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1.
Life Sci ; 248: 117475, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32119963

RESUMO

AIMS: Liver fibrosis is a crucial pathological feature which could result in cirrhosis and hepatocarcinoma. But until now, there is no favourable treatment for it. Apigenin (APG) is a flavonoid, which exhibits efficient anti-liver fibrosis activity, but its underlying mechanisms were rarely studied. So this work aims to estimate the potential therapeutic action of APG on liver fibrosis rats and to gain insight into its system-level mechanisms. MAIN METHODS: Hepatic fibrosis was induced by CCl4 in Wistar rats, and APG was given in the light of the regimen. Biochemical indexes, histopathological change and immunohistochemistry of liver were evaluated. The optimal effect group of APG was selected for further transcriptomic and proteomic analysis. KEY FINDINGS: APG ameliorated liver fibrosis via reducing the levels of AST, ALT, ALP, LDH, Hyp, TP, TB, DB, HA, LN, PCIII and IV-C, mitigating fibrosis and inflammation of liver in H&E and Masson staining. Mechanistically, APG elevated the activity of ALB, SOD and GSH-PX with reducing the level of MDA. The results of microarray and TMT revealed that 4919 genes and 4876 proteins were differentially expressed in the APG and model groups. Besides, transcriptomics and proteomics analyses unfolded 120 overlapped proteins, enriched in 111 GO terms containing apoptotic process, angiogenesis, cell migration and proliferation, etc. Meanwhile, KEGG pathway analysis showed that 26 pathways containing HIF-1/MAPK/eNOS/VEGF/PI3K/Akt signaling pathway, regulation of actin cytoskeleton and focal adhesion mostly. SIGNIFICANCE: APG can ameliorate CCl4-induced liver fibrosis via VEGF-mediated FAK phosphorylation through the MAPKs, PI3K/Akt, HIF-1, ROS, and eNOS pathways, which may hopefully become the anti-liver fibrosis activity of natural product.


Assuntos
Anti-Inflamatórios/farmacologia , Apigenina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Albuminas/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Bilirrubina/sangue , Tetracloreto de Carbono/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proteômica/métodos , Ratos , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Expert Opin Pharmacother ; 21(3): 261-273, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31914336

RESUMO

Introduction: Hepatitis C virus (HCV) is estimated to infect approximately 70 million people worldwide. If left untreated, chronic infection can progress to cirrhosis, liver failure or hepatocellular carcinoma. The advent of new direct-acting antivirals (DAA) has revolutionized patients' chances of treatment and viral elimination. Currently, several DAA options are available on the market.Areas covered: This review focuses on the pharmacokinetics, efficacy, tolerability and safety profile of DCV-TRIO, a twice-daily fixed-dose combination of daclatasvir, asunaprevir and beclabuvir approved in Japan for the treatment of genotype 1 HCV infection.Expert opinion: The DCV-TRIO combination achieved good response rates in genotype 1 patients (SVR12 ≥ 95% in naïve subtype 1b), independently from IL28B genotype, cirrhotic status and prior interferon exposure. On the other hand, unsatisfying response rates were reported in DAA-experienced patients and the risk of RAS selection should not be underestimated. Moreover, DCV-TRIO lacks differentiation from its earlier-launched DAA rivals, presents an inconvenient twice-daily dosing schedule and is not recommended in patients with advanced liver and kidney disease. All these drawbacks considerably limit its effective commercial potential. However, it can be a therapeutic option against HCV in tailored approaches according to the needs of different markets across the world.Abbreviations AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ASV: asunaprevir; AUC: area under the curve; BCRP: Breast Cancer Resistance Protein; BCV: boceprevir; BID: bis in die; CI: confidence intervals; CLcr: creatinine clearance; DAA: direct acting antivirals; DCV: daclatasvir; EC50: Half maximal effective concentration; GT: genotype; HCV: Hepatitis C virus; IFN: Interferon; NHL: non-Hodgkin lymphoma; OATP: Organic anion transporting polypeptides; OR: odds ratio; P-gp: P-glycoprotein; PK: pharmacokinetics; QD: quo die; RAS: resistance-associated substitutions; SVR: sustained virological response; USD: Unites States dollar.


