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1.
Chem Biol Interact ; 308: 377-384, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150631

RESUMO

Among the primary neoplasias that affect the liver, hepatocellular carcinoma (HCC) is the most frequent and the third leading cause of death related to cancer. Several risk factors predispose individuals to HCC such as nonalcoholic fatty liver disease (NAFLD), whose incidence has significantly increased worldwide. ß-ionone (ßI) isoprenoid is a known chemopreventive of hepatocarcinogenesis. However, the effects of this compound on NAFLD isolated or in association with hepatocarcinogenesis have not yet been evaluated. A high-fat emulsion administered for 6 weeks resulted in NAFLD in male rats, and oral treatment with ßI during this period significantly attenuated its development. Moreover, the presence of NAFLD potentiated hepatocarcinogenesis induced by the resistant hepatocyte (RH) model in these animals by increasing the number and percentage of the liver section area occupied by placental glutathione S-transferase (GST-P)-positive persistent preneoplastic lesions (pPNLs), that are thought to evolve into HCC. This indicates that this NAFLD/RH protocol is suitable for studies of the influence of NAFLD on the HCC development. Therefore, here we also investigated the chemopreventive effect of ßI under these two associated conditions. In this context, ßI reduced the number and percentage of the liver section area occupied by pPNLs, as well as cell proliferation and the number of oval cells, which are considered potential targets for the development of HCC. Thus, ßI presents not only a promising inhibitory effect on NAFLD isolated but also chemopreventive activity when it is associated with hepatocarcinogenesis.


Assuntos
Carcinoma Hepatocelular/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Norisoprenoides/uso terapêutico , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Glutationa Transferase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/patologia , Norisoprenoides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Triglicerídeos/análise
2.
J Agric Food Chem ; 67(27): 7726-7737, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31203627

RESUMO

Fructose as a daily sweetener is widely recognized as a risk catalyst for nonalcoholic fatty liver disease (NAFLD). The aim of current study is to evaluate the effects and molecular mechanism by which polyphenol-rich loquat fruit extract (LFP) prevents NAFLD in mice fed 30% fructose water (HF) for 8 weeks. Administration of LFP to HF-fed mice mitigated abnormal body weight, disordered lipid metabolism, oxidative stress, and inflammation through a mechanism regulated by the AKT, ChREBP/SREBP-1c, Nrf2, and TLR4/MyD88/TRIF pathways. LFP caused a significant decrease in the endotoxin content (16.67-12.7 EU/mL) in the liver of HF-fed mice. LFP not only improved HF-induced breakage of the intestinal barrier via interacting with tight junction proteins (ZO-1, occludin), mucin, and immunoreaction in the colon but also maintained normal colonic Firmicutes/Bacteroidetes ratios and the relative abundance of Veillonella in HF-fed mice. Our results suggest that LFP may serve as a nutritional agent for protecting liver in HF-fed mice.


Assuntos
Eriobotrya , Frutose/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Animais , Dieta , Frutose/administração & dosagem , Frutas/química , Glucose/metabolismo , Inflamação/prevenção & controle , Intestinos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos
3.
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
4.
J Oleo Sci ; 68(6): 581-589, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31092797

RESUMO

Non-alcoholic fatty liver disease (NAFLD), a common chronic liver disease characterized by hepatic steatosis, affects 30-40% of the population in the world. The seed of Euryale ferox salisb. possesses several pharmacological actions, including metabolic syndrome. However, the seed coat of E. ferox was usually discarded as waste, which contains comparatively abundant polyphenols, and its biological activity has been rarely investigated. In this work, we evaluate the hepatoprotective effect of E. ferox seed coat extract (EFSCE), in NAFLD mice induced by high-fat diet (HFD). The HPLC-MS analysis indicated that the main components of EFSCE were polyphenols. And then, mice were treated with HFD for 4 weeks to induce NAFLD. The result showed that the body weight, weight of adipose tissue, the ratio of liver to body weight in NAFLD mice increased compared with control group. In addition, blood lipids parameters including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL) also increased in NAFLD mouse model. It was showed that, after treated with EFSCE (15 and 30 mg/kg/day) for 4 weeks, the body weight, lipids deposition in the liver and blood lipids in HFD-induced NAFLD mice markedly reduced. Compared with NAFLD mice, EFSCE administration could also prevent malondialdehyde (MDA) overproduction and strengthen Superoxide Dismutase (SOD) activity to counteract oxidative stress. Moreover, EFSCE was also found effective in reducing alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in HFD-induced NAFLD model, which indicated liver injury in NAFLD. Therefore, EFSCE (rich in polyphenols) is indicated as bioactive nature product for HFD-induced NAFLD treatment, by eliminating lipid accumulation and oxidative stress via regulation of IRs-1 and CYP2E1.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Dieta Hiperlipídica/efeitos adversos , Proteínas Substratos do Receptor de Insulina/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Nymphaeaceae/química , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Sementes/química , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos ICR , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Polifenóis/análise , Estimulação Química , Superóxido Dismutase/metabolismo
5.
Planta Med ; 85(8): 678-688, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31026873

