Silymarin and caffeine combination ameliorates experimentally-induced hepatic fibrosis through down-regulation of LPAR1 expression

• Published in: Biomedicine & pharmacotherapy 2018-05, Vol.101, p.49-57
• Main Authors: Eraky, Salma M., El-Mesery, Mohamed, El-Karef, Amro, Eissa, Laila A., El-Gayar, Amal M.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - administration & dosage; Caffeine; Caffeine - administration & dosage; Connective tissue growth factor; Down-Regulation - drug effects; Down-Regulation - physiology; Drug Therapy, Combination; Gene Expression; Liver Cirrhosis - chemically induced; Liver Cirrhosis - drug therapy; Liver Cirrhosis - metabolism; Liver fibrosis; Lysophosphatidic acid receptor 1; Male; Rats; Rats, Sprague-Dawley; Receptors, Lysophosphatidic Acid - antagonists & inhibitors; Receptors, Lysophosphatidic Acid - biosynthesis; Receptors, Lysophosphatidic Acid - genetics; Silymarin; Silymarin - administration & dosage; Thioacetamide - toxicity; Transforming growth factor beta 1
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2018.02.064

A Proposed hepatoprotective effect of silymarin, caffeine, and combination through LPAR1. [Display omitted] Lysophosphatidic acid is a lipid mediator that is supposed to be implicated in hepatic fibrosis. Silymarin and caffeine are natural compounds known for their anti-inflammatory and antioxidant effects. Our study aimed to explore the effect of silymarin, caffeine, and their combination on lysophosphatidic acid receptor 1 (LPAR1) pathway in thioacetamide (TAA)-induced hepatic fibrosis. Hepatic fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 200 mg/kg of TAA twice a week for 8 weeks. Silymarin (50 mg/kg), caffeine (50 mg/kg), and their combination (50 mg/kg silymarin + 50 mg/kg caffeine) were orally given to rats every day for 8 weeks along with TAA injection. Liver functions were measured. Histopathological examination of liver tissues was performed using hematoxylin and eosin and Masson’s trichrome staining. mRNA expressions of LPAR1, transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), and alpha smooth muscle actin (α-SMA) were measured using RT-PCR. LPAR1 tissue expression was scored using immunohistochemistry. Silymarin, caffeine, and their combination significantly improved liver function. They caused significant decrease in fibrosis and necro-inflammatory scores. Combination of silymain and caffeine caused a significant decrease in the necro-inflammatory score than the single treatment with silymarin or caffeine. In addition, silymarin, caffeine, and their combination significantly decreased hepatic LPAR1, TGF-β1, CTGF, and α-SMA gene expressions and LPAR1 tissue expression. Silymarin, caffeine, and their combination protect against liver fibrosis through down-regulation of LPAR1, TGF-β1, and CTGF.