Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt.
J Biochem Mol Toxicol. 2022 Sep;36(9):e23129. doi: 10.1002/jbt.23129. Epub 2022 Jun 8.
Despite the extensive therapeutic uses of diclofenac, it may cause several adverse effects, including hepatorenal injury. The antioxidant and anti-inflammatory properties of resveratrol, a polyphenolic compound, make the agent effective in ameliorating a variety of drug-induced injuries. This study investigated the potential beneficial effects of resveratrol on diclofenac-induced hepatorenal toxicity and explored the role of miR-144 and its relationship to oxidative stress and inflammation triggered by diclofenac. Rats were divided into four groups: control; diclofenac group received diclofenac (10 mg/kg/day, intraperitoneal [ip]) for 7 days; prevention group received resveratrol concomitantly with diclofenac for 7 days; and the treatment group received diclofenac for 7 days followed by resveratrol (20 mg/kg/day, per oral) for another 7 days. Diclofenac administration induced a significant increase in serum hepatorenal biomarkers and histopathological aberrations. In addition, diclofenac upregulated miR-144 while reducing nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels and glutathione (GSH) content. Moreover, diclofenac induced tissue inflammation and apoptosis as evidenced by increased protein expression of nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), and caspase-3. Intriguingly, resveratrol prevention or treatment significantly mitigated the toxic effects of diclofenac as manifested by normalization of the hepatorenal functions and amelioration of the histopathological changes. Resveratrol also triggered miR-144 downregulation with Nrf2 upregulation. Consequently, resveratrol showed hepatorenal antioxidant, anti-inflammatory, and antiapoptotic activities as manifested by improvement in the antioxidant markers along with a decline in NF-κB, TNF-α, and caspase-3 expressions. In conclusion, this study demonstrates a potential therapeutic role of resveratrol in mitigating diclofenac-induced hepatorenal insult, possibly via modulating miR-144/Nrf2/GSH axis.
尽管双氯芬酸有广泛的治疗用途，但它可能会引起几种不良反应，包括肝肾功能损伤。白藜芦醇是一种多酚化合物，具有抗氧化和抗炎特性，可有效改善多种药物引起的损伤。本研究探讨了白藜芦醇对双氯芬酸诱导的肝肾功能毒性的潜在有益作用，并探讨了 miR-144 的作用及其与双氯芬酸引发的氧化应激和炎症的关系。将大鼠分为四组：对照组；双氯芬酸组每天腹腔注射双氯芬酸（10mg/kg），共 7 天；预防组同时给予双氯芬酸和白藜芦醇 7 天；治疗组先腹腔注射双氯芬酸 7 天，再口服白藜芦醇（20mg/kg）7 天。双氯芬酸给药导致血清肝肾功能生物标志物和组织病理学异常显著增加。此外，双氯芬酸上调了 miR-144，同时降低了核因子红细胞 2 相关因子 2（Nrf2）蛋白水平和谷胱甘肽（GSH）含量。此外，双氯芬酸诱导组织炎症和细胞凋亡，表现为核因子 kappa B（NF-κB）、肿瘤坏死因子-α（TNF-α）和半胱氨酸天冬氨酸蛋白酶-3（caspase-3）蛋白表达增加。有趣的是，白藜芦醇的预防或治疗显著减轻了双氯芬酸的毒性作用，表现为肝肾功能的正常化和组织病理学变化的改善。白藜芦醇还触发了 miR-144 的下调和 Nrf2 的上调。因此，白藜芦醇表现出肝肾功能的抗氧化、抗炎和抗凋亡作用，表现为抗氧化标志物的改善以及 NF-κB、TNF-α 和 caspase-3 表达的下降。总之，本研究表明白藜芦醇在减轻双氯芬酸诱导的肝肾功能损伤方面具有潜在的治疗作用，可能是通过调节 miR-144/Nrf2/GSH 轴。
