Adverse Effects of Anti-Covid-19 Drug Candidates and Alcohol on Cellular Stress Responses of Hepatocytes.
Adverse Effects of Anti-Covid-19 Drug Candidates and Alcohol on Cellular Stress Responses of Hepatocytes.
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DOI：
10.1002/hep4.1887
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发表时间：
2022-06
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
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作者：
在大流行期间，地塞米松(DEX)、瑞美西韦(RDV)、羟氯喹(HCQ)、他西格宁(TG)、甲磺酸卡莫司坦(CaM)和普拉曲辛(Pralatrexate)被重新用于治疗冠状病毒病2019年(新冠肺炎)。然而，与抗COVID治疗相关的对肝脏的副作用尚不清楚。用HEPG2、HuH7和/或原代人肝细胞研究了这些药物在0-30μM时的细胞应激。地塞米松或RDV诱导内质网应激，X-box结合蛋白1增加，自噬反应增加，微管相关蛋白1A/1B轻链3(LC3-II)积聚增加。Dex和RDV对肝细胞的应激反应具有相加作用，进一步增加激活转录因子4和C/EBP同源蛋白1(CHOP)的表达，并导致细胞死亡。乙醇(50 MM)和地塞米松诱导的细胞应激反应比地塞米松和RDV更强。丙氨蝶呤诱导高尔基体碎裂，细胞周期停滞于G0/G1期，激活多聚腺苷二磷酸核糖聚合酶-1(PARP)和半胱氨酸天冬氨酸氨基转移酶(Caspase)，细胞死亡。丙氨蝶呤和乙醇对细胞死亡介质Bim、caspase3和PARP有协同作用。蛋白水解酶抑制剂CaM和Tg诱导自噬反应和线粒体应激，导致线粒体膜电位改变，B细胞淋巴瘤2和细胞色素C。TG和HCQ诱导UNC-51自噬反应标志物，如自噬激活激酶、LC3-II、Beclin1和ATG5，以及严重的内质网应激标志物CHOP。结论：抗新冠肺炎药物，特别是与药物或酒精药物合用，可引起肝细胞应激反应和肝细胞损伤。
During the pandemic, dexamethasone (DEX), remdesivir (RDV), hydroxychloroquine (HCQ), thapsigargin (TG), camostat mesylate (CaM), and pralatrexate were repurposed drugs for coronavirus disease 2019 (COVID‐19). However, the side effects on the liver associated with the anti‐COVID therapies are unknown. Cellular stresses by these drugs at 0‐30 μM were studied using HepG2, Huh7, and/or primary human hepatocytes. DEX or RDV induced endoplasmic reticulum stress with increased X‐box binding protein 1 and autophagic response with increased accumulation of microtubule‐associated protein 1A/1B‐light chain 3 (LC3‐II). DEX and RDV had additive effects on the stress responses in the liver cells, which further increased expression of activating transcription factor 4 and C/EBP homology protein 1 (CHOP), and cell death. Alcohol pretreatment (50 mM) and DEX induced greater cellular stress responses than DEX and RDV. Pralatrexate induced Golgi fragmentation, cell cycle arrest at G0/G1 phase, activations of poly (ADP‐ribose) polymerase‐1 (PARP) and caspases, and cell death. Pralatrexate and alcohol had synergistic effects on the cell death mediators of Bim, caspase3, and PARP. The protease inhibitor CaM and TG induced autophagic response and mitochondrial stress with altered mitochondrial membrane potential, B‐cell lymphoma 2, and cytochrome C. TG and HCQ induced autophagic response markers of Unc‐51 like autophagy activating kinase, LC3‐II, Beclin1, and Atg5, and severe ER stress marker CHOP. Conclusion: These results suggest that the anti‐COVID‐19 drugs, especially with drug–drug or alcohol–drug combinations, cause cellular stress responses and injuries in the liver cells.
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DOI：
10.3390/v13020234
发表时间：
2021-02-03
期刊：
Viruses
影响因子：
--
作者：
Al-Beltagi S;Preda CA;Goulding LV;James J;Pu J;Skinner P;Jiang Z;Wang BL;Yang J;Banyard AC;Mellits KH;Gershkovich P;Hayes CJ;Nguyen-Van-Tam J;Brown IH;Liu J;Chang KC
通讯作者：
Chang KC
地塞米松诱导的 Krüppel 样因子 9 表达促进肝糖异生和高血糖
影响因子：
15.9
作者：
Cui, Anfang;Fan, Heng;Chang, Yongsheng
通讯作者：
Chang, Yongsheng
影响因子：
3.7
作者：
Bae JY;Lee GE;Park H;Cho J;Kim J;Lee J;Kim K;Kim JI;Park MS
通讯作者：
Park MS
影响因子：
4.1
作者：
Guengerich FP
通讯作者：
Guengerich FP
影响因子：
64.8
作者：
Alter G;Yu J;Liu J;Chandrashekar A;Borducchi EN;Tostanoski LH;McMahan K;Jacob-Dolan C;Martinez DR;Chang A;Anioke T;Lifton M;Nkolola J;Stephenson KE;Atyeo C;Shin S;Fields P;Kaplan I;Robins H;Amanat F;Krammer F;Baric RS;Le Gars M;Sadoff J;de Groot AM;Heerwegh D;Struyf F;Douoguih M;van Hoof J;Schuitemaker H;Barouch DH
通讯作者：
Barouch DH