Downregulation of redox imbalance and iNOS/NF-ĸB/caspase-3 signalling with zinc supplementation prevents urotoxicity of cyclophosphamide-induced hemorrhagic cystitis in rats.

AIM: Cyclophosphamide (CYP) chemotherapy induces bladder toxicity and hemorrhagic cystitis in cancer patients constituting a current clinical concern. Oxidative inflammatory cascades have been implicated as the mechanism contributing to CYP bladder urotoxicity. We thus assayed to explore whether zinc (Zn) supplementation could mitigate CYP-induced urotoxicity and evaluate the possible underlying mechanism in rats. MAIN METHOD: Rats were orally administered Zn (100 mg/kg b.w./day) for 10 days against urotoxicity induced by single injection of CYP (150 mg/kg b.w., ip) on day 7. KEY FINDINGS: CYP significantly depressed bladder activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH) levels, whereas malondialdehyde level was increased prominently. In addition, CYP induced marked increases in the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and nitric oxide (NO) confirmed by histological alterations. CYP prominently increased bladder inducible nitric oxide synthase (iNOS) activity, nuclear factor-kappa B (NF-ĸB) and expression of caspase-3 protein. Zinc supplementation considerably abrogated the bladder urotoxicity by restoring redox balance, proinflammatory and apoptotic cascades and alleviated histopathological changes. SIGNIFICANCE: This is the first to reveal zinc potential to prevent CYP-induced urotoxic hemorrhagic cystitis via restoring redox balance and enhancing anti-inflammatory and antiapoptotic mechanisms in rat bladder.

Nephroprotective Effect of Moringa Oleifera Seed Oil on Gentamicin-Induced Nephrotoxicity in Rats: Biochemical Evaluation of Antioxidant, Anti-inflammatory, and Antiapoptotic Pathways.

Objective: Gentamicin is an efficacious aminoglycoside antibiotic widely used to treat life-threatening Gram-negative bacteria infections. However, its specific non-targeted induction of nephrotoxicity is a worrying clinical challenge. The study explored the nephroprotective effect of Moringa oleifera seed oil (MOO) against gentamicin-induced oxidative nephrotoxicity, pro-inflammation, and apoptosis in male Wistar rats.Method: Twenty-four rats divided into 4 groups (n = 6) were administered MOO (5 ml/kg) for 16 days and/or gentamicin (100 mg/kg bw/d, ip) injected from day 11 to day 16. The renal antioxidant enzyme activities reduced glutathione, lipid peroxidation, and serum renal markers. Urea and creatinine levels were estimated. The renal expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) were determined. Renal levels of inducible nitric oxide synthase (iNOS), nuclear factor-ĸB (NF-ĸB), and caspase-3 were determined to detect possible mechanism of inflammation and apoptosis with histology.Results: MOO prominently reduced serum creatinine and urea levels with amelioration of histopathological abrasions induced by gentamicin (GM). It significantly depressed oxidative stress through lowering of renal malondialdehyde (MDA) and elevation of renal superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, and reduced glutathione (GSH) level. MOO restored renal content of IL-1ß, IL-6, TNF-α, and NO, coupled with the mechanistic downregulation of NF-ĸB, iNOS, and caspase-3 activities. The histopathological alterations were ameliorated by MOO.Conclusions: MOO possesses marked nephroprotective effect against GM-induced renal damage via modulating oxidative stress, inflammation, and apoptosis in Wistar rats.