Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 890
Filtrar
1.
J Ethnopharmacol ; 266: 113432, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33011367

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Veronica ciliata Fisch. is a traditional medical herb that present in more than 100 types of Tibetan medicine prescriptions, most of which are used for liver disease therapy. Iridoid glycosides have been identified as the major active components of V.ciliata with a variety of biological activities. AIMS OF THE STUDY: The aim of this study is to explore the protective effect and potential mechanism of n-Butanol extract (BE) and iridoid glycosides (IG) from V.ciliata against ɑ-naphthyl isothiocyanate (ANIT)-induced hepatotoxicity and cholestasis in mice. MATERIALS AND METHODS: Mice were intragastrically (i.g.) given BE and IG at different dose or positive control ursodeoxycholic acid (UCDA) once a day for 14 consecutive days, and were treated with ANIT to cause liver injury on day 12th. Serum levels of hepatic injury markers and cholestasis indicators, liver index and liver histopathology were measured to evaluate the effect of BE and IG on liver injury caused by ANIT. The protein levels of tumor necrosis factor-α (TNF-α), nuclear factor kappa B(NF-κB), interleukin-6 (IL-6), Na+/taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and the levels of oxidative stress indicators in liver tissue were investigated to reveal the underlying protective mechanisms of BE and IG against ANIT-induced hepatotoxicity and cholestasis. RESULTS: The n-Butanol extract (BE) and iridoid glycosides (IG) isolated from V.ciliata significantly decreased serum level of cholestatic liver injury markers aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), total bile acid (TBA), total bilirubin (TBIL), and direct bilirubin (DBIL) in ANIT-treated mice. Histopathology of the liver tissue showed that pathological damages were relieved upon BE and IG treatment. Meanwhile, the results indicated BE and IG notably restored relative liver weights, inhibited oxidative stress induced by ANIT through increasing hepatic level of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and decreasing hepatic content of malondialdehyde (MDA). Western blot revealed that BE and IG inhibited the expression of pro-inflammatory factors TGF-α, IL-6 and NF-κB. Furthermore, the decreased protein expression of bile acid transporters NTCP, BSEP, MRP2 were upregulated by BE and IG in a dose-dependent manner. CONCLUSION: The results have demonstrated that BE and IG exhibited a dose-dependently protective effect against ANIT-induced liver injury with acute intrahepatic cholestasis in mice, which might be related to the regulation of oxidative stress, inflammatory response and bile acid transport. In addition, these findings pointed out that iridoid glycosides as main active components of V.ciliata play a critical role in hepatoprotective effect of V.ciliata.


Assuntos
Colestase/tratamento farmacológico , Glicosídeos Iridoides/farmacologia , Extratos Vegetais/farmacologia , Veronica/química , 1-Butanol/química , 1-Naftilisotiocianato , Animais , Ácidos e Sais Biliares/metabolismo , Transporte Biológico/efeitos dos fármacos , Colestase/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glicosídeos Iridoides/administração & dosagem , Glicosídeos Iridoides/isolamento & purificação , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Medicina Tradicional Tibetana , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem
2.
Zhongguo Zhong Yao Za Zhi ; 45(21): 5273-5279, 2020 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-33350245

