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1.
Life Sci ; 276: 119424, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785334

RESUMO

AIM: To investigate the potential role of IL37 in hepatic ischemia reperfusion injury and its underlying molecular mechanism. METHODS: C57BL/6 mouse and hepatocytes were used to establish the hepatic ischemia reperfusion (IR) and the hypoxia reoxygenation (HR) injury model in vivo and in vitro, separately. Total extraction of tissue and cell protein expressions of LC3B, Beclin1, p62, cleaved caspase3, caspase3, bax, bcl2, AMPK, mTOR, ULK1 were detected by western blot. IL37 mRNA and protein level were detected by RT-qPCR and western blot. ALT and AST serum level were measured by microplate readers. H&E staining was used to assess the tissue sections. Autophagy was measured by TEM and confocal laser microscopy. Apoptosis in tissue and cell were detected by TUNEL staining. RESULTS: Autophagy was aberrantly activated by H2R6 and I1R12. Both exogenous IL37 and endogenous IL37 exerted protective effects on hepatocytes by affecting both autophagy-related proteins, specifically, by suppressing LC3B II and Beclin1 expression and increasing p62 levels and apoptosis-related proteins specifically, by inhibiting cleaved caspase3 and Bax expression and increasing Bcl2 expression during HR. Furthermore, endogenous IL37 inactivated AMPK and ULK1 phosphorylation and promoted mTOR phosphorylation in hepatocytes. Furthermore, in vivo experiments, serum liver enzyme measurements, TUNEL assays, and histological assessments, as well as other typical evaluations, showed the protective effect of IL37 overexpression in mice. CONCLUSION: Endogenous and exogenous IL37 were found to ameliorate hepatic ischemia reperfusion injury by inhibiting excessive autophagy and apoptosis, these effects may be connected with the modulation of AMPK/mTOR/ULK1 signalling complex.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia , Interleucina-1/metabolismo , Hepatopatias/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Regulação da Expressão Gênica , Interleucina-1/genética , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Serina-Treonina Quinases TOR/genética
3.
J Agric Food Chem ; 69(5): 1675-1683, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33494608

RESUMO

Cadmium (Cd) is a heavy metal, which is widely used in the industry and daily life. It has a long half-life, so large amounts of Cd can accumulate in humans and become toxic. Chlorogenic acid (CGA) can eliminate free radicals and inhibit lipid peroxidation and is mainly used to prevent metal toxicity. In the present study, mice are given CGA by intraperitoneal injection or gavage, respectively, to explore the mechanism of preventing Cd toxicity. In acute Cd-exposed mice, CGA treatment (ip) alleviated Cd-induced oxidative damage and reduced the production of NO and MPO in the liver and kidney tissues, while TLR4 expression levels did not change significantly. After 8 weeks of Cd exposure, CGA administration (gavage) significantly alleviated gut dysbiosis by decreasing the Firmicutes to Bacteroidetes ratio, enhancing the relative abundances of bacteria, including Ruminiclostridium_9, Alloprevotella, and Rikenella, and inhibiting the activation of the TLR4/MyD88/NF-κB signaling pathway. These findings suggested that protection mechanisms underlying the oral administration of CGA against the Cd-induced hepatorenal injury was related to the regulation of the intestinal flora balance. CGA can be used as an effective component in daily diet to prevent Cd toxicity.


Assuntos
Cádmio/toxicidade , Ácido Clorogênico/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias/prevenção & controle , Administração Oral , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Disbiose/etiologia , Disbiose/metabolismo , Disbiose/microbiologia , Disbiose/prevenção & controle , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/microbiologia , Masculino , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
4.
J Ethnopharmacol ; 266: 113454, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33065254

