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1.
J Agric Food Chem ; 67(44): 12208-12218, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31608624

RESUMO

To explore the role of apple polyphenol extract (APE) in ameliorating hepatic steatosis and the potential mechanisms involved, we conducted this study. Thirty-three male C57BL/6 mice were randomly divided into three groups: high-fat diet (HFD) with aseptic water ig. (CON), HFD with 125 or 500 mg/(kg·bw·day) APE ig., namely 100 or 400 mg/(kg·bw·day) apple polyphenols (LAP or HAP) for 12 weeks. Compared with the CON group, the APE treatment significantly decreased the body weight gain and increased the ratio of serum albumin/globulin. High dose of APE treatment significantly decreased the liver weight, reduced the hepatic contents of triglyceride and cholesterol, and improved the histopathological features of hepatic steatosis, accompanied by significantly upregulated protein expressions of LKB1, phosphorylated-AMPK, phosphorylated-ACC, and SIRT1, downregulated mTOR, p70 s6k, and HMGCR in the liver, increased mRNA expressions of Ampk and Cyp27a1, and reduced expressions of Srebp-1c, Fas, and Hmgcr. Our data provided new evidence supporting the preventive role of 500 mg/(kg·bw·day) APE treatment in the HFD-induced hepatic steatosis in C57BL/6 mice via the LKB1/AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácido Clorogênico/administração & dosagem , Fígado Gorduroso/tratamento farmacológico , Flavonoides/administração & dosagem , Proteínas Serina-Treonina Quinases/metabolismo , Taninos/administração & dosagem , Proteínas Quinases Ativadas por AMP/genética , Animais , Colesterol , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/genética , Triglicerídeos/metabolismo
2.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1869-1875, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342715

RESUMO

To study the effects of ellagic acid(EA)on inflammation and oxidative stress in mice with fatty liver disease induced by AKT gene transfection,the 20 female FVB mice were randomly divided into normal control group,model group and ellagic acid administration group(150,300 mg·kg~(-1)·d~(-1))(n=5).EA experimental groups and model group were using a high pressure into the tail vein transfection plasmid AKT.The next day,EA was started to administered continuously for 5 weeks after the AKT gene transfection,while the model group and the normal control group were given the same amount of saline.After the administration,the liver tissue and serum of mice were taken.HE and oil red O staining were using to observe the histopathological changes in liver;liver function to detect the serum and liver tissue as well as MDA and SOD levels;real-time quantitative PCR(RT-qPCR)was used to measure the mR-NA expression of NF-κB and TNF-α;Western blot and immunohistochemistry were used to measure the expression of NF-κB,TNF-αand COX-2 in liver tissue.RESULTS:: show that after AKT gene transfection,the model group had significant increase in the serum levels of AST,ALT,elevated the levels of MDA and decreased the levels of SOD in serum and liver tissue,aggravated histopathology degeneration and Liver inflammation,and significantly higher expression of NF-κB,TNF-α,IL-6,COX-2 and other inflammatory-related factors in liver tissue.EA administration group significant reductions in the serum levels of AST,ALT,and improved in hepatocyte fatty degeneration and liver inflammation,lower the levels of MDA and increased the levels of SOD in serum and liver tissue,and significant reductions in the expression of NF-κB,TNF-α,IL-6 and COX-2 in liver tissue.These results suggest that EA has obvious anti-inflammatory effect and inhibits oxidative stress and EA has a significant therapeutic effecton AKT gene inducing fatty liver,and the mechanism possibly by inhibiting inflammatory factors of NF-κB,TNF-α,IL-6,COX-2 and anti-oxidative stress-related.


Assuntos
Ácido Elágico/farmacologia , Fígado Gorduroso/tratamento farmacológico , Inflamação/tratamento farmacológico , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/genética , Animais , Fígado Gorduroso/genética , Feminino , Camundongos , Distribuição Aleatória , Transfecção
3.
J Agric Food Chem ; 67(25): 7136-7146, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31240929