RESUMO

Abrus pulchellus subsp. mollis (Hance) Verdc. (Leguminosae) is a well-known edible plant usually added to soups and beverages. In this study, vicenin-2 (1: ), isoschaftoside (2: ), schaftoside (3: ), and their enrichment fraction, total flavonoid C-glycosides, derived from the extracts of A. mollis, were firstly found to prevent nonalcoholic fatty liver disease both in vitro and in vivo. In the in vitro study, total flavonoid C-glycosides decreased the lipid accumulation in oleic acid-treated HepG2 cells. The mechanisms of total flavonoid C-glycosides are involved in the regulation of peroxisome proliferator-activated receptor α and its downstream, and the reduction of proinflammatory cytokines. In high-fat diet-induced fatty liver rats, total flavonoid C-glycosides decreased the levels of glutamic-oxalacetic transaminease and glutamic-pyruvic transaminase, and decreased the lipid accumulation both in the liver and blood without affecting food intake. In addition, total flavonoid C-glycosides also increased the activities of the antioxidant enzyme system in vivo. In conclusion, total flavonoid C-glycosides are active components of A. mollis on nonalcoholic fatty liver disease, and can be used in functional food and supplements for nonalcoholic fatty liver disease prevention and treatment.


Assuntos
Abrus/química , Glicosídeos/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , PPAR alfa/metabolismo , Fitoterapia , Extratos Vegetais/uso terapêutico , Animais , Dieta , Glicosídeos/química , Glicosídeos/isolamento & purificação , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Células RAW 264.7 , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
6.
J Agric Food Chem ; 67(19): 5306-5317, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30892882

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a typical chronic liver disease highly correlated with metabolic syndrome. Growing prevalence of NAFLD is supposed to be linked with the unhealthy lifestyle, especially high-calorie diet and lacking enough exercise. Currently, there is no validated pharmacological therapy for NAFLD except for weight reduction. However, many dietary strategies had preventive effects on the development of liver steatosis or its progression. As one of the most common beverages, green tea contains abundant bioactive compounds possessing antioxidant, lipid-lowering, and anti-inflammatory effects, as well as improving insulin resistance and gut dysbiosis that can alleviate the risk of NAFLD. Hence, in this review, we summarized the studies of green tea and its components on NAFLD from animal experiments and human interventions and discussed the potential mechanisms. Available evidence suggested that tea consumption is promising to prevent NAFLD, and further mechanisms and clinical studies need to be investigated.


Assuntos
Camellia sinensis/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Chá/metabolismo , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Camellia sinensis/química , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Chá/química
7.
Nutrients ; 11(3)2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30818779

RESUMO

Chlorogenic acids (CGA) are the most abundant phenolic compounds in green coffee beans and in the human diet and have been suggested to mitigate several cardiometabolic risk factors. Here, we aimed to evaluate the effect of a water-based standardized green coffee extract (GCE) on cardiometabolic parameters in ApoE-/- mice and to explore the potential underlying mechanisms. Mice were fed an atherogenic diet without (vehicle) or with GCE by gavage (equivalent to 220 mg/kg of CGA) for 14 weeks. We assessed several metabolic, pathological, and inflammatory parameters and inferred gut microbiota composition, diversity, and functional potential. Although GCE did not reduce atherosclerotic lesion progression or plasma lipid levels, it induced important favorable changes. Specifically, improved metabolic parameters, including fasting glucose, insulin resistance, serum leptin, urinary catecholamines, and liver triglycerides, were observed. These changes were accompanied by reduced weight gain, decreased adiposity, lower inflammatory infiltrate in adipose tissue, and protection against liver damage. Interestingly, GCE also modulated hepatic IL-6 and total serum IgM and induced shifts in gut microbiota. Altogether, our results reveal the cooccurrence of these beneficial cardiometabolic effects in response to GCE in the same experimental model and suggest potential mediators and pathways involved.