RESUMO

This paper aimed to investigate the protective effect and mechanism of the Tibetan medicine Ershiwuwei Songshi Pills on α-naphthalene isothiocyanate(ANIT)-induced cholestatic liver injury in rats based on the farnesol X receptor(FXR) signaling pathway. SD rats were randomly divided into blank group, model group, ursodeoxycholic acid(UDCA) group, Tibetan medicine Ershiwuwei Songshi Pills low, medium and high dose groups(0.09, 0.18, 0.36 g·kg~(-1)). A prophylactic dosing regimen was used in the experiment. From the 1 st to 4 th days, the UDCA group and the Tibetan medicine Ershiwuwei Songshi Pills suspension groups received prophylactic gavage administration; on the 5 th day, the blank control group was given an equal volume of olive oil blank reagent, and the remaining groups were given ANIT modeling reagent. Administration was continued on day 5 to 6 in each administration group. Forty-eight hours after modeling on the 7 th day, blood was collected from the femoral artery of rats. Serum alkaline phosphatase(ALP), alanine aminotransferase(ALT), aspartate aminotransferase(AST), direct bilirubin(DBIL), total bilirubin(TBIL), and total bile acid(TBA) levels were detected, and liver histopathological changes were observed. The relative expression changes of FXR, SHP, CYP7 A1, MRP2, MRP3, NTCP, BSEP mRNA in liver tissues were detected by Real-time fluorescence quantitative method, and the expression changes of FXR, SHP, UGT2 B4 protein in liver tissues were detected by Western blot. The results showed that the Tibetan medicine Ershiwuwei Songshi Pills significantly reduced the levels of ALT, ALP, DBIL, TBIL and TBA in the serum of the ANIT mo-del rats(P<0.01, P<0.05), significantly up-regulated the mRNA expressions of SHP and NTCP(P<0.01, P<0.05), significantly down-regulated the mRNA expression of CYP7 A1 and MRP3(P<0.01, P<0.05); and significantly up-regulated the protein expressions of FXR and SHP(P<0.01, P<0.05). The Tibetan medicine Ershiwuwei Songshi Pills have an obvious protective effect on ANIT-induced cholestatic liver injury in rats, and its mechanism may be related to the bile acid metabolism mediated by the FXR signaling pathway.


Assuntos
Colestase , Medicina Tradicional Tibetana , Animais , Colestase/tratamento farmacológico , Colestase/genética , Fígado , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
3.
Life Sci ; 259: 118352, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32860804

RESUMO

AIMS: Lipopolysaccharide (LPS) induces inflammatory cholestasis by impairing expression, localization, and function of carriers involved in bile formation, e.g. bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2). A specific therapy against this disease is still lacking. Therefore, we evaluated the anticholestatic effects of spironolactone (SL), a PXR ligand that regulates bile salt homeostasis, up-regulates Mrp2, and bears anti-inflammatory properties. MAIN METHODS: Male Wistar rats were divided into four groups: Control, SL (83.3 mg/kg/day of SL, i.p., for 3 days), LPS (2.5 mg/kg/day, i.p., at 8 am of the last 2 days, and 1.5 mg/kg/day at 8 pm of the last day), and SL + LPS. Biliary and plasma parameters and the expression, function, and localization of Mrp2 and Bsep were evaluated. KEY FINDINGS: SL partially prevented LPS-induced drop of basal bile flow by normalizing the bile salt-independent fraction of bile flow (BSIBF), via improvement of glutathione output. This was due to a recovery in Mrp2 transport function, the major canalicular glutathione transporter, estimated by monitoring the output of its exogenously administered substrate dibromosulfophthalein. SL counteracted the LPS-induced downregulation of Mrp2, but not that of Bsep, at both mRNA and protein levels. LPS induced endocytic internalization of both transporters, visualized by immunofluorescence followed by confocal microscopy, and SL partially prevented this relocalization. SL did not prevent the increase in IL-1ß, IL-6, and TNF-α plasma levels. SIGNIFICANCE: SL prevents the impairment in Mrp2 expression and localization, and the resulting recovery of Mrp2 function normalizes the BSIBF by improving glutathione excretion.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Colestase/tratamento farmacológico , Espironolactona/uso terapêutico , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Bile/metabolismo , Colestase/sangue , Colestase/metabolismo , Citocinas/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
5.
Nat Biomed Eng ; 4(7): 743-753, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32632227

RESUMO

Most patients with cholangiocarcinoma (CCA) develop extrahepatic malignant biliary obstructions, which require palliative drainage to normalize bilirubin levels and to improve the patients' overall survival. Here, we report that the infusion of methotrexate-containing plasma-membrane microvesicles derived from apoptotic human tumour cells into the bile-duct lumen of patients with extrahepatic CCA mobilized and activated neutrophils and relieved biliary obstruction in 25% of the patients. Neutrophil recruitment by the microvesicles was associated with an increase in uridine diphosphate glucose and complement C5, and led to the degradation of the stromal barrier of CCA. The microvesicles induced pyroptosis of CCA cells through a gasdermin E-dependent pathway, and their intracellular contents released upon CCA-cell death activated patient-derived macrophages into producing proinflammatory cytokines, which attracted a secondary wave of neutrophils to the tumour site. Our findings suggest a possible treatment for the alleviation of obstructive extrahepatic CCA with few adverse effects, and highlight the potential of tumour-cell-derived microvesicles as drug carriers for antitumour therapies.


