D-Carvone Attenuates CCl(4)-Induced Liver Fibrosis in Rats by Inhibiting Oxidative Stress and TGF-ß 1/SMAD3 Signaling Pathway

SIMPLE SUMMARY: Liver fibrosis is a challenging global health problem resulting in a significant morbidity and mortality rates worldwide due to its rapid progression to cirrhosis and hepatocellular carcinoma. Therefore, identifying nontoxic therapies with precise curative effects to slow the progression of liver fibrosis comprises one of the most popular and high-priority areas of current research. D-carvone is a naturally occurring monoterpene abundant in the essential oil of aromatic plants such as caraway and spearmint. In the present study, the protective impact of D-carvone on carbon tetrachloride (CCl(4))-induced liver fibrosis in rats was evaluated. Administration of D-carvone significantly enhanced liver functions, oxidant/antioxidant balance as well as liver histology. D-carvone ameliorated the progression of liver fibrosis, evident by the decreased collagen deposition (fibrosis score) and the reduced expression of the pro-fibrogenic markers TGF-β1 and SMAD3 in the liver. These findings reveal the anti-fibrotic effects of D-carvone and suggest that D-carvone could be a promising candidate for therapeutic intervention of liver fibrosis and other oxidative stress-related hepatic diseases. ABSTRACT: D-carvone is a natural monoterpene found in abundance in the essential oil of aromatic medicinal plants with a wide range of pharmacological values. However, the impact of D-carvone on liver fibrosis remains unclear. This study aimed to evaluate the anti-fibrotic potential of D-carvone in a rat model of liver fibrosis and to clarify the possible underlying mechanisms. Liver fibrosis was induced in rats by carbon tetrachloride, CCl(4) (2.5 mL/kg, interperitoneally every 72 h for 8 weeks). Oral treatment of rats with D-carvone (50 mg/kg, daily) started on the 3rd week of CCl(4) administration. D-carvone significantly enhanced liver functions (ALT, AST), oxidant/antioxidant status (MDA, SOD, GSH, total antioxidant capacity; TAC), as well as histopathological changes. Moreover, D-carvone effectively attenuated the progression of liver fibrosis, evident by the decreased collagen deposition and fibrosis score by Masson trichrome staining (MT) and α-SMA protein expression. Moreover, D-carvone administration resulted in a significant downregulation of the pro-fibrogenic markers TGF-β1 and SMAD3 and upregulation of MMP9. These findings reveal the anti-fibrotic effect of D-carvone and suggest regulation of the TGF-β1/SMAD3 pathway, together with the antioxidant activity as a mechanistic cassette, underlines this effect. Therefore, D-carvone could be a viable candidate for inhibiting liver fibrosis and other oxidative stress-related hepatic diseases. Clinical studies to support our hypothesis are warranted.