Cell Biology and Toxicology最新文献

{"title":"Identification of gastric cancer stem cells with CD44 and Lgr5 double labelling and their initial roles on gastric cancer malignancy and chemotherapy resistance.","authors":"Zhida Chen, Yunhe Gao, Pengfei Zhang, Yi Liu, Bo Wei, Lin Chen, Hongqing Xi","doi":"10.1007/s10565-024-09960-8","DOIUrl":"10.1007/s10565-024-09960-8","url":null,"abstract":"<p><p>Accumulating evidences have indicated that cancer stem cells (CSCs) can initiate tumor progression and cause recurrence after therapy. However, specific markers of gastric CSCs (GCSCs) from different origins have not been comprehensively revealed. Here, we further detected whether cell populations labelled with CD44 and Lgr5, well-recognized stem markers for gastric cancer (GC), can better emphasize cancer initiation, therapeutic resistance and recurrence. Flow cytometry was utilized to sort the CD44 + Lgr5 + and CD44 + Lgr5- cells from GC cell line HGC-27 and primary GC cells. The influences of CD44 and Lgr5 GCSCs on the malignant behaviors and their potential mechanisms was investigated, respectively. In our study, we reported the identification and validation of CD44 + Lgr5 + cells that presented stronger stemness characteristics, as evidenced by increase of sphere forming ability, elevation of stem cell transcriptional activity. Additionally, CD44 + Lgr5 + double positive cells have lower apoptosis, greater chemotherapy resistance, and higher EMT capacity and LC3 density compared with CD44 + Lgr5- cells. Tumor xenograft experiments also verified the faster carcinogenesis of CD44 + Lgr5 + GCSCs. Furthermore, a series of key proteins in the Wnt, Hedgehog, Notch, and TGF-β pathways were elevated in the CD44 + Lgr5 + double positive subpopulation, except for Notch 1 and Smad 1. In conclusion, the binding of CD44 and Lgr5 can serve as a precise GCSCs marker that initiate malignant progression and chemotherapy resistance in GC by activating Wnt, Hedgehog, Notch, TGF-β pathways. Those evidences raise the needs to target both markers simultaneously as a potential approach for the GC treatment.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"12"},"PeriodicalIF":5.3,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E2F1-driven CENPM expression promotes glycolytic reprogramming and tumorigenicity in glioblastoma.","authors":"Zhiqiang Yi, Yanfei Jia, Runchun Lu, Chunwei Li, Long Wen, Xiangdong Yin, Junfei Yi, Liang Li","doi":"10.1007/s10565-024-09945-7","DOIUrl":"10.1007/s10565-024-09945-7","url":null,"abstract":"<p><p>Centromere protein M (CENPM), traditionally associated with chromosome segregation, is now recognized for its significant role in cancer biology. Particularly in glioblastoma (GBM), where less is known about CENPM compared to other centromere proteins (CENPs), it appears crucially involved in regulating tumor cell proliferation, invasion, and metabolic reprogramming-key factors in GBM's aggressiveness. Initial analyses using the GEPIA database (TCGA/GTEx datasets) reveal distinct patterns of CENPM expression in GBM, suggesting its potential as a therapeutic target. Our study manipulated CENPM expression through shRNA-mediated knockdown and vector-based overexpression in GBM cell lines LN229 and U251. Knockdown resulted in a 50% reduction in cell proliferation and a 70% decrease in invasion, accompanied by diminished glycolytic markers such as glucose consumption, lactate production, and ATP levels. Conversely, overexpression of CENPM enhanced both metabolic activity and invasive capacities. The introduction of the glycolytic inhibitor 2-DG effectively reversed the effects of CENPM modulation, highlighting a dependency on glycolytic pathways. Moreover, we identified E2F1 as a key regulator of CENPM, linking it to GBM's metabolic alterations. In vivo studies using a BALB/c nude mouse xenograft model demonstrated that CENPM knockdown significantly inhibits tumor growth, with treated groups showing a 60% reduction in tumor volume over four weeks. These findings underscore the E2F1-CENPM axis as a promising target for therapeutic strategies, aiming to disrupt the metabolic and invasive pathways facilitated by CENPM in GBM. These insights establish a foundation for targeting the metabolic dependencies of tumor cells, potentially leading to innovative treatments for GBM.