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Adhatoda vasica Nees., which existed in a large; number of Tibetan medicine prescriptions for hepatopathy, used as an adjuvant to treat liver diseases. HYPOTHESIS/PURPOSE: Oxidative stress is the key player in the development and progression of liver pathogenesis. In recent years, research is increasingly being focused on exploitation of the active components from medicinal plants to combat the liver oxidative injury. In our study, we aimed to screen the active principles from A. vasica and clarify whether they could relieve oxidative damage induced by tert-Butyl hydroperoxide (t-BHP) and its potential mechanism via activating AMPK/p62/Nrf2 pathway. MATERIALS AND METHODS: Ultra performance liquid chromatography (UPLC) was adopted for analysis of chemical composition in the extracts. Furthermore, the antioxidant activity of the fractions was evaluated using DPPH, ABTS and reducing power assay. Along with this, the compounds in this fraction with highest antioxidant activity were analyzed using UPLC-MS. Based on this, the condition for extracting flavonoids of this subfraction was optimized via response surface method. CCK-8 assay was used to detect cell viability. Detection kits were used to measure the activity changes of AST, ALT, LDH and CAT as well as MDA and GSH levels induced by t-BHP. Detection of reactive oxygen species (ROS) production was used DCFH-DA probe. DAPI staining and flow cytometry was used to detect cell apoptosis. In terms of the mechanistic studies, the expression of proteins involved in AMPK/p62/Nrf2 pathway was measured using western blotting. RESULTS: Eventually, 70% ethanol extract from leaf of A. vasica was chosen due to its highest active components compared with other extracts. Further, ethyl acetate fraction derived from 70% ethanol extract in A. vasica (AVEA) possess highest ability for scavenging DPPH and ABTS free radicals as well as strongest reducing power than other fractions. Chemical composition analysis showed that AVEA contained 17 compounds, including 1 quinazoline alkaloid, 12 flavonoid-C-glycosides and 4 flavonoid-O-glycosides. In addition, the conditions (ratio of solid-liquid 1:14, the concentration of ethanol 73%, and the temperature 65 °C) were selected to enrich the flavonoids in AVEA. Furthermore, AVEA could attenuate t-BHP induced hepatocyte damage via increasing the cell viability, restoring abnormal the activities of AST, ALT, LDH and CAT as well as the levels of MDA and GSH. ROS fluorescence intensity was reduced by AVEA. Meanwhile, it could inhibit the cell apoptosis of BRL 3 A cells, as evidenced by restoration of cell morphology and decreasing the number of apoptotic cells. Further mechanistic studies indicated AVEA could promote p-AMPK expression to further induce autophagy adaptor-p62 protein expression, which could autophagic degradation of Keap1, leading to Nrf2 release and translocation into nucleus to induce antioxidant genes (HO-1, NQO-1, GCLC and GCLM) expression. CONCLUSION: In our study, AVEA was first to screen as the active fraction in A. vasica with alkaloids and abundant flavones. Moreover, the fraction potentiates its beneficial aspect by displaying the protective role on relieving t-BHP induced oxidative stress and activating AMPK/p62/Nrf2 pathway. AVEA helps maintain the redox homeostasis of hepatic cells and could be considered as an effective candidate against oxidative stress related liver disorders.


Assuntos
Adhatoda/química , Hepatopatias/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Fator 2 Relacionado a NF-E2/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Ratos , Ratos Endogâmicos BUF , Espécies Reativas de Oxigênio/metabolismo , terc-Butil Hidroperóxido
5.
Life Sci ; 257: 118130, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32710950

RESUMO

BACKGROUND AND OBJECTIVES: Sepsis is a life-threatening organ dysfunction syndrome arising from uncontrolled inflammatory responses. Liver injury is a crucial factor for the prognosis of sepsis. Camptothecins (CPTs) have been reported to suppress the inflammatory response induced by sepsis. G2, a CPT-bile acid conjugate, has been demonstrated the property of liver targeting in our previous research. This study aimed to research the effects of G2 on liver injury induced by cecal ligation and puncture (CLP). METHODS: C57BL/6 mice were subjected to CLP surgery, and effects of G2 on liver damage and survival rates of CLP-induced mice were evaluated. To detect the related markers of hepatic injury or neutrophil infiltration, inflammatory cytokines and protein levels, hematoxylin-eosin staining assay, corresponding Detection Kits assay, ELISA and Western blot analysis were performed. RESULTS: Intraperitoneal administration of G2 reduced liver injury and enhanced the survival rates in mice with sepsis. Treatment with G2 decreased the levels of hepatic injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum of mice induced by CLP. The hepatic level of neutrophil infiltration marker myeloperoxidase (MPO) was reduced in G2 administration group. And the levels of serum inflammatory cytokines, including Tumor Necrosis Factor-α (TNFα), Interleukin-6 (IL-6) and IL-1ß, were decreased by G2. Furthermore, the results of Western blot analysis indicated that G2 suppressed the up-regulation of NF-κB p-P65 and p-IκBα. It suggested that G2 suppressed the activation of NF-κB signaling pathway. CONCLUSION: G2 alleviated sepsis-induced liver injury via inhibiting the NF-κB signaling pathway.


