Thymoquinone modulates oxidative stress and inflammation, correcting mercury-induced HO-1/NRF/Trx pathway disruption in experimental rat hepatorenal system: an in vivo and in silico study.

Abstract

This study evaluated the effect of thymoquinone (TQ) on the hepatorenal system of rats intoxicated with mercury (HgCl₂). Forty male Wistar rats (± 150 g) were randomised into five cohorts (n = 8) and treated for 28 consecutive days as follows: control, HgCl₂ (20 µg/L) alone, TQ (5 mg/kg) alone, HgCl₂ + TQ1 (20 µg/L + 2.5 mg/kg) and HgCl₂ + TQ2 (20 µg/L + 5 mg/kg). Subsequently, HgCl₂-induced derangement in the rats' hepatorenal function was evaluated via biochemical, oxidative, inflammatory, apoptosis biomarkers and histopathological alterations. We observed that co-treatment with TQ preserved organosomatic indices in rats deprecated by HgCl₂ treatment alone. TQ reduced hepatorenal biomarkers of toxicity-hepatic transaminases, creatine and urea-in the serum elevated in HgCl₂ alone treated rats. TQ averted HgCl₂-induced depletion of antioxidant enzymes, glutathione, and total sulfhydryl groups. TQ significantly (p < 0.05) lessened oxidative stress in the examined organs, exemplified by decreased reactive oxygen and nitrogen species, lipid peroxidation, and xanthine oxidase exacerbated by HgCl₂ alone treatment. Additionally, TQ enhanced cellular antioxidant response to oxidative stress by increases in thioredoxin, thioredoxin reductase, nuclear factor erythroid 2-related factor-2 and heme oxygenase-1 in HgCl₂ co-treated animals. Moreover, TQ alleviated HgCl₂-induced inflammation by significantly downregulating myeloperoxidase, nitric oxide, and interleukin-10 and assuaged apoptosis by decreasing caspase-3 and caspase-9 activities in the experimental rat hepatorenal system. Additionally, TQ interacted with the binding packets of Keap1 and TBK with low Kd values of 4.63 × 10⁻⁵ M and 1.54 × 10⁻⁴ M, respectively. Taken together, the findings of this study demonstrate the likely protective benefit incumbent on TQ as an antioxidant, anti-inflammatory and anti-apoptotic compound conferring protection against chemical-induced hepatorenal toxicity, including HgCl₂ in this instance.