Assuntos
Benzazepinas/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Indóis/administração & dosagem , Isoquinolinas/administração & dosagem , Sulfonamidas/administração & dosagem , Antivirais/uso terapêutico , Combinação de Medicamentos , Genótipo , Hepacivirus/efeitos dos fármacos , Humanos , Cirrose Hepática/prevenção & controle , Resposta Viral Sustentada , Comprimidos , Resultado do Tratamento
3.
Life Sci ; 240: 117096, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760097

RESUMO

Aim Liver fibrosis represents a massive global health burden with limited therapeutic options. Thus, the need for curative options is evident. Thus, this study aimed to assess the potential antifibrotic effect of honokiol in Concanavalin A (Con A) induced immunological model of liver fibrosis as well the possible underlying molecular mechanisms. METHODS: Male Sprague-Dawley rats were treated with either Con A (20 mg/kg, IV) and/or honokiol (10 mg/kg, orally) for 4 weeks. Hepatotoxicity indices were as well as histopathological evaluation was done. Hepatic fibrosis was assessed by measuring alpha smooth muscle actin (α-SMA) expression and collagen fibers deposition by Masson's trichrome stain and hydroxyproline content. To elucidate the underlying molecular mechanisms, the effect of honokiol on oxidative stress, inflammatory markers as well as transforming growth factor beta (TGF-ß)/SMAD and mitogen-activated protein kinase (MAPK) pathways was assessed. KEY FINDINGS: Honokiol effectively reversed the hepatotoxicity indices elevations and abnormal histopathological changes induced by Con A. Besides, honokiol attenuated Con A-induced liver fibrosis by down-regulation of hydroxyproline levels, α-SMA expression together with a marked decrease in collagen fibers deposition. Mechanistically Con A induced oxidative stress, provocation of inflammatory responses and activation of TGF-ß/SMAD/MAPK pathways. Contrariwise, honokiol co-treatment significantly restored antioxidant defence mechanisms, down-regulated inflammatory cascades and inhibited TGF-ß/SMAD/MAPK signaling pathways. CONCLUSION: The results provide an evidence for the promising antifibrotic effect of honokiol that could be partially due to suppressing oxidative stress and inflammatory processes as well as inhibition of TGF-ß/SMAD/MAPK signaling pathways.


Assuntos
Compostos de Bifenilo/uso terapêutico , Lignanas/uso terapêutico , Cirrose Hepática/prevenção & controle , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Actinas/metabolismo , Animais , Concanavalina A , Hidroxiprolina/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida
4.
Food Chem Toxicol ; 135: 111044, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31830547

RESUMO

Hemistepsin A (HsA), isolated from Hemistepta lyrata (Bunge) Bunge, has the ability to ameliorate hepatitis in mice. However, the effects of H. lyrata and HsA on other types of liver disease have not been explored. In this report, we investigated the effects of H. lyrata and HsA on liver fibrosis and the underlying molecular mechanisms in activated hepatic stellate cells (HSCs). Based on cell viability-guided isolation, we found HsA was the major natural product responsible for H. lyrata-mediated cytotoxicity in LX-2 cells. HsA significantly decreased the viability of LX-2 cells and primary activated HSCs, increased the binding of Annexin V, and altered the expression of apoptosis-related proteins, suggesting that HsA induces apoptosis in activated HSCs. HsA reduced the phosphorylation of IKKε and the transactivation of nuclear factor-κB (NF-κB). Moreover, HsA decreased the phosphorylation of Akt and its downstream signaling molecules. Transfection experiments suggested that inhibition of NF-κB or Akt is essential for HsA-induced apoptosis of HSCs. In a CCl4-induced liver fibrosis model, HsA administration significantly decreased ALT and AST activities. Furthermore, HsA attenuated CCl4-mediated collagen deposits and profibrogenic genes expression in hepatic tissue. Thus, HsA may serve as a natural product for managing liver fibrosis through inhibition of NF-κB/Akt-dependent signaling.