Assuntos
Ácidos e Sais Biliares/uso terapêutico , Camptotecina/uso terapêutico , Hepatopatias/etiologia , NF-kappa B/metabolismo , Sepse/complicações , Transdução de Sinais/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Ácidos e Sais Biliares/administração & dosagem , Western Blotting , Camptotecina/administração & dosagem , Citocinas/sangue , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Hepatopatias/metabolismo , Hepatopatias/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peroxidase/metabolismo
7.
Adv Exp Med Biol ; 1238: 23-37, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32323178

RESUMO

Over the last few decades, intestinal microbial communities have been considered to play a vital role in host liver health. Acute liver injury (ALI) is the manifestation of sudden hepatic injury and arises from a variety of causes. The studies of dysbiosis in gut microbiota provide new insight into the pathogenesis of ALI. However, the relationship of gut microbiota and ALI is not well understood, and the contribution of gut microbiota to ALI has not been well characterized. In this chapter, we integrate several major pathogenic factors in ALI with the role of gut microbiota to stress the significance of gut microbiota in prevention and treatment of ALI.


Assuntos
Disbiose , Microbioma Gastrointestinal , Hepatopatias/prevenção & controle , Hepatopatias/terapia , Fígado/lesões , Fígado/patologia , Doença Aguda/terapia , Humanos
9.
Cochrane Database Syst Rev ; 3: CD012056, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227478

RESUMO

BACKGROUND: Cystic fibrosis is an autosomal recessive inherited defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in abnormal regulation of salt and water movement across the membranes. In the liver this leads to focal biliary fibrosis resulting in progressive portal hypertension and end-stage liver disease in some individuals. This can be asymptomatic, but may lead to splenomegaly and hypersplenism, development of varices and variceal bleeding, and ascites; it has negative impact on overall nutritional status and respiratory function in this population. Prognosis is poor once significant portal hypertension is established. The role and outcome of various interventions for managing advanced liver disease (non-malignant end stage disease) in people with cystic fibrosis is currently unidentified. This is an updated version of a previously published review. OBJECTIVES: To review and assess the efficacy of currently available treatment options for preventing and managing advanced liver disease in children and adults with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 19 November 2019. We also searched the reference lists of relevant articles and reviews and online trials registries. Date of last search: 01 January 2020. SELECTION CRITERIA: Any published and unpublished randomised controlled trials and quasi-randomised controlled trials of advanced liver disease in cystic fibrosis with cirrhosis or liver failure, portal hypertension or variceal bleeding (or both). DATA COLLECTION AND ANALYSIS: Authors independently examined titles and abstracts to identify potentially relevant trials, but none were eligible for inclusion in this review. MAIN RESULTS: A comprehensive search of the literature did not identify any published eligible randomised controlled trials. AUTHORS' CONCLUSIONS: In order to develop the best source of evidence, there is a need to undertake randomised controlled trials of interventions for preventing and managing advanced liver disease in adults and children with cystic fibrosis.


