RESUMO
The transcription factor Nrf2 is a key regulator for hepatic induction of detoxifying enzymes, antioxidative stress genes and Mrp efflux transporters. We aimed to investigate whether Nrf2 activation counteracts liver injury associated with cholestasis. The role of Nrf2 activation in counteracting cholestatic liver injury was studied using a bile duct-ligation (BDL) model of Keap1 gene-knockdown (Keap1-kd) mice that represent the sustained activation of Nrf2 in the liver. Upon Nrf2 activation, Keap1-kd mice showed large increases in Mrp efflux transporters, detoxifying enzymes and antioxidative stress genes in the livers. After BDL, the number of hepatic parenchymal necrosis and the reactive oxygen species content were significantly smaller in the livers of the Keap1-kd mice than in those of the WT mice. Moreover, the increase in serum bilirubin levels was attenuated in the Keap1-kd mice. In conclusion, the results suggest a hepatoprotective role of sustained Nrf2 activation against liver injury associated with cholestasis.
Assuntos
Colestase/complicações , Regulação da Expressão Gênica , Icterícia Obstrutiva/complicações , Hepatopatias/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas do Citoesqueleto/genética , Técnicas de Silenciamento de Genes , Proteína 1 Associada a ECH Semelhante a Kelch , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/genéticaRESUMO
Ursodeoxycholic acid (UDCA) is widely used for the therapy of liver dysfunction. In this study, we investigated the protective effect of UDCA in concanavalin A-induced mouse liver injury. The treatment with UDCA at oral doses of 50 and 150 mg/kg at 2 h before concanavalin A injection significantly reduced the elevated plasma levels of aminotransferases and the incidence of liver necrosis compared with concanavalin A-injected control group without affecting the concentrations of liver hydrophobic bile acids. UDCA significantly inhibited elevated levels of tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2), and interleukin 6 (IL-6) in blood of concanavalin A-injected mice. To clarify the influence of UDCA on production of cytokines, we examined intrahepatic mRNA expressions and the protein levels of TNF-alpha, MIP-2, interferon-gamma (IFN-gamma), IL-4, IL-6, and IL-10 at 1 h after concanavalin A injection. The treatment with UDCA significantly decreased the intrahepatic levels of TNF- alpha and MIP-2, whereas this compound showed no clear effect on IFN-gamma, IL-4, IL-6, or IL-10. Furthermore, UDCA significantly decreased myeloperoxidase activity as well as MIP-2 level in the liver and histological examination of liver tissue revealed that intrasinusoidal accumulation of neutrophils was decreased markedly by UDCA. In addition, UDCA significantly inhibited the production of TNF-alpha and MIP-2 when cultured with nonparenchymal and lymph node cells. In conclusion, these findings suggest that UDCA protects concanavalin A-induced liver injury in mice by inhibiting intrahepatic productions of TNF-alpha and MIP-2, and the infiltration of neutrophils into the liver.
Assuntos
Colagogos e Coleréticos/farmacologia , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas , Quimiocina CXCL2/antagonistas & inibidores , Colagogos e Coleréticos/administração & dosagem , Concanavalina A/toxicidade , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon gama/efeitos dos fármacos , Interferon gama/metabolismo , Interleucinas/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
AIM: To investigate the effects of ursodeoxycholic acid (UDCA) on chenodeoxycholic acid (CDCA)-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the liver. METHODS: Liver injury was induced in hamsters by administration of 0.5% (w/w) CDCA in their feed for 7 d. UDCA (50 mg/kg and 150 mg/kg) was administered for the last 3 d of the experiment. RESULTS: At the end of the experiment, serum alanine aminotransferase (ALT) increased more than 10 times and the presence of liver injury was confirmed histologically. Marked increase in bile acids was observed in the liver. The amount of total bile acids increased approximately three-fold and was accompanied by the increase in hydrophobic bile acids, CDCA and lithocholic acid (LCA). UDCA (50 mg/kg and 150 mg/kg) improved liver histology, with a significant decrease (679.3 +/- 77.5 U/L vs 333.6 +/- 50.4 U/L and 254.3 +/- 35.5 U/L, respectively, P < 0.01) in serum ALT level. UDCA decreased the concentrations of the hydrophobic bile acids, and as a result, a decrease in the total bile acid level in the liver was achieved. CONCLUSION: The results show that UDCA improves oral CDCA-induced liver damage in hamsters. The protective effects of UDCA appear to result from a decrease in the concentration of hydrophobic bile acids, CDCA and LCA, which accumulate and show the cytotoxicity in the liver.