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"4"},"PeriodicalIF":5.3,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NMF typing and machine learning algorithm-based exploration of preeclampsia-related mechanisms on ferroptosis signature genes.","authors":"Xuemin Liu, Di Zhang, Hui Qiu","doi":"10.1007/s10565-024-09963-5","DOIUrl":"10.1007/s10565-024-09963-5","url":null,"abstract":"<p><strong>Background: </strong>Globally, pre-eclampsia (PE) poses a major threat to the health and survival of pregnant women and fetuses, contributing significantly to morbidity and mortality. Recent studies suggest a pathological link between PE and ferroptosis. We aim to utilize non-negative matrix factorization (NMF) clustering and machine learning algorithms to pinpoint disease-specific genes related to the process of ferroptosis in PE and investigate likely underlying biochemistry mechanisms.</p><p><strong>Methods: </strong>The acquisition of four microarray datasets from the Gene Expression Omnibus (GEO) repository, the integration of these datasets, and the elimination of batch effects formed the core procedure. Genes related to ferroptosis in PE (DE-FRG) were identified. NMF clustering was performed on DE-FRG for unsupervised analysis, generating a heatmap for clustering validation via principal component analysis. Immunocyte infiltration differences between different subtypes were compared to elucidate the impact of ferroptosis on immune infiltration in the placental tissue of PE patients. The application of weighted gene co-expression network analysis (WGCNA) revealed important module genes linked to sample subtypes and disease status. The screening of PE feature genes involved employing SVM, RF, GLM, and XGB machine learning algorithms, and their predictive performance was validated using various analyses and an external dataset. The iRegulon tool was utilized to predict upstream transcription factors associated with ferroptosis feature genes, from which differentially expressed transcription factors were screened to construct a \"Transcription Factor-FRG-ferroptosis\" regulatory network. Finally, in vitro (cultured cells) and in vivo (rat) models were utilized to evaluate the regulatory mechanisms of ferroptosis in normal and PE placental tissues.</p><p><strong>Results: </strong>Differential analysis of the four merged GEO datasets identified 41 DE-FRGs. NMF clustering based on DE-FRGs revealed two PE subtypes. Immunocyte infiltration analysis indicated significant differences in immune levels between these subtypes. Further WGCNA analysis identified module genes associated with PE and these two subtypes. Subsequently, we developed an integrated machine learning model incorporating five FRGs and validated its predictive efficacy using various analyses and an external validation dataset. Finally, based on the transcription factor ARID3A and ferroptosis feature genes EPHB3 and PAPPA2, we constructed a \"Transcription Factor-FRG-ferroptosis\" regulatory network, with in vitro and in vivo experiments confirming that ARID3A promotes the progression of PE and ferroptosis by activating the expression of EPHB3 and PAPPA2.</p><p><strong>Conclusion: </strong>This analytical journey illuminated a critical regulatory nexus in PE, underscoring the central influence of ARID3A on PE through ferroptosis-mediated pathways.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"14"},"PeriodicalIF":5.3,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise training alleviates neuronal apoptosis and re-establishes mitochondrial quality control after cerebral ischemia by increasing SIRT3 expression.","authors":"Wenwen Wu, Zengyu Wei, Zhiyun Wu, Jianmin Chen, Ji Liu, Manli Chen, Jinjin Yuan, Zhijian Zheng, Zijun Zhao, Qiang Lin, Nan Liu, Hongbin Chen","doi":"10.1007/s10565-024-09957-3","DOIUrl":"10.1007/s10565-024-09957-3","url":null,"abstract":"<p><p>Existing evidence indicates that exercise training can enhance neural function by regulating mitochondrial quality control (MQC), which can be impaired by cerebral ischemia, and that sirtuin-3 (SIRT3), a protein localized in mitochondria, is crucial in maintaining mitochondrial functions. However, the relationship among exercise training, SIRT3, and MQC after cerebral ischemia remains obscure. This study attempted to elucidate the relationship among exercise training, SIRT3 and MQC after cerebral ischemia in rats. Male adult SD rats received tMCAO after the transfection of adeno-associated virus encoding either sirtuin-3 (AAV-SIRT3) or