Assuntos
Apoptose/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Lactonas/farmacologia , Cirrose Hepática/prevenção & controle , Sesquiterpenos/farmacologia , Animais , Linhagem Celular Transformada , Clorofórmio/farmacologia , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Camundongos , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Gastroenterology ; 158(1): 215-225.e6, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31574268

RESUMO

BACKGROUND & AIMS: There have been conflicting results from studies comparing the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection treated with tenofovir disoproxil fumarate (TDF) vs those treated with entecavir. We compared the effects of TDF vs entecavir on HCC risk in a large cohort of patients with chronic HBV infection in China. METHODS: We performed a retrospective study of consecutive adults with chronic HBV infection who initially received treatment with entecavir or TDF, for at least 6 months, from January 2008 through June 2018. Patients who had cancers or liver transplantation before or within the first 6 months of treatment were excluded. Propensity score weighting and 1:5 matching were used to balance the clinical characteristics between the 2 groups. Fine-Gray model was used to adjust for competing risk of death and liver transplantation. RESULTS: We analyzed data from 29,350 patients (mean age, 52.9 ± 13.2 years; 18,685 men [63.7%]); 1309 were first treated with TDF (4.5%) and 28,041 were first treated with entecavir (95.5%). TDF-treated patients were younger (mean age, 43.2 years vs 53.4 years) and a lower proportion had cirrhosis (38 patients [2.9%] vs 3822 patients treated with entecavir [13.6%]). At a median follow-up time of 3.6 years after treatment began (interquartile range, 1.7-5.0 years), 8 TDF-treated patients (0.6%) and 1386 entecavir-treated patients (4.9%) developed HCC. Patients' clinical characteristics were comparable after propensity score weighting. TDF treatment was associated with a lower risk of HCC than entecavir treatment after propensity score weighting (weighted subdistribution hazard ratio, 0.36; 95% confidence interval 0.16-0.80; P = .013) and 1:5 matching (weighted subdistribution hazard ratio, 0.39; 95% confidence interval 0.18-0.84; P = .016). CONCLUSIONS: In a retrospective analysis of 29,350 patients with chronic HBV infection in China, treatment with TDF was associated with a lower risk of HCC than treatment with entecavir, over a median follow-up time of 3.6 years.


Assuntos
Antivirais/administração & dosagem , Carcinoma Hepatocelular/prevenção & controle , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Tenofovir/administração & dosagem , Adulto , Assistência ao Convalescente , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , China/epidemiologia , Progressão da Doença , Feminino , Guanina/administração & dosagem , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Incidência , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Cirrose Hepática/epidemiologia , Cirrose Hepática/prevenção & controle , Cirrose Hepática/virologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
6.
Zhonghua Gan Zang Bing Za Zhi ; 27(9): 721-724, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31594101

RESUMO

Clinically, hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high rate of morbidity and mortality. Hepatitis B virus infection is the main cause of hepatocellular carcinoma in China and it is a serious threat to people's health. Antiviral drugs such as nucleos(t)ide analogues and interferon can inhibit viral replication and liver fibrosis progression and reduce the occurrence of hepatitis B-related HCC. This article reviews the effects of different antiviral therapy on the occurrence of hepatitis B-related hepatocellular carcinoma in recent years.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/virologia , Hepatite B/tratamento farmacológico , Neoplasias Hepáticas/virologia , China , Vírus da Hepatite B , Humanos , Cirrose Hepática/prevenção & controle , Cirrose Hepática/virologia
7.
Nat Rev Gastroenterol Hepatol ; 16(10): 631-641, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31477873

RESUMO

Chronic hepatitis B virus (HBV) infection is a serious problem owing to its worldwide distribution and potential adverse sequelae that include cirrhosis and/or hepatocellular carcinoma. Current antiviral therapies have much improved outcomes, but few patients achieve the ultimate goal of hepatitis B surface antigen (HBsAg) loss (functional cure). As hepatitis B e antigen (HBeAg)-negative chronic HBV infection is the final phase prior to HBsAg loss, the management of patients in this phase together with quantification of HBsAg has attracted increasing clinical and research interest. This Review integrates the findings from research in HBsAg kinetics and discusses how they might inform our understanding and management of HBeAg-negative chronic HBV infection. Studies have shown that HBsAg levels are highly predictive of the presence of inactive HBV infection and that serial changes in HBsAg levels might predict HBsAg loss within 1-3 years. Data also suggest that quantitative HBsAg monitoring is important during hepatitis flare and antiviral therapy, especially in the timing of the decision to stop therapy and to start off-therapy retreatment. These findings have shed new light on the natural course of HBV infection and might lead to optimization of the management of HBeAg-negative chronic HBV infection and contribute to the paradigm shift from indefinite to finite therapy for patients with HBV infection.


