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1.
Phytomedicine ; 81: 153426, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33341026

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, and it is closely associated to obesity, type 2 diabetes mellitus, and dyslipidemia. Medicinal cannabis and some neutral cannabinoids have been suggested as a potential therapy for liver diseases. HYPOTHESIS: Δ9-tetrahydrocannabinolic acid (Δ9-THCA), the non-psychotropic precursor of Δ9-THC, is one of the most abundant cannabinoids presents in Cannabis Sativa. However, its biological activities have been poorly investigated. Herein, we studied the antifibrotic and antiinflammatory activities of Δ9-THCA in two different animal models of liver injury, providing a rationale for additional studies on the medicinal use of this cannabinoid in the treatment of liver fibrosis and the management of NAFLD. STUDY DESIGN: The antifibrotic activity of Δ9-THCA in vitro was investigated in the cell lines LX-2 and NIH-3T3-Col1A2-luc. Non-alcoholic liver fibrosis was induced in mice by CCl4 treatment or, alternatively, by 23-week high fat diet (HFD) feeding. Δ9-THCA was administered daily intraperitoneally during the CCl4 treatment or during the last 3 weeks in HFD-fed mice. METHODS: TGFß-induced profibrotic gene expression was analyzed by luciferase and qPCR assays. Liver fibrosis and inflammation were assessed by immunochemistry and qPCR. Blood glucose, insulin, leptin and triglyceride levels were measured in HFD mice. RESULTS: Δ9-THCA inhibited the expression of Tenascin C (TNC) and Col3A1 induced by TGFß in LX-2 cells and the transcriptional activity of the Col1A2 promoter in fibroblasts. Δ9-THCA significantly attenuated CCl4-induced liver fibrosis and inflammation and reduced T cell and macrophage infiltration. Mice fed HFD for 23 weeks developed severe obesity (DIO), fatty liver and marked liver fibrosis, accompanied by immune cell infiltration. Δ9-THCA, significantly reduced body weight and adiposity, improved glucose tolerance, and drastically attenuated DIO-induced liver fibrosis and immune cell infiltration. CONCLUSIONS: Δ9-THCA prevents TGFß-induced fibrotic markers in vitro and liver inflammation and fibrogenesis in vivo, providing a rationale for additional studies on the medicinal use of this cannabinoid, as well as cannabis preparations containing it, for the treatment of liver fibrosis and the management of NAFLD.


Assuntos
Dronabinol/farmacologia , Hepatite/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Cannabis/química , Tetracloreto de Carbono/toxicidade , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatite/etiologia , Hepatite/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicações , Obesidade/etiologia
2.
PLoS One ; 15(12): e0244514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382757

RESUMO

BACKGROUND: Nut consumption has been associated with reduced inflammation, insulin resistance, and oxidative stress. However, the influence on the prevalence and severity of non-alcoholic fatty liver disease (NAFLD) has yet to be evaluated. METHODS: 4655 subjects were included as part of a colorectal carcinoma screening program (SAKKOPI) between 07/2010 and 07/2019 and analyzed 2020. Patients were characterized using biochemical and metabolic parameters, as well as a detailed questionnaire on dietary habits. The diagnosis of NAFLD was established using abdominal ultrasound. Consumption of nuts was graded as: no consumption or <1 time/week, 1-6 times/week, 1 time/day and ≥2 times/day. RESULTS: Mean age was 58.5±9.8years with a mean BMI of 26.5±4.7kg/m2. 2058 (44.2%) patients suffered from the metabolic syndrome, 2407 (51.6%) had arterial hypertension, 2287 (49.1%) showed prediabetes/diabetes, 1854 (39.4%) had dyslipidemia and 1984 patients (43.5%) were diagnosed with NAFLD. Prevalence of metabolic syndrome (1219 [48.7%] vs. 605 [40.2%] vs. 189 [37.4%] vs. 45 [31.7%], p<0.001) and NALFD (1184 [48.1%] vs. 594 [40.7%] vs. 158 [31.7%] vs. 48 [34.0%], p<0.001). On multivariable logistic regression analysis adjusting for potential confounders and dietary patterns, nut consumption ≥1time/day was inversely associated with NAFLD in the overall cohort (adjusted Odds ratio[aOR]: 0.719 [95%CI:0.558-0.926], p = 0.011). However, following subgroup analysis, this inverse association was only confirmed in male patients (aOR: 0.589 [95%CI: 0.411-0.844], p = 0.004) but not in females (aOR: 0.886 [95%CI: 0.616-1.275], p = 0.515). Moreover, patients who consumed nuts 1-6 times/week had a significantly lower prevalence of advanced fibrosis (Fib-4 score >2.67: aOR: 0.551 [95%CI: 0.338-0.898], p = 0.017; Forns-Index >6.9: aOR: 0.585 [95%CI: 0.402-0.850], p = 0.005). CONCLUSIONS: Nut consumption might exert beneficial effects on the prevalence of NAFLD in males. The negative association with advanced fibrosis warrants further investigation.


