Cell Biology and Toxicology最新文献

{"title":"Computational approaches identify a transcriptomic fingerprint of drug-induced structural cardiotoxicity.","authors":"Victoria P W Au Yeung, Olga Obrezanova, Jiarui Zhou, Hongbin Yang, Tara J Bowen, Delyan Ivanov, Izzy Saffadi, Alfie S Carter, Vigneshwari Subramanian, Inken Dillmann, Andrew Hall, Adam Corrigan, Mark R Viant, Amy Pointon","doi":"10.1007/s10565-024-09880-7","DOIUrl":"https://doi.org/10.1007/s10565-024-09880-7","url":null,"abstract":"<p><p>Structural cardiotoxicity (SCT) presents a high-impact risk that is poorly tolerated in drug discovery unless significant benefit is anticipated. Therefore, we aimed to improve the mechanistic understanding of SCT. First, we combined machine learning methods with a modified calcium transient assay in human-induced pluripotent stem cell-derived cardiomyocytes to identify nine parameters that could predict SCT. Next, we applied transcriptomic profiling to human cardiac microtissues exposed to structural and non-structural cardiotoxins. Fifty-two genes expressed across the three main cell types in the heart (cardiomyocytes, endothelial cells, and fibroblasts) were prioritised in differential expression and network clustering analyses and could be linked to known mechanisms of SCT. This transcriptomic fingerprint may prove useful for generating strategies to mitigate SCT risk in early drug discovery.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466370","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":"SPACA6P-AS: a trailblazer in breast cancer pathobiology and therapeutics.","authors":"Wenjie Feng, Yiling Jiang, Lijun Zeng, Yuhan Ouyang, Hailong Li, Yuanbin Tang, Lunqi Luo, Lianjie Ouyang, Liming Xie, Yeru Tan, Yuehua Li","doi":"10.1007/s10565-024-09870-9","DOIUrl":"10.1007/s10565-024-09870-9","url":null,"abstract":"<p><strong>Objective: </strong>The primary objective of this investigation is to delve into the involvement of the long noncoding RNA (lncRNA) SPACA6P-AS in breast cancer (BC) development, focusing on its expression pattern, association with clinical-pathological features, impact on prognosis, as well as its molecular and immunological implications.</p><p><strong>Methods: </strong>Bioinformatics analysis was conducted utilizing RNA sequencing data of 1083 BC patients from the TCGA database. Functional exploration of SPACA6P-AS was carried out through the construction of survival curves, GO and KEGG enrichment analysis, and single-sample gene set enrichment analysis (ssGSEA). Furthermore, its functionality was validated through in vitro cell experiments and in vivo nude mouse model experiments.</p><p><strong>Results: </strong>SPACA6P-AS showed a remarkable increase in expression levels in BC tissues (p < 0.001) and demonstrated a close relationship to poor prognosis (overall survival HR = 1.616, progression-free interval HR = 1.40, disease-specific survival HR = 1.54). Enrichment analysis revealed that SPACA6P-AS could impact biological functions such as protease regulation, endopeptidase inhibitor activity, taste receptor activity, taste transduction, and maturity-onset diabetes of the young pathway. ssGSEA analysis indicated a negative correlation between SPACA6P-AS expression and immune cell infiltration like dendritic cells and neutrophils, while a positive correlation was observed with central memory T cells and T helper 2 cells. Results from in vitro and in vivo experiments illustrated that silencing SPACA6P-AS significantly inhibited the proliferation, migration, and invasion capabilities of BC cells. In vitro experiments also highlighted that dendritic cells with silenced SPACA6P-AS exhibited enhanced capabilities in promoting the proliferation of autologous CD3 + T cells and cytokine secretion. These discoveries elucidate the potential multifaceted roles of SPACA6P-AS in BC, including its potential involvement in modulating immune cell infiltration in the tumor microenvironment.</p><p><strong>Conclusion: </strong>The high expression of lncRNA SPACA6P-AS in BC is closely linked to poor prognosis and may facilitate tumor progression by influencing specific biological processes, signaling pathways, and the immune microenvironment. The regulatory role of SPACA6P-AS positions it as a prospective biomarker and target for therapeutic approaches for BC diagnosis and intervention.