Assuntos
Fibrose Cística/complicações , Hepatopatias/terapia , Adulto , Criança , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Hemorragia Gastrointestinal/prevenção & controle , Humanos , Hipertensão Portal/prevenção & controle , Hepatopatias/etiologia , Hepatopatias/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Toxicol Appl Pharmacol ; 395: 114978, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234387

RESUMO

Parasympathetic nervous system dysfunction is common in patients with liver disease. We have previously shown that muscarinic acetylcholine receptors (mAchRs) play an important role in the regulation of hepatic fibrosis and that the receptor agonists and antagonists affect hepatocyte proliferation. However, little is known about the impact of the different mAchR subtypes and associated signaling pathways on liver injury. Here, we treated the human liver cell line HL7702 with 10 mmol/L carbon tetrachloride (CCL4) to induce hepatocyte damage. We found that CCL4 treatment increased the protein levels of group I mAchRs (M1, M3, M5) but reduced the expression of group II mAchRs (M2, M4) and activated the Nrf2/ARE and MAPK signaling pathways. Although overexpression of M1, M3, or M5 led to hepatocyte damage with an intact Nrf2/ARE pathway, overexpression of M2 or M4 increased, and siRNA-mediated knockdown of either M2 or M4 decreased the protein levels of Nrf2 and its downstream target genes. Moreover, CCL4 treatment increased serum ALT levels more significantly, but only induced slight changes in the expression of mAchRs, NQO1 and HO1, while reducing the expression of M2 and M4 in liver tissues of Nrf2-/- mice compared to wild type mice. Our findings suggest that group II mAchRs, M2 and M4, activate the Nrf2/ARE signaling pathway, which regulates the expression of M2 and M4, to protect the liver from CCL4-induced injury.


Assuntos
Elementos de Resposta Antioxidante/fisiologia , Hepatopatias/fisiopatologia , Fator 2 Relacionado a NF-E2/fisiologia , Receptor Muscarínico M2/fisiologia , Receptor Muscarínico M4/fisiologia , Receptores Muscarínicos/fisiologia , Transdução de Sinais/fisiologia , Animais , Tetracloreto de Carbono/farmacologia , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Hepatócitos , Hepatopatias/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/genética , RNA Interferente Pequeno/farmacologia , Receptor Muscarínico M2/genética , Receptor Muscarínico M4/genética , Receptores Muscarínicos/genética , Transdução de Sinais/efeitos dos fármacos
11.
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
12.
Phytomedicine ; 68: 153153, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32018210

RESUMO

BACKGROUD: Cholestasis, accompanied by the accumulation of bile acids in body, may ultimately cause liver failure and cirrhosis. There have been limited therapies for cholesteric disorders. Therefore, development of appropriate therapeutic drugs for cholestasis is required. Picroside II is a bioactive component isolated from Picrorhiza scrophulariiflora Pennell, its mechanistic contributions to the anti-cholestasis effect have not been fully elucidated, especially the role of picroside II on bile acid homeostasis via nuclear receptors remains unclear. PURPOSE: This study was designed to investigate the hepatoprotective effect of picroside II against alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury and elucidate the mechanisms in vivo and in vitro. METHODS: The ANIT-induced cholestatic mouse model was used with or without picroside II treatment. Serum and bile biochemical indicators, as well as liver histopathological changes were examined. siRNA, Dual-luciferase reporter, quantitative real-time PCR and Western blot assay were used to demonstrate the farnesoid X receptor (FXR) pathway in the anti-cholestasis effects of picroside II in vivo and in vitro. RESULTS: Picroside II exerted hepatoprotective effect against ANIT-induced cholestasis by impaired hepatic function and tissue damage. Picroside II increased bile acid efflux transporter bile salt export pump (Bsep), uptake transporter sodium taurocholate cotransporting polypeptide (Ntcp), and bile acid metabolizing enzymes sulfate transferase 2a1 (Sult2a1) and UDP-glucuronosyltransferase 1a1 (Ugt1a1), whereas decreased the bile acid synthesis enzymes cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1). In addition, expression of FXR and the target gene Bsep was increased, whereas aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARα) and their corresponding target genes were not significantly influenced by picroside II under cholestatic conditions. Furthermore, regulation of transporters and enzymes involved in bile acid homeostasis by picroside II were abrogated by FXR silencing in mouse primary cultured hepatocytes. Dual-luciferase reporter assay performed in HepG2 cells demonstrated FXR activation by picroside II. CONCLUSION: Our findings demonstrate that picroside II exerts protective effect on ANIT-induced cholestasis possibly through FXR activation that regulates the transporters and enzymes involved in bile acid homeostasis. Picroside II might be an effective approach for the prevention and treatment of cholestatic liver diseases.


