School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
Jiangxi Provincial People's Hospital, Nanchang 330012, China.
Molecules. 2023 Jun 15;28(12):4793. doi: 10.3390/molecules28124793.
Genipin has been the focus of research as a multifunctional compound for the treatment of pathogenic diseases. However, hepatotoxicity caused by oral genipin raises concerns about its safety. To obtain novel derivatives with low toxicity and efficacy, we synthesized methylgenipin (MG), a new compound, using structural modification, and investigated the safety of MG administration. The results showed that the LD of oral MG was higher than 1000 mg/kg, no mice died or were poisoned during the experiment in the treatment group, and there was no significant difference in biochemical parameters and liver pathological sections compared with the control. Importantly, MG (100 mg/kg/d) treatment for 7 days reduced alpha-naphthylisothiocyanate (ANIT)-induced increases in liver index, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), and total bilirubin (TBIL) levels. Histopathology demonstrated that MG could treat ANIT-induced cholestasis. In addition, using proteomics to investigate the molecular mechanism of MG in the treatment of a liver injury may be related to enhancing antioxidant function. Kit validation showed that ANIT induced an increase in malondialdehyde (MDA) and a decrease in superoxide dismutase (SOD) and glutathione (GSH) levels, while the MG pretreatments, both of which were significantly reversed to some extent, suggested that MG may alleviate ANIT-induced hepatotoxicity by enhancing endogenous antioxidant enzymes and inhibiting oxidative stress injury. In this study, we demonstrate that the treatment of mice with MG does not cause impaired liver function and provide an investigation of the efficacy of MG against ANIT-induced hepatotoxicity, laying the foundation for the safety evaluation and clinical application of MG.
京尼平作为一种多功能化合物，已成为治疗多种疾病的研究热点。然而，口服京尼平引起的肝毒性引起了人们对其安全性的关注。为了获得毒性低、疗效好的新型衍生物，我们采用结构修饰的方法合成了新化合物甲基京尼平（MG），并研究了 MG 给药的安全性。结果表明，MG 的口服 LD 大于 1000mg/kg，实验组在实验过程中无 1 只小鼠死亡或中毒，与对照组相比，生化参数和肝病理切片无显著差异。重要的是，MG（100mg/kg/d）治疗 7 天可降低α-萘基异硫氰酸酯（ANIT）诱导的肝指数、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（AKP）和总胆红素（TBIL）水平升高。组织病理学表明，MG 可治疗 ANIT 诱导的胆汁淤积。此外，利用蛋白质组学研究 MG 治疗肝损伤的分子机制可能与增强抗氧化功能有关。试剂盒验证表明，ANIT 诱导丙二醛（MDA）增加，超氧化物歧化酶（SOD）和谷胱甘肽（GSH）水平降低，而 MG 预处理在一定程度上显著逆转了这些变化，提示 MG 可能通过增强内源性抗氧化酶和抑制氧化应激损伤来减轻 ANIT 诱导的肝毒性。在本研究中，我们证明了 MG 治疗小鼠不会导致肝功能受损，并对 MG 治疗 ANIT 诱导的肝毒性的疗效进行了研究，为 MG 的安全性评价和临床应用奠定了基础。