RESUMO

Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) are organosulfur phytochemicals rich in cruciferous vegetables. We investigated the antiobesity and antihepatosteatosis activities of BITC and PEITC and the working mechanisms involved. C57BL/6J mice were fed a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.5 (L) or 1 g/kg (H) BITC or PEITC for 18 weeks. Compared with the HFD group, BITC or PEITC decreased the final body weight of mice in a dose-dependent manner [39.0 ± 3.1 (HFD), 34.4 ± 3.2 (BITC-L), 32.4 ± 2.8 (BITC-H), 36.2 ± 4.4 (PEITC-L), and 32.8 ± 2.9 (PEITC-H) g, p < 0.05], relative weight of epididymal fat [5.7 ± 0.4 (HFD), 4.7 ± 0.7 (BITC-L), 3.7 ± 0.3 (BITC-H), 4.4 ± 1.0 (PEITC-L), and 3.2 ± 0.6 (PEITC-H) %, p < 0.05], hepatic triglycerides [98.4 ± 6.0 (HFD), 81.0 ± 8.9 (BITC-L), 63.5 ± 5.6 (BITC-H), 69.3 ± 5.6 (PEITC-L), and 49.4 ± 2.9 (PEITC-H) mg/g, p < 0.05], and plasma total cholesterol [140 ± 21.3 (HFD), 109 ± 5.6 (BITC-L), 101 ± 11.3 (BITC-H), 126 ± 8.3 (PEITC-L), and 91.8 ± 12.7 (PEITC-H) mg/dL, p < 0.05]. Q-PCR and immunoblotting assays revealed that BITC and PEITC suppressed the expression of liver X receptor α, sterol regulatory element-binding protein 1c, stearoyl-CoA desaturase 1, fatty acid synthase, and acetyl-CoA carboxylase in both epididymal adipose and liver tissues. After a single oral administration of 85 mg/kg BITC or PEITC, the maximum plasma concentrations ( Cmax) of BITC and PEITC were 5.8 ± 2.0 µg/mL and 4.3 ± 1.9 µg/mL, respectively. In 3T3-L1 adipocytes, BITC and PEITC dose-dependently reduced adipocyte differentiation and cell cycle was arrested in G0/G1 phase. These findings indicate that BITC and PEITC ameliorate HFD-induced obesity and fatty liver by down-regulating adipocyte differentiation and the expression of lipogenic transcription factors and enzymes.


Assuntos
Adipogenia/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Isotiocianatos/administração & dosagem , Obesidade/tratamento farmacológico , Animais , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/fisiopatologia
4.
J Agric Food Chem ; 67(21): 5957-5967, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31066268

RESUMO

d- chiro-Inositol (DCI) is a biologically active component found in tartary buckwheat, which can reduce hyperglycemia and ameliorate insulin resistance. However, the mechanism underlying the antidiabetic effects of DCI remains largely unclear. This study investigated the effects and underlying molecular mechanisms of DCI on hepatic gluconeogenesis in mice fed a high fat diet and saturated palmitic acid-treated hepatocytes. DCI attenuated free fatty acid uptake by the liver via lipid trafficking inhibition, reduced diacylglycerol deposition, and hepatic PKCε translocation. Thus, DCI could improve insulin sensitivity by suppressing hepatic gluconeogenesis. Subsequent analyses revealed that DCI decreased hepatic glucose output and the expression levels of PEPCK and G6 Pase in insulin resistant mice through PKCε-IRS/PI3K/AKT signaling pathway. Likewise, such effects of DCI were confirmed in HepG2 cells with palmitate-induced insulin resistance. These findings indicate a novel pathway by which DCI prevents hepatic gluconeogenesis, reduces lipid deposition, and ameliorates insulin resistance via regulation of PKCε-PI3K/AKT axis.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Inositol/administração & dosagem , Resistência à Insulina , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Quinase C-épsilon/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/genética , Proteína Quinase C-épsilon/genética , Proteínas Proto-Oncogênicas c-akt/genética
5.
J Agric Food Chem ; 67(22): 6241-6247, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31117508

RESUMO

A question in cell culture and dietary studies on protection by flavonoids against conditions such as hepatocyte steatosis is whether effects might be due to phenolic breakdown/digestion products. In HepG2 hepatocytes, treatment with quercetin, cyanidin, or their phenolic breakdown/digestion products (protocatechuic acid, 2,4,6-trihydroxybenzaldehyde, and caffeic acid), starting 2 h prior to oleic acid for 24 h, protected similarly against increases in intracellular lipid and reactive oxygen species and decreased mitochondrial membrane potential. Cyanidin or the phenolic products also protected against decreased mitochondrial content. After preincubation for only 1 h (to limit spontaneous degradation) and removal prior to oleic acid, only the phenolic products protected against decreased mitochondrial content, and without adding oleic acid, only protocatechuic acid and caffeic acid, and less so cyanidin, induced mitochondrial content. The results suggest that phenolic breakdown/digestion products of cyanidin and quercetin contribute to the protective effects in vitro, and perhaps in vivo.


Assuntos
Antocianinas/farmacologia , Fígado Gorduroso/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Fenóis/metabolismo , Quercetina/farmacologia , Antocianinas/química , Antocianinas/metabolismo , Fígado Gorduroso/metabolismo , Flavonoides/química , Flavonoides/metabolismo , Flavonoides/farmacologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Mitocôndrias/metabolismo , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Fenóis/química , Fenóis/farmacologia , Quercetina/química , Quercetina/metabolismo , Espécies Reativas de Oxigênio/metabolismo
6.
Nat Commun ; 10(1): 2172, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092829