Assuntos
Carcinoma Hepatocelular/virologia , Antígenos da Hepatite B/imunologia , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/imunologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/prevenção & controle , Progressão da Doença , Antígenos de Superfície da Hepatite B/imunologia , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/imunologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/prevenção & controle
8.
Med Sci Monit ; 25: 6615-6623, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31479436

RESUMO

Primary hepatocellular carcinoma (HCC) is the fifth most frequently reported malignancy, and it is also the second most common cause of cancer-related deaths worldwide. Although most HCC cases have been reported to develop from cirrhosis, accumulating data suggest that HCC is also closely related to non-cirrhotic chronic liver disease. Traditionally, HCC was thought to develop mostly from cirrhosis; however, an increasing number of reports have found that HCC can develop directly from inflammation without cirrhosis. The incidence of HCC in non-cirrhotic liver (HCC-NCL) is high, especially in developed countries. Studies have found that the most common cause of HCC-NCL is neglected fatty liver disease. This type of HCC has unique clinical characteristics and is closely related to metabolic disorders. Unfortunately, the prevention of HCC-NCL has not received enough attention worldwide, and there is also a lack of specific screening methods and clinical guidelines. This article mainly reviews the etiology, incidence, clinical characteristics, and screening markers of HCC-NCL to improve the understanding and prevention of this disease.


Assuntos
Carcinoma Hepatocelular/complicações , Cirrose Hepática/complicações , Neoplasias Hepáticas/complicações , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/prevenção & controle , Carcinoma Hepatocelular/terapia , Humanos , Cirrose Hepática/epidemiologia , Cirrose Hepática/prevenção & controle , Cirrose Hepática/terapia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/terapia , Prognóstico
9.
Nutrients ; 11(9)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31510077

RESUMO

High tissue iron levels are a risk factor for multiple chronic diseases including type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). To investigate causal relationships and underlying mechanisms, we used an established NAFLD model-mice fed a high fat diet with supplemental fructose in the water ("fast food", FF). Iron did not affect excess hepatic triglyceride accumulation in the mice on FF, and FF did not affect iron accumulation compared to normal chow. Mice on low iron are protected from worsening of markers for non-alcoholic steatohepatitis (NASH), including serum transaminases and fibrotic gene transcript levels. These occurred prior to the onset of significant insulin resistance or changes in adipokines. Transcriptome sequencing revealed the major effects of iron to be on signaling by the transforming growth factor beta (TGF-ß) pathway, a known mechanistic factor in NASH. High iron increased fibrotic gene expression in vitro, demonstrating that the effect of dietary iron on NASH is direct. Conclusion: A lower tissue iron level prevents accelerated progression of NAFLD to NASH, suggesting a possible therapeutic strategy in humans with the disease.


Assuntos
Ferro na Dieta/administração & dosagem , Ferro/deficiência , Cirrose Hepática/prevenção & controle , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Ração Animal , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Frutose , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Ferro/sangue , Ferro na Dieta/sangue , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais
10.
World J Gastroenterol ; 25(29): 3842-3848, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31413522

RESUMO

Although hepatocellular carcinoma (HCC) is as prevalent as ever as a cancer-related mortality, and some would even argue that it is increasing, the pattern of its etiologies has been changing. Specifically, the domination of viral hepatitis C virus is being overcome, partly because of the emergence of the antiviral treatments, and partly because of the significant increase, especially in developed countries, of the combination of obesity, diabetes, metabolic syndrome, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. This editorial will explore the interconnection of this group of diseases and how they are linked to HCC. More importantly, it will argue that this shift in HCC etiology essentially means that we have to change how we approach the treatment of HCC, by changing our focus (and resources) to earlier stages of the disease development in order to prevent the appearance and progression of HCC.


Assuntos
Carcinoma Hepatocelular/etiologia , Cirrose Hepática/etiologia , Neoplasias Hepáticas/etiologia , Fígado/patologia , Síndrome Metabólica/complicações , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/prevenção & controle , Progressão da Doença , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/prevenção & controle , Síndrome Metabólica/patologia , Síndrome Metabólica/terapia
11.
World J Gastroenterol ; 25(30): 4172-4180, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31435171

RESUMO

Lysosomal acid lipase (LAL) plays a key role in intracellular lipid metabolism. Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage, as observed in two recessive autosomal genetic diseases, Wolman disease and Cholesterol ester storage disease. Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency. By contrast, few reliable data are available on the modulation of LAL activity in vivo and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene. In the last few years, a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease (NAFLD), suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease. Patients with NAFLD show a significant, progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis. Among cirrhosis of different etiologies, those with cryptogenic cirrhosis show the most significant reductions of LAL activity. These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD. Moreover, the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting.


