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1.
Am J Physiol Gastrointest Liver Physiol ; 318(2): G211-G224, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31709830

RESUMO

Nonalcoholic steatohepatitis (NASH) has increased in Western countries due to the prevalence of obesity. Current interests are aimed at identifying the type and function of immune cells that infiltrate the liver and key factors responsible for mediating their recruitment and activation in NASH. We investigated the function and phenotype of CD8+ T cells under obese and nonobese NASH conditions. We found an elevation in CD8 staining in livers from obese human subjects with NASH and cirrhosis that positively correlated with α-smooth muscle actin, a marker of hepatic stellate cell (HSC) activation. CD8+ T cells were elevated 3.5-fold in the livers of obese and hyperlipidemic NASH mice compared with obese hepatic steatosis mice. Isolated hepatic CD8+ T cells from these mice expressed a cytotoxic IL-10-expressing phenotype, and depletion of CD8+ T cells led to significant reductions in hepatic inflammation, HSC activation, and macrophage accumulation. Furthermore, hepatic CD8+ T cells from obese and hyperlipidemic NASH mice activated HSCs in vitro and in vivo. Interestingly, in the lean NASH mouse model, depletion and knockdown of CD8+ T cells did not impact liver inflammation or HSC activation. We demonstrated that under obese/hyperlipidemia conditions, CD8+ T cell are key regulators of the progression of NASH, while under nonobese conditions they play a minimal role in driving the disease. Thus, therapies targeting CD8+ T cells may be a novel approach for treatment of obesity-associated NASH.NEW & NOTEWORTHY Our study demonstrates that CD8+ T cells are the primary hepatic T cell population, are elevated in obese models of NASH, and directly activate hepatic stellate cells. In contrast, we find CD8+ T cells from lean NASH models do not regulate NASH-associated inflammation or stellate cell activation. Thus, for the first time to our knowledge, we demonstrate that hepatic CD8+ T cells are key players in obesity-associated NASH.


Assuntos
Linfócitos T CD8-Positivos/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/patologia , Animais , Células Estreladas do Fígado/efeitos dos fármacos , Hepatite/patologia , Humanos , Hiperlipidemias/patologia , Interleucina-10/biossíntese , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade/etiologia , Receptores de LDL/genética , Receptores de LDL/metabolismo
2.
Am J Physiol Gastrointest Liver Physiol ; 318(2): G298-G304, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31813234

RESUMO

In liver cirrhosis, oxidative stress plays a major role in promoting liver inflammation and fibrosis. Mitochondria dysregulation is responsible for excessive reactive oxygen species production. Therefore, in an experimental model of cirrhosis, we investigated the effect of mitochondria-targeted antioxidant mitoquinone. Liver cirrhosis was induced in Spraque-Dawley rats by common bile duct ligation (CBDL). Mitoquinone (10 mg·kg-1·day-1, oral gavage) or vehicle was administered from 3rd to 28th day after CBDL, when animals were euthanized; liver oxidative stress, inflammation, fibrosis, mitophagy were evaluated; and in vivo and ex vivo hemodynamic studies were performed. In cirrhotic rats, mitoquinone prevented liver inflammation, hepatocyte necrosis, and fibrosis at histological examination; decreased circulating TNF-α, gene expression of transforming growth factor-ß1, collagen type 1a1, TNF-α, IL-6, IL-1ß, tissue inhibitor of metalloproteinase-1, matrix metalloproteinase (MMP)-2, and MMP-13; and reduced hepatic oxidative stress, as shown by reduced oxidative carbonylation of the proteins, by modulating antioxidants catalase, Mn superoxide dismutase, and Cu/Zn superoxide dismutase. Furthermore, mitoquinone attenuated apoptosis by reducing hepatic protein expression of cleaved caspase-3. A selective removal of dysfunctional mitochondria was improved by mitoquinone, as shown by the increase in Parkin translocation to mitochondria. Treatment with mitoquinone normalized the weight of the spleen; however, it increased portal blood flow and reduced splenic artery intrahepatic resistance, suggesting an effect on resistance index. Mitochondria-targeted antioxidant mitoquinone improves liver inflammation and fibrosis in cirrhotic rats by reducing hepatic oxidative stress, preventing apoptosis, and promoting removal of dysfunctional mitochondria. Therefore, it may represent a promising strategy for the prevention and treatment of liver cirrhosis.


Assuntos
Antioxidantes/farmacologia , Hepatite/patologia , Hepatite/prevenção & controle , Cirrose Hepática/patologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Ubiquinona/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Citocinas/sangue , Fibrose , Hemodinâmica/efeitos dos fármacos , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Baço/patologia , Ubiquinona/farmacologia
3.
J Ethnopharmacol ; 248: 112361, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31683033

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine Forsythiae Fructus is the dried fruit of Forsythia suspensa (Thunb.) Vahl. It is commonly used to clear heat and detoxify, reduce swelling and disperse knot, and evacuate wind and heat. AIM OF THE STUDY: Inflammation is involved in liver fibrosis. Phillygenin (PHI) is a kind of lignans extracted and separated from Forsythiae Fructus, which has been reported to have a good anti-inflammatory effect. Therefore, we aimed to explore whether PHI has a therapeutic effect on liver fibrosis caused by inflammation. MATERIALS AND METHODS: Firstly, the induction of the LX2 cells inflammatory model and fibrosis model by LPS with different concentrations were studied. Then, high, medium and low doses PHI was given for intervention therapy. The secretion of IL-6, IL-1ß and TNF-α inflammatory factors were detected by ELISA kit, and the expression of collagen I and α-SMA was detected by Western blot and RT-qPCR. The possible mechanism of PHI on TLR4/MyD88/NF-κB signal pathway was studied by computer-aided drug design software and the results were further verified by Western blot and RT-qPCR experiments. RESULTS: The results showed that LPS could promote the expression of IL-6, IL-1ß and TNF-α and the expression of collagen I and α-SMA, indicating that LPS could induce inflammation and fibrosis in LX2 cells. PHI could inhibit LX2 cell activation and fibrotic cytokine expression by inhibiting LPS-induced pro-inflammatory reaction. Molecular docking results showed that PHI could successfully dock with TLR4, MyD88, IKKß, p65, IκBα, and TAK1 proteins. Subsequently, Western blot and qPCR results further proved that PHI could inhibit the proteins expression in TLR4/MyD88/NF-κB signal pathway which were consistent with the molecular docking results. CONCLUSION: PHI can inhibit LPS-induced pro-inflammatory reaction and LX2 cell activation through TLR4/MyD88/NF-κB signaling pathway, thereby inhibiting liver fibrosis.


Assuntos
Anti-Inflamatórios/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Hepatite/prevenção & controle , Lignanas/farmacologia , Lipopolissacarídeos/toxicidade , Cirrose Hepática/prevenção & controle , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Actinas/metabolismo , Linhagem Celular , Colágeno Tipo I/metabolismo , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite/metabolismo , Hepatite/patologia , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
5.
BMC Gastroenterol ; 19(1): 191, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744461

RESUMO

BACKGROUND: Syphilis is a common disease that has been researched and focused on for many years, however, syphilitic hepatitis has not been well-recognized. We report this case of syphilitic hepatitis with intrahepatic cholestasis and liver granulomas to make a deeper impression. CASE PRESENTATION: A 47-year-old male was admitted with jaundice and rashes. The laboratory examination showed abnormal liver enzymes with significant increases in ALP and GGT but mild increases in ALT and AST. His HBV surface antigen was weakly positive, with negative HIV antibody, HCV antibody, and undetectable HBV DNA. The rapid plasma reagin test and the Treponema pallidum particle assay tests for Syphilis were both positive. Abdominal ultrasonography and magnetic resonance cholangiopancreatography revealed the normal biliary tract, liver, and spleen. The liver pathological examination showed cholangiocyte inflammation and micro-granulomas with coagulation necrosis. After 2 months of benzathine penicillin treatment, his liver enzyme decreased rapidly and remained normal after 1-year of follow-up. CONCLUSIONS: Increased liver enzymes, intrahepatic cholestasis and liver granulomas with well-response to antibiotics may provide clues for the diagnosis of syphilitic hepatitis.