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449778","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":"Endosome mediated nucleocytoplasmic trafficking and endomembrane allocation is crucial to polyglutamine toxicity.","authors":"Yuyu Nan, Wenfeng Chen, Fei Chen, Lili Wei, Aiyuan Zeng, Xiaohui Lin, Wenbin Zhou, Yufeng Yang, Qinghua Li","doi":"10.1007/s10565-024-09891-4","DOIUrl":"10.1007/s10565-024-09891-4","url":null,"abstract":"<p><p>Aggregation of aberrant proteins is a common pathological hallmark in neurodegeneration such as polyglutamine (polyQ) and other repeat-expansion diseases. Here through overexpression of ataxin3 C-terminal polyQ expansion in Drosophila gut enterocytes, we generated an intestinal obstruction model of spinocerebellar ataxia type3 (SCA3) and reported a new role of nuclear-associated endosomes (NAEs)-the delivery of polyQ to the nucleoplasm. In this model, accompanied by the prominently increased RAB5-positive NAEs are abundant nucleoplasmic reticulum enriched with polyQ, abnormal nuclear envelope invagination, significantly reduced endoplasmic reticulum, indicating dysfunctional nucleocytoplasmic trafficking and impaired endomembrane organization. Consistently, Rab5 but not Rab7 RNAi further decreased polyQ-related NAEs, inhibited endomembrane disorganization, and alleviated disease model. Interestingly, autophagic proteins were enriched in polyQ-related NAEs and played non-canonical autophagic roles as genetic manipulation of autophagic molecules exhibited differential impacts on NAEs and SCA3 toxicity. Namely, the down-regulation of Atg1 or Atg12 mitigated while Atg5 RNAi aggravated the disease phenotypes both in Drosophila intestines and compound eyes. Our findings, therefore, provide new mechanistic insights and underscore the fundamental roles of endosome-centered nucleocytoplasmic trafficking and homeostatic endomembrane allocation in the pathogenesis of polyQ diseases.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11189978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426318","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":"Correction to: Pum2-Mff axis fine-tunes mitochondrial quality control in acute ischemic kidney injury.","authors":"Jin Wang, Pingjun Zhu, Sam Toan, Ruibing Li, Jun Ren, Hao Zhou","doi":"10.1007/s10565-024-09886-1","DOIUrl":"10.1007/s10565-024-09886-1","url":null,"abstract":"","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11176236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310140","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":"LncRNA KIFAP3-5:1 inhibits epithelial-mesenchymal transition of renal tubular cell through PRRX1 in diabetic nephropathy.","authors":"Lei Du, Yinfei Lu, Jingyi Wang, Yijia Zheng, Huan Li, Yunfei Liu, Xiaoling Wu, Jieling Zhou, Lei Wang, Linlin He, Jiasen Shi, Liu Xu, Xizhi Li, Qian Lu, Xiaoxing Yin","doi":"10.1007/s10565-024-09874-5","DOIUrl":"10.1007/s10565-024-09874-5","url":null,"abstract":"<p><p>Long noncoding RNAs play an important role in several pathogenic processes in diabetic nephropathy, but the relationship with epithelial-mesenchymal transition in DN is unclear. Herein, we found that KIFAP3-5:1 expression was significantly down-regulated in DN plasma samples, db/db mouse kidney tissues and high glucose treated renal tubular epithelial cells compared to normal healthy samples and untreated cells. Overexpression of KIFAP3-5:1 improved renal fibrosis in db/db mice and rescued epithelial-mesenchymal transition of high glucose cultured renal tubular epithelial cells. The silence of KIFAP3-5:1 will exacerbate the progression of EMT. Mechanistically, KIFAP3-5:1 was confirmed to directly target to the -488 to -609 element of the PRRX1 promoter and negatively modulate PRRX1 mRNA and protein expressions. Furthermore, rescue assays demonstrated that the knockdown of PRRX1 counteracted the KIFAP3-5:1 low expression-mediated effects on EMT in hRPTECs cultured under high glucose. The plasma KIFAP3-5:1 of DN patients is highly correlated with the severity of renal dysfunction and plays an important role in the prediction model of DN diseases. These findings suggested that KIFAP3-5:1 plays a critical role in regulation of renal EMT and fibrosis through suppress PRRX1, and highlight the clinical potential of KIFAP3-5:1 to assist in the diagnosis of diabetic nephropathy.