu.edu.cn
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No.  77DOI: 10.1186/s11658-024-00592-8 Volume 29 (2024) - 29:77
Title LINC00330/CCL2 AXIS-MEDIATED ESCC TAM REPROGRAMMING AFFECTS TUMOR PROGRESSION
Authors Lijun Zhao1*† , Gengchao Wang2†, Haonan Qi1†, Lili Yu1 , Huilong Yin1 , Ruili Sun1 , Hongfei Wang1 , Xiaofei Zhu1* and Angang Yang3*
Abstract Background: Tumor-associated macrophages (TAMs) significantly influence the progression, metastasis, and recurrence of esophageal squamous cell carcinoma (ESCC). The aberrant expression of long noncoding RNAs (lncRNAs) in ESCC has been established, yet the role of lncRNAs in TAM reprogramming during ESCC progression remains largely unexplored.
Methods: ESCC TAM-related lncRNAs were identified by intersecting differentially expressed lncRNAs with immune-related lncRNAs and performing immune cell infiltration analysis. The expression profile and clinical relevance of LINC00330 were examined using the TCGA database and clinical samples. The LINC00330 overexpression and interference sequences were constructed to evaluate the effect of LINC00330 on ESCC progression. Single-cell sequencing data, CIBERSORTx, and GEPIA were utilized to analyze immune cell infiltration within the ESCC tumor microenvironment and to assess the correlation between LINC00330 and TAM infiltration. ESCC-macrophage coculture experiments were conducted to investigate the influence of LINC00330 on TAM reprogramming and its subsequent effect on ESCC progression. The interaction between LINC00330 and C–C motif ligand 2 (CCL2) was confirmed through transcriptomic sequencing, subcellular localization analysis, RNA pulldown, silver staining, RNA immunoprecipitation, and other experiments.
Results: LINC00330 is significantly downregulated in ESCC tissues and strongly associated with poor patient outcomes. Overexpression of LINC00330 inhibits ESCC progression, including proliferation, invasion, epithelial–mesenchymal transition, and tumorigenicity in vivo. LINC00330 promotes TAM reprogramming, and LINC00330-mediated TAM reprogramming inhibits ESCC progression. LINC00330 binds to the CCL2 protein and inhibits the expression of CCL2 and downstream signaling pathways. CCL2 is critical for LINC00330-mediated TAM reprogramming and ESCC progression.
Conclusions: LINC00330 inhibited ESCC progression by disrupting the CCL2/CCR2 axis and its downstream signaling pathways in an autocrine fashion; and by impeding CCL2-mediated TAM reprogramming in a paracrine manner. The new mechanism of TAM reprogramming mediated by the LINC00330/CCL2 axis may provide potential strategies for targeted and immunocombination therapies for patients with ESCC.
Keywords ESCC, TAM reprogramming, LINC00330, CCL2
Address and Contact Information 1 Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
2 State Key Laboratory of Liver Research, Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
3 The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an, Shanxi, China
*Corresponding author: lijun_zhao123@163.com; zhuxf@xxmu.edu.cn; agyang@fmmu.edu.cn
† Lijun Zhao, Gengchao Wang, and Haonan Qi contributed equally to this work.
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No.  78DOI: 10.1186/s11658-024-00594-6 Volume 29 (2024) - 29:78
Title SR PROTEINS IN CANCER: FUNCTION, REGULATION, AND SMALL INHIBITOR
Authors
Abstract Alternative splicing of pre-mRNAs is a fundamental step in RNA processing required for gene expression in most metazoans. Serine and arginine-rich proteins (SR proteins) comprise a family of multifunctional proteins that contain an RNA recognition motif (RRM) and the ultra-conserved arginine/serine-rich (RS) domain, and play an important role in precise alternative splicing. Increasing research supports SR proteins as also functioning in other RNA-processing-related mechanisms, such as polyadenylation, degradation, and translation. In addition, SR proteins interact with N6-methyladenosine (m6A) regulators to modulate the methylation of ncRNA and mRNA. Dysregulation of SR proteins causes the disruption of cell differentiation and contributes to cancer progression. Here, we review the distinct biological characteristics of SR proteins and their known functional mechanisms during carcinogenesis. We also summarize the current inhibitors that directly target SR proteins and could ultimately turn SR proteins into actionable therapeutic targets in cancer therapy.
Keywords SR proteins, RNA processing, Splicing, m6A modifcation, Tumor treatment
Address and Contact Information 1 Systems Biology Laboratory, Shantou University Medical College (SUMC), 22 Xinling Road, Shantou 515041, China
2 Department of Cardiology, First Affiliated Hospital of Shantou University Medical College, Shantou, China
*Corresponding author: jzxu01@stu.edu.cn
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No.  79DOI: 10.1186/s11658-024-00595-5 Volume 29 (2024) - 29:79
Title IMPAIRED SYNAPTIC PLASTICITY AND DECREASED GLUTAMATERGIC NEURON EXCITABILITY INDUCED BY SIRT1/BDNF DOWNREGULATION IN THE HIPPOCAMPAL CA1 REGION ARE INVOLVED IN POSTOPERATIVE COGNITIVE DYSFUNCTION
Authors Wei‐Feng Wu1†, Chen Chen1†, Jia‐Tao Lin1†, Xin‐Hao Jiao1†, Wei Dong1, Jie Wan1, Qiang Liu1, Yong‐Kang Qiu1, Ao Sun1, Yi‐Qi Liu1, Chun‐Hui Jin1, He Huang1, Hui Zheng2*, Cheng‐Hua Zhou3* and Yu‐Qing Wu1*
Abstract Background: Postoperative cognitive dysfunction (POCD) is a common complication after anesthesia/surgery, especially among elderly patients, and poses a significant threat to their postoperative quality of life and overall well-being. While it is widely accepted that elderly patients may experience POCD following anesthesia/surgery, the exact mechanism behind this phenomenon remains unclear. Several studies have indicated that the interaction between silent mating type information regulation 2 homologue 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) is crucial in controlling cognitive function and is strongly linked to neurodegenerative disorders. Hence, this research aims to explore how SIRT1/BDNF impacts cognitive decline caused by anesthesia/surgery in aged mice.
Methods: Open field test (OFT) was used to determine whether anesthesia/surgery affected the motor ability of mice, while the postoperative cognitive function of 18 months old mice was evaluated with Novel object recognition test (NORT), Object location test (OLT) and Fear condition test (FC). The expressions of SIRT1 and other molecules were analyzed by western blot and immunofluorescence staining. The hippocampal synaptic plasticity was detected by Golgi staining and Long-term potentiation (LTP). The effects of SIRT1 and BDNF overexpression as well as chemogenetic activation of glutamatergic neurons in hippocampal CA1 region of 18 months old vesicular glutamate transporter 1 (VGLUT1) mice on POCD were further investigated.
Results: The research results revealed that older mice exhibited cognitive impairment following intramedullary fixation of tibial fracture. Additionally, a notable decrease in the expression of SIRT1/BDNF and neuronal excitability in hippocampal CA1 glutamatergic neurons was observed. By increasing levels of SIRT1/BDNF or enhancing glutamatergic neuron excitability in the CA1 region, it was possible to effectively mitigate synaptic plasticity impairment and ameliorate postoperative cognitive dysfunction.
Conclusions: The decline in SIRT1/BDNF levels leading to changes in synaptic plasticity and neuronal excitability in older mice could be a significant factor contributing to cognitive impairment after anesthesia/surgery.
Keywords SIRT1, Postoperative cognitive dysfunction, General anesthesia, Synaptic plasticity, Hippocampus
Address and Contact Information 1 Jiangsu Province Key Laboratory of Anesthesiology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou 221004, China
2 Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
3 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
*Corresponding author: zhenghui@cicams.ac.cn; chzhou77@xzhmu.edu.cn; xzmcyqwu@163.com † Wei-Feng Wu, Chen Chen, Jia-Tao Lin and Xin-Hao Jiao contributed equally to this work.
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No.  80DOI: 10.1186/s11658-024-00599-1 Volume 29 (2024) - 29:80
Title SGLT2 INHIBITOR PROMOTES MITOCHONDRIAL DYSFUNCTION AND ER-PHAGY IN COLORECTAL CANCER CELLS
Authors Camilla Anastasio1, Isabella Donisi1, Vitale Del Vecchio2, Antonino Colloca1, Luigi Mele2, Celestino Sardu3, Rafaele Marfella3, Maria Luisa Balestrieri1 and Nunzia D’Onofrio1*
Abstract Background: Sodium-glucose transporter 2 (SGLT2) inhibitors (iSGLT2) are approved medications for type 2 diabetes. Recent studies indicate that iSGLT2 inhibit the growth of some cancer cells. However, the mechanism(s) remains to be fully elucidated.
Methods: The SGLT2 levels were determined in normal colon CCD 841 CoN and, HCT 116, HT-29, SW480 and LoVo colorectal cancer (CRC) cell lines by quantitative real-time PCR and western blot. The effect of iSGLT2 canagliflozin on cell proliferation was examined using CCK-8, as its role on CRC cells metabolism and tumorigenesis has been evaluated by XF HS Seahorse Bioanalyzer and flow cytometric analyses. Transient gene silencing experiments and analysis of protein–protein interaction network were conducted to evaluate the SGLT2 molecular targets in CRC cells.
Results: Data showed that the treatment with iSGLT2 (50 µM) for 72 h induced cell cycle arrest (p < 0.001), impaired glucose and energetic metabolism (p < 0.001), promoted apoptotic cell death and ER stress flowing into autophagy (p < 0.001) in HCT 116 and HT-29 cells. These cellular events were accompanied by sirtuin 3 (SIRT3) upregulation (p < 0.01), as also supported by SIRT3 transient silencing experiments resulting in the attenuation of the effects of iSGLT2 on the cellular metabolic/energetic alterations and the induction of programmed cell death. The identification and validation of dipeptidyl peptidase 4 (DPP4) as potential common target of SGLT2 and SIRT3 were also assessed.
Conclusions: These results deepened knowledge on the iSGLT2 contribution in limiting CRC tumorigenesis unveiling the SGLT2/SIRT3 axis in the cytotoxic mechanisms.
Keywords iSGLT2, Metabolic alterations, Mitochondrial dysfunction, SIRT3, ER-stress, Colorectal cancer cells
Address and Contact Information 1 Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
2 Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Via Luciano Armanni 5, 80138 Naples, Italy
3 Department of Advanced Clinical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
*Corresponding author: nunzia.donofrio@unicampania.it
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No.  81DOI: 10.1186/s11658-024-00602-9 Volume 29 (2024) - 29:81
Title Dysregulated dendritic cells in sepsis: functional impairment and regulated cell death
Authors Li‐yu Zheng1†, Yu Duan2†, Peng‐yi He1†, Meng‐yao Wu1, Shu‐ting Wei1, Xiao‐hui Du3*, Ren‐qi Yao1,3* and Yong‐ming Yao1*
Abstract Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Studies have indicated that immune dysfunction plays a central role in the pathogenesis of sepsis. Dendritic cells (DCs) play a crucial role in the emergence of immune dysfunction in sepsis. The major manifestations of DCs in the septic state are abnormal functions and depletion in numbers, which are linked to higher mortality and vulnerability to secondary infections in sepsis. Apoptosis is the most widely studied pathway of number reduction in DCs. In the past few years, there has been a surge in studies focusing on regulated cell death (RCD). This emerging field encompasses various forms of cell death, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death (ADCD). Regulation of DC’s RCD can serve as a possible therapeutic focus for the treatment of sepsis. Throughout time, numerous tactics have been devised and effectively implemented to improve abnormal immune response during sepsis progression, including modifying the functions of DCs and inhibiting DC cell death. In this review, we provide an overview of the functional impairment and RCD of DCs in septic states. Also, we highlight recent advances in targeting DCs to regulate host immune response following septic challenge.
Keywords Sepsis, Dendritic cells, Functional impairment, Regulated cell death, Immunomodulation
Address and Contact Information 1 Translational Medicine Research Center, Medical Innovation Research Division of the Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing 100853, China
2 Department of Critical Care Medicine, Affiliated Chenzhou Hospital (the First People’s Hospital of Chenzhou), Southern Medical University, Chenzhou 423000, China
3 Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing 100853, China
*Corresponding author: duxiaohui301@sina.com; yaorenqixx1995@163.com; c_f@sina.com
† Li-yu Zheng, Yu Duan and Peng-yi He have contributed equally to this manuscript.
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No.  82DOI: 10.1186/s11658-024-00596-4 Volume 29 (2024) - 29:82
Title LIPOTOXIC HEPATOCYTE DERIVED LIMA1 ENRICHED SMALL EXTRACELLULAR VESICLES PROMOTE HEPATIC STELLATE CELLS ACTIVATION VIA INHIBITING MITOPHAGY
Authors Shihui Li1,2†, Fuji Yang1,2†, Fang Cheng1,2, Ling Zhu3 and Yongmin Yan1,3,4*
Abstract Background: Hepatic stellate cells (HSCs) play a crucial role in the development of fibrosis in non-alcoholic fatty liver disease (NAFLD). Small extracellular vesicles (sEV) act as mediators for intercellular information transfer, delivering various fibrotic factors that impact the function of HSCs in liver fibrosis. In this study, we investigated the role of lipotoxic hepatocyte derived sEV (LTH-sEV) in HSCs activation and its intrinsic mechanisms.
Methods: High-fat diet (HFD) mice model was constructed to confirm the expression of LIMA1. The relationship between LIMA1-enriched LTH-sEV and LX2 activation was evaluated by measurement of fibrotic markers and related genes. Levels of mitophagy were detected using mt-keima lentivirus. The interaction between LIMA1 and PINK1 was discovered through database prediction and molecular docking. Finally, sEV was injected to investigate whether LIMA1 can accelerate HFD induced liver fibrosis in mice.
Results: LIMA1 expression was upregulated in lipotoxic hepatocytes and was found to be positively associated with the expression of the HSCs activation marker α-SMA. Lipotoxicity induced by OPA led to an increase in both the level of LIMA1 protein in LTH-sEV and the release of LTH-sEV. When HSCs were treated with LTH-sEV, LIMA1 was observed to hinder LX2 mitophagy while facilitating LX2 activation. Further investigation revealed that LIMA1 derived from LTH-sEV may inhibit PINK1-Parkin-mediated mitophagy, consequently promoting HSCs activation. Knocking down LIMA1 significantly attenuates the inhibitory effects of LTH-sEV on mitophagy and the promotion of HSCs activation.
Conclusions: Lipotoxic hepatocyte-derived LIMA1-enriched sEVs play a crucial role in promoting HSCs activation in NAFLD-related liver fibrosis by negatively regulating PINK1 mediated mitophagy. These findings provide new insights into the pathological mechanisms involved in the development of fibrosis in NAFLD.
Keywords Nonalcoholic fatty liver disease, LIMA1, Hepatic stellate cells, Mitophagy, Small extracellular vesicles
Address and Contact Information 1 Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University, Changzhou 213017, China
2 Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
3 Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated With Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou 213017, China
4 Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine, Jiangsu University, Changzhou 213017, China
*Corresponding author: yym@ujs.edu.cn
† Shihui Li and Fuji Yang have contributed equally to this work.
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No.  83DOI: 10.1186/s11658-024-00598-2 Volume 29 (2024) - 29:83
Title ZBP1 INHIBITS THE REPLICATION OF Senecavirus A bY ENHANCING NF-κB SIGNALING PATHWAY MEDIATED ANTIVIRAL RESPONSE IN PORCINE ALVEOLAR MACROPHAGE 3D4/21 CELLS
Authors Huizi Li1†, Tingting Zheng1†, Ming Chen1, Xiaoling Lei1, Shuo Li1, Xijiao Chen1, Shishi Wang1 and Zhangyong Ning1,2*
Abstract Background: Senecavirus A (SVA) caused porcine idiopathic vesicular disease (PIVD) showing worldwide spread with economic losses in swine industry. Although some progress has been made on host factors regulating the replication of SVA, the role of Z-DNA binding protein 1 (ZBP1) remains unclear.
Methods: The expression of ZBP1 in SVA-infected 3D/421 cells was analyzed by quantitative real-time PCR (qRT-PCR) and western blot. Western blot and qRT-PCR were used to detect the effects of over and interference expression of ZBP1 on SVA VP2 gene and protein. Viral growth curves were prepared to measure the viral proliferation. The effect on type I interferons (IFNs), interferon-stimulated genes (ISGs), and pro-inflammatory cytokines in SVA infection was analyzed by qRT-PCR. Western blot was used to analysis the effect of ZBP1 on NF-κB signaling pathway and inhibitor are used to confirm.
Results: ZBP1 is shown to inhibit the replication of SVA by enhancing NF-κB signaling pathway mediated antiviral response. SVA infection significantly up-regulated the expression of ZBP1 in 3D4/21 cells. Infection of cells with overexpression of ZBP1 showed that the replication of SVA was inhibited with the enhanced expression of IFNs (IFN-α, IFN-β), ISGs (ISG15, PKR, and IFIT1) and pro-inflammatory cytokines (IL-6, IL-8, and TNF-α), while, infected-cells with interference expression of ZBP1 showed opposite effects. Further results showed that antiviral effect of ZBP1 is achieved by activation the NF-κB signaling pathway and specific inhibitor of NF-κB also confirmed this.
Conclusions: ZBP1 is an important host antiviral factor in SVA infection and indicates that ZBP1 may be a novel target against SVA.
Keywords ZBP1, SVA, NF-κB
Address and Contact Information 1 College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
2 Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming 525000, China
*Corresponding author: ningzhyong@scau.edu.cn
† Huizi Li and Tingting Zheng have contributed equally to this work.
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No.  84DOI: 10.1186/s11658-024-00601-w Volume 29 (2024) - 29:84
Title AGR2-MEDIATED UNCONVENTIONAL SECRETION OF 14-3-3ε AND α-ACTININ-4, RESPONSIVE TO ER STRESS AND AUTOPHAGY, DRIVES CHEMOTAXIS IN CANINE MAMMARY TUMOR CELLS
Authors Stephen Hsien‐Chi Yuan1†, Chih‐Ching Wu2,3,4,5,6†, Yu‐Chih Wang7, Xiu‐Ya Chan2, Hao‐Wei Chu2,6, Youngsen Yang8 and Hao‐Ping Liu1,9*
Abstract Background: Canine mammary tumors (CMTs) in intact female dogs provide a natural model for investigating metastatic human cancers. Our prior research identified elevated expression of Anterior Gradient 2 (AGR2), a protein disulfide isomerase (PDI) primarily found in the endoplasmic reticulum (ER), in CMT tissues, highly associated with CMT progression. We further demonstrated that increased AGR2 expression actively influences the extracellular microenvironment, promoting chemotaxis in CMT cells. Unraveling the underlying mechanisms is crucial for assessing the potential of therapeutically targeting AGR2 as a strategy to inhibit a pro-metastatic microenvironment and impede tumor metastasis.
Methods: To identify the AGR2-modulated secretome, we employed proteomics analysis of the conditioned media (CM) from two CMT cell lines ectopically expressing AGR2, compared with corresponding vector-expressing controls. AGR2-regulated release of 14-3-3ε (gene: YWHAE) and α-actinin 4 (gene: ACTN4) was validated through ectopic expression, knockdown, and knockout of the AGR2 gene in CMT cells. Extracellular vesicles derived from CMT cells were isolated using either differential ultracentrifugation or size exclusion chromatography. The roles of 14-3-3ε and α-actinin 4 in the chemotaxis driven by the AGR2-modulated CM were investigated through gene knockdown, antibody-mediated interference, and recombinant protein supplement. Furthermore, the clinical relevance of the release of 14-3-3ε and α-actinin 4 was assessed using CMT tissue-immersed saline and sera from CMT-afflicted dogs.
Results: Proteomics analysis of the AGR2-modulated secretome revealed increased abundance in 14-3-3ε and α-actinin 4. Ectopic expression of AGR2 significantly increased the release of 14-3-3ε and α-actinin 4 in the CM. Conversely, knockdown or knockout of AGR2 expression remarkably reduced their release. Silencing 14-3-3ε or α-actinin 4 expression diminished the chemotaxis driven by AGR2-modulated CM. Furthermore, AGR2 controls the release of 14-3-3ε and α-actinin 4 primarily via non-vesicular routes, responding to the endoplasmic reticulum (ER) stress and autophagy activation. Knockout of AGR2 resulted in increased α-actinin 4 accumulation and impaired 14-3-3ε translocation in autophagosomes. Depletion of extracellular 14-3-3ε or α-actinin 4 reduced the chemotaxis driven by AGR2-modulated CM, whereas supplement with recombinant 14-3-3ε in the CM enhanced the CM-driven chemotaxis. Notably, elevated levels of 14-3-3ε or α-actinin 4 were observed in CMT tissue-immersed saline compared with paired non-tumor samples and in the sera of CMT dogs compared with healthy dogs.
Conclusion: This study elucidates AGR2’s pivotal role in orchestrating unconventional secretion of 14-3-3ε and α-actinin 4 from CMT cells, thereby contributing to paracrine-mediated chemotaxis. The insight into the intricate interplay between AGR2-involved ER stress, autophagy, and unconventional secretion provides a foundation for refining strategies aimed at impeding metastasis in both canine mammary tumors and potentially human cancers.
Keywords
Address and Contact Information 1 Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan.
2 Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
3 Department of Otolaryngology‐Head and Neck Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
4 Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
5 Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
6 Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
7 Graduate Institute of Veterinary Pathology, College of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan.
8 Department of Oncology, Taichung Veterans General Hospital, Taichung, Taiwan.
9 Biotechnology Center, National Chung Hsing University, Taichung 40227, Taiwan.
*Corresponding author: hpliu@dragon.nchu.edu.tw
† Stephen Hsien-Chi Yuan and Chih-Ching Wu contributed equally to this work and shared the first authorship.
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No.  85DOI: 10.1186/s11658-024-00597-3 Volume 29 (2024) - 29:85
Title FLEXIBLE Atg1/ULK COMPLEX COMPOSITION ACTIVATES SELECTIVE AUTOPHAGY FOR PHOSPHATE STARVATION
Authors Yijia Fangma1, Zhong Chen1 and Yanrong Zheng1*
Abstract The molecular basis for bulk autophagy activation due to a deficiency in essential nutrients such as carbohydrates, amino acids, and nitrogen is well understood. Given autophagy functions to reduce surplus to compensate for scarcity, it theoretically possesses the capability to selectively degrade specific substrates to meet distinct metabolic demands. However, direct evidence is still lacking that substantiates the idea that autophagy selectively targets specific substrates (known as selective autophagy) to address particular nutritional needs. Recently, Gross et al. found that during phosphate starvation (P-S), rather than nitrogen starvation (N-S), yeasts selectively eliminate peroxisomes by dynamically altering the composition of the Atg1/ULK kinase complex (AKC) to adapt to P-S. This study elucidates how the metabolite sensor Pho81 flexibly interacts with AKC and guides selective autophagic clearance of peroxisomes during P-S, providing novel insights into the metabolic contribution of autophagy to special nutritional needs.
Keywords Atg1/ULK kinase complex, Phosphate starvation, Selective autophagy, Pexophagy
Address and Contact Information 1 Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
*Corresponding author: yanrong_zh@zju.edu.cn
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No.  86DOI: 10.1186/s11658-024-00604-7 Volume 29 (2024) - 29:86
Title RETRACTION NOTE: THE NOVEL CIRCULAR RNA circ-CAMK2A ENHANCES LUNG ADENOCARCINOMA METASTASIS BY REGULATING THE miR-615-5p/FIBRONECTIN 1 PATHWAY
Authors Jiahui Du1, Guangzhao Zhang1, Hongli Qiu1, Haifeng Yu1 and Wuying Yuan1*
Abstract Retraction Note: Cellular & Molecular Biology Letters (2019) 24:72
https://doi.org/10.1186/s11658-019-0198-1

The Editor-in-Chief has retracted this article after concerns were raised about the data reported. The journal was initially contacted by the authors to report concerns about the reproducibility of their results. The authors were then unable to provide raw data upon request by the publisher. The Editor-in-Chief no longer has confidence in the reliability of the findings and conclusions of this article.

All authors agree with this retraction.
Keywords
Address and Contact Information 1 Minimally Invasive Surgery, Henan Provincial Chest Hospital, No. 1 Weiwu Road, Jinshui District, Zhengzhou 450000, People’s Republic of China *Corresponding author: yuanwuying321@yeah.net The original article can be found online at https://doi.org/10.1186/s11658-019-0198-1
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No.  87DOI: 10.1186/s11658-024-00600-x Volume 29 (2024) - 29:87
Title APOE2 PROTECTS AGAINST Aβ PATHOLOGY BY IMPROVING NEURONAL MITOCHONDRIAL FUNCTION THROUGH ERRα SIGNALING
Authors Zhiyuan Ning1,2,3†, Ying Liu1,2,3†, Mengyao Wan1,2,3†, You Zuo1,2, Siqi Chen2,3, Zhongshan Shi1,2, Yongteng Xu1,2, Honghong Li1,2, Ho Ko4, Jing Zhang5, Songhua Xiao1,2*, Daji Guo1,2,3* and Yamei Tang1,2,3,6,7*
Abstract Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear.
Methods: We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively.
Results: The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aβ). Moreover, APOE2 overexpression alleviates Aβ1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aβ1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aβ injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice.
Conclusions: APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.
Keywords Alzheimer’s disease, Apolipoprotein E, Beta-amyloid (Aβ), Neuron, Mitochondria, ESRRA
Address and Contact Information 1 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
2 Brain Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
3 Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, China.
4 Division of Neurology, Department of Medicine and Therapeutics & Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
5 Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou, China.
6 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
7 Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
*Corresponding author: xiaosh@mail.sysu.edu.cn; guodj5@mail.sysu.edu.cn; tangym@mail.sysu.edu.cn
† Zhiyuan Ning, Ying Liu and Mengyao Wan have contributed equally to this work and share first authorship.
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No.  88DOI: 10.1186/s11658-024-00605-6 Volume 29 (2024) - 29:88
Title α-KETOGLUTARATE ALLEVIATES OSTEOARTHRITIS BY INHIBITING FERROPTOSIS VIA THE ETV4/SLC7A11/GPX4 SIGNALING PATHWAY
Authors Rong He1†, Yuchi Wei1†, Zeyu Peng1, Jie Yang1, Zhenwei Zhou2, Ailin Li1, Yongji Wu1, Mingyue Wang1, Xiangyan Li2, Daqing Zhao2, Zhonghua Liu3*, Haisi Dong2* and Xiangyang Leng1*
Abstract Osteoarthritis (OA) is the most common degenerative joint disorder that causes disability in aged individuals, caused by functional and structural alterations of the knee joint. To investigate whether metabolic drivers might be harnessed to promote cartilage repair, a liquid chromatography–mass spectrometry (LC–MS) untargeted metabolomics approach was carried out to screen serum biomarkers in osteoarthritic rats. Based on the correlation analyses, α-ketoglutarate (α-KG) has been demonstrated to have antioxidant and anti-inflammatory properties in various diseases. These properties make α-KG a prime candidate for further investigation of OA. Experimental results indicate that α-KG significantly inhibited H2O2-induced cartilage cell matrix degradation and apoptosis, reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione (GSH)/glutathione disulfide (GSSG) levels, and upregulated the expression of ETV4, SLC7A11 and GPX4. Further mechanistic studies observed that α-KG, like Ferrostatin-1 (Fer-1), effectively alleviated Erastin-induced apoptosis and ECM degradation. α-KG and Fer-1 upregulated ETV4, SLC7A11, and GPX4 at the mRNA and protein levels, decreased ferrous ion (Fe2+) accumulation, and preserved mitochondrial membrane potential (MMP) in ATDC5 cells. In vivo, α-KG treatment inhibited ferroptosis in OA rats by activating the ETV4/SLC7A11/GPX4 pathway. Thus, these findings indicate that α-KG inhibits ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway, thereby alleviating OA. These observations suggest that α-KG exhibits potential therapeutic properties for the treatment and prevention of OA, thereby having potential clinical applications in the future.