Assuntos
Colagogos e Coleréticos/farmacologia , Hepatopatias/prevenção & controle , Ácido Ursodesoxicólico/farmacologia , Alanina Transaminase/sangue , Animais , Ácidos e Sais Biliares/metabolismo , Peso Corporal/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas , Ácido Quenodesoxicólico , Cricetinae , Ingestão de Alimentos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/patologia , MesocricetusRESUMO
BACKGROUND: There continues to be a need for new therapies to treat ALS. OBJECTIVE: Provide an overview of safety for edaravone in ALS patients during the first six cycles of treatment. METHODS: Analysis was based on three randomised, placebo-controlled clinical trials. Endpoints included treatment-emergent adverse events (TEAEs), including AEs leading to discontinuation, serious adverse events (SAEs), and deaths. RESULTS: The analysis included a total of 368 patients (184 in the edaravone group and placebo group, respectively). Of those, 94.6% of the edaravone group and 90.2% of placebo group completed six cycles of therapy. Baseline characteristics were comparable between the two groups. TEAE incidence in the edaravone group and placebo group was 87.5% and 87.0%, respectively. TEAEs ocurring at ≥2% incidence in the edaravone group compared to placebo were contusion (14.7% vs. 8.7%), gait disturbance (12.5% vs. 9.2%), headache (8.2% vs. 5.4%), eczema (6.5% vs. 2.2%), dermatitis contact (6.0% vs. 3.3%), respiratory disorder (4.3% vs. 1.1%), and glucose urine present (3.8% vs. 1.6%). There was no imbalance in TEAEs leading to discontinuation (2.2% [edaravone], and 5.4% [placebo]). SAE incidence was 17.4% in the edaravone group and 22.3% in placebo group. Treatment-emergent deaths occurred in 2.2% in the edaravone group and 1.1% in placebo group, all respiratory in nature and attributed to worsening ALS. CONCLUSION: Data collected from three double-blind assessments found that while some TEAEs were more common in the edaravone group compared to placebo, the overall incidences of SAEs, deaths, and discontinuations due to AEs were similar or less for edaravone compared to placebo.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/tratamento farmacológico , Antipirina/análogos & derivados , Sequestradores de Radicais Livres/uso terapêutico , Segurança do Paciente , Adulto , Idoso , Esclerose Lateral Amiotrófica/epidemiologia , Antipirina/efeitos adversos , Antipirina/uso terapêutico , Método Duplo-Cego , Edaravone , Feminino , Sequestradores de Radicais Livres/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente/normas , Transtornos Respiratórios/induzido quimicamente , Transtornos Respiratórios/epidemiologiaRESUMO
Ursodeoxycholic acid (UDCA) is a bile acid, which is present in human bile at a low concentration of only 3% of total bile acids. It is a 7beta-hydroxy epimer of the primary bile acid chenodeoxycholic acid (CDCA). UDCA is isolated from the Chinese drug 'Yutan' a powder preparation derived from the dried bile of adult bears. For centuries, Yutan has been used in the treatment of hepatobiliary disorders. In Japan, it has also been in widespread use as a folk medicine from the mid-Edo period. In Japan, not only basic studies such as isolation, crystallization, definition of the chemical structure and establishment of the synthesis of UDCA have been conducted but clinical studies have been conducted. First reports on the effects of UDCA in patients with liver diseases came from Japan as early as 1961. In the 1970s, the first prospective study of patients with gallbladder stones treated with UDCA demonstrating gallstone dissolution was reported. In late 1980s, a number of controlled trials on the use of UDCA in primary biliary cirrhosis (PBC) were reported. Since then, a variety of clinical studies have shown the beneficial effect of UDCA in liver disease worldwide. To date, UDCA is utilized for the treatment of PBC for which it is the only drug approved by the U.S. Food and Drug Administration (FDA). In recent years, with the advent of molecular tools, the mechanisms of action of bile acids and UDCA have been investigated, and various bioactivities and pharmacological effects have been revealed. Based on the results of these studies, the bioactive substances in bile acids that are involved in digestive absorption may play important roles in signal transduction pathways. Furthermore, the mechanisms of action of UDCA is evidently involved. We reveal the physicochemical properties of UDCA as bile acid and overview the established pharmacological effects of UDCA from its metabolism. Furthermore, we overview the current investigations into the mechanism of action of UDCA in liver disease.