Assuntos
Comportamento Alimentar/fisiologia , Cirrose Hepática/epidemiologia , Síndrome Metabólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Nozes , Adulto , Idoso , Inquéritos sobre Dietas/estatística & dados numéricos , Progressão da Doença , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/prevenção & controle , Masculino , Síndrome Metabólica/prevenção & controle , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Prevalência , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais
3.
Nutrients ; 13(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374297

RESUMO

Background: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. Methods: Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and ß-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. Results: The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. Conclusion: The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Creatina/administração & dosagem , Doxorrubicina/toxicidade , Inflamação/prevenção & controle , Cirrose Hepática/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Animais , Senescência Celular/efeitos dos fármacos , Suplementos Nutricionais , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Ratos , Ratos Sprague-Dawley
4.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 279-282, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981286

RESUMO

Objective: To investigate the effects of ceramide pathway on the inhibition of artesunate (Art) to hepatic fibrosis.Methods: LX-2 cells were divided into control group, Art treated group with 350 µmol/L, fumonisin B1 (FB1) treated group with 6 µmol/L, and Co-administration group of artesunate 350 µmol/L and fumonisin B1 6 µmol/L. There were 7 compound holes in each group. After 24 hours of treatment, the cells and supernatant were collected and detected. The expressions of homo sapiens longevity assurance homologue 2 (LASS2), peroxisome proliferators-activated receptors-γ (PPAR-γ) and Caspase-3 were evaluated by Western blot, the content of ceramide was evaluated by HPLC-FLD method, MTT assay was adopted to measure the rate of proliferation of LX-2 cells. The content of hydroxyproline was determined by digestive method. Results: Compared with the control group, the expression of ceramide synthase protein and the ceramide content were increased significantly, the proliferation of LX-2 cells was inhibited significantly, the expressions of PPAR-γ and Caspase-3 protein were up-regulated and the secretion of hydroxyproline was inhibited in Art treated group (P<0.05). In FB1 treated group, the protein expression of ceramide synthase and the ceramide content were decreased significantly, the proliferation of LX-2 cells was increased significantly, the expressions of PPAR-γ and Caspase-3 protein were down-regulated, and the secretion of hydroxyproline was increased (P<0.05). Compared with the Art alone group, the combination of the two drugs could significantly reduce the effects of Art on the expression of ceramide synthase protein and the increase of ceramide content, and attenuate the effects of Art on the cell proliferation , PPAR-γ, Caspase-3 protein expression and hydroxyproline level of LX-2 cells (P<0.05). Conclusion: Artesunate could inhibit hepatic fibrosis by increasing the content of ceramide through the ceramide synthase-ceramide pathway.


Assuntos
Artesunato , Ceramidas , Cirrose Hepática , Oxirredutases , Artesunato/farmacologia , Proliferação de Células/efeitos dos fármacos , Ceramidas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/enzimologia , Cirrose Hepática/prevenção & controle , Oxirredutases/metabolismo
5.
Life Sci ; 260: 118245, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791144

RESUMO

AIMS: Bisphenol A (BPA) has been shown to induce liver fibrosis in rodents. Therefore, this study examined the protective effect of a triple combination of curcumin (Cur), N-acetyl cysteine (NAC) and propolis (Prp) extract against BPA-induced hepatic fibrosis. METHODS: 100 Wistar male rats were equally assigned into 10 groups; one group was designated as control. 10 rats were gavaged with BPA (50 mg/kg/day) for 8 wk and left un-treated (BPA group). The remaining 80 rats were divided into 8 groups, distributed in 2 models. Protective model: rats were daily co-treated with BPA and Cur (100 mg/kg, p.o) or NAC (150 mg/kg, p.o) or Prp (200 mg/kg, p.o) or their combination for 8 wk. Preventive model: rats were daily treated with Cur or NAC or Prp or their combination for 4 wk before BPA administration and then in the same manner as protective model. KEY FINDINGS: Current treatment interventions significantly alleviated BPA-induced hepatic damage and fibrosis. They also restored pro-oxidant/antioxidant balance, shifted cytokine balance towards the anti-inflammatory side, decreasing interleukin-1ß/interleukin-10 ratio. Moreover, these compounds seem to exert anti-apoptotic effects by increasing the immunoexpression of B-cell lymphoma 2 in hepatocytes and decreasing hepatic caspase-3 content. Finally, they ameliorated extracellular matrix turn over through down-regulation of matrix metalloproteinase-9 and up-regulation of tissue inhibitor of matrix metalloproteinase-2 genetic expression. SIGNIFICANCE: Current treatments guarded against BPA-induced hepatic fibrosis due to their antioxidant, anti-inflammatory and anti-apoptotic properties, decreasing extracellular matrix turnover. Interestingly, the triple therapy provided hepatoprotection superior to monotherapy. Besides, prophylactic and concurrent treatments seem to be more effective than concurrent treatments.


