Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia; Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Int Immunopharmacol. 2021 Oct;99:107925. doi: 10.1016/j.intimp.2021.107925. Epub 2021 Jul 1.
Cisplatin is a chemotherapeutic agent that induces multiorgan toxicity side effect due to induction of inflammation, apoptosis and disruption of intracellular antioxidant pathways. Betulin is a natural triterpenoid that has been shown to counteract cisplatin-induced nephrotoxicity. In this study, we investigated the ameliorative effect of betulin against cisplatin-promoted hepatotoxicity in rats. Moreover, we studied the molecular mechanism underlying betulin's effect. Single intraperitoneal injection (i.p.) of 10 mg/kg of cisplatin, was used to induce acute liver injury in rats. To assess betulin effect, a dose of 8 mg/kg (i.p.) was daily administered for 10 days. Betulin significantly improved serum Aspartate transaminase (AST), Alanine transaminase (ALT), albumin and total bilirubin levels in comparison with cisplatin group. Histopathologically, betulin restored cisplatin-deteriorated liver structural features and hepatic fibrosis. Mechanistically, betulin reduced hepatic oxidative stress as indicated by increased total antioxidant capacity and decreased malondialdehyde levels compared to cisplatin group. In addition, betulin reduced hepatic inflammation via significant inhibition of NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome, caspase-1 and interleukin-1β (IL-1β) levels. Intriguingly, betulin did not affect the expression levels of the mitotic kinase NIMA-related kinase 7 (Nek7), an NLRP3 interacting/activating protein. Last, Betulin induced anti-apoptotic effects as denoted by significant downregulation of P53 and Bax apoptotic proteins, upregulation of the anti-apoptotic protein, BCL2 and reduction of caspases 8, -9 and -3. This study is the first to provide evidence that betulin might be beneficial as a safe therapeutic approach to manage cisplatin-induced hepatotoxicity via targeting inflammatory and apoptotic pathways.
顺铂是一种化疗药物，由于诱导炎症、细胞凋亡和细胞内抗氧化途径的破坏，会引起多器官毒性副作用。白桦脂醇是一种天然的三萜类化合物，已被证明可以对抗顺铂引起的肾毒性。在这项研究中，我们研究了白桦脂醇对大鼠顺铂诱导的肝毒性的改善作用。此外，我们研究了白桦脂醇作用的分子机制。单次腹腔注射（i.p.）10mg/kg 的顺铂可诱导大鼠急性肝损伤。为了评估白桦脂醇的效果，每天给予 8mg/kg（i.p.）的剂量，共 10 天。与顺铂组相比，白桦脂醇显著改善了血清天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、白蛋白和总胆红素水平。组织病理学上，白桦脂醇恢复了顺铂恶化的肝脏结构特征和肝纤维化。在机制上，白桦脂醇通过增加总抗氧化能力和降低丙二醛水平来减轻肝氧化应激，与顺铂组相比。此外，白桦脂醇通过显著抑制 NOD 样受体富含吡啶结构域蛋白 3（NLRP3）炎性小体、半胱天冬酶-1 和白细胞介素-1β（IL-1β）水平来减轻肝炎症。有趣的是，白桦脂醇不影响有丝分裂激酶 NIMA 相关激酶 7（Nek7）的表达水平，Nek7 是 NLRP3 相互作用/激活蛋白。最后，白桦脂醇诱导抗凋亡作用，表现为 P53 和 Bax 凋亡蛋白的显著下调，抗凋亡蛋白 BCL2 的上调，以及半胱天冬酶 8、-9 和 -3 的减少。这项研究首次提供证据表明，白桦脂醇可能是一种有益的安全治疗方法，通过靶向炎症和凋亡途径来管理顺铂引起的肝毒性。
