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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
World J Gastroenterol ; 21(23): 7155-64, 2015 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-26109801


AIM: To evaluate the protective effect of bicyclol against bile duct ligation (BDL)-induced hepatic fibrosis in rats. METHODS: Sprague-Dawley male rats underwent BDL and sham-operated animals were used as healthy controls. The BDL rats were divided into two groups which received sterilized PBS or bicyclol (100 mg/kg per day) orally for two consecutive weeks. Serum, urine and bile were collected for biochemical determinations. Liver tissues were collected for histological analysis and a whole genome oligonucleotide microarray assay. Reverse transcription-polymerase chain reaction and Western blotting were used to verify the expression of liver fibrosis-related genes. RESULTS: Treatment with bicyclol significantly reduced liver fibrosis and bile duct proliferation after BDL. The levels of alanine aminotransferase (127.7 ± 72.3 vs 230.4 ± 69.6, P < 0.05) and aspartate aminotransferase (696.8 ± 232.6 vs 1032.6 ± 165.8, P < 0.05) were also decreased by treatment with bicyclol in comparison to PBS. The expression changes of 45 fibrogenic genes and several fibrogenesis-related pathways were reversed by bicyclol in the microarray assay. Bicyclol significantly reduced liver mRNA and/or protein expression levels of collagen 1a1, matrix metalloproteinase 2, tumor necrosis factor, tissue inhibitors of metalloproteinases 2, transforming growth factor-ß1 and α-smooth muscle actin. CONCLUSION: Bicyclol significantly attenuates BDL-induced liver fibrosis by reversing fibrogenic gene expression. These findings suggest that bicyclol might be an effective anti-fibrotic drug for the treatment of cholestatic liver disease.

Ductos Biliares/cirurgia , Compostos de Bifenilo/farmacologia , Cirrose Hepática Biliar/prevenção & controle , Fígado/efeitos dos fármacos , Animais , Bile/metabolismo , Biomarcadores/sangue , Biomarcadores/urina , Proliferação de Células/efeitos dos fármacos , Citoproteção , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Biliar/etiologia , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/patologia , Masculino , Ratos Sprague-Dawley
Cardiovasc Diabetol ; 11: 104, 2012 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-22950360


BACKGROUND: Many patients who survive a myocardial infarction (MI) remain at risk of sudden cardiac death despite revascularization and optimal medical treatment. We used the modified moving average (MMA) method to assess the utility of T-wave alternans (TWA) and heart rate turbulence (HRT) as risk markers in MI patients with or without diabetes mellitus (DM). METHODS: We prospectively enrolled 248 consecutive patients: 96 with MI (post-MI patients); 77 MI with DM (post-MI + DM patients); 75 controls without cardiovascular disease (group control). Both TWA and HRT were measured on ambulatory electrocardiograms (AECGs). HRT was assessed by two parameters ─ turbulence onset (TO) and turbulence slope (TS). HRT was considered positive when both TO ≥0% and TS ≤2.5 ms/R-R interval were met. The endpoint was cardiac mortality. RESULTS: TWA values differed significantly between MI and controls. Post-MI + DM patients had higher TWA values than post-MI patients (58 ± 21 µV VS 52 ± 18 µV, P = 0.029). Impaired HRT--increased TO and decreased TS were observed in MI patients with or without DM. During follow-up of 578 ± 146 days, cardiac death occurred in ten patients and three of them suffered sudden cardiac death (SCD). Multivariate analysis determined that a HRT-positive outcome [HR (95% CI): 5.01, 1.33-18.85; P = 0.017], as well as the combination of abnormal TWA (≥47 µV) and positive HRT had significant association with the endpoint [HR (95% CI): 9.08, 2.21-37.2; P = 0.002)]. CONCLUSION: This study indicates that AECGs-based TWA and HRT can predict cardiac mortality in MI patients with or without DM. Combined analysis TWA and HRT may be a convenient and useful method of identifying patients at high risk for cardiovascular death.

Morte Súbita Cardíaca/etiologia , Complicações do Diabetes/mortalidade , Eletrocardiografia Ambulatorial , Frequência Cardíaca , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China/epidemiologia , Humanos , Análise Multivariada , Infarto do Miocárdio/complicações , Infarto do Miocárdio/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo