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1.
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
2.
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
3.
Acta Biochim Biophys Sin (Shanghai) ; 51(11): 1087-1095, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31609412

RESUMO

Autophagy, a metabolic pathway that plays an important role in maintaining the dynamic balance of cells, has two types, i.e. non-selective autophagy and selective autophagy. The role of non-selective autophagy is primarily to allow cells to circulate nutrients in an energy-limited environment, while selective autophagy primarily cleans up the organelles inside the cells to maintain the cell structure. The NLRP3 inflammasome is an innate immune response produced by the organism that can promote the secretion of interleukin-1ß and interleukin-18 through caspase-1 activation and resist the damage of some pathogens. However, when the NLRP3 inflammasome is overactivated, it can cause various inflammatory diseases, such as inflammatory liver disease and inflammatory bowel disease. Many previous studies have shown that autophagy can inhibit the NLRP3 inflammasome, while in recent years, new studies have found that autophagy can also promote the NLRP3 inflammasome in some cases, and the NLRP3 inflammasome can, in turn, affect autophagy. In this review, the interaction between autophagy and the NLRP3 inflammasome is explored, and then the application of this interaction in disease treatment is discussed.


Assuntos
Autofagia/fisiologia , Hepatite/metabolismo , Inflamassomos/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Ratos
4.
Eur J Med Chem ; 179: 182-195, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254920

RESUMO

A series of (1,2,4)triazole[4,3-a]pyridine (TZP) derivatives have been designed and synthesized. Compound 8d was identified as having the most potent inhibitory activity on NO release in response to lipopolysaccharide (LPS) stimulation and inhibition of the migration induced by MCP-1 protein on RAW264.7 macrophages. Based on the screening data, an immunofluorescence assay and a real-time qPCR assay were conducted, indicating that compound 8d suppressed NF-κB p65 translocation and expression of inflammatory genes by concanavalin A (Con A)-induced RAW264.7 macrophages. More importantly, 8d also exhibited potent efficacy, alleviating Con A-induced hepatitis by downregulating the levels of plasma alanine transaminase (ALT), aspartate transaminase (AST) and inflammatory infiltration in a mouse autoimmune hepatitis (AIH) model. In addition, the flow cytometry (FCM) data showed that compound 8d inhibited the accumulation of MDSCs in the liver of Con A-induced mice. These findings raise the possibility that compound 8d might serve as a potential agent for the treatment of AIH.


Assuntos
Concanavalina A/antagonistas & inibidores , Hepatite/tratamento farmacológico , Piridinas/farmacologia , Triazóis/farmacologia , Animais , Sobrevivência Celular , Células Cultivadas , Concanavalina A/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Feminino , Hepatite/metabolismo , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Óxido Nítrico/análise , Óxido Nítrico/biossíntese , Piridinas/síntese química , Piridinas/química , Células RAW 264.7 , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
5.
Food Funct ; 10(6): 3514-3534, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31144698

RESUMO

This study was conducted to investigate the beneficial effects and possible mechanism of action of mangiferin (MF) in alcohol hepatitis (AH) rats. Building on our previous study, the damage-associated molecular patterns (DAMPs), lipid metabolic disorder and mitochondrial dysfunction were investigated. MF effectively regulated the abnormal liver function, the levels of alcohol, FFAs and metal elements in serum. More importantly, MF improved the expression levels of mRNA and protein of PPAR-γ, OPA-1, Cav-1, EB1, NF-κB p65, NLRP3, Cas-1 and IL-1ß, and decreased the positive protein expression rates of HSP90, HMGB1, SYK, CCL20, C-CAS-3, C-PARP and STARD1. Additionally, MF decreased the levels of fumarate, cAMP, xanthurenic acid and d-glucurone-6,3-lactone, and increased the levels of hippuric acid and phenylacetylglycine, and then adjusted the changes of phenylalanine metabolism, TCA cycle and ascorbate and aldarate metabolic pathways. The above results suggested that MF can effectively prevent AH by modulating specific AH-associated genes, potential biomarkers and metabolic pathways in AH rats, etc.