Assuntos
Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Esterol Esterase/deficiência , Doença de Wolman/patologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Ésteres do Colesterol/metabolismo , Progressão da Doença , Teste em Amostras de Sangue Seco , Terapia de Reposição de Enzimas/métodos , Humanos , Metabolismo dos Lipídeos/genética , Fígado/patologia , Cirrose Hepática/prevenção & controle , Testes de Função Hepática/métodos , Lisossomos/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Índice de Gravidade de Doença , Esterol Esterase/sangue , Esterol Esterase/genética , Esterol Esterase/uso terapêutico , Triglicerídeos/metabolismo , Doença de Wolman/tratamento farmacológico , Doença de Wolman/genética
12.
Pak J Pharm Sci ; 32(3): 1033-1042, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278717

RESUMO

Ketoconazole is a first orally available anti-fungal drug which has been reported as a potent inhibitor of human cytochrome P-450. The present study was designed to examine the heptoprotective effect of ketoconazole in both in vitro and in vivo liver injury models. Hepatocyte injury was induced by 8mM CCl4 while hepatic fibrosis model was established by injecting 1 ml/kg CCl4 followed by treatment with ketoconazole. Effect of ketoconazole treatment on injured hepatocytes was determined by lactate dehydrogenase release and trypan blue assay. Analysis of ketoconazole treatment and prevention on liver fibrosis was assessed by sirius red staining, masson trichome staining, PCR and liver function tests for bilirubin and alanine transaminase (ALAT).A significant reduction (P<0.05) in LDH release and reduced number of dead cells was observed in hepatocytes treated with ketoconazole. Sirus red and masson trichome stainings showed reduced levels of collagen in both treated and preventive groups and down regulation of alpha smooth muscle actin was observed with up-regulations of MMP-2, CK-8 and CK-18. Hepatic functional assessment demonstrated reduced serum levels of bilirubin and ALAT. Treatment of fibrotic liver with ketoconazole improves hepatic microenvironment and enhanced reduction of liver injury after fibrosis. Cytochrome P-450 inhibitors seems a favored therapeutic option in attenuation of liver fibrosis.


Assuntos
Hepatócitos/efeitos dos fármacos , Cetoconazol/farmacologia , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Actinas/genética , Animais , Tetracloreto de Carbono/toxicidade , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , L-Lactato Desidrogenase/metabolismo , Fígado/fisiologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Testes de Função Hepática , Masculino , Metaloproteinase 2 da Matriz/genética , Camundongos Endogâmicos C57BL
13.
PLoS Negl Trop Dis ; 13(6): e0007474, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194740

RESUMO

During Schistosoma infection, lack of B cells results in more severe granulomas, inflammation, and fibrosis in the liver, but the mechanisms underlying this pathology remain unclear. This study was to clarify the mechanisms underpinning the immunomodulation of B cells in mice infected with Schistosoma japonicum (S. japonicum). We found that B cell deficiency led to aggravated liver pathology, as demonstrated by increases in the size of the egg-associated granulomas, alanine transaminase levels, and collagen deposition. Compared with infected wild-type (WT) mice, infected B cell-deficient (µMT) mice showed increased infiltration of Ly6Chi monocytes and higher levels of proinflammatory cytokines and chemokines. Furthermore, B1 cells were increased significantly in the liver of WT mice following S. japonicum infection. Adoptively transferring B1 cells, but not B2 cells, to µMT mice significantly reduced liver pathology and liver infiltration of Ly6Chi monocytes. Additionally, secretion of IL-10 from hepatic B cells increased significantly in infected WT mice and this IL-10 was mainly derived from B1 cells. Adoptively transferring B1 cells purified from WT mice, but not from IL-10-deficient mice, to µMT mice significantly reduced liver pathology and liver infiltration of Ly6Chi monocytes. These reductions were accompanied by decreases in the expression levels of chemokines and inflammatory cytokines. Taken together, these data indicated that after S. japonicum infection, an increased number of hepatic B1 cells secrete IL-10, which inhibits the expression of chemokines and cytokines and suppresses the infiltration of Ly6Chi monocytes into the liver thereby alleviating liver early inflammation and late fibrosis.