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11176233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310141","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":"The COP9 signalosome stabilized MALT1 promotes Non-Small Cell Lung Cancer progression through activation of NF-κB pathway.","authors":"Yinghui Wang, Xuyi Deng, Jing Xie, Tianhao Lu, Rui Qian, Zhi Guo, Xin Zeng, Jing Liao, Zhenhua Ding, Meijuan Zhou, Xinli Niu","doi":"10.1007/s10565-024-09888-z","DOIUrl":"10.1007/s10565-024-09888-z","url":null,"abstract":"<p><p>MALT1 has been implicated as an upstream regulator of NF-κB signaling in immune cells and tumors. This study determined the regulatory mechanisms and biological functions of MALT1 in non-small cell lung cancer (NSCLC). In cell culture and orthotopic xenograft models, MALT1 suppression via gene expression interference or protein activity inhibition significantly impaired malignant phenotypes and enhanced radiation sensitivity of NSCLC cells. CSN5, the core subunit of COP9 signalosome, was firstly verified to stabilize MALT1 via disturbing the interaction with E3 ligase FBXO3. Loss of FBXO3 in NSCLC cells reduced MALT1 ubiquitination and promoted its accumulation, which was reversed by CSN5 interference. An association between CSN5/FBXO3/MALT1 regulatory axis and poor prognosis in NSCLC patients was identified. Our findings revealed the detail mechanism of continuous MALT1 activation in NF-κB signaling, highlighting its significance as predictor and potential therapeutic target in NSCLC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11169058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305463","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":"HNRNPA2B1 stabilizes NFATC3 levels to potentiate its combined actions with FOSL1 to mediate vasculogenic mimicry in GBM cells.","authors":"Hanting Wang, Yiwen Shi, Xinxin Zhou, Lu Zhang, Aodan Yang, Dabo Zhou, Teng Ma","doi":"10.1007/s10565-024-09890-5","DOIUrl":"10.1007/s10565-024-09890-5","url":null,"abstract":"<p><strong>Background: </strong>Vasculogenic mimicry (VM) is an enigmatic physiological feature that influences blood supply within glioblastoma (GBM) tumors for their sustained growth. Previous studies identify NFATC3, FOSL1 and HNRNPA2B1 as significant mediators of VEGFR2, a key player in vasculogenesis, and their molecular relationships may be crucial for VM in GBM.</p><p><strong>Aims: </strong>The aim of this study was to understand how NFATC3, FOSL1 and HNRNPA2B1 collectively influence VM in GBM.</p><p><strong>Methods: </strong>We have investigated the underlying gene regulatory mechanisms for VM in GBM cell lines U251 and U373 in vitro and in vivo. In vitro cell-based assays were performed to explore the role of NFATC3, FOSL1 and HNRNPA2B1 in GBM cell proliferation, VM and migration, in the context of RNA interference (RNAi)-mediated knockdown alongside corresponding controls. Western blotting and qRT-PCR assays were used to examine VEGFR2 expression levels. CO-IP was employed to detect protein-protein interactions, ChIP was used to detect DNA-protein complexes, and RIP was used to detect RNA-protein complexes. Histochemical staining was used to detect VM tube formation in vivo.</p><p><strong>Results: </strong>Focusing on NFATC3, FOSL1 and HNRNPA2B1, we found each was significantly upregulated in GBM and positively correlated with VM-like cellular behaviors in U251 and U373 cell lines. Knockdown of NFATC3, FOSL1 or HNRNPA2B1 each resulted in decreased levels of VEGFR2, a key growth factor gene that drives VM, as well as the inhibition of proliferation, cell migration and extracorporeal VM activity. Chromatin immunoprecipitation (ChIP) studies and luciferase reporter gene assays revealed that NFATC3 binds to the promoter region of VEGFR2 to enhance VEGFR2 gene expression. Notably, FOSL1 interacts with NFATC3 as a co-factor to potentiate the DNA-binding capacity of NFATC3, resulting in enhanced VM-like cellular behaviors. Also, level of NFATC3 protein in cells was enhanced through HNRNPA2B1 binding of NFATC3 mRNA. Furthermore, RNAi-mediated silencing of NFATC3, FOSL1 and HNRNPA2B1 in GBM cells reduced their capacity for tumor formation and VM-like behaviors in vivo.</p><p><strong>Conclusion: </strong>Taken together, our findings identify NFATC3 as an important mediator of GBM tumor growth through its molecular and epistatic interactions with HNRNPA2B1 and FOSL1 to influence VEGFR2 expression and VM-like cellular behaviors.