Assuntos
Álcoois/efeitos adversos , Hepatite/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Xantonas/administração & dosagem , Animais , Glicina/análogos & derivados , Glicina/metabolismo , Hepatite/etiologia , Hepatite/genética , Hepatite/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Xanturenatos/metabolismo
6.
Am J Physiol Endocrinol Metab ; 317(1): E99-E108, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31039009

RESUMO

This study aimed to investigate the function of hepatic myeloid differentiation primary response gene 88 (MyD88), a central adaptor of innate immunity, in metabolism. Although its role in inflammation is well known, we have recently discovered that MyD88 can also mediate energy, lipid, and glucose metabolism. More precisely, we have reported that mice harboring hepatocyte-specific deletion of MyD88 (Myd88ΔHep) were predisposed to glucose intolerance, liver fat accumulation, and inflammation. However, the molecular events explaining the onset of hepatic disorders and inflammation remain to be elucidated. To investigate the molecular mechanism, Myd88ΔHep and wild-type (WT) mice were challenged by two complementary approaches affecting liver lipid metabolism and immunity. The first approach consisted of a short-term exposure to high-fat diet (HFD), whereas the second was an acute LPS injection. We discovered that upon 3 days of HFD Myd88ΔHep mice displayed an increase in liver weight and liver lipids compared with WT mice. Moreover, we found that bile acid and oxysterol metabolism were deeply affected by the absence of hepatic MyD88. Our data suggest that the negative feedback loop suppressing bile acid synthesis was impaired (i.e., ERK activity was decreased) in Myd88ΔHep mice. Finally, the predisposition to inflammation sensitivity displayed by Myd88ΔHep mice may be caused by the accumulation of 25-hydroxycholesterol, an oxysterol linked to inflammatory response and metabolic disorders. This study highlights the importance of MyD88 on both liver fat accumulation and cholesterol-derived bioactive lipid synthesis. These are two key features associated with metabolic syndrome. Therefore, investigating the regulation of hepatic MyD88 could lead to discovery of new therapeutic targets.


Assuntos
Hepatite/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Oxisteróis/metabolismo , Animais , Ácidos e Sais Biliares/biossíntese , Dieta Hiperlipídica , Hepatócitos/metabolismo , Hidroxicolesteróis/metabolismo , Imunidade , Metabolismo dos Lipídeos/genética , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética
7.
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
8.
Biotech Histochem ; 94(6): 449-458, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30916587

RESUMO

Obesity is a chronic disease that is characterized by increased body fat owing to imbalance between consumed and expended energy. Inflammation generally is accompanied by accumulation of excess lipid in adipose tissue and liver. High mobility group box-1 (HMGB1) participates in the pathogenesis of inflammatory diseases. We investigated the relation of the number of HMGB1 positive cells to body mass index (BMI), liver inflammation and the number of Kupffer cells. We divided 18 female Wistar albino rats into two groups: group 1, untreated control fed normal commercial rat diet and group 2, obese rats fed a special diet containing 40% fat. The plasma concentrations of cholesterol, glucose, superoxide dismutase enzyme (SOD) and catalase activities were measured for all animals. The numbers of hepatocytes, Kupffer cells and HMGB1 positive cells were counted using stereological methods. The mean numbers of Kupffer cells and HMGB1 positive cells were higher for group 2 than for group 1. The concentrations of plasma cholesterol and glucose levels also were higher in group 2. Plasma levels of SOD and catalase were significantly lower in group 2 compared to group 1. The number of HMGB1 cells was related directly to BMI and inflammation. The role of HMGB1 was demonstrated for the liver of the obese group. We demonstrated the relations among HMGB1, BMI, obesity and inflammation.


Assuntos
Proteína HMGB1/metabolismo , Hepatite/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Obesidade/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Modelos Animais de Doenças , Feminino , Inflamação/patologia , Fígado/patologia , Obesidade/metabolismo , Ratos Wistar
9.
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
10.
Mol Med Rep ; 19(4): 2561-2568, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720104