Keywords Osteoarthritis, α-ketoglutarate, Ferroptosis, ETV4/SLC7A11/GPX4 signaling pathway
Address and Contact Information 1 College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, Jilin Province, China
2 Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, Jilin Province, China
3 Department of orthopaedics, The Third Affiliated Hospital of Changchun University of Chinese Medicine, Changchun 130117, Jilin Province, China
*Corresponding author: 945769043@qq.com; adonghaisi@163.com; lengxiangy@163.com
† Rong He and Yuchi Wei contributed equally to this study.
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No.  89DOI: 10.1186/s11658-024-00606-5 Volume 29 (2024) - 29:89
Title CircR-LOOP: A NOVEL RNA:DNA INTERACTION ON GENOME INSTABILITY
Authors Xinming Su1,2, Yaojie Feng3, Ruixiu Chen1,2 and Shiwei Duan1,2*
Abstract CircR-loop, a recently unearthed regulatory mechanism situated at the crossroads of circular RNA and DNA interactions, constitute a subset of R-loop. This circR-loop have emerged as a crucial player in pivotal regulatory functions within both animal and plant systems. The journey into the realm of circR-loop commenced with their discovery within the human mitochondrial genome, where they serve as critical directors of mitochondrial DNA replication. In the plant kingdom, circR-loop wield influence over processes such as alternative splicing and centromere organization, impacting the intricacies of floral development and genome stability, respectively. Their significance extends to the animal domain, where circR-loop has captured attention for their roles in cancer-related phenomena, exerting control over transcription, chromatin architecture, and orchestrating responses to DNA damage. Moreover, their involvement in nuclear export anomalies further underscores their prominence in cellular regulation. This article summarizes the important regulatory mechanisms and physiological roles of circR-loop in plants and animals, and offers a comprehensive exploration of the methodologies employed for the identification, characterization, and functional analysis of circR-loop, underscoring the pressing need for innovative approaches that can effectively distinguish them from their linear RNA counterparts while elucidating their precise functions. Lastly, the article sheds light on the challenges and opportunities that lie ahead in the field of circR-loop research, emphasizing the vital importance of continued investigations to uncover their regulatory roles and potential applications in the realm of biology. In summary, circR-loop represents a captivating and novel regulatory mechanism with broad-reaching implications spanning the realms of genetics, epigenetics, and disease biology. Their exploration opens new avenues for comprehending gene regulation and holds significant promise for future therapeutic interventions.
Keywords CircRNA, R-Loops, RNA–DNA interactions, Gene regulation, Regulatory mechanism
Address and Contact Information 1 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
2 Department of Clinical Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
3 Department of Nursing, Hangzhou City University, Hangzhou, Zhejiang, China
*Corresponding author: duansw@hzcu.edu.cn
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No.  90DOI: 10.1186/s11658-024-00603-8 Volume 29 (2024) - 29:90
Title ACE2 MEDIATES TRYPTOPHAN ALLEVIATION ON DIARRHEA BY REPAIRING INTESTINE BARRIER INVOLVED MTOR PATHWAY
Authors Jinze Li1, Yingli Yan1, Yang Fu1, Zhe Chen1, Yongjie Yang1, Yu Li1, Jie Pan2, Feiwu Li3, Cuifang Zha1, Kai Miao4, Lukuyu Ben5, Muhammad Kashif Saleemi6, Yongwen Zhu1, Hui Ye1, Lin Yang1* and Wence Wang1*
Abstract The membrane-delimited receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), angiotensin-converting enzyme 2 (ACE2), which is expressed in the intestine, collaborates with broad neutral amino acid transporter 1 (B0AT1). Tryptophan (Trp) is transported into intestinal epithelial cells by ACE2 and B0AT1. However, whether ACE2 and its binding protein B0AT1 are involved in Trp-mediated alleviation of intestinal injury is largely unknown. Here, we used weaned piglets and IPEC-J2 cells as models and found that ACE2/B0AT1 alleviated lipopolysaccharide (LPS)-induced diarrhea and promoted intestinal barrier recovery via transport of Trp. The levels of the aryl hydrocarbon receptor (AhR) and mechanistic target of rapamycin (mTOR) pathways were altered by ACE2. Dietary Trp supplementation in LPS-treated weaned piglets revealed that Trp alleviated diarrhea by promoting ACE2/B0AT1 expression, and examination of intestinal morphology revealed that the damage to the intestinal barrier was repaired. Our study demonstrated that ACE2 accompanied by B0AT1 mediated the alleviation of diarrhea by Trp through intestinal barrier repair via the mTOR pathway.
Keywords ACE2, Tryptophan, B0AT1, mTOR, Aryl hydrocarbon receptor
Address and Contact Information 1 State Key Laboratory of Swine and Poultry Breeding Industry and Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
2 Zhuhai Tianjiao Technology Co., LTD, Zhuhai 519000, China
3 Hunan New Wellful Co., LTD, Changsha 410005, China
4 Cancer Center, Faculty of Health Sciences, University of Macau, Macau 999078, China
5 International Livestock Research Institute, Nairobi 00100, Kenya
6 Department of Pathology, University of Agriculture Faisalabad, Faisalabad 38040, Pakistan
*Corresponding author: yanglin@scau.edu.cn; wangwence@scau.edu.cn
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No.  91DOI: 10.1186/s11658-024-00608-3 Volume 29 (2024) - 29:91
Title CUPROPTOSIS IN CANCER: BIOLOGICAL IMPLICATIONS AND THERAPEUTIC OPPORTUNITIES
Authors Liping Li1, Houfeng Zhou1 and Chenliang Zhang2*
Abstract Cuproptosis, a newly identified copper (Cu)-dependent form of cell death, stands out due to its distinct mechanism that sets it apart from other known cell death pathways. The molecular underpinnings of cuproptosis involve the binding of Cu to lipoylated enzymes in the tricarboxylic acid cycle. This interaction triggers enzyme aggregation and proteotoxic stress, culminating in cell death. The specific mechanism of cuproptosis has yet to be fully elucidated. This newly recognized form of cell death has sparked numerous investigations into its role in tumorigenesis and cancer therapy. In this review, we summarized the current knowledge on Cu metabolism and its link to cancer. Furthermore, we delineated the molecular mechanisms of cuproptosis and summarized the roles of cuproptosis-related genes in cancer. Finally, we offered a comprehensive discussion of the most recent advancements in Cu ionophores and nanoparticle delivery systems that utilize cuproptosis as a cutting-edge strategy for cancer treatment.
Keywords Copper, Cuproptosis, Tumorigenesis, Tumor therapy, Metabolism, Drug resistance
Address and Contact Information 1 Department of Pharmacy, Chengdu Fifth People’s Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
2 Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People’s Republic of China
*Corresponding author: zhangchenliang@wchscu.edu.cn
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No.  92DOI: 10.1186/s11658-024-00607-4 Volume 29 (2024) - 29:92
Title A SPECIFIC SUPER-ENHANCER ACTUATED BY BERBERINE REGULATES EGFR-MEDIATED RAS–RAF1–MEK1/2–ERK1/2 PATHWAY TO INDUCE NASOPHARYNGEAL CARCINOMA AUTOPHAGY
Authors Yao Wu1,2, Qunying Jia1, Qi Tang2, Lin Chen2, Hongyu Deng1, Yingchun He2 and Faqing Tang1,2*
Abstract Nasopharyngeal carcinoma (NPC), primarily found in the southern region of China, is a malignant tumor known for its highly metastatic characteristics. The high mortality rates caused by the distant metastasis and disease recurrence remain unsolved clinical problems. In clinic, the berberine (BBR) compound has widely been in NPC therapy to decrease metastasis and disease recurrence, and BBR was documented as a main component with multiple anti-NPC effects. However, the mechanism by which BBR inhibits the growth and metastasis of nasopharyngeal carcinoma remains elusive. Herein, we show that BBR effectively inhibits the growth, metastasis, and invasion of NPC via inducing a specific super enhancer (SE). From a mechanistic perspective, the RNA sequencing (RNA-seq) results suggest that the RAS–RAF1–MEK1/2–ERK1/2 signaling pathway, activated by the epidermal growth factor receptor (EGFR), plays a significant role in BBR-induced autophagy in NPC. Blockading of autophagy markedly attenuated the effect of BBR-mediated NPC cell growth and metastasis inhibition. Notably, BBR increased the expression of EGFR by transcription, and knockout of EGFR significantly inhibited BBR-induced microtubule associated protein 1 light chain 3 (LC3)-II increase and p62 inhibition, proposing that EGFR plays a pivotal role in BBR-induced autophagy in NPC. Chromatin immunoprecipitation sequencing (ChIP-seq) results found that a specific SE existed only in NPC cells treated with BBR. This SE knockdown markedly repressed the expression of EGFR and phosphorylated EGFR (EGFR-p) and reversed the inhibition of BBR on NPC proliferation, metastasis, and invasion. Furthermore, BBR-specific SE may trigger autophagy by enhancing EGFR gene transcription, thereby upregulating the RAS–RAF1–MEK1/2–ERK1/2 signaling pathway. In addition, in vivo BBR effectively inhibited NPC cells growth and metastasis, following an increase LC3 and EGFR and a decrease p62. Collectively, this study identifies a novel BBR-special SE and established a new epigenetic paradigm, by which BBR regulates autophagy, inhibits proliferation, metastasis, and invasion. It provides a rationale for BBR application as the treatment regime in NPC therapy in future.
Keywords BBR, EGFR, Autophagy, Super-enhancer, Nasopharyngeal carcinoma
Address and Contact Information 1 Hunan Key Laboratory of Oncotarget Gene and Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University and Hunan Cancer Hospital, Changsha 410013, China
2 The First Clinical College of Traditional Chinese Medicine of Hunan University of Chinese Medicine, and Hunan Cancer Hospital, Changsha 410007, China
*Corresponding author: tangfq@hnca.org.cn
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No.  93DOI: 10.1186/s11658-024-00612-7 Volume 29 (2024) - 29:93
Title LncRNA TRPM2-AS PROMOTES ENDOMETRIAL CARCINOMA PROGRESSION AND ANGIOGENESIS VIA TARGETING miR-497-5p/SPP1 AXIS
Authors Hanbo Ma1,2,3, Fengyun Weng4, Xiaowen Tong3, Huaifang Li3*, Yinan Yao3* and Jiangjing Yuan1,2*
Abstract Background: Anti-angiogenic therapy has become one of the effective treatment methods for tumors. Long noncoding RNAs (lncRNAs) are emerging as important regulators of tumorigenesis and angiogenesis in EC. However, the underlying mechanisms of lncRNA TRPM2-AS in EC are still not clear.
Methods: We screened the differently expressed lncRNAs that were highly associated with poor prognosis and angiogenesis of EC by bioinformatics analysis, and constructed a ceRNA network based on the prognostic lncRNAs. The subcellular localization of TRPM2-AS was determined by fluorescence in situ hybridization (FISH) and nuclear cytoplasmic fractionation assay. CCK-8, EdU, transwell, western blot, qRT-PCR and endothelial tube formation assay were used to evaluate the effects of TRPM2-AS on the proliferation, invasion, migration of EC cells and angiogenesis. The targeted microRNA (miRNA) of TRPM2-AS was predicted by bioinformatic methods. The interaction between TRPM2-AS and miR497-5p, miR497-5p and SPP1 were analyzed by RNA immunoprecipitation and dual-luciferase reporter assay. A subcutaneous tumor model was used to explore TRPM2-AS’s function in vivo. CIBERSORT was used to analyze the correlation between TRPM2-AS and immune cell immersion in EC.
Results: We found that the expression of TRPM2-AS and SPP1 was aberrantly upregulated, while miR-497-5p expression was significantly downregulated in EC tissues and cells. TRPM2-AS was closely correlated with the angiogenesis and poor prognosis in EC patients. Mechanistically, TRPM2-AS could sponge miR-497-5p to release SPP1, thus promoting the proliferation, invasion and migration of EC cells and angiogenesis of HUVECs. Knockdown of TRPM2-AS in xenograft mouse model inhibited tumor proliferation and angiogenesis in vivo. In addition, TRPM2-AS plays a vital role in regulating the tumor immune microenvironment of EC, overexpression of TRPM2-AS in EC cells stimulated the polarization of M2 macrophages and angiogenesis through secreting SPP1 enriched exosomes.
Conclusion: The depletion of TRPM2-AS inhibits the oncogenicity of EC by targeting the miR-497-5p/SPP1 axis. This study offers a better understanding of TRPM2-AS’s role in regulating angiogenesis and provides a novel target for EC treatment.
Keywords LncRNA TRPM2-AS, Endometrial carcinoma, Angiogenesis, MiR-497-5p, SPP1
Address and Contact Information 1 Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
2 Shanghai Key Laboratory of Embryo Original Diseases, Shanghai 200030, China
3 Department of Obstetrics and Gynecology, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai 200065, China
4 Department of Obstetrics and Gynecology, Shangyu People’s Hospital of Shaoxing, Zhejiang 312300, China
*Corresponding author: huaifangli@126.com; yinanyao@126.com; drtracy80@sina.com
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No.  94DOI: 10.1186/s11658-024-00609-2 Volume 29 (2024) - 29:94
Title IMPAIRMENT OF α-TUBULIN AND F-ACTIN INTERACTIONS OF GJB3 INDUCES ANEUPLOIDY IN UROTHELIAL CELLS AND PROMOTES BLADDER CANCER CELL INVASION
Authors Junnan Liu1,7†, Xue Wang1,8†, Wencheng Jiang1, Anca Azoitei1, Tim Eiseler2, Markus Eckstein3, Arndt Hartmann3, Stephan Stilgenbauer4, Mohamed Elati5, Meike Hohwieler6, Alexander Kleger6, Axel John1, Felix Wezel1, Friedemann Zengerling1, Christian Bolenz1 and Cagatay Günes1*
Abstract Background: We have previously identified an unsuspected role for GJB3 showing that the deficiency of this connexin protein induces aneuploidy in human and murine cells and accelerates cell transformation as well as tumor formation in xenograft models. The molecular mechanisms by which loss of GJB3 leads to aneuploidy and cancer initiation and progression remain unsolved.
Methods: GJB3 expression levels were determined by RT-qPCR and Western blot. The consequences of GJB3 knockdown on genome instability were assessed by metaphase chromosome counting, multinucleation of cells, by micronuclei formation and by the determination of spindle orientation. Interactions of GJB3 with α-tubulin and F-actin was analyzed by immunoprecipitation and immunocytochemistry. Consequences of GJB3 deficiency on microtubule and actin dynamics were measured by live cell imaging and fluorescence recovery after photobleaching experiments, respectively. Immunohistochemistry was used to determine GJB3 levels on human and murine bladder cancer tissue sections. Bladder cancer in mice was chemically induced by BBN-treatment.
Results: We find that GJB3 is highly expressed in the ureter and bladder epithelium, but it is downregulated in invasive bladder cancer cell lines and during tumor progression in both human and mouse bladder cancer. Downregulation of GJB3 expression leads to aneuploidy and genomic instability in karyotypically stable urothelial cells and experimental modulation of GJB3 levels alters the migration and invasive capacity of bladder cancer cell lines. Importantly, GJB3 interacts both with α-tubulin and F-actin. The impairment of these interactions alters the dynamics of these cytoskeletal components and leads to defective spindle orientation.
Conclusion: We conclude that deregulated microtubule and actin dynamics have an impact on proper chromosome separation and tumor cell invasion and migration. Consequently, these observations indicate a possible role for GJB3 in the onset and spreading of bladder cancer and demonstrate a molecular link between enhanced aneuploidy and invasive capacity cancer cells during tumor cell dissemination.
Keywords Spindle orientation, Chromosomal imbalance, Invadopodia, Metastasis, MIBC
Address and Contact Information 1 Department of Urology, Ulm University Hospital, Helmholtzstr. 10, 89081 Ulm, Germany
2 Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
3 Institute of Pathology, Friedrich-Alexander University, Erlangen, Germany
4 Department of Internal Medicine III, Ulm University, Ulm, Germany
5 CANTHER, ONCOLille Institute, University of Lille, CNRS, UMR 1277, Inserm U9020, 59045 Lille Cedex, France
6 Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany
7 Present Address: Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
8 Present Address: Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
*Corresponding author: Cagatay.guenes@uniklinik-ulm.de
† Junnan Liu and Xue Wang have contributed equally to this work.
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No.  95DOI: 10.1186/s11658-024-00610-9 Volume 29 (2024) - 29:95
Title RUNX1, FUS, AND ELAVL1-INDUCED circPTPN22 PROMOTE GASTRIC CANCER CELL PROLIFERATION, MIGRATION, AND INVASION THROUGH miR-6788-5p/PAK1 AXIS-MEDIATED AUTOPHAGY
Authors Shuo Ma1,2,3†, Yanhua Xu1,4†, Xinyue Qin1, Mei Tao1, Xinliang Gu1, Lei Shen1, Yinhao Chen5, Ming Zheng1, Shiyi Qin1, Guoqiu Wu2,3* and Shaoqing Ju1*
Abstract Background: An increasing number of studies have demonstrated the association of circular RNAs (circRNAs) with the pathological processes of various diseases and their involvement in the onset and progression of multiple cancers. Nevertheless, the functional roles and underlying mechanisms of circRNAs in the autophagy regulation of gastric cancer (GC) have not been fully elucidated.
Methods: We used transmission electron microscopy and the mRFP-GFP-LC3 dual fluorescent autophagy indicator to investigate autophagy regulation. The cell counting kit-8 assay, colony formation assay, 5-ethynyl-2′-deoxyuridine incorporation assay, Transwell assay, and Western blot assay were conducted to confirm circPTPN22’s influence on GC progression. Dual luciferase reporter assays validated the binding between circPTPN22 and miR-6788-5p, as well as miR-6788-5p and p21-activated kinase-1 (PAK1). Functional rescue experiments assessed whether circPTPN22 modulates PAK1 expression by competitively binding miR-6788-5p, affecting autophagy and other biological processes in GC cells. We investigated the impact of circPTPN22 on in vivo GC tumors using a nude mouse xenograft model. Bioinformatics tools predicted upstream regulatory transcription factors and binding proteins of circPTPN22, while chromatin immunoprecipitation and ribonucleoprotein immunoprecipitation assays confirmed the binding status.
Results: Upregulation of circPTPN22 in GC has been shown to inhibit autophagy and promote cell proliferation, migration, and invasion. Mechanistically, circPTPN22 directly binds to miR-6788-5p, subsequently regulating the expression of PAK1, which activates protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) phosphorylation. This modulation ultimately affects autophagy levels in GC cells. Additionally, runt-related transcription factor 1 (RUNX1) negatively regulates circPTPN22 expression, while RNA-binding proteins such as FUS (fused in sarcoma) and ELAVL1 (recombinant ELAV-like protein 1) positively regulate its expression. Inhibition of the autophagy pathway can increase FUS expression, further upregulating circPTPN22 in GC cells, thereby exacerbating the progression of GC.
Conclusion: Under the regulation of the transcription factor RUNX1 and RNA-binding proteins FUS and ELAVL1, circPTPN22 activates the phosphorylation of Akt and Erk through the miR-6788-5p/PAK1 axis, thereby modulating autophagy in GC cells. Inhibition of autophagy increases FUS, which in turn upregulates circPTPN22, forming a positive feedback loop that ultimately accelerates the progression of GC.
Keywords circPTPN22, Gastric cancer, Autophagy, miR-6788-5p, PAK1
Address and Contact Information 1 Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, NO.20, Nantong 226001, Jiangsu, China
2 Center of Clinical Laboratory Medicine, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, Jiangsu, China
3 Diagnostics Department, Medical School of Southeast University, Nanjing 210009, Jiangsu, China
4 Department of Laboratory Medicine, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou 225000, Jiangsu, China
5 Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital Bonn, Bonn, Germany
*Corresponding author: 101008404@seu.edu.cn; jsq814@hotmail.com
† Shuo Ma and Yanhua Xu contributed equally to this article.
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No.  96DOI: 10.1186/s11658-024-00620-7 Volume 29 (2024) - 29:96
Title CORRECTION: LOW-INTENSITY PULSED ULTRASOUND (LIPUS) ENHANCES THE ANTI-INFLAMMATORY EFFECTS OF BONE MARROW MESENCHYMAL STEM CELLS (BMSCs)-DERIVED EXTRACELLULAR VESICLES
Authors Xueke Li1,2,3†, Yi Zhong1,2,3†, Wuqi Zhou1,2,3, Yishu Song1,2,3, Wenqu Li1,2,3, Qiaofeng Jin1,2,3, Tang Gao1,2,3, Li Zhang1,2,3* and Mingxing Xie1,2,3*
Abstract Correction: Cellular & Molecular Biology Letters (2023) 28:9 https://doi.org/10.1186/s11658-023-00422-3
Following publication of the original article [1], the authors identifed an error in Fig. 3D. The pictures used in the C-EVs and LIPUS-EVs groups of CD11b+ in Fig. 3D were inadvertently placed by mistake. We have double checked the original data and found that the inadvertent errors occurred during picture compilation, and this correction does not afect the scientifc conclusions of the article.
Keywords circPTPN22, Gastric cancer, Autophagy, miR-6788-5p, PAK1
Address and Contact Information 1 Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
2 Clinical Research Center for Medical Imaging in Hubei Province, Wuhan 430022, China
3 Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
*Corresponding author: zli429@hust.edu.cn; xiemx@hust.edu.cn
† Xueke Li and Yi Zhong have contributed equally to this work.
The original article can be found online at https://doi.org/10.1186/s11658-023-00422-3.
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No.  97DOI: 10.1186/s11658-024-00611-8 Volume 29 (2024) - 29:97
Title WTAP/IGF2BP3-MEDIATED GBE1 EXPRESSION ACCELERATES THE PROLIFERATION AND ENHANCES STEMNESS IN PANCREATIC CANCER CELLS VIA UPREGULATING c-Myc
Authors Weiwei Jin1,2†, Yanru Yao3†, Yuhan Fu3†, Xiangxiang Lei3, Wen Fu4, Qiliang Lu4, Xiangmin Tong1, Qiuran Xu1*,Wei Su5,6* and Xiaoge Hu1*
Abstract Background: Pancreatic cancer (PC) is one of the most malignant cancers with highly aggressiveness and poor prognosis. N6-methyladenosine (m6A) have been indicated to be involved in PC development. Glucan Branching Enzyme 1 (GBE1) is mainly involved in cell glycogen metabolism. However, the function of GBE1 and Whether GBE1 occurs m6A modification in PC progression remains to be illustrated.
Methods: The clinical prognosis of GBE1 was analyzed through online platform. The expression of GBE1 was obtained from online platform and then verified in normal and PC cell lines. Lentivirus was used to generated GBE1 stable-overexpression or knockdown PC cells. Cell Counting Kit (CCK-8), colony formation assay, sphere formation assay and flow cytometry assay were conducted to analyze cell proliferation and stemness ability in vitro. Subcutaneous and orthotopic mouse models were used to verify the function of GBE1 in vivo. RNA immunoprecipitation (RIP) assay, RNA stability experiment and western blots were conducted to explore the molecular regulation of GBE1 in PC.
Results: GBE1 was significantly upregulated in PC and associated with poor prognosis of PC patients. Functionally, GBE1 overexpression facilitated PC cell proliferation and stemness-like properties, while knockdown of GBE1 attenuated the malignancy of PC cells. Importantly, we found the m6A modification of GBE1 RNA, and WTAP and IGF2BP3 was revealed as the m6A regulators to increase GBE1 mRNA stability and expression. Furthermore, c-Myc was discovered as a downstream gene of GBE1 and functional rescue experiments showed that overexpression of c-Myc could rescue GBE1 knockdown-induced PC cell growth inhibition.
Conclusions: Our study uncovered the oncogenic role of GBE1/c-Myc axis in PC progression and revealed WTAP/IGF2BP3-mediated m6A modification of GBE1, which highlight the potential application of GBE1 in the targeted therapy of PC.
Keywords Pancreatic cancer, GBE1, m6A modifcation, IGF2BP3, WTAP, Proliferation
Address and Contact Information 1 Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
2 General Surgery, Cancer Center, Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
3 Hangzhou Medical College, Hangzhou, China
4 The Medical College of Qingdao University, Qingdao, China
5 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
6 Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
*Corresponding author: xuqiuran@hmc.edu.cn; sagowei@outlook.com; huxiaoge2008xmu@163.com
† Weiwei Jin, Yanru Yao and Yuhan Fu contribute equally to this study.
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No.  98DOI: 10.1186/s11658-024-00613-6 Volume 29 (2024) - 29:98
Title EMERGING ROLE OF GLUTATHIONE PEROXIDASE 4 IN MYELOID CELL LINEAGE DEVELOPMENT AND ACUTE MYELOID LEUKEMIA
Authors Patrick Auberger1,2*†, Cécile Favreau3, Coline Savy1,2, Arnaud Jacquel1,2 and Guillaume Robert1,2*†
Abstract Phospholipid Hydroperoxide Gluthatione Peroxidase also called Glutathione Peroxidase 4 is one of the 25 described human selenoproteins. It plays an essential role in eliminating toxic lipid hydroxy peroxides, thus inhibiting ferroptosis and favoring cell survival. GPX4 is differentially expressed according to myeloid differentiation stage, exhibiting lower expression in hematopoietic stem cells and polymorphonuclear leucocytes, while harboring higher level of expression in common myeloid progenitors and monocytes. In addition, GPX4 is highly expressed in most of acute myeloid leukemia (AML) subtypes compared to normal hematopoietic stem cells. High GPX4 expression is consistently correlated to poor prognosis in patients suffering AML. However, the role of GPX4 in the development of the myeloid lineage and in the initiation and progression of myeloid leukemia remains poorly explored. Given its essential role in the detoxification of lipid hydroperoxides, and its overexpression in most of myeloid malignancies, GPX4 inhibition has emerged as a promising therapeutic strategy to specifically trigger ferroptosis and eradicate myeloid leukemia cells. In this review, we describe the most recent advances concerning the role of GPX4 and, more generally ferroptosis in the myeloid lineage and in the emergence of AML. We also discuss the therapeutic interest and limitations of GPX4 inhibition alone or in combination with other drugs as innovative therapies to treat AML patients.
Keywords GPX4, Ferroptosis, Myeloid diferentiation, Myeloid leukemia, AML, Small molecule inhibitors, Therapeutic strategies
Address and Contact Information 1 University of Nice Cote d’Azur (UniCA), Nice, France
2 Mediterranean Centre for Molecular Medicine, C3M, Inserm U1065, Team 2 “Innovative Therapies in Myeloid Leukemia”, Nice, France
3 Centre Hospitalier Universitaire, Nice, France
*Corresponding author: patrick.auberger@inserm.fr; guillaume.robert@inserm.fr
† Patrick Auberger and Guillaume Robert contributed equally.
