Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.
Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.
Biochem Biophys Res Commun. 2023 Dec 10;685:149168. doi: 10.1016/j.bbrc.2023.149168. Epub 2023 Oct 28.
Diclofenac (DIC) is one of the most commonly prescribed non-steroidal anti-inflammatory drugs and has been shown to cause oxidative stress and liver injury. The current study investigated protective effects of metformin against DIC-induced hepatic toxicity in both in vitro and in vivo models. For the in vitro study, HepG2 cells were exposed to DIC in the presence or absence of metformin. The effect of metformin on cell viability was evaluated by MTT assay. Oxidative stress parameters (malondialdehyde (MDA), total thiol molecules (TTM), and total antioxidant capacity (TAC)) were assessed. For the in vivo study, thirty-six male Wistar rats were randomly divided into 6 groups. These groups were normal saline, metformin (200 mg/kg), DIC (50 mg/kg/day), DIC + metformin (50, 100, and 200 mg/kg/day). Histopathological studies and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), albumin, direct and total bilirubin were measured. Also, oxidative stress parameters were assessed in liver tissue. Furthermore, expression of glutathione peroxidase (GPX)-1, -3, and -4, catalase (CAT), superoxide dismutase (SOD)-1, and -3 was examined using the real-time PCR method in hepatic tissue. In the in vitro study, metformin significantly prevented DIC-induced loss in cell viability in HepG2 cells. Metformin markedly reduced DIC-induced elevation of MDA levels and increased the TAC and TTM levels. In the in vivo study, metformin significantly prevented DIC-induced changes in hematological and histological markers. Administration of metformin significantly improved oxidative stress parameters in liver tissue. In addition, metformin increased the expression of antioxidant enzymes. Our results suggest that metformin exerts a significant protective effect against DIC-induced hepatic toxicity.
双氯芬酸（DIC）是最常用的处方非甾体抗炎药之一，已被证明可引起氧化应激和肝损伤。本研究在体外和体内模型中研究了二甲双胍对 DIC 诱导的肝毒性的保护作用。在体外研究中，将 HepG2 细胞暴露于存在或不存在二甲双胍的 DIC 中。通过 MTT 测定评估二甲双胍对细胞活力的影响。评估氧化应激参数（丙二醛（MDA），总巯基分子（TTM）和总抗氧化能力（TAC））。在体内研究中，将 36 只雄性 Wistar 大鼠随机分为 6 组。这些组为生理盐水，二甲双胍（200mg/kg），DIC（50mg/kg/天），DIC+二甲双胍（50、100 和 200mg/kg/天）。测量组织病理学研究和血清中天冬氨酸氨基转移酶（AST），丙氨酸氨基转移酶（ALT），碱性磷酸酶（ALP），乳酸脱氢酶（LDH），白蛋白，直接和总胆红素的水平。还评估了肝组织中的氧化应激参数。此外，使用实时 PCR 法检查肝组织中谷胱甘肽过氧化物酶（GPX）-1、-3 和 -4、过氧化氢酶（CAT）、超氧化物歧化酶（SOD）-1 和 -3 的表达。在体外研究中，二甲双胍显着防止 DIC 诱导的 HepG2 细胞活力丧失。二甲双胍显着降低 DIC 诱导的 MDA 水平升高，并增加 TAC 和 TTM 水平。在体内研究中，二甲双胍显着防止 DIC 引起的血液学和组织学标志物变化。二甲双胍的给药显着改善了肝组织中的氧化应激参数。此外，二甲双胍增加了抗氧化酶的表达。我们的结果表明，二甲双胍对 DIC 诱导的肝毒性具有显着的保护作用。