RESUMO

The present study aimed to assess the protective effects of tetramethylpyrazine (TMP) on the livers of mice fed a high fat diet. The mice were divided into five groups: Regular diet; high fat diet; simvastatin­treated; and low and high dose TMP­treated groups. The results demonstrated that, compared with the control group, serum glucose, total cholesterol (TC) and low­density lipoprotein cholesterol levels were increased in the model group. Additionally, compared with the model group, simvastatin lowered the TC level, whereas TMP did not. Compared with the control group, the level of malondialdehyde (MDA) in the liver tissue was increased and the level of glutathione peroxidase (GSH­pX) in the liver tissue was decreased in the model group. Furthermore, compared with the model group, TMP decreased the level of MDA and increased the level of GSH­Px; however, simvastatin did not have these effects. Immunohistochemistry and western blotting were performed; the results showed that, compared with the control group, the levels of inflammatory factors (tumor necrosis factor­α and interleukin­6) in the liver tissue were increased, and the ratio of phosphorylated (p)­nuclear factor κB (NF­κB)/NF­κB was also increased in the model group. The addition of TMP and simvastatin demonstrated that, compared with the model group, the inflammatory factor levels and the ratio of p­NF­κB/NF­κB were decreased. In addition, liver lipid deposition was examined in the model group using hematoxylin and eosin staining and Oil Red O staining, and the results showed that TMP and simvastatin reduced liver lipid deposition. Furthermore, compared with the control group, the reactive oxygen species (ROS) level in the liver tissue was increased. Compared with that in the model group, TMP and simvastatin decreased the ROS level. In conclusion, TMP, similar to simvastatin, exerted a notable hepatoprotective effect on mice fed a high fat diet with non­alcoholic fatty liver disease, by inhibiting inflammatory factors and the p­NF­κB/ROS signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Dieta Hiperlipídica/efeitos adversos , Hepatite/etiologia , Hepatite/metabolismo , Pirazinas/farmacologia , Animais , Biomarcadores , Biópsia , Glicemia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Hepatite/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
11.
Biomed Pharmacother ; 112: 108638, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784928

RESUMO

Vindoline, an indole alkaloid present in the leaves of Catharanthus roseus plant, has been recently reported to have insulotropic effects. This present study evaluated the possible hepatoprotective effects of vindoline in a type 2 diabetes mellitus rat model. Diabetes mellitus was induced by exposing rats to 10% fructose water for two weeks followed by a single intraperitoneal injection of 40 mg/kg body weight of streptozotocin (STZ). Rats were randomly divided into six groups (n = 8) and treated daily for 6 weeks with the vehicle via oral gavage, vindoline (20 mg/kg) or glibenclamide (5 mg/kg). Weekly fasting blood glucose (FBG) levels and body weight were measured and recorded. Administration of vindoline significantly (p < 0.05) reduced FBG by 15% when compared to the diabetic controls. Vindoline significantly (p < 0.05) decreased diabetes-induced hepatic injury shown by decreased levels of serum alanine transferase (ALT) (-42%), aspartate aminotransferase (AST) (-42%) and alkaline phosphatase (-62%) compared to the diabetic controls. The oxygen radical absorbance capacity and the activities of superoxide dismutase (SOD) and catalase (CAT) were also improved following treatment with vindoline. The results also showed decreased levels of pro-inflammatory cytokines such as TNF-ɑ by (-41%) and IL-6 (-28%) which may have also contributed to the reduction of serum triglycerides (-65%) in the diabetic group treated with vindoline. Histopathological findings showed improvement of both the hepatic and pancreatic tissues following vindoline treatment. Overall, these findings suggest that vindoline may protect the diabetic hepatic tissue from injury via antioxidant, anti-inflammatory and anti-hypertriglyceredemia mechanisms thereby retarding the development of diabetic complications.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Hepatite/prevenção & controle , Hipertrigliceridemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Vimblastina/análogos & derivados , Animais , Glicemia/análise , Catharanthus/química , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glibureto/uso terapêutico , Hepatite/imunologia , Hepatite/metabolismo , Hepatite/patologia , Insulina/sangue , Testes de Função Hepática , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Ratos Wistar , Vimblastina/uso terapêutico
12.
Toxins (Basel) ; 11(1)2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30621122