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No.  99DOI: 10.1186/s11658-024-00618-1 Volume 29 (2024) - 29:99
Title EPIGENETIC CONTROL OF SKELETAL MUSCLE ATROPHY
Authors Wenpeng Liang1,2†, Feng Xu3†, Li Li4, Chunlei Peng5, Hualin Sun1, Jiaying Qiu2* and Junjie Sun1*
Abstract Skeletal muscular atrophy is a complex disease involving a large number of gene expression regulatory networks and various biological processes. Despite extensive research on this topic, its underlying mechanisms remain elusive, and effective therapeutic approaches are yet to be established. Recent studies have shown that epigenetics play an important role in regulating skeletal muscle atrophy, influencing the expression of numerous genes associated with this condition through the addition or removal of certain chemical modifications at the molecular level. This review article comprehensively summarizes the different types of modifications to DNA, histones, RNA, and their known regulators. We also discuss how epigenetic modifications change during the process of skeletal muscle atrophy, the molecular mechanisms by which epigenetic regulatory proteins control skeletal muscle atrophy, and assess their translational potential. The role of epigenetics on muscle stem cells is also highlighted. In addition, we propose that alternative splicing interacts with epigenetic mechanisms to regulate skeletal muscle mass, offering a novel perspective that enhances our understanding of epigenetic inheritance’s role and the regulatory network governing skeletal muscle atrophy. Collectively, advancements in the understanding of epigenetic mechanisms provide invaluable insights into the study of skeletal muscle atrophy. Moreover, this knowledge paves the way for identifying new avenues for the development of more effective therapeutic strategies and pharmaceutical interventions.
Keywords Skeletal muscle atrophy, epigenetic, Ubiquitin–proteasome, m6A, Histone modifcations
Address and Contact Information 1 Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co‐Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 26001, China
2 Department of Prenatal Screening and Diagnosis Center, Afliated Maternity and Child Health Care Hospital of Nantong University, Nantong 226001, China
3 Department of Endocrinology, Afliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong 226001, China
4 Nantong Center for Disease Control and Prevention, Medical School of Nantong University, Nantong 226001, China
5 Department of Medical Oncology, Tumor Hospital Afliated to Nantong University, Nantong 226000, China
*Correspondence: qiujiaying@ntu.edu.cn; jjsun@ntu.edu.cn
† Wenpeng Liang and Feng Xu have contributed equally to this work.
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No.  100DOI: 10.1186/s11658-024-00614-5 Volume 29 (2024) - 29:100
Title NEW MECHANISTIC UNDERSTANDING OF OSTEOCLAST DIFFERENTIATION AND BONE RESORPTION MEDIATED BY P2X7 RECEPTORS AND PI3K-Akt-GSK3β SIGNALING
Authors Jiajia Lu1,2†, Xiaojian Shi3†, Qiang Fu2†, Yaguang Han2†, Lei Zhu2†, Zhibin Zhou4*, Yongchuan Li1* and Nan Lu1*
Abstract Objective: Osteoporosis is a global health issue characterized by decreased bone mass and microstructural degradation, leading to an increased risk of fractures. This study aims to explore the molecular mechanism by which P2X7 receptors influence osteoclast formation and bone resorption through the PI3K-Akt-GSK3β signaling pathway.
Methods: An osteoporosis mouse model was generated through ovariectomy (OVX) in normal C57BL/6 and P2X7f/f; LysM-cre mice. Osteoclasts were isolated for transcriptomic analysis, and differentially expressed genes were selected for functional enrichment analysis. Metabolite analysis was performed using liquid chromatography-tandem mass spectrometry (LC–MS/MS), and multivariate statistical analysis and pattern recognition were used to identify differential lipid metabolism markers and their distribution. Bioinformatics analyses were conducted using the Encyclopedia of Genes and Genomes database and the MetaboAnalyst database to assess potential biomarkers and create a metabolic pathway map. Osteoclast precursor cells were used for in vitro cell experiments, evaluating cell viability and proliferation using the Cell Counting Kit 8 (CCK-8) assay. Osteoclast precursor cells were induced to differentiate into osteoclasts using macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-beta ligand (RANKL), and tartrate-resistant acid phosphatase (TRAP) staining was performed to compare differentiation morphology, size, and quantity between different groups. Western blot analysis was used to assess the expression of differentiation markers, fusion gene markers, and bone resorption ability markers in osteoclasts. Immunofluorescence staining was employed to examine the spatial distribution and quantity of osteoclast cell skeletons, P2X7 protein, and cell nuclei, while pit assay was used to evaluate osteoclast bone resorption ability. Finally, in vivo animal experiments, including micro computed tomography (micro-CT), hematoxylin and eosin (HE) staining, TRAP staining, and immunohistochemistry, were conducted to observe bone tissue morphology, osteoclast differentiation, and the phosphorylation level of the PI3K-Akt-GSK3β signaling pathway.
Results: Transcriptomic and metabolomic data collectively reveal that the P2X7 receptor can impact the pathogenesis of osteoporosis through the PI3K-Akt-GSK3β signaling pathway. Subsequent in vitro experiments showed that cells in the Sh-P2X7 + Recilisib group exhibited increased proliferative activity (1.15 versus 0.59), higher absorbance levels (0.68 versus 0.34), and a significant increase in resorption pit area (13.94 versus 3.50). Expression levels of osteoclast differentiation-related proteins MMP-9, CK, and NFATc1 were markedly elevated (MMP-9: 1.72 versus 0.96; CK: 2.54 versus 0.95; NFATc1: 3.05 versus 0.95), along with increased fluorescent intensity of F-actin rings. In contrast, the OE-P2X7 + LY294002 group showed decreased proliferative activity (0.64 versus 1.29), reduced absorbance (0.34 versus 0.82), and a significant decrease in resorption pit area (5.01 versus 14.96), accompanied by weakened expression of MMP-9, CK, and NFATc1 (MMP-9: 1.14 versus 1.79; CK: 1.26 versus 2.75; NFATc1: 1.17 versus 2.90) and decreased F-actin fluorescent intensity. Furthermore, in vivo animal experiments demonstrated that compared with the wild type (WT) + Sham group, mice in the WT + OVX group exhibited significantly increased levels of CTX and NTX in serum (CTX: 587.17 versus 129.33; NTX: 386.00 versus 98.83), a notable decrease in calcium deposition (19.67 versus 53.83), significant reduction in bone density, increased trabecular separation, and lowered bone mineral density (BMD). When compared with the KO + OVX group, mice in the KO + OVX + recilisib group showed a substantial increase in CTX and NTX levels in serum (CTX: 503.50 versus 209.83; NTX: 339.83 versus 127.00), further reduction in calcium deposition (29.67 versus 45.33), as well as decreased bone density, increased trabecular separation, and reduced BMD.
Conclusion: P2X7 receptors positively regulate osteoclast formation and bone resorption by activating the PI3K-Akt-GSK3β signaling pathway.
Keywords Osteoporosis, Osteoclasts, P2X7 receptors, PI3K-Akt-GSK3β signaling pathway, Transcriptomics, Metabolomics
Address and Contact Information 1 Department of Orthopedic Trauma, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, 1279 Sanmen Road, Shanghai 200434, China
2 Department of Orthopedic Trauma, Shanghai Changzheng Hospital, Shanghai 200434, China
3 Department of Orthopedic Trauma, Haimen People’s Hospital of Jiangsu Province, Nantong 226100, China
4 Department of Orthopaedics, General Hospital of Northern Theater Command, No. 83, Culture Road, Shenhe District, Shenyang 110016, Liaoning, China
*Corresponding author: Zhibin_zhou0613@163.com; lyccyl229@tongji.edu.cn; nanlu_1981@tongji.edu.cn
† Jiajia Lu, Xiaojian Shi, Qiang Fu, Yaguang Han, and Lei Zhu are co-first authors.
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No.  101DOI: 10.1186/s11658-024-00617-2 Volume 29 (2024) - 29:101
Title THE MARINE-DERIVED HIF-1α INHIBITOR, YARDENONE 2, REDUCES PROSTATE CANCER CELL PROLIFERATION BY TARGETING HIF-1 TARGET GENES
Authors Siyong Peng1,2, Yingbo Guo1,2, Marie Irondelle1,2, Abigail Mazzu1,2, Michel Kahi1,2, Paula Ferreira Montenegro3, Frédéric Bost1,2 and Nathalie M. Mazure1,2*
Abstract Background: Prostate cancer (PCa) ranks as the second most prevalent cancer in men, with advanced stages posing significant treatment challenges. Given its solid tumor nature, PCa is highly susceptible to hypoxia, a condition associated with resistance to radiation and chemotherapy, metastasis, and unfavorable patient outcomes. Hypoxia-inducible factors (HIFs) play a pivotal role in cancer cell adaptation to hypoxic environments, contributing to treatment resistance. Consequently, inhibitors targeting HIFs hold promise for cancer therapy.
Methods: In this study, we aimed to characterize novel HIF-1α inhibitors including Sodwanones A (1), B (2), C (3), G (4) and Yardenone 2 (5) isolated from marine sponges belonging to the Axinella genus. Our investigation evaluated the impact of these compounds on various aspects of HIF-1α regulation, including stabilization, nuclear localization, expression of HIF-1 target genes (while sparing HIF-2 target genes), cellular metabolism, as well as cell proliferation and viability in prostate cells under hypoxic conditions.
Results: Our findings revealed that among the compounds tested, Yardenone 2 exhibited notable effects in hypoxia: it destabilized HIF-1α at the protein level, decreased its nuclear localization, selectively altered the expression of HIF-1 target genes, and restrained cell proliferation in aggressive PC3 prostate cancer cells as well as in an MSK-PCa3 patient-derived organoid line. Moreover, it affected the morphology of these organoid. Yardenone 2 was also compared to Docetaxel, a specific microtubule inhibitor and a drug used in the treatment of prostate cancer. The comparison between the two compounds revealed notable differences, such as a lack of specificity to hypoxic cells of Docetaxel.
Conclusion: These results mark the first demonstration that Yardenone 2 functions as a cytostatic-like inhibitor impacting microtubules, specifically targeting hypoxic cancer cells. This discovery suggests a promising avenue for novel therapeutic interventions in prostate cancer.
Keywords Docetaxel, HIF-1 inhibitor, Hypoxia, Marine microenvironment, Microtubules, Prostate cancer, Yardenone
Address and Contact Information 1 Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale, Nice, France
2 Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Labellisée Ligue Nationale Contre le Cancer, Nice, France
3 Institut de Chimie de Nice, Université Côte d’Azur, CNRS UMR 7272, 06108 Nice, France
*Corresponding author: Nathalie.mazure@univ-cotedazur.fr
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No.  102DOI: 10.1186/s11658-024-00621-6 Volume 29 (2024) - 29:102
Title CORRECTION: METHYLATED lncRNAs SUPPRESS APOPTOSIS OF GASTRIC CANCER STEM CELLS VIA THE lncRNA–miRNA/PROTEIN AXIS
Authors Yuan Ci1, Yuan Zhang1 and Xiaobo Zhang1*
Abstract Correction:Cellular & Molecular Biology Letters (2024) 29:51
https://doi.org/10.1186/s11658-024-00568-8
Following publication of the original article [1], the authors identifed that an incorrect image was used for the control “β-tubulin” of the 4th lane “METTL3-silenced GCSC-HGC MIR22HG” of Fig. 3M.
Keywords
Address and Contact Information 1 College of Life Sciences, Laboratory for Marine Biology and Biotechnology of Pilot National Laboratory for Marine Science and Technology (Qingdao), Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhejiang University, Hangzhou 310058, People’s Republic of China
*Corresponding author: zxb0812@zju.edu.cn
The original article can be found online at https://doi.org/10.1186/s11658-024-00568-8.
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No.  103DOI: 10.1186/s11658-024-00616-3 Volume 29 (2024) - 29:103
Title EXTRACHROMOSOMAL CIRCULAR DNA PROMOTES PROSTATE CANCER PROGRESSION THROUGH THE FAM84B/CDKN1B/MYC/WWP1 AXIS
Authors Wei Jin1, Zhenqun Xu1, Yan Song1 and Fangjie Chen2*
Abstract Background: Extrachromosomal circular DNA (eccDNA), a kind of circular DNA that originates from chromosomes, carries complete gene information, particularly the oncogenic genes. This study aimed to examine the contributions of FAM84B induced by eccDNA to prostate cancer (PCa) development and the biomolecules involved.
Methods: The presence of eccDNA in PCa cells and the FAM84B transcripts that eccDNA carries were verified by outward and inward PCR. The effect of inhibition of eccDNA synthesis on FAM84B expression in PCa cells was analyzed by knocking down Lig3. The impact of FAM84B on the growth and metastases of PCa cells was verified by Cell Counting Kit-8 (CCK8), EdU, transwell assays, and a xenograft mouse model. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) and dual-luciferase reporter assays were carried out to examine the effect of FAM84B/MYC on WWP1 transcription, and a co-immunoprecipitation (Co-IP) assay was conducted to verify the modification of CDKN1B by WWP1. The function of this molecular axis in PCa was explored by rescue assays.
Results: The inhibited eccDNA synthesis significantly downregulated FAM84B in PCa cells, thereby attenuating the growth and metastasis of PCa. FAM84B promoted the transcription of WWP1 by MYC by activating the expression of MYC coterminous with the 8q24.21 gene desert in a beta catenin-dependent approach. WWP1 transcription promoted by MYC facilitated the ubiquitination and degradation of CDKN1B protein and inversely attenuated the repressive effect of CDKN1B on MYC expression. Exogenous overexpression of CDKN1B blocked FAM84B-activated MYC/WWP1 expression, thereby inhibiting PCa progression.
Conclusions: FAM84B promoted by eccDNA mediates degradation of CDKN1B via MYC/WWP1, thereby accelerating PCa progression.
Keywords Extrachromosomal circular DNA, FAM84B, Prostate cancer, CDKN1B, MYC/ WWP1
Address and Contact Information 1 Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110001, Liaoning, People’s Republic of China
2 Department of Medical Genetics, China Medical University, No. 77, Puhe Road, Shenbei New District, Shenyang 110022, Liaoning, People’s Republic of China
*Corresponding author: chenf@cmu.edu.cn
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No.  104DOI: 10.1186/s11658-024-00615-4 Volume 29 (2024) - 29:104
Title BIOPHYSICAL CHARACTERIZATION OF THE PHASE SEPARATION OF TDP-43 DEVOID OF THE C-TERMINAL DOMAIN
Authors Tommaso Staderini1,2,3, Alessandra Bigi1, Clément Lagrève1,4, Isabella Marzi1, Francesco Bemporad1 and Fabrizio Chiti1*
Abstract Background: Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP), amyotrophic lateral sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE) are associated with deposition of cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons. One complexity of this process lies in the ability of TDP-43 to form liquid-phase membraneless organelles in cells. Previous work has shown that the recombinant, purified, prion-like domain (PrLD) forms liquid droplets in vitro, but the behaviour of the complementary fragment is uncertain.
Methods: We have purified such a construct without the PrLD (PrLD-less TDP-43) and have induced its phase separation using a solution-jump method and an array of biophysical techniques to study the morphology, state of matter and structure of the TDP-43 assemblies.
Results: The fluorescent TMR-labelled protein construct, imaged using confocal fluorescence, formed rapidly (< 1 min) round, homogeneous and 0.5–1.0 µm wide assemblies which then coalesced into larger, yet round, species. When labelled with AlexaFluor488, they initially exhibited fluorescence recovery after photobleaching (FRAP), showing a liquid behaviour distinct from full-length TDP-43 and similar to PrLD. The protein molecules did not undergo major structural changes, as determined with circular dichroism and intrinsic fluorescence spectroscopies. This process had a pH and salt dependence distinct from those of full-length TDP-43 and its PrLD, which can be rationalized on the grounds of electrostatic forces.
Conclusions: Similarly to PrLD, PrLD-less TDP-43 forms liquid droplets in vitro through liquid–liquid phase separation (LLPS), unlike the full-length protein that rather undergoes liquid–solid phase separation (LSPS). These results offer a rationale of the complex electrostatic forces governing phase separation of full-length TDP-43 and its fragments. On the one hand, PrLD-less TDP-43 has a low pI and oppositively charged domains, and LLPS is inhibited by salts, which attenuate inter-domain electrostatic attractions. On the other hand, PrLD is positively charged due to a high isoionic point (pI) and LLPS is therefore promoted by salts and pH increases as they both reduce electrostatic repulsions. By contrast, full-length TDP-43 undergoes LSPS most favourably at its pI, with positive and negative salt dependences at lower and higher pH, respectively, depending on whether repulsive or attractive forces dominate, respectively.
Keywords Liquid–liquid phase separation, LLPS, Liquid–solid phase separation, Self- assembly, Motor neuron diseases, Electrostatics, RNA-binding proteins
Address and Contact Information 1 Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
2 Present Address: Department of Chemistry “Ugo Schif”, University of Florence, 50019 Florence, Italy
3 Present Address: Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, 50019 Florence, Italy
4 Present Address: Chimie ParisTech-PSL, École Nationale Supérieur de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris, France
*Corresponding author: fabrizio.chiti@unif.it
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No.  105DOI: 10.1186/s11658-024-00619-0 Volume 29 (2024) - 29:105
Title MONITORING CORRELATES OF SARS-CoV-2 INFECTION IN CELL CULTURE USING A TWO-PHOTON-ACTIVE CALCIUM-SENSITIVE DYE
Authors Domokos Máthé1,2,3*†, Gergely Szalay4,5†, Levente Cseri5,6†, Zoltán Kis7, Bernadett Pályi7, Gábor Földes8,9, Noémi Kovács2, Anna Fülöp6, Áron Szepesi4,5, Polett Hajdrik1, Attila Csomos6,10, Ákos Zsembery11, Kristóf Kádár11, Gergely Katona12, Zoltán Mucsi5,6,13*, Balázs József Rózsa4,5,12* and Ervin Kovács12,14*
Abstract Background: The organism-wide effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection are well studied, but little is known about the dynamics of how the infection spreads in time among or within cells due to the scarcity of suitable high-resolution experimental systems. It has been reported that SARS-CoV-2 infection pathways converge at calcium influx and subcellular calcium distribution changes. Imaging combined with a proper staining technique is an effective tool for studying subcellular calcium-related infection and replication mechanisms at such resolutions.
Methods: Using two-photon (2P) fluorescence imaging with our novel Ca-selective dye, automated image analysis and clustering analysis were applied to reveal titer and variant effects on SARS-CoV-2-infected Vero E6 cells.
Results: The application of a new calcium sensor molecule is shown, combined with a high-end 2P technique for imaging and identifying the patterns associated with cellular infection damage within cells. Vero E6 cells infected with SARS-CoV-2 variants, D614G or B.1.1.7, exhibit elevated cytosolic calcium levels, allowing infection monitoring by tracking the cellular changes in calcium level by the internalized calcium sensor. The imaging provides valuable information on how the level and intracellular distribution of calcium are perturbed during the infection. Moreover, two-photon calcium sensing allowed the distinction of infections by two studied viral variants via cluster analysis of the image parameters. This approach will facilitate the study of cellular correlates of infection and their quantification depending on viral variants and viral load.
Conclusions: We propose a new two-photon microscopy-based method combined with a cell-internalized sensor to quantify the level of SARS-CoV-2 infection. We optimized the applied dye concentrations to not interfere with viral fusion and viral replication events. The presented method ensured the proper monitoring of viral infection, replication, and cell fate. It also enabled distinguishing intracellular details of cell damage, such as vacuole and apoptotic body formation. Using clustering analysis, 2P microscopy calcium fluorescence images were suitable to distinguish two different viral variants in cell cultures. Cellular harm levels read out by calcium imaging were quantitatively related to the initial viral multiplicity of infection numbers. Thus, 2P quantitative calcium imaging might be used as a correlate of infection or a correlate of activity in cellular antiviral studies.
Keywords Viral infections, SARS-CoV-2, Two-photon microscopy, Calcium sensors, Fluorescence imaging
Address and Contact Information 1 Department of Biophysics and Radiation Biology, Semmelweis University, Tűzoltó utca 37-47, 1094 Budapest, Hungary.
2 In Vivo Imaging Advanced Core Facility, Hungarian Centre of Excellence for Molecular Medicine, Tűzoltó utca 37-47, 1094 Budapest, Hungary.
3 HUN-REN Physical Virology Research Group, Semmelweis University, Tűzoltó utca 37-47, 1094 Budapest, Hungary.
4 Laboratory of 3D Functional Network and Dendritic Imaging, HUN-REN Institute of Experimental Medicine, Szigony utca 43, 1083 Budapest, Hungary.
5 BrainVisionCenter, Liliom utca 43-45, 1094 Budapest, Hungary.
6 Femtonics Ltd., Tűzoltó utca 59, 1094 Budapest, Hungary.
7 National Center for Public Health, Albert Flórián út 2-6, 1097 Budapest, Hungary.
8 National Heart and Lung Institute, Imperial College London, Du Cane Road, London W12 0NN, UK.
9 Heart and Vascular Center, Semmelweis University, Városmajor utca. 68, 1122 Budapest, Hungary.
10 Hevesy György PhD School of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, 1117 Budapest, Hungary.
11 Department of Oral Biology, Faculty of Dentistry, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary.
12 Two-Photon Measurement Technology Group, The Faculty of Information Technology, Pázmány Péter Catholic University, Szigony utca 50/A, 1083 Budapest, Hungary.
13 Institute of Chemistry, Faculty of Materials Science and Engineering, University of Miskolc, Egyetem tér 1, 3515 Miskolc, Hungary. 14Institute of Materials and Environmental Chemistry, HUN-REN Research Centre for Natural Sciences, Magyar Tudósok körútja 2, 1117 Budapest, Hungary.
*Corresponding author: mathe.domokos@med.semmelweis-univ.hu; zmucsi@femtonics.eu; rozsa.balazs@koki.hu; kovacs.ervin@ttk.hu
† Domokos Máthé, Gergely Szalay and Levente Cseri contributed equally to this work.
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No.  106DOI: 10.1186/s11658-024-00622-5 Volume 29 (2024) - 29:106
Title N6-methyladenosine-modified SRPK1 promotes aerobic glycolysis of lung adenocarcinoma via PKM splicing
Authors Anqi Wang1,2†, Yuanyuan Zeng1,2,3†, Weijie Zhang1,2, Jian Zhao1,2, Lirong Gao1,2, Jianjun Li1,2,3, Jianjie Zhu1,2,3, Zeyi Liu1,2,3* and Jian‐an Huang1,2,3*
Abstract Background: The RNA N6-methyladenosine (m6A) modification has become an essential hotspot in epigenetic modulation. Serine–arginine protein kinase 1 (SRPK1) is associated with the pathogenesis of various cancers. However, the m6A modification of SRPK1 and its association with the mechanism of in lung adenocarcinoma (LUAD) remains unclear.
Methods: Western blotting and polymerase chain reaction (PCR) analyses were carried out to identify gene and protein expression. m6A epitranscriptomic microarray was utilized to the assess m6A profile. Loss and gain-of-function assays were carried out elucidate the impact of METTL3 and SRPK1 on LUAD glycolysis and tumorigenesis. RNA immunoprecipitation (RIP), m6A RNA immunoprecipitation (MeRIP), and RNA stability tests were employed to elucidate the SRPK1’s METTL3-mediated m6A modification mechanism in LUAD. Metabolic quantification and co-immunoprecipitation assays were applied to investigate the molecular mechanism by which SRPK1 mediates LUAD metabolism.
Results: The epitranscriptomic microarray assay revealed that SRPK1 could be hypermethylated and upregulated in LUAD. The main transmethylase METTL3 was upregulated and induced the aberrant high m6A levels of SRPK1. Mechanistically, SRPK1’s m6A sites were directly methylated by METTL3, which also stabilized SRPK1 in an IGF2BP2-dependent manner. Methylated SRPK1 subsequently promoted LUAD progression through enhancing glycolysis. Further metabolic quantification, co-immunoprecipitation and western blot assays revealed that SRPK1 interacts with hnRNPA1, an important modulator of PKM splicing, and thus facilitates glycolysis by upregulating PKM2 in LUAD. Nevertheless, METTL3 inhibitor STM2457 can reverse the above effects in vitro and in vivo by suppressing SRPK1 and glycolysis in LUAD.
Conclusion: It was revealed that in LUAD, aberrantly expressed METTL3 upregulated SRPK1 levels via an m6A-IGF2BP2-dependent mechanism. METTL3-induced SRPK1 fostered LUAD cell proliferation by enhancing glycolysis, and the small-molecule inhibitor STM2457 of METTL3 could be an alternative novel therapeutic strategy for individuals with LUAD.
Keywords m6A modifcation, Glycolysis, METTL3, SRPK1, Lung adenocarcinoma
Address and Contact Information 1 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
2 Institute of Respiratory Diseases, Soochow University, Suzhou 215006, China
3 Suzhou Key Laboratory for Respiratory Diseases, Suzhou 215006, China
*Corresponding author: liuzeyisuda@163.com; zeyiliu@suda.edu.cn; huang_jian_an@163.com
† Anqi Wang and Yuanyuan Zeng contributed equally.
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No.  107DOI: 10.1186/s11658-024-00624-3 Volume 29 (2024) - 29:107
Title CROSSTALK BETWEEN SUMOylation AND OTHER POST-TRANSLATIONAL MODIFICATIONS IN BREAST CANCER
Authors Bajin Wei1†, Fan Yang2†, Luyang Yu3,4* and Cong Qiu3,4*
Abstract Breast cancer represents the most prevalent tumor type and a foremost cause of mortality among women globally. The complex pathophysiological processes of breast cancer tumorigenesis and progression are regulated by protein post-translational modifications (PTMs), which are triggered by different carcinogenic factors and signaling pathways, with small ubiquitin-like modifier (SUMOylation) emerging as a particularly pivotal player in this context. Recent studies have demonstrated that SUMOylation does not act alone, but interacts with other PTMs, such as phosphorylation, ubiquitination, acetylation, and methylation, thereby leading to the regulation of various pathological activities in breast cancer. This review explores novel and existing mechanisms of crosstalk between SUMOylation and other PTMs. Typically, SUMOylation is regulated by phosphorylation to exert feedback control, while also modulates subsequent ubiquitination, acetylation, or methylation. The crosstalk pairs in promoting or inhibiting breast cancer are protein-specific and site-specific. In mechanism, alterations in amino acid side chain charges, protein conformations, or the occupation of specific sites at specific domains or sites underlie the complex crosstalk. In summary, this review centers on elucidating the crosstalk between SUMOylation and other PTMs in breast cancer oncogenesis and progression and discuss the molecular mechanisms contributing to these interactions, offering insights into their potential applications in facilitating novel treatments for breast cancer.
Keywords Breast cancer, Post-translational modifcations, SUMOylation, Crosstalk
Address and Contact Information 1 The Department of Breast Surgery, Key Laboratory of Organ Transplantation, Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
2 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
3 MOE Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zijingang Campus, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
4 Cancer Center, Zhejiang University, Hangzhou, China
*Correspondence: luyangyu@zju.edu.cn; congqiu@zju.edu.cn
† Bajin Wei and Fan Yang contributed equally to this work.
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No.  108DOI: 10.1186/s11658-024-00625-2 Volume 29 (2024) - 29:108
Title PALMITOYLATION OF SYNAPTIC PROTEINS: ROLES IN FUNCTIONAL REGULATION AND PATHOGENESIS OF NEURODEGENERATIVE DISEASES
Authors Jiaying Peng1†, Danchan Liang1† and Zhonghao Zhang1,2*
Abstract Palmitoylation is a type of lipid modification that plays an important role in various aspects of neuronal function. Over the past few decades, several studies have shown that the palmitoylation of synaptic proteins is involved in neurotransmission and synaptic functions. Palmitoyl acyltransferases (PATs), which belong to the DHHC family, are major players in the regulation of palmitoylation. Dysregulated palmitoylation of synaptic proteins and mutated/dysregulated DHHC proteins are associated with several neurodegenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD). In this review, we summarize the recent discoveries on the subcellular distribution of DHHC proteins and analyze their expression patterns in different brain cells. In particular, this review discusses how palmitoylation of synaptic proteins regulates synaptic vesicle exocytotic fusion and the localization, clustering, and transport of several postsynaptic receptors, as well as the role of palmitoylation of other proteins in regulating synaptic proteins. Additionally, some of the specific known associations of these factors with neurodegenerative disorders are explored, with a few suggestions for the development of therapeutic strategies. Finally, this review provides possible directions for future research to reveal detailed and specific mechanisms underlying the roles of synaptic protein palmitoylation.