Assuntos
Colestase/prevenção & controle , Cinamatos/farmacologia , Glucosídeos Iridoides/farmacologia , Hepatopatias/prevenção & controle , Receptores Citoplasmáticos e Nucleares/metabolismo , 1-Naftilisotiocianato/toxicidade , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Ácidos e Sais Biliares/genética , Ácidos e Sais Biliares/metabolismo , Colestase/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/efeitos dos fármacos , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia
13.
Expert Opin Drug Deliv ; 17(2): 237-253, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32003249

RESUMO

Background: The poor biopharmaceutical properties of thymoquinone (TQ) obstruct its development as a hepatoprotective agent. To surmount the delivery challenges of TQ, phospholipid nanoconstructs (PNCs) were constructed.Method: PNCs were constructed employing microemulsification technique and systematic optimization by three-factor three level Box-Behnken design.Result: Optimized PNC composition exhibited nano size (<100 nm), spherical morphology, within acceptable range of polydispersity index (0.55), high drug entrapment efficiency (>90%), controlled drug release pattern, and neutral surface charge (zeta potential of -0.65 mV). After oral administration of a single dose of PNC, it showed a relative bioavailability of 386.03% vis-à-vis plain TQ suspension. Further, TQ-loaded PNC demonstrated significant enhanced hepato-protective effect vis-à-vis pure TQ suspension and silymarin, as evidenced by reduction in the ALP, ALT, AST, bilirubin, and albumin level and ratified by histopathological analysis.Conclusion: TQ-loaded PNCs can be efficient nano-platforms for the management of hepatic disorders and promising drug delivery systems to enhance oral bioavailability of this hydrophobic molecule.


Assuntos
Benzoquinonas/administração & dosagem , Benzoquinonas/farmacocinética , Nanopartículas/administração & dosagem , Fosfolipídeos/administração & dosagem , Fosfolipídeos/farmacocinética , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/prevenção & controle , Nanopartículas/química , Ratos Wistar , Suspensões
14.
J Stroke Cerebrovasc Dis ; 29(2): 104562, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31836361

RESUMO

INTRODUCTION: Recent studies have indicated that the damaging effects of stroke are not only limited to the brain. We sought to examine the changes of liver and renal enzymes in the acute phase of ischemic stroke and to investigate possible explanations and therapeutic options, concerning in particular the functional alterations of peripheral organs after administration of an anti-inflammatory agent. MATERIAL/METHODS: Twelve-week-old Wistar male rats were randomly divided into control and Cyclosporine groups (n = 10 each). Cyclosporine was given orally by gavage for 5 days prior to cerebral ischemia at a total volume of 15 mg/kg/day. All animals were subjected to 60 minutes focal ischemia by filament occlusion of the middle cerebral artery. Serum concentrations of Creatinine, Urea, SGOT, SGPT, and γGT were determined at the time before surgery and after 60 minutes brain ischemia. RESULTS: Comparing data of 2 time-points, in both groups the serum liver enzyme levels increased progressively during the ischemic period. The liver enzymes and Urea were significantly lower in the Cyclosporine group than in the control group and the levels of Creatinine were slightly higher in the Cyclosporine group, in both time-points. CONCLUSIONS: The detection of high liver enzyme serum levels in the acute phase of ischemic stroke implies the secondary effect of cerebral infraction on the peripheral organs and particularly on the liver function. Cyclosporine seems to exhibit a protective activity and to affect both liver and renal function after ischemic stroke.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Ciclosporina/farmacologia , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/complicações , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Rim/enzimologia , Rim/fisiopatologia , Nefropatias/sangue , Nefropatias/etiologia , Nefropatias/fisiopatologia , Fígado/enzimologia , Fígado/fisiopatologia , Hepatopatias/sangue , Hepatopatias/etiologia , Hepatopatias/fisiopatologia , Masculino , Ratos Wistar , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo
15.
Am J Pathol ; 190(2): 358-371, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31783007