Assuntos
Hepatite/microbiologia , Sífilis/diagnóstico , Antibacterianos/uso terapêutico , Colestase Intra-Hepática/patologia , Granuloma/patologia , Hepatite/diagnóstico , Hepatite/tratamento farmacológico , Hepatite/patologia , Humanos , Fígado/enzimologia , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Penicilina G Benzatina/uso terapêutico , Sífilis/tratamento farmacológico , Sífilis/patologia , Treponema pallidum/isolamento & purificação
6.
Chin Med J (Engl) ; 132(20): 2438-2445, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31651516

RESUMO

BACKGROUND: Adiponectin is the most abundant adipokines that plays critical roles in the maintenance of energy homeostasis as well as inflammation regulation. The half-life of adiponectin is very short and the small-molecule adiponectin receptor agonist has been synthesized recently. In the present study, the potential roles of AdipoRon, an adiponectin receptor agonist, in a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute hepatitis was explored. METHODS: BALB/c mice (n = 144, male) were divided into three sets. In set 1, 32 mice were randomized into four groups: the control group, the AdipoRon group, the LPS/D-Gal group, and the AdipoRon + LPS/D-Gal group. The mice in set 1 were sacrificed after LPS/D-Gal treatment, and the plasma samples were collected for detection of tumor necrosis factor-alpha (TNF-α). In set 2, the 32 mice were also divided into four groups similar to that of set 1. The mice were sacrificed 6 h after LPS/D-Gal injection and plasma samples and liver were collected. In set 3, 80 mice (divided into four groups, n = 20) were used for survival observation. The survival rate, plasma aminotransferases, histopathological damage were measured and compared between these four groups. RESULTS: AdipoRon suppressed the elevation of plasma aminotransferases (from 2106.3 ±â€Š781.9 to 286.8 ±â€Š133.1 U/L for alanine aminotransferase, P < 0.01; from 566.5 ±â€Š243.4 to 180.1 ±â€Š153.3 U/L for aspartate aminotransferase, P < 0.01), attenuated histopathological damage and improved the survival rate (from 10% to 60%) in mice with LPS/D-Gal-induced acute hepatitis. Additionally, AdipoRon down-regulated the production of TNF-α (from 328.6 ±â€Š121.2 to 213.4 ±â€Š52.2 pg/mL, P < 0.01), inhibited the activation of caspase-3 (from 2.04-fold to 1.34-fold of the control), caspase-8 (from 2.03-fold to 1.31-fold of the control), and caspase-9 (from 2.14-fold to 1.43-fold of the control), and decreased the level of cleaved caspase-3 (0.28-fold to that of the LPS/D-Gal group). The number of terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling-positive apoptotic hepatocytes in LPS/D-Gal-exposed mice also reduced. CONCLUSIONS: These data indicated that LPS/D-Gal-induced acute hepatitis was effectively attenuated by the adiponectin receptor agonist AdipoRon, implying that AdipoRon might become a new reagent for treatment of acute hepatitis.


Assuntos
Hepatite/tratamento farmacológico , Piperidinas/uso terapêutico , Receptores de Adiponectina/agonistas , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Modelos Animais de Doenças , Galactosamina , Hepatite/metabolismo , Hepatite/patologia , Hepatócitos/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Crescimento Transformador alfa/sangue
7.
Am J Pathol ; 189(12): 2400-2413, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31539521

RESUMO

High-fat diet (HFD)-induced inflammation is associated with a variety of health risks. The systemic pentraxin serum amyloid P (SAP) inhibits inflammation. SAP activates the high-affinity IgG receptor Fcγ receptor I (FcγRI; CD64) and the lectin receptor dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN; CD209). Herein, we show that for mice on an HFD, injections of SAP and a synthetic CD209 ligand (1866) reduced HFD-increased adipose and liver tissue inflammation, adipocyte differentiation, and lipid accumulation in adipose tissue. HFD worsened glucose tolerance test results and caused increased adipocyte size; for mice on an HFD, SAP improved glucose tolerance test results and reduced adipocyte size. Mice on an HFD had elevated serum levels of IL-1ß, IL-23, interferon (IFN)-ß, IFN-γ, monocyte chemoattractant protein 1 [MCP-1; chemokine (C-C motif) ligand 2 (CCL2)], and tumor necrosis factor-α. SAP reduced serum levels of IL-23, IFN-ß, MCP-1, and tumor necrosis factor-α, whereas 1866 reduced IFN-γ. In vitro, SAP, but not 1866, treated cells isolated from white fat tissue (stromal vesicular fraction) produced the anti-inflammatory cytokine IL-10. HFD causes steatosis, and both SAP and 1866 reduced it. Conversely, compared with control mice, SAP knockout mice fed on a normal diet had increased white adipocyte cell sizes, increased numbers of inflammatory cells in adipose and liver tissue, and steatosis; and these effects were exacerbated on an HFD. SAP and 1866 may inhibit some, but not all, of the effects of a high-fat diet.


