Paracetamol (PAR) is a commonly used antipyretic and analgesic agent, but its excessive usage can induce liver damage and major health consequences. Interleukin-35 (IL-35) is utilized to treat immunological disorders, intestinal illness, arthritis, allergic disease, hepatitis, and cancer. Thymoquinone (THYO) is also effective against a wide range of disorders. Consequently, this study sought out to explore the ameliorative effects of IL-35 and THYO against PAR-induced hepatotoxicity in rats. Sixty male rats were separated into six groups (10 rats/group): I control (0.5 mL NaCl, 0.9%/rat via oral gavage); II (IL-35), and III (TYHO) received intraperitoneal (i.p) injection of IL-35 (200 ng/kg) or THYO (0.5 mg/kg), respectively. Group IV (PAR) received 600 mg/kg of PAR orally; V (PAR + IL-35) and VI (PAR + TYHO); rats received 600 mg/kg of PAR orally and i.p injection of IL-35 (200 ng/kg) or THYO (0.5 mg/kg), respectively. Administration of IL-35 or THYO markedly mitigated the increasing in the levels of liver parameters triggered by PAR and noticeable enhancement of antioxidant and immunological markers were observed. Additionally, IL-35 or THYO decreased TNF-α, NF-κB, IL-10, IL-6 and IFN-γ in contrast to the PAR control group. Moreover, levels of Capase-3, and cytochrome C were significantly reduced by THYO or IL35, while, levels of Bcl-2 were markedly increased. Furthermore, significant downregulation of IL1-β, TNF-α, TGF-β, and Caspas-3 genes, as well as significant upregulation of Bcl-2 and IL-10 expression were detected. In conclusion, IL-35 and THYO insulated liver from PAR toxicity by mitigating oxidative stress, tissue damage, inflammation, and apoptosis.
Oxidative stress is involved in the pathogenesis of a number of diseases including hypertension and renal failure. There is enhanced expression of nicotinamide adenine dinucleotide (NADPH oxidase) and therefore production of hydrogen peroxide (H2O2) during renal disease progression. This study investigated the effect of apocynin, an NADPH oxidase inhibitor and catalase, an H2O2 scavenger on Cyclosporine A (CsA) nephrotoxicity in Wistar-Kyoto rats. Rats received CsA (25mg/kg/day via gavage) and were assigned to vehicle, apocynin (2.5mmol/L p.o.), catalase (10,000U/kg/day i.p.) or apocynin plus catalase for 14 days. Renal functional and hemodynamic parameters were measured every week, and kidneys were harvested at the end of the study for histological and NADPH oxidase 4 (NOX4) assessment. Oxidative stress markers and blood urea nitrogen (BUN) were measured. CsA rats had higher plasma malondialdehyde (by 340%) and BUN (by 125%), but lower superoxide dismutase and total antioxidant capacity (by 40%, all P<0.05) compared to control. CsA increased blood pressure (by 46mmHg) and decreased creatinine clearance (by 49%, all P<0.05). Treatment of CsA rats with apocynin, catalase, and their combination decreased blood pressure to near control values (all P<0.05). NOX4 mRNA activity was higher in the renal tissue of CsA rats by approximately 63% (P<0.05) compared to controls but was reduced in apocynin (by 64%), catalase (by 33%) and combined treatment with apocynin and catalase (by 84%) compared to untreated CsA rats. Treatment of CsA rats with apocynin, catalase, and their combination prevented hypertension and restored renal functional parameters and tissue Nox4 expression in this model. NADPH inhibition and H2O2 scavenging is an important therapeutic strategy during CsA nephrotoxicity and hypertension.
Averrhoa carambola is a species of tree native to tropical Southeast Asia. It possesses antioxidant and anti-hyperlipidemia effects and has traditionally been used to treat a variety of ailments. However, the presence of oxalic acid in its fruits might restrict its consumption by individuals suffering from kidney disease, and caramboxin can cause neurotoxicity. In this study, we evaluated the acute and sub-chronic toxicity of the methanolic extract of A. carambola leaves (MEAC) in male and female rats. In the acute study, female rats were given a single oral dose of 5000 mg/kg of MEAC and closely examined for distinct indications of toxic effects during the first 4 h, periodically for 48 h, and daily thereafter for 14 days. Rats of both sexes were employed in the sub-chronic investigation for the 28-day repeated dose oral toxicity study. Results of the acute study revealed the safety of MEAC up to a dose of 5000 mg/kg where the rats did not show changes or signs of toxicity. In the sub-chronic toxicity study, MEAC (250, 500, and 1000 mg/kg) administration did not affect the body weight, food, and water consumption, motor coordination, behavior, or mental alertness in the treated rats. In addition, no variations in hematological or biochemical markers were found in MEAC-treated rats. In conclusion, these findings pinpoint the safety of MEAC at doses up to 5000 mg/kg. The leaves of A. carambola could be safely consumed by people with kidney disease to treat other ailments.