RESUMO

Liver sinusoidal endothelial cells (LSECs) control organ functions, metabolism, and development through the secretion of angiokines. LSECs express hepatocyte growth factor (Hgf), which is involved in prenatal development, metabolic homeostasis, and liver regeneration. This study aimed to elucidate the precise contribution of LSEC-derived Hgf in physiological homeostasis and liver regeneration. Stab2-iCretg/wt;Hgffl/fl (HgfΔLSEC) mice were generated to abrogate Hgf expression selectively in LSECs from early fetal development onwards, to study global development, metabolic and endothelial zonation, and organ functions as well as liver regeneration in response to 70% partial hepatectomy (PH). Although zonation and liver/body weight ratios were not altered, total body weight and total liver weight were reduced in HgfΔLSEC. Necrotic organ damage was more marked in HgfΔLSEC mice, and regeneration was delayed 72 hours after PH. This was associated with decreased hepatocyte proliferation at 48 hours after PH. Molecularly, HgfΔLSEC mice showed down-regulation of Hgf/c-Met signaling and decreased expression of Deptor in hepatocytes. In vitro knockdown of Deptor was associated with decreased proliferation. Therefore, angiocrine Hgf controls hepatocyte proliferation and susceptibility to necrosis after partial hepatectomy via the Hgf/c-Met axis involving Deptor to prevent excessive organ damage.


Assuntos
Tamanho Corporal , Proliferação de Células , Fator de Crescimento de Hepatócito/fisiologia , Hepatócitos/citologia , Hepatopatias/prevenção & controle , Regeneração Hepática , Organogênese/fisiologia , Animais , Moléculas de Adesão Celular Neuronais/fisiologia , Endotélio/citologia , Endotélio/metabolismo , Feminino , Hepatectomia , Hepatócitos/fisiologia , Homeostase , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Camundongos , Camundongos Knockout , Comunicação Parácrina , Transdução de Sinais
16.
Am J Physiol Gastrointest Liver Physiol ; 318(1): G41-G52, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31604032

RESUMO

Infants receiving long-term parenteral nutrition (PN) develop PN-associated liver disease (PNALD). We previously (Ng K et al. JPEN J Parenter Enteral Nutr 40: 656-671, 2016. doi:10.1177/0148607114567900.) showed that PN containing soy-based lipid supplemented with vitamin E (α-tocopherol) prevents the development of PNALD. We hypothesize that this occurs via vitamin E activation of pregnane X receptor (PXR)-mediated pathways involved in bile acid metabolism. Neonatal piglets received PN for 14 days containing Intralipid (IL; soy-based lipid emulsion), IL supplemented with 12.6 mg·kg-1·day-1 vitamin E (VITE), or IL with 10 mg·kg-1·day-1 Rifadin IV (RIF), a PXR agonist. Pigs treated with IL and VITE, but not RIF, developed cholestasis and hyperbilirubinemia, markers of liver disease. The hepatic PXR target genes CYP3A29 and UGT1A6 increased during RIF treatment. RIF also modestly increased metabolism of chenodeoxycholic acid to the more hydrophilic bile acid hyocholic acid. Serum fibroblast growth factor (FGF)-19, a key regulator in suppressing hepatic bile acid synthesis, significantly increased in the RIF group. We conclude rifampicin modified markers of PNALD development by increased metabolism of bile acids and potentially suppressed bile acid synthesis. Vitamin E was ineffective at high lipid doses in preventing PNALD.NEW & NOTEWORTHY Intravenous vitamin E and rifampicin were administered to neonatal piglets receiving parenteral nutrition to determine their efficacy in reducing the progression of parenteral nutrition-associated liver disease (PNALD). Rifampicin increased serum FGF-19 concentrations and synthesis of the bile acid hyocholic acid which led to a reduction of PNALD parameters at 2 wk of administration. This result has potential clinical implications for the use of rifampicin as a safe and inexpensive treatment for short-term development of PNALD.


