背景:醋酸铅(PbAc),一种危险的重金属,由于广泛的工业暴露,对人类健康和环境构成重大威胁。PbAc暴露主要通过氧化应激和关键调节途径的破坏导致肝损伤。了解这些机制和探索保护剂对于减轻PbAc诱导的肝毒性至关重要。因此,我们的目的是研究与PbAc诱导的肝损伤有关的分子途径,集中于Sirt-1,Nrf2(HO-1,NQO1和SOD),Akt-1/GSK3β,m-TOR,P53此外,我们的目的是评估熊果苷的保肝作用,口服和腹膜内给药,确定最有效的交付方式。
方法:进行计算机分析以鉴定与Sirt-1和AKT-1/GSK-3B途径相关的蛋白质网络。研究了熊果苷的药效学特性,然后进行分子对接研究,以阐明其与所选蛋白质网络的相互作用。对随机分配到6个不同治疗组的成年雄性大鼠进行体内临床前研究,包括PbAc暴露和熊果苷口服或腹膜内治疗的PbAc暴露。
结果:PbAc暴露导致肝脏氧化应激,MDA水平升高和SIRT-1抑制证明,破坏抗氧化途径并激活抗自噬和促凋亡途径,最终导致肝细胞坏死。口服和腹膜内给予熊果苷有效地改变了这些作用,腹膜内递送在减轻PbAc诱导的组织学方面显示出优异的疗效,免疫学,和生化改变。
结论:这项研究提供了对PbAc诱导的肝损伤的分子机制的见解,并强调了熊果苷的肝保护潜力。这些发现表明熊果苷,特别是当腹膜内给药时,有望成为对抗PbAc诱导的肝毒性的治疗剂。
BACKGROUND: Lead acetate (PbAc), a hazardous heavy metal, poses significant threats to human health and the environment because of widespread industrial exposure. PbAc exposure leads to liver injury primarily through oxidative stress and the disruption of key regulatory pathways. Understanding these mechanisms and exploring protective agents are vital for mitigating PbAc-induced hepatotoxicity. Therefore, we aimed to investigate the molecular pathways implicated in PbAc-induced liver damage, focusing on Sirt-1, Nrf2 (HO-1, NQO1, and SOD), Akt-1/GSK3β, m-TOR, and P53. Additionally, we aimed to assess the hepatoprotective effects of
arbutin, which is administered orally and intraperitoneally, to determine the most effective delivery method.
METHODS: In silico analyses were conducted to identify relevant protein networks associated with Sirt-1 and AKT-1/GSK-3B pathways. The pharmacodynamic properties of
arbutin were examined, followed by molecular docking studies to elucidate its interactions with the selected protein network. In vivo preclinical studies were carried out on adult male rats randomly assigned to 6 different treatment groups, including PbAc exposure and PbAc exposure treated with
arbutin either orally or intraperitoneally.
RESULTS: PbAc exposure led to hepatic oxidative stress, as evidenced by elevated MDA levels and SIRT-1 inhibition, disrupting antioxidant pathways and activating antiautophagic and proapoptotic pathways, ultimately resulting in hepatocyte necrosis. Both oral and intraperitoneal
arbutin administration effectively modifed these effects, with intraperitoneal delivery showing superior efficacy in mitigating PbAc-induced histological, immunological, and biochemical alterations.
CONCLUSIONS: This study provides insights into the molecular mechanisms underlying PbAc-induced liver injury and highlights the hepatoprotective potential of arbutin. These findings suggest that
arbutin, particularly when administered intraperitoneally, holds promise as a therapeutic agent for combating PbAc-induced hepatotoxicity.