Assuntos
Apolipoproteínas E/metabolismo , Coffea/química , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/microbiologia , Animais , Apolipoproteínas E/genética , Aterosclerose , Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/microbiologia , Cirrose Hepática/prevenção & controle , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Extratos Vegetais/química
8.
World J Gastroenterol ; 25(8): 955-966, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30833801

RESUMO

BACKGROUND: Procyanidins have beneficial effects on metabolic syndrome and antimicrobial activity, but the mechanisms underlying these effects are unclear. AIM: To investigate the effects of procyanidin B2 (PB2) on non-alcoholic fatty liver disease and to explore the possible mechanism. METHODS: Thirty male New Zealand white rabbits were randomized into three groups. All of them were fed either a high-fat-cholesterol diet (HCD) or chow diet. HCD-fed rabbits were treated with vehicle or PB2 daily for 12 wk. Body weight and food intake were evaluated once a week. Serum biomarkers, such as total cholesterols, triglycerides, and aspartate transaminase, were detected. All rabbits were sacrificed and histological parameters of liver were assessed by hematoxylin and eosin-stained sections. Moreover, several lipogenic genes and gut microbiota (by 16S rRNA sequencing) were investigated to explore the possible mechanism. RESULTS: The HCD group had higher body weight, liver index, serum lipid profile, insulin resistance, serum glucose, and hepatic steatosis compared to the CHOW group. PB2 treatment prevented HCD-induced increases in body weight and hypertriglyceridemia in association with triglyceride accumulation in the liver. PB2 also ameliorated low-grade inflammation, which was reflected by serum lipopolysaccharides and improved insulin resistance. In rabbit liver, PB2 prevented the upregulation of steroid response element binding protein 1c and fatty acid synthase and the downregulation of carnitine palmitoyltransferase, compared to the HCD group. Moreover, HCD led to a decrease of Bacteroidetes in gut microbiota. PB2 significantly improved the proportions of Bacteroidetes at the phylum level and Akkermansia at the genus level. CONCLUSION: Our results indicate the possible mechanism of PB2 to improve HCD-induced features of metabolic syndrome and provide a new dietary supplement.


Assuntos
Biflavonoides/farmacologia , Catequina/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/prevenção & controle , Proantocianidinas/farmacologia , Substâncias Protetoras/farmacologia , Animais , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/genética , Bacteroidetes/isolamento & purificação , Biflavonoides/uso terapêutico , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Catequina/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Microbioma Gastrointestinal/genética , Humanos , Resistência à Insulina , Lipopolissacarídeos/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/sangue , Obesidade/etiologia , Proantocianidinas/uso terapêutico , Substâncias Protetoras/uso terapêutico , RNA Ribossômico 16S/isolamento & purificação , Coelhos , Resultado do Tratamento , Triglicerídeos/sangue
9.
Indian J Gastroenterol ; 38(1): 55-60, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30796701

RESUMO

BACKGROUND: It is known that diet plays a pivotal role in the pathogenesis and management of nonalcoholic fatty liver disease (NAFLD); however, the knowledge on the role of different food groups such as legumes is not enough. METHODS: We designed this study to assess the relationship between legume intake and risk of NAFLD in framework of a case-control study among Tehrani adults. One hundred and ninety-six newly diagnosed patients with NAFLD and 803 controls were studied, and their dietary intake was assessed using a valid and reliable food frequency questionnaire. Conditional logistic regression was used to determine the odds ratio (OR) of NAFLD per increase of one serving/week dietary legumes, lentil, and beans adjusting for potential confounders. RESULTS: In energy-adjusted model, greater intake of legumes, lentils, and beans was associated with a lower risk of NAFLD. These risk associations remained significant after adjusting for all known risk factors of NAFLD. OR of NAFLD in adjusted models for higher dietary intake of legumes, lentils, and beans were 0.73 (0.64-0.84), 0.61 (0.46-0.78), and 0.35 (0.17-0.74), respectively. CONCLUSION: Our findings suggest that higher intake of total legumes (beans, lentils, and peas) was associated with lower risk of NAFLD.