RESUMO
The protective action of ursodeoxycholic acid (UDCA) in cholestatic liver diseases may be mediated by choleresis, detoxification, and cytoprotection against oxidative stress. Nrf2, one transcription factor, serves as a cellular stress sensor and is a key regulator for hepatic induction of detoxifying enzymes, antioxidative stress genes, and numerous Mrp family members. We aimed to investigate whether UDCA induces hepatic Mrp expression along with that of detoxifying enzymes and antioxidative stress genes via the Nrf2 transcriptional pathway. The protein level, subcellular localization, and mRNA level of Mrp family members were assessed in livers of Keap1 gene-knockdown (Keap1-kd) mice and those of UDCA-fed wild-type (WT) and Nrf2 gene-null (Nrf2-null) mice. Nuclear levels of Nrf2 in livers of Keap1-kd mice markedly increased, resulting in constitutive activation of Nrf2. Keap1-kd mice have high-level expression of hepatic Mrp2, Mrp3, and Mrp4 relative to WT mice. UDCA potently increased nuclear Nrf2 expression level in livers of WT mice, and the treatment showed maximal hepatic induction of Mrp2, Mrp3, and Mrp4 in association with enhanced membranous localizations in an Nrf2-dependent manner. UDCA similarly increased nuclear Nrf2 expression level in rat hepatocytes. Chromatin immunoprecipitation assays using mouse hepatocytes revealed the binding of Nrf2 to antioxidant response elements in the promoter regions of Mrp2, Mrp3, and Mrp4. These findings demonstrate an important role of Nrf2 in the induction of Mrp family members in livers and suggest that a therapeutic mechanism of UDCA action is, via Nrf2 activation, a stimulation of detoxification and antioxidative stress systems, along with Mrp-mediated efflux transport.
Assuntos
Antioxidantes/metabolismo , Fígado/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/fisiologia , Fator 2 Relacionado a NF-E2/fisiologia , Ácido Ursodesoxicólico/farmacologia , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/fisiologia , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Regulação para CimaRESUMO
INTRODUCTION AND AIM: To examine the involvement of cholecystokinin (CCK) in the basal pancreatic exocrine, we investigated the effect of loxiglumide (CR1505), a CCK1 receptor antagonist, on basal pancreatic exocrine secretion in conscious rats. METHODOLOGY: After the basal collection of pancreatic juice for 1 hour, loxiglumide (10 mg/kg/h) or saline was infused via the femoral vein continuously for 2 hours. RESULTS: Loxiglumide significantly suppressed the basal pancreatic protein and amylase outputs. However, loxiglumide did not alter the basal pancreatic juice volume. CONCLUSIONS: These results demonstrate that loxiglumide suppresses basal pancreatic exocrine secretion in normal rats. They also suggest that CCK is involved in basal pancreatic exocrine in conscious rats and that loxiglumide may be useful as a therapeutic agent for pancreatitis, even during fasting, by attenuating the basal pancreatic exocrine burden on the pancreas.