Assuntos
Linfócitos B/imunologia , Hepatite/complicações , Hepatite/prevenção & controle , Cirrose Hepática/prevenção & controle , Monócitos/imunologia , Schistosoma japonicum/imunologia , Esquistossomose Japônica/complicações , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatite/imunologia , Fatores Imunológicos/metabolismo , Cirrose Hepática/imunologia , Masculino , Camundongos Endogâmicos C57BL
14.
Minerva Med ; 110(5): 401-409, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31081312

RESUMO

BACKGROUND: Obesity, type 2 diabetes (T2D), dyslipidemia, arterial hypertension as well as hepatic steatosis (HS) are common conditions that can affect clinical outcomes of patients with chronic hepatitis C (CHC) who achieved sustained virologic response (SVR). The aim of this study was to assess the impact of metabolic cofactors on the occurrence of clinical events during follow-up (FU) in a group of CHC long-term responders (LTRs) to interferon- (IFN) based therapy. METHODS: A total of 5172 medical records of CHC patients enrolled from 1990 to 2011 were examined; 1034 of 5172 (20%) patients were treated with IFN-based therapy and 382 of 1034 (37%) of them achieved SVR. A total of 188 (49%) LTRs underwent liver biopsy before antiviral treatment. Data on liver and cardiometabolic events such as cirrhosis and its complications, hepatocellular carcinoma, coronary artery disease, arterial hypertension, impaired fasting glucose (IFG)/type 2 diabetes (T2D) and dyslipidemia, were collected over time. RESULTS: The mean age of the whole cohort was 46±12 years and 114/188 (61%) patients were males. HS was found in 82 of 188 (43.6%) patients and most of them were infected by HCV genotype 3a. The prevalence of obesity, IFG/T2D, dyslipidemia and arterial hypertension was 4.3%, 6.9%, 37.2%, and 5.9%, and was similarly distributed among patients with and without HS. Cirrhosis was histologically diagnosed in 18 of 188 (9.6%) patients. After a median follow-up of 11 years (range 3-21 years), the cumulative incidence of cardiovascular events, IFG/T2D and dyslipidemia was higher in CHC-LTRs who had HS at baseline compared to those without HS (1.2%, 2.3%, and 3.0% vs. 0.4%, 0.8%, and 2.5%, respectively). At multivariable Cox regression analysis, HS was significantly associated to the development of cardiovascular events and IFG/T2D (HR=5.2, 95% CI: 1.3-20.7, P=0.019, and HR=2.6, 95% CI: 1.1-6.2, P=0.027, respectively). CONCLUSIONS: In CHC-LTRs, HS at baseline may predispose to the development of cardiovascular events and T2D during follow-up emphasizing the importance of an accurate counseling in order to prevent extra-hepatic complications.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/metabolismo , Interferons/uso terapêutico , Adulto , Biópsia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Comorbidade , Dislipidemias/complicações , Dislipidemias/epidemiologia , Dislipidemias/metabolismo , Feminino , Seguimentos , Genótipo , Glucose/metabolismo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Hipertensão/metabolismo , Insulina/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/metabolismo , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
15.
Diagn Interv Radiol ; 25(3): 231-237, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31063137

RESUMO

PURPOSE: It is not easy to determine whether balloon angioplasty or stenting should be performed in patients with portal vein stenosis after liver transplantation. We aimed to propose appropriate indication by evaluating long-term outcomes of balloon angioplasty and stent insertion in adult liver transplant patients. METHODS: We retrospectively reviewed 31 patients with portal vein stenosis among 1369 patients who underwent adult liver transplantation from January 2001 to December 2015. When stenosis was confirmed by venography, angioplasty was performed first. When there was no flow improvement or pressure gradient was not decreased after angioplasty, stent insertion was performed. We also performed primary stent insertion without angioplasty for diffuse stenosis, kinking, external compression, and near occlusion of portal vein in venography. We assessed patency in patients who underwent percutaneous transluminal angioplasty and stent insertion through regular outpatient follow-up and evaluated technical and clinical success and long-term results. RESULTS: Technical success was 85% and 100% in balloon angioplasty and stent insertion, respectively. Clinical success was achieved in 78% of balloon angioplasties and in 100% of stent insertions. At 1, 5, and 10 years after balloon angioplasty, patency rates were 87%, 82%, and 68% respectively, and the rates of stent patency were all 100%. Portal vein size measured during the operation of patients with and without recurrence were 19±4.2 mm and 19±3.0 mm (P = 0.956), respectively. The balloon size of patients with and without recurrence were 11±1.95 mm and 14±1.66 mm, respectively (P = 0.013), when balloon angioplasty was performed after stenosis diagnosis. CONCLUSION: Stent insertion can be considered when fibrotic changes are expected due to repeated inflammation and when the balloon size to be used is small. Balloon angioplasty seems less risky for anastomotic ruptures in portal vein stenosis in the early post liver transplantation period.