Assuntos
Acetilcisteína/administração & dosagem , Compostos Benzidrílicos/toxicidade , Curcumina/administração & dosagem , Cirrose Hepática/prevenção & controle , Fenóis/toxicidade , Própole/administração & dosagem , Acetilcisteína/farmacologia , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Curcumina/farmacologia , Quimioterapia Combinada , Inflamação/sangue , Interleucinas/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Masculino , Própole/farmacologia , Ratos , Ratos Wistar
6.
Chem Biol Interact ; 329: 109213, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32739323

RESUMO

Phytoestrogens are plant-derived substances with a similar structure to 17-beta-estradiol, which have protective roles in estrogen-dependent diseases. Isoflavones, the most well-known subgroup of phytoestrogens, play protective roles against chemicals-induced liver injuries through several molecular mechanisms. Hepatoprotective effects of isoflavones are, partly, associated with their antioxidant, anti-inflammatory, immunomodulatory, and anti-fibrotic properties. Besides, isoflavones can reduce gut-derived endotoxins, accelerate alcohol metabolism, stimulate detoxification of hepatotoxic chemicals, suppress the bioactivation of these chemicals, inhibit hepatocytes apoptosis, and restore autophagy activity during chemicals-induced liver diseases. This review provides a summary of the molecular mechanisms underlying the hepatoprotective effects of isoflavones. It seems that further studies are needed to investigate the hepatoprotective potential of isoflavones in patients with different stages of chemicals-induced liver injuries.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Isoflavonas/metabolismo , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Inflamação/prevenção & controle , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia
7.
Gene ; 758: 144946, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32649978

RESUMO

Hepatic injury is one of the most challenging diseases in clinical medicine. Hepatic injury is accompanied by hepatocyte apoptosis and leads to hepatic fibrosis and cirrhosis, which may cause liver cancer and increased mortality. Therefore, it is essential to investigate the regulation mechanism and therapeutic strategies for hepatic injury. In the study, the effects of Thymosin ß4 (Tß4) on Long intergenic noncoding RNA-p21 (lincRNA-p21)-mediated liver injury were investigated. Results showed that lincRNA-p21 overexpression promoted hepatocytes apoptosis, which was blocked by Tß4. Besides, Tß4 reversed the levels of cleaved caspase-3 and caspase-9 induced by lincRNA-p21. LincRNA-p21 overexpression also caused the pathological injury and fibrosis in hepatic tissues and increased the levels of fibrosis-related proteins (Collagen I, α-SMA and TIMP-1), and induced hydroxyproline and ALT production. However, Tß4 reversed the effects of overexpression of lincRNA-p21 on hepatic injury and fibrosis. In vitro experiments, after lincRNA-p21 was overexpressed in hepatic stellate cells (HSCs), the proliferation ability and the levels of HSCs markers α-SMA and Desmin were increased. However, Tß4 reversed the effects of lincRNA-p21 on HSCs. Furthermore, the PI3K-AKT-NF-κB pathway was activated by lincRNA-p21, which was then reversed by the Tß4 administration. After the mice treated by insulin-like growth factor-1 (IGF-1) (the activator of PI3K-AKT), the inhibitory effect of Tß4 on activated the PI3K-AKT-NF-κB pathway was abrogated. Besides, IGF-1 abolished the protective effects of Tß4 on hepatic apoptosis and fibrosis induced by lincRNA-p21. Therefore, Tß4 reversed. lincRNA-p21-mediated liver injury through inhibiting PI3K-AKT-NF-κB pathway. Tß4 may be a promising drug for fibrosis therapy.


