Diallyl disulfide ameliorates methotrexate‐induced nephropathy in rats: Molecular studies and network pharmacology analysis

Abstract

Methotrexate (MTX) is a promising chemotherapeutic agent. Its medical use is limited by induced nephropathy. Our study was designed to explore the reno‐protective effect of diallyl disulfide (DADS), an organosulfur compound of garlic oil, on MTX‐induced nephropathy. Adult rats were randomly divided into 4 groups; normal control, DADS (50 mg kg–1 day–1, p.o.), MTX (20 mg/kg, i.p.) and DADS+MTX. DADS significantly decreased serum creatinine, urea, uric acid, and albumin levels with an improvement of final body weight. Additionally, DADS markedly attenuated MTX‐induced elevations in renal MDA and NO2‐ contents with an increase in GSH content and SOD activity. Mechanistically, DADS effectively down‐regulated mRNA expression level of renal p38 and NF‐κB. Additionally, DADS positively regulated the NRF2 gene with a remarkable inhibition of Keap‐1 gene. Furthermore, DADS up‐regulated BCL2 protein and remarkably suppressed the expression of both BAX and caspase‐3 proteins. Overall, DADS has favorable renal protection against MTX‐induced nephropathy via modulation of Keap‐1/NRF2, p38/NF‐κB, and BCL2/BAX/caspase‐3 signaling. Practical applications Diallyl disulfide is one of the organosulfur compounds of garlic oil. Our study demonstrated that DADS substantially alleviated the decline of kidney function and renal injury induced by MTX. The antioxidative, anti‐inflammatory, and anti‐apoptotic properties may constitute an important part of its therapeutic applications via regulation of p38/NF‐κB, Keap‐1/NRF2, and BCL2/BAX/caspase‐3 signaling pathways. Therefore, DADS could be a potential therapeutic adjunct in cancer chemotherapy to decrease the associated side effects of MTX. It should be further explored clinically as a protective agent for MTX‐treated cancer patients.

Protective Effect of Pycnogenol against Methotrexate-Induced Hepatic, Renal, and Cardiac Toxicity: An In Vivo Study

“…In our investigations, we observed a significant drop in the activity of the CAT and SOD enzymes, as well as a decrease in the levels of GSH and ATP in the MTX-treated groups. These results are in agreement with previous studies that reported that MTX treatment led to reduced GSH, SOD, and CAT activity, as well as elevated MDA [50][51][52]. Notably, the magnitude of GSH detected (pg/g tissue) in our experiments is lower than previously reported studies values.…”

Anti-Hyperuricemic, Anti-Arthritic, Hemolytic Activity and Therapeutic Safety of Glycoconjugated Triazole-Phthalimides

“…Then, the Huisgen 1,3-dipolar cycloaddition reaction condition (CuI/Et 3 N/CH 2 Cl 2 ) was employed to prepare glycoconjugated triazole-phthalimides F2, F3 and F4 in good yields (68-90%). The molecular structure of the phthalimide syntheses was confirmed by IR, 13 C NMR, and 1 H NMR by the similarity of the spectra reported by Assis et al [33] and Silva Júnior et al [34].…”

“…The infrared spectra were recorded on an IFS66 Bruker spectrophotometer using KBr discs. 1 H and 13 C NMR were obtained on Varian Unity Plus-300 and Varian UNMRS 400 MHz spectrometers using CDCl 3 or DMSO-d 6 as a solvent. The polarimeter used was the Krüss, of 10 cm path length and a concentration of the solution in g/100 mL.…”

“…White solid; 68% yield; mp: 103-106 • C; [α] D 25 + 37.9 (c 1, CH 2 Cl 2 ). The 1 H and 13 C NMR data were derived from the literature [33,34].…”

“…Hyperuricemia can lead to complications such as heart failure, high blood pressure, kidney failure and diabetes mellitus [ 11 ]. In addition, several drugs used to treat other comorbidities can increase serum uric acid levels, such as diuretics, especially thiazides [ 12 ], immunosuppressants such as Ciclosporin [ 3 ], cytotoxic chemotherapy [ 13 ], and Levodopa [ 14 ], among other pharmaceutical formulations [ 15 , 16 ].…”