Assuntos
Tecido Adiposo/patologia , Moléculas de Adesão Celular/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/prevenção & controle , Hepatite/prevenção & controle , Lectinas Tipo C/metabolismo , Obesidade/complicações , Receptores de Superfície Celular/metabolismo , Componente Amiloide P Sérico/metabolismo , Tecido Adiposo/metabolismo , Animais , Moléculas de Adesão Celular/genética , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Hepatite/etiologia , Hepatite/patologia , Resistência à Insulina , Lectinas Tipo C/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Superfície Celular/genética , Componente Amiloide P Sérico/genética
8.
Microb Pathog ; 137: 103736, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31505263

RESUMO

Respiratory infections such as SARS-CoV in humans are often accompanied by mild and self-limiting hepatitis. As a respiratory disease, influenza A virus (IAV) infection can lead to hepatitis, but the mechanism remains unclear. This study aimed to investigate the occurrence of hepatitis by establishing a model for infected mice for three different subtypes of respiratory IAVs (H1N1, H5N1, and H7N2). Histological analysis was performed, and results showed increase serum aminotransferase (ALT and AST) levels and evident liver injury on days 3 and 7, especially on day 5 post infection. Immunohistochemistry (IHC) results indicated a wide distribution of IAV's positive signals in the liver of infected mice. Real-time PCR results further revealed a similar viral titer to IHC that presented a remarkedly positive correlation with histology injury. All these data showed that the mouse model suitably contributed valuable information about the mechanism underlying the occurrence of hepatitis induced by respiratory influenza virus.


Assuntos
Hepatite/etiologia , Vírus da Influenza A/patogenicidade , Influenza Humana/complicações , Fígado/lesões , Animais , Modelos Animais de Doenças , Feminino , Hepatite/patologia , Humanos , Vírus da Influenza A Subtipo H1N1 , Virus da Influenza A Subtipo H5N1 , Vírus da Influenza A Subtipo H7N2 , Influenza Humana/virologia , Fígado/patologia , Fígado/virologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/complicações , Infecções por Orthomyxoviridae/virologia , Transaminases/sangue , Carga Viral , Replicação Viral
9.
Int Immunopharmacol ; 75: 105808, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419710

RESUMO

AIMS: Immune mediated liver injury includes activation of different immune pathways that requires various modalities to control their consequences. The current study involves evaluation of retinoic acid (RA) modulatory effects on immune responses induced in concanavalin A (ConA) model of acute hepatitis. MAIN METHODS: Mice were divided as follows: Control group; RA group: received 35 mg/kg RA; ConA group: received 15 mg/kg ConA; ConA + RA group: received ConA and RA as described. Liver function biomarkers were measured in addition to malondialdehyde as lipid peroxidation biomarker. Liver tissue sections were scored for necro-inflammation, neutrophils infiltration, CD4+ T cells infiltration and NF-κb positive cells. Effect on hepatic levels of TNF-α, IL-4, IL-10 and MCP-1 was evaluated as well. KEY FINDINGS: Injection of RA before ConA significantly (p < 0.001) decreased ALT, AST and LDH levels compared to their levels in ConA group. Hepatic infiltration of neutrophils and CD4+ T cells was markedly (p < 0.001) reduced by RA. Hepatic injury, necrosis and expression of NF-κb were significantly decreased by RA when injected before ConA challenge. A significant decrease in the measured cytokines TNF-α and IL-4 was observed in ConA + RA group in addition to a decrease in MCP-1 level. On the other hand, IL-10 was significantly increased in the latter group compared to ConA group. SIGNIFICANCE: RA can protect against ConA-induced hepatitis through: interrupting early inflammatory response as neutrophils, monocytes and CD4+ T cells infiltration, modulating IL-4 level and subsequent production of TNF-α and NF-κb activation, mitigating second inflammatory responses through increasing IL-10 liver production.


Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Citocinas/imunologia , Hepatite/imunologia , Tretinoína/farmacologia , Animais , Linfócitos T CD4-Positivos/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A , Hepatite/patologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Transdução de Sinais/efeitos dos fármacos
10.
Intern Med ; 58(24): 3537-3543, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31366800

RESUMO

A 70-year-old woman was referred to our hospital due to symptoms of dry eyes, dry mouth, and epigastric pain. Computed tomography showed distal pancreatic swelling, liver edge dullness and surface irregularities. Serum anti-nuclear antibody titers, immunoglobulin G and IgG4 levels were elevated. Autoimmune pancreatitis (AIP) was diagnosed based on endoscopic findings and a histopathological examination. Her AIP improved after starting prednisolone treatment. A liver biopsy revealed interface hepatitis with lymphoplasmacyte and IgG4-positive plasma cell infiltration. In addition, non-alcoholic steatohepatitis (NASH) was diagnosed based on the presence of parenchymal steatosis, ballooning hepatocytes, and pericellular fibrosis. We experienced a unique liver disease case showing IgG4-related liver disease overlapping with NASH.


Assuntos
Pancreatite Autoimune/complicações , Hepatite/complicações , Imunoglobulina G/sangue , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Pâncreas/patologia , Adulto , Idoso , Anticorpos Antinucleares/sangue , Pancreatite Autoimune/diagnóstico , Biópsia , Análise Química do Sangue , Feminino , Hepatite/patologia , Humanos , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Prednisolona/uso terapêutico , Tomografia Computadorizada por Raios X
11.
Semin Diagn Pathol ; 36(6): 404-414, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31405537

RESUMO

Acute hepatitis and acute liver failure are severe medical conditions that require early clinical intervention. Histopathologic findings on a liver biopsy or a liver explant may help identify the underlying etiology or provide an important direction for further clinical, laboratory and radiographical investigation. This review is divided into two main portions. The first portion concentrates on various etiologies and discusses unique histologic features that can be associated with specific etiologies. The second portion describes the general morphologic features based on which the diagnosis of acute hepatitis and acute liver failure are made. Histopathologic distinction between collapse and cirrhosis and limitations of histopathologic assessment for underlying etiologies are addressed in this portion. Another focus of this review is non-necrotic acute liver failure, which typically features diffuse microvesicular steatosis secondary to various etiologies causing mitochondrial dysfunction. Molecular testing serves an increasingly important role in the diagnosis and management of this group of disorders.


Assuntos
Hepatite/patologia , Falência Hepática Aguda/patologia , Doenças Mitocondriais/patologia , Doença Aguda , Biópsia , Humanos
12.
Am J Physiol Gastrointest Liver Physiol ; 317(4): G387-G397, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31411894

RESUMO

The cardiac glycoside digoxin was identified as a potent suppressor of pyruvate kinase isoform 2-hypoxia-inducible factor-α (PKM2-HIF-1α) pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin to reduce nonalcoholic steatohepatitis (NASH) by the clinically relevant oral route in mice and analyzed the cellular basis for this effect with differential involvement of liver cell subsets. C57BL/6J male mice were placed on a high-fat diet (HFD) for 10 wk and started concurrently with the gavage of digoxin (2.5, 0.5, 0.125 mg/kg twice a week) for 5 wk. Digoxin significantly reduced HFD-induced hepatic damage, steatosis, and liver inflammation across a wide dosage range. The lowest dose of digoxin (0.125 mg/kg) showed significant protective effects against liver injury and sterile inflammation. Consistently, digoxin attenuated HIF-1α sustained NLRP3 inflammasome activation in macrophages. We have reported for the first time that PKM2 is upregulated in hepatocytes with hepatic steatosis, and digoxin directly improved hepatocyte mitochondrial dysfunction and steatosis. Mechanistically, digoxin directly bound to PKM2 and inhibited PKM2 targeting HIF-1α transactivation without affecting PKM2 enzyme activation. Thus, oral digoxin showed potential to therapeutically inhibit liver injury in NASH through the regulation of PKM2-HIF-1α pathway activation with involvement of multiple cell types. Because of the large clinical experience with oral digoxin, this may have significant clinical applicability in human NASH.NEW & NOTEWORTHY This study is the first to assess the therapeutic efficacy of oral digoxin on nonalcoholic steatohepatitis (NASH) in a high-fat diet (HFD) mouse model and to determine the divergent of cell type-specific effects. Oral digoxin reduced liver damage, steatosis, and inflammation in HFD mice. Digoxin attenuated hypoxia-inducible factor (HIF)-1α axis-sustained inflammasome activity in macrophages and hepatic oxidative stress response in hepatocytes via the regulation of PKM2-HIF-1α axis pathway activation. Oral digoxin may have significant clinical applicability in human NASH.