RESUMO

Inducing mitochondrial uncoupling (mUncoupling) is an attractive therapeutic strategy for treating metabolic diseases because it leads to calorie-wasting by reducing the efficiency of oxidative phosphorylation (OXPHOS) in mitochondria. Here we report a safe mUncoupler, OPC-163493, which has unique pharmacokinetic characteristics. OPC-163493 shows a good bioavailability upon oral administration and primarily distributed to specific organs: the liver and kidneys, avoiding systemic toxicities. It exhibits insulin-independent antidiabetic effects in multiple animal models of type I and type II diabetes and antisteatotic effects in fatty liver models. These beneficial effects can be explained by the improvement of glucose metabolism and enhancement of energy expenditure by OPC-163493 in the liver. Moreover, OPC-163493 treatment lowered blood pressure, extended survival, and improved renal function in the rat model of stroke/hypertension, possibly by enhancing NO bioavailability in blood vessels and reducing mitochondrial ROS production. OPC-163493 is a liver-localized/targeted mUncoupler that ameliorates various complications of diabetes.


Assuntos
Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Desacopladores/farmacologia , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Cricetulus , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Modelos Animais de Doenças , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Feminino , Células Hep G2 , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Hipertensão/mortalidade , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Análise de Sobrevida , Desacopladores/farmacocinética , Desacopladores/uso terapêutico
7.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075962

RESUMO

This study focuses on the effect of honokiol (HON) on glucose homeostasis, insulin resistance, dyslipidemia, hepatic steatosis, and inflammation in type 2 diabetic db/db mice. Male C57BL/KsJ-db/db mice were fed a normal diet with or without HON (0.02%, w/w) or pioglitazone (PIO, anti-diabetic agent, 0.01%, w/w) for 5 weeks. Blood biomarker, tissue morphology and enzymatic and genetic parameters were determined. PIO significantly decreased food intake, fasting blood glucose, and glycosylated hemoglobin (HbA1c) levels, but markedly increased body weight, adipose tissue weight, and plasma leptin levels. HON did not significantly affect food intake, body weight, or levels of plasma leptin and blood glucose. However, HON led to significant decreases in adipose tissue weight, plasma insulin, blood HbA1c and HOMA-IR levels and improved glucose tolerance. The anti-diabetic and anti-adiposity effects of HON were partially related to the inhibition of gluconeogenic enzymes and their mRNA expression in the liver; and the inhibition of lipogenic enzymes in adipose tissue, respectively. Unlike PIO, HON did not affect dyslipidemia, but ameliorated hepatic steatosis by inhibiting hepatic lipogenic enzymes activity. Moreover, HON exhibited anti-inflammatory effects similar to PIO. These results suggest that HON can protect against type 2 diabetes by improving insulin resistance, glucose and lipid metabolism, and inflammation.


Assuntos
Compostos de Bifenilo/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Inflamação/tratamento farmacológico , Resistência à Insulina , Lignanas/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Compostos de Bifenilo/farmacologia , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/sangue , Dislipidemias/complicações , Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Fígado Gorduroso/patologia , Comportamento Alimentar/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Leptina/sangue , Lignanas/farmacologia , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos
8.
Fish Shellfish Immunol ; 91: 293-305, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100441

RESUMO

Excessive lipid accumulation and chemical abuse can induce fatty liver diseases in fish, but the underlying mechanism and therapies are unknown. The present study aims to evaluate the effects of Xiaochaihu Decoction (XCHD) on the growth performance, lipid metabolism and antioxidant function of hybrid grouper in vitro and in vivo, and provide evidence as to whether it can be potentially used as a medicine for liver diseases in aquaculture. In vitro, steatosis model of hybrid grouper primary hepatocytes were incubated for 48 h in control or lipid emulsion (LE)-containing medium with or without 24 h post-treatment with XCHD. XCHD treatment reversed the LE-induced intracellular lipid accumulation, cell viability and hepatocytes morphological structure. In vivo, a total of 300 hybrid grouper with an average initial weight of 25.43 ±â€¯0.18 g were fed diets containing five graded levels of XCHD at 150-1200 mg/kg diet for 8 weeks. After that, a challenge trial was conducted by injection of D-GalN/LPS to induce liver injury. As a result, dietary supplementation with 150-300 mg/kg XCHD diets can significant improve growth performance and feed utilization (P < 0.05). Dietary XCHD down-regulated the expression of lipogenic-related genes (G6PD, DGAT2 and ME1) and up-regulated lipolysis-related genes (ATGL, PPARα and LPL) expression in the liver of hybrid grouper. Livers challenged with D-GalN/LPS exhibited extensive areas of vacuolization with the disappearance of nuclei and the loss of hepatic architecture. These pathological alterations were ameliorated by XCHD treatment. XCHD significantly down-regulated the D-GalN/LPS induced apoptosis-related genes caspase-3, caspase-9 and p53 mRNA expression and up-regulated the antioxidant-related genes CAT and MnSOD mRNA expression in dose dependent manner, respectively. XCHD potently reduced hepatic lipid accumulation and enhanced antioxidant capability in hybrid grouper and may be a potential fish-feed additive to prevent fatty liver diseases onset and progression.


