ABSTRACT
BACKGROUND: Methotrexate (MTX) is an antineoplastic/immunosuppressive drug, whose clinical use is impeded owing to its serious adverse effects; one of which is acute kidney injury (AKI). Most of MTX complications emerged from the provoked pro-oxidant-, pro-inflammatory- and pro-apoptotic effects. Quillaja saponaria bark saponin (QBS) is a bioactive triterpene that has been traditionally used as an antitussive, anti-inflammatory supplement, and to boost the immune system due to its potent antioxidant- and anti-inflammatory activities. However, the protective/therapeutic potential of QBS against AKI has not been previously evaluated. This study aimed to assess the modulatory effect of QBS on MTX-induced reno-toxicity. METHODS: Thirty-two male rats were divided into 4-groups. Control rats received oral saline (group-I). In group-II, rats administered QBS orally for 10-days. In group-III, rats were injected with single i.p. MTX (20 mg/kg) on day-5. Rats in group-IV received QBS and MTX. Serum BUN/creatinine levels were measured, as kidney-damage-indicating biomarkers. Renal malondialdehyde (MDA), reduced-glutathione (GSH) and nitric-oxide (NOx) were determined, as oxidative-stress indices. Renal expression of TNF-α protein and Nrf-2/Keap-1 mRNAs were evaluated as regulators of inflammation. Renal Bcl-2/cleaved caspase-3 immunoreactivities were evaluated as apoptosis indicators. RESULTS: Exaggerated kidney injury upon MTX treatment was evidenced histologically and biochemically. QBS attenuated MTX-mediated renal degeneration, oxidant-burden enhancement, excessive inflammation, and proapoptotic induction. Histopathological analysis further confirmed the reno-protective microenvironment rendered by QBS. CONCLUSIONS: In conclusion, our results suggest the prophylactic and/or therapeutic effects of QBS in treating MTX-induced AKI. Such reno-protection is most-likely mediated via Nrf-2 induction that interferes with oxidant load, inflammatory pathways, and proapoptotic signaling.
ABSTRACT
AIMS: Consumption of nutraceuticals without enough data regarding their interactions has raised safety concerns. Importantly, consumption of some natural-products in health-compromised conditions has caused liver injury due to the evolved pro-oxidant load. This study evaluates the safety of quercetin (QUR), as an extensively-used flavonoid owing to its antioxidant and hepatoprotective activities, in normal- and lipopolysaccharides (LPS)-primed livers, and to investigate the influence of the LPS-induced mild inflammatory/febrile condition on QUR effects. MAIN METHODS: For liver priming, a non-injurious LPS dose that mediates limited inflammation/mild fever was chosen. Selection of QUR dose/duration of treatment, for a coherent combination-regimen, was also adopted. Single LPS i.p injection (1.5 mg/kg)/oral QUR (20 mg/kg/day, IG) for 5-days was the optimal regimen for the combination group. On day-6, serum ALT/AST/ALP levels were measured, as liver-damage biomarkers. Hepatic; MDA/GSH were determined, as oxidative-stress measures, Bcl-2/cleaved-caspase-3 were assessed as apoptosis biomarkers, IL-6 expression/NF-κB/Nrf-2 immunoreactivities were evaluated as regulators for inflammation. KEY FINDINGS: Exaggerated hepatic injury was seen upon QUR treatment in LPS-presensitized mice; as evidenced by liver histopathological degeneration, which was confirmed by biochemical elevations of serum AST/ALT/ALP, along with oxidant-burden increase (↑MDA/↓GSH) and molecular augmentation of inflammation (NF-κB/IL-6 activation) that led to enhancement of proapoptotic signaling (caspase-3 activation/Bcl-2 inhibition). Such events were accompanied by potentiation of endogenous anti-inflammatory/antioxidant response (↑ hepatic Nrf-2). SIGNIFICANCE: The study highlights caution when QUR is consumed in health-compromised conditions, by revealing the role of fever/mild inflammation in enhancing liver toxicity upon QUR utilization, which was not apparent with moderate consumption of QUR-alone.
