Alsahli Tariq G, Alharbi Khalid Saad, Alenezi Sattam Khulaif, Alqahtani Reem, Afzal Muhammad, Sayyed Nadeem
Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, 51452, Al Qassim, Saudi Arabia.
Sci Rep. 2025 Jul 26;15(1):27203. doi: 10.1038/s41598-025-09675-8.
A potent anticancer drug, doxorubicin (DOX), has substantial off-target hepatotoxicity, which limits its clinical use. The current study aimed to investigate the hepatoprotective effect of aegeline against DOX- induced hepatotoxicity in rats. Four groups of rats were randomly divided into following: Group I- Control (saline), group II - DOX, group III DOX + aegeline (5 mg/kg/p.o.), and group IV DOX + aegeline (10 mg/kg/p.o.). Various biochemical parameters such as alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin, oxidative stress markers such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO), inflammatory markers such as interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), nuclear factor kappa-B (NF-κB) and apoptosis markers, i.e. Bax (Bcl-2-associated X protein), B-cell lymphoma 2 (Bcl2), caspase-3 and caspase-9 were performed. Additionally, histopathology and molecular docking were performed. Administration of aegeline at both tested doses led to a significant (P < 0.05) reduction in liver enzyme levels such as ALT, ALP, and AST-in rats with DOX-induced hepatotoxicity, indicating improved liver function. Antioxidant defenses were also markedly enhanced in the aegeline-treated groups, as evidenced by increased levels of GSH, SOD, and CAT compared to the DOX-only group. In terms of inflammation, aegeline treatment significantly (P < 0.05) lowered the concentrations of key inflammatory cytokines, including IL-6, IL-1β, TNF-α, and the transcription factor NF-κB. This suggests a strong anti-inflammatory effect. Regarding apoptosis, the expression levels of pro-apoptotic markers-Caspase-3, Caspase-9, and Bax were notably decreased in the aegeline-treated rats, while levels of the anti-apoptotic protein Bcl-2 were elevated, pointing to a protective role against DOX-induced cell death. Molecular docking analysis further supported these findings, showing favorable interactions between aegeline and several target proteins. Notably, aegeline exhibited the strongest binding affinity with Bcl-2 (- 6.568 kcal/mol), primarily through hydrophobic interactions, suggesting potential molecular targets contributing to its therapeutic effects. The present study accredited the hepatoprotective effect of aegeline (5 and 10 mg/kg) by ameliorating Dox-induced hepatotoxicity in an experimental animal model.
一种强效抗癌药物阿霉素（DOX）具有显著的脱靶肝毒性，这限制了其临床应用。当前研究旨在探究埃吉琳对大鼠阿霉素诱导的肝毒性的肝保护作用。将四组大鼠随机分为以下几组：第一组为对照组（生理盐水），第二组为DOX组，第三组为DOX + 埃吉琳（5毫克/千克/口服）组，第四组为DOX + 埃吉琳（10毫克/千克/口服）组。检测了各种生化参数，如丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、碱性磷酸酶（ALP）、总胆红素；氧化应激标志物，如超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽（GSH）、丙二醛（MDA）、一氧化氮（NO）；炎症标志物，如白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）、肿瘤坏死因子α（TNF-α）、核因子κB（NF-κB）；以及凋亡标志物，即Bax（Bcl-2相关X蛋白）、B细胞淋巴瘤2（Bcl2）、半胱天冬酶-3和半胱天冬酶-9。此外，还进行了组织病理学和分子对接研究。给予两种测试剂量的埃吉琳均能显著（P < 0.05）降低阿霉素诱导的肝毒性大鼠的肝酶水平，如ALT、ALP和AST，表明肝功能得到改善。与仅用DOX处理的组相比，埃吉琳处理组的抗氧化防御能力也显著增强，表现为GSH、SOD和CAT水平升高。在炎症方面，埃吉琳处理显著（P < 0.05）降低了关键炎症细胞因子的浓度，包括IL-6、IL-1β、TNF-α以及转录因子NF-κB。这表明其具有强大的抗炎作用。关于凋亡，在埃吉琳处理的大鼠中，促凋亡标志物半胱天冬酶-3、半胱天冬酶-9和Bax的表达水平显著降低，而抗凋亡蛋白Bcl-2的水平升高，表明对阿霉素诱导的细胞死亡具有保护作用。分子对接分析进一步支持了这些发现，显示埃吉琳与几种靶蛋白之间存在良好的相互作用。值得注意的是，埃吉琳与Bcl-2表现出最强的结合亲和力（-6.568千卡/摩尔），主要通过疏水相互作用，表明其治疗作用可能涉及潜在的分子靶点。本研究证实了埃吉琳（5毫克/千克和10毫克/千克）通过改善实验动物模型中阿霉素诱导的肝毒性而具有肝保护作用。