Keywords Palmitoylation, Synaptic proteins, Palmitoyl acyltransferases, DHHC, Neurodegenerative diseases
Address and Contact Information 1 Shenzhen Key Laboratory of Marine Bioresources and Ecology, Brain Disease and Big Data Research Institute, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China
2 Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China
*Corresponding author: zzh@szu.edu.cn
† Jiaying Peng and Danchan Liang contributed equally to this work.
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No.  109DOI: 10.1186/s11658-024-00628-z Volume 29 (2024) - 29:109
Title METTL3-MEDIATED m6A MODIFICATION OF circGLIS3 PROMOTES PROSTATE CANCER PROGRESSION AND REPRESENTS A POTENTIAL TARGET FOR ARSI THERAPY
Authors Xiaofeng Cheng1,2, Heng Yang1,2, Yujun Chen1,2, Zhenhao Zeng3, Yifu Liu1,2, Xiaochen Zhou1,2, Cheng Zhang1,2, An Xie1,2* and Gongxian Wang1,2*
Abstract Background: Circular RNAs (circRNAs) have been shown to be involved in tumorigenesis and progression. However, the role of circGLIS3 (hsa_circ_0002874) in prostate cancer (PCa) has yet not been reported.
Methods: Candidate circRNA were determined through comprehensive analysis of public datasets, PCa cell lines, and tissues data. A series of cellular functional assays, including CCK-8, colony formation, wound healing, and transwell assays were performed. Subsequently, RNA sequencing, RNA immunoprecipitation, methylated RNA immunoprecipitation, microRNA pulldown, luciferase reporter assay, and western blot were used to explore the underlying molecular mechanisms. Moreover, the xenograft tumor mouse model was established to elucidate the function of circGLIS3.
Results: CircGLIS3, derived from exon 2 of the parental GLIS3 gene, was identified as a novel oncogenic circRNA in PCa that was closely associated with the biochemical recurrence. Its expression levels were upregulated in PCa tissues and cell lines as well as enzalutamide high-resistant cells. The cellular functional assays revealed that circGLIS3 promoted PCa cell proliferation, migration, and invasion. METTL3-mediated N6-methyladenosine (m6A) modification maintained its upregulation by enhancing its stability. Mechanically, CircGLIS3 sponged miR-661 to upregulate MDM2, thus regulating the p53 signaling pathway to promote cell proliferation, migration, and invasion. Furthermore, in vitro and in vivo experiments, the knockdown of circGLIS3 improved the response of PCa cells to ARSI therapies such as enzalutamide.
Conclusions: METTL3-mediated m6A modification of circGLIS3 regulates the p53 signaling pathway via the miR-661/MDM2 axis, thereby facilitating PCa progression. Meanwhile, this study unveils a promising potential target for ARSI therapy for PCa.
Keywords Prostate cancer, Circular RNA, M6A modifcation, ARSI therapy
Address and Contact Information 1 Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, Jiangxi, China
2 Jiangxi Institute of Urology, Nanchang 330000, Jiangxi, China
3 Department of Urology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330000, Jiangxi, China
*Corresponding author: xiean1979@ncu.edu.cn; wanggx-mr@126.com
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No.  110DOI: 10.1186/s11658-024-00626-1 Volume 29 (2024) - 29:110
Title PTBP1 KNOCKDOWN IMPAIRS AUTOPHAGY FLUX AND INHIBITS GASTRIC CANCER PROGRESSION THROUGH TXNIP-MEDIATED OXIDATIVE STRESS
Authors Shimin Wang1†, Xiaolin Wang1†, Changhong Qin1, Ce Liang1, Wei Li2, Ai Ran1, Qiang Ma1, Xiaojuan Pan1, Feifei Yang1, Junwu Ren1, Bo Huang3, Yuying Liu1, Yuying Zhang1, Haiping Li1, Hao Ning1, Yan Jiang1 and Bin Xiao1*
Abstract Background: Gastric cancer (GC) is a prevalent malignant tumor, and the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) has been identified as a crucial factor in various tumor types. Moreover, abnormal autophagy levels have been shown to significantly impact tumorigenesis and progression. Despite this, the precise regulatory mechanism of PTBP1 in autophagy regulation in GC remains poorly understood.
Methods: To assess the expression of PTBP1 in GC, we employed a comprehensive approach utilizing western blot, real-time quantitative polymerase chain reaction (RT–qPCR), and bioinformatics analysis. To further identify the downstream target genes that bind to PTBP1 in GC cells, we utilized RNA immunoprecipitation coupled with sequencing (si-PTBP1 RNA-seq). To evaluate the impact of PTBP1 on gastric carcinogenesis, we conducted CCK-8 assays, colony formation assays, and GC xenograft mouse model assays. Additionally, we utilized a transmission electron microscope, immunofluorescence, flow cytometry, western blot, RT–qPCR, and GC xenograft mouse model experiments to elucidate the specific mechanism underlying PTBP1’s regulation of autophagy in GC.
Results: Our findings indicated that PTBP1 was significantly overexpressed in GC tissues compared with adjacent normal tissues. Silencing PTBP1 resulted in abnormal accumulation of autophagosomes, thereby inhibiting GC cell viability both in vitro and in vivo. Mechanistically, interference with PTBP1 promoted the stability of thioredoxin-interacting protein (TXNIP) mRNA, leading to increased TXNIP-mediated oxidative stress. Consequently, this impaired lysosomal function, ultimately resulting in blockage of autophagic flux. Furthermore, our results suggested that interference with PTBP1 enhanced the antitumor effects of chloroquine, both in vitro and in vivo.
Conclusion: PTBP1 knockdown impairs GC progression by directly binding to TXNIP mRNA and promoting its expression. Based on these results, PTBP1 emerges as a promising therapeutic target for GC.
Keywords GC, Autophagy, PTBP1, TXNIP, Chloroquine
Address and Contact Information 1 College of Pharmacy, Chongqing Medical University, Chongqing 400016, People’s Republic of China
2 Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing 400030, People’s Republic of China
3 Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou, People’s Republic of China
*Correspondinga author: binxiaocqmu@cqmu.edu.cn
† Shimin Wang and Xiaolin Wang have contributed equally to this work.
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No.  111DOI: 10.1186/s11658-024-00630-5 Volume 29 (2024) - 29:111
Title NXPH4 MEDIATED BY m5C CONTRIBUTES TO THE MALIGNANT CHARACTERISTICS OF COLORECTAL CANCER VIA INHIBITING HIF1A DEGRADATION
Authors Lei Yang1,2†, Jiawen Shi1†, Mingyang Zhong1,3†, Pingping Sun1,2, Xiaojing Zhang1,2, Zhengyi Lian1,3, Hang Yin1, Lijun Xu1,3, Guyin He1,3, Haiyan Xu1, Han Wu3, Ziheng Wang4, Kai Miao4* and Jianfei Huang1,2*
Abstract Objective: Colorectal cancer (CRC) is a form of malignancy that exhibits a comparatively elevated occurrence and fatality rate. Given the relatively slower progress in diagnostic and therapeutic approaches for CRC, there is a need to investigate more accurate and efficient biomarkers.
Methods: Core regulatory genes were screened using the TCGA database, and the expression of neurexophilin 4 (NXPH4) and its prognostic implications were validated using tissue microarray staining. The assessment of NXPH4 functions involved a range of experiments, including cellular, organoid, and murine models. Furthermore, a regulatory network between m5C, NXPH4, and HIF1A was established through several in vitro experiments.
Results: The overexpression of NXPH4 is associated with unfavorable prognoses in patients with CRC and hepatocellular carcinoma. Additionally, it facilitates the progression of malignant tumors both in laboratory settings and in living organisms of colorectal carcinoma. Our research also reveals that NXPH4 mRNA can avoid degradation through RNautophagy, relying on an m5C-dependent mechanism. Moreover, NXPH4 amplifies the HIF signaling pathway and stabilizes HIF1A by competitively binding to PHD4.
Conclusions: NXPH4, regulated by m5C, promotes malignant tumor progression and regulates the HIF pathway. Consequently, targeting NXPH4 through molecular therapies could potentially serve as an efficacious therapeutic strategy for the management of CRC exhibiting elevated NXPH4 expression.
Keywords NXPH4, m5C modifcation, Colorectal cancer (CRC), RNautophagy, HIF signaling pathway
Address and Contact Information 1 Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Department of Oncology, Medical School of Nantong University, Nantong 226001, Jiangsu, China
2 Department of Clinical Biobank and Institute of Oncology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
3 Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China
4 MOE Frontier Science Centre for Precision Oncology, University of Macau, Macau SAR 999078, China
*Corresponding author: kaimiao@um.edu.mo; jfhuang@ntu.edu.cn
† Lei Yang, Jiawen Shi and Mingyang Zhong contributed equally to this work.
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No.  112DOI: 10.1186/s11658-024-00629-y Volume 29 (2024) - 29:112
Title CLDN6 INHIBITS BREAST CANCER GROWTH AND METASTASIS THROUGH SREBP1-MEDIATED RAS PALMITOYLATION
Authors Qiu Jin1, Da Qi1, Mingzi Zhang2, Huinan Qu3, Yuan Dong1, Minghao Sun1 and Chengshi Quan1*
Abstract Background: Breast cancer (BC) ranks as the third most fatal malignant tumor worldwide, with a strong reliance on fatty acid metabolism. CLDN6, a candidate BC suppressor gene, was previously identified as a regulator of fatty acid biosynthesis; however, the underlying mechanism remains elusive. In this research, we aim to clarify the specific mechanism through which CLDN6 modulates fatty acid anabolism and its impact on BC growth and metastasis.
Methods: Cell function assays, tumor xenograft mouse models, and lung metastasis mouse models were conducted to evaluate BC growth and metastasis. Human palmitic acid assay, triglyceride assay, Nile red staining, and oil red O staining were employed to investigate fatty acid anabolism. Reverse transcription polymerase chain reaction (RT–PCR), western blot, immunohistochemistry (IHC) assay, nuclear fractionation, immunofluorescence (IF), immunoprecipitation and acyl–biotin exchange (IP-ABE), chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, and co-immunoprecipitation (Co-IP) were applied to elucidate the underlying molecular mechanism. Moreover, tissue microarrays of BC were analyzed to explore the clinical implications.
Results: We identified that CLDN6 inhibited BC growth and metastasis by impeding RAS palmitoylation both in vitro and in vivo. We proposed a unique theory suggesting that CLDN6 suppressed RAS palmitoylation through SREBP1-modulated de novo palmitic acid synthesis. Mechanistically, CLDN6 interacted with MAGI2 to prevent KLF5 from entering the nucleus, thereby restraining SREBF1 transcription. The downregulation of SREBP1 reduced de novo palmitic acid synthesis, hindering RAS palmitoylation and subsequent endosomal sorting complex required for transport (ESCRT)-mediated plasma membrane localization required for RAS oncogenic activation. Besides, targeting inhibition of RAS palmitoylation synergized with CLDN6 to repress BC progression.
Conclusions: Our findings provide compelling evidence that CLDN6 suppresses the palmitic acid-induced RAS palmitoylation through the MAGI2/KLF5/SREBP1 axis, thereby impeding BC malignant progression. These results propose a new insight that monitoring CLDN6 expression alongside targeting inhibition of palmitic acid-mediated palmitoylation could be a viable strategy for treating oncogenic RAS-driven BC.
Keywords CLDN6, SREBP1, Fatty acid, RAS, Palmitoylation, Breast cancer
Address and Contact Information 1 The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun 130021, Jilin, China
2 The Zilkha Neurogenetic Institute, Department of Physiology and Neuroscience Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles 90033, CA, US
3 Department of Histology and Embryology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun 130021, Jilin, China
*Corresponding author: quancs@jlu.edu.cn
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No.  113DOI: 10.1186/s11658-024-00623-4 Volume 29 (2024) - 29:113
Title TRIPTOLIDE-INDUCED CUPROPTOSIS IS A NOVEL ANTITUMOR STRATEGY FOR THE TREATMENT OF CERVICAL CANCER
Authors Yanxia Xiao1, Jiameng Yin1, Pu Liu1, Xin Zhang1, Yajun Lin1* and Jun Guo1*
Abstract Background:
Cuproptosis is a unique copper-dependent form of cell death that is highly correlated with the metabolic state of cells. Triptolide exerts pharmacological activity by altering the regulation of metal ions. Cuproptosis is poorly understood in cancer, so in this study, we explored whether triptolide could induce cuproptosis in cervical cancer cells.
Methods:
The human cervical cancer cell lines HeLa and SiHa, which primarily rely on oxidative phosphorylation, were treated with triptolide. Cell viability, proliferation and migration, copper levels and cuproptosis-related protein levels were evaluated in these cell lines. The copper ion chelator tetrathiomolybdate (TTM) was administered to determine whether it could reverse the cuproptosis induced by triptolide. In addition, a nude mouse cervical cancer xenograft model was established to determine the effects of triptolide on cuproptosis in isolated tumor tissues.
Results:
The copper concentration increased with triptolide treatment. The levels of cuproptosis -related proteins, such as FDX1, LIAS, and DLAT, in the HeLa and SiHa cell lines decreased with triptolide treatment. XIAP, the target of triptolide, played a role in cuproptosis by regulating COMMD1. The level of copper exporters (ATP7A/B) decreased, but the level of the copper importer (CTR1) did not change with triptolide treatment. Furthermore, triptolide inhibited cervical cancer growth and induced cuproptosis in vivo.
Conclusions:
In summary, we report a new antitumor mechanism by which triptolide disrupted intracellular copper homeostasis and induced cuproptosis in cervical cancer by regulating the XIAP/COMMD1/ATP7A/B axis.
Keywords Cuproptosis, Triptolide, XIAP, COMMD1, Cervical cancer
Address and Contact Information 1 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, NO.1 Da HuaRoad, DongDan, Beijing 100730, People’s Republic of China
*Corresponding autor: linyajun2000@126.com; guojun850515@163.com
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No.  114DOI: 10.1186/s11658-024-00634-1 Volume 29 (2024) - 29:114
Title PTEROSTILBENE IMPROVES NEUROLOGICAL DYSFUNCTION AND NEUROINFLAMMATION AFTER ISCHAEMIC STROKE VIA HDAC3/Nrf1-MEDIATED MICROGLIAL ACTIVATION
Authors Yuhua Chen1,2†, Wei He3†, Junlin Qiu4, Yangyang Luo5, Chenlong Jiang5, Feng Zhao6, Hong Wei1, Jiao Meng1,2, Tianlin Long1, Xin Zhang1, Lingjian Yang7, Quanhua Xu1, Juning Wang2 and Chi Zhang8*
Abstract Background: Stroke is a type of acute brain damage that can lead to a series of serious public health challenges. Demonstrating the molecular mechanism of stroke-related neural cell degeneration could help identify a more efficient treatment for stroke patients. Further elucidation of factors that regulate microglia and nuclear factor (erythroid-derived 2)-like 1 (Nrf1) may lead to a promising strategy for treating neuroinflammation after ischaemic stroke. In this study, we investigated the possible role of pterostilbene (PTS) in Nrf1 regulation in cell and animal models of ischaemia stroke.
Methods: We administered PTS, ITSA1 (an HDAC activator) and RGFP966 (a selective HDAC3 inhibitor) in a mouse model of middle cerebral artery occlusion–reperfusion (MCAO/R) and a model of microglial oxygen‒glucose deprivation/reperfusion (OGD/R). The brain infarct size, neuroinflammation and microglial availability were also determined. Dual-luciferase reporter, Nrf1 protein stability and co-immunoprecipitation assays were conducted to analyse histone deacetylase 3 (HDAC3)/Nrf1-regulated Nrf1 in an OGD/R-induced microglial injury model.
Results: We found that PTS decreased HDAC3 expression and activity, increased Nrf1 acetylation in the cell nucleus and inhibited the interaction of Nrf1 with p65 and p65 accumulation, which reduced infarct volume and neuroinflammation (iNOS/Arg1, TNF-α and IL-1β levels) after ischaemic stroke. Furthermore, the CSF1R inhibitor PLX5622 induced elimination of microglia and attenuated the therapeutic effect of PTS following MCAO/R. In the OGD/R model, PTS relieved OGD/R-induced microglial injury and TNF-α and IL-1β release, which were dependent on Nrf1 acetylation through the upregulation of HDAC3/Nrf1 signalling in microglia. However, the K105R or/and K139R mutants of Nrf1 counteracted the impact of PTS in the OGD/R-induced microglial injury model, which indicates that PTS treatment might be a promising strategy for ischaemia stroke therapy.
Conclusion: The HDAC3/Nrf1 pathway regulates the stability and function of Nrf1 in microglial activation and neuroinflammation, which may depend on the acetylation of the lysine 105 and 139 residues in Nrf1. This mechanism was first identified as a potential regulatory mechanism of PTS-based neuroprotection in our research, which may provide new insight into further translational applications of natural products such as PTS.
Keywords Ischaemic stroke, PTS, HDAC3, Nrf1 acetylation, Neuroinfammation
Address and Contact Information 1 Department of Neurosurgery, Academy of Traditional Chinese Medicine, Bijie Traditional Chinese Medicine Hospital, Bijie 551700, China.
2 Department of Medical Science Research Center, Peihua University, Xi’an 710125, Shaanxi, China.
3 Department of Neurosurgery, Qilu Hospital of Shandong University (Qingdao), Qingdao 266000, Shandong, China.
4 Department of Cardiology, First Hospital of Northwestern University, Xi’an 710043, Shaanxi, China.
5 School of Life Sciences, Northwest University, Xi’an 710069, Shaanxi, China.
6 Department of Sport Medicine, Sports Medicine Institute, Peking University Third Hospital, Beijing 100191, China.
7 School of Chemistry & Chemical Engineering, Ankang University, Ankang 725000, China.
8 Department of Neurosurgery, The Institute of Skull Base Surgery and Neurooncology at Hunan Province, Xiangya Hospital, Central South University, NO. 87 Xiangya Road, Changsha 410008, China.
*Corresponding author: zhangchi25@csu.edu.cn
† Yuhua Chen and Wei He are the co-frst author with same contribution.
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No.  115DOI: 10.1186/s11658-024-00635-0 Volume 29 (2024) - 29:115
Title SINGLE-CELL RNA SEQUENCING IDENTIFIES INHERENT ABNORMALITIES OF ADIPOSE-DERIVED STEM CELLS FROM NONLESIONAL SITES OF PATIENTS WITH LOCALIZED SCLERODERMA
Authors Xuanyu Liu1†, Zhujun Li2†, Hayson Chenyu Wang3, Meng Yuan1, Jie Chen2, Jiuzuo Huang2, Nanze Yu2, Zhou Zhou1* and Xiao Long2*
Abstract Background: Localized scleroderma (LoS) is an autoimmune disorder that primarily affects the skin, and is often treated with autologous fat grafting (AFG). Nevertheless, the retention rate of AFG in patients with LoS is typically low. We hypothesize that the low retention rate may be partially attributed to the inherent abnormalities of adipose-derived stem cells (ASCs) from nonlesional sites of patients with LoS.
Methods: We performed a comparative analysis of the single-cell transcriptome of the SVF from nonlesional sites of patients with LoS and healthy donors, including cellular compositional analysis, differential expression analysis, and high-dimensional weighted gene coexpression network analysis. Experimental validation with fluorescence-activated cell sorting and bleomycin-induced skin fibrosis mice models were conducted.
Results: We found a significant reduction in the relative proportion of CD55high interstitial progenitors in ASCs under the condition of LoS. Differential expression analysis revealed inherent abnormalities of ASCs from patients with LoS, including enhanced fibrogenesis, reduced anti-inflammatory properties, and increased oxidative stress. Compared with CD55low ASCs, CD55high ASCs expressed significantly higher levels of secreted protein genes that had functions related to anti-inflammation and tissue regeneration (such as CD55, MFAP5, and METRNL). Meanwhile, CD55high ASCs expressed significantly lower levels of secreted protein genes that promote inflammation, such as chemokine and complement protein genes. Furthermore, we provided in vivo experimental evidence that CD55hig ASCs had superior treatment efficacy compared with CD55low ASCs in bleomycin-induced skin fibrosis mice models.
Conclusions: We found that the low retention rate of AFG may be partially ascribed to the reduced pool of interstitial progenitor cells (CD55high) present within the ASC population in patients with LoS. We demonstrated the potential for improving the efficacy of AFG in the treatment of LoS by restoring the pool of interstitial progenitors within ASCs. Our study has significant implications for the field of translational regenerative medicine.
Keywords Localized scleroderma, Adipose-derived stem cells, Stromal vascular fraction, CD55, Single-cell RNA sequencing
Address and Contact Information 1 State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
2 Department of Plastic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
3 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
*Corresponding author: zhouzhou@fuwaihospital.org; pumclongxiao@126.com
† Xuanyu Liu and Zhujun Li contributed equally to this manuscript.
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No.  116DOI: 10.1186/s11658-024-00633-2 Volume 29 (2024) - 29:116
Title LYSOSOME QUALITY CONTROL IN HEALTH AND NEURODEGENERATIVE DISEASES
Authors Veronica Ferrari1, Barbara Tedesco1, Marta Cozzi1, Marta Chierichetti1, Elena Casarotto1, Paola Pramaggiore1, Laura Cornaggia1, Ali Mohamed1, Guglielmo Patelli2, Margherita Piccolella1, Riccardo Cristofani1, Valeria Crippa1, Mariarita Galbiati1, Angelo Poletti1*† and Paola Rusmini1†
Abstract Lysosomes are acidic organelles involved in crucial intracellular functions, including the degradation of organelles and protein, membrane repair, phagocytosis, endocytosis, and nutrient sensing. Given these key roles of lysosomes, maintaining their homeostasis is essential for cell viability. Thus, to preserve lysosome integrity and functionality, cells have developed a complex intracellular system, called lysosome quality control (LQC). Several stressors may affect the integrity of lysosomes, causing Lysosomal membrane permeabilization (LMP), in which membrane rupture results in the leakage of luminal hydrolase enzymes into the cytosol. After sensing the damage, LQC either activates lysosome repair, or induces the degradation of the ruptured lysosomes through autophagy. In addition, LQC stimulates the de novo biogenesis of functional lysosomes and lysosome exocytosis. Alterations in LQC give rise to deleterious consequences for cellular homeostasis. Specifically, the persistence of impaired lysosomes or the malfunctioning of lysosomal processes leads to cellular toxicity and death, thereby contributing to the pathogenesis of different disorders, including neurodegenerative diseases (NDs). Recently, several pieces of evidence have underlined the importance of the role of lysosomes in NDs. In this review, we describe the elements of the LQC system, how they cooperate to maintain lysosome homeostasis, and their implication in the pathogenesis of different NDs.
Keywords Lysosome, Galectins, Neurodegeneration, Lysosomal membrane permeabilization, Lysosome quality control
Address and Contact Information 1 Dipartimento di Scienze Farmacologiche e Biomolecolari “Rodolfo Paoletti”, Università degli Studi di Milano, Dipartimento Di Eccellenza, 2018‐2027 Milan, Italy
2 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
*Corresponding author: angelo.poletti@unimi.it
† Angelo Poletti and Paola Rusmini contributed equally to the work.
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No.  117DOI: 10.1186/s11658-024-00637-y Volume 29 (2024) - 29:117
Title INVERSE CORRELATION BETWEEN TP53 GENE STATUS AND PD-L1 PROTEIN LEVELS IN A MELANOMA CELL MODEL DEPENDS ON AN IRF1/SOX10 REGULATORY AXIS
Authors Lucia Martinkova1*, Pavlina Zatloukalova1, Martina Kucerikova1,2, Nela Friedlova1,3, Zuzana Tylichova1, Filip Zavadil‐Kokas1, Ted Robert Hupp1,4, Philip John Coates1 and Borivoj Vojtesek1*
Abstract Background: PD-L1 expression on cancer cells is an important mechanism of tumor immune escape, and immunotherapy targeting the PD-L1/PD1 interaction is a common treatment option for patients with melanoma. However, many patients do not respond to treatment and novel predictors of response are emerging. One suggested modifier of PD-L1 is the p53 pathway, although the relationship of p53 pathway function and activation is poorly understood.
Methods: The study was performed on human melanoma cell lines with various p53 status. We investigated PD-L1 and proteins involved in IFNγ signaling by immunoblotting and mRNA expression, as well as membrane expression of PD-L1 by flow cytometry. We evaluated differences in the ability of NK cells to recognize and kill target tumor cells on the basis of p53 status. We also investigated the influence of proteasomal degradation and protein half-life, IFNγ signaling and p53 activation on biological outcomes, and performed bioinformatic analysis using available data for melanoma cell lines and melanoma patients.
Results: We demonstrate that p53 status changes the level of membrane and total PD-L1 protein through IRF1 regulation and show that p53 loss influences the recently discovered SOX10/IRF1 regulatory axis. Bioinformatic analysis identified a dependency of SOX10 on p53 status in melanoma, and a co-regulation of immune signaling by both transcription factors. However, IRF1/PD-L1 regulation by p53 activation revealed complicated regulatory mechanisms that alter IRF1 mRNA but not protein levels. IFNγ activation revealed no dramatic differences based on TP53 status, although dual p53 activation and IFNγ treatment confirmed a complex regulatory loop between p53 and the IRF1/PD-L1 axis.
Conclusions: We show that p53 loss influences the level of PD-L1 through IRF1 and SOX10 in an isogenic melanoma cell model, and that p53 loss affects NK-cell cytotoxicity toward tumor cells. Moreover, activation of p53 by MDM2 inhibition has a complex effect on IRF1/PD-L1 activation. These findings indicate that evaluation of p53 status in patients with melanoma will be important for predicting the response to PD-L1 monotherapy and/or dual treatments where p53 pathways participate in the overall response.
Keywords IFNγ, IRF1, PD-L1, p53, SOX10
Address and Contact Information 1 RECAMO, Masaryk Memorial Cancer Institute, 602 00 Brno, Czech Republic
2 National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic
3 Department of Experimental Biology, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic
4 Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland EH4 2XR, UK
*Corresponding author: lucia.haronikova@mou.cz; vojtesek@mou.cz
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No.  118DOI: 10.1186/s11658-024-00627-0 Volume 29 (2024) - 29:118
Title Hsa_circ_0000520 SUPPRESSES VASCULOGENIC MIMICRY FORMATION AND METASTASIS IN BLADDER CANCER THROUGH Lin28a/PTEN/PI3K SIGNALING
Authors Chunyu Zhang1,2,3, Jiao Hu1,2, Zhi Liu1,2, Hao Deng1,2, Jiatong Xiao1,2, Zhenglin Yi1,2, Yunbo He1,2, Zicheng Xiao1,2, Jinliang Huang1,2, Haisu Liang1,2, Benyi Fan1,2, Zhihua Wang3*, Jinbo Chen1,2* and Xiongbing Zu1,2,4*
Abstract Background: Vasculogenic mimicry (VM) is a potential cause of resistance to antiangiogenic therapy and is closely related to the malignant progression of tumors. It has been shown that noncoding RNAs play an important role in the formation of VM in malignant tumors. However, the role of circRNAs in VM of bladder cancer and the regulatory mechanisms are unclear.