Assuntos
Ácidos e Sais Biliares/metabolismo , Emulsões Gordurosas Intravenosas , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , Nutrição Parenteral , Fosfolipídeos , Receptor de Pregnano X/agonistas , Rifampina/farmacologia , Óleo de Soja , Vitamina E/farmacologia , Animais , Animais Recém-Nascidos , Ácidos e Sais Biliares/biossíntese , Colestase/etiologia , Colestase/metabolismo , Colestase/prevenção & controle , Citocromo P-450 CYP3A/metabolismo , Modelos Animais de Doenças , Emulsões , Glucuronosiltransferase/metabolismo , Hiperbilirrubinemia/etiologia , Hiperbilirrubinemia/metabolismo , Hiperbilirrubinemia/prevenção & controle , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Receptor de Pregnano X/metabolismo , Transdução de Sinais , Sus scrofa
17.
Lancet ; 395(10219): 226-239, 2020 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-31791690

RESUMO

This final report of the Lancet Commission into liver disease in the UK stresses the continuing increase in burden of liver disease from excess alcohol consumption and obesity, with high levels of hospital admissions which are worsening in deprived areas. Only with comprehensive food and alcohol strategies based on fiscal and regulatory measures (including a minimum unit price for alcohol, the alcohol duty escalator, and an extension of the sugar levy on food content) can the disease burden be curtailed. Following introduction of minimum unit pricing in Scotland, alcohol sales fell by 3%, with the greatest effect on heavy drinkers of low-cost alcohol products. We also discuss the major contribution of obesity and alcohol to the ten most common cancers as well as measures outlined by the departing Chief Medical Officer to combat rising levels of obesity-the highest of any country in the west. Mortality of severely ill patients with liver disease in district general hospitals is unacceptably high, indicating the need to develop a masterplan for improving hospital care. We propose a plan based around specialist hospital centres that are linked to district general hospitals by operational delivery networks. This plan has received strong backing from the British Association for Study of the Liver and British Society of Gastroenterology, but is held up at NHS England. The value of so-called day-case care bundles to reduce high hospital readmission rates with greater care in the community is described, along with examples of locally derived schemes for the early detection of disease and, in particular, schemes to allow general practitioners to refer patients directly for elastography assessment. New funding arrangements for general practitioners will be required if these proposals are to be taken up more widely around the country. Understanding of the harm to health from lifestyle causes among the general population is low, with a poor knowledge of alcohol consumption and dietary guidelines. The Lancet Commission has serious doubts about whether the initiatives described in the Prevention Green Paper, with the onus placed on the individual based on the use of information technology and the latest in behavioural science, will be effective. We call for greater coordination between official and non-official bodies that have highlighted the unacceptable disease burden from liver disease in England in order to present a single, strong voice to the higher echelons of government.


Assuntos
Alcoolismo/epidemiologia , Hepatopatias/epidemiologia , Hepatopatias/prevenção & controle , Obesidade/epidemiologia , Bebidas Alcoólicas/economia , Alcoolismo/complicações , Alcoolismo/terapia , Comércio , Redes Comunitárias/organização & administração , Comorbidade , Efeitos Psicossociais da Doença , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Legislação sobre Alimentos , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Transplante de Fígado/estatística & dados numéricos , Obesidade/complicações , Pacotes de Assistência ao Paciente , Escócia , Reino Unido/epidemiologia
18.
Oxid Med Cell Longev ; 2019: 6565283, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827690

