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Br J Pharmacol ; 177(2): 372-387, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31621893


BACKGROUND AND PURPOSE: This study investigates the antifibrotic activities and potential mechanisms of costunolide (COS), a natural sesquiterpene compound. EXPERIMENTAL APPROACH: Rats subjected to bile duct ligation and mice challenged with CCl4 were used to study the antifibrotic effects of COS in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 also served as an in vitro liver fibrosis models. The expression of fibrogenic genes and signaling proteins in the neurogenic locus notch homologue protein 3 (Notch3)-hairy/enhancer of split-1 (HES1) pathway was examined using western blot and/or real-time PCR. Notch3 degradation was analysed using immunofluorescence and coimmunoprecipitation. KEY RESULTS: In animals, COS administration attenuated hepatic histopathological injury and collagen accumulation and reduced the expression of fibrogenic genes. COS time- and dose-dependently suppressed the levels of fibrotic markers in LX-2 cells and mouse pHSCs. Mechanistic studies showed COS destabilized Notch3 and subsequently inhibited the Notch3-HES1 pathway, thus inhibiting HSC activation. Furthermore, COS blocked the WW domain-containing protein 2 (WWP2)/protein phosphatase 1G (PPM1G) interaction and enhanced the effect of WWP2 on Notch3 degradation. CONCLUSIONS AND IMPLICATIONS: COS exerted potent antifibrotic effects in vitro and in vivo by disrupting the WWP2/PPM1G complex, promoting Notch3 degradation and inhibiting the Notch3/HES1 pathway. This indicates that COS may be a potential therapeutic candidate for the treatment of liver fibrosis.

Biochem Pharmacol ; 164: 152-164, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30978324


The conversion of cholesterol to bile acids (BAs) contributes to the elimination of total cholesterol from the body. In addition, manipulating BA homeostasis by modulating cholesterol 7α-hydroxylase (CYP7A1) may affect the metabolic processing of cholesterol, exerting therapeutic effects on hypercholesterolemia and cardiovascular diseases. Multiple mechanisms (such as various nuclear receptors and regulatory factors) are involved in CYP7A1 modulation. Recently, microRNAs, protein degradation pathways, and the gut microbiota have been identified to participate in these sophisticated networks. In this review, research progress on the regulatory mechanism of CYP7A1 is summarized.

Colesterol 7-alfa-Hidroxilase/metabolismo , Colesterol/metabolismo , Microbioma Gastrointestinal/fisiologia , Homeostase/fisiologia , Animais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo
Acta Pharmacol Sin ; 40(7): 895-907, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30573812


The manipulation of bile acid (BA) homeostasis by blocking the ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) may have therapeutic effects in nonalcoholic fatty liver disease. We developed a novel ASBT inhibitor, an N-(3,4-o-dichlorophenyl)-2-(3-trifluoromethoxy) benzamide derivative referred to as IMB17-15, and investigated its therapeutic effects and the molecular mechanisms underlying the effects. Syrian golden hamsters were challenged with high-fat diet (HFD) to induce NAFLD and were subsequently administered 400 mg/kg IMB17-15 by gavage daily for 21 days. Serum, liver, and fecal samples were collected for further analysis. Plasma concentration-time profiles of IMB17-15 were also constructed. The human hepatocyte cell line HL-7702 was treated with Oleic acid (OA) with or without IMB17-15. Western blotting and real-time PCR were used to study the molecular mechanisms of IMB17-15. We found that IMB17-15 inhibited ASBT and subsequently suppressed ileal farnesoid X receptor (FXR) and FXR-activated fibroblast growth factor15/19 (FGF15/19) expression, which reduced the hepatic phosphorylated extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) levels and upregulated the cholesterol 7α-hydroxylase (CYP7A1) activity. Additionally, IMB17-15 stimulated adenosine monophosphate (AMP)-activated protein kinase (AMPKα) phosphorylation and enhanced peroxisome proliferator activated receptor α (PPARα) expression and thus promoted triglyceride (TG) oxidation and high-density lipoprotein cholesterol (HDL-c) metabolism through an ASBT-independent mechanism. In conclusion, a novel ASBT inhibitor known as IMB17-15 protected hamsters against HFD-induced NFALD by manipulating BA and lipid homeostasis. IMB17-15 also reduced lipid deposition in human hepatic cell lines, indicating that it may be useful as a therapy for NAFLD patients.