Methods: Firstly, hsa_circ_0000520 was identified to have circular character by Sanger sequencing and Rnase R assays. Secondly, the potential clinical value of hsa_circ_0000520 was explored by quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH) of clinical specimens. Thirdly, the role of hsa_circ_0000520 in bladder cancer invasion, migration, and VM formation was examined by in vivo and in vitro experiments. Finally, the regulatory mechanisms of hsa_circ_0000520 in the malignant progression of bladder cancer were elucidated by RNA binding protein immunoprecipitation (RIP), RNA pulldown, co-immunoprecipitation (co-IP), qRT-PCR, Western blot (WB), and fluorescence co-localization.
Results: Hsa_circ_0000520 was characterized as a circular RNA and was lowly expressed in bladder cancer compared with the paracancer. Bladder cancer patients with high expression of hsa_circ_0000520 had better survival prognosis. Functionally, hsa_circ_0000520 inhibited bladder cancer invasion, migration, and VM formation. Mechanistically, hsa_circ_0000520 acted as a scaffold to promote binding of UBE2V1/UBC13 to Lin28a, further promoting the ubiquitous degradation of Lin28a, improving PTEN mRNA stability, and inhibiting the phosphorylation of the PI3K/AKT pathway. The formation of hsa_circ_0000520 in bladder cancer was regulated by RNA binding protein QKI.
Conclusions: Hsa_circ_0000520 inhibits metastasis and VM formation in bladder cancer and is a potential target for bladder cancer diagnosis and treatment.
Keywords Bladder cancer, Hsa_circ_0000520, Metastasis, Vasculogenic mimicry, PI3K/ AKT pathway
Address and Contact Information 1 Department of Urology, Xiangya Hospital, Central South University, Changsha, China
2 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
3 Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
4 Department of Urology, Hunan Provincial People’s Hospital, the First Afliated Hospital of Hunan Normal University, Changsha, China
*Corresponding author: zhwang_hust@hotmail.com; chenjinbo@csu.edu.cn; zuxbxy@csu.edu.cn
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No.  119DOI: 10.1186/s11658-024-00631-4 Volume 29 (2024) - 29:119
Title PAEONIFLORIN PROTECTS HEPATOCYTES FROM APAP-INDUCED DAMAGE THROUGH LAUNCHING AUTOPHAGY VIA THE MAPK/mTOR SIGNALING PATHWAY
Authors Xinyu Deng1, Yubing Li1, Yuan Chen1, Qichao Hu1, Wenwen Zhang1, Lisheng Chen1, Xiaohua Lu3*, Jinhao Zeng2*, Xiao Ma1* and Thomas Eferth3*
Abstract Background: Drug-induced liver injury (DILI) is gradually becoming a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). Paeoniflorin (PF) has a wide range of therapeutic effects to alleviate a variety of hepatic diseases. However, the relationship between them is still poorly investigated in current studies.
Purpose: This work aimed to explore the protective effects of PF on APAP-induced hepatic damage and researched the potential molecular mechanisms.
Methods: C57BL/6J male mice were injected with APAP to establish DILI model and were given PF for five consecutive days for treatment. Aiming to clarify the pharmacological effects, the molecular mechanisms of PF in APAP-induced DILI was elucidated by high-throughput and other techniques.
Results: The results demonstrated that serum levels of ALP, γ-GT, AST, TBIL, and ALT were decreased in APAP mice by the preventive effects of PF. Moreover, PF notably alleviated hepatic tissue inflammation and edema. Meanwhile, the results of TUNEL staining and related apoptotic factors coincided with the results of transcriptomics, suggesting that PF inhibited hepatocyte apoptosis by regulated MAPK signaling. Besides, PF also acted on reactive oxygen species (ROS) to regulate the oxidative stress for recovery the damaged mitochondria. More importantly, transmission electron microscopy showed the generation of autophagosomes after PF treatment, and PF was also downregulated mTOR and upregulated the expression of autophagy markers such as ATG5, ATG7, and BECN1 at the mRNA level and LC3, p62, ATG5, and ATG7 at the protein level, implying that the process by which PF exerted its effects was accompanied by the occurrence of autophagy. In addition, combinined with molecular dynamics simulations and western blotting of MAPK, the results suggested p38 as a direct target for PF on APAP. Specifically, PF-activated autophagy through the downregulation of MAPK/mTOR signaling, which in turn reduced APAP injury.
Conclusions: Paeoniflorin mitigated liver injury by activating autophagy to suppress oxidative stress and apoptosis via the MAPK/mTOR signaling pathway. Taken together, our findings elucidate the role and mechanism of paeoniflorin in DILI, which is expected to provide a new therapeutic strategy for the development of paeoniflorin.
Keywords Acetaminophen, Cell death, Drug-induced liver injury, Natural products, Oxidative stress, Signal transduction
Address and Contact Information 1 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
2 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
3 Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz 55128, Germany
*Corresponding author: xiaohulu@uni-mainz.de; zengjinhao@cdutcm.edu.cn; tobymaxiao@cdutcm.edu.cn; eferth@uni-mainz.de
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No.  120DOI: 10.1186/s11658-024-00640-3 Volume 29 (2024) - 29:120
Title GLUCOKINASE (GCK) IN DIABETES: FROM MOLECULAR MECHANISMS TO DISEASE PATHOGENESIS
Authors Yasmin Abu Aqel1†, Aldana Alnesf1,2†, Idil I. Aigha1, Zeyaul Islam3, Prasanna R. Kolatkar2,3, Adrian Teo4,5,6 and Essam M. Abdelalim1,2*
Abstract Glucokinase (GCK), a key enzyme in glucose metabolism, plays a central role in glucose sensing and insulin secretion in pancreatic β-cells, as well as glycogen synthesis in the liver. Mutations in the GCK gene have been associated with various monogenic diabetes (MD) disorders, including permanent neonatal diabetes mellitus (PNDM) and maturity-onset diabetes of the young (MODY), highlighting its importance in maintaining glucose homeostasis. Additionally, GCK gain-of-function mutations lead to a rare congenital form of hyperinsulinism known as hyperinsulinemic hypoglycemia (HH), characterized by increased enzymatic activity and increased glucose sensitivity in pancreatic β-cells. This review offers a comprehensive exploration of the critical role played by the GCK gene in diabetes development, shedding light on its expression patterns, regulatory mechanisms, and diverse forms of associated monogenic disorders. Structural and mechanistic insights into GCK’s involvement in glucose metabolism are discussed, emphasizing its significance in insulin secretion and glycogen synthesis. Animal models have provided valuable insights into the physiological consequences of GCK mutations, although challenges remain in accurately recapitulating human disease phenotypes. In addition, the potential of human pluripotent stem cell (hPSC) technology in overcoming current model limitations is discussed, offering a promising avenue for studying GCK-related diseases at the molecular level. Ultimately, a deeper understanding of GCK’s multifaceted role in glucose metabolism and its dysregulation in disease states holds implications for developing targeted therapeutic interventions for diabetes and related disorders.
Keywords Glucokinase, Glucose, Insulin, Diabetes, Mutations, Stem cells, Beta cells, Pancreas, Liver
Address and Contact Information 1 Laboratory of Pluripotent Stem Cell Disease Modeling, Translational Medicine Division, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar
2 College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar
3 Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
4 Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Proteos, Singapore, Singapore
5 Department of Biochemistry and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
6 Precision Medicine Translational Research Programme (PM TRP), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
*Corresponding author: emohamed3@sidra.org
† Yasmin Abu Aqel and Aldana Alnesf contributed equally to this review.
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No.  121DOI: 10.1186/s11658-024-00632-3 Volume 29 (2024) - 29:121
Title MicroRNAs IN METABOLISM FOR PRECISION TREATMENT OF LUNG CANCER
Authors Giovanna Carrà1,2*, Jessica Petiti3, Federico Tolino4, Rita Vacca5 and Francesca Orso4*
Abstract The dysregulation of miRNAs in lung cancer has been extensively documented, with specific miRNAs acting as both tumor suppressors and oncogenes, depending on their target genes. Recent research has unveiled the regulatory roles of miRNAs in key metabolic pathways, such as glycolysis, the tricarboxylic acid cycle, fatty acid metabolism, and autophagy, which collectively contribute to the aberrant energy metabolism characteristic of cancer cells. Furthermore, miRNAs are increasingly recognized as critical modulators of the tumor microenvironment, impacting immune response and angiogenesis. This review embarks on a comprehensive journey into the world of miRNAs, unraveling their multifaceted roles, and more notably, their emerging significance in the context of cancer, with a particular focus on lung cancer. As we navigate this extensive terrain, we will explore the fascinating realm of miRNA-mediated metabolic rewiring, a phenomenon that plays a pivotal role in the progression of lung cancer and holds promise in the development of novel therapeutic strategies.
Keywords Lung cancer, Metabolism, Metabolic reprogramming, miRNAs
Address and Contact Information 1 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
2 San Luigi Gonzaga Hospital, Orbassano, Italy
3 Division of Advanced Materials Metrology and Life Sciences, Istituto Nazionale di Ricerca Metrologica (INRiM), 10135 Turin, Italy
4 Department of Translational Medicine (DIMET), University of Eastern Piedmont, Novara, Italy
5 Molecular Biotechnology Center “Guido Tarone”, University of Torino, Turin, Italy
*Corresponding author: giovanna.carra@unito.it; francesca.orso@uniupo.it
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No.  122DOI: 10.1186/s11658-024-00636-z Volume 29 (2024) - 29:122
Title IDENTIFICATION OF ZINC FINGER MIZ-TYPE CONTAINING 2 AS AN ONCOPROTEIN ENHANCING NAD-DEPENDENT PROTEIN DEACETYLASE sirtuin-1 DEACETYLASE ACTIVITY TO REGULATE Wnt AND Hippo PATHWAYS IN NON-SMALL-CELL LUNG CANCER
Authors Xueting Gan1†, Yuheng Feng1†, Yang Liu1†, Xuyong Lin1, Xinmiao Yu2*, Xuezhu Rong3* and Qiang Han1*
Abstract Background: Zinc finger MIZ-type containing 2 (ZMIZ2) can function as a coactivator and participate in the progression of certain malignant tumors; however, its expression and underlying molecular mechanism in non-small-cell lung cancer (NSCLC) remains unknown. In this study, we aim to analyze the expression of ZMIZ2 and its tumorigenic function in NSCLC, identifying its related factors.
Methods: ZMIZ2 expression in NSCLC tissue samples and cell lines was examined using immunohistochemistry and western blotting; its biological role was investigated using in vivo and in vitro assays. The association between ZMIZ2 and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was demonstrated using mass spectrometry and immunoprecipitation experiments. Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG)-based enrichment analysis, luciferase reporter assay, and real-time quantitative polymerase chain reaction (RT–qPCR) were conducted to verify the impact of ZMIZ2–SIRT1 combination on Hippo/Wnt pathways.
Results: ZMIZ2 was highly expressed in NSCLC and positively associated with advanced pTNM staging, lymph node metastasis, and poor overall survival. Functional experiments revealed that ZMIZ2 promotes the proliferation, migration, and invasiveness of lung cancer cells—establishing its role as a promoter of oncogenes. Molecular mechanism studies identified SIRT1 as an assisted key factor interacting with ZMIZ2. KEGG enrichment analysis revealed that ZMIZ2 is closely related to Wnt/Hippo pathways; ZMIZ2–SIRT1 interaction enhanced SIRT1 deacetylase activity. Direct downregulation of intranuclear β-catenin and yes-associated protein (YAP) acetylation levels occurred independently of upstream proteins in Wnt/Hippo pathways; transcriptional activities of β-catenin-transcription factor 4 (TCF4) and YAP–TEA domain family transcription factors (TEADs) were amplified.
Conclusions: ZMIZ2 promotes the malignant phenotype of lung cancer by regulating Wnt/Hippo pathways through SIRT1, providing an experimental basis for discovering novel biomarkers and developing tumor-targeted drugs.
Keywords ZMIZ2, SIRT1, Non-small-cell lung cancer, Wnt and Hippo signaling pathway
Address and Contact Information 1 Department of Pathology, Shenbei New Area, College of Basic Medical Sciences and the First Hospital of China Medical University. No, 77 Puhe Road, Shenyang 110122, Liaoning Province, People’s Republic of China
2 Department of Surgical Oncology and Breast Surgery, the First Hospital of China Medical University, Shenyang. No. 155 Nanjing North Street, Heping Area, Shenyang 110001, Liaoning Province, People’s Republic of China
3 Department of Pathology, the First Hospital of China Medical University. No, 155 Nanjing North Street, Heping Area, Shenyang 110001, Liaoning Province, People’s Republic of China
*Corresponding author: yujinshui@163.com; rxz-168@163.com; hanqiangcmu@outlook.com
† Xueting Gan, Yuheng Feng and Yang Liu have contributed equally to this work.
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No.  123DOI: 10.1186/s11658-024-00641-2 Volume 29 (2024) - 29:123
Title THE ICF2 GENE Zbtb24 SPECIFICALLY REGULATES THE DIFFERENTIATION OF B1 CELLS VIA PROMOTING HEME SYNTHESIS
Authors He Gao1†, Ying Zhao2†, Sai Zhao1†, Xiao‐Qiu Dai1, Xiao‐Yuan Qin1, Wei‐Long Zheng1, Ting‐Ting He1, Nan Zhang1, Can Zhu1, Hong‐Min Wang1, Wen Pan1, Xue‐Mei Zhu1, Xiao‐Ming Gao1, Jian‐Feng Dai1*, Fang‐Yuan Gong3* and Jun Wang1*
Abstract Background: Loss-of-function mutations of ZBTB24 cause immunodeficiency, centromeric instability, and facial anomalies syndrome 2 (ICF2). ICF2 is a rare autosomal recessive disorder with immunological defects in serum antibodies and circulating memory B cells, resulting in recurrent and sometimes fatal respiratory and gastrointestinal infections. The genotype–phenotype correlation in patients with ICF2 indicates an essential role of ZBTB24 in the terminal differentiation of B cells.
Methods: We used the clustered regularly interspaced short palindromic repeats (CRISPER)/Cas9 technology to generate B cell specific Zbtb24-deficient mice and verified the deletion specificity and efficiency by quantitative polymerase chain reaction (Q-PCR) and western blotting analyses in fluorescence-activated cell sorting (FACS)-sorted cells. The development, phenotype of B cells and in vivo responses to T cell dependent or independent antigens post immunization were analyzed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Adoptive transfer experiment in combination with in vitro cultures of FACS-purified B cells and RNA-Seq analysis were utilized to specifically determine the impact of Zbtb24 on B cell biology as well as the underlying mechanisms.
Results: Zbtb24 is dispensable for B cell development and maintenance in naive mice. Surprisingly, B cell specific deletion of Zbtb24 does not evidently compromise germinal center reactions and the resulting primary and secondary antibody responses induced by T cell dependent antigens (TD-Ags), but significantly inhibits T cell independent antigen-elicited antibody productions in vivo. At the cellular level, Zbtb24-deficiency specifically impedes the plasma cell differentiation of B1 cells without impairing their survival, activation and proliferation in vitro. Mechanistically, Zbtb24-ablation attenuates heme biosynthesis partially through mTORC1 in B1 cells, and addition of exogenous hemin abrogates the differentiation defects of Zbtb24-null B1 cells.
Conclusions: Zbtb24 seems to regulate antibody responses against TD-Ags B cell extrinsically, but it specifically promotes the plasma cell differentiation of B1 cells via heme synthesis in mice. Our study also suggests that defected B1 functions contribute to recurrent infections in patients with ICF2.
Keywords ICF2, Zbtb24, B1 cells, Plasma cell diferentiation, Heme synthesis
Address and Contact Information 1 Institutes of Biology and Medical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Infection and Immunity, Suzhou Medical College of Soochow University, Suzhou 215123, China
2 Department of Pathophysiology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China
3 Department of Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China
*Corresponding author: daijianfeng@suda.edu.cn; gongfangyuan@suda.edu.cn; jwang79@suda.edu.cn
† He Gao, Ying Zhao and Sai Zhao contribute equally to this work.
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No.  124DOI: 10.1186/s11658-024-00639-w Volume 29 (2024) - 29:124
Title TETRASPANIN 3 PROMOTES NSCLC CELL PROLIFERATION VIA REGULATION OF β1 INTEGRIN INTRACELLULAR RECYCLING
Authors Yao Zhang1†, Chenglong Wang2†, Yitong Xu3*† and Hongbo Su3*†
Abstract Background: The involvement of tetraspanins in cancer development has been widely implicated. In this study, the function and molecular mechanisms of tetraspanin 3 (TSPAN3) in non-small cell lung cancer (NSCLC) cells were explored.
Methods: Tissue samples from patients diagnosed with NSCLC were analyzed by immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR) to indicate the involvement of TSPAN3 in cancer progression. In the meantime, we also performed exhaustive mechanistic studies using A549 and H460 cells in vitro through a variety of methods including western blotting, real-time PCR, immunofluorescent staining, coimmunoprecipitation, cell proliferation assay, and nocodazole (NZ) washout assay. Proper statistical analysis was implemented wherever necessary in this study.
Results: TSPAN3 was found to be highly expressed in lung cancer cells and tissues. Moreover, high levels of TSPAN3 positively correlated with poor differentiation, lymph node involvement, advanced pathological tumor-node-metastasis stage, and poor prognosis in patients with NSCLC. TSPAN3 showed potential to promote the proliferation of NSCLC cells in vitro and in vivo. Specifically, TSPAN3 was found to interact with β1 integrin via the LEL domain, thereby facilitating the sorting of β1 integrin into Rab11a endosomes and promoting β1 integrin recycling and upregulation.
Conclusions: Our findings reveal TSPAN3 may represent a potentially valuable therapeutic target for NSCLC.
Keywords β1 integrin, Tetraspanin 3, Non-small cell lung carcinoma, Rab11a
Address and Contact Information 1 Department of Pathology, the First Hospital and Basic Medical Sciences College of China Medical University, Shenyang 110001, China
2 Department of Pain, the First Hospital of China Medical University, Shenyang 110001, China
3Department of Pathology, the First Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang 110001, Liaoning, China
*Corresponding author: ytxu@cmu.edu.cn; hbsu@cmu.edu.cn
† Yao Zhang and Chenglong Wang have authors contributed equally to this work.
† Hongbo Su and Yitong Xu contributed equally to this work.
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No.  125DOI: 10.1186/s11658-024-00638-x Volume 29 (2024) - 29:125
Title mTOR/miR-142-3p/PRAS40 SIGNALING CASCADE IS CRITICAL FOR TUBEROUS SCLEROSIS COMPLEX-ASSOCIATED RENAL CYSTOGENESIS
Authors Shuyun Zhao1†, Shuai Hao1†, Jiasheng Zhou1†, Xinran Chen1†, Tianhua Zhang1,2, Zhaolai Qi1, Ting Zhang1,2, Sajid Jalal1, Chuanxin Zhai1, Lu Yin1, Yufei Bo1, Hongming Teng1,2, Yue Wang1,2, Dongyan Gao3, Hongbing Zhang4 and Lin Huang1,2*
Abstract Background: Patients with tuberous sclerosis complex (TSC) develop renal cysts and/or angiomyolipomas (AMLs) due to inactive mutations of either TSC1 or TSC2 and consequential mTOR hyperactivation. The molecular events between activated mTOR and renal cysts/AMLs are still largely unknown.
Methods: The mouse model of TSC-associated renal cysts were constructed by knocking out Tsc2 specifically in renal tubules (Tsc2f/f; ksp-Cre). We further globally deleted PRAS40 in these mice to investigate the role of PRAS40. Tsc2−/− cells were used as mTOR activation model cells. Inhibition of DNA methylation was used to increase miR-142-3p expression to examine the effects of miR-142-3p on PRAS40 expression and TSC-associated renal cysts.
Results: PRAS40, a component of mTOR complex 1, was overexpressed in Tsc2-deleted cell lines and mouse kidneys (Tsc2f/f; ksp-Cre), which was decreased by mTOR inhibition. mTOR stimulated PRAS40 expression through suppression of miR-142-3p expression. Unleashed PRAS40 was critical to the proliferation of Tsc2−/− cells and the renal cystogenesis of Tsc2f/f; ksp-Cre mice. In contrast, inhibition of DNA methylation increased miR-142-3p expression, decreased PRAS40 expression, and hindered cell proliferation and renal cystogenesis.
Conclusions: Our data suggest that mTOR activation caused by TSC2 deletion increases PRAS40 expression through miR-142-3p repression. PRAS40 depletion or the pharmacological induction of miR-142-3p expression impaired TSC2 deficiency-associated renal cystogenesis. Therefore, harnessing mTOR/miR-142-3p/PRAS40 signaling cascade may mitigate hyperactivated mTOR-related diseases.
Keywords Tuberous sclerosis complex, mTOR, PRAS40, Renal cystogenesis, miRNA
Address and Contact Information 1 Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, People’s Republic of China
2 Liaoning Provincial Key Laboratory of Medical Cellular and Molecular Biology, Dalian Medical University, Dalian 116044, Liaoning, People’s Republic of China
3 Department of Pharmacology, Dalian Medical University, Dalian 116044, Liaoning, People’s Republic of China
4 State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, People’s Republic of China
*Corresponding author: lhuang@dmu.edu.cn
† Shuyun Zhao, Shuai Hao, Jiasheng Zhou, and Xinran Chen have contributed equally.
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No.  126DOI: 10.1186/s11658-024-00643-0 Volume 29 (2024) - 29:126
Title THE ONCOGENIC ADAMTS1–VCAN–EGFR CYCLIC AXIS DRIVES ANOIKIS RESISTANCE AND INVASION IN RENAL CELL CARCINOMA
Authors Yu‐Ching Wen1,2†, Yung‐Wei Lin1,2,3†, Kuo‐Hao Ho4†, Yi‐Chieh Yang4,5, Feng‐Ru Lai4, Chih‐Ying Chu4, Ji‐Qing Chen4,6, Wei‐Jiunn Lee2,4,7* and Ming‐Hsien Chien4,8,9,10*
Abstract Background: Metastasis, the leading cause of renal cell carcinoma (RCC) mortality, involves cancer cells resisting anoikis and invading. Until now, the role of the matrix metalloproteinase (MMP)-related enzyme, A disintegrin and metalloprotease with thrombospondin motifs 1 (ADAMTS1), in RCC anoikis regulation remains unclear.
Methods: The clinical significance of ADAMTS1 and its associated molecules in patients with RCC was investigated using data from the Gene Expression Omnibus (GEO) and TCGA datasets. Human phosphoreceptor tyrosine kinase (RTK) array, luciferase reporter assays, immunoprecipitation (IP) assays, western blotting, and real-time reverse-transcription quantitative polymerase chain reaction (RT–qPCR) were used to elucidate the underlying mechanisms of ADAMTS1. Functional assays, including anoikis resistance assays, invasion assays, and a Zebrafish xenotransplantation model, were conducted to assess the roles of ADAMTS1 in conferring resistance to anoikis in RCC.
Results: This study found elevated ADAMTS1 transcripts in RCC tissues that were correlated with a poor prognosis. ADAMTS1 manipulation significantly affected cell anoikis through the mitochondrial pathway in RCC cells. Human receptor tyrosine kinase (RTK) array screening identified that epidermal growth factor receptor (EGFR) activation was responsible for ADAMTS1-induced anoikis resistance and invasion. Further investigations revealed that enzymatically active ADAMTS1-induced versican V1 (VCAN V1) proteolysis led to EGFR transactivation, which in turn, through positive feedback, regulated ADAMTS1. Additionally, ADAMTS1 can form a complex with p53 to influence EGFR signaling. In vivo, VCAN or EGFR knockdown reversed ADAMTS1-induced prometastatic characteristics of RCC. A clinical analysis revealed a positive correlation between ADAMTS1 and VCAN or the EGFR and patients with RCC with high ADAMTS1 and VCAN expression had the worst prognoses.
Conclusions: Our results collectively uncover a novel cyclic axis involving ADAMTS1–VCAN–EGFR, which significantly contributes to RCC invasion and resistance to anoikis, thus presenting a promising therapeutic target for RCC metastasis.
Keywords ADAMTS1, VCAN, EGFR, Anoikis, Metastasis, Renal cell carcinoma
Address and Contact Information 1 Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
2 Department of Urology, School of Medicine, College of Medicine and TMU Research Center of Urology and Kidney (TMU‐RCUK), Taipei Medical University, Taipei, Taiwan.
3 International Master/PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
4 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu‐Hsing Street, Taipei 11031, Taiwan.
5 Department of Medical Research, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan.
6 Department of Cancer Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
7 Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, 111 Xinglong Rd., Sec. 3, Wenshan Dist, Taipei 11696, Taiwan.
8 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
9 Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
10 Traditional Herbal Medicine Research Center, Taipei Medical University Hospital Taipei, Taipei, Taiwan.
*Corresponding author: wjlee@tmu.edu.tw; mhchien1976@gmail.com
† Yu-Ching Wen, Yung-Wei Lin and Kuo-Hao Ho have contributed equally to this work.
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No.  127DOI: 10.1186/s11658-024-00644-z Volume 29 (2024) - 29:127
Title A NOVEL PROTEIN SPECC1-415aa ENCODED BY N6-METHYLADENOSINE MODIFIED circSPECC1 REGULATES THE SENSITIVITY OF GLIOBLASTOMA TO TMZ
Authors Cheng Wei1†, Dazhao Peng1†, Boyuan Jing1†, Bo Wang1, Zesheng Li1, Runze Yu1, Shu Zhang1, Jinquan Cai3*, Zhenyu Zhang2*, Jianning Zhang1* and Lei Han1*
Abstract Background: Circular RNAs (circRNAs) can influence a variety of biological functions and act as a significant role in the progression and recurrence of glioblastoma (GBM). However, few coding circRNAs have been discovered in cancer, and their role in GBM is still unknown. The aim of this study was to identify coding circRNAs and explore their potential roles in the progression and recurrence of GBM.
Methods: CircSPECC1 was screened via circRNAs microarray of primary and recurrent GBM samples. To ascertain the characteristics and coding ability of circSPECC1, we conducted a number of experiments. Afterward, through in vivo and in vitro experiments, we investigated the biological functions of circSPECC1 and its encoded novel protein (SPECC1-415aa) in GBM, as well as their effects on TMZ sensitivity.
Results: By analyzing primary and recurrent GBM samples via circRNAs microarray, circSPECC1 was found to be a downregulated circRNA with coding potential in recurrent GBM compared with primary GBM. CircSPECC1 suppressed the proliferation, migration, invasion, and colony formation abilities of GBM cells by encoding a new protein known as SPECC1-415aa. CircSPECC1 restored TMZ sensitivity in TMZ-resistant GBM cells by encoding the new protein SPECC1-415aa. The m6A reader protein IGF2BP1 can bind to circSPECC1 to promote its expression and stability. Mechanistically, SPECC1-415aa can bind to ANXA2 and competitively inhibit the binding of ANXA2 to EGFR, thus resulting in the inhibition of the phosphorylation of EGFR (Tyr845) and its downstream pathway protein AKT (Ser473). In vivo experiments showed that the overexpression of circSPECC1 could combine with TMZ to treat TMZ-resistant GBM, thereby restoring the sensitivity of TMZ-resistant GBM to TMZ.
Conclusions: CircSPECC1 was downregulated in recurrent GBM compared with primary GBM. The m6A reader protein IGF2BP1 could promote the expression and stability of circSPECC1. The sequence of SPECC1-415aa, which is encoded by circSPECC1, can inhibit the binding of ANXA2 to EGFR by competitively binding to ANXA2 and inhibiting the phosphorylation of EGFR and AKT, thereby restoring the sensitivity of TMZ-resistant GBM cells to TMZ.
