The present study aims to investigate the hepatoprotective effect of taurine (TAU) alone or in combination with silymarin (SIL) on CCl₄-induced liver damage. Twenty five male rats were randomized into 5 groups: normal control (vehicle treated), toxin control (CCl₄ treated), CCl₄+TAU, CCl₄+SIL and CCl₄+TAU+SIL. CCl₄ provoked significant increases in the levels of hepatic TBARS, NO and NOS compared to control group, but the levels of endogenous antioxidants such as SOD, GPx, GR, GST and GSH were significantly decreased. Serum pro-inflammatory and fibrogenic cytokines including TNF-α, TGF-β1, IL-6, leptin and resistin were increased while the anti-inflammatory (adiponectin) cytokine was decreased in all treated rats. Our results also showed that CCl₄ induced an increase in liver injury parameters like serum ALT, AST, ALP, GGT and bilirubin. In addition, a significant increase in liver tissue hydroxyproline (a major component of collagen) was detected in rats exposed to CCl₄. Moreover, the concentrations of serum TG, TC, HDL-C, LDL-C, VLDL-C and FFA were significantly increased by CCl₄. Both TAU and SIL (i.e., antioxidants) post-treatments were effectively able to relieve most of the above mentioned imbalances. However, the combination therapy was more effective than single applications in reducing TBARS levels, NO production, hydroxyproline content in fibrotic liver and the activity of serum GGT. Combined treatment (but not TAU- or SIL-alone) was also able to effectively prevent CCl₄-induced decrease in adiponectin serum levels. Of note, the combined post-treatment with TAU+SIL (but not monotherapy) normalized serum FFA in CCl₄-treated rats. The biochemical results were confirmed by histological and ultrastructural changes as compared to CCl₄-poisoned rats. Therefore, on the basis of our work, TAU may be used in combination with SIL as an additional adjunct therapy to cure liver diseases such as fibrosis, cirrhosis and viral hepatitis.

Rutin, a food derived-polyphenolic bioflavonoid, has been acknowledged for several health benefits. This study aims to explore the ameliorative effects of rutin against carbon tetrachloride (CCl₄) toxicity in male rats. Adult male rats were given either CCl₄ (30% in olive oil, 3 ml/kg b.w. intraperitoneally) alone or in combination with rutin (70 mg/kg intragastrically) twice a week for 4 weeks. Our data showed that rutin mitigated CCl₄ hepatorenal damage, as indicated by diagnostic markers (i.e., transaminases, alkaline phosphatase, total bilirubin, total protein, albumin, urea, uric acid and creatinine), and histopathological findings. In addition, CCl₄ induced profound elevation of free radical generation and oxidative stress, as evidenced by increasing lipid peroxidation and reducing catalase, superoxide dismutase and glutathione peroxidase activities in liver, kidney and testicular tissues; these effects were suppressed by coexposure with rutin. Moreover, the increase in the levels of serum triglycerides, cholesterol, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol induced by CCl₄ was effectively counteracted by rutin. The decrease in the level of high-density lipoprotein cholesterol in the CCl₄ group was also counteracted by rutin treatment. Interestingly, the decreased levels of hormonal mediators associated with sperm production, including serum testosterone, luteinizing hormone and follicle-stimulating hormone, and the impaired sperm quality induced by CCl₄ were reversed by rutin. Data from the current study clearly demonstrated that rutin supplementation could at least partly overcome CCl₄-induced hepatotoxicity, nephrotoxicity and reproductive toxicity by antioxidant and antidyslipidemic effects.

The current work aims to study the nephroprotective potential of naringin (NG), a flavanone derived from citrus fruits, in methotrexate (MTX)-induced renal toxicity. Thirty male rats were divided into five groups; control group (IP saline), MTX group (IP single dose, 20 mg/kg), and three groups co-treated with MTX and naringin (IP daily dose; 20, 40, and 80 mg/kg, respectively). Kidney tissues were used to investigate renal function, oxidative stress, lipid peroxidation, and caspase-3 activity. Biochemical cytokine analysis was performed in addition to ultrastructural examinations of kidney tissue. When compared to the MTX-treated rats, MTX+NG significantly reduced the levels of urea, creatinine, MDA, NO, TNFα, IL-6, and caspase-3 activity. A significant increase in the levels of the antioxidant enzymes and GSH were also noted. Additionally, naringin ameliorated the apparent ultrastructural changes observed in the glomeruli and renal tubules of MTX-intoxicated rats. Noticeable structural improvements of glomerular lesions, proximal, and distal convoluted tubular epithelium were observed in MTX+NG treated animals, including podocytes with regular foot processes, perfectly organized filtration barrier, no signs of GBM thickening, organized brush border, and normal architecture of microvilli. Naringin (80 mg/kg) had the maximum amelioration effect. To the best of our knowledge, this is the first study to investigate the ultrastructural manifestations of naringin and/or MTX on the kidney of rats. Taken all, naringin has a potent therapeutic effect and can be used in adjuvant therapy to prevent MTX-induced nephrotoxicity. Nevertheless, the molecular mechanism underlying the nephroprotective capacity of naringin needs further investigation.