Assuntos
Angioplastia com Balão/métodos , Constrição Patológica/terapia , Cirrose Hepática/terapia , Transplante de Fígado/estatística & dados numéricos , Veia Porta/patologia , Adulto , Angioplastia com Balão/efeitos adversos , Constrição Patológica/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Cirrose Hepática/prevenção & controle , Masculino , Pessoa de Meia-Idade , Flebografia , Veia Porta/diagnóstico por imagem , Complicações Pós-Operatórias/patologia , Estudos Retrospectivos , Stents/normas , Resultado do Tratamento
16.
Life Sci ; 229: 200-209, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047894

RESUMO

AIMS: The rapeseed protein derived peptide DHNNPQIR (named as RAP-8) has been previously reported to possess antioxidant activity and alleviate liver fibrosis. The purpose of the present study was to investigate the potential crucial pathways involved in ameliorating liver fibrosis of RAP-8. MAIN METHODS: Next-generation sequencing of messenger RNA (RNA-Seq) analysis of the fibrotic and RAP-8 treated mice was performed. Western blot, qPCR and flow cytometry detection analysis were conducted to measure cell cycle and oxidative stress in LX-2 cells and liver samples. KEY FINDINGS: 588 overlapped differentially expressed genes were obtained from a batch of genes RAP-8 altered. Gene Ontology enrichment analysis revealed that changes in the most significant modules were mainly enriched in cell division, nuclear division and mitotic cell cycle process, while alterations in Kyoto Encyclopedia of Genes and Genomes were mainly enriched in cell cycle. Thereafter, according to the co-expression network analysis, the regulations of three core genes (Cenpp, Cyp2c55, Serpinh1) were verified that might be targets for treating liver fibrosis. Furthermore, through experimental verification, we demonstrated that RAP-8 induced cell cycle arrest and prevents oxidation stress. SIGNIFICANCE: As a promising therapeutic candidate for hepatic fibrosis treating, RAP-8 exhibited anti-fibrotic effects via exerting cell cycle arrest and inhibiting oxidative stress.


Assuntos
Brassica rapa/química , Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Proteínas de Plantas/farmacologia , Animais , Perfilação da Expressão Gênica , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
Med Sci (Paris) ; 35(5): 431-439, 2019 May.
Artigo em Francês | MEDLINE | ID: mdl-31115326

RESUMO

Despite the existence of an effective vaccine, HBV infects 257 million people worldwide and is the cause of the majority of HCC. With an annual mortality rate of 887 000 patients in 2015, this cancer is the second deadliest. Low-income countries such as ones in sub-Saharan Africa are the most at risk due to the limited access to healthcare. To overcome this and born from an international research collaboration within an EU project, the Prolifica study aimed at evaluating a screen-and-treat program to prevent HBV complications, and more particularly HCC. Based on communities, facilities and hospitals HBsAg+ detection, the study lasted from 2011 to 2016. From the "cost effectiveness" feasibility of such a program to the development of simple scores for antiviral treatment, Prolifica uncovered data of crucial importance in a region with low HBV infection awareness, transmissions modes and prevention means which could have impacts on public health policies.