Assuntos
Dieta , Ingestão de Alimentos/fisiologia , Fabaceae , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Adulto , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Comportamento de Redução do Risco
10.
Int J Biol Macromol ; 130: 68-78, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30797009

RESUMO

We isolated and characterized a Mussel polysaccharide, α-D-glucan (MP-A), from Mytilus coruscus earlier. In this work, the pharmacological activity and mechanisms of MP-A as an oral supplement for non-alcoholic fatty liver disease (NAFLD) were explored. High fat diet (HFD) was utilized to induce NAFLD in Sprague Dawley male rats and MP-A (0.6 g/kg) was supplemented for 4 weeks. The results showed that MP-A supplementation reduced blood lipid levels, intrahepatic lipid accumulation and NAFLD activity score in HFD-fed rats. Additionally, the analysis of 16S rDNA sequencing on gut microbiota samples revealed that HFD could induce microbial dysbiosis. However, MP-A supplementation could remodel gut microbiota structure, inhibit LPS-TLR4-NF-κB pathway activation, and restrain subsequent inflammation factors secretion. Furthermore, MP-A regulated the lipid metabolism by promoting the production of short chain fatty acids and suppressing PPAR γ and SREBP-1c expression. Our results support that MP-A can prevent against NAFLD and act as an oral supplementation for hepatoprotection via modulating gut microbiota and related gut-liver axis signaling pathways.


Assuntos
Bivalves/química , Microbioma Gastrointestinal/efeitos dos fármacos , Glucanos/farmacologia , Homeostase/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangue , Triglicerídeos/metabolismo
11.
Curr Pharm Biotechnol ; 20(3): 197-214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30806308

RESUMO

BACKGROUND: Liver ailments are among the leading causes of death; they originate from viral infections, chronic alcoholism, and autoimmune illnesses, which may chronically be precursors of cirrhosis; furthermore, metabolic syndrome may worsen those hepatopathies or cause Non-alcoholic Fatty Liver Disease (NAFLD) that may advance to non-alcoholic steatohepatitis (NASH). Cirrhosis is the late-stage liver disease and can proceed to hepatocellular carcinoma (HCC). Pharmacological treatment options for liver diseases, cirrhosis, and HCC, are limited, expensive, and not wholly effective. The use of medicinal herbs and functional foods is growing around the world as natural resources of bioactive compounds that would set the basis for the development of new drugs. Review and Conclusion: Plant and food-derived sterols and triterpenoids (TTP) possess antioxidant, metabolic-regulating, immunomodulatory, and anti-inflammatory activities, as well as they are recognized as anticancer agents, suggesting their application strongly as an alternative therapy in some chronic diseases. Thus, it is interesting to review current reports about them as hepatoprotective agents, but also because they structurally resemble cholesterol, sexual hormones, corticosteroids and bile acids due to the presence of the steroid nucleus, so they all can share pharmacological properties through activating nuclear and membrane receptors. Therefore, sterols and TTP appear as a feasible option for the prevention and treatment of chronic metabolic-related liver diseases, cirrhosis, and HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Fígado/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Fitosteróis/uso terapêutico , Triterpenos/uso terapêutico , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/prevenção & controle , Humanos , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/prevenção & controle , Síndrome Metabólica/metabolismo , Síndrome Metabólica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Fitosteróis/química , Fitosteróis/farmacologia , Triterpenos/química , Triterpenos/farmacologia
12.
Biol Pharm Bull ; 42(2): 255-260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30713255

