Vildagliptin attenuates doxorubicin-induced hepatotoxicity via activating Nrf2/HO-1 and SIRT1 and suppressing NF-κB signals in rats.

IF 2.9 4区医学 Q3 IMMUNOLOGY

Immunopharmacology and Immunotoxicology Pub Date : 2025-03-27 DOI:10.1080/08923973.2025.2482863

Heba M Mahmoud, Emad H M Hassanein, Marwa M Khalaf

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引用次数: 0

Abstract

Background: Doxorubicin (DOX) is an anticancer commonly employed in cancer treatment. However, the clinical application of DOX is associated with hepatotoxicity. Vildagliptin is an anti-hyperglycemic agent that inhibits the dipeptidyl peptidase-4 enzyme. Besides being used in managing type-2 diabetes, vildagliptin showed potential anti-inflammatory, antioxidant, and other activities.

Objective: Our investigation targeted the hepatoprotective effects of vildagliptin against DOX-induced hepatotoxicity.

Methods: Vildagliptin was given in a dose of 30 mg/kg, once daily; p.o. for 2 weeks while DOX was injected in a single dose of 30 mg/kg, i.p.

Results: Vildagliptin effectively decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, while it effectively elevated serum total protein (TP) level. Histologically, vildagliptin administration resulted in significant hepatoprotective efficacy with abundant figures of normal hepatocytes. Moreover, vildagliptin considerably decreased lipid peroxidation biomarker malondialdehyde (MDA), and the cytokines interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and cyclooxygenase (COX)-2, while it remarkably boosted the antioxidative defenses of glutathione (GSH) and catalase (CAT). Dual antioxidant and anti-inflammatory activities were mediated by upregulating nuclear factor (erythroid-derived 2)-like 2 (Nrf2), silent information regulator 1 (SIRT1), and heme oxygenase (HO-1) and suppressing the nuclear factor kappa B (NF-κB) signals. Finally, vildagliptin alleviated apoptosis by downregulating hepatic p53 and cytochrome (Cyt)-C.

Conclusion: Our findings suggest that vildagliptin improved hepatocellular architecture and reduced hepatic oxidative injury, inflammation, and apoptosis associated with DOX treatment.

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维格列汀通过激活Nrf2/HO-1和SIRT1以及抑制NF-κB信号来减弱大鼠阿霉素诱导的肝毒性。

背景：多柔比星（DOX）是一种常用的抗癌药物。然而，DOX的临床应用与肝毒性有关。维格列汀是一种抑制二肽基肽酶-4酶的抗高血糖药物。除了用于治疗2型糖尿病外，维格列汀还显示出潜在的抗炎、抗氧化和其他活性。目的：研究维格列汀对dox致肝毒性的保护作用。方法：维格列汀给药30 mg/kg，每日1次；结果：维格列汀可有效降低血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）活性，提高血清总蛋白（TP）水平。组织学上，维格列汀具有明显的肝保护作用，正常肝细胞数量丰富。此外，维格列汀显著降低脂质过氧化生物标志物丙二醛（MDA）、细胞因子白素(IL)-6、肿瘤坏死因子-α (TNF-α)和环氧化酶(COX)-2，同时显著增强谷胱甘肽（GSH）和过氧化氢酶（CAT）的抗氧化防御能力。双抗氧化和抗炎活性是通过上调核因子（红源性2）样2 （Nrf2）、沉默信息调节因子1 （SIRT1）和血红素加氧酶（HO-1）和抑制核因子κB （NF-κB）信号介导的。最后，维格列汀通过下调肝脏p53和细胞色素(Cyt)-C来减轻细胞凋亡。结论：我们的研究结果表明，维格列汀改善肝细胞结构，减少与DOX治疗相关的肝氧化损伤、炎症和凋亡。

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来源期刊

Immunopharmacology and Immunotoxicology 医学-毒理学

CiteScore

5.40

自引率

0.00%

发文量

133

审稿时长

4-8 weeks

期刊介绍： The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal. The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome. With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more. Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).