Assuntos
Hepatite B/complicações , Cirrose Hepática/prevenção & controle , Cirrose Hepática/virologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/virologia , África ao Sul do Saara , Política de Saúde , Acesso aos Serviços de Saúde/estatística & dados numéricos , Hepatite B/diagnóstico , Hepatite B/prevenção & controle , Antígenos de Superfície da Hepatite B/sangue , Humanos , Pobreza
18.
Indian J Med Res ; 149(1): 9-17, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-31115369

RESUMO

Hepatocellular carcinoma (HCC) is the sixth most common cancer in world and third largest cause of cancer-related deaths. The last few decades have witnessed the emergence of non-viral causes of HCC, the most important being non-alcoholic fatty liver disease (NAFLD). NAFLD ranges from simple steatosis in the absence of excessive alcohol intake to non-alcoholic steatohepatitis (NASH) with or without cirrhosis. About 3-15 per cent of the obese patients with NASH progress to cirrhosis and about 4-27 per cent of NASH with cirrhosis patients transform to HCC. It is also known that HCC can develop de novo in patients with NASH without the presence of cirrhosis. Yearly cumulative incidence of NASH-related HCC is low (2.6%) compared to four per cent of viral-HCC. NAFLD has been associated with risk factors such as metabolic syndrome, insulin resistance, altered gut flora and persistent inflammation. Due to alarming rise in metabolic diseases, both in the developing as well as the developed world, it is expected that the incidence of NAFLD/NASH-HCC would rise manifold in future. No definite guidelines have been drawn for surveillance and management of NAFLD/NASH-associated HCC. It is thus important to discuss the entity of HCC in NAFLD at length with special focus on its epidemiology, risk factors, pathophysiology, diagnosis, clinical presentation and prevention.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/prevenção & controle , Humanos , Resistência à Insulina/genética , Cirrose Hepática/complicações , Cirrose Hepática/genética , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/prevenção & controle , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Fatores de Risco
19.
World J Gastroenterol ; 25(15): 1783-1796, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31057294

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a complex disorder that has evolved in recent years as the leading global cause of chronic liver damage. The main obstacle to better disease management pertains to the lack of approved pharmacological interventions for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-fibrosis-the severe histological forms. Over the past decade, tremendous advances have been made in NAFLD research, resulting in the discovery of disease mechanisms and novel therapeutic targets. Hence, a large number of pharmacological agents are currently being tested for safety and efficacy. These drugs are in the initial pharmacological phases (phase 1 and 2), which involve testing tolerability, therapeutic action, and pharmacological issues. It is thus reasonable to assume that the next generation of NASH drugs will not be available for clinical use for foreseeable future. The expected delay can be mitigated by drug repurposing or repositioning, which essentially relies on identifying and developing new uses for existing drugs. Here, we propose a drug candidate selection method based on the integration of molecular pathways of disease pathogenesis into network analysis tools that use OMICs data as well as multiples sources, including text mining from the medical literature.


Assuntos
Reposicionamento de Medicamentos , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Progressão da Doença , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/efeitos dos fármacos
20.
J Photochem Photobiol B ; 195: 27-32, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31051327

RESUMO

Platinum and Curcumin conjugation using green chemistry is an attempt to enhance the curcumin effectiveness as an anti-fibrosis. In this study, Platinum and curcumin were conjugated to direct curcumin into the liver. Curcumin platinum nanoparticles (C-PtNPs) were formed by changing curcumin concentration at pH 10. The successful formation of C-PtNPs was recognized with the help of Fourier transform infrared (FTIR) and UV-visible spectrophotometers. The particle size and morphology were studied with the help of dynamic light scattering (DLS) and High-resolution transmission electron microscopy (HR-TEM) respectively. The antimicrobial activity of C-PtNPs, was examined against gram positive and gram negative bacteria. Moreover, the NIH/3 T3 cells were used to test the C-PtNPs activity of modifying initial fibrosis indication. The favorable condition for the synthesis of CPt-NPs was by using curcumin 1.5 mM at pH 10. When compared with free curcumin, C-Pt-NPs exhibited higher activity for decreased production of collagen by NIH/3 T3 cells. Altogether, the formation of C-PtNPs by conjugation of platinum to curcumin is assuring for the curcumin directing to treat the hepatic fibrosis.


Assuntos
Anti-Infecciosos/síntese química , Curcumina/química , Nanopartículas Metálicas/química , Platina/química , Animais , Anti-Infecciosos/farmacologia , Sobrevivência Celular , Curcumina/farmacologia , Curcumina/uso terapêutico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Cirrose Hepática/prevenção & controle , Camundongos , Microscopia Eletrônica de Transmissão , Células NIH 3T3 , Espectroscopia de Infravermelho com Transformada de Fourier
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