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation, which is the most common form of chronic liver disease. Multiple clinical studies using natural compounds such as flavonoids have been conducted to treat NAFLD. In the present study, the pharmacological effect of Citrus aurantium L. (Rutaceae) peel extract (CAE), which contains over 27% of polymethoxyflavone nobiletin, on NAFLD was evaluated using a high-fat diet (HFD) animal model susceptible to developing NAFLD. C57BL/6 mice were fed an HFD (60% kcal of energy derived from fat) for 8 weeks to induce obesity. Obese mice were randomly allocated to four groups of eight mice each (HFD alone, HFD with silymarin, HFD with 50 mg/kg CAE, and HFD with 100 mg/kg CAE). After 8 weeks of treatment, all mice were euthanized, and plasma and liver tissues were analyzed biochemically and histopathologically. The results indicate that CAE treatment significantly reduced HFD-induced NAFLD, as shown by decreased serum lipid index and prevented liver histopathology. The expression of genes involved in lipid synthesis including free fatty acid (FFA), peroxisome-proliferator-activated receptor γ (PPAR-γ), sterol receptor element binding protein 1c (SREBP-1c), and fatty acid synthesis enzyme was suppressed by CAE treatment. Moreover, compared to untreated mice, CAE-treated HFD mice showed decreased pro-inflammatory cytokine expression. These results demonstrated that CAE prevented HFD-induced NAFLD by reducing plasma levels of triglyceride and cholesterol and de novo lipid synthesis.


Assuntos
Citrus/química , Flavonoides/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR gama/biossíntese , PPAR gama/genética , Extratos Vegetais/farmacologia , Proteínas Quinases/metabolismo , Distribuição Aleatória , Silimarina/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Receptor fas/metabolismo
13.
Food Funct ; 10(2): 1073-1084, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30720827

RESUMO

This study aimed to compare the hypolipidaemic activities of different Monascus pigments (yellow, red and orange pigments) and elucidate their possible regulatory mechanisms on lipid and cholesterol metabolism in rats fed on a high-fat diet (HFD). Results showed that oral administrations of Monascus yellow, red and orange pigments can markedly alleviate the disturbance of lipid metabolism through ameliorating the serum lipid levels and suppressing hepatic lipid accumulation and steatosis. Meanwhile, the excretion of fecal cholesterol, triacylglycerols and bile acids was also promoted by the oral administrations of different Monascus pigments (MPs). Furthermore, Monascus pigment (MP) supplementation produced significant structural changes in the intestinal microbiota of HFD-fed rats, and modulated the relative abundance of functionally related microbial phylotypes compared with the HFD group in particular. Key phylotypes in response to the HFD and Monascus pigment (MP) intervention were found to strongly correlate with the lipid metabolism disorder associated parameters using Spearman's correlation coefficient. Some beneficial gut microbiota (such as Oscillibacter sp., Ruminococcus albus, Clostridium sp., etc.) were found to be negatively correlated with the serum and hepatic lipid indicator. Moreover, Monascus pigment (MP) treatments regulated the mRNA expression levels of the genes responsible for lipid and cholesterol metabolism. In general, different Monascus pigments (MPs) regulate the homeostasis of lipid and cholesterol metabolism through different regulatory pathways. These findings illustrated that not only Monascus yellow pigments, but also Monascus red and orange pigments have the potential to ameliorate lipid metabolic disorders, and therefore could be used as potential functional food ingredients for the prevention or treatment of hyperlipidemia and gut microbiota dysbiosis.


Assuntos
Produtos Biológicos , Disbiose/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Monascus/química , Pigmentos Biológicos/farmacologia , Animais , Dieta Hiperlipídica , Fezes/química , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Pigmentos Biológicos/química , Ratos , Ratos Wistar
14.
PLoS One ; 14(1): e0210068, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30689650

