Combined carvacrol and cilostazol ameliorate ethanol-induced liver fibrosis in rats: Possible role of SIRT1/Nrf2/HO-1 pathway

被引：12

作者：

Abu-Risha, Sally E. ^{[1
]}

Sokar, Samia S. ^{[1
]}

Elbohoty, Heba R. ^{[1
,2
]}

Elsisi, Alaa E. ^{[1
]}

机构：

[1] Tanta Univ, Fac Pharm, Dept Pharmacol & Toxicol, Tanta, Egypt

[2] Tanta Univ, Fac Pharm, Dept Pharmacol & Toxicol, Tanta 31527, Egypt

来源：

INTERNATIONAL IMMUNOPHARMACOLOGY | 2023年 / 116卷

关键词：

Alcohol; Carvacrol; Cilostazol; Hepatic fibrosis; Oxidative stress; SIRT1; INDUCED HEPATIC-FIBROSIS; CELL APOPTOSIS; INJURY; INHIBITION; ACTIVATION; SIRT1; MICE; PATHOGENESIS; INFLAMMATION; MECHANISMS;

D O I：

10.1016/j.intimp.2023.109750

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Carvacrol is a natural phenolic monoterpenoid, and cilostazol is a selective phosphodiesterase-3 inhibitor with antioxidant, anti-inflammatory and antiapoptotic effects. This experiment aimed to explore the hepatoprotective effects of carvacrol and cilostazol alone and in combination against alcoholic liver fibrosis (ALF), and the un-derlying mechanisms, using silymarin as a reference anti-fibrotic product.ALF was induced by oral administration of ethanol (1 ml/100 g/day) thrice per week. Silymarin (100 mg/kg), carvacrol (70 mg/kg), cilostazol (50 mg/kg), or carvacrol + cilostazol combination were administered daily and concurrently with ethanol for six weeks. Hepatic changes were evaluated by quantifying serum biomarkers of liver injury, hepatic MDA, GSH and NOx as oxidative stress markers, interleukin (IL)-10 as an anti-inflammatory cytokine, 4-hydroxyproline (4-HYP) as a collagen synthesis indicator, transforming growth factor (TGF)-beta 1 as a profibrogenic cytokine, alpha-smooth muscle actin (alpha-SMA) as a marker of hepatic stellate cells (HSCs) activation, histopathological (necroinflammation and fibrosis) scores and hepatic sirtuin-1 (SIRT1), nuclear factor-erythroid 2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1) mRNA levels.Our results showed that carvacrol, cilostazol, and their combination significantly ameliorated ethanol-induced hepatic fibrosis manifested as improving hepatic functions and histopathological features, attenuating alpha-SMA immunostaining, reducing TGF-beta 1 and 4-HYP levels, suppressing oxidative injury and elevating IL-10 contents. Such effects were accompanied by upregulating SIRT1, Nrf2 and HO-1 genes.This work disclosed for the first time the hepatoprotective effect of carvacrol against ALF and, to a greater extent, with carvacrol + cilostazol combination that could be partially accredited to SIRT1/Nrf2/HO-1 pathway with consequent antioxidant, anti-inflammatory, and anti-fibrotic features.

引用

页数：13