Assuntos
Bass , Medicamentos de Ervas Chinesas/metabolismo , Fígado Gorduroso/veterinária , Doenças dos Peixes/tratamento farmacológico , Ração Animal/análise , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Bass/crescimento & desenvolvimento , Bass/metabolismo , Dieta/veterinária , Suplementos Nutricionais/análise , Medicamentos de Ervas Chinesas/administração & dosagem , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Feminino , Doenças dos Peixes/induzido quimicamente , Galactosamina/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino
9.
Int J Mol Sci ; 20(10)2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31126043

RESUMO

Phytochemicals are known to benefit human health by modulating various cellular processes, including cell proliferation, apoptosis, and inflammation. Due to the potential use of phytochemicals as therapeutic agents against human diseases such as cancer, studies are ongoing to elucidate the molecular mechanisms by which phytochemicals affect cellular functions. It has recently been shown that phytochemicals may regulate the expression of microRNAs (miRNAs). MiRNAs are responsible for the fine-tuning of gene expression by controlling the expression of their target mRNAs in both normal and pathological cells. This review summarizes the recent findings regarding phytochemicals that modulate miRNA expression and promote human health by exerting anticancer, photoprotective, and anti-hepatosteatosis effects. Identifying miRNAs modulated by phytochemicals and understanding the regulatory mechanisms mediated by their target mRNAs will facilitate the efforts to maximize the therapeutic benefits of phytochemicals.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , MicroRNAs/genética , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Fígado Gorduroso/genética , Fígado Gorduroso/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Promoção da Saúde , Humanos , Neoplasias/genética , Neoplasias/prevenção & controle , Compostos Fitoquímicos/farmacologia , Substâncias Protetoras/farmacologia
10.
FEBS Open Bio ; 9(4): 643-652, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30984539

RESUMO

The rise in the incidence of nonalcoholic steatohepatitis (NASH) has necessitated the development of an effective prevention methodology. An antidiabetic drug, belonging to the group of sodium glucose cotransporter 2 (SGLT2) inhibitors, has been tested for its therapeutic effect on NASH; however, no studies to date have demonstrated the preventive effect of an SGLT2 inhibitor on the histological progression of steatosis and fibrosis in a sequential manner in animal models. In the present study, we examined the effect of the SGLT2 inhibitor, tofogliflozin (Tofo), on NASH liver tissue using medaka as an animal model, maintaining a feeding amount and drug concentration in all animal bodies. We generated a medaka NASH model by feeding d-rR/Tokyo medaka a high-fat diet and administered Tofo by dissolving the drug directly in the water of the feeding tank. Thereafter, the effects of Tofo on body weight (BW), liver weight, hepatotoxicity, fatty infiltration, and fibrotic changes in the liver were examined. We report here that SGLT2 is expressed in medaka fish and that Tofo inhibits the accumulation of fatty tissue and delays the progression of liver fibrosis in the medaka NASH model by inhibiting increases in blood sugar, serum lipids, and transaminase, irrespective of changes in BW. These results suggest that Tofo is effective for treating NASH and that the medaka model may be useful for developing new therapeutic drugs for this disease.


Assuntos
Compostos Benzidrílicos/farmacologia , Fígado Gorduroso/tratamento farmacológico , Proteínas de Peixes/metabolismo , Glucosídeos/farmacologia , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Proteínas de Peixes/antagonistas & inibidores , Fígado/metabolismo , Oryzias
11.
Oxid Med Cell Longev ; 2019: 9417498, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31015892

RESUMO

Syzygium cumini is used worldwide for the treatment of metabolic syndrome-associated outcomes. Previously, we described the antihypertriglyceridemic effect of the hydroethanolic extract of S. cumini leaf (HESc) in monosodium L-glutamate- (MSG-) induced obese rats. This study sought to investigate the molecular mechanisms underlying the antihypertriglyceridemic effect of HESc in MSG-obese rats. Newborn male Wistar rats were injected subcutaneously with MSG (4.0 g/kg/day, obese group) or saline 1.25% (1.0 mL/kg/day, lean group), from 2nd through 10th postnatal day. At 8 weeks old, obese rats started to be orally treated with HESc (0.5 or 1.0 g/kg/day, n = 7) or saline 0.9% (1 mL/kg/day, n = 7). Lean rats received saline solution (1 mL/kg/day, n = 7). Upon 8-week treatment, animals were euthanized for blood and tissue collection. Another set of adult nonobese Wistar rats was used for the assessment of HESc acute effects on Triton WR1339-induced hypertriglyceridemia. HESc reduced weight gain, as well as adipose tissue fat pads, without altering food intake of obese rats. HESc restored fasting serum glucose, triglycerides, total cholesterol, and free fatty acids, as well as insulin sensitivity, to levels similar to lean rats. Additionally, HESc halved the triglyceride content into very low-density lipoprotein particles, as well as healed liver steatosis, in obese rats. Hepatic protein expression of the endoplasmic reticulum chaperone GRP94 was decreased by HESc, which also downregulated the hepatic triglyceride secretion pathway by reducing the splicing of X-box binding protein 1 (XBP-1s), as well as protein disulfide isomerase (PDI) and microsomal triglyceride transfer protein (MTP) translational levels. This action was further corroborated by the acute inhibitory effect of HESc on triglyceride accumulation on Triton WR1339-treated rats. Our data support the downregulation of the XBP-1s/PDI/MTP axis in the liver of MSG-obese rats as a novel feasible mechanism for the antihypertriglyceridemic effect promoted by the polyphenolic phytocomplex present in S. cumini leaf.