SIRT3 knockdown (AAV-sh-SIRT3) into the ipsilateral striata and cortex. Subsequently, the animals were randomly selected for exercise training. The index changes were measured by transmission electron microscopy, Western blot analysis, nuclear magnetic resonance imaging, TUNEL staining, and immunofluorescence staining, etc. The results revealed that after cerebral ischemia, exercise training increased SIRT3 expression, significantly improved neural function, alleviated infarct volume and neuronal apoptosis, maintained the mitochondrial structural integrity, and re-established MQC. The latter promoted mitochondrial biogenesis, balanced mitochondrial fission/fusion, and enhanced mitophagy. These favorable benefits were reversed after SIRT3 interference. In addition, a cellular OGD/R model showed that the increased SIRT3 expression alleviates neuronal apoptosis and re-establishes mitochondrial quality control by activating the β-catenin pathway. These findings suggest that exercise training may optimize mitochondrial quality control by increasing the expression of SIRT3, thereby improving neural functions after cerebral ischemia, which illuminates the mechanism underlying the exercise training-conferred neural benefits and indicates SIRT3 as a therapeutic strategy for brain ischemia.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"10"},"PeriodicalIF":5.3,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3, m6A modification, and EGR1: interplay affecting myocardial I/R injury outcomes.","authors":"Chen Huang, Xun Zhang, Shi-Xiong Wu, Qing Chang, Zhi-Kun Zheng, Jing Xu","doi":"10.1007/s10565-024-09937-7","DOIUrl":"10.1007/s10565-024-09937-7","url":null,"abstract":"<p><p>The occurrence of severe myocardial ischemia/reperfusion (I/R) injury is associated with the clinical application of reestablishment technique for heart disease, and understanding its underlying mechanisms is currently an urgent issue. Prior investigations have demonstrated the potential enhancement of MIRI through EGR1 suppression, although the precise underlying regulatory pathways require further elucidation. The core focus of this investigation is to examine the molecular pathways through EGR1 regulates mitophagy-mediated myocardial cell pyroptosis and its impact on MIRI. Cardiomyocyte hypoxia/reoxygenation (H/R) injury models and mouse models of myocardial I/R injury were used to investigate the involvement of EGR1 in regulating mitophagy-mediated myocardial cell pyroptosis in myocardial I/R injury. The research outcomes demonstrated that under H/R conditions, EGR1 expression was upregulated and inhibited the JAK2/STAT3 pathway, leading to enhanced mitophagy and disrupted mitochondrial fusion/fission dynamics, ultimately resulting in myocardial cell pyroptosis. Further research revealed that the upregulation of EGR1 expression was mediated by methyltransferase like 3 (METTL3)-mediated m6A modification of EGR1 mRNA and depended on the binding of insulin like growth factor 2 mrna binding protein 2 (IGF2BP2) to the N6-methyladenosine (m6A) modification site to enhance mRNA stability. In vivo animal experiments confirmed that METTL3 upregulated EGR1 expression through IGF2BP2 and suppressed activation of the janus kinase 2 (JAK2) /signal transducer and activator of transcription 3 (STAT3) pathway, thereby inhibiting mitophagy, disrupting mitochondrial dynamics, promoting myocardial cell pyroptosis, and exacerbating I/R injury.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"7"},"PeriodicalIF":5.3,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SS18-SSX drives TYK2 expression to activate STAT3/Bcl2 axis, facilitating apoptosis evasion and advancing synovial sarcoma progression.","authors":"Wenjing Qin, Changliang Peng, Xianhe Yang, Alan Jiang, Nanshan Zhong, Yunyun Liu, Xiaochun Zhang, Angela C Hirbe, Mei Ma, Xin Yue","doi":"10.1007/s10565-024-09952-8","DOIUrl":"10.1007/s10565-024-09952-8","url":null,"abstract":"<p><p>Synovial sarcoma (SS) is a rare soft tissue sarcoma characterized by high-grade malignancy and poor prognosis. Preliminary research indicates that apoptosis evasion is a key factor in SS progression, primarily attributed to the overexpression of anti-apoptotic genes. However, the mechanisms underlying this phenomenon are still not fully understood. This study aims to investigate the factors responsible for apoptosis evasion, evaluate their potential as targets for