Nephroprotective Potential of 1,3,4-Oxadiazole Derivative Against Methotrexate-Induced Nephrotoxicity in Rats by Upregulating Nrf2 and Downregulating NF-κB and TNF-α Signaling Pathways

IF 3.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zubaria Rafique, Muhammad Aabid, Humaira Nadeem, Ayema Rehman, Jehan zeb Khan, Muhammad Waqas, Nadeem Irshad
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引用次数: 0

Abstract

Nephrotoxicity is a prominent complication of methotrexate (MTX) therapy that limits clinicians in its extensive use. MTX triggers oxidative burden and inflammation, so the nephroprotective potential of the synthetic derivative of 1,3,4-oxadiazole (5b) was explored in this research. Male Wistar rats were divided into four groups i.e., control group, MTX group, 5b (5 mg/kg) + MTX group and 5b (10 mg/kg) + MTX group, respectively. All treatments were given, intraperitoneally (i.p.) during 12 days of the animal model. The MTX-induced nephrotoxicity was evaluated by renal function markers i.e., serum creatinine (Cret), blood urea nitrogen (BUN), and albumin (Alb). Furthermore, antioxidant markers, catalase (CAT), glutathione-S-transferase (GST), and reduced glutathione (GSH), and oxidative stress, markers lipid peroxidase (LPO) and nitric oxide (NO), were analyzed. Pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were also calculated. DNA damage was assessed by the comet assay. Histopathological staining (Hematoxylin and eosin, Masson's trichrome) was done and immunohistochemistry was performed against Caspase-3, Nrf2, HO-1, TLR-4, TNF-α, and NF-κB. A significant improvement in the serum Cret, BUN, and Alb was observed in (5b) treated groups. Antioxidant markers were elevated, oxidative stress markers and pro-inflammatory cytokines were reduced, moreover, histopathological analysis revealed less tissue damage in (5b) administered groups. Immunohistochemistry showed increased immune expression of Nrf2 and HO-1 and decreased expression of TLR-4, TNF-α, Caspase-3, and NF-κB in 5b (5 mg/kg) + MTX group and 5b (10 mg/kg) + MTX group as compared to the MTX group. Hence, the results of this study favor the use of (5b) against MTX-induced nephrotoxicity.

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来源期刊
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.
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