Assuntos
Digoxina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Hepatócitos/enzimologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Piruvato Quinase/antagonistas & inibidores , Ativação Transcricional/efeitos dos fármacos , Animais , Linhagem Celular , Dieta Hiperlipídica , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Piruvato Quinase/metabolismo
14.
Korean J Gastroenterol ; 73(5): 248-259, 2019 May 25.
Artigo em Coreano | MEDLINE | ID: mdl-31132831

RESUMO

The hepatobiliary system is one of the most common sites of extraintestinal manifestation in patients with inflammatory bowel disease (IBD). The progression of IBD can lead to a primary hepatobiliary manifestation and can occur secondary to multiple drugs or accompanying viral infections. Primary sclerosing cholangitis is the representative hepatobiliary manifestation of IBD, particularly in ulcerative colitis. Although most agents used in the treatment of IBD are potentially hepatotoxic, the risk of serious hepatitis or liver failure is low. The prevalence of HBV and HCV in IBD is similar to the general population, but the clinical concern is HBV reactivation associated with immunosuppressive therapy. Patients undergoing cytotoxic chemotherapy or immunosuppressive therapy with a moderate to high risk of HBV reactivation require prophylactic antiviral therapy. On the other hand, HCV has little risk of reactivation. Patients with IBD are more likely to have nonalcoholic fatty liver disease than the general population and tend to occur at younger ages. IBD and cholelithiasis are closely related, especially in Crohn's disease.


Assuntos
Doenças Biliares/patologia , Hepatite/patologia , Doenças Inflamatórias Intestinais/patologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças Biliares/complicações , Doenças Biliares/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/complicações , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colangite Esclerosante/complicações , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/patologia , Microbioma Gastrointestinal , Hepatite/complicações , Humanos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Trombose Venosa/complicações , Trombose Venosa/patologia
15.
Phys Med Biol ; 64(17): 175023, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31051490

RESUMO

Dynamic 18F-FDG PET with tracer kinetic modeling has the potential to noninvasively evaluate human liver inflammation using the FDG blood-to-tissue transport rate K 1. Accurate kinetic modeling of dynamic liver PET data and K 1 quantification requires the knowledge of dual-blood input function from the hepatic artery and portal vein. While the arterial input function can be derived from the aortic region on dynamic PET images, it is difficult to extract the portal vein input function accurately from PET images. The optimization-derived dual-input kinetic modeling approach has been proposed to overcome this problem by jointly estimating the portal vein input function and FDG tracer kinetics from time activity curve fitting. In this paper, we further characterize the model properties by analyzing the structural identifiability of the model parameters using the Laplace transform and practical identifiability using computer simulation based on fourteen patient datasets. The theoretical analysis has indicated that all the kinetic parameters of the dual-input kinetic model are structurally identifiable, though subject to local solutions. The computer simulation results have shown that FDG K 1 can be estimated reliably in the whole-liver region of interest with reasonable bias, standard deviation, and high correlation between estimated and original values, indicating of practical identifiability of K 1. The result has also demonstrated the correlation between K 1 and histological liver inflammation scores is reliable. FDG K 1 quantification by the optimization-derived dual-input kinetic model is promising for assessing liver inflammation.


Assuntos
Simulação por Computador , Hepatite/diagnóstico por imagem , Fígado/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Fluordesoxiglucose F18 , Hepatite/patologia , Humanos , Cinética , Fígado/irrigação sanguínea , Circulação Hepática , Compostos Radiofarmacêuticos
16.
Semin Liver Dis ; 39(3): 275-282, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31100758