Assuntos
Antitussígenos/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Colestase/tratamento farmacológico , Metotrexato/uso terapêutico , Animais , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Medula Óssea , Morte Celular , Colangiocarcinoma/diagnóstico por imagem , Colangiocarcinoma/patologia , Colestase/diagnóstico por imagem , Colestase/patologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Perfusão
6.
Chin J Nat Med ; 18(3): 211-218, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32245591

RESUMO

Cholestasis is caused by the obstacle of bile formation or secretion and can develop into severe liver diseases. We previously reported the ethanol extract of Schisandra sphenanthera (Wuzhi tablet, WZ) can significantly protect against lithocholic acid (LCA)-induced intrahepatic cholestasis in mice, partially due to the activation of PXR pathway and promotion of liver regeneration. However, the effect of WZ on the bile acids profile and gut microbiome in cholestastic mice remain unknown. In this study, the effect of WZ against LCA-induced liver injury was evaluated and its effect on the bile acids metabolome and gut microbiome profiles in cholestastic mice was further investigated. Targeted metabolomics analysis was performed to examine the change of bile acids in the serum, liver, intestine and feces. The change of intestinal flora were detected by the genomics method. Targeted metabolomics analysis revealed that WZ enhanced the excretion of bile acids from serum and liver to intestine and feces. Genomics analysis of gut microbiome showed that WZ can reverse LCA-induced gut microbiome disorder to the normal level. In conclusion, WZ protects against LCA-induced cholestastic liver injury by reversing abnormal bile acids profiles and alteration of gut microbiome.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colestase/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal , Extratos Vegetais/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Colestase/induzido quimicamente , Ácido Litocólico , Masculino , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Schisandra/química , Comprimidos
7.
Toxicol Appl Pharmacol ; 394: 114956, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171571

RESUMO

Proper enterocytic proliferation/differentiation, besides providing adequate adherens junctions (AJ) integrity, are responsible for strengthening of the gut barrier that acts as a first line defense against endotoxemia. However, the preferential role of the underlying PI3K/Akt (PKB) axis in triggering enterocytic proliferation/differentiation signaling and AJ assembly is still obscure in sepsis. Additionally, the potential involvement of dipeptidyl peptidase (DPP)-IV in cholestatic sepsis has not yet been reported. Common bile duct ligation (CBDL) insult was performed in adult male Sprague-Dawley rats except for sham operated animals; three doses of vildagliptin (VLD3, 10 and 30 mg/kg/d; p.o) were administered for 10 consecutive days post CBDL. VLD3/10/30 dose-dependently decreased DPP-IV and elevated GLP-1, IGF-1, PI3K, pS473-Akt (PKB), pS9-GSK-3ß, pS133-CREB and cyclin-D1. VLD3/10 reduced fever, portal/aortic endotoxin and IgG, body weight loss as well as ileal NF-κB, TNF-α, MPO, TBARS, subepithelial/pericryptal and submucosal collagen deposition, vimentin immunoreactivity, N-cadherin, Zeb1 and pY654-ß-catenin but increased E-cadherin, NPSH and colon/spleen indices - effects that were quite the opposite of VLD30. Accordingly, maintaining proper enterocytic proliferation/differentiation and phosphorylation inputs consequent to adequate DPP-IV inhibition is integral to AJ assembly in cholestatic sepsis; however, perturbed signals by excessive suppression of the enzyme activity induce toxic effects manifested as AJ disassembly and EMT, hence gut leakage and overt endotoxemia.