Keywords Glioblastoma, circSPECC1, Protein encoded, Chemoresistance, m6A modifcation
Address and Contact Information 1 Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China
2 Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Jian She Dong Road 1, Zhengzhou 480082, Henan Province, China
3 Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150086, China
*Corresponding author: caijinquan666777@126.com; fcczhangzy1@zzu.edu.cn; jianningzhang2021@163.com; superhanlei@tmu.edu.cn
† Cheng Wei, Dazhao Peng and Boyuan Jing contributed equally.
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No.  128DOI: 10.1186/s11658-024-00645-y Volume 29 (2024) - 29:128
Title ENDOMETRIAL REGENERATION CELL-DERIVED EXOSOMES LOADED WITH siSLAMF6 INHIBIT CARDIAC ALLOGRAFT REJECTION THROUGH THE SUPPRESSION OF DESIALYLATION MODIFICATION
Authors Yini Xu1,2†, Shaohua Ren1,2†, Hongda Wang1,2†, Yafei Qin4, Tong Liu1,2, Chenglu Sun1,2, Yiyi Xiao1,2, Bo Shao1,2, Jingyi Zhang1,2, Qiang Chen1,2, Pengyu Zhao1,2, Guangmei Yang1,2, Xu Liu1,2 and Hao Wang1,2,3*
Abstract Backgrounds: Acute transplant rejection is a major component of poor prognoses for organ transplantation. Owing to the multiple complex mechanisms involved, new treatments are still under exploration. Endometrial regenerative cells (ERCs) have been widely used in various refractory immune-related diseases, but the role of ERC-derived exosomes (ERC-Exos) in alleviating transplant rejection has not been extensively studied. Signaling lymphocyte activation molecule family 6 (SLAMF6) plays an important role in regulating immune responses. In this study, we explored the main mechanism by which ERC-Exos loaded with siSLAMF6 can alleviate allogeneic transplant rejection.
Methods: C57BL/6 mouse recipients of BALB/c mouse kidney transplants were randomly divided into four groups and treated with exosomes. The graft pathology was evaluated by H&E staining. Splenic and transplanted heart immune cell populations were analyzed by flow cytometry. Recipient serum cytokine profiles were determined by enzyme-linked immunosorbent assay (ELISA). The proliferation and differentiation capacity of CD4+ T cell populations were evaluated in vitro. The α-2,6-sialylation levels in the CD4+ T cells were determined by SNA blotting.
Results: In vivo, mice treated with ERC-siSLAMF6 Exo achieved significantly prolonged allograft survival. The serum cytokine profiles of the recipients were significantly altered in the ERC-siSLAMF6 Exo-treated recipients. In vitro, we found that ERC-siSLAMF6-Exo considerably downregulated α-2,6-sialyltransferase (ST6GAL1) expression in CD4+ T cells, and significantly reduced α-2,6-sialylation levels. Through desialylation, ERC-siSLAMF6 Exo therapy significantly decreased CD4+ T cell proliferation and inhibited CD4+ T cell differentiation into Th1 and Th17 cells while promoting regulatory T cell (Treg) differentiation.
Conclusions: Our study indicated that ERC-Exos loaded with siSLAMF6 reduce the amount of sialic acid connected to α-2,6 at the end of the N-glycan chain on the CD4+ T cell surface, increase the number of therapeutic exosomes endocytosed into CD4+ T cells, and inhibit the activation of T cell receptor signaling pathways, which prolongs allograft survival. This study confirms the feasibility of using ERC-Exos as natural carriers combined with gene therapy, which could be used as a potential therapeutic strategy to alleviate allograft rejection.
Keywords Signaling lymphocyte activation molecule family 6 (SLAMF6), Cardiac allograft rejection, Endometrial regeneration cell-derived exosome, Desialylation, Modifcation
Address and Contact Information 1 Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China
2 Tianjin General Surgery Institute, 154 Anshan Road, Heping District, Tianjin, 300052, China
3 Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, 154 Anshan Road, Heping District, Tianjin 300052, China
4 Department of Vascular Surgery, Henan Provincial People’s Hospital, The Affiliated People’s Hospital of Zhengzhou University, Zhengzhou 450003, Henan, China
*Corresponding author: hwangca272@hotmail.com; hwang1@tmu.edu.cn
† Yini Xu, Shaohua Ren, and Hongda Wang have contributed equally to this article.
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No.  129DOI: 10.1186/s11658-024-00642-1 Volume 29 (2024) - 29:129
Title THE ROLE AND THERAPEUTIC POTENTIAL OF ITACONATE IN LUNG DISEASE
Authors Ruyuan He1†, Yifan Zuo1†, Ke Yi1†, Bohao Liu2, Congkuan Song1*, Ning Li1* and Qing Geng1*
Abstract Lung diseases triggered by endogenous or exogenous factors have become a major concern, with high morbidity and mortality rates, especially after the coronavirus disease 2019 (COVID-19) pandemic. Inflammation and an over-activated immune system can lead to a cytokine cascade, resulting in lung dysfunction and injury. Itaconate, a metabolite produced by macrophages, has been reported as an effective anti-inflammatory and anti-oxidative stress agent with significant potential in regulating immunometabolism. As a naturally occurring metabolite in immune cells, itaconate has been identified as a potential therapeutic target in lung diseases through its role in regulating inflammation and immunometabolism. This review focuses on the origin, regulation, and function of itaconate in lung diseases, and briefly discusses its therapeutic potential.
Keywords Itaconate, Metabolite, Infammation, Immunometabolism, Macrophage, Lung diseases
Address and Contact Information 1 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Hubei Province, 99 Zhangzhidong Road, Wuhan 430060, China
2 Department of Thoracic Surgery, Jilin University, Changchun, China
*Corresponding author: sck2018@whu.edu.cn; md.lining@whu.edu.cn; gengqingwhu@whu.edu.cn
† Ruyuan He, Yifan Zuo, and Ke Yi have contributed equally to this work.
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No.  130DOI: 10.1186/s11658-024-00646-x Volume 29 (2024) - 29:130
Title CASPASE-8 IN INFLAMMATORY DISEASES: A POTENTIAL THERAPEUTIC TARGET
Authors Wangzheqi Zhang1†, Chenglong Zhu1†, Yan Liao1†, Miao Zhou2*, Wenyun Xu3* and Zui Zou1*
Abstract Caspase-8, a renowned cysteine-aspartic protease within its enzyme family, initially garnered attention for its regulatory role in extrinsic apoptosis. With advancing research, a growing body of evidence has substantiated its involvement in other cell death processes, such as pyroptosis and necroptosis, as well as its modulatory effects on inflammasomes and proinflammatory cytokines. PANoptosis, an emerging concept of cell death, encompasses pyroptosis, apoptosis, and necroptosis, providing insight into the often overlapping cellular mortality observed during disease progression. The activation or deficiency of caspase-8 enzymatic activity is closely linked to PANoptosis, positioning caspase-8 as a key regulator of cell survival or death across various physiological and pathological processes. Aberrant expression of caspase-8 is closely associated with the development and progression of a range of inflammatory diseases, including immune system disorders, neurodegenerative diseases (NDDs), sepsis, and cancer. This paper delves into the regulatory role and impact of caspase-8 in these conditions, aiming to elucidate potential therapeutic strategies for the future intervention.
Keywords Caspase-8, Apoptosis, Necroptosis, Pyroptosis, PANoptosis, Infammatory disease
Address and Contact Information 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
2 Department of Anesthesiology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University, Nanjing 210009, Jiangsu, China
3 Department of Anesthesiology, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China
*Correspondence: zhoumiao@jszlyy.com.cn; xuwenyun@smmu.edu.cn; zouzui@smmu.edu.cn
† Wangzheqi Zhang, Chenglong Zhu and Yan Liao have contributed equally to this research.
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No.  131DOI: 10.1186/s11658-024-00647-w Volume 29 (2024) - 29:131
Title RESEARCH PROGRESS OF ANKYRIN REPEAT DOMAIN 1 PROTEIN: AN UPDATED REVIEW
Authors Xusan Xu1†, Xiaoxia Wang2†, Yu Li3, Riling Chen3, Houlang Wen4*, Yajun Wang5* and Guoda Ma1*
Abstract Ankyrin repeat domain 1 (Ankrd1) is an acute response protein that belongs to the muscle ankyrin repeat protein (MARP) family. Accumulating evidence has revealed that Ankrd1 plays a crucial role in a wide range of biological processes and diseases. This review consolidates current knowledge on Ankrd1’s functions in myocardium and skeletal muscle development, neurogenesis, cancer, bone formation, angiogenesis, wound healing, fibrosis, apoptosis, inflammation, and infection. The comprehensive profile of Ankrd1 in cardiovascular diseases, myopathy, and its potential as a candidate prognostic and diagnostic biomarker are also discussed. In the future, more studies of Ankrd1 are warranted to clarify its role in diseases and assess its potential as a therapeutic target.
Keywords Ankrd1, Cardiovascular diseases, Skeletal muscle diseases, Angiogenesis, Tumor therapy
Address and Contact Information 1 Maternal and Child Research Institute, Shunde Women and Children Hospital, Guangdong Medical University, Foshan 528300, China
2 Department of Neurology, Longjiang Hospital, Foshan 528300, China
3 Department of Pediatrics, Shunde Women and Children Hospital, Guangdong Medical University, Foshan 528300, China
4 Medical Genetics Laboratory, Shunde Women and Children Hospital, Guangdong Medical University, Foshan 528300, China
5 Respiratory Research Institute, Shunde Women and Children Hospital, Guangdong Medical University, Foshan 528300, China
*Corresponding author: whlang197000@163.com; wangyajuny1977@aliyun.com; sihan1107@126.com
† Xusan Xu and Xiaoxia Wang have contributed equally to this paper.
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No.  132DOI: 10.1186/s11658-024-00652-z Volume 29 (2024) - 29:132
Title TRANSACTIVATION OF THE EGF RECEPTOR AS A NOVEL DESENSITIZATION MECHANISM FOR G PROTEIN-COUPLED RECEPTORS, ILLUSTRATED BY DOPAMINE D2-LIKE AND Β2 ADRENERGIC RECEPTORS
Authors Dooti Kundu1, Xiao Min1, Shujie Wang1, Lulu Peng1, Xinru Tian1, Mengling Wang1 and Kyeong‐Man Kim1*
Abstract Transactivation of epidermal growth factor receptors (EGFR) provides intricate control over multiple regulatory cellular processes that merge the diversity of G protein-coupled receptors (GPCRs) with the robust signaling capacities of receptor tyrosine kinases. Contrary to the typical assertions, our findings demonstrate that EGFR transactivation contributes to the desensitization of GPCRs. Repeated agonist stimulation of certain GPCRs enhanced EGFR transactivation, triggering a series of cellular events associated with GPCR desensitization. This effect was observed in receptors undergoing desensitization (D3R, K149C-D2R, β2AR) but not in those resistant to desensitization (D2R, C147K-D3R, D4R, β2AR mutants lacking GRK2 or GRK6 phosphorylation sites). The EGFR inhibitor AG1478 prevented both desensitization and the associated cellular events. Similarly, these cellular events were also observed when cells were treated with EGF, but only in GPCRs that undergo desensitization. These findings suggest that EGFR transactivation diversifies pathways involved in ERK activation through the EGFR signaling system and also mediates GPCR desensitization. Alongside the widely accepted steric hindrance model, these findings offer new insights into understanding the mechanisms of GPCR desensitization, which occurs through complex cellular processes.
Keywords GPCR, EGFR, Transactivation, Desensitization, Arrestin, Deubiquitination
Address and Contact Information 1 Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang‐Ju 61186, Korea
*Corresponding author: kmkim@jnu.ac.kr
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No.  133DOI: 10.1186/s11658-024-00648-9 Volume 29 (2024) - 29:133
Title CORRECTION: EXTRACELLULAR VESICLES DERIVED FROM CD4 + T CELLS CARRY DGKK TO PROMOTE SEPSIS-INDUCED LUNG INJURY BY REGULATING OXIDATIVE STRESS AND INFLAMMATION
Authors Guo‐wei Tu1†, Yi Zhang2†, Jie‐fei Ma3†, Jun‐yi Hou1 , Guang‐wei Hao1 , Ying Su1 , Jing‐chao Luo1 , Lulu Sheng4* and Luo Z1,3,5,6*
Abstract Correction: Cellular & Molecular Biology Letters (2023) 28:24
https://doi.org/10.1186/s11658-023-00435-y

Following publication of the original article [1], the authors identifed a similarity between the image labeled “CLP+shNC” in Fig. 6C of their article and an image in another publication from their hospital (PubMed: 34616481, Figure 5a). Upon careful investigation, the authors discovered that the image in question had been incorrectly labeled. Te error occurred unintentionally due to the fact that two research teams from hospital, both studying acute lung injury, were working in the same laboratory. Tis resulted in an accidental mislabeling of the H&E histopathology slides because of an incorrect slide number in the shared platform.
Keywords
Address and Contact Information 1 Cardiac Intensive Care Center, Zhongshan Hospital, Fudan University, Shanghai, China
2 Biomedical Research Center, Institute for Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China
3 Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
4 Department of Emergency Medicine, Shanghai Jiao Tong University Afliated Sixth People’s Hospital, Shanghai, China
5 Shanghai Key Laboratory of Lung Infammation and Injury, Shanghai, China
6 Department of Critical Care Medicine, Shanghai Xuhui Central Hospital, ZhongshanXuhui Hospital, Fudan University, Shanghai, China
*Corresponding author: yl20111211856@sjtu.edu.cn; luo.zhe@zs-hospital.sh.cn
† Guo-wei Tu, Yi Zhang and Jie-fei Ma contributed equally to this article and are co-frst authors.
The original article can be found online at https://doi.org/10.1186/s11658-​023-​00435-y
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No.  134DOI: 10.1186/s11658-024-00653-y Volume 29 (2024) - 29:134
Title Chemokine CXCL13–CXCR5 signaling in neuroinflammation and pathogenesis of chronic pain and neurological diseases
Authors Kaige Zheng1†, Muyan Chen1†, Xingjianyuan Xu1†, Peiyi Li1, Chengyu Yin1, Jie Wang2* and Boyi Liu1*
Abstract Chronic pain dramatically affects life qualities of the sufferers. It has posed a heavy burden to both patients and the health care system. However, the current treatments for chronic pain are usually insufficient and cause many unwanted side effects. Chemokine C–X–C motif ligand 13 (CXCL13), formerly recognized as a B cell chemokine, binds with the cognate receptor CXCR5, a G-protein-coupled receptor (GPCR), to participate in immune cell recruitments and immune modulations. Recent studies further demonstrated that CXCL13–CXCR5 signaling is implicated in chronic pain via promoting neuroimmune interaction and neuroinflammation in the sensory system. In addition, some latest work also pointed out the involvement of CXCL13–CXCR5 in the pathogenesis of certain neurological diseases, including ischemic stroke and amyotrophic lateral sclerosis. Therefore, we aim to outline the recent findings in regard to the involvement of CXCL13–CXCR5 signaling in chronic pain as well as certain neurological diseases, with the focus on how this chemokine signaling contributes to the pathogenesis of these neurological diseases via regulating neuroimmune interaction and neuroinflammation. Strategies that can specifically target CXCL13–CXCR5 signaling in distinct locations may provide new therapeutic options for these neurological diseases.
Keywords Chemokine, Neuroinfammation, Pain, Astrocyte, Neuron, CXCL13
Address and Contact Information 1 Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
2 Department of Rehabilitation in Traditional Chinese Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
*Corresponding author: wangjiee@zju.edu.cn; boyi.liu@foxmail.com
† K.Z., M.C., and X.X. contributed equally to this work.
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No.  135DOI: 10.1186/s11658-024-00654-x Volume 29 (2024) - 29:135
Title RESEARCH PROGRESS OF MUC1 IN GENITOURINARY CANCERS
Authors Weipu Mao1*†, Houliang Zhang1†, Keyi Wang2*, Jiang Geng3,4* and Jianping Wu1*
Abstract MUC1 is a highly glycosylated transmembrane protein with a high molecular weight. It plays a role in lubricating and protecting mucosal epithelium, participates in epithelial cell renewal and differentiation, and regulates cell adhesion, signal transduction, and immune response. MUC1 is expressed in both normal and malignant epithelial cells, and plays an important role in the diagnosis, prognosis prediction and clinical monitoring of a variety of tumors and is expected to be a new therapeutic target. This article reviews the structural features, expression regulation mechanism, and research progress of MUC1 in the development of genitourinary cancers and its clinical applications.
Keywords MUC1, Genitourinary cancers, Diagnosis, Therapeutic target
Address and Contact Information 1 Department of Urology, Afliated Zhongda Hospital of Southeast University, No. 87 Dingjiaqiao, Gulou District, Nanjing 210009, Jiangsu, China
2 Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
3 Department of Urology, Bengbu First People’s Hospital, Bengbu, People’s Republic of China
4 Department of Urology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, People’s Republic of China
*Corresponding author: maoweipu88@163.com; wangkeyi0910@163.com; gengjiangsn@sina.com; doctorwujianping@126.com
† Weipu Mao and Houliang Zhang have contributed equally to this work.
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No.  136DOI: 10.1186/s11658-024-00651-0 Volume 29 (2024) - 29:136
Title UPREGULATION OF ENAH BY A PI3K/AKT/Β-CATENIN CASCADE PROMOTES ORAL CANCER CELL MIGRATION AND GROWTH VIA AN ITGB5/Src aXIS
Authors Xiu‐Ya Chan1†, Kai‐Ping Chang2,3†, Chia‐Yu Yang1,2,3,4, Chiao‐Rou Liu1, Chu‐Mi Hung1, Chun‐Chueh Huang1, Hao‐Ping Liu6 and Chih‐Ching Wu1,2,3,5*
Abstract Background: Oral cancer accounts for 2% of cancer-related deaths globally, with over 90% of cases being oral cavity squamous cell carcinomas (OSCCs). Approximately 50% of patients with OSCC succumb to the disease within 5 years, primarily due to the advanced stage at which it is typically diagnosed. This underscores an urgent need to identify proteins related to OSCC progression to develop effective diagnostic and therapeutic strategies.
Methods: To identify OSCC progression-related proteins, we conducted integrated proteome and transcriptome analyses on cancer tissues from patients and patient-derived xenograft (PDX) model mice. We investigated the role of protein-enabled homolog (ENAH), identified as an OSCC progression-associated protein, through proliferation, transwell migration, and invasion assays in OSCC cells. The mechanisms underlying ENAH-mediated functions were elucidated using gene knockdown and ectopic expression techniques in OSCC cells.
Results: ENAH was identified as a candidate associated with OSCC progression based on integrated analyses, which showed increased ENAH levels in primary OSCC tissues compared with adjacent noncancerous counterparts, and sustained overexpression in the cancer tissues of PDX models. We confirmed that level of ENAH is increased in OSCC tissues and that its elevated expression correlates with poorer survival rates in patients with OSCC. Furthermore, the upregulation of ENAH in OSCC cells results from the activation of the GSK3β/β-catenin axis by the EGFR/PI3K/AKT cascade. ENAH expression enhances cell proliferation and mobility by upregulating integrin β5 in oral cancer cells.
Conclusions: The upregulation of ENAH through a PI3K/AKT/β-catenin signaling cascade enhances oral cancer cell migration and growth via the ITGB5/Src axis. These findings offer a new interpretation of the ENAH function in the OSCC progression and provide crucial information for developing new OSCC treatment strategies.
Keywords Protein-enabled homolog (ENAH), Oral cavity squamous cell carcinoma(OSCC), Patient-derived xenograft (PDX), Integrin β5 (ITGB5), Proteomics, GSK3β/β-catenin signaling
Address and Contact Information 1 Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
2 Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
3 Department of Otolaryngology‐Head and Neck Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
4 Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
5 Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
6 Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
*Corresponding author: luckywu@mail.cgu.edu.tw
† Xiu-Ya Chan and Kai-Ping Chang contributed equally to this work and shared the frst authorship.
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No.  137DOI: 10.1186/s11658-024-00658-7 Volume 29 (2024) - 29:137
Title HUMAN Gb3/CD77 SYNTHASE: A GLYCOSYLTRANSFERASE AT THE CROSSROADS OF IMMUNOHEMATOLOGY, TOXICOLOGY, AND CANCER RESEARCH
Authors Katarzyna Szymczak‐Kulus1*, Marcin Czerwinski1 and Radoslaw Kaczmarek1
Abstract Human Gb3/CD77 synthase (α1,4-galactosyltransferase, P1/Pk synthase, UDP-galactose: β-d-galactosyl-β1-R 4-α-d-galactosyltransferase, EC 2.4.1.228) forms Galα1 → 4Gal structures on glycosphingolipids and glycoproteins. These glycans are recognized by bacterial adhesins and toxins. Globotriaosylceramide (Gb3), the major product of Gb3/CD77 synthase, is a glycosphingolipid located predominantly in plasma membrane lipid rafts, where it serves as a main receptor for Shiga toxins released by enterohemorrhagic Escherichia coli and Shigella dysenteriae of serotype 1. On the other hand, accumulation of glycans formed by Gb3/CD77 synthase contributes to the symptoms of Anderson–Fabry disease caused by α-galactosidase A deficiency. Moreover, variation in Gb3/CD77 synthase expression and activity underlies the P1PK histo-blood group system. Glycosphingolipids synthesized by the enzyme are overproduced in colorectal, gastric, pancreatic, and ovarian cancer, and elevated Gb3 biosynthesis is associated with cancer cell chemo- and radioresistance. Furthermore, Gb3/CD77 synthase acts as a key glycosyltransferase modulating ovarian cancer cell plasticity. Here, we describe the role of human Gb3/CD77 synthase and its products in the P1PK histo-blood group system, Anderson–Fabry disease, and bacterial infections. Additionally, we provide an overview of emerging evidence that Gb3/CD77 synthase and its glycosphingolipid products are involved in cancer metastasis and chemoresistance.
Keywords glycosyltransferase, glycosphingolipid, glycoprotein, blood group, cancer, Anderson-Fabry disease, Shiga toxin, chemoresistance
Address and Contact Information 1 Laboratory of Glycobiology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53‐114 Wroclaw, Poland
*Corresponding author: katarzyna.szymczak-kulus@hirszfeld.pl
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No.  138DOI: 10.1186/s11658-024-00659-6 Volume 29 (2024) - 29:138
Title THE ROLE OF REACTIVE OXYGEN SPECIES IN SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2) INFECTION-INDUCED CELL DEATH
Authors Jiufeng Xie1, Cui Yuan1, Sen Yang1, Zhenling Ma1, Wenqing Li1, Lin Mao1, Pengtao Jiao2* and Wei Liu1*
Abstract Coronavirus disease 2019 (COVID-19) represents the novel respiratory infectious disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is characterized by rapid spread throughout the world. Reactive oxygen species (ROS) account for cellular metabolic by-products, and excessive ROS accumulation can induce oxidative stress due to insufficient endogenous antioxidant ability. In the case of oxidative stress, ROS production exceeds the cellular antioxidant capacity, thus leading to cell death. SARS-CoV-2 can activate different cell death pathways in the context of infection in host cells, such as neutrophil extracellular trap (NET)osis, ferroptosis, apoptosis, pyroptosis, necroptosis and autophagy, which are closely related to ROS signalling and control. In this review, we comprehensively elucidated the relationship between ROS generation and the death of host cells after SARS-CoV-2 infection, which leads to the development of COVID-19, aiming to provide a reasonable basis for the existing interventions and further development of novel therapies against SARS-CoV-2.
Keywords SARS-CoV-2, COVID-19, Reactive oxygen species, Cell death, Antiviral therapy
Address and Contact Information 1 College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
2 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
*Corresponding author: pengtaojiao66@126.com; liuv@henau.edu.cn
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No.  139DOI: 10.1186/s11658-024-00655-w Volume 29 (2024) - 29:139
Title EARLY AND LATE PHASES OF LIVER SINUSOIDAL ENDOTHELIAL CELL (LSEC) DEFENESTRATION IN MOUSE MODEL OF SYSTEMIC INFLAMMATION
Authors Izabela Czyzynska‐Cichon1†, Jerzy Kotlinowski2†, Oliwia Blacharczyk3, Magdalena Giergiel4, Konrad Szymanowski3, Sara Metwally3, Kamila Wojnar‐Lason1,6, Ewelina Dobosz5, Joanna Koziel5, Malgorzata Lekka3, Stefan Chlopicki1,6 and Bartlomiej Zapotoczny3*
Abstract Background: Liver sinusoidal endothelial cells (LSECs) have transcellular pores, called fenestrations, participating in the bidirectional transport between the vascular system and liver parenchyma. Fenestrated LSECs indicate a healthy phenotype of liver while loss of fenestrations (defenestration) in LSECs is associated with liver pathologies.
Methods: We introduce a unique model of systemic inflammation triggered by the deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) characterised by progressive alterations in LSEC phenotype. We implement multiparametric characterisation of LSECs by using novel real-time atomic force microscopy supported with scanning electron microscopy and quantitative fluorescence microscopy. In addition, we provide genetic profiling, searching for characteristic genes encoding proteins that might be connected with the structure of fenestrations.
Results: We demonstrate that LSECs in Mcpip1fl/flLysMCre display two phases of defenestration: the early phase, with modest defenestration that was fully reversible using cytochalasin B and the late phase, with severe defenestration that is mostly irreversible. By thorough analysis of LSEC porosity, elastic modulus and actin abundance in Mcpip1fl/flLysMCre and in response to cytochalasin B, we demonstrate that proteins other than actin must be additionally responsible for inducing open fenestrations. We highlight several genes that were severely affected in the late but not in the early phase of LSEC defenestration shedding a light on complex structure of individual fenestrations.
Conclusions: The presented model of LSEC derived from Mcpip1fl/flLysMCre provides a valuable reference for developing novel strategies for LSEC refenestration in the early and late phases of liver pathology.
Keywords Mcpip1, Fenestration, Actin cytoskeleton, Liver, LSEC, Forced sieving
Address and Contact Information 1 Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30‐348 Krakow, Poland
2 Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30‐387 Krakow, Poland
3 Institute of Nuclear Physics Polish Academy of Sciences, 31342 Krakow, Poland
4 Centre for Nanometer‐Scale Science and Advanced Materials (NANOSAM), Faculty of Physics, Astronomy, and Applied Computer Science, Jagiellonian University, Krakow, Poland
5 Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30‐387 Krakow, Poland
6 Department of Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, 31‐531 Krakow, Poland
*Corresponding author: bartlomiej.zapotoczny@if.edu.pl
† Izabela Czyzynska-Cichon and Jerzy Kotlinowski contributed equally to this manuscript.
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No.  140DOI: 10.1186/s11658-024-00649-8 Volume 29 (2024) - 29:140
Title m6A-MODIFIED circCacna1c REGULATES NECROPTOSIS AND ISCHEMIC MYOCARDIAL INJURY BY INHIBITING HNRNPF ENTRY INTO THE NUCLEUS
Authors Yi Jia1, Xiaosu Yuan1, Luxin Feng1,2, Qingling Xu1, Xinyu Fang1, Dandan Xiao1, Qi Li1,3, Yu Wang1, Lin Ye1, Peiyan Wang1, Xiang Ao1* and Jianxun Wang1*
Abstract Background: Circular RNAs (circRNAs) are differentially expressed in various cardiovascular diseases, including myocardial infarction (MI) injury. However, their functional role in necroptosis-induced loss of cardiomyocytes remains unclear. We identified a cardiac necroptosis-associated circRNA transcribed from the Cacna1c gene (circCacna1c) to investigate the involvement of circRNAs in cardiomyocyte necroptosis.