Assuntos
Regulação para Baixo , Hipertrigliceridemia/tratamento farmacológico , Fígado/metabolismo , Obesidade/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Transdução de Sinais/efeitos dos fármacos , Syzygium/química , Tecido Adiposo/metabolismo , Animais , Animais Recém-Nascidos , Proteínas de Transporte/metabolismo , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/sangue , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/fisiopatologia , Glicolipídeos/sangue , Hipertrigliceridemia/sangue , Hipertrigliceridemia/fisiopatologia , Lipoproteínas VLDL/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Masculino , Obesidade/sangue , Obesidade/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Polifenóis/química , Isomerases de Dissulfetos de Proteínas/metabolismo , Ratos Wistar , Glutamato de Sódio , Triglicerídeos/sangue , Proteína 1 de Ligação a X-Box/metabolismo
12.
Biomed Res Int ; 2019: 4805926, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30937311

RESUMO

Shuangyu Tiaozhi Granule (STG) is composed of two kinds of Chinese medicinal herbs in dioscorea, which are used for managing cholesterol levels in patients with hypercholesterolemia in traditional Chinese medicine (TCM). However, the potential molecular mechanisms of administration of STG in hypercholesterolemia remain unknown. In this study, we investigated the effects of STG on hepatic cholesterol metabolism in high cholesterol (HC) diet-induced hypercholesterolemic rat models and simvastatin was used as a positive control. Male Sprague Dawley (SD) rats were fed general or HC diet, respectively. After 4 weeks of feeding, HC diet-induced hypercholesterolemic rats were fed HC diet, STG at 5% (w/w) or 10% (w/w) mixed in the HC diet, or HC diet combined with simvastatin gavages (4 mg·kg-1·d-1) for 4 or 8 weeks. STG treatment decreased body weight gain, liver weight ratio, serum lipids levels and hepatic lipids accumulation in rats fed a HC diet. Moreover, the effects of STG on decreasing body weight and lowering liver cholesterol levels were in dose- and time-dependent. Furthermore, STG or simvastatin treatment decreased the mRNA and protein levels of HMGCR and SREBP-2 in liver. The ACAT-2 and CYP7A1 mRNA expression were significantly decreased in HC diet supplemented with STG, while the mRNA levels of LDLR were markedly increased. STG attenuates hypercholesterolemia via inhibiting SREBP-2 signaling pathway activation and increasing hepatic uptake genes expression, providing a novel idea of TCM keeping cholesterol levels down for the clinical application.


Assuntos
Colesterol na Dieta/administração & dosagem , Colesterol/biossíntese , Medicamentos de Ervas Chinesas/uso terapêutico , Comportamento Alimentar , Hipercolesterolemia/tratamento farmacológico , Animais , Peso Corporal/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia , Hidroximetilglutaril-CoA Redutases/metabolismo , Hipercolesterolemia/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Modelos Biológicos , Tamanho do Órgão/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
13.
Drugs ; 79(7): 751-766, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30989634