RESUMO

Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Tabernaemontana divaricate, attenuates hepatic fibrosis in mice. We have previously shown that CnP inhibits non-alcoholic steatohepatitis (NASH) using a methionine-choline-deficient (MCD) diet-fed mouse model. However, little is known about the CnP mediated inhibition of hepatic steatosis in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mouse models. CnP (0.5 and 1 µg/g/body weight) was co-administered along with a high-fat diet to male BALB/c mice. After nine weeks of administering the high-fat diet, hepatic steatosis, triglyceride, and hepatic fat metabolism-related markers were examined. Administration of a high-fat diet for 9 weeks was found to induce hepatic steatosis. CnP dose-dependently attenuated the high-fat diet-induced hepatic steatosis. The diet also attenuated hepatic peroxisome proliferator-activated receptor alpha (PPARA) mRNA levels. PPARA is known to be involved in ß-oxidation. CnP upregulated the mRNA levels of hepatic PPARA and its target genes, such as carnitine palmitoyl transferase 1 (CPT1) and CPT2, in a dose-dependent manner in the liver. Furthermore, levels of hepatic ß-hydroxybutyrate, which is a type of ketone body, were increased by CnP in a dose-dependent manner. Finally, CnP increased the expression of the autophagosomal marker LC3-II and decreased the expression of p62, which are known to be selectively degraded during autophagy. These results indicate that CnP inhibits hepatic steatosis through the stimulation of ß-oxidation and autophagy in the liver. Therefore, CnP might prove to be a suitable therapeutic target for NAFLD.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Alcaloides de Vinca/farmacologia , Animais , Autofagia/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Fígado Gorduroso/etiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos BALB C , Hepatopatia Gordurosa não Alcoólica/etiologia , PPAR alfa/genética , PPAR alfa/metabolismo
15.
J Int Med Res ; 47(3): 1250-1263, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30678506

RESUMO

OBJECTIVE: To examine the effects of arnebin-1 on nonalcoholic fatty liver disease (NAFLD) induced by a high-fat diet (HFD). METHODS: Male Sprague-Dawley rats were fed an HFD for 10 weeks and then treated with arnebin-1 at a dose of 5, 10 or 20 mg/kg/day by gavage for a further 12 weeks of a 22-week HFD. Peripheral blood and liver tissues were collected for biochemical and histopathological examination. The mechanisms of arnebin-1 on liver fibrosis and insulin resistance (IR) were determined by Western blotting and real-time quantitative polymerase chain reaction. RESULTS: Arnebin-1 treatment attenuated the increase of total cholesterol, triglycerides, low-density lipoprotein cholesterol, aspartate aminotransferase and alanine aminotransferase in serum and lipid accumulation in the livers of HFD-fed rats. Furthermore, arnebin-1 abrogated HFD-induced liver fibrosis and the increase of fibrotic biomarkers. The HFD-induced decrease of hepatic proliferator-activated receptor γ and pro-matrix-metalloproteinase (MMP)-9 levels and the increase of tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were reversed after arnebin-1. Arnebin-1 attenuated IR through activating the insulin receptor substrate-1/Akt/mTOR signalling pathway. CONCLUSION: This study demonstrated that arnebin-1 ameliorates NAFLD, in part, by attenuating hepatic fibrosis and IR, suggesting that arnebin-1 may be a therapeutic agent for NAFLD treatment.


Assuntos
Resistência à Insulina , Cirrose Hepática/tratamento farmacológico , Naftoquinonas/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Substâncias Protetoras/administração & dosagem , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Ratos , Ratos Sprague-Dawley
16.
Mol Nutr Food Res ; 63(8): e1800930, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30680920

RESUMO

SCOPE: Modulation of intestinal microbiota has emerged as a new therapeutic approach for non-alcoholic fatty liver disease (NAFLD). Herein, it is addressed whether gut microbiota modulation by quercetin and intestinal microbiota transplantation can influence NAFLD development. METHODS AND RESULTS: Gut microbiota donor mice are selected according to their response to high-fat diet (HFD) and quercetin in terms of obesity and NAFLD-related biomarkers. Germ-free recipients displayed metabolic phenotypic differences derived from interactions between microbiota transplanted, diets, and quercetin. Based on the evaluation of hallmark characteristics of NAFLD, it is found that gut microbiota transplantation from the HFD-non-responder donor and the HFD-fed donor with the highest response to quercetin results in a protective phenotype against HFD-induced NAFLD, in a mechanism that involves gut-liver axis alteration blockage in these receivers. Gut microbiota from the HFD-responder donor predisposed transplanted germ-free mice to NAFLD. Divergent protective and deleterious metabolic phenotypes exhibited are related to definite microbial profiles in recipients, highlighting the predominant role of Akkermansia genus in the protection from obesity-associated NAFLD development. CONCLUSIONS: The results provide scientific support for the prebiotic capacity of quercetin and the transfer of established metabolic profiles through gut microbiota transplantation as a protective strategy against the development of obesity-related NAFLD.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Quercetina/farmacologia , Animais , Endotoxemia/etiologia , Endotoxemia/terapia , Ácidos Graxos Voláteis/metabolismo , Inflamassomos , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/microbiologia , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/microbiologia , Verrucomicrobia/fisiologia
17.
Redox Biol ; 21: 101092, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30605883