Assuntos
Apoptose/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/lesões , RNA Longo não Codificante/genética , Timosina/farmacologia , Actinas/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Hepatócitos/patologia , Proteínas I-kappa B/antagonistas & inibidores , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Inibidor Tecidual de Metaloproteinase-1/metabolismo
8.
Life Sci ; 256: 117909, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512009

RESUMO

Hepatic fibrosis (HF) is a wound-healing response that occurs during chronic liver injury and features by an excessive accumulation of extracellular matrix (ECM) components. Activation of hepatic stellate cell (HSC), the leading effector in HF, is responsible for overproduction of ECM. It has been documented that transforming growth factor-ß1 (TGF-ß1) stimulates superfluous accumulation of ECM and triggers HSCs activation mainly via canonical Smad-dependent pathway. Also, the pro-fibrogenic TGF-ß1 is correlated with generation of reactive oxygen species (ROS) and inhibition of antioxidant mechanisms. Moreover, involvement of oxidative stress (OS) can be clearly elucidated as a fundamental event in liver fibrogenesis. Nuclear factor erythroid 2-related factor 2-antioxidant response elements (Nrf2-AREs) pathway, a group of OS-mediated transcription factors with diverse downstream targets, is associated with the induction of diverse detoxifying enzymes and the most pivotal endogenous antioxidative system. More specifically, Nrf2-AREs pathway has recently assigned as a new therapeutic target for cure of HF. The overall goal of this review will focus on recent findings about activation of Nrf2-AREs-mediated antioxidant and suppression of profibrotic TGF-ß1/Smad3 pathway in the liver, providing an overview of recent advances in transcriptional repressors that dislocated during HF formation, and highlighting possible novel therapeutic targets for liver fibrosis.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Antioxidantes/metabolismo , Descoberta de Drogas , Matriz Extracelular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Humanos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
9.
Adv Clin Exp Med ; 29(6): 683-693, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32598580

RESUMO

BACKGROUND: Hepatic fibrosis is a health concern worldwide, and it is of great importance to develop effective therapeutic targets. The small heterodimer partner (SHP) is a regulator of lipid and bile acid metabolism in the liver. OBJECTIVES: The objective of this study was to investigate the contribution of SHP to hepatic fibrosis and the underlying mechanism. MATERIAL AND METHODS: An in vivo rat model of hepatic fibrosis was created through treatment with carbon tetrachloride. We used arginine-glycine-aspartic acid-poly (ethylene glycol)-polyethyleneimine (RGD-PEG-PEI) for the specific transfer of SHP into hepatic stellate cells (HSC). The level of gene expression was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The LX2 cell line was selected for the in vitro assay. Artificial activation of LX2 in vitro was conducted through treatment with platelet-derived growth factor-BB (PDGF-BB), and autophagy was activated using rapamycin. Gain and loss of function assays were performed using a SHP-expressing plasmid or siRNA-SHP. Both qRT-PCR and western blotting were utilized to detect the level of gene expression. RESULTS: RGD-PEG-PEI-mediated the specific transduction of SHP into HSC in the liver and effectively increased the expression of SHP in the rat liver. After treatment with RGD-PEG-PEI-SHP, downregulation of liver fibrosis-associated genes was observed. The results of the in vitro assay indicated that SHP attenuated the stimulating effect of PDGF-BB on the activation of LX2 cells. Overexpression of SHP leads to significant downregulation of HSC activation-associated molecular factors, including α-smooth muscle actin, tissue inhibitor of metalloproteinase-1, and type I collagen. Conversely, increased expression of these molecules could be observed following knockdown of SHP. Furthermore, SHP affected fibrosis by inhibiting autophagy activated through treatment with rapamycin in LX2 cells. Overexpression of SHP may prevent liver fibrogenesis through inhibition of autophagy in HSC. CONCLUSIONS: The SHP may prevent liver fibrogenesis through inhibition of autophagy in HSC. A SHP-targeting therapy-based anti-fibrosis strategy possesses potential for application to the treatment of liver fibrosis.


Assuntos
Autofagia , Células Estreladas do Fígado , Cirrose Hepática , Animais , Tetracloreto de Carbono , Células Estreladas do Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Ratos , Inibidor Tecidual de Metaloproteinase-1
10.
Am J Physiol Endocrinol Metab ; 319(2): E305-E314, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32516028