RESUMO

AIM: Our aim was to assess the efficacy and safety of mipomersen through a systematic review of the literature and a meta-analysis of the available clinical studies. METHODS: A systematic literature search in SCOPUS, PubMed Medline, ISI Web of Science and Google Scholar databases was conducted up to January 20, 2019, in order to identify clinical trials assessing the effect of mipomersen on lipoproteins, and the safety profile of mipomersen. Effect sizes for lipid changes were expressed as weighted mean differences (WMD) and 95% confidence intervals (CI). For safety analysis, odd ratios (OR) and 95% CI were calculated using the Mantel-Haenszel method. Data were pooled from 13 clinical studies comprising 49 arms, which included 1053 subjects overall, with 729 in the active-treated arm and 324 in the control arm. RESULTS: Meta-analysis of data suggested that mipomersen significantly reduced low-density lipoprotein cholesterol (WMD - 1.52, 95% CI - 1.85 to - 1.19; p < 0.001), total cholesterol (WMD - 1.55, 95% CI - 1.97 to - 1.13; p < 0.001), non-high-density lipoprotein cholesterol (non-HDL-C) (WMD - 1.66, 95% CI - 2.06 to - 1.27; p < 0.001), lipoprotein(a) (WMD - 0.99, 95% CI - 1.37 to - 0.62; p < 0.001), apolipoprotein B (WMD - 1.66, 95% CI - 2.04 to - 1.27; p < 0.001), triglycerides (WMD -0.61, 95% CI - 0.76 to - 0.46, p < 0.001), very-low-density lipoprotein cholesterol (WMD - 0.58, 95% CI - 0.73 to - 0.43; p < 0.001) and apolipoprotein A-I (WMD - 0.25, 95% CI - 0.51 to - 0.001; p = 0.049) without affecting HDL-C levels (WMD 0.11, 95% CI - 0.03 to 0.26; p = 0.124). However, treatment with mipomersen was positively associated with an increased risk of discontinuation of treatment (OR 3.02, 95% CI 1.96-4.65; p < 0.001), injection-site reaction (OR 11.41, 95% CI 7.88-16.52; p < 0.001), hepatic steatosis (OR 4.96, 95% CI 1.99-12.39; p = 0.001), hepatic enzymes elevation (OR 3.61, 95% CI 2.09-6.24; p < 0.001) and flu-like symptoms (OR 2.02, 95% CI 1.45-2.81; p < 0.001). CONCLUSION: Despite favourable effects on the lipid profile, some concerns are reinforced from the safety profile. As a matter of fact, mipomersen therapy is more likely discontinued and associated with increased risk of injection-site reactions, hepatic steatosis, hepatic enzyme elevation, and flu-like symptoms.


Assuntos
Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacologia , Adolescente , Adulto , Idoso , Apolipoproteína A-I/metabolismo , LDL-Colesterol/metabolismo , Fígado Gorduroso/tratamento farmacológico , Feminino , Humanos , Lipídeos , Lipoproteína(a)/metabolismo , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Triglicerídeos/metabolismo
14.
Biomed Res Int ; 2019: 5920485, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881991

RESUMO

Qushi Huayu Decoction (QHD), an important clinically proved herbal formula, has been reported to be effective in treating fatty liver induced by high-fat diet in rats. However, the mechanism of action has not been clarified at the metabolic level. In this study, a urinary metabolomic method based on gas chromatography-mass spectrometry (GC-MS) coupled with pattern recognition analysis was performed in three groups (control, model, and QHD group), to explore the effect of QHD on fatty liver and its mechanism of action. There was obvious separation between the model group and control group, and the QHD group showed a tendency of recovering to the control group in metabolic profiles. Twelve candidate biomarkers were identified and used to explore the possible mechanism. Then, a pathway analysis was performed using MetaboAnalyst 3.0 to illustrate the pathways of therapeutic action of QHD. QHD reversed the urinary metabolite abnormalities (tryptophan, uridine, and phenylalanine, etc.). Fatty liver might be prevented by QHD through regulating the dysfunctions of phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, and tryptophan metabolism. This work demonstrated that metabolomics might be helpful for understanding the mechanism of action of traditional Chinese medicine for future clinical evaluation.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Fígado Gorduroso/tratamento farmacológico , Metabolômica , Triglicerídeos/urina , Animais , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/urina , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Medicina Tradicional Chinesa , Metaboloma/genética , Ratos
15.
Biomed Pharmacother ; 111: 926-933, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841472

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a prevalent disease that is highly associated with the metabolic syndrome and type II diabetes. The development of in vivo models that reflect all nuances of the human NASH pathology is essential for drug discovery and development. We aimed to further characterise a dietary induced model of NASH both biochemically and histologically. In addition, we also investigated whether pioglitazone and liraglutide, drugs that have both been investigated as potential NASH treatments, could modulate the pathological changes induced by the NASH diet. Furthermore, to aid the translation of data from pre-clinical in vivo models, we aimed to adapt the NASH Clinical Research Network (CRN) histological score system for use in rodent studies. METHODS: Sprague Dawley rats were fed a high-fat diet (HFD) for 9 weeks, after which they were switched to a high fat, high cholesterol and cholate diet (HFCC) for 12 weeks. The rats were divided into treatment groups, receiving either 30 mg/kg pioglitazone p.o. SID or liraglutide s.c. 200 µg/kg BID or the respective vehicles. Serum levels of triglycerides (TG), cholesterol (Chol), LDL, HDL, AST and ALT, as well as body weight were assessed in all subjects. Upon termination, the liver was weighed and evaluated histologically using modified NASH-CRN criteria. RESULTS: HFCC feeding induced severe hepatic injury and hepatomegaly as indicated by significant increases in AST, ALT and an increased liver weight. Additionally, HFCC feeding induced dyslipidaemia, significant increases in circulating cholesterol and LDL were observed. No obesogenic effect of the HFCC diet was observed, though the diet did induce insulin resistance. Histological analysis showed that the HFCC diet induced several NASH like features, though it did not induce the development of severe fibrosis. However, microgranulomas were often prevalent in addition to lobular inflammatory foci. Pioglitazone showed little efficacy upon both biochemical and histological features. However, liraglutide induced weight loss, improved glycaemic control, reduced ALT and AST and showed some beneficial effects upon steatosis and lobular inflammation. CONCLUSION: Similar to previous reports we have shown that the atherogenic diet, HFCC, induces a phenotype akin to that seen in human NASH patients. Despite inducing all histological features of NASH, HFCC feeding does not promote the development of significant fibrosis within rodents. Pioglitazone and liraglutide have been investigated as potential NASH treatments. Within this model of NASH we have shown that pioglitazone has little efficacy, whereas liraglutide reduced the levels of circulating aminotransferases and had some beneficial effects upon NASH histological parameters.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Liraglutida/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR gama/agonistas , Pioglitazona/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Glicemia/efeitos dos fármacos , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/sangue , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos , Ratos Sprague-Dawley , Roedores/sangue , Roedores/metabolismo , Triglicerídeos/sangue
16.
Int J Mol Sci ; 20(5)2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30862092

