ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Yiren Xiong,Zuqing Hu,Di Ouyang,Meilin Tang,Jiayi He,Shanshan He,Renyi Liu,Zhenjie Gao,Ying Chen,Dalin Hu
Lead is a widespread environmental pollutant with serious adverse effects on human health, but the mechanism underlying its toxicity remains elusive. This study aimed to investigate the role of miR-584–5p / Ykt6 axis in the toxic effect of lead on HK-2 cells and the related mechanism. Our data suggested that lead exposure caused significant cytotoxicity, DNA and chromosome damage to HK-2 cells. Mechanistically, lead exposure down-regulated miR-584–5p and up-regulated Ykt6 expression, consequently, autophagosomal number and autophagic flux increased, lysosomal number and activity decreased, exosomal secretion increased. Interestingly, when miR-584–5p level was enhanced with mimic, autophagosomal number and autophagic flux decreased, lysosomal number and activity increased, ultimately, exosomal secretion was down-regulated, which resulted in significant aggravated toxic effects of lead. Further, directly blocking exosomal secretion with inhibitor GW4869 also resulted in exacerbated toxic effects of lead. Herein, we conclude that miR-584–5p / Ykt6 - mediated autophagy - lysosome - exosome pathway may be a critical route affecting the toxic effects of lead on HK-2 cells. We provide a novel insight into the mechanism underlying the toxicity of lead on human cells.
研究领域:
毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2026
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IF 10.6
Chanlin Fang,Weijie Gu,You Weng,Shanshan Di,Xinquan Wang,Yuanxiang Jin
6PPD, a widely used antioxidant in tires, has emerged as an environmental contaminant linked to cardiotoxicity in aquatic organisms, yet the molecular mechanism underlying 6PPD-induced cardiac injury remains unclear. Here, the mechanisms of 6PPD induced cardiotoxicity were investigated utilizing a combination of in vivo zebrafish and in vitro cardiomyocyte models. We found that 6PPD exposure caused cardiac dysfunction, myocardial injury, and pathological remodeling, accompanied by impaired autophagic flux, mitochondrial damage, and cardiomyocyte apoptosis. Mechanistically, 6PPD markedly downregulated YKT6, a SNARE protein essential for autophagosome-lysosome fusion, in both heart of zebrafish and H9C2 cells. Molecular dynamics simulations predicted a potential xenobiotic-protein interaction between 6PPD and YKT6 that restricted its conformational flexibility. Moreover, loss of YKT6 disrupted autophagosome maturation and promoted P62 accumulation, whereas YKT6 overexpression restored autophagosome-lysosome fusion, alleviated mitochondrial injury, and rescued 6PPD-induced cardiomyocyte dysfunction. Consistently, overexpressing YKT6 in adult zebrafish hearts through pericardial injection can also reduce the accumulation of P62 and heart damage. Overall, our findings suggest that 6PPD-induced cardiotoxicity involves YKT6 suppression, which is associated with impaired autophagosome-lysosome fusion and mitochondrial dysfunction, contributing to cardiomyocyte apoptosis in zebrafish. Thus, it was possible that restoring YKT6 emerged as a promising strategy to mitigate 6PPD-associated cardiac injury.
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
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2026
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IF 4.7
Qi-Hao Li,Tian-Ze Li,Yong-Cui Wang,Yao Yang,Ji-Jun Chen
Hepatocellular carcinoma (HCC) remains a highly malignant cancer with limited treatment options. HCC cells (HCCs) activate hepatic stellate cells (HSCs) and transform them into cancer-associated fibroblasts (CAFs), forming a vicious cycle for hepatocarcinogenesis. Therefore, inhibition of the communication between HCCs and HSCs is expected to emerge as a novel strategy for HCC treatment. Artematrolide F (AF), a sesquiterpenoid dimers (SDs) isolated from Artemisia atrovirens , exhibited significantly inhibitory activity on tumor cells in our previous report, but its mechanism remains unknown. This further study demonstrated that AF significantly inhibited the proliferation, colony formation and metastasis of HCCs. Notably, the inhibitory effect was enhanced when HCCs were cocultured with HSCs, suggesting that AF may suppress tumor progression through regulating the crosstalk of HCCs and HSCs. The vesicular transport protein YKT6 was identified as a target of AF through integrating bioinformatics analysis and machine learning model, which were verified by DARTS, CETSA, molecular docking, molecular dynamics simulation, and knockdown experiments. Further mechanistic research revealed that AF targeting YKT6 disrupted the crosstalk between HSCs and HCCs, suppressed HSC-driven tumor proliferation by inhibiting extracellular vesicles (EVs) secretion from HCCs, and blocked tumor autophagy by disrupting vesicular transport. These findings demonstrate that AF could serve as a novel therapeutic candidate for HCC treatment through regulating YKT6 to suppress HCCs–HSCs communication, block EV-dependent tumor progression, and inhibit tumor autophagy.
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DOI
PubMed
高影响因子
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