RESUMO

Obesity promotes nonalcoholic fatty liver disease (NAFLD). The intestinal microbiota contributes to NAFLD progression through a gut-to-liver pathway that promotes inflammation and fibrosis. Gut microbiota-derived factors can travel to the liver and activate immune responses in liver resident cells to promote inflammation and NAFLD. Little is known about bacterial sensors or immune responses that can protect against NAFLD. We tested whether the bacterial cell wall sensor nucleotide-binding oligomerization domain-containing (NOD)2 protects against diet-induced NAFLD in mice. Whole body deletion of NOD2 exacerbated liver steatosis and fibrosis in mice fed a NAFLD-promoting diet. Mice with a hepatocyte-specific deletion of NOD2 (Nod2-/-HKO) also had higher liver steatosis and fibrosis compared with littermate wild-type mice (WT) fed a NAFLD-promoting diet. Hepatocyte-specific NOD2 deletion altered the composition of the gut microbiome. Nod2-/-HKO mice had increased relative abundance of Clostridiales and lower Erysipelotrichaceae among other changes in cecal bacteria compared with littermate WT mice. Hepatocyte-specific NOD2 deletion altered a transcriptional program of liver inflammation, metabolism, and fibrosis. Nod2-/-HKO mice had higher levels of transcripts involved in lipid and cholesterol metabolism. Nod2-/-HKO mice had higher transcript levels of transforming growth factor-ß and collagen isoforms, which coincided with higher levels of liver collagen compared with WT mice. These data show that bacterial cell wall sensing within hepatocytes can engage retrograde cross-talk from the liver to the gut, where liver immunity communicates with the gut to influence the intestinal host-microbe relationship during diet-induced NAFLD, and NOD2 within the hepatocyte confers protection from liver steatosis and fibrosis.


Assuntos
Disbiose/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Cirrose Hepática/fisiopatologia , Fígado/fisiopatologia , Proteína Adaptadora de Sinalização NOD2/fisiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Animais , Dieta , Disbiose/prevenção & controle , Hepatócitos/química , Hepatócitos/fisiologia , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD2/deficiência , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Receptor Cross-Talk
11.
Medicine (Baltimore) ; 99(19): e20296, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384521

RESUMO

BACKGROUND: Hepatic fibrosis (HF) is the common pathological basis of chronic liver disease (CLD). Many data indicate that serum vitamin D (VD) levels in patients with liver fibrosis are significantly lower than those without liver fibrosis, and lower level of serum 1,25(OH)2D3 is also an independent risk factor for patients with liver fibrosis combined with other diseases. VD has the functions of anti-fibrosis, regulating cell proliferation and differentiation, anti-inflammatory, and immune regulation, Therefore, serum 1,25(OH)2D3 level may be negatively correlated with the progression of liver fibrosis. But there is absent convincing evidence-based medicine to confirm the efficacy of VD supplementation for CLD. Thus, we aimed to conduct this meta-analysis to summarize the efficacy of VD supplementation on the progression of fibrosis in patients with CLD. METHODS: The study only selects clinical randomized controlled trials of VD supplementation for CLD. We will search each database from the built-in until September 2020. The English literature mainly searches Cochrane Library, Pubmed, EMBASE, and Web of Science. While the Chinese literature comes from CNKI, CBM, VIP, and Wangfang database. Meanwhile, we will retrieve clinical trial registries and gray literature. Two researchers worked independently on literature selection, data extraction and quality assessment. The dichotomous data is represented by relative risk (RR), and the continuous is expressed by mean difference (MD) or standard mean difference (SMD), eventually the data is synthesized using a fixed effect model (FEM) or a random effect model (REM) depending on the heterogeneity. The serum VD level, hepatic function and serological indexes of hepatic fibrosis were evaluated as the main outcomes. While several secondary outcomes were also evaluated in this study. The statistical analysis of this Meta-analysis was conducted by RevMan software version 5.3. RESULTS: This meta-analysis will further determine the beneficial efficacy of VD supplementation on the progression of fibrosis in patients with CLD. CONCLUSION: This study determines the positive efficacy of VD supplementation for CLD. ETHICS AND DISSEMINATION: This review is based solely on a secondary study of published literatures and does not require ethics committee approval. Its conclusion will be disseminated in conference papers, magazines or peer-reviewed journals. REGISTRATION NUMBER: INPLASY202040054.


Assuntos
Suplementos Nutricionais , Cirrose Hepática/prevenção & controle , Hepatopatias/complicações , Vitamina D/administração & dosagem , Doença Crônica , Progressão da Doença , Humanos , Cirrose Hepática/etiologia , Testes de Função Hepática , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Risco , Vitamina D/sangue
12.
Gastroenterol Clin North Am ; 49(2): 215-238, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389360

RESUMO

Despite the availability of a protective vaccine for over 3 decades, the number of persons with chronic hepatitis B virus (HBV) infection remains high. These persons are at risk for cirrhosis and hepatocellular carcinoma. Current treatment is effective at inhibiting viral replication and reducing complications of chronic HBV infection, but is not curative. There is a need for novel, finite therapy that can cure chronic HBV infection. Several agents are in early-phase development and can be broadly viewed as agents that target the virus directly or indirectly or the host immune response. This article highlights key developments in antiviral/immunomodulatory therapy, the rationale for these approaches, and possible therapeutic regimens.


