Regulation of Cr(VI)-Induced Premature Senescence in L02 Hepatocytes by ROS-Ca(2+)-NF-κB Signaling.
Regulation of Cr(VI)-Induced Premature Senescence in L02 Hepatocytes by ROS-Ca(2+)-NF-κB Signaling.
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ROS-Ca2 -NF-κB 信号调节 Cr(VI) 诱导的 L02 肝细胞过早衰老
DOI：
10.1155/2022/7295224
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发表时间：
2022
影响因子：
--
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Zhang Y;Yang G;Huang S;Yang X;Yuan F;Song Y;Liu S;Yu X
应激诱导的早衰可能参与了急性肝损伤的发病机制。六价铬[Cr(VI)]是一种常见的与肝损伤相关的环境污染物，可能导致L02肝细胞过早衰老。然而，关于肝细胞在铬(VI)暴露中过早衰老的潜在机制仍然知之甚少。在本研究中，我们发现长期暴露于铬(VI)的L02肝细胞会导致提前衰老，其特征是β-半乳糖苷酶活性升高，衰老相关的异染色质灶，G1期停滞，细胞增殖下降。此外，铬(VI)诱导的衰老L02肝细胞中IL-6和成纤维细胞生长因子23(FGF23)等炎症相关因子表达上调，线粒体产生的活性氧(ROS)积累伴随细胞内钙离子(Ca~(2+))浓度和核因子-kappaB(NF-κB)活性升高。值得注意的是，N-乙酰半胱氨酸对ROS的抑制不仅可以减轻铬(VI)诱导的细胞衰老，而且还可以减少细胞内钙离子的升高，激活核因子-κB，以及IL-6/FGF23的分泌。有趣的是，细胞内钙离子螯合剂BAPTA-AM可部分逆转铬(VI)对L02肝细胞早衰的毒性作用和IL-6/FGF23水平的升高。此外，利用核因子-κB抑制剂吡咯烷二硫代氨基甲酸酯，我们证实了核因子-κB介导的IL-6/FGF23调节铬(VI)诱导的L02肝细胞的早衰，而胞内钙离子浓度不受二硫代氨基甲酸酯的影响。据我们所知，我们的数据首次报道了ROS-Ca~(2+)-NF-κB信号通路在铬(VI)诱导的早衰中的作用。我们的结果为进一步探索针对与过早衰老相关的铬(VI)诱导的慢性肝损伤的创新干预策略和治疗提供了线索。
Stress-induced premature senescence may be involved in the pathogeneses of acute liver injury. Hexavalent chromium [Cr(VI)], a common environmental pollutant related to liver injury, likely leads to premature senescence in L02 hepatocytes. However, the underlying mechanisms regarding hepatocyte premature senility in Cr(VI) exposure remain poorly understood. In this study, we found that chronic exposure of L02 hepatocytes to Cr(VI) led to premature senescence characterized by increased β-galactosidase activity, senescence-associated heterochromatin foci, G1 phase arrest, and decreased cell proliferation. Additionally, Cr(VI)-induced senescent L02 hepatocytes showed upregulated inflammation-related factors, such as IL-6 and fibroblast growth factor 23 (FGF23), which also exhibited reactive oxygen species (ROS) accumulation derived from mitochondria accompanied with increased concentration of intracellular calcium ions (Ca2+) and activity of nuclear factor kappa B (NF-κB). Of note is that ROS inhibition by N-acetyl-Lcysteine pretreatment not only alleviated Cr(VI)-induced premature senescence but also reduced the elevated intracellular Ca2+, activated NF-κB, and secretion of IL-6/FGF23. Intriguingly, the toxic effect of Cr(VI) upon premature senescence of L02 hepatocytes and increased levels of IL-6/FGF23 could be partially reversed by the intracellular Ca2+ chelator BAPTA-AM pretreatment. Furthermore, by utilizing the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that NF-κB mediated IL-6/FGF23 to regulate the Cr(VI)-induced L02 hepatocyte premature senescence, whilst the concentration of intracellular Ca2+ was not influenced by PDTC. To the best of our knowledge, our data reports for the first time the role of ROS-Ca2+-NF-κB signaling pathway in Cr(VI)-induced premature senescence. Our results collectively shed light on further exploration of innovative intervention strategies and treatment targeting Cr(VI)-induced chronic liver damage related to premature senescence.
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DOI：
10.1002/hep.30228
发表时间：
2019-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Franca A;Carlos Melo Lima Filho A;Guerra MT;Weerachayaphorn J;Loiola Dos Santos M;Njei B;Robert M;Xavier Lima C;Vieira Teixeira Vidigal P;Banales JM;Ananthanarayanam M;Leite MF;Nathanson MH
通讯作者：
Nathanson MH
影响因子：
5.2
作者：
Krick, Stefanie;Helton, Eric Scott;Barnes, Jarrod W.
通讯作者：
Barnes, Jarrod W.
影响因子：
9
作者：
Janikiewicz J;Szymański J;Malinska D;Patalas-Krawczyk P;Michalska B;Duszyński J;Giorgi C;Bonora M;Dobrzyn A;Wieckowski MR
通讯作者：
Wieckowski MR
影响因子：
3.8
作者：
Chen, Qiao Yi;Murphy, Anthony;Costa, Max
通讯作者：
Costa, Max
影响因子：
8.9
作者：
Lv, Yueying;Jiang, Huijie;Zhang, Zhigang
通讯作者：
Zhang, Zhigang