RESUMO

The present study aimed to investigate the molecular mechanisms underlying the anti-obesity effect of flavonoid eriodictyol (ED) supplementation in mice fed with a high-fat diet (HFD). C57BL/6N mice were fed with normal diet (ND), HFD (40 kcal% fat), or HFD + 0.005% (w/w) ED for 16 weeks. In HFD-induced obese mice, dietary ED supplementation significantly alleviated dyslipidemia and adiposity by downregulating the expression of lipogenesis-related genes in white adipose tissue (WAT), while enhancing fecal lipid excretion. ED additionally improved hepatic steatosis and decreased the production of pro-inflammatory cytokines by downregulating the expression of hepatic enzymes and the genes involved in lipogenesis and upregulating the expression of hepatic fatty acid oxidation-related enzymes and genes. In addition, ED improved insulin resistance (IR) by suppressing hepatic gluconeogenesis, enhancing glucose utilization, and modulating the production and release of two incretin hormones, namely gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Taken together, the current findings indicated that ED can protect against diet-induced obesity and related metabolic disturbances, including dyslipidemia, inflammation, fatty liver disease, and IR in diet-induced obese mice.


Assuntos
Adiposidade/efeitos dos fármacos , Suplementos Nutricionais , Fígado Gorduroso/metabolismo , Flavanonas/farmacologia , Inflamação/metabolismo , Resistência à Insulina , Obesidade/etiologia , Obesidade/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipocinas/metabolismo , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Notificação de Doenças , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico
17.
Biomed Pharmacother ; 114: 108781, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30903919

RESUMO

AIMS: Activation of brown adipose tissue (BAT) thermogenesis could contribute to energy expenditure, which is critical for the treatment of obesity and type 2 diabetes mellitus (T2DM). In the present study, we aimed to systematically investigate whether traditional Chinese medication Jinlida (JLD) granules could improve metabolic disorders and activate BAT thermogenesis in C57BL/6 J mice fed with a high-fat diet (HFD). METHODS: In the present study, JLD (3.8 g/kg) in 0.5% of carboxymethyl cellulose (CMC) solution was administrated daily by oral gavage to HFD-induced mice for 15 weeks. The body weight, biochemical analysis, histology analysis, intraperitoneal glucose and insulin tolerance (OGTT and ITT) tests were measured to explore metabolic disorders. Cold tolerance test, real-time PCR (qRT-PCR), immunohistochemistry, and western blot were performed to evaluate BAT function. RESULTS: As results, JLD treatment significantly ameliorated HFD-induced obesity and fat mass gain, maintained glucose and lipid homeostasis, and improved hepatic steatosis and inflammation. More importantly, we observed that JLD markedly activated BAT thermogenesis in HFD-induced obese mice. Moreover, our data confirmed that JLD promoted mitochondrial biogenesis and fatty acid oxidation metabolism in BAT. CONCLUSIONS: These data suggested that JLD could improve metabolic disorders in associated with activation of BAT thermogenesis via enhancement of mitochondrial biogenesis and fatty acid oxidation metabolism, thus providing a new pharmacological evidence for the clinical usage of JLD in T2DM treatment.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Doenças Metabólicas/tratamento farmacológico , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Termogênese/efeitos dos fármacos
18.
Fish Shellfish Immunol ; 88: 496-507, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30826414