Assuntos
Colestase/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Enterócitos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Sepse/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colestase/tratamento farmacológico , Ducto Colédoco/lesões , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Íleo/patologia , Ligadura , Masculino , Ratos , Ratos Sprague-Dawley , Sepse/tratamento farmacológico , Vildagliptina/farmacologia , Vimentina/metabolismo , Perda de Peso/efeitos dos fármacos
8.
Phytother Res ; 34(6): 1291-1309, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32026542

RESUMO

Cholestasis is a common manifestation of decreased bile flow in various liver diseases. It results in fibrosis and even cirrhosis without proper treatment. It is believed that a wide range of factors, including transporter dysfunction, oxidative stress, inflammatory damage, and immune disruption, can cause cholestasis. In recent years, natural products have drawn much attention for specific multiple-target activities in diseases. Many attempts have been made to investigate the anticholestatic effects of natural products with advanced technology. This review summarizes recent studies on the biological activities and mechanisms of recognized compounds for cholestasis treatment. Natural products, including various flavonoids, phenols, acids, quinones, saponins, alkaloids, glycosides, and so on, function as comprehensive regulators via ameliorating oxidative stress, inflammation, and apoptosis, restoring bile acid balance with hepatic transporters, and adjusting immune disruption. Moreover, in this progress, nuclear factor erythroid 2-related factor 2, reactive oxygen species production, heme oxygenase-1, NF-κB, cholesterol 7 alpha-hydroxylase, and farnesoid X receptors are thought as main targets for the activity of natural products. Therefore, this review presents the detailed mechanisms that include multiple targets and diverse signalling pathways. Natural products are the valuable when seeking novel therapeutic agents to treat cholestatic liver diseases.


Assuntos
Produtos Biológicos/uso terapêutico , Colestase/tratamento farmacológico , Colestase/prevenção & controle , Hepatopatias/tratamento farmacológico , Hepatopatias/prevenção & controle , Animais , Humanos
9.
Medicine (Baltimore) ; 99(3): e18855, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011505

RESUMO

RATIONALE: Prolonged cholestasis is a rare complication associated with endoscopic retrograde cholangiopancreatography (ERCP). PATIENT CONCERNS: A 68-year-old man who presented with worsening cholestasis after ERCP for the removal of a common bile duct stone. DIAGNOSIS: Total bilirubin increased up to 35.2 mg/dL after the 21st day post-ERCP. A percutaneous liver biopsy was performed and drug-related cholestasis was suspected as occurring as a result of the contrast agent. INTERVENTIONS: Oral ursodeoxycholic acid and cholestyramine were prescribed to the patient. OUTCOMES: By the 7th week post-ERCP, the patient's symptoms and markers of physiological health began to resolve. The bilirubin returned to normal levels on the 106th day post-ERCP. We reviewed the literature for studies of 9 patients with jaundice more than 30 days post-ERCP, the peak of total serum bilirubin occurred on 16th ±â€Š7th days and the recovery followed after mean time of 54th ±â€Š22th days. LESSONS: Although the cholestasis was prolonged, the outcome was favorable after medical therapy. There were no long-term consequences for the patient.


Assuntos
Colangiopancreatografia Retrógrada Endoscópica , Colestase/induzido quimicamente , Meios de Contraste/efeitos adversos , Idoso , Colagogos e Coleréticos/uso terapêutico , Colestase/tratamento farmacológico , Resina de Colestiramina/uso terapêutico , Quimioterapia Combinada , Humanos , Masculino , Ácido Ursodesoxicólico/uso terapêutico
10.
Arch. argent. pediatr ; 118(1): S12-S49, 2020-02-00. tab, ilus
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1096510

RESUMO

La presencia de ictericia en la etapa neonatal puede responder a diversas causas, desde situaciones fisiológicas hasta enfermedades graves. En los neonatos de término que persisten ictéricos más allá de los 14 días de vida, debe determinarse si la hiperbilirrubinemia es no conjugada o conjugada para establecer, a la brevedad, el plan de estudios etiológicos y la terapéutica correspondiente. La hiperbilirrubinemia conjugada (colestasis) refleja una disfunción hepática en la mayoría de los casos, cuyas consecuencias son alteraciones del flujo biliar secundarias a anormalidades estructurales o moleculares del hígado y/o del tracto biliar.Durante la última década, los nuevos estudios moleculares revolucionaron el abordaje de los pacientes colestáticos, lo que permitió el diagnóstico de diversas entidades genéticas. La etiología de la hiperbilirrubinemia del primer trimestre debe determinarse con urgencia, ya que, en muchos casos, el tratamiento instituido de modo precoz puede modificar sustancialmente la evolución de la enfermedad o salvar la vida del paciente.