Methods: To investigate the role of circCacna1c during oxidative stress, H9c2 cells and neonatal rat cardiomyocytes were treated with hydrogen peroxide (H22O2) to induce reactive oxygen species (ROS)-induced cardiomyocyte death. The N6-methyladenosine (m6A) modification level of circCacna1c was determined by methylated RNA immunoprecipitation quantitative polymerase chain reaction (MeRIP–qPCR) analysis. Additionally, an RNA pull-down assay was performed to identify interacting proteins of circCacna1c in cardiomyocytes, and the regulatory role of circCacna1c in target protein expression was tested using a western blotting assay. Furthermore, the MI mouse model was constructed to analyze the effect of circCacna1c on heart function and cardiomyocyte necroptosis.
Results: The expression of circCacna1c was found to be reduced in cardiomyocytes exposed to oxidative stress and in mouse hearts injured by MI. Overexpression of circCacna1c inhibited necroptosis of cardiomyocytes induced by hydrogen peroxide and MI injury, resulting in a significant reduction in myocardial infarction size and improved cardiac function. Mechanistically, circCacna1c directly interacts with heterogeneous nuclear ribonucleoprotein F (Hnrnpf) in the cytoplasm, preventing its nuclear translocation and leading to reduced Hnrnpf levels within the nucleus. This subsequently suppresses Hnrnpf-dependent receptor-interacting protein kinase 1 (RIPK1) expression. Furthermore, fat mass and obesity-associated protein (FTO) mediates demethylation of m6A modification on circCacna1c during necrosis and facilitates degradation of circCacna1c.
Conclusion: Our study demonstrates that circCacna1c can improve cardiac function following MI-induced heart injury by inhibiting the Hnrnpf/RIPK1-mediated cardiomyocyte necroptosis. Therefore, the FTO/circCacna1c/Hnrnpf/RIPK1 axis holds great potential as an effective target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.
Keywords circCacna1c, Cardiomyocyte necroptosis, Myocardial infarction, N6-methyladenosine, Hnrnpf
Address and Contact Information 1 School of Basic Medicine, Qingdao University, Qingdao 266071, China
2 Department of Cardiology, The Afliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China
3 School of Nursing, Qingdao University, Qingdao 266071, China
*Corresponding author: xiangao2016@163.com; wangjx@qdu.edu.cn
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No.  141DOI: 10.1186/s11658-024-00661-y Volume 29 (2024) - 29:141
Title MULTIFUNCTIONAL ACYLTRANSFERASE HBO1: A KEY REGULATORY FACTOR FOR CELLULAR FUNCTIONS
Authors Zhanhuan Su1,2, Yang Zhang2, Jingqiong Tang3, Yanhong Zhou2* and Chen Long1*
Abstract HBO1, also known as KAT7 or MYST2, is a crucial histone acetyltransferase with diverse cellular functions. It typically forms complexes with protein subunits or cofactors such as MEAF6, ING4, or ING5, and JADE1/2/3 or BRPF1/2/3, where the BRPF or JADE proteins serve as the scaffold targeting histone H3 or H4, respectively. The histone acetylation mediated by HBO1 plays significant roles in DNA replication and gene expression regulation. Additionally, HBO1 catalyzes the modification of proteins through acylation with propionyl, butyryl, crotonyl, benzoyl, and acetoacetyl groups. HBO1 undergoes ubiquitination and degradation by two types of ubiquitin complexes and can also act as an E3 ubiquitin ligase for the estrogen receptor α (ERα). Moreover, HBO1 participates in the expansion of medullary thymic epithelial cells (mTECs) and regulates the expression of peripheral tissue genes (PTGs) mediated by autoimmune regulator (AIRE), thus inducing immune tolerance. Furthermore, HBO1 influences the renewal of hematopoietic stem cells and the development of neural stem cells significantly. Importantly, the overexpression of HBO1 in various cancers suggests its carcinogenic role and potential as a therapeutic target. This review summarizes recent advancements in understanding HBO1’s involvement in acylation modification, DNA replication, ubiquitination, immunity, and stem cell renewal.
Keywords HBO1, Acetylation, Ubiquitylation, DNA replication, Immune regulation
Address and Contact Information 1 Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
2 Cancer Research Institute, Basic School of Medicine, Central South University, Changsha 410078, Hunan, China
3 Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
*Corresponding author: zhouyanhong@csu.edu.cn; longchen301@csu.edu.cn
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No.  142DOI: 10.1186/s11658-024-00662-x Volume 29 (2024) - 29:142
Title THE CROSSTALK BETWEEN ALTERNATIVE SPLICING AND CIRCULAR RNA IN CANCER: PATHOGENIC INSIGHTS AND THERAPEUTIC IMPLICATIONS
Authors Hongkun Hu1, Jinxin Tang1, Hua Wang1, Xiaoning Guo1*, Chao Tu1,2,3* and Zhihong Li1,2,3*
Abstract RNA splicing is a fundamental step of gene expression. While constitutive splicing removes introns and joins exons unbiasedly, alternative splicing (AS) selectively determines the assembly of exons and introns to generate RNA variants corresponding to the same transcript. The biogenesis of circular RNAs (circRNAs) is inextricably associated with AS. Back-splicing, the biogenic process of circRNA, is a special form of AS. In cancer, both AS and circRNA deviate from the original track. In the present review, we delve into the intricate interplay between AS and circRNAs in the context of cancer. The relationship between AS and circRNAs is intricate, where AS modulates the biogenesis of circRNAs and circRNAs in return regulate AS events. Beyond that, epigenetic and posttranscriptional modifications concurrently regulate AS and circRNAs. On the basis of this modality, we summarize current knowledge on how splicing factors and other RNA binding proteins regulate circRNA biogenesis, and how circRNAs interact with splicing factors to influence AS events. Specifically, the feedback loop regulation between circRNAs and AS events contributes greatly to oncogenesis and cancer progression. In summary, resolving the crosstalk between AS and circRNA will not only provide better insight into cancer biology but also provoke novel strategies to combat cancer.
Keywords Alternative splicing, Circular RNA, Histone modifcation, N6-methyladenosine modifcation, Splicing factor
Address and Contact Information 1 Department of Orthopaedics, Hunan Key Laboratory of Tumor Models and Individualized Medicine, Hunan Engineering Research Center of Artifcial Intelligence-Based Medical Equipment, The Second Xiangya Hospital of Central South University, Changsha 410011, China
2 Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, China
3 Hunan Engineering Research Center of Artifcial Intelligence-Based Medical Equipment, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
*Corresponding author: guoxiaoning@csu.edu. cn; tuchao@csu.edu.cn; lizhihong@csu.edu.cn
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No.  143DOI: 10.1186/s11658-024-00657-8 Volume 29 (2024) - 29:143
Title DIFFERENT AMYLOID Β42 PREPARATIONS INDUCE DIFFERENT CELL DEATH PATHWAYS IN THE MODEL OF SH-SY5Y NEUROBLASTOMA CELLS
Authors Alp Yigit Özdemir1, Kateřina Hofbauerová2, Vladimír Kopecký Jr.2, Jiří Novotný1 and Vladimír Rudajev1*
Abstract Amyloid β42 (Aβ42) plays a decisive role in the pathology of Alzheimer’s disease. The Aβ42 peptide can aggregate into various supramolecular structures, with oligomers being the most toxic form. However, different Aβ species that cause different effects have been described. Many cell death pathways can be activated in connection with Aβ action, including apoptosis, necroptosis, pyroptosis, oxidative stress, ferroptosis, alterations in mitophagy, autophagy, and endo/lysosomal functions. In this study, we used a model of differentiated SH-SY5Y cells and applied two different Aβ42 preparations for 2 and 4 days. Although we found no difference in the shape and size of Aβ species prepared by two different methods (NaOH or NH4OH for Aβ solubilization), we observed strong differences in their effects. Treatment of cells with NaOH-Aβ42 mainly resulted in damage of mitochondrial function and increased production of reactive oxygen species, whereas application of NH4OH-Aβ42 induced necroptosis and first steps of apoptosis, but also caused an increase in protective Hsp27. Moreover, the two Aβ42 preparations differed in the mechanism of interaction with the cells, with the effect of NaOH-Aβ42 being dependent on monosialotetrahexosylganglioside (GM1) content, whereas the effect of NH4OH-Aβ42 was independent of GM1. This suggests that, although both preparations were similar in size, minor differences in secondary/tertiary structure are likely to strongly influence the resulting processes. Our work reveals, at least in part, one of the possible causes of the inconsistency in the data observed in different studies on Aβ-toxicity pathways.
Keywords Amyloid β42, Alzheimer's disease, Cell death, Apoptosis, Necroptosis, Reactive oxygen species, GM1
Address and Contact Information 1 Department of Physiology, Faculty of Sciences, Charles University, Viničná 7, 12844 Prague 2, Czech Republic
2 Institute of Physics, Faculty of Mathematics and Physics, Charles University, Ke Karlovu 5, 12116 Prague 2, Czech Republic
*Corresponding author: rudajev@natur.cuni.cz
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No.  144DOI: 10.1186/s11658-024-00656-9 Volume 29 (2024) - 29:144
Title THE miR-1269a/PCDHGA9/CXCR4/β-cATENIN PATHWAY PROMOTES COLORECTAL CANCER INVASION AND METASTASIS
Authors Haitao Mei1,2,3†, Qingshan Luo2†, Junyong Weng3,5†, Jialing Hao2, Jinfeng Cai2, Runkai Zhou2, Ce Bian3, Ye Yingzi6, Luo Shengzheng4 and Wen Yugang2*
Abstract Background: Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. This research focuses on investigating the impact and underlying molecular mechanisms of protocadherin gamma subfamily A, 9 (PCDHGA9) on the invasion and metastasis of CRC, aiming to identify more precise molecular markers for the diagnosis and prognosis of CRC.
Methods: PCDHGA9 expression was detected using quantitative real-time quantitative polymerase chain reaction (RT-qPCR) in 63 pairs of colorectal cancer tissues. Differential gene expression from high-throughput sequencing was analyzed using ingenuity pathway analysis (IPA) to explore the biological functions of PCDHGA9 and its potential regulated genes. Bioinformatics tools were employed to explore potential upstream regulatory microRNAs of PCDHGA9. Dual-luciferase assays were performed to demonstrate the regulation between PCDHGA9 and miR-1269a. Protein mass spectrometry suggested an interaction between PCDHGA9 and HOXA1. JASPAR predicted that HOXA1 may act as a transcription factor of CXCR4. Coimmunoprecipitation, dual-luciferase assays, and nuclear–cytoplasmic fractionation experiments confirmed the molecular mechanism involving PCDHGA9, CXCR4, HOXA1, and β-catenin. Transwell, wound healing, and western blot assays were conducted to confirm the impact of PCDHGA9, miR-1269a, and CXCR4 on the invasion, metastasis, and epithelial–mesenchymal transition (EMT) functions of CRC cells in in vitro experiments. A whole-body fluorescence imaging system was used to evaluate the combined impact of miR-1269a and PCDHGA9 on the invasion and metastasis of CRC in in vivo experiments.
Results: The expression of PCDHGA9 was found to be lower in CRC tissues compared with their corresponding adjacent tissues. Low expression of PCDHGA9 potentially correlated with worse prognosis and increased chances of invasion and metastasis in CRC. miR-1269a was highly expressed in CRC tissues and acted as a negative regulator for PCDHGA9, promoting invasion, migration, and EMT of CRC cells. PCDHGA9’s interaction with HOXA1 downregulated CXCR4, a transcription factor, leading to accumulation of β-catenin and further promoting invasion, migration, and EMT of CRC cells.
Conclusions: PCDHGA9, acting as a tumor suppressor, is downregulated by miR-1269a. The low level of PCDHGA9 activates the Wnt/β-catenin pathway by releasing its interaction with HOXA1, promoting the expression of CXCR4, and causing invasion, migration, and EMT in CRC.
Keywords CRC, PCDHGA9, miR-1269a, HOXA1, CXCR4, β-Catenin
Address and Contact Information 1 Department of Gastrointestinal Surgery, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Shanghai 200071, China
2 Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 85 Wujin Road, Shanghai 200080, China
3 Department of Colorectal Surgery, Changzheng Hospital, Navy Medical University, 415 Fengyang Road, Shanghai 200003, China
4 Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 85 Wujin Road, Shanghai 200080, China
5 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China
6 Department of Infectious Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China
*Corresponding author: wenyg1502@hotmail.com
† Haitao Mei, Qingshan Luo, and Junyong Weng contributed equally to this work.
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No.  145DOI: 10.1186/s11658-024-00664-9 Volume 29 (2024) - 29:145
Title KPNB1-ATF4 INDUCES BNIP3-DEPENDENT MITOPHAGY TO DRIVE ODONTOBLASTIC DIFFERENTIATION IN DENTAL PULP STEM CELLS
Authors Zeying Zhang1, Di Yang1, Xiaoyuan Yan1, Qiujing Qiu1, Jiajie Guo1*† and Lihong Qiu1*†
Abstract Background: Differentiating dental pulp stem cells (DPSCs) into odontoblasts is a critical process for tooth self-repair and dentine‒pulp engineering strategies in the clinic. However, the mechanism underlying the regulation of DPSC odontoblastic differentiation remains largely unknown. Here, we demonstrated that BCL-2 interacting protein 3 (BNIP3)-dependent mitophagy is associated with importin subunit beta-1 (KPNB1)-activating transcription factor 4 (ATF4), which promotes DPSC odontoblastic differentiation.
Methods: The key genes involved in DPSC odontogenic differentiation were identified via bioinformatics. Stable silencing or overexpression of BNIP3 was performed to investigate its impact on DPSC differentiation in vitro (n ≥ 3). To explore the role of BNIP3 in vivo, tooth root fragments loaded with the hydrogel-transfected DPSC complex were implanted into nude mice (n ≥ 6). Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) polymerase chain reaction (PCR) were conducted to explore the binding site of ATF4 to the BNIP3 promoter (n ≥ 3). Mitochondrial function experiments were performed to investigate the impact of ATF4-BNIP3 on mitochondria (n ≥ 3). Immunoprecipitation (IP) mass spectrometry (MS) was used to investigate the interaction between ATF4 and its binding protein, KPNB1. Plasmids containing wild-type (WT)/mutant (MUT)-nuclear localization signal (NLS) forms of ATF4 were constructed to determine the specific amino acid residues recognized by KPNB1 and their effects on DPSC odontoblastic differentiation (n ≥ 3).
Results: Compared with those in the control group, the levels of autophagy and mitophagy, especially BNIP3-dependent mitophagy, were greater in the DPSC odontoblastic differentiation group (P < 0.05). Genetic silencing or overexpression of BNIP3 demonstrated that BNIP3 expression was positively correlated with the transition of DPSCs into odontoblasts both in vitro and in vivo (P < 0.05). ATF4 regulates the expression of BNIP3 by directly binding to approximately −1292 to −1279 bp and approximately −1185 to −1172 bp within the BNIP3 promoter region, which is associated with mitophagy and mitochondrial reactive oxygen species (mtROS) levels (P < 0.05). Moreover, ATF4 increased mitophagy, mitochondrial function, and cell differentiation potential via BNIP3 (P < 0.05). Mechanistically, KPNB1 is a novel interacting protein of ATF4 that specifically recognizes amino acids (aa) 280–299 within ATF4 to control its translocation into the nucleus and subsequent transcription and differentiation processes (P < 0.05).
Conclusions: We reported that the critical role of KPNB1/ATF4/BNIP3 axis-dependent mitophagy could provide new cues for the regeneration of the dental pulp‒dentin complex in DPSCs.
Keywords Dental pulp stem cell, Odontoblastic diferentiation, Mitophagy, ATF4, BNIP3, KPNB1
Address and Contact Information 1 Department of Endodontics, School and Hospital of Stomatology, Liaoning Provincial Key Laboratory of Oral Diseases, China Medical University, 117 Nanjing North Street, Heping District, Shenyang, Liaoning 110002, People’s Republic of China
*Correspondence: guojiajie@cmu.edu.cn; lhqiu@cmu.edu.cn
† Jiajie Guo and Lihong Qiu should be considered joint corresponding author.
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No.  146DOI: 10.1186/s11658-024-00665-8 Volume 29 (2024) - 29:146
Title SENP3 MEDIATES deSUMOylation OF SIX1 TO PROMOTE PROSTATE CANCER PROLIFERATION AND MIGRATION
Authors Zhenlong Shao1,2†, Shutong Liu2†, Wenshuang Sun2†, Xuefen Zhuang2, Shusha Yin2, Ji Cheng2, Xiaohong Xia1, Yuning Liao1,2*, Jinbao Liu1,2* and Hongbiao Huang1,2*
Abstract Background: Sentrin/SUMO-specific protease 3 (SENP3) is essential to regulate protein stability and function in normal and cancer cells. Nevertheless, its role and action mechanisms in prostate cancer (PCa) remain elusive. Thus, clarification of SENP3’s involvement and the SUMOylation process in PCa is pivotal for discovering potential targets and understanding SUMOylation dynamics.
Methods: Cell viability, EdU staining, live cell imaging, and cell cycle assays were used to determine proliferation of PCa cells. Transwell and wound-healing assays were used to detect migration of PCa cells. The interaction between SENP3 and SIX1 was determined by co-immunoprecipitation, western blotting, and immunofluorescence assays. Xenograft models established on NOD-SCID mice were used to evaluate in vivo effects post SENP3 knockdown. Immunohistochemistry was performed to investigate the expression of SENP3 in PCa tissues.
Results: This study found that SENP3 is highly expressed in PCa cell lines and tissues from PCa patients. Overexpressed SENP3 is associated with metastatic malignancy in PCa. Various in vivo and in vitro experiments confirmed that SENP3 promotes the proliferation and migration of PCa. In addition, SENP3 interacts with the SD domain of SIX1 and mediates its deSUMOylation and protein stability. Lys154 (K154) is required for the SUMOylation of SIX1. More importantly, SENP3 promotes the malignancy of PCa through the regulation of SIX1.
Conclusions: We unravel the significant role of SENP3 in regulating protein stability of SIX1 and progression of PCa, which may deepen our understanding of the SUMOylation modification and provide a promising target for management of metastatic PCa.
Keywords SUMOylation, SENP3, SIX1, Prostate cancer, Tumor progression
Address and Contact Information 1 Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou 510095, China
2 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modifcation and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, Guangdong, China
*Correspondence: 2019990003@gzhmu.edu. cn; jliu@gzhmu.edu.cn; huanghongbiao@gzhmu.edu.cn
† Zhenlong Shao, Shutong Liu and Wenshuang Sun contributed equally to this work.
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No.  147DOI: 10.1186/s11658-024-00667-6 Volume 29 (2024) - 29:147
Title SALIVARY GLAND PROTECTIVE AND ANTIINFLAMMATORY EFFECTS OF GENISTEIN IN SJÖGREN’S SYNDROME BY INHIBITING Xist/ACSL4-MEDIATED FERROPTOSIS FOLLOWING BINDING TO ESTROGEN RECEPTOR-ALPHA
Authors Tianjiao Mao1†, Wei Wei2†, Bo Chen1†, Yixin Chen1, Shuqi Liang1, Guiping Chen1, Zhuoyuan Liu1, Xiaodan Wu1, Lihong Wu1, Xiaomeng Li3, Nobumoto Watanabe4,5, Kevin H. Mayo6, Janak L. Pathak1* and Jiang Li1*
Abstract Background: Sjögren’s syndrome (SS) is an autoimmune disease with limited effective treatment options. This study aimed to explore the underlying mechanism by which genistein–estrogen receptor alpha (ERα) complex targets X-inactive specific transcript (Xist) then leads to the inhibition of ferroptosis by regulating acyl-CoA synthetase long-chain family member 4 (ACSL4) expression in salivary gland epithelial cells (SGECs) to attenuate SS.
Methods: The effects of genistein treatment on the progression and underlying mechanism of SS were investigated using nondiabetic obese (NOD)/LtJ mice in vivo and Interferon-γ (IFNγ)-treated SGECs in vitro. Water intake and saliva flow rate were measured to evaluate the severity of xerostomia. Hematoxylin–eosin staining, real-time quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay were conducted to examine the pathological lesions. Western blotting and immunohistochemistry analysis were used to evaluate the protein expression. RNA sequencing and RNA fluorescence in situ hybridization were employed to verify the relationship between Xist and ACSL4. Surface plasmon resonance, molecular docking, and molecular dynamics were used to investigate the binding between genistein and ERα. Furthermore, a chromatin immunoprecipitation assay was used to analyze ERα–XIST promoter interactions. The levels of malondialdehyde, glutathione, Fe2+, and mitochondrial changes were measured to evaluate ferroptosis of SGECs.
Results: In NOD/LtJ mice, a ferroptosis phenotype was observed in salivary glands, characterized by downregulated Xist and upregulated X chromosome inactivation gene Acsl4. Genistein significantly alleviated SS symptoms, upregulated the Xist gene, and downregulated Acsl4 expression. Genistein upregulated Xist expression in the salivary gland of NOD/LtJ mice via the ERα signaling pathway. It downregulated Acsl4 and ferroptosis in the salivary glands of NOD/LtJ mice. IFNγ-treatment induced inflammation and ferroptosis in SGECs. Genistein binding to ERα upregulated XIST, and aquaporin 5 expression, downregulated ACSL4, and SS antigen B expression, and reversed ferroptosis in SGECs. Genistein mitigated inflammation and ferroptosis in SGECs by upregulated-XIST-mediated ACSL4 gene silencing.
Conclusions: Genistein binding to ERα targets Xist, leading to inhibiting ferroptosis by regulating ACSL4 expression in SGECs. This finding provides evidence for genistein as a treatment for SS and identifies Xist as a novel drug target for SS drug development, offering great promise for improving SS outcomes.
Keywords Genistein, Sjögren’s syndrome, Salivary gland epithelial cells, Ferroptosis, XIST, ACSL4
Address and Contact Information 1 School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Medical University, Guangzhou 510140, China
2 Department of Prosthodontics, School and Hospital of Stomatology, Jilin University, Changchun 130012, China
3 KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 510140, China
4 Bioprobe Application Research Unit, RIKEN-Max Planck Joint Research Division, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan
5 Graduate School of Medical & Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
6 Biochemistry, Molecular Biology, and Biophysics, Health Sciences Center, University of Minnesota, Minneapolis, MN 55455, USA
*Correspondence: j.pathak@gzhmu.edu.cn; ljiang@gzhmu.edu.cn
† Tianjiao Mao, Wei Wei, and Bo Chen contributed equally and share first authorship.
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No.  148DOI: 10.1186/s11658-024-00668-5 Volume 29 (2024) - 29:148
Title SINGLE-CELL VIEW AND A NOVEL PROTECTIVE MACROPHAGE SUBSET IN PERIVASCULAR ADIPOSE TISSUE IN T2DM
Authors Jiaxuan Li1,4,5†, Zhenyu Tian1†, Tongxue Zhang1, Jiajia Jin1, Xinjie Zhang6, Panpan Xie7, Haiyan Lin3, Junfei Gu1,2,3, Yingjie Wu4,5, Xiaowei Wang1, Shucui Zhang1, Xuefang Yan1, Dong Guo8*, Zhe Wang2,3* and Qunye Zhang1*
Abstract Background: Vasculopathy underlies diabetic complications, with perivascular adipose tissue (PVAT) playing crucial roles in its development. However, the changes in the cellular composition and function of PVAT, including the specific cell subsets and mechanisms implicated in type 2 diabetes mellitus (T2DM) vasculopathy, remain unclear.
Methods: To address the above issues, we performed single-cell RNA sequencing on the stromal vascular fraction (SVF) of PVAT from normal and T2DM rats. Then, various bioinformatics tools and functional experiments were used to investigate the characteristic changes in the cellular profile of diabetic PVAT SVF, their implications, and the underlying mechanisms.
Results: Our study reveals the single-cell landscape of the SVF of PVAT, demonstrating its considerable heterogeneity and significant alterations in T2DM, including an enhanced inflammatory response and elevated proportions of macrophages and natural killer (NK) cells. Moreover, macrophages are critical hubs for cross-talk among various cell populations. Notably, we identified a decreased Pdpn+ macrophage subpopulation in the PVAT of T2DM rats and confirmed this in mice and humans. In vitro and in vivo studies demonstrated that Pdpn+ macrophages alleviated insulin resistance and modulated adipokine/cytokine expression in adipocytes via the Pla2g2d-DHA/EPA-GPR120 pathway. This subset also enhances the function of vascular endothelial and smooth muscle cells, inhibits vascular inflammation and oxidative stress, and improves vasodilatory function, thereby protecting blood vessels.
Conclusion: Pdpn+ macrophages exhibit significant vascular protective effects by alleviating insulin resistance and modulating adipokine/cytokine expression in PVAT adipocytes. This macrophage subtype may therefore play pivotal roles in mitigating vascular complications in T2DM. Our findings also underscore the critical role of immune-metabolic cross-talk in maintaining tissue homeostasis.
Keywords Diabetes, PVAT, SVF, Single-cell, Pdpn+ macrophage
Address and Contact Information 1 Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan 250012, China.
2 Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China.
3 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China.
4 Shandong Provincial Hospital, Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Science, Jinan 250021, China.
5 Key Laboratory of Endocrine Glucose and Lipids Metabolism and Brain Aging, Chinese Ministry of Education, Shandong First Medical University, Jinan 250021, China.
6 Department of Biology, University College London, London NW1 2HE, UK.
7 Department of Breast and Thyroid Surgery, Liaocheng People’s Hospital, Liaocheng 252000, China
8 Department of Neurology, Liaocheng People’s Hospital, Liaocheng 252000, China.
*Corresponding author: guodonglc@126.com; wangzhe.zqy@email.sdu.edu.cn; wz.zhangqy@sdu.edu.cn
† Jiaxuan Li and Zhenyu Tian have contributed equally.
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No.  149DOI: 10.1186/s11658-024-00672-9 Volume 29 (2024) - 29:149
Title ACID-SENSING ION CHANNEL-1 CONTRIBUTES TO THE FAILURE OF MYELIN SHEATH REGENERATION FOLLOWING SPINAL CORD INJURY BY TRANSCELLULAR DELIVERY OF PGE2
Authors Zuomeng Wu1,2†, Tianyu Han1,2†, Yixiang Dong1,2, Wang Ying3, Huang Fang4, Yunlei Liu5, Peiwen Song1,2* and Cailiang Shen1,2*
Abstract Background: Traumatic injuries to spinal cord lead to severe motor, sensory, and autonomic dysfunction. The accumulation of inhibitory compounds plays a pivotal role in the secondary damage to sparing neural tissue and the failure of axonal regeneration and remyelination. Acid-sensing ion channel-1(ASIC1A) is widely activated following neurotrauma, including spinal cord injury (SCI). However, its role in SCI remains elusive.
Methods: The effects of acidic environment on the differentiation and genes changes of neural stem cells (NSCs) were assessed by immunofluorescence staining and RNA-sequencing analysis, respectively. The expression of ASIC1A and prostaglandin endoperoxide synthase 2 (PTGS2) were detected by western blot and immunofluorescence staining. The concentration of prostaglandin E2 (PGE2) within NSC-derived extracellular vesicles were evaluated by ELISA. Small-interfering RNAs (siRNAs) were used to knock down Asic1a and Ptgs2 expression in NSCs. The myelin sheath regeneration and axonal remyelination in rats and Asic1a-KO mice were assessed by immunofluorescence staining.