Assuntos
Antivirais/administração & dosagem , Hepatite B/terapia , Imunomodulação , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/prevenção & controle , Feminino , Hepatite B/complicações , Hepatite B/prevenção & controle , Hepatite B/virologia , Vírus da Hepatite B , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Masculino , Prevalência
13.
Gastroenterol Clin North Am ; 49(2): 301-314, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389364

RESUMO

The cure of chronic hepatitis C infection has a major impact on the morbidity and mortality of infected patients. It is now clear that sustained virologic response improves overall survival and significantly reduces the risk of liver failure, fibrosis progression, need of liver transplantation, and incidence of hepatocellular carcinoma. Moreover, hepatitis C eradication improves a broad range of extrahepatic manifestations, such as dermatologic, neoplastic, cardiovascular, and endocrine, and improves quality of life.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Qualidade de Vida , Resposta Viral Sustentada , Antivirais/administração & dosagem , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/prevenção & controle , Doenças Cardiovasculares , Crioglobulinemia , Diabetes Mellitus , Quimioterapia Combinada , Hepacivirus , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Linfoma não Hodgkin
14.
Chem Biol Interact ; 324: 109098, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278740

RESUMO

This study evaluates the possible protective effects of gallic acid (GaA) and ferulic acid (FeA) against an experimentally induced liver fibrosis by thioacetamide (TAA) in rats. Animals were divided into: Control group, GaA group (20 mg/kg/day, p.o), FeA (20 mg/kg/day, p.o), TAA group (receiving 250 mg/kg twice/week, I.P), TAA + GaA group, TAA + FeA group (received the same previous doses) and TAA+silymarin group (received silymarin at 100 mg/kg/day+TAA as mentioned above). After 6 consecutive weeks, animals were sacrificed and the assessment of liver functions, oxidative stress biomarkers and histopathological examination of the liver tissues were performed. In addition, the effect on TGF-ß1/Smad3 signaling and the expression of miR-21, miR-30 and miR-200 were evaluated. The results showed that administration of GaA or FeA with TAA induced a significant reduction in serum ALT, AST and ALP activities and protected the integrity of liver tissues. Furthermore, they increased the activities of the hepatic antioxidant enzymes; superoxide dismutase and catalase while decreased malondialdehyde content to a normal level. The hepatic expression of TGF-ß1, phosphorylated and total Smad3 proteins were significantly decreased. In addition, miR-21 expression was downregulated while miR-30 and miR-200 expressions were upregulated by administration of gallic acid or ferulic acid. In conclusion, gallic and ferulic acids exhibit hepatoprotective and antioxidant effects against TAA-induced liver fibrosis in rats. These effects are mediated through inhibition of TGF-ß1/Smad3 signaling and differentially regulating the hepatic expression level of miR-21, miR-30 and miR-200.


Assuntos
Ácidos Cumáricos/uso terapêutico , Ácido Gálico/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Substâncias Protetoras/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Regulação para Baixo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , MicroRNAs/metabolismo , Ratos Wistar , Proteína Smad3/metabolismo , Tioacetamida , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
15.
PLoS Genet ; 16(4): e1008629, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32282858

RESUMO

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.


Assuntos
Fígado Gorduroso/genética , Fígado Gorduroso/prevenção & controle , Predisposição Genética para Doença , Cirrose Hepática/genética , Cirrose Hepática/prevenção & controle , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto/genética , Oxirredutases/genética , Alelos , LDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Conjuntos de Dados como Assunto , Fígado Gorduroso/sangue , Fígado Gorduroso/enzimologia , Feminino , Homozigoto , Humanos , Fígado/enzimologia , Cirrose Hepática/sangue , Cirrose Hepática/enzimologia , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática Alcoólica/enzimologia , Cirrose Hepática Alcoólica/genética , Cirrose Hepática Alcoólica/prevenção & controle , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade
16.
Ann Surg ; 272(1): 32-39, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32224733