RESUMO

Aflatoxin B1 (AFB1), a mycotoxin found in food and feed, is immunotoxic to animals and poses significant threat to the food industry and animal production. The primary target of AFB1 is the liver. To overcome aflatoxin toxicity, probiotic-mediated detoxification has been proposed. In the present study, to investigate the protective effects and molecular mechanisms of Lactobacillus bulgaricus or Lactobacillus rhamnosus against liver inflammatory responses to AFB1, mice were administered with AFB1 (300 µg/kg) and/or Lactobacillus intragastrically for 8 weeks. AML12 cells were cultured and treated with AFB1, BAY 11-7082 (an NF-κB inhibitor), and different concentrations of L. bulgaricus or L. rhamnosus. The body weight, liver index, histopathological changes, biochemical indices, cytokines, cytotoxicity, and activation of the NF-κB signaling pathway were measured. AFB1 exposure caused changes in liver histopathology and biochemical functions, altered inflammatory response, and activated the NF-κB pathway. Supplementation of L. bulgaricus or L. rhamnosus significantly prevented AFB1-induced liver injury and alleviated histopathological changes and inflammatory response by decreasing NF-κB p65 expression. The results of in vitro experiments revealed that L. rhamnosus evidently protected against AFB1-induced inflammatory response and decreased NF-κB p65 expression when compared with L. bulgaricus. These findings indicated that AFB1 exposure can cause inflammatory response by inducing hepatic injury, and supplementation of L. bulgaricus or L. rhamnosus can produce significant protective effect against AFB1-induced liver damage and inflammatory response by regulating the activation of the NF-κB signaling pathway.


Assuntos
Aflatoxina B1 , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Hepatite/prevenção & controle , Lactobacillus , Micotoxicose/prevenção & controle , Probióticos/uso terapêutico , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatite/metabolismo , Hepatite/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Micotoxicose/metabolismo , Micotoxicose/patologia , NF-kappa B/metabolismo , Transdução de Sinais
13.
Hepatol Int ; 13(1): 42-50, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30474802

RESUMO

Drug hepatotoxicity is the leading cause of acute liver failure (ALF) in the developed countries. The early diagnosis and treatment are still problematic, and one important reason is the lack of reliable mechanistic biomarkers and therapeutic targets; therefore, searching for new biomarkers and therapeutic targets is urgent. Drug hepatotoxicity induces severe liver cells damage and death. Dead and damaged cells release endogenous damage-associated molecular patterns (DAMPs). Increased circulating levels of DAMPs (HMGB1, histones and DNA) can reflect the severity of drug hepatotoxicity. Elevated plasma HMGB1 concentrations can serve as early and sensitive mechanistic biomarker for clinical acetaminophen hepatotoxicity. DAMPS significantly contribute to liver injury and inhibiting the release of DAMPs ameliorates experimental hepatotoxicity. In addition, HMGB1 mediates 80% of gut bacterial translocation (BT) during acetaminophen toxicity. Gut BT triggers systemic inflammation, leading to multiple organ injury and mortality. Moreover, DAMPs can trigger and extend sterile inflammation, which contributes to early phase liver injury but improves liver regeneration at the late phase of acetaminophen overdose, because anti-inflammatory treatment reduces liver injury at early phase but impairs liver regeneration at late phase of acetaminophen toxicity, whereas pro-inflammatory therapy improves late phase liver regeneration. DAMPs are promising mechanistic biomarkers and could also be the potential therapeutic targets for drug hepatotoxicity. DAMPs-triggered sterile inflammation contributes to liver injury at early phase but improves liver regeneration at later phase of acetaminophen hepatotoxicity; therefore, anti-inflammatory therapy would be beneficial at early phase but should be avoided at the late phase of acetaminophen overdose.


Assuntos
Alarminas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Acetaminofen/efeitos adversos , Analgésicos não Entorpecentes/efeitos adversos , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Citocinas/fisiologia , DNA/metabolismo , DNA/fisiologia , Proteína HMGB1/metabolismo , Proteína HMGB1/fisiologia , Hepatite/diagnóstico , Hepatite/metabolismo , Hepatite/fisiopatologia , Histonas/fisiologia , Humanos , Macrófagos do Fígado/fisiologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/diagnóstico , Regeneração Hepática/fisiologia
14.
J Hepatol ; 70(1): 87-96, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30218679