RESUMO

Cholestatic liver injury, due to obstruction of the biliary tract or genetic defects, is often accompanied by progressive inflammation and liver fibrosis. Methane-rich saline (MRS) has anti-inflammatory properties. However, whether MRS can provide protective effect in cholestatic liver injury is still unclear. In this study, Sprague-Dawley rats received bile duct ligation (BDL) to generate a cholestatic model followed by MRS treatment (10 mL/kg, ip treatment) every 12 h after the operation to explore the potential protective mechanism of MRS in cholestatic liver injury. We found that MRS effectively improved liver function, alleviated liver pathological damage, and localized infiltration of inflammatory cells. MRS treatment decreased the expression of hepatic fibrosis-associated proteins to alleviate liver fibrosis. Furthermore, MRS treatment suppressed the TLR4/NF-κB pathway and further reduced the levels of proinflammatory factors. Downregulation of NF-κB subsequently reduced the NLRP3 expression to inhibit pyroptosis. Our data indicated that methane treatment prevented cholestatic liver injury via anti-inflammatory properties that involved the TLR4/NF-κB/NLRP3 signaling pathway.


Assuntos
Colestase/complicações , Inflamassomos/efeitos dos fármacos , Hepatopatias/prevenção & controle , Metano/farmacologia , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Cloreto de Sódio/farmacologia , Receptor 4 Toll-Like/metabolismo , Animais , Ductos Biliares , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/etiologia , Inflamação/patologia , Inflamação/prevenção & controle , Ligadura , Hepatopatias/etiologia , Hepatopatias/patologia , Masculino , NF-kappa B/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 4 Toll-Like/genética
19.
Oxid Med Cell Longev ; 2019: 7861290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827701

RESUMO

Liver ischemia/reperfusion (IR) injury is a common phenomenon after liver resection and transplantation, which often results in liver graft dysfunction such as delayed graft function and primary nonfunction. The mammalian target of rapamycin (mTOR) is an evolutionarily highly conserved serine/threonine protein kinase, which coordinates cell growth and metabolism through sensing environmental inputs under physiological or pathological conditions, involved in the pathophysiological process of IR injury. In this review, we mainly present current evidence of the beneficial role of mTOR in modulating inflammation and autophagy under liver IR to provide some evidence for the potential therapies for liver IR injury.


Assuntos
Autofagia , Inflamação/complicações , Hepatopatias/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Serina-Treonina Quinases TOR/administração & dosagem , Animais , Humanos , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
20.
Oxid Med Cell Longev ; 2019: 9714302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827717

RESUMO

Morinda citrifolia (Rubiaceae) or Noni was previously reported to have leaf with broad therapeutic property whereas the fruit was rarely described as medicinal. Ironically, extensive research and review has been done on the fruit and little was known about the therapeutic activity of the leaf as a medicinal food. The aim of this study was to investigate the therapeutic effects of Morinda citrifolia (MC) ethanolic leaf extract on the hepatic structure and function in postmenopausal rats fed with thermoxidized palm oil (TPO) diet. Thirty eight female Sprague Dawley rats were divided into five groups: sham (Sham), ovariectomized (OVX), ovariectomized and treated with simvastatin 10 mg/kg (OVX+ST), ovariectomized and supplemented with low dose MC 500 mg/kg (OVX+MCLD), and ovariectomized and supplemented with high dose MC 1000 mg/kg (OVX+MCHD). All the ovariectomized groups were fed with TPO diet whereas the Sham group was fed with normal diet. Consumption of TPO diet in postmenopausal rats resulted in obesity, significantly elevated (P < 0.05) liver oxidative stress marker; malondialdehyde (MDA), diffuse microvesicular steatosis, and defective mitochondria. Treatment with MC leaf extract prevented hepatic steatosis by significantly increasing (P < 0.05) the liver antioxidant enzyme SOD and GPx, significantly increasing (P < 0.05) ALP, decreasing liver lipids infiltration, preventing mitochondrial damage, and overall maintaining the normal liver histology and ultrastructure. In conclusion, we provided detailed histological and ultrastructural evidence showing hepatoprotective effects of MC leaf extract through its antioxidant mechanism.


Assuntos
Hepatopatias/prevenção & controle , Morinda/química , Ovariectomia/efeitos adversos , Óleo de Palmeira/toxicidade , Fitoterapia , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Animais , Feminino , Temperatura Alta , Lipídeos/análise , Hepatopatias/etiologia , Hepatopatias/patologia , Oxirredução , Folhas de Planta/química , Ratos , Ratos Sprague-Dawley
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