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.

Moringa oleifera seed oil or virgin coconut oil supplementation abrogates cerebral neurotoxicity induced by antineoplastic agent methotrexate by suppression of oxidative stress and neuro-inflammation in rats.

Methotrexate (MTX) is an effective antineoplastic drug associated with wide organ toxicity. Accumulating evidence implicates oxidative stress to be a leading underlying mechanism of MTX-induced neurotoxicity. The study explores antioxidant potential of virgin coconut oil (VCO) or Moringa oleifera seed oil (MOO) in MTX-induced oxidative stress-mediated cerebral neurotoxicity and inflammation in rats. Rats treated with VCO or MOO (5 ml/kg bw) for 17 days were administered MTX (20 mg/kg, intraperitoneally) on day 14 only. Cerebral activities of acetylcholinesterase, antioxidant enzymes, lipid peroxidation, reduced glutathione and nitric oxide levels as well as cytokines were evaluated. MTX-induced neurotoxic alterations were significantly abrogated by MOO and VCO supplementation via inhibition of cholinesterase, oxidative stress, and anti-inflammatory mechanisms. VCO and MOO showed comparable antioxidant potentials with the standards in DPPH and FRAP assays. VCO and MOO are promising natural oils for modulating MTX neurotoxicity in cancer patients. PRACTICAL APPLICATIONS: Methotrexate chemotherapy induces neurotoxicity in cancer patients, and this is a source of worry for clinicians. This study reports, for the first time, the beneficial health effects of functional food oils, Moringa oleifera seed oil, and virgin coconut oil against anticancer drug methotrexate-induced cerebral neurotoxicity. Supplementation of these natural oils may be beneficial in the prevention of cerebral neurotoxic side effect in cancer patients undergoing methotrexate chemotherapy.

Abrogation of Hepatic Damage Induced by Anticancer Drug Methotrexate by Zobo (Hibiscus sabdariffa extract) Supplementation via Targeting Oxidative Hepatotoxicity in Rats.

Clinical use of methotrexate (MTX) in cancer chemotherapy is limited due to its side effects, notably associated with increased oxidative stress and hepatotoxicity. Zobo is an aqueous extract of Hibiscus sabdariffa known to contain natural antioxidants. The present study investigated the hepatoprotective effect of zobo drink (ZD) on MTX-induced oxidative stress and hepatotoxicity in rats. Rats randomized to control group received distilled water orally; MTX group received intraperitoneal (ip) injection of MTX (20 mg/kg) on day 11; ZD + MTX group was administered ZD (10 ml/kg) for 14 days and was injected with MTX on day 11. Three days after MTX injection, enzyme markers of liver injury, protein profile, and bilirubin were assessed in serum. Hepatic activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and level of lipid peroxidation were estimated. Histopathological changes were carried out on the liver tissue. MTX induced prominent oxidative hepatotoxicity demonstrated by significant (p < .01) increases in serum liver enzymes and bilirubin, while protein profile was markedly reduced (p < .05). Hepatic activities of SOD, CAT, and GPx considerably decreased, whereas lipid peroxidation increased significantly in the MTX group compared to control. By contrast, ZD administration attenuated and restored the markers of liver injury, hepatic antioxidant enzymes, and lipid peroxidation near to control, while histopathological alterations were ameliorated compared to the MTX group. ZD affords superior protection against MTX-induced oxidative hepatotoxicity via improvement in antioxidant defense systems in rats. ZD could be a potent natural product against hepatotoxicity associated with MTX chemotherapy in cancer patients.

Antioxidant and anti-inflammatory effects of virgin coconut oil supplementation abrogate acute chemotherapy oxidative nephrotoxicity induced by anticancer drug methotrexate in rats.

BACKGROUND: Methotrexate (MTX) is an efficacious anticancer agent constrained in clinical use due to its toxicity on non-targeted tissue, a considerable source of worry to clinicians. Because the toxicity is associated with oxidative stress and inflammation, the study explored antioxidant and anti-inflammatory effect of virgin coconut oil (VCO) supplementation in nephrotoxicity induced by MTX in rats. METHODS: Rats were randomized into 4 groups (n=6) as follows: Control group; MTX group injected with single dose of MTX (20mg/kg, ip) on day 14; VCO (5%)+MTX and VCO (15%)+MTX groups were pre-treated with VCO diet and injected with single dose of MTX (20mg/kg, ip) on day 14. After 3 days of MTX injection, serum kidney markers, renal activities of antioxidant enzymes and glutathione (GSH) content were determined. Lipid peroxidation level and inflammatory markers- interleukin-6 (IL-6), nitric oxide (NO) and C-reactive protein (CRP) were estimated in kidney. Histopathological alterations were examined for kidney damage. RESULTS: MTX nephrotoxicity was evidenced by markedly elevated serum renal markers along with significant decreases in renal GSH and activities of antioxidant enzymes confirmed by histopathology. Lipid peroxidation level, IL-6, NO and CRP markedly increased compared to control. VCO supplementation prior to MTX injection attenuated MTX-induced oxidative nephrotoxicity via prominent increases in GSH and antioxidant enzyme activities in a dose-dependent manner. The renal inflammatory markers and MDA depleted considerably compared to MTX control group. Histopathological alterations were mitigated to confirm the biochemical indices. CONCLUSION: VCO supplementation demonstrates nephroprotective activity by attenuating MTX oxidative nephrotoxicity via antioxidant and anti-inflammatory activities in kidney. Our results suggested that VCO may benefit cancer patients on MTX chemotherapy against kidney injury.