RESUMO

BACKGROUND & AIMS: The progression of hepatosteatosis to non-alcoholic steatohepatitis (NASH) is a critical step in the pathogenesis of hepatocellular cancer. However, the underlying mechanism(s) for this progression is essentially unknown. This study was designed to determine the role of miR-378 in regulating NASH progression. METHODS: We used immunohistochemistry, luciferase assays and immunoblotting to study the role of miR-378 in modulating an inflammatory pathway. Wild-type mice kept on a high-fat diet (HFD) were injected with miR-378 inhibitors or a mini-circle expression system containing miR-378, to study loss and gain-of functions of miR-378. RESULTS: MiR-378 expression is increased in livers of dietary obese mice and patients with NASH. Further studies revealed that miR-378 directly targeted Prkag2 that encodes AMP-activated protein kinase γ 2 (AMPKγ2). AMPK signaling negatively regulates the NF-κB-TNFα inflammatory axis by increasing deacetylase activity of sirtuin 1. By targeting Prkag2, miR-378 reduced sirtuin 1 activity and facilitated an inflammatory pathway involving NF-κB-TNFα. In contrast, miR-378 knockdown induced expression of Prkag2, increased sirtuin 1 activity and blocked the NF-κB-TNFα axis. Additionally, knockdown of increased Prkag2 offset the inhibitory effects of miR-378 inhibitor on the NF-κB-TNFα axis, suggesting that AMPK signaling mediates the role of miR-378 in facilitating this inflammatory pathway. Liver-specific expression of miR-378 triggered the development of NASH and fibrosis by activating TNFα signaling. Ablation of TNFα in miR-378-treated mice impaired the ability of miR-378 to facilitate hepatic inflammation and fibrosis, suggesting that TNFα signaling is required for miR-378 to promote NASH. CONCLUSION: MiR-378 plays a key role in the development of hepatic inflammation and fibrosis by positively regulating the NF-κB-TNFα axis. MiR-378 is a potential therapeutic target for the treatment of NASH. LAY SUMMARY: The recent epidemic of obesity has been associated with a sharp rise in the incidence of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism(s) remains poorly described and effective therapeutic approaches against NAFLD are lacking. The results establish that microRNA-378 facilitates the development of hepatic inflammation and fibrosis and suggests the therapeutic potential of microRNA-378 inhibitor for the treatment of NAFLD.


Assuntos
Regulação da Expressão Gênica , Hepatite/genética , Cirrose Hepática/genética , MicroRNAs/genética , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Biópsia , Modelos Animais de Doenças , Progressão da Doença , Hepatite/metabolismo , Hepatite/patologia , Humanos , Immunoblotting , Imuno-Histoquímica , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/biossíntese , Transdução de Sinais
15.
Front Biosci (Landmark Ed) ; 24: 1-17, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468644

RESUMO

Fibroblast activation protein (FAP) belongs to the dipeptidyl peptidase IV (DPP4; CD26) gene family. Other related genes in this family of enzyme include DPP4, 8 and 9. The FAP serine protease has the rare property of both dipeptidyl peptidase and endopeptidase activities capable of cleaving the post-proline bond at two or more residues from the N-terminus. FAP is involved in a variety of biological processes but its expression in healthy tissues is low. In contrast, FAP is significantly elevated in pathological conditions such as at sites of tissue remodelling and repair. Its differential pattern of expression in diseases supports the emerging concept for FAP as a potential disease biomarker as well as a useful therapeutic target for drug intervention. This review summarizes the current knowledge of FAP, particularly its diagnostic and pathological significance in liver fibrosis.


Assuntos
Biomarcadores/metabolismo , Gelatinases/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/metabolismo , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Gelatinases/antagonistas & inibidores , Gelatinases/genética , Expressão Gênica , Células Estreladas do Fígado/efeitos dos fármacos , Hepatite/tratamento farmacológico , Hepatite/genética , Hepatite/metabolismo , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Terapia de Alvo Molecular/métodos , Serina Endopeptidases/genética
16.
J Nutr Biochem ; 63: 35-43, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30321750