anti-apoptotic interventions, and analyze their mechanisms in detail. Our findings reveal that tyrosine kinase 2 (TYK2) is upregulated in highly malignant SS. Through in vitro as well as in vivo functional analyses, we have demonstrated that, TYK2 significantly accelerates SS cells progression. Mechanistically, TYK2 activates STAT3, which promotes the expression of BCL2, an anti-apoptotic gene. Inhibition of STAT3 activation using specific inhibitors can disrupt the TYK2-enhanced expression of Bcl2, indicating that the TYK2/STAT3/Bcl2 axis is a key regulatory pathway mediating apoptosis evasion in SS. Furthermore, our investigation into the upstream regulation of TYK2 reveals that the fusion protein SS18-SSX enhances the transcriptional activity of TYK2 by binding to the promoter region of the TYK2 gene, thereby increasing its expression levels. Thus, the TYK2/STAT3/Bcl2 axis is a crucial mechanism through which SS18-SSX mediates apoptosis evasion in SS cells. In conclusion, our findings contribute to understanding how SS18-SSX-driven TYK2 expression mediates apoptosis evasion mechanisms and propose targeting TYK2 as a strategy to induce apoptosis in SS.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"8"},"PeriodicalIF":5.3,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"eEF2K alleviates doxorubicin-induced cardiotoxicity by inhibiting GSK3β and improving autophagy dysfunction.","authors":"Junjie Guan, Hongwei Mo, Vicheth Virak, Runze Guo, Dongdong Que, Wenjie Yu, Xuwei Zhang, Jing Yan, Yuxi Wang, Yashu Yang, Bowen Rui, Guanlin Huang, Deshu Chen, Chongbin Zhong, Pingzhen Yang","doi":"10.1007/s10565-024-09966-2","DOIUrl":"10.1007/s10565-024-09966-2","url":null,"abstract":"<p><p>Doxorubicin-induced cardiotoxicity (DIC) poses a threat to the health and prognosis of cancer patients. It is important to find a safe and effective method for the prevention and treatment of DIC. eEF2K, which is a highly conserved α-kinase, is thought to be a therapeutic target for several human diseases. Nonetheless, it is still uncertain if eEF2K contributes to the cardiotoxic effects caused by doxorubicin (DOX). Our research revealed that eEF2K expression decreased in the DIC. eEF2K was overexpressed through adeno-associated virus in vivo and adenovirus in vitro, which presented alleviative cardiomyocyte death and cell atrophy induced by DOX. Autophagy dysfunction is one of important mechanisms in DIC. As a result, autophagic function was evaluated using Transmission electron microscopy in vivo, as well as LysoSensor and mRFPGFP-LC3 puncta in vitro. eEF2K overexpression improves DOX-induced autophagy blockade. In addition, eEF2K knockdown aggravated autophagy blockade and cardiomyocyte injury in DIC model. eEF2K also phosphorylated and inhibited GSK3β in DIC model. AR-A014418 (ARi), known for selectively inhibiting GSK3β, countered the effects of eEF2K knockdown, which aggravated autophagy blockade in the DIC. In conclusion, this study proposes that eEF2K alleviates DIC by inhibiting GSK3β and improving autophagy dysfunction. eEF2K is a promising therapeutic target against DIC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"15"},"PeriodicalIF":5.3,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting protein tyrosine phosphatase non-receptor type 6 (PTPN6) as a therapeutic strategy in acute myeloid leukemia.","authors":"Xiaoou Wang, Zhenggang Li, Jing Shen, Lin Liu","doi":"10.1007/s10565-024-09965-3","DOIUrl":"10.1007/s10565-024-09965-3","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid progenitor cells. Despite advancements in treatment, the prognosis for AML patients remains poor, highlighting the need for novel therapeutic targets. Protein Tyrosine Phosphatase Non-Receptor Type 6 (PTPN6), also known as SHP-1, is a critical regulator of hematopoietic cell signaling and has been implicated in various leukemias. This study investigates the therapeutic potential of targeting PTPN6 in AML. We employed both in vitro and in vivo models to evaluate the effects of PTPN6 inhibition on AML cell proliferation, apoptosis, and differentiation. Our results demonstrate that PTPN6 inhibition leads to a significant reduction in AML cell viability, induces apoptosis, and promotes differentiation of leukemic cells into mature myeloid cells. Mechanistic studies revealed that PTPN6 inhibition disrupts key signaling pathways involved in AML pathogenesis, including the JAK/STAT and PI3K/AKT pathways. Furthermore, the combination of PTPN6 inhibitors with standard chemotherapeutic agents exhibited a synergistic effect, enhancing the overall therapeutic efficacy. These findings suggest that PTPN6 is a promising therapeutic target in AML and warrants further investigation into the development of PTPN6 inhibitors for clinical application in AML treatment.