Benzamidas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Simportadores/antagonistas & inibidores , Animais , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular , Citocinas/metabolismo , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Masculino , Mesocricetus , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade
Acta Pharmacol Sin ; 39(2): 213-221, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28748913


Cholestatic liver diseases are important causes of liver cirrhosis and liver transplantation, but few drugs are available for treatment. D-chiro-inositol (DCI), an isomer of inositol found in many Leguminosae plants and in animal viscera, is used clinically for the treatment of polycystic ovary syndrome (PCOS) and diabetes mellitus. In this study, we investigated whether DCI exerted an anti-cholestatic effect and its underlying mechanisms. A cholestatic rat model was established via bile duct ligation (BDL). After the surgery, the rats were given DCI (150 mg·kg-1·d-1) in drinking water for 2 weeks. Oral administration of DCI significantly decreased the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and attenuated bile duct proliferation, parenchymal necrosis and fibrosis in BDL rats. Furthermore, DCI treatment significantly increased the serum and bile levels of total bile acid (TBA), and decreased TBA levels in the liver. Moreover, DCI treatment significantly increased expression of the genes encoding bile acid transporters BSEP (Abcb11) and MRP2 (Abcc2) in liver tissues. DCI treatment also markedly decreased hepatic CD68 and NF-kappaB (NF-κB) levels, significantly decreased the serum and hepatic MDA levels, markedly increased superoxide dismutase activity in both serum and liver tissues. Using whole-genome oligonucleotide microarray, we revealed that DCI treatment altered the expression profiles of oxidation reduction-related genes in liver tissues. Collectively, DCI effectively attenuates BDL-induced hepatic bile acid accumulation and decreases the severity of injury and fibrosis by improving bile acid secretion, repressing inflammation and decreasing oxidative stress. The results suggest that DCI might be beneficial for patients with cholestatic disorders.

Ácidos e Sais Biliares/metabolismo , Colestase/prevenção & controle , Inositol/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Alanina Transaminase/sangue , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Aspartato Aminotransferases/sangue , Ductos Biliares/cirurgia , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Inositol/administração & dosagem , Ligadura , Fígado/patologia , Cirrose Hepática/prevenção & controle , Masculino , NF-kappa B/metabolismo , Substâncias Protetoras/administração & dosagem , Ratos Sprague-Dawley , Estereoisomerismo , Superóxido Dismutase/metabolismo
J Asian Nat Prod Res ; 19(2): 109-113, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28133978


Hepatic fibrosis is a wound-healing response to chronic liver injury caused by various pathogenesis, such as hepatitis virus infection, drugs toxicity and autoimmune imbalances. Autophagy, a cellular process degrading damaged organelles or aggregative proteins, participates in multiple human diseases including hepatic fibrosis. However, the precise role of autophagy in the pathogenesis of hepatic fibrosis is yet to be elucidated. Accumulated evidences indicate that several nature compounds exhibit anti-fibrotic potential through modulating autophagy activity. For a better understanding of the relationships among autophagy, hepatic fibrosis, and autophagy-regulating nature compounds, this review highlights the recent advancement of nature compounds treating hepatic fibrosis through regulating autophagy.

Autofagia , Cirrose Hepática/tratamento farmacológico , Animais , Humanos , Fígado/metabolismo , Estrutura Molecular , Transdução de Sinais
Yao Xue Xue Bao ; 52(2): 189-97, 2017 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-29979499


Bile acids play critical roles in the regulation of metabolism and absorption of lipids. The ileal apical sodium-dependent bile acid transporter (ASBT) located at the enterocyte brush border is responsible for the reuptake of bile acids and the maintenance of bile acid homeostasis. Recently, a number of investigations have been made concerning the regulation and control of ASBT and the relationship between ASBT and intestinal inflammation, tumorigenesis, diabetes mellitus and hyperlipemia, which suggests ASBT as a potential therapeutic target of these diseases. In this review, advances in the study of above-mentioned issues were summarized.

Ácidos e Sais Biliares/fisiologia , Íleo/fisiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/fisiologia , Simportadores/fisiologia , Transporte Biológico , Homeostase , Humanos , Intestinos/fisiopatologia