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide lacking universally accepted therapies. Studies suggest that coffee consumption is associated with a reduced risk of NAFLD; however, molecular mechanisms and ingredients involved remain to be fully understood. Here, we determined the effects of regular intake of decaffeinated coffee on the development of NAFLD in mice, and molecular mechanisms involved. METHODS: Female C57BL/6J mice (n = 6-7/ group) were pair-fed either a liquid control diet (C) or fat-, fructose- and cholesterol-rich diet (FFC) +/- decaffeinated coffee (DeCaf, 6 g/kg BW) for 4 days or 6 weeks. Indices of liver damage, hepatic inflammation and parameters of insulin resistance and intestinal permeability as well as nitric oxide system were determined. RESULTS: Early signs of insulin resistance and non-alcoholic steatohepatitis (NASH) found after 6 weeks of FFC feeding were significantly lower in FFC+DeCaf-fed mice when compared to FFC-fed animals. Moreover, elevation of portal endotoxin levels and loss of tight junction proteins in proximal small intestine found in FFC-fed mice were significantly attenuated in FFC+DeCaf-fed animals. These beneficial effects of DeCaf were associated with a protection against the significant induction of inducible NO-synthase protein levels and 3-nitrotyrosine protein adducts found in proximal small intestine of FFC-fed mice. Similar protective effects of DeCaf were also found in mice fed the FFC diet short-term. CONCLUSION: Our results suggest that protective effects of DeCaf on the development of NAFLD are at least in part related to maintaining intestinal barrier function.


Assuntos
Café , Comportamento Alimentar , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Biomarcadores , Estresse do Retículo Endoplasmático , Feminino , Glucose/metabolismo , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Peroxidação de Lipídeos , Fígado/metabolismo , Fígado/patologia , Camundongos , Óxido Nítrico/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Permeabilidade , Receptor 4 Toll-Like/metabolismo
18.
Yakugaku Zasshi ; 139(1): 47-51, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30606928

RESUMO

Although many treatments for type 2 diabetes mellitus (T2DM) have been developed, the quality of life for people with T2DM still tends to be lower than in those without the disease. Thus, the development of new T2DM treatments and prevention methods is required. Genetic predisposition and environmental factors are understood to be involved in the onset and pathology of T2DM. Therefore, we have attempted to explore genes and foods with potential for use in the treatment and prevention of T2DM. LipoQuality, which describes the functional features of diverse lipid species, has recently been a focus of study in the pathology of metabolic diseases. Phospholipids, the major components of biological membranes, are known to change in composition during the development of obesity and diabetes. Therefore, for our research, we focused on genes that regulate the composition of phospholipids. We examined the effects of such genes on T2DM using an improved adenovirus vector that demonstrates safer, higher, and longer-term transgene expression than that of the conventional adenovirus vector. We also found that certain foods inhibit the progression of non-alcoholic fatty liver disease, which is related to T2DM. In this review, we introduce our research results, demonstrating how genes and food independently contribute to the mechanisms of T2DM pathology.


Assuntos
Adenoviridae , Diabetes Mellitus Tipo 2/prevenção & controle , Diabetes Mellitus Tipo 2/terapia , Alimento Funcional , Vetores Genéticos , Fosfolipídeos , Vaccinium macrocarpon , 1-Acilglicerofosfocolina O-Aciltransferase/fisiologia , Animais , Diabetes Mellitus Tipo 2/etiologia , Interação Gene-Ambiente , Humanos , Fígado/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Estresse Oxidativo , Fosfolipídeos/metabolismo
19.
Yakugaku Zasshi ; 139(1): 53-60, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30606929

