Methoxyeugenol deactivates hepatic stellate cells and attenuates liver fibrosis and inflammation through a PPAR-γ and NF-kB mechanism

被引:50
作者
Basso, Bruno de Souza [1 ]
Haute, Gabriela Viegas [1 ]
Ortega-Ribera, Marti [2 ]
Luft, Carolina [1 ]
Antunes, Gessica Luana [1 ]
Bastos, Matheus Scherer [1 ]
Carlessi, Leonardo Pfeiff [1 ]
Levorse, Vitor Giancarlo [1 ]
Cassel, Eduardo [3 ]
Fagundes Donadio, Marcio Vinicius [1 ]
Santarem, Eliane Romanato [1 ]
Gracia-Sancho, Jordi [2 ]
de Oliveira, Jarbas Rodrigues [1 ]
机构
[1] Pontifical Catholic Univ Rio Grande Sul PUCRS, Sch Hlth & Life Sci, Porto Alegre, RS, Brazil
[2] IDIBAPS Biomed Res Inst CIBEREHD, Barcelona Hepat Hemodynam Lab, Liver Vasc Biol Res Grp, Barcelona, Spain
[3] Pontifical Catholic Univ Rio Grande do Sul PUCRS, Sch Technol, Porto Alegre, RS, Brazil
关键词
Liver disease; Antifibrotic drugs; Nutraceutical; HSCs; Liver inflammation; Chronic liver disease; Cirrhosis; PROLIFERATOR-ACTIVATED RECEPTOR; MYRISTICA-FRAGRANS; ESSENTIAL OIL; PROPOLIS; ANTIOXIDANT; VALIDATION; METABOLISM; APOPTOSIS; EXTRACT;
D O I
10.1016/j.jep.2021.114433
中图分类号
Q94 [植物学];
学科分类号
071001 ;
摘要
Ethnopharmacological relevance: Studies have shown interest in nutraceuticals for the prevention of liver diseases. Methoxyeugenol, is a molecule found in foods, such as nutmeg (Myristica fragrans Houtt.) and Brazilian red propolis. These two sources of methoxyeugenol, propolis and nutmeg, are used in folk medicine for the treatment of hepatic and gastrointestinal disorders, although little is known about their effects on the prevention of liver fibrosis. Natural PPAR (Peroxisome proliferator-activated receptor) agonists would represent unique molecules for therapy, considering the lack of therapeutics to treat liver fibrosis in chronic liver disease. Thus, investigation on new alternatives are necessary, including the search for natural compounds from renewable and sustainable sources. Liver fibrosis is a pathological process characterized by an exacerbated cicatricial response in the hepatic tissue, which compromises liver function. Therefore, inhibition of HSC (hepatic stellate cell) activation and hepatocyte damage are considered major strategies for the development of new anti-fibrotic treatments. Aim of the study: This study aimed to investigate the effects of methoxyeugenol treatment on HSC phenotype modulation in human and murine cells, hepatocyte damage prevention, and protective effects in vivo, in order to evaluate its therapeutic potential for liver fibrosis prevention. Methods: We investigated the effects of methoxyeugenol in (i) in vitro models using human and murine HSC and hepatocytes, and (ii) in vivo models of CCl4 (carbon tetrachloride) -induced liver fibrosis in mice. Results: We herein report that methoxyeugenol decreases HSC activation through the activation of PPAR-gamma, ultimately inducing a quiescent phenotype highlighted by an increase in lipid droplets, loss of contraction ability, and a decrease in the proliferative rate and mRNA expression of fibroblast markers. In addition, methoxyeugenol prevented hepatocytes from oxidative stress damage. Moreover, in mice submitted to chronic liver disease through CCl4 administration, methoxyeugenol decreased the inflammatory profile, liver fibrosis, mRNA expression of fibrotic genes, and the inflammatory pathway signaled by NF-kB (Nuclear factor kappa B). Conclusion: We propose methoxyeugenol as a novel and potential therapeutic approach to treat chronic liver disease and fibrosis.
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页数:12
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