Neonatal jaundice may be due to different causes, ranging from physiological conditions to severe diseases. In term neonates with persistent jaundice beyond 14 days of life, it should be determined whether hyperbilirubinemia is unconjugated or conjugated, in order to study the etiology and start early treatment. In the majority of cases, conjugated hyperbilirubinemia (cholestasis) is a sign of liver dysfunction possibly associated with alterations in the bile flow secondary to structural or molecular abnormalities of the liver and/or the biliary tract. Over the past decade, new molecular studies have revolutionized the approach of cholestatic patients, leading to the identification of different genetic entities. It is important to determine the etilogy of neonatal hyperbilirubinemia since in many cases early treatment will substantially improve morbidity and mortality.


Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Colestase/diagnóstico , Colestase/genética , Colestase/imunologia , Colestase Intra-Hepática/genética , Hiperbilirrubinemia Neonatal/diagnóstico , Hiperbilirrubinemia Neonatal/etiologia , Colestase/etiologia , Colestase/tratamento farmacológico , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/tratamento farmacológico
11.
Aliment Pharmacol Ther ; 51(1): 90-109, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31762074

RESUMO

BACKGROUND: Improved knowledge of the molecular pathophysiology and immunopathogenesis of cholestatic liver diseases in recent years has led to an increased interest in developing novel therapies. Patients with cholestatic liver disease often require different approaches to assessment and management of suspected drug-induced liver injury (DILI) compared to those with healthy livers and those with parenchymal liver diseases. At present, there are no regulatory guidelines or society position papers, that systematically address best practices pertaining to detection of DILI in these patients. AIMS: To outline best practices for detection, assessment and management of suspected acute DILI during clinical trials in adults with the cholestatic liver diseases - Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). METHODS: This is one of the several papers developed by the IQ DILI Initiative, which is comprised of members from 16 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. The contents are the result of an extensive literature review, as well as in-depth discussions among industry, regulatory and academic DILI experts, to achieve consensus recommendations on DILI-related issues occurring during clinical trials for cholestatic liver diseases. RESULTS: Recommended best practices are outlined pertaining to hepatic eligibility criteria, monitoring of liver tests, approach to a suspected DILI signal, and hepatic discontinuation rules. CONCLUSIONS: This paper provides a framework for the approach to detection, assessment and management of suspected acute DILI occurring during clinical trials in adults with cholestatic liver disease.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/terapia , Colestase/tratamento farmacológico , Ensaios Clínicos como Assunto , Consenso , Cirrose Hepática Biliar/tratamento farmacológico , Adulto , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/patologia , Doença Crônica , Ensaios Clínicos como Assunto/estatística & dados numéricos , Indústria Farmacêutica/organização & administração , Indústria Farmacêutica/normas , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática Biliar/patologia , Testes de Função Hepática , Sociedades Farmacêuticas/normas
12.
Annu Rev Pharmacol Toxicol ; 60: 503-527, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31506007

RESUMO

Though ursodeoxycholic acid (UDCA) remains the baseline treatment for most cholestatic liver diseases, UDCA treatment leaves approximately one-third of patients with primary biliary cholangitis (PBC) and all patients with primary sclerosing cholangitis (PSC) at risk for disease progression. New anticholestatic agents, including nuclear receptor agonists, choleretics, and bile acid synthesis suppressors, will likely increase response rates to therapy in PBC and PSC. Strategies that target early immune-mediated injury have so far been disappointing, hampered by the lack of biomarkers to detect early disease states, which then could profit from immunomodulatory therapy. Future concepts need to personalize treatments according to disease stage, progression, and phase, and to combine multiple drugs to target different pathogenic pathways.