Results: Following injury to the spinal cord, ASIC1A was found to be colocalized and upregulated in NSCs. ASIC1A activation prevents the differentiation of NSCs into oligodendrocytes by upregulating PTGS2, which leads to increased production and release of PGE2 within extracellular vesicles (EVs). ASIC1A or PTGS2 deficiency in NSCs counters the ASIC1A-related effects on mediating NSC differentiation by reducing PGE2 expression within NSC-derived EVs. Furthermore, intervention in ASIC1A signaling by administration of ASIC1A inhibitors or genetic deletion of ASIC1A demonstrated a pronounced advantage in enhancing myelin sheath regeneration and axonal remyelination.
Conclusions: The activation of ASIC1A prevents NSC differentiation into oligodendrocytes via the transcellular NSC-to-NSC delivery of PGE2, resulting in the failure of myelin sheath regeneration and axonal remyelination following SCI. The inhibition of ASIC1A presents a promising therapeutic strategy for the treatment of SCI.
Keywords Spinal cord injury, Neural stem cells, Acid-sensing ion channel, Prostaglandin endoperoxide synthase 2
Address and Contact Information 1 Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People’s Republic of China
2 Laboratory of Spinal and Spinal Cord Injury Regeneration and Repair, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People’s Republic of China
3 Department of Medical Imaging, The First Affiliated Hospital of Anhui Medical University, Hefei, China
4 Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of USTC, Hefei 230032, People’s Republic of China
5 Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People’s Republic of China
*Corresponding author: 185045864@qq.com; shenclspine@163.com
† Zuomeng Wu and Tianyu Han have contributed equally to this work and should be considered co-first authors.
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No.  150DOI: 10.1186/s11658-024-00670-x Volume 29 (2024) - 29:150
Title EXERCISE PROMOTES SKELETAL MUSCLE GROWTH IN ADOLESCENTS VIA MODULATING Mettl3-MEDIATED m6A METHYLATION OF MyoD IN MUSCLE SATELLITE CELLS
Authors Shujing Feng1,2†, Hao Zhou1†, Xingzuan Lin3†, Siyuan Zhu4†, Huifang Chen2, Han Zhou1, Ru Wang2, Peng Wang1*, Xiexiang Shao1* and Jianhua Wang1,2*
Abstract Background: Exercise exerts positive impacts on skeletal muscle health and homeostasis. Emerging evidence suggests that m6A methylation is involved in various physiological processes. However, the impact of exercise on adolescent skeletal muscle growth and the underlying epigenetic mechanisms remain poorly understood.
Methods: The lower-limb skeletal muscles were harvested from exercise and control groups to compare the skeletal muscle growth in adolescents. mRNA sequencing was conducted to explore the mechanisms underlying enhanced skeletal muscle growth following exercise. The effects and mechanisms of Mettl3-mediated m6A methylation on adolescent skeletal muscle growth were investigated using muscle satellite cell (MuSC)-specific Mettl3 knockout (KO) mice. The potential function of MyoD for skeletal muscle growth in adolescents was explored by phenotypes after overexpression and evaluation of in vivo myogenesis. Additionally, the effects of the methyl donor betaine on adolescent skeletal muscle growth were investigated in vitro and in vivo.
Results: Exercise could promote skeletal muscle growth in adolescents. Sequencing data analysis and confirmation assays uncovered that exercise significantly increased Mettl3-mediated m6A methylation and elevated the expression levels of activation marker MyoD in MuSCs. Establishment of MuSC-specific Mettl3 KO mice further demonstrated that Mettl3-mediated m6A methylation in MyoD contributed to skeletal muscle growth during adolescence. Mettl3-mediated m6A methylation regulated MyoD mRNA stability at the posttranscriptional level in MuSCs, with a functional site at 234 bp A. Increased expression of MyoD could contribute to myogenesis of adolescent MuSCs. Furthermore, the methyl donor betaine could enhance MyoD expression, contributing to MuSCs activation and skeletal muscle growth in adolescents by boosting m6A methylation levels.
Conclusions: Exercise promoted skeletal muscle growth in adolescents through facilitating MyoD mRNA stability of MuSCs in a Mettl3-mediated m6A-dependent manner. The methyl donor betaine could be a potential alternative to exercise for promoting adolescent skeletal muscle growth by directly augmenting the global levels of m6A methylation. These findings may provide a theoretical foundation for encouraging daily fitness exercise and ensuring healthy growth in adolescents.
Keywords Exercise, Adolescent skeletal muscle growth, MuSCs, Mettl3, m6A methylation, Betaine
Address and Contact Information 1 Xinhua Hospital affiiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
2 School of Exercise and Health, Shanghai University of Sport, Shanghai, China
3 Department of Sports Medicine, Peking University Third Hospital, Institute of Sports Medicine of Peking University, Beijing, China
4 Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai, China
*Correspondiing author: shikaiyulu371325@163.com; shaoxiexiang@hotmail.com; wangjianhua@xinhuamed.com.cn
† Shujing Feng, Hao Zhou, Xingzuan Lin and Siyuan Zhu contributed equally to this work.
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No.  151DOI: 10.1186/s11658-024-00663-w Volume 29 (2024) - 29:151
Title DYNAMIC REGULATION OF PROXIMAL TUBULAR AUTOPHAGY FROM INJURY TO REPAIR AFTER ISCHEMIC KIDNEY DAMAGE
Authors Yuhong Gong1†, Wei Zhu2†, Yongqiang Li3†, Tao Lu4, Jiexing Tan1, Changsheng He1, Luodan Yang5*, Yufeng Zhu1* and Li Gong1*
Abstract Background: The role of proximal tubular autophagy in repairing kidney injury following ischemia remains unclear.
Methods: In this study, we utilized mice with conditional deletion of the Atg5 gene in proximal tubules and monitored the long-term dynamic regulation of autophagy following ischemic acute kidney injury (AKI).
Results: The results showed that Atg5-deficient proximal tubule epithelial cells exhibited damaged mitochondria, concentric membranes, and lysosomal accumulation 24 h after ischemia/reperfusion. However, 28 days after ischemia/reperfusion, concentric membrane bodies remained, but lysosomal accumulation was no longer observed. Notably, the absence of Atg5 in renal tubular epithelial cells impaired renal function and led to increased tubular cell proliferation and oxidative stress in the early stage of injury. However, during the repair period following AKI, Atg5 deficiency exhibited no significant difference in the expression of proliferating cell nuclear antigen (PCNA) and 4-hydoxynonenal (4HNE), suggesting that the improvement in renal fibrosis associated with Atg5 deficiency is unlikely to result from its effect on cell proliferation or reactive oxygen species levels. Additionally, Atg5 deficiency inhibits the secretion of profibrotic factor fibroblast growth factor 2 (FGF2) from the early stage of renal injury to the recovery stage of AKI, indicating that autophagy-specific regulation of FGF2 secretion is a dynamic process overlapping with other stages of injury. Furthermore, increased co-localization of ATG5 with 4HNE and FGF2 was observed in patient samples.
Conclusion: In summary, our results suggest that the dynamic regulation of autophagy on key molecules involved in kidney injury and repair varies with the stage of kidney injury.
Keywords Autophagy, Proximal tubule, Acute kidney injury, Interstitial fbrosis
Address and Contact Information 1 Experimental Animal Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
2 Department of Infectious Diseases, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
3 Department of General Practice, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
4 Changzhou Geriatric Hospital Affiliated to Soochow University, Changzhou No. 7 People’s Hospital, Changzhou 213011, China
5 School of Physical Education and Sports Science, South China Normal University, Guangzhou 510006, China
*Corresponding author: luodanyang@m.scnu.edu.cn; 13025105616@163.com; gongli009@126.com
† Yuhong Gong, Wei Zhu and Yongqiang Li have contributed equally to this work.
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No.  152DOI: 10.1186/s11658-024-00650-1 Volume 29 (2024) - 29:152
Title THE miR-6240 TARGET GENE Igf2bp3 PROMOTES MYOBLAST FUSION BY ENHANCING MYOMAKER mRNA STABILITY
Authors Yuxin Huang1,2,4†, Wei Wang1,3,4†, Xinhao Fan1,3,4, Xiaoqin Liu1,4, Weiwei Liu1,2,4, Zishuai Wang1,4, Yixing Li2, Yalan Yang1,4* and Zhonglin Tang1,4*
Abstract Background: Myoblast fusion plays a crucial role in myogenesis. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) functions as an RNA N6-methyladenosine reader and exerts important roles in various biological processes. While our prior study suggested Igf2bp3 contributes to myogenesis, its molecular regulatory mechanism is largely unclear.
Methods: Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were used for gene expression analysis. siRNA and CRISPRi technologies were conducted to knockdown the expression of Igf2bp3. CRISPR/Cas9 technology was performed to knockout Igf2bp3. The Igf2bp3 overexpression vector was designed using the pcDNA3.1(+) vector. Immunofluorescence detection was employed for subcellular localization and cell differentiation analysis. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU) assays were conducted for cell proliferation and fusion detection. The dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were utilized for regulatory mechanism analysis of Igf2bp3.
Results: The overexpression of Igf2bp3 enhances myoblast fusion while knockdown of Igf2bp3 blocks the formation of myotubes. miR-6240 promotes myoblast proliferation while preventing myoblast differentiation and fusion by targeting the 3′ untranslated rgion (UTR) of Igf2bp3. Notably, the impacts of miR-6240 mimics on myoblast proliferation, differentiation, and fusion can be effectively counteracted by the overexpression of Igf2bp3. Moreover, our findings elucidate a direct interaction between Igf2bp3 and the myoblast fusion factor myomaker (Mymk). Igf2bp3 binds to Mymk to enhance its mRNA stability. This interaction results in increased expression of Mymk and heightened myoblast fusion.
Conclusions: Our study unveils Igf2bp3 as a novel post-transcriptional regulator of myoblast fusion through the miR-6240/Mymk axis, significantly contributing to our understanding of skeletal muscle development.
Keywords Igf2bp3, Myobalst fusion, Mymk, mRNA stability, miR-6240, Myogenesis
Address and Contact Information 1 Kunpeng Institute of Modern Agriculture at Foshan, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Foshan 528226, China
2 Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention; College of Animal Science and Technology, Guangxi University, Nanning 530004, Guangxi, China
3 Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education and Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Afairs, Huazhong Agricultural University, Wuhan 430070, China
4 Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518124, China
*Corresponding author: yangyalan@caas.cn; tangzhonglin@caas.cn
† Yuxin Huang and Wei Wang contributed equally to this work.
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No.  153DOI: 10.1186/s11658-024-00669-4 Volume 29 (2024) - 29:155
Title INTER- AND INTRACELLULAR MITOCHONDRIAL COMMUNICATION: SIGNALING HUBS IN AGING AND AGE-RELATED DISEASES
Authors Meng Zhang1†, Jin Wei1†, Chang He2†, Liutao Sui2, Chucheng Jiao2, Xiaoyan Zhu2* and Xudong Pan1*
Abstract Mitochondria are versatile and complex organelles that can continuously communicate and interact with the cellular milieu. Deregulated communication between mitochondria and host cells/organelles has significant consequences and is an underlying factor of many pathophysiological conditions, including the process of aging. During aging, mitochondria lose function, and mitocellular communication pathways break down; mitochondrial dysfunction interacts with mitochondrial dyscommunication, forming a vicious circle. Therefore, strategies to protect mitochondrial function and promote effective communication of mitochondria can increase healthy lifespan and longevity, which might be a new treatment paradigm for age-related disorders. In this review, we comprehensively discuss the signal transduction mechanisms of inter- and intracellular mitochondrial communication, as well as the interactions between mitochondrial communication and the hallmarks of aging. This review emphasizes the indispensable position of inter- and intracellular mitochondrial communication in the aging process of organisms, which is crucial as the cellular signaling hubs. In addition, we also specifically focus on the status of mitochondria-targeted interventions to provide potential therapeutic targets for age-related diseases.
Keywords Mitochondrial communication, Mitochondrial dysfunction, Aging, Age- related diseases, Signaling hubs
Address and Contact Information 1 Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China 2 Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
*Corresponding author: zxysdjm@qdu.edu.cn; drpan022@qdu.edu.cn
† Meng Zhang, Jin Wei and Chang He have contributed equally to this work.
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No.  154DOI: 10.1186/s11658-024-00673-8 Volume 29 (2024) - 29:154
Title MATERNAL HIGH-FAT DIET ORCHESTRATES OFFSPRING HEPATIC CHOLESTEROL METABOLISM VIA MEF2A HYPERMETHYLATION-MEDIATED CYP7A1 SUPPRESSION
Authors Ling Zhang1, Wenyu Zou1, Shixuan Zhang1, Honghua Wu1, Ying Gao1, Junqing Zhang1 and Jia Zheng1*
Abstract Background: Maternal overnutrition, prevalent among women of childbearing age, significantly impacts offspring health throughout their lifetime. While DNA methylation of metabolic-related genes mediates the transmission of detrimental effects from maternal high-fat diet (HFD), its role in programming hepatic cholesterol metabolism in offspring, particularly during weaning, remains elusive.
Methods: Female C57BL/6 J mice were administered a HFD or control diet, before and during, gestation and lactation. Hepatic cholesterol metabolism genes in the liver of offspring were evaluated in terms of their expression. The potential regulator of cholesterol metabolism in the offspring’s liver was identified, and the function of the targeted transcription factor was evaluated through in vitro experiments. The methylation level of the target transcription factor was assessed using the MassARRAY EpiTYPER platform. To determine whether transcription factor expression is influenced by DNA methylation, in vitro experiments were performed using 5-azacitidine and Lucia luciferase activity assays.
Results: Here, we demonstrate that maternal HFD results in higher body weight and hypercholesterolemia in the offspring as early as weaning age. Maternal HFD feeding exacerbates hepatic cholesterol accumulation in offspring primarily by inhibiting cholesterol elimination to bile acids, with a significant decrease of hepatic cholesterol 7α-hydroxylase (CYP7A1). RNA-seq analysis identified myocyte enhancer factor 2A (MEF2A) as a key transcription factor in the offspring liver, which was significantly downregulated in offspring of HFD-fed dams. MEF2A knockdown led to CYP7A1 downregulation and lipid accumulation in HepG2 cells, while MEF2A overexpression reversed this effect. Dual luciferase reporter assays confirmed direct modulation of CYP7A1 transcription by MEF2A. Furthermore, the reduced MEF2A expression was attributed to DNA hypermethylation in the Mef2a promoter region. This epigenetic modification manifested as early as the fetal stage.
Conclusions: This study provides novel insights into how maternal HFD orchestrates hepatic cholesterol metabolism via MEF2A hypermethylation-mediated CYP7A1 suppression in offspring at weaning.
Keywords maternal HFD, hepatic cholesterol metabolism, MEF2A, CYP7A1, DNA methylation, ofspring
Address and Contact Information 1 Department of Endocrinology, Peking University First Hospital, No. 8 Xishiku Ave, Xicheng, Beijing 100034, People’s Republic of China
*Corresponding author: zhengjia@bjmu.edu.cn
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No.  155DOI: 10.1186/s11658-024-00671-w Volume 29 (2024) - 29:155
Title DECODING THE ENIGMATIC ESTROGEN PARADOX IN PULMONARY HYPERTENSION: DELVING INTO ESTROGEN METABOLITES AND METABOLIC ENZYMES
Authors Qiang You1,2†, Hequn Song3†, Ziming Zhu4, Jinzheng Wang4, Ruixin Wang5, Mingjia Du5, Yingjie Fu6*, Jinxiang Yuan7* and Rubin Tan1*
Abstract Pulmonary hypertension (PH) presents a puzzling sex bias, being more prevalent in women yet often less severe than in men, and the underlying reasons remain unclear. Studies using animal models, and limited clinical data have revealed a protective influence of exogenous estrogens, known as the estrogen paradox. Research suggests that beyond its receptor-mediated effects, estrogen acts through metabolites such as 2-ME2, 4-OHE2, and 16-OHE2, which are capable of exhibiting protective or detrimental effects in PH, prompting the need to explore their roles in PH to untangle sex differences and the estrogen paradox. Hypoxia disrupts the balance of estrogen metabolites by affecting the enzymes responsible for estrogen metabolism. Delving into the role of these metabolic enzymes not only illuminates the sex difference in PH but also provides a potential rationale for the estrogen paradox. This review delves into the intricate interplay between estrogen metabolites, metabolic enzymes, and PH, offering a deeper understanding of sex-specific differences and the perplexing estrogen paradox in the context of this condition.
Keywords Pulmonary hypertension, Estrogen, Hypoxia, Estrogen metabolites, CYPs, HSD17B
Address and Contact Information 1 Department of Physiology, Basic Medical School, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
2 School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong, China
3 First Clinical Medical School, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
4 College of Second Clinical Medical, Jining Medical University, Jining 272067, Shandong, China
5 School of Nursing, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
6 School of Pharmacy, Jining Medical University, Rizhao 276826, Shandong, China
7 Lin He’s Academician Workstation of New Medicine and Clinical Translation, Jining Medical University, Jining 272067, Shandong, China
*Correspondinga author: pilipili@163.com; yuanjinxiang18@163.com; tanrubin11@126.com
† Qiang You and Hequn Song contributed equally to this work.
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No.  156DOI: 10.1186/s11658-024-00674-7 Volume 29 (2024) - 29:156
Title ELONGATION FACTOR 2 IN CANCER: A PROMISING THERAPEUTIC TARGET IN PROTEIN TRANSLATION
Authors Xuechao Jia1,2†, Chuntian Huang1,3†, Fangfang Liu5*, Zigang Dong2,4,6,7* and Kangdong Liu2,4,6,7*
Abstract Aberrant elongation of proteins can lead to the activation of oncogenic signaling pathways, resulting in the dysregulation of oncogenic signaling pathways. Eukaryotic elongation factor 2 (eEF2) is an essential regulator of protein synthesis that precisely elongates nascent peptides in the protein elongation process. Although studies have linked aberrant eEF2 expression to various cancers, research has primarily focused on its structure, highlighting a need for deeper exploration into its molecular functions. In this review, recent advancements in the structure, guanosine triphosphatase (GTPase) activity, posttranslational modifications, regulatory factors, and inhibitors of eEF2 are summarized. These findings provide a comprehensive cognition on the critical role of eEF2 and its potential as a therapeutic target in cancer. Furthermore, this review highlights important unanswered questions that warrant investigation in future research.
Keywords Elongation factor 2, Cancer, Inhibitors, Protein elongation, Regulators
Address and Contact Information 1 Henan International Joint Laboratory of TCM Syndrome and Prescription in Signaling, Traditional Chinese Medicine (Zhong Jing) School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan, China
2 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, Henan, China
3 Department of Pathology and Pathophysiology, School of Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan, China
4 China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, Henan, China
5 Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
6 Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou 450001, Henan, China
7 The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou 450000, Henan, China
*Corresponding author: fiu89@zzu.edu.cn; dongzg@zzu.edu.cn; kdliu@zzu.edu.cn
† Xuechao Jia and Chuntian Huang have contributed equally to this work.
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No.  157DOI: 10.1186/s11658-024-00676-5 Volume 29 (2024) - 29:157
Title EXOSOME-DERIVED PROTEINS IN GASTRIC CANCER PROGRESSION, DRUG RESISTANCE, AND IMMUNE RESPONSE
Authors Jiayu Wang2,3†, Huan Zhang2†, Juntao Li3, Xiangyu Ni2,3, Wenying Yan4,5,6*, Yueqiu Chen1* and Tongguo Shi2,3*
Abstract Gastric cancer (GC) represents a prevalent malignancy globally, often diagnosed at advanced stages owing to subtle early symptoms, resulting in a poor prognosis. Exosomes are extracellular nano-sized vesicles and are secreted by various cells. Mounting evidence indicates that exosomes contain a wide range of molecules, such as DNA, RNA, lipids, and proteins, and play crucial roles in multiple cancers including GC. Recently, with the rapid development of mass spectrometry-based detection technology, researchers have paid increasing attention to exosomal cargo proteins. In this review, we discussed the origin of exosomes and the diagnostic and prognostic roles of exosomal proteins in GC. Moreover, we summarized the biological functions of exosomal proteins in GC processes, such as proliferation, metastasis, drug resistance, stemness, immune response, angiogenesis, and traditional Chinese medicine therapy. In summary, this review synthesizes current advancements in exosomal proteins associated with GC, offering insights that could pave the way for novel diagnostic and therapeutic strategies for GC in the foreseeable future.
Keywords Gastric cancer, Exosome, Exosomal protein, Biomarker, Drug resistance, Immune response, Therapy
Address and Contact Information 1 Department of Cardiovascular Surgery of The First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215007, China
2 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 East Ganjiang Road, Suzhou 215000, China
3 Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
4 Department of Bioinformatics, School of Biology and Basic Medical Sciences, Suzhou Medical College of Soochow University, 199 Renai Road, Suzhou 215123, China
5 Center for Systems Biology, Soochow University, Suzhou, China
6 Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Suzhou, China
*Corresponding author: wyyan@suda.edu.cn; chenyq@suda.edu.cn; shitg@suda.edu.cn
† Jiayu Wang and Huan Zhang have contributed equally.
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No.  158DOI: 10.1186/s11658-024-00677-4 Volume 29 (2024) - 29:158
Title WNT4 PROMOTES THE SYMMETRIC FISSION OF CRYPT IN RADIATION-INDUCED INTESTINAL EPITHELIAL REGENERATION
Authors Jingyang Cheng1,2, Haiyong Wu1,2 and Yanmei Cui1,2*
Abstract Background: Radiotherapy for pelvic malignant tumors inevitably causes intestinal tissue damage. The regeneration of intestinal epithelium after radiation injury relies mainly on crypt fission. However, little is known about the regulatory mechanisms of crypt fission events.
Methods: The effects of WNT4 on crypt regeneration and the symmetry of crypt fission were examined using a mouse small intestinal organoid culture model. Three-dimensional (3D) reconstructed images of organoids were applied to assess the symmetry of crypt fission and Paneth cell localization upon manipulation of WNT4 expression. The effect of WNT4 on the expression of β-catenin target genes was analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). The in vivo effect of WNT4 overexpression mediated by adeno-associated virus (AAV) on symmetric fission of crypt was investigated using a radiation-injured mouse model.
Results: WNT4 has a special function of promoting symmetric fission of small intestinal crypts, although it inhibits budding, stemness, and cell proliferation on organoids. WNT4 promotes the correct localization of Paneth cells in the crypt base by regulating the expression of EphB3, thereby promoting the symmetric fission of small intestinal crypts. WNT4 negatively regulates the canonical WNT/β-catenin signaling pathway, and it promotes symmetric crypt fission in a ROR2 receptor-dependent manner. Moreover, in patients and animal models of radiation-induced intestinal injury, we found that the regenerated crypts are irregular in size and shape, Paneth cells are mislocalized, and the expression of WNT4 is decreased while EphB3 is increased. Importantly, restoration of WNT4 expression mediated by AAV effectively promotes symmetric crypt fission and thus improves the regularity of regenerating crypts in mice with radiation-induced injury.
Conclusions: Our study highlights the critical role of WNT4 in the regulation of crypt fission and provides WNT4 as a potential therapeutic target for radiation enteritis.
Keywords WNT4, Crypt fssion, Paneth cell, Epithelial regeneration
Address and Contact Information 1 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China
2 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China
*Corresponding author: cuiyanmei@mail.sysu.edu.cn
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No.  159DOI: 10.1186/s11658-024-00675-6 Volume 29 (2024) - 29:159
Title ENPP2 PROMOTES PROGRESSION AND LIPID ACCUMULATION VIA AMPK/SREBP1/FAS PATHWAY IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors Liyan Lu1, Xinting Hu1, Yang Han1, Hua Wang1, Zheng Tian2, Ya Zhang1,2,3* and Xin Wang1,2,3*
Abstract Background: Disorders of lipid metabolism are critical factors in the progression of chronic lymphocytic leukemia (CLL). However, the characteristics of lipid metabolism and related regulatory mechanisms of CLL remain unclear.
Methods: Hence, we identified altered metabolites and aberrant lipid metabolism pathways in patients with CLL by ultra-high-performance liquid chromatography-mass spectrometry-based non-targeted lipidomics. A combination of transcriptomics and lipidomics was used to mine relevant target molecule and downstream signaling pathway. In vitro cellular assays, quantitative real-time polymerase chain reaction (qRT-PCR), western blot, fluorescent staining, RNA sequencing, and coimmunoprecipitation were used to monitor the molecular levels as well as to explore the underlying mechanisms.
Results: Significant differences in the content of 52 lipid species were identified in CLL samples and healthy controls. Functional analysis revealed that alterations in glycerolipid metabolism, glycerophospholipid metabolism, sphingolipid metabolism, and metabolic pathways had the greatest impact on CLL. On the basis of the area under the curve value, a combination of three metabolites (phosphatidylcholine O-24:2_18:2, phosphatidylcholine O-35:3, and lysophosphatidylcholine 34:3) potentially served as a biomarker for the diagnosis of CLL. Furthermore, utilizing integrated lipidomic, transcriptomic, and molecular studies, we reveal that ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) plays a crucial role in regulating oncogenic lipogenesis. ENPP2 expression was significantly elevated in patients with CLL compared with normal cells and was validated in an independent cohort. Moreover, ENPP2 knockdown and targeted inhibitor PF-8380 treatment exerted an antitumor effect by regulating cell viability, proliferation, apoptosis, cell cycle, and enhanced the drug sensitivity to ibrutinib. Mechanistically, ENPP2 inhibited AMP-activated protein kinase (AMPK) phosphorylation and promoted lipogenesis through the sterol regulatory element-binding transcription factor 1 (SREBP-1)/fatty acid synthase (FAS) signaling pathway to promote lipogenesis.
Conclusions: Taken together, our findings unravel the lipid metabolism characteristics of CLL. Moreover, we demonstrate a previously unidentified role and mechanism of ENPP2 in regulation of lipid metabolism, providing a novel therapeutic target for CLL treatment.
Keywords Chronic lymphocytic leukemia, Lipidomics, Lipid metabolism, ENPP2, PF- 8380, AMPK, LPL
Address and Contact Information 1 Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Add: No.324, Jingwu Road, Jinan 250021, Shandong, China
2 Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China
3 Taishan Scholars Program of Shandong Province, Jinan 250021, Shandong, China
*Corresponding author: maryzhangya@gmail.com; xinw007@126.com
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No.  160DOI: 10.1186/s11658-024-00683-6 Volume 29 (2024) - 29:160
Title Retraction Note: Inhibition of PAD4 enhances radiosensitivity and inhibits aggressive phenotypes of nasopharyngeal carcinoma cells
Authors Hao Chen1†, Min Luo1†, Xiangping Wang1, Ting Liang1, Chaoyuan Huang1, Changjie Huang1* and Lining Wei2*
Abstract The Original Article was published on 16 March 2021

Retraction Note: Cellular & Molecular Biology Letters (2021) 26:9 https://doi.org/10.1186/s11658-021-00251-2

The Editor-in-Chief has retracted this article because of concerns regarding the soundness of the data presented. After publication, the authors informed the journal that the invasion and Western blot data reported in this work are incorrect and that they had not personally conducted these experiments. In light of this and previous concerns involving figures presented in this article, the Editor-in-Chief therefore no longer has confidence in the results and conclusions presented in this article.

The authors agree with this retraction.
Keywords
Address and Contact Information 1 Department of Endoscopy, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
2 Department of Oncology, The Second Nanning People’s Hospital, Jiangnan District, No.13 Dancun Road, Nanning 530031, Guangxi, China
*Corresponding author: hcj1215423068@hotmail.com; weilininggudy@163.com
† Hao Chen and Min Luo contributed equally to this work.
The original article can be found online at https://doi.org/10.1186/s11658-021-00251-2.
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