RESUMO

OBJECTIVE: This study sought to compare trends in the development of cirrhosis between patients with NAFLD who underwent bariatric surgery and a well-matched group of nonsurgical controls. SUMMARY OF BACKGROUND DATA: Patients with NAFLD who undergo bariatric surgery generally have improvements in liver histology. However, the long-term effect of bariatric surgery on clinically relevant liver outcomes has not been investigated. METHODS: From a large insurance database, patients with a new NAFLD diagnosis and at least 2 years of continuous enrollment before and after diagnosis were identified. Patients with traditional contraindications to bariatric surgery were excluded. Patients who underwent bariatric surgery were identified and matched 1:2 with patients who did not undergo bariatric surgery based on age, sex, and comorbid conditions. Kaplan-Meier analysis and Cox proportional hazards modeling were used to evaluate differences in progression from NAFLD to cirrhosis. RESULTS: A total of 2942 NAFLD patients who underwent bariatric surgery were identified and matched with 5884 NAFLD patients who did not undergo surgery. Cox proportional hazards modeling found that bariatric surgery was independently associated with a decreased risk of developing cirrhosis (hazard ratio 0.31, 95% confidence interval 0.19-0.52). Male gender was associated with an increased risk of cirrhosis (hazard ratio 2.07, 95% confidence interval 1.31-3.27). CONCLUSIONS: Patients with NAFLD who undergo bariatric surgery are at a decreased risk for progression to cirrhosis compared to well-matched controls. Bariatric surgery should be considered as a treatment strategy for otherwise eligible patients with NAFLD. Future bariatric surgery guidelines should include NAFLD as a comorbid indication when determining eligibility.


Assuntos
Cirurgia Bariátrica , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade Mórbida/cirurgia , Adolescente , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco
17.
Obes Facts ; 13(2): 144-151, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32200381

RESUMO

BACKGROUND: Referral to weight loss programmes is the only effective treatment for non-alcoholic fatty liver disease (NAFLD). Clinicians should advise weight loss and screen for liver fibrosis using the Enhanced Liver Fibrosis (ELF) score. AIM: To examine if the ELF score changes with weight loss. DESIGN AND SETTING: Randomised controlled trial (ISRCTN85485463) in UK primary care during 2007-2008. METHOD: Adults with a BMI of 27-35 kg/m2 and ≥1 risk factor for obesity-related disease were randomised to attend a community weight loss programme (n = 45) or receive usual weight loss advice from a practice nurse (n = 28). Weight and the ELF score were measured at baseline and 1 year. Analysis of covariance examined mean changes in the ELF score between groups and its relationship with weight loss. RESULTS: Mean (SD) BMI was 31.10 kg/m2 (2.55) with evidence of moderate levels of liver fibrosis at baseline (mean ELF score: 8.93 [0.99]). There was no evidence that the community weight loss programme reduced the ELF score compared with usual care (difference +0.13 points, 95% CI: -0.25 to 0.52) despite greater weight loss (difference: -2.66 kg, 95% CI: -5.02 to -0.30). Mean weight loss in the whole cohort was 7.8% (5.9). There was no evidence of an association between weight change and change in ELF; the coefficient for a 5% weight loss was -0.15 (95% CI: -0.30 to 0.0002). CONCLUSION: We found no evidence that the ELF score changed meaningfully following moderate weight loss. Clinicians should not use the ELF score to measure improvements in NAFLD fibrosis following weight loss programmes.


Assuntos
Biomarcadores/metabolismo , Cirrose Hepática/diagnóstico , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia , Perda de Peso/fisiologia , Programas de Redução de Peso , Adulto , Idoso , Biomarcadores/análise , Estudos de Coortes , Feminino , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Resultado do Tratamento
18.
Life Sci ; 248: 117475, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32119963

RESUMO

AIMS: Liver fibrosis is a crucial pathological feature which could result in cirrhosis and hepatocarcinoma. But until now, there is no favourable treatment for it. Apigenin (APG) is a flavonoid, which exhibits efficient anti-liver fibrosis activity, but its underlying mechanisms were rarely studied. So this work aims to estimate the potential therapeutic action of APG on liver fibrosis rats and to gain insight into its system-level mechanisms. MAIN METHODS: Hepatic fibrosis was induced by CCl4 in Wistar rats, and APG was given in the light of the regimen. Biochemical indexes, histopathological change and immunohistochemistry of liver were evaluated. The optimal effect group of APG was selected for further transcriptomic and proteomic analysis. KEY FINDINGS: APG ameliorated liver fibrosis via reducing the levels of AST, ALT, ALP, LDH, Hyp, TP, TB, DB, HA, LN, PCIII and IV-C, mitigating fibrosis and inflammation of liver in H&E and Masson staining. Mechanistically, APG elevated the activity of ALB, SOD and GSH-PX with reducing the level of MDA. The results of microarray and TMT revealed that 4919 genes and 4876 proteins were differentially expressed in the APG and model groups. Besides, transcriptomics and proteomics analyses unfolded 120 overlapped proteins, enriched in 111 GO terms containing apoptotic process, angiogenesis, cell migration and proliferation, etc. Meanwhile, KEGG pathway analysis showed that 26 pathways containing HIF-1/MAPK/eNOS/VEGF/PI3K/Akt signaling pathway, regulation of actin cytoskeleton and focal adhesion mostly. SIGNIFICANCE: APG can ameliorate CCl4-induced liver fibrosis via VEGF-mediated FAK phosphorylation through the MAPKs, PI3K/Akt, HIF-1, ROS, and eNOS pathways, which may hopefully become the anti-liver fibrosis activity of natural product.