Assuntos
Colagogos e Coleréticos/uso terapêutico , Colestase/tratamento farmacológico , Animais , Colagogos e Coleréticos/farmacologia , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/fisiopatologia , Colestase/fisiopatologia , Doença Crônica , Progressão da Doença , Humanos , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/fisiopatologia , Receptores Citoplasmáticos e Nucleares/agonistas , Ácido Ursodesoxicólico/uso terapêutico
13.
Hum Pathol ; 96: 39-47, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31669893

RESUMO

Drug-induced liver injury (DILI) is a challenging and constantly changing field. The pathologist plays a key role in interpreting liver biopsies by classifying the pattern of injury, grading the severity of injury, and evaluating for other possible causes. Reports of iatrogenic liver injury are reviewed here with a focus on total parenteral nutrition (ie, intestinal failure-associated liver disease [IFALD]) and immune checkpoint inhibitors (ICIs). The hallmark features of IFALD are cholestasis and steatosis. Cholestasis is more common in infants, whereas steatosis and steatohepatitis are more commonly seen in older children and adults. Infants tend to have a faster progression to fibrosis and cirrhosis. Perivenular fibrosis and ductopenia may also be seen in IFALD. Although fish oil-based lipid emulsions can reverse cholestasis, recent studies have shown persistent or progressive fibrosis. ICI-induced liver injury usually presents as an acute hepatitis with features similar to those seen in idiopathic autoimmune hepatitis and drug-induced autoimmune hepatitis. However, it lacks a prominent plasma cell infiltrate and serological markers of autoimmune hepatitis. Other features such as fibrin ring granulomas and cholangitis have also been reported in association with ICIs. Treatment for ICI-induced liver injury includes corticosteroids and other immunosuppressants.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Colestase/etiologia , Fígado Gorduroso/etiologia , Doença Iatrogênica , Fígado/efeitos dos fármacos , Nutrição Parenteral Total/efeitos adversos , Biópsia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/tratamento farmacológico , Colestase/patologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia , Humanos , Fígado/patologia , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
14.
Clin J Gastroenterol ; 13(1): 79-82, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31286423

RESUMO

A 42-year-old woman was admitted to our hospital with cholestatic liver injury. Serological examination revealed anti-mitochondrial M2 antibody positivity and anti-nuclear antibody and anti-smooth muscle antibody negativity. Histological examination of the first liver biopsy revealed chronic nonsuppurative destructive cholangitis with epithelioid granulomas. Ursodeoxycholic acid therapy successfully treated her cholestasis. Sixteen months later, she developed acute icteric hepatitis with elevation of serum aspartate and alanine aminotransferase levels. Anti-mitochondrial M2 positivity and anti-nuclear antibody and anti-smooth muscle antibody negativity persisted at that time. However, it became clear that anti-liver kidney microsomal type 1 antibody was positive. Histological examination of the second liver biopsy demonstrated scarce interface hepatitis and evident parenchymal inflammation and centrilobular zonal necrosis. Her liver biochemical test results promptly improved with the addition of prednisolone therapy. Considering the findings, she was diagnosed with primary biliary cholangitis-type 2 autoimmune hepatitis overlap syndrome. According to a literature review, this is an extremely rare autoimmune overlap syndrome.


Assuntos
Autoanticorpos/imunologia , Hepatite Autoimune/imunologia , Cirrose Hepática Biliar/imunologia , Proteínas Mitocondriais/imunologia , Adulto , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Colagogos e Coleréticos/uso terapêutico , Colestase/tratamento farmacológico , Colestase/etiologia , Feminino , Glucocorticoides/uso terapêutico , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/metabolismo , Hepatite Autoimune/patologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/patologia , Prednisolona/uso terapêutico , Ácido Ursodesoxicólico/uso terapêutico
15.
Intern Med ; 58(22): 3283-3287, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31735738

RESUMO

The anti-programmed cell death-1 protein monoclonal antibody, pembrolizumab is an immune checkpoint inhibitor. While it improves the prognoses of patients with advanced non-small-cell lung cancer, it has been reported to induce various kinds of immune-related adverse events, including hepatotoxicity. Despite the frequency of hepatotoxicity, there is only limited information available regarding the pathophysiology and treatment. We herein report a 48-year-old man with lung adenocarcinoma who was treated with pembrolizumab and developed cholestatic liver injury. In this case, the importance of evaluating the histology of hepatotoxicity and the effectiveness of ursodeoxycholic acid for cholestatic liver injury is indicated.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Colestase/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Colestase/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Ácido Ursodesoxicólico/uso terapêutico
16.
Curr Opin Pharmacol ; 49: 60-70, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31590120