RESUMO

Hepatocyte demise as well as signals released by stressed hepatocytes have been now recognized as important triggers of liver inflammation. While traditional concepts classically viewed hepatocyte cell death to occur by either a nonlytic, noninflammatory form (apoptosis), or lytic, proinflammatory nonregulated cell death (necrosis), recent studies have provided evidence for additional mechanisms that can contribute to both acute and chronic liver damage. Two novel forms of cell death, pyroptosis and necroptosis, are of particular importance as they are highly regulated and intrinsically proinflammatory. Additionally, stressed hepatocytes may also release signals to attract and activate monocytes into proinflammatory macrophages. In this review, the authors discuss recent developments supporting the role of novel triggers of liver inflammation in various forms of liver injury and their potential translational implications.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Hepatite/fisiopatologia , Cirrose Hepática/fisiopatologia , Necroptose , Piroptose , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatite/patologia , Hepatócitos/metabolismo , Humanos , Cirrose Hepática/patologia
17.
Life Sci ; 236: 116464, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078546

RESUMO

The function of liver is highly dependent on mitochondria producing ATP for biosynthetic and detoxifying properties. Accumulating evidence indicates that most hepatic disorders are characterized by profound mitochondrial dysfunction. Mitochondrial dysfunction not only exhibits mitochondrial DNA (mtDNA) damage and depletion, but also releases mtDNA. mtDNA is a closed circular molecule encoding 13 of the polypeptides of the oxidative phosphorylation system. Extensive mtDNA lesions could exacerbate mitochondrial oxidative stress and subsequently cause damage to hepatocytes. When mtDNA leaves the confines of mitochondria to the cytosolic and extracellular environment, it can act as damage-associated molecular patterns (DAMPs) to trigger the inflammatory response through the Toll-like receptor 9, inflammasomes, and stimulator of interferon genes (STING) pathways and further exacerbate hepatocellular damage and even remote organs injury. In addition, mtDNA also plays a vital role in hepatitis B virus (HBV)-related liver injury and hepatocellular carcinoma (HCC). In this review, we describe mtDNA alterations during liver injury, focusing on the mechanisms of mtDNA-mediated liver inflammation and oxidative stress injury.


Assuntos
DNA Mitocondrial/genética , Hepatite/patologia , Inflamassomos , Estresse Oxidativo , Animais , Hepatite/genética , Humanos
18.
Gastroenterology ; 157(3): 777-792.e14, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31078624

RESUMO

BACKGROUND & AIMS: We studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models of NASH. METHODS: We stimulated mouse and human fibroblasts, HSCs, or hepatocytes with IL11 and other cytokines and analyzed them by imaging, immunoblot, and functional assays and enzyme-linked immunosorbent assays. Mice were given injections of IL11. Mice with disruption of the interleukin 11 receptor subunit alpha1 gene (Il11ra1-/-) mice and Il11ra1+/+ mice were fed a high-fat methionine- and choline-deficient diet (HFMCD) or a Western diet with liquid fructose (WDF) to induce steatohepatitis; control mice were fed normal chow. db/db mice were fed with methionine- and choline-deficient diet for 12 weeks and C57BL/6 NTac were fed with HFMCD for 10 weeks or WDF for 16 weeks. Some mice were given intraperitoneal injections of anti-IL11 (X203), anti-IL11RA (X209), or a control antibody at different timepoints on the diets. Livers and blood were collected; blood samples were analyzed by biochemistry and liver tissues were analyzed by histology, RNA sequencing, immunoblots, immunohistochemistry, hydroxyproline, and mass cytometry time of flight assays. RESULTS: HSCs incubated with cytokines produced IL11, resulting in activation (phosphorylation) of ERK and expression of markers of fibrosis. Livers of mice given injections of IL11 became damaged, with increased markers of fibrosis, hepatocyte cell death and inflammation. Following the HFMCD or WDF, livers from Il11ra1-/- mice had reduced steatosis, fibrosis, expression of markers of inflammation and steatohepatitis, compared to and Il11ra1+/+ mice on the same diets. Depending on the time of administration of anti-IL11 or anti-IL11RA antibodies to wild-type mice on the HFMCD or WDF, or to db/db mice on the methionine and choline-deficient diet, the antibodies prevented, stopped, or reversed development of fibrosis and steatosis. Blood samples from Il11ra1+/+ mice fed the WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1-/- mice fed WDF, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1. CONCLUSIONS: Neutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with diet-induced steatohepatitis. These antibodies also improve the cardiometabolic profile of mice and might be developed for the treatment of NASH.