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"11"},"PeriodicalIF":5.3,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-21-loaded bone marrow mesenchymal stem cell-derived exosomes inhibit pyroptosis by targeting MALT1 to repair chemotherapy-induced premature ovarian insufficiency.","authors":"Lichao Tang, Yutao Yang, Mingxin Yang, Jiaxin Xie, Aiping Zhuo, Yanhong Wu, Mengli Mao, Youhong Zheng, Xiafei Fu","doi":"10.1007/s10565-024-09946-6","DOIUrl":"10.1007/s10565-024-09946-6","url":null,"abstract":"<p><p>Chemotherapy is essential for treating malignant tumors, but it can cause premature ovarian insufficiency (POI). Recent studies suggest that exosomes enriched with miR-21 (miR-21-Exo) may help mitigate POI, though the underlying mechanisms remain largely unexplored. This research investigates how miR-21-Exo influences chemotherapy-induced POI using an experimental model where KGN cells are exposed to cisplatin. We assessed the impact of miR-21 on cellular activity and generated miR-21 overexpressing bone marrow mesenchymal stem cells (miR-21-BMSC) via lentiviral modification. Isolated miR-21-Exo was analyzed for its effects on cellular function. Bioinformatics identified Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein 1 (MALT1) as a target of miR-21. We confirmed that miR-21-Exo regulates MALT1 and the NF-κB signaling pathway to prevent cell pyroptosis. Further studies in a rat model demonstrated the therapeutic potential and safety of miR-21-Exo. Overall, our findings highlight a novel strategy for addressing chemotherapy-induced POI by modulating MALT1 and the NF-κB pathway, offering significant therapeutic implications.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"3"},"PeriodicalIF":5.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JAG1 mediates apoptosis in herpes simplex keratitis by suppressing autophagy via ROS/JAG1/NOTCH1/pULK1 signaling pathway.","authors":"Jingyao Chang, Yao Yao, Xinghong Sun, Wenzhe Wang, Haochen Qian, Yumeilan Liu, Chunyan Xue, Wei Ye, Feng Jiang","doi":"10.1007/s10565-024-09968-0","DOIUrl":"10.1007/s10565-024-09968-0","url":null,"abstract":"<p><p>Herpes simplex keratitis (HSK), an ocular disease resulted from herpes simplex virus type 1 (HSV-1) infection, leads to the majority of infectious corneal blindness worldwide. The apoptosis of corneal epithelial cells (CECs) resulted from HSV-1 disrupts the epithelial barrier and exacerbates the infection; however, there is no definitive cure for HSK. Jagged1 (JAG1), one of the primary functional ligands for NOTCH receptors, plays a crucial role in regulating apoptosis and autophagy; however, its role in HSK is unclear. Our transcriptome analysis showed JAG1 was significantly upregulated in HSV-1-infected human CECs. We aimed to explore JAG1's role in regulating apoptosis in HSV-1-infected human CECs and in HSK mice. HSV-1 infection induced apoptosis and reactive oxygen species (ROS) generation in CECs. HSV-1 also activated the JAG1/NOTCH1 signaling pathway. The ROS scavenger N-acetylcysteine significantly mitigated these effects. Additionally, inhibiting the JAG1/NOTCH1 pathway with short hairpin RNA against JAG1 or a NOTCH1 inhibitor (N-[N-{3,5-difuorophenacetyl}-1-alanyl]-S-phenylglycine t-butyl ester [DAPT]) alleviated HSV-1-induced CEC apoptosis. Transmission electron microscopy and western blotting revealed that HSV-1 infection suppressed ULK1-mediated autophagy in CECs, while DAPT treatment enhanced autophagy by suppressing ULK1 phosphorylation. The activation of autophagy by rapamycin treatment markedly reduced ROS levels and apoptosis in HSV-1-infected CECs, revealing a synergistic effect between the suppressed autophagy and increased ROS levels, ultimately leading to apoptosis. Thus, HSV-1 induces CEC apoptosis by suppressing autophagy through ROS/JAG1/NOTCH1/pULK1 signaling pathway in vitro and in vivo, providing potential therapeutic targets for HSK.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"1"},"PeriodicalIF":5.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}