The Protective Effects of Saxagliptin and Cilostazol in an Experimental Model of Cyclophosphamide-Induced Nephrotoxicity in Rats: Targeting iNOS/NF-kB and Nrf-2/HO-1 Pathways

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-03-02 DOI:10.1002/jbt.70196

Monira A. Seleem, Ola M. Salem, Eman Basha, Hoda A. Ibrahim, Amira Mostafa Elshamy, Asmaa R. Azzam, Radwa Ismail, Abdallah A. Homouda, Alaa Elkordy, Heba Faheem

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Abstract

Cyclophosphamide (CYP) is an extensively used immunosuppressive drug and chemotherapeutic agent for various malignancies. Nevertheless, its use is limited due to adverse effects, including nephrotoxicity. Saxagliptin is a DPP4 inhibitor, while cilostazol serves as an antiplatelet agent. Their nephroprotective effects arise from antioxidant and anti-inflammatory properties. This study investigated the potential protective effects of Saxagliptin and Cilostazol in rats with kidney damage induced by CYP. Five equal groups of 50 male Wistar rats were randomly categorised as Group I (Control group), Group II: CYP untreated nephrotoxicity–induced group, Group III: Nephrotoxicity-induced group treated with saxagliptin, Group IV: Nephrotoxicity-induced group treated with cilostazol, and Group V: Nephrotoxicity-induced group treated with saxagliptin and cilostazol. Renal tissues and blood samples were collected for biochemical analysis of urea, creatinine, and acute kidney injury biomarkers, including Kim-1 and NGAL. Additionally, oxidative stress and inflammatory biomarkers such as GSH, MDA, TNF-α and IL-1β were assessed, along with gene expression of Nrf-2/HO-1 and NF-kB. Immunohistochemical analysis of iNOS, and histopathological study were also conducted. Saxagliptin and cilostazol ameliorated the nephrotoxicity induced by CYP, as indicated by improvements in urea, creatinine, and acute kidney injury biomarkers Kim-1 and NGAL. Furthermore, there was a decrease in oxidative stress via the upregulation of Nrf-2/HO-1, increased levels of GSH, downregulation of MDA and decreased inflammation via the downregulation of TNF-α, IL-1β and iNOS/NF-kB. The combination of saxagliptin and cilostazol demonstrated a significant improvement compared to using each agent individually. The combination of Saxagliptin/Cilostazol is superior to monotherapy by either of each alone in preventing CYP-induced nephrotoxicity.

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环磷酰胺（CYP）是一种广泛使用的免疫抑制剂，也是治疗各种恶性肿瘤的化疗药物。然而，由于其不良反应，包括肾毒性，它的使用受到了限制。沙格列汀是一种 DPP4 抑制剂，而西洛他唑则是一种抗血小板药物。它们对肾脏的保护作用来自于抗氧化和抗炎特性。本研究调查了沙格列汀和西洛他唑对 CYP 诱导的肾损伤大鼠的潜在保护作用。将 50 只雄性 Wistar 大鼠随机分为五组，第一组（对照组）、第二组（未经 CYP 治疗的肾毒性诱导组）、第三组（使用沙格列汀治疗的肾毒性诱导组）、第四组（使用西洛他唑治疗的肾毒性诱导组）和第五组（使用沙格列汀和西洛他唑治疗的肾毒性诱导组）。收集肾组织和血液样本，用于尿素、肌酐和急性肾损伤生物标志物（包括 Kim-1 和 NGAL）的生化分析。此外，还评估了氧化应激和炎症生物标志物，如 GSH、MDA、TNF-α 和 IL-1β，以及 Nrf-2/HO-1 和 NF-kB 的基因表达。还对 iNOS 进行了免疫组化分析，并进行了组织病理学研究。沙格列汀和西洛他唑改善了 CYP 诱导的肾毒性，尿素、肌酐、急性肾损伤生物标志物 Kim-1 和 NGAL 均有所改善。此外，通过上调 Nrf-2/HO-1、提高 GSH 水平、下调 MDA 和通过下调 TNF-α、IL-1β 和 iNOS/NF-kB 降低炎症，氧化应激也有所减少。与单独使用每种药物相比，沙格列汀和西洛他唑的联合治疗效果显著。在预防 CYP 诱导的肾毒性方面，沙格列汀/西洛他唑联合用药优于单药治疗。

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来源期刊

Journal of Biochemical and Molecular Toxicology 生物-毒理学

CiteScore

5.80

自引率

2.80%

发文量

277

审稿时长

6-12 weeks

期刊介绍： The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.