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11166796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305462","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":"Retraction Note: FoxM1-mediated RFC5 expression promotes temozolomide resistance.","authors":"Wan-Xin Peng, Xiu Han, Chun-Li Zhang, Lu Ge, Feng-Yi Du, Jie Jin, Ai-Hua Gong","doi":"10.1007/s10565-024-09887-0","DOIUrl":"10.1007/s10565-024-09887-0","url":null,"abstract":"","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11162392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293190","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":"The microRNA Let-7 and its exosomal form: Epigenetic regulators of gynecological cancers.","authors":"Fei Wang, Chundi Zhou, Yanping Zhu, Maryam Keshavarzi","doi":"10.1007/s10565-024-09884-3","DOIUrl":"10.1007/s10565-024-09884-3","url":null,"abstract":"<p><p>Many types of gynecological cancer (GC) are often silent until they reach an advanced stage, and are therefore often diagnosed too late for effective treatment. Hence, there is a real need for more efficient diagnosis and treatment for patients with GC. During recent years, researchers have increasingly studied the impact of microRNAs cancer development, leading to a number of applications in detection and treatment. MicroRNAs are a particular group of tiny RNA molecules that regulate regular gene expression by affecting the translation process. The downregulation of numerous miRNAs has been observed in human malignancies. Let-7 is an example of a miRNA that controls cellular processes as well as signaling cascades to affect post-transcriptional gene expression. Recent research supports the hypothesis that enhancing let-7 expression in those cancers where it is downregulated may be a potential treatment option. Exosomes are tiny vesicles that move through body fluids and can include components like miRNAs (including let-7) that are important for communication between cells. Studies proved that exosomes are able to enhance tumor growth, angiogenesis, chemoresistance, metastasis, and immune evasion, thus suggesting their importance in GC management.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11153289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247738","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":"Deoxynivalenol induces m⁶A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro.","authors":"Peirong Xu, Yulan Zhao, Yue Feng, Mindie Zhao, Ruqian Zhao","doi":"10.1007/s10565-024-09872-7","DOIUrl":"10.1007/s10565-024-09872-7","url":null,"abstract":"<p><p>Hippocampal neurons maintain the ability of proliferation throughout life to support neurogenesis. Deoxynivalenol (DON) is a mycotoxin that exhibits brain toxicity, yet whether and how DON affects hippocampal neurogenesis remains unknown. Here, we use mouse hippocampal neuron cells (HT-22) as a model to illustrate the effects of DON on neuron proliferation and to explore underlying mechanisms. DON exposure significantly inhibits the proliferation of HT-22 cells, which is associated with an up-regulation of cell cycle inhibitor p21 at both mRNA and protein levels. Global and site-specific m⁶A methylation levels on the 3'UTR of p21 mRNA are significantly increased in response to DON treatment, whereas inhibition of m⁶A hypermethylation significantly alleviates DON-induced cell cycle arrest. Further mechanistic studies indicate that the m⁶A readers YTHDF1 and IGF2BP1 are responsible for m⁶A-mediated increase in p21 mRNA stability. Meanwhile, 3'UTR of E3 ubiquitin ligase TRIM21 mRNA is also m⁶A hypermethylated, and another m⁶A reader YTHDF2 binds to the m⁶A sites, leading to decreased TRIM21 mRNA stability. Consequently, TRIM21 suppression impairs ubiquitin-mediated p21 protein degradation. Taken together, m⁶A-mediated upregulation of p21, at both post-transcriptional and post-translational levels, contributes to DON-induced inhibition of hippocampal neuron proliferation. These results may provide new insights for epigenetic therapy of neurodegenerative diseases.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11150311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236267","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}