RESUMO

High-fat diet (HFD)-fed mice show obesity with development of liver steatosis and a proinflammatory state without establishing an inflammatory reaction. The aim of this work was to assess the hypothesis that eicosapentaenoic acid (EPA) plus hydroxytyrosol (HT) supplementation prevents the inflammatory reaction through enhancement in the hepatic resolvin content in HFD-fed mice. Male C57BL/6J mice were fed an HFD or a control diet and supplemented with EPA (50 mg/kg/day) and HT (5 mg/kg/day) or their respective vehicles for 12 weeks. Measurements include liver levels of EPA, DHA and palmitate (gas chromatography), liver resolvins and triglyceride (TG) and serum aspartate transaminase (AST) (specific kits) and hepatic and serum inflammatory markers (quantitative polymerase chain reaction and enzyme-linked immunosorbent assay). Compared to CD, HFD induced body weight gain, liver steatosis and TG accumulation, with up-regulation of proinflammatory markers in the absence of histological inflammation or serum AST changes; these results were accompanied by higher hepatic levels of resolvins RvE1, RvE2, RvD1 and RvD2, with decreases in EPA and DHA contents. EPA+HT supplementation in HFD feeding synergistically reduced the steatosis score over individual treatments and increased the hepatic levels of EPA, DHA and resolvins, with attenuation of proinflammatory markers. Lack of progression of HFD-induced proinflammatory state into overt inflammation is associated with resolvin up-regulation, which is further increased by EPA+HT supplementation eliciting steatosis attenuation. These findings point to the importance of combined protocols in hepatoprotection due to the involvement of cross-talk mechanisms, which increase effectiveness and diminish dosages, avoiding undesirable effects.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Ácido Eicosapentaenoico/farmacologia , Hepatite/dietoterapia , Fígado/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Animais , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Ácidos Graxos/metabolismo , Hepatite/etiologia , Hepatite/metabolismo , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Álcool Feniletílico/farmacologia
17.
Gut ; 68(7): 1311-1322, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30121625

RESUMO

OBJECTIVE: Aldehyde dehydrogenase 2 (ALDH2), a key enzyme to detoxify acetaldehyde in the liver, exists in both active and inactive forms in humans. Individuals with inactive ALDH2 accumulate acetaldehyde after alcohol consumption. However, how acetaldehyde affects T-cell hepatitis remains unknown. DESIGN: Wild-type (WT) and Aldh2 knockout (Aldh2 -/-) mice were subjected to chronic ethanol feeding and concanavalin A (ConA)-induced T-cell hepatitis. Effects of acetaldehyde on T-cell glucose metabolism were investigated in vitro. Human subjects were recruited for binge drinking and plasma cortisol and corticosterone measurement. RESULTS: Ethanol feeding exacerbated ConA-induced hepatitis in WT mice but surprisingly attenuated it in Aldh2 -/- mice despite higher acetaldehyde levels in Aldh2 -/- mice. Elevation of serum cytokines and their downstream signals in the liver post-ConA injection was attenuated in ethanol-fed Aldh2 -/- mice compared to WT mice. In vitro exposure to acetaldehyde inhibited ConA-induced production of several cytokines without affecting their mRNAs in mouse splenocytes. Acetaldehyde also attenuated interferon-γ production in phytohaemagglutinin-stimulated human peripheral lymphocytes. Mechanistically, acetaldehyde interfered with glucose metabolism in T cells by inhibiting aerobic glycolysis-related signal pathways. Finally, compared to WT mice, ethanol-fed Aldh2 -/- mice had higher levels of serum corticosterone, a well-known factor that inhibits aerobic glycolysis. Blockade of corticosterone partially restored ConA-mediated hepatitis in ethanol-fed Aldh2 -/- mice. Acute alcohol drinking elevated plasma cortisol and corticosterone levels in human subjects with higher levels in those with inactive ALDH2 than those with active ALDH2. CONCLUSIONS: ALDH2 deficiency is associated with elevated acetaldehyde and glucocorticoids post-alcohol consumption, thereby inhibiting T-cell activation and hepatitis.


Assuntos
Aldeído-Desidrogenase Mitocondrial/fisiologia , Bebedeira/metabolismo , Glucose/metabolismo , Hepatite/metabolismo , Hepatite/prevenção & controle , Linfócitos T/fisiologia , Animais , Bebedeira/patologia , Concanavalina A , Corticosterona/sangue , Modelos Animais de Doenças , Etanol , Hepatite/etiologia , Humanos , Hidrocortisona/sangue , Camundongos
18.
Biomed Pharmacother ; 110: 692-699, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30553196