Assuntos
Anticorpos Neutralizantes/farmacologia , Hepatite/prevenção & controle , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Interleucina-11/antagonistas & inibidores , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Morte Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite/genética , Hepatite/metabolismo , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/deficiência , Subunidade alfa de Receptor de Interleucina-11/genética , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/efeitos dos fármacos , Células THP-1
19.
Hepatobiliary Pancreat Dis Int ; 18(3): 255-265, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31027910

RESUMO

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury remains a significant problem in clinical practice. Sphingosine kinase 1 (SphK1) phosphorylates sphingosine to sphingosine-1-phosphate (S1P) which participates in multiple bioactive processes. However, little is known about the role of SphK1 in hepatic I/R injury. This study aimed to investigate the effect of SphK1 knockout on liver I/R injury and to explore underlying mechanisms. METHODS: SphK1 knockout and wild type mice were subjected to 70% partial hepatic I/R. Serum alanine aminotransferase was determined to indicate the degree of liver damage. Hematoxylin-eosin staining and TUNEL assay were used to assess histological changes and hepatocellular apoptosis, respectively. Immunohistochemistry was performed to detect the expression and translocation of phosphorylated p65 and signal transducer and activator of transcription 3 (STAT3). Western blotting was used to determine the expression of S1P receptor 1 (S1PR1), phosphorylated p65 and STAT3. Real-time PCR was used to demonstrate the changes of proinflammatory cytokines. Oxidative stress markers were also determined through biochemical assays. RESULTS: SphK1 knockout significantly ameliorated I/R-induced liver damage, mitigated liver tissue necrosis and apoptosis compared with wild type control. I/R associated inflammation was alleviated in SphK1 knockout mice as demonstrated by attenuated expression of S1PR1 and reduced phosphorylation of nuclear factor kappa B p65 and STAT3. The proinflammatory cytokines interleukin-1ß, interleukin-6 and tumor necrosis factor-α were also inhibited by SphK1 genetic deletion. The oxidative stress markers were lower in SphK1 knockout mice after I/R injury than wild type mice. CONCLUSIONS: Knockout of SphK1 significantly alleviated damage after hepatic I/R injury, possibly through inhibiting inflammation and oxidative stress. SphK1 may be a novel and potent target in clinical practice in I/R-related liver injury.


Assuntos
Mediadores da Inflamação/metabolismo , Fígado/irrigação sanguínea , Estresse Oxidativo , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose , Citocinas/metabolismo , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Hepatite/enzimologia , Hepatite/genética , Hepatite/patologia , Fígado/enzimologia , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Receptores de Esfingosina-1-Fosfato/metabolismo , Fator de Transcrição RelA/metabolismo
20.
Methods Mol Biol ; 1951: 189-207, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30825154

RESUMO

The NLRP3 inflammasome is a cellular sensor of danger signals such as extracellular ATP or abnormally accumulating molecules like crystals. Activation of NLRP3 by such compounds triggers a sterile inflammatory response that may be involved in numerous pathologies including rheumatoid arthritis, atherosclerosis, diabetes, and Alzheimer's disease. A better understanding of the mechanisms that govern NLRP3 inflammasome activation is an important step toward the development of novel therapeutic strategies to dampen over-activation of the immune system. Recent findings demonstrate that ligand-activated nuclear receptors regulate the NLRP3 inflammasome pathway, thus representing possible therapeutic targets. It is therefore important to assess the potential of these putative targets in the regulation of the NLRP3 inflammasome activation in the most appropriate pathophysiological models. Fulminant hepatitis (FH) results from massive hepatocyte apoptosis, hemorrhagic necrosis, and inflammation. Low doses of LPS in combination with the specific hepatotoxic agent D-galactosamine (D-GalN) promote liver injury in mice and induce the production of inflammatory cytokines associated with increased NLRP3 protein and caspase 1 activity, thus recapitulating the clinical picture of FH in humans. We provide a simple method to examine the involvement of nuclear receptors in NLRP3-driven fulminant hepatitis, consisting in the induction of FH, in the isolation of liver macrophages, and in the extraction and analysis of RNA content.


Assuntos
Hepatite/etiologia , Hepatite/metabolismo , Inflamassomos/metabolismo , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Galactosamina/efeitos adversos , Expressão Gênica , Hepatite/patologia , Humanos , Macrófagos do Fígado/imunologia , Macrófagos do Fígado/metabolismo , Lipopolissacarídeos/efeitos adversos , Falência Hepática Aguda/patologia , Camundongos , Transdução de Sinais
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