RESUMO

Chronic liver diseases with different etiologies represent a major public health issue worldwide. Liver fibrosis is the common feature of almost all chronic liver diseases and remains a key determinant of clinical prognosis. Over the last two decades, basic science studies have uncovered molecular mechanisms underlying the pathophysiology of chronic liver diseases, leading to the recent development of new anti-fibrotic drugs. These new drugs target different steps in the pathophysiology of chronic liver injury: metabolism of glucose, lipids and bile acids, apoptosis, inflammation and fibrosis. Many targets are shared between non-alcoholic steatohepatitis (NASH) and cholestatic diseases, explaining why some drugs have been assessed concurrently in both conditions. This review reports the most recent clinical trials designed to treat liver fibrosis, with a special focus on NASH and cholestatic diseases.


Assuntos
Colestase/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Doença Crônica , Ensaios Clínicos como Assunto , Humanos , Fígado/metabolismo
18.
Toxicol Appl Pharmacol ; 380: 114697, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31394158

RESUMO

Liver cholestasis is a complex disease of broad etiologies. Hedgehog (Hh) signaling has been shown to play a pivotal role in modulating liver repair post cholestatic liver injury. We here investigated the role of vitamin D in experimental liver cholestasis induced by bile-duct ligation (BDL) in rats. Male Sprague Dawley rats underwent BDL surgery and two weeks post-surgery; vitamin D was administered daily for two weeks. Serum markers of hepatocellular integrity were measured and fibrosis was detected by measuring α-SMA and hepatic TGF-ß1 as well as hepatic collagen content. Hh signaling was evaluated by measuring Smo and Gli1 levels. Histopathological examination of hepatic tissue was performed. Vitamin D alleviated obstructive cholestatic damage as illustrated by total bilirubin as well as gamma glutamyl transferase (γ-GT) serum levels. It also alleviated hepatocellular damage as suggested by reducing elevated serum aminotransferases induced by BDL. Antifibrotic activity of vitamin D was confirmed by decrease in mRNA and protein expression of α-SMA, as well as collagen content in hepatic tissue. Furthermore, vitamin D suppressed BDL-induced elevated hepatic TGF-ß1 mRNA and protein levels. BDL activated Hh signaling and upregulated its upstream component smoothened (Smo) and downstream target gene Gli1. Treatment with vitamin D reduced Smo mRNA levels and suppressed hepatic Gli1 mRNA and protein levels. Molecular docking of vitamin D to Smo revealed that vitamin D binds similarly to its endogenous cholesterol ligand and blocks its activation. These results demonstrate that vitamin D mitigated cholestatic liver injury through inhibiting Hh signaling.


Assuntos
Colecalciferol/uso terapêutico , Colestase/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Vitaminas/uso terapêutico , Animais , Ductos Biliares , Colecalciferol/farmacologia , Colestase/genética , Colestase/metabolismo , Colestase/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Proteínas Hedgehog/metabolismo , Ligadura , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Transdução de Sinais , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Vitaminas/farmacologia , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
19.
J Ethnopharmacol ; 245: 112103, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31336134