RESUMO

Glycyrrhizin, a triterpenoid compound, has been reported to be an anti-inflammatory agent for the treatment of a variety of inflammatory diseases including hepatitis. However, the mechanism by which glycyrrhizin inhibits inflammation is unclear. Using a Con A-induced hepatitis model in mice, we found that administration of glycyrrhizin ameliorates Con A-induced liver injury, which manifests as reduction in the production of inflammatory cytokines IFN-γ, IL-6 and IL-17, as well as serum alanine aminotransferase (ALT). Blockade of IL-17 dramatically mitigates liver injury resulting from Con A challenge. Interestingly, at both the mRNA and protein levels, the endogenous alarmin inflammatory molecule high-mobility group box 1 (HMGB1) is significantly decreased in mice injected with glycyrrhizin combined with Con A compared to those injected with Con A alone. In contrast, the administration of glycyrrhizin with Con A challenge up-regulates the production of IL-25. Furthermore, an increase in the proportion of protective lymphocyte subset, Gr-1+ CD11b+ (Myeloid-Derived Suppressor Cell, MDSCs), could be induced by increased IL-25 to restrain immune cell activation and favor the resolution of detrimental immune reactions caused by Con A challenge. The results indicate that glycyrrhizin plays a protective role in Con A-induced hepatitis. This protective role is particularly associated with reducing the production of IL-17 and enhancing the expression of IL-25. The present study may provide a new strategy for the treatment of acute hepatitis in the clinical setting.


Assuntos
Concanavalina A/toxicidade , Ácido Glicirrízico/uso terapêutico , Hepatite/tratamento farmacológico , Hepatite/metabolismo , Interleucina-17/biossíntese , Interleucinas/biossíntese , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ácido Glicirrízico/farmacologia , Interleucina-17/antagonistas & inibidores , Interleucinas/agonistas , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Front Immunol ; 9: 2398, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386344

RESUMO

Neurotransmitters have been shown to regulate immune responses, and thereby are critically related to autoimmune diseases. Here we showed that depletion of dopaminergic neurons significantly promoted activation of hepatic iNKT cells and augmented concanavalin A (Con A)-induced liver injury. The suppressive effect of dopamine on iNKT cells was mediated by D1-like receptor-PKA pathway. Clearance of gut microbiota by antibiotic cocktail reduced synthesis of dopamine in intestines and exacerbated liver damage, and that could be restored by recovery of gut microbiota or replenishment of D1-like receptor agonist. Our results demonstrate that peripheral dopamine controlled by gut microbes inhibits IL4 and IFNγ production in iNKT cells and suppresses iNKT cell-mediated hepatitis. Together, we propose a gut microbe-nervous system-immune system regulatory axis in modulating autoimmune hepatitis.


Assuntos
Dopamina/metabolismo , Microbioma Gastrointestinal , Hepatite/etiologia , Hepatite/metabolismo , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Animais , Biomarcadores , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citocinas/biossíntese , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Hepatite/patologia , Camundongos , Camundongos Transgênicos , Receptores de Dopamina D1/metabolismo
20.
BMJ Case Rep ; 20182018 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-30275022

RESUMO

Hypoxic hepatitis is a rather common complication of heart, circulatory or respiratory failure. We present the case of a patient with hypoxic hepatitis in the setting of heart failure and dehydration from furosemide as a reminder of an important clinical lesson. The pathogenesis of hypoxia (especially in the case of heart failure) is explained by a two-hit mechanism in which the liver at risk of hypoxic injury by passive hepatic congestion (right heart failure) is subsequently exposed to systemic hypoperfusion, which leads to a marked and transient elevation of aminotransferases. In the case presented, the use of furosemide (at least partially) promoted the second hit because it helped to generate hypotension and splanchnic hypovolaemia and favoured hepatic hypoxia.


Assuntos
Desidratação/induzido quimicamente , Furosemida/efeitos adversos , Insuficiência Cardíaca/complicações , Hepatite/etiologia , Doença Hepática Induzida por Substâncias e Drogas , Desidratação/complicações , Desidratação/terapia , Diagnóstico Diferencial , Diuréticos/efeitos adversos , Ecocardiografia/métodos , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Hepatite/metabolismo , Humanos , Hipóxia/induzido quimicamente , Hepatopatias/complicações , Hepatopatias/metabolismo , Pessoa de Meia-Idade , Resultado do Tratamento
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