RESUMO

Adiponectin, the most abundant adipose tissue-derived adipocytokine, improves insulin sensitivity and has anti-inflammatory properties. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is a key molecule in the multimerization of adiponectin (i.e., activation of adiponectin). In mice, liver-specific knockout of the Dsba-L gene impaired the mitochondrial function in hepatocytes and exacerbated the high-fat-diet-induced fatty liver. In addition, the DsbA-L mRNA level is negatively correlated with body mass index (BMI) in humans. We recently investigated the clinical impact of the DsbA-L gene on lifestyle-related diseases in Japanese subjects. We confirmed the influence of the common DsbA-L rs1917760 polymorphism on the multimerization of adiponectin, as well as the association of the polymorphism with the risk of obesity and non-alcoholic fatty liver disease, using prediction models based on a non-linear mixed effect model and/or structural equation models among elderly participants in a health screening program. We also observed a decreasing effect of DsbA-L polymorphism on the DsbA-L mRNA level in peripheral blood mononuclear cells, and an increasing effect of the polymorphism on the prevalence of excessive weight among schizophrenia patients at a high risk for obesity. These findings suggest that DsbA-L may be a key molecule associated with the development and progression of obesity and its related diseases. Therefore, genotyping the DsbA-L polymorphism and identifying patients at a high risk of developing obesity may help prevent obesity and its complications by facilitating targeted prevention and treatment programs for high-risk individuals.


Assuntos
Adiponectina/metabolismo , Estudos de Associação Genética , Glutationa Transferase/genética , Obesidade/genética , Farmacogenética , Multimerização Proteica/genética , Adiponectina/fisiologia , Animais , Índice de Massa Corporal , Humanos , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/prevenção & controle , Obesidade/terapia , Polimorfismo Genético , RNA Mensageiro , Risco
20.
Phytomedicine ; 53: 134-142, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30668392

RESUMO

BACKGROUD: Non-alcoholic fatty liver disease (NAFLD) is currently evolving as the most common liver disease worldwide. Dyslipidemia, pathoglycemia and insulin resistance are the major risk factors for the development of NAFLD. To date, no effective drug therapies for this condition have been approved. PURPOSE: The present study was to investigate the protective effects of yangonin, a kavalactone isolated from Kava, against NAFLD and further elucidate the mechanisms in vivo and in vitro. STUDY DESIGN: A high-fat diet (HFD) induced mouse NAFLD model was used with or without yangonin treatment. METHODS: The body weight, relative liver weight and serum biochemical indicators were measured. H&E and Oil Red O staining were used to identify the amelioration of the liver histopathological changes. Serum and hepatic triglyceride, free fatty acids and total cholesterol were analyzed. siRNA, quantitative real-time PCR and Western blot assay were used to clarify the mechanisms underlying yangonin protection. RESULTS: Yangonin had obvious protective effects against NAFLD via farnesoid X receptor (FXR) activation. Through FXR activation, yangonin attenuated lipid accumulation in the liver via inhibition of hepatic lipogenesis-related protein including sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthetase (FAS), acetyl-CoA carboxylase 1 (ACC1) and stearoyl-CoA desaturase 1 (SCD1). Besides, yangonin promoted lipid metabolism through an induction in genes required for lipoprotein lipolysis and fatty acid ß-oxidation. Furthermore, yangonin modulated blood glucose homeostasis through regulation of gluconeogenesis-related gene phosphoenol pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), and glycogen synthesis-related gene glycogen synthase kinase 3ß (GSK3ß) and pyruvate dehydrogenase (PDase). Also, yangonin increased insulin sensitivity through upregulating phosphorylation of insulin responsive substrate 1, 2 (IRS-1 and IRS-2). Then, in vivo and in vitro evidence further demonstrated the involvement of FXR activation in yangonin hepatoprotection. CONCLUSIONS: Yangonin protects against NAFLD due to its activation of FXR signalling to inhibit hepatic lipogenesis and gluconeogenesis, and to promote lipid metabolism and glycogen synthesis, as well as insulin sensitivity.


Assuntos
Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Pironas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Glicogênio/metabolismo , Insulina/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Substâncias Protetoras/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Triglicerídeos/sangue , Triglicerídeos/metabolismo
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