Assuntos
Anti-Inflamatórios/farmacologia , Apigenina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Albuminas/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Bilirrubina/sangue , Tetracloreto de Carbono/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proteômica/métodos , Ratos , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
J Card Surg ; 35(4): 845-853, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32112668

RESUMO

BACKGROUND: Currently, non-valved conduits are preferred for extracardiac total cavo-pulmonary connection (TCPC). However, previous work has failed to provide objective data comparing the postoperative outcome between non-valved TCPCs and bovine jugular vein valved xenograft (BJV) TCPCs. Hence, the objective of this study is to compare the postoperative outcomes in extracardiac TCPC patients who received BJV vs synthetic non-valved conduits and evaluate the effect of BJV on liver fibrosis. METHODS: Of 206 patients who had extracardiac TCPC from 2002 to 2017 were divided into three groups. Group A (n = 66) received BJV, group B (n = 37) received PET conduits and group C (n = 103) received polytetrafluoroethylene (PTFE) tube. Study endpoints were hospital outcomes, conduits thrombosis, reinterventions, and survival. Liver stiffness and fibrosis were assessed in eight patients with BJV. RESULTS: Preoperative parameters were comparable among groups. Thrombosis was significantly lower in group C (P < .0003) but no difference between groups A and B (P = .951). Reinterventions did not differ significantly among groups (Log-rank P = .598). Hospital deaths occurred in seven patients (3.4%). There was no difference in survival between groups (Log-rank P = .221). The median liver stiffness score was 18.65 kPa and the eight patients had advanced liver fibrosis (grade F3-4) in group A. CONCLUSION: PTFE is the recommended conduit for TCPC with a lower risk of thrombosis compared to BJV and PET. BJV conduits in TCPC circuits may not protect against liver fibrosis. BJV should not be considered as an option for TCPC.


Assuntos
Bioprótese , Técnica de Fontan/métodos , Cardiopatias Congênitas/cirurgia , Veias Jugulares/transplante , Cirrose Hepática/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Artéria Pulmonar/anormalidades , Artéria Pulmonar/cirurgia , Trombose/prevenção & controle , Transplante Heterólogo/efeitos adversos , Veia Cava Inferior/anormalidades , Veia Cava Inferior/cirurgia , Animais , Bioprótese/efeitos adversos , Bovinos , Criança , Pré-Escolar , Feminino , Humanos , Cirrose Hepática/etiologia , Masculino , Politetrafluoretileno , Complicações Pós-Operatórias/etiologia , Trombose/etiologia , Resultado do Tratamento
20.
J Nat Med ; 74(3): 513-524, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32193805

RESUMO

Liver fibrosis is a pathological manifestation induced by chronic liver injury and may cause cirrhosis and liver cancer with the chronic progression of fibrosis. During the onset and progression of liver fibrosis, the activation of hepatic stellate cells (HSCs) is the core mechanism for the secretion of many extracellular matrices to induce fibrosis. Lignans are reportedly the main effective components of Schisandra chinensis with good anti-fibrosis effects. In this study, we compared the inhibiting effects of the seven lignan components from S. chinensis on HSC activation. We found that the seven lignans inhibited the activation of human HSCs (LX-2) in various degrees. Among all lignans, schisanhenol showed the best effect in inhibiting the activation of LX-2 with a dose-effect relationship. Sal also inhibited the phosphorylations of Smad1, Smad2, Smad3, extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and nuclear transcription factor-κB (NF-κB), as well as downregulated Smad4. All these findings suggested that schisanhenol may ameliorate liver fibrosis by inhibiting the transforming growth factor ß (TGF-ß)/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. Remarkably, schisanhenol may be a potential anti-liver fibrosis drug and warrants further research.


Assuntos
Ciclo-Octanos/farmacologia , Células Estreladas do Fígado/metabolismo , Lignanas/farmacologia , Cirrose Hepática/prevenção & controle , Compostos Policíclicos/farmacologia , Schisandra/química , Linhagem Celular , Frutas/química , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Cirrose Hepática/patologia , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad1/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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