EVALUATION OF THE SYNERGISTIC PROTECTIVE EFFECTS OF VITAMIN C, N-ACETYLCYSTEINE, AND SODIUM FERULATE ON INFLAMMATION, OXIDATIVE STRESS, AND NEPHROTOXICITY IN 5-FLUOROURACIL-TREATED RATS

The current research aimed to assess the protective effects of a mixture of natural products (N.P.), containing vitamin C, N-acetylcysteine (NAC), and sodium ferulate, against 5-fluorouracil (5-FU)-induced inflammation, nephrotoxicity, and oxidative stress in rats. Forty male rats were divided into four groups: a control group (G1), a N.P. mix-treated group given daily/orally (G2), a 5-FU-treated group administered intraperitoneal injections of 15 mg/kg body weight for 4 consecutive days, 6 mg/kg body weight for 4 alternative days, and 15 mg/kg body weight on day 14 (G3), and a group treated with 5-FU+N.P. mix (G4). The 5-FU treatment induced severe changes in immunity and biochemical parameters like elevated serum creatinine and urea levels, and disturbed electrolyte balance (P<0.05). Oxidative stress in the kidneys was also extremely high, as reflected by enhanced malondialdehyde and nitric oxide, and suppressed the antioxidants (SOD, CAT, GSH). The proinflammatory cytokines (IL-1β, IL-6, TNF-α, INF-γ) and complements were also significantly upregulated, while anti-inflammatory (IL-10, TGF-β) and T-cell functional cytokines (IL-2, IL-4, IL-12) were significantly suppressed. Moreover, the histological examination showed massive renal tubular necrosis and glomerular atrophy. The immunohistochemistry also revealed overexpression of proapoptotic markers; while flow cytometry determined increased apoptosis and depletion of CD3⁺CD4⁺T-helper lymphocytes. In contrast, co-treatment with 5-FU+N.P. mix substantially alleviated these pathological changes. It normalized biochemical parameters, reduced oxidative stress, improved antioxidant status, suppressed proinflammatory cytokines, and preserved renal histoarchitecture and T-cell numbers (P<0.05). These findings may validate the efficacy of the used N.P. mix as a nephroprotective, immune-modulating adjuvant in chemotherapy.