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cholestasis is a clinical syndrome caused by toxic bile acid retention that will lead to serious liver diseases. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only two FDA-approved drugs for its treatment. Thus, there is a clear need to develop new therapeutic approaches for cholestasis. Here, anti-cholestasis effects of the lignans from a traditional Chinese herbal medicine, Schisandra sphenanthera, were investigated as well as the involved mechanisms. MATERIALS AND METHODS: Adult male C57BL/6J mice were randomly divided into 9 groups including the control group, LCA group, LCA with specific lignan treatment of Schisandrin A (SinA), Schisandrin B (SinB), Schisandrin C (SinC), Schisandrol A (SolA), Schisandrol B (SolB), Schisantherin A (StnA) and Schisantherin B (StnB), respectively. Mice were treated with each drug (qd) for 7 days, while the administration of lithocholic acid (LCA) (bid) was launched from the 4th day. Twelve hours after the last LCA injection, mice were sacrificed and samples were collected. Serum biochemical measurement and histological analysis were conducted. Metabolomics analysis of serum, liver, intestine and feces were performed to study the metabolic profile of bile acids. RT-qPCR and Western blot analysis were conducted to determine the hepatic expression of genes and proteins related to bile acid homeostasis. Dual-luciferase reporter gene assay was performed to investigate the transactivation effect of lignans on human pregnane X receptor (hPXR). RT-qPCR analysis was used to detect induction effects of lignans on hPXR-targeted genes in HepG2 cells. RESULTS: Lignans including SinA, SinB, SinC, SolA, SolB, StnA, StnB were found to significantly protect against LCA-induced intrahepatic cholestasis, as evidenced by significant decrease in liver necrosis, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) activity. More importantly, serum total bile acids (TBA) and total bilirubin (Tbili) were also significantly reduced. Metabolomics analysis revealed these lignans accelerated the metabolism of bile acids and increased the bile acid efflux from liver into the intestine or feces. Gene analysis revealed these lignans induced the hepatic expressions of PXR-target genes such as Cyp3a11 and Ugt1a1. Luciferase reporter gene assays illustrated that these bioactive lignans can activate hPXR. Additionally, they can all upregulate hPXR-regulate genes such as CYP3A4, UGT1A1 and OATP2. CONCLUSION: These results clearly demonstrated the lignans from Schisandra sphenanthera exert hepatoprotective effects against LCA-induced cholestasis by activation of PXR. These lignans may provide an effective approach for the prevention and treatment of cholestatic liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Colestase/tratamento farmacológico , Lignanas/uso terapêutico , Receptor de Pregnano X/genética , Substâncias Protetoras/uso terapêutico , Schisandra , Animais , Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/induzido quimicamente , Colestase/metabolismo , Colestase/patologia , Fezes/química , Células HEK293 , Células Hep G2 , Humanos , Mucosa Intestinal/metabolismo , Lignanas/farmacologia , Ácido Litocólico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia
20.
Zhongguo Zhong Yao Za Zhi ; 44(13): 2709-2718, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31359681

RESUMO

To screen the active ingredients of Gardenia jasminoides and potential targets,and investigate the mechanisms against cholestasis based on network pharmacology technology. Twenty-one active components of G. jasminoides were retrieved and the target sites were screened by using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform( TCMSP). Cytoscape3. 2. 1 was used to construct the component-target network. Two hundred and eight targets related to cholestasis were searched and screened through Dis Ge NET,KEGG and OMIM databases. The key targets of G. jasminoides components and cholestasis were integrated and screened,and the component-target-disease network was constructed with Cytoscape 3. 2. 1 software to screen out the core network whose freedom degree was greater than the average value. The Clue GO plug-in of Cytoscape 3. 2. 1 software was used to analyze the biological processes and pathway enrichment of G. jasminoides in regulation of cholestasis. GO biological process analysis revealed 17 biological processes,involving 3 signaling biological processes related to cholestasis,i.e. acute inflammatory response,positive regulation of reactive oxygen species metabolic process,and nitric oxide biosynthetic process. KEGG-KEEG-305 terms and REACTOME pathways analysis revealed 17 regulatory pathways,involving 4 signaling pathways related to cholestasis,i.e. metabolism of xenobiotics by cytochrome P450,nuclear receptor transcription pathway,GPVI-mediated activation cascade and platelet activation. It was found that aqueous extract of G. jasminoides could improve serum biochemical abnormalities in ANIT-induced cholestasis rats. Aqueous extract of G. jasminoides could decrease the protein and mRNA expression levels of ESR1 in liver tissues,and increase the protein and mRNA expression levels of PPARG,NOS2,F2 R,NOS3,and NR3 C1. To sum up,the possible mechanisms of G. jasminoides against cholestasis may be related with the above three processes and four pathways.


Assuntos
Colestase/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Gardenia/química , Extratos Vegetais/farmacologia , Animais , Medicina Tradicional Chinesa , Ratos , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...