RESUMO

In this study, two experiments were performed to explore the effect of Radix Bupleuri extracts (RBE) on growth, lipid deposition and metabolism and immune response of hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀) using in vitro and in vivo models. In vitro, we used 2 ml/L 20% lipid emulsion (LE)-induced steatosis in hybrid grouper primary hepatocytes, then RBE (200, 400 and 800 µg/ml) was added to the hepatocytes after (post-treatment) the incubation with 20% LE (2 ml/L) in the culture medium. We found that RBE markedly increased cell viability, which were consistent with hepatocytes morphological structure examination and lipid metabolism and immune related genes study. The above result suggested that RBE has a protective effect on this model of hepatocytes damage. In vivo, five graded levels of RBE at 0, 200, 400, 800 and 1600 mg/kg diet were supplemented to a basal diet with 15% lipid levels (high lipid), and fed to a total of 300 hybrid grouper with an average initial weight of 25.58 ±â€¯0.05 g for 8 weeks. Growth performance, liver histology, plasma biochemical parameters, and expression of genes involved in lipid metabolism and immune-related were measured. The study indicated that dietary RBE significantly improved growth performance and feed utilization and reduced hepatosomatic index. Dietary supplementation with 200-800 mg/kg RBE diets effectively decreased serum ALP, ALT, AST and LDH contents in fish. Furthermore, adipogenesis relative mRNA levels of DGAT2, G6PD, ME1 and DGKα in fish fed 200-400 mg/kg RBE diets were lower (P < 0.05) than in those fed RBE0 diets, while dietary supplementation with 200-800 mg/kg RBE diets up-regulated lipolysis-related genes (CPT1, LPL and PPARα) expression in the liver of hybrid grouper. Moreover, dietary RBE down-regulated the expression of apoptosis-related genes (caspase-9), up-regulated the expression of antioxidant genes (CAT) and immune-related genes (MHC2, IKKα and TGF-ß1). Thus, our data suggest that RBE suppressed lipid accumulation and enhanced immune capability in hybrid grouper both in vitro and in vivo. These results offer new insight into RBE as a hepatoprotective in fish.


Assuntos
Bass/imunologia , Suplementos Nutricionais/análise , Fígado Gorduroso/veterinária , Hepatócitos/metabolismo , Metabolismo dos Lipídeos , Extratos Vegetais/administração & dosagem , Ração Animal/análise , Animais , Apoptose , Bass/genética , Bass/crescimento & desenvolvimento , Caspase 9/genética , Sobrevivência Celular , Células Cultivadas , Fígado Gorduroso/tratamento farmacológico , Feminino , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Hibridização Genética , Lipólise , Fígado/imunologia , Fígado/metabolismo , Masculino , Raízes de Plantas/química , RNA Mensageiro
19.
Drugs ; 79(Suppl 1): 39-44, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30706422

RESUMO

L-ornithine L-aspartate (LOLA) has been known as an effective ammonia-lowering agent for more than 50 years with good evidence in hepatic encephalopathy. Administration of LOLA removes ammonia via two distinct mechanisms: by synthesis of urea and by the synthesis of glutamine via the enzyme glutamine synthetase. While LOLA has been used in cirrhosis and acute liver injury settings, it is less clear if LOLA could be used in non-alcoholic fatty liver disease (NAFLD). NAFLD and the progressive form non-alcoholic steatohepatitis (NASH) are currently the leading causes of chronic liver disease worldwide, with roughly 25% of the world population affected by NAFLD. Consequences of NASH are end-stage liver disease and cardiovascular morbidity and mortality. As the basis for NAFLD is excess calorie uptake and excess adipose tissue mass, the conservative therapeutic approach is weight loss by intense lifestyle change. However, no pharmacological treatment options are currently approved. LOLA is being investigated as a pharmacological tool to ameliorate liver injury in NAFLD on the basis that it lowers liver ammonia concentrations and supplies anti-oxidative glutamine and glutathione. Indirect hepatoprotective effects currently under investigation could also be beneficial.


Assuntos
Dipeptídeos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Amônia/sangue , Animais , Antioxidantes/metabolismo , Dipeptídeos/administração & dosagem , Dipeptídeos/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Glutamina/metabolismo , Glutationa/metabolismo , Humanos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Transdução de Sinais
20.
Chin J Nat Med ; 17(1): 3-14, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30704621

RESUMO

Metabolic syndrome characterized by obesity, hyperglycemia and liver steatosis is becoming prevalent all over the world. Herein, a water insoluble polysaccharide (WIP) was isolated and identified from the sclerotium of Poria cocos, a widely used Traditional Chinese Medicine. WIP was confirmed to be a (1-3)-ß-D-glucan with an average Mw of 4.486 × 106 Da by NMR and SEC-RI-MALLS analyses. Furthermore, oral treatment with WIP from P. cocos significantly improved glucose and lipid metabolism and alleviated hepatic steatosis in ob/ob mice. 16S DNA sequencing analysis of cecum content from WIP-treated mice indicated the increase of butyrate-producing bacteria Lachnospiracea, Clostridium. It was also observed that WIP treatment elevated the level of butyrate in gut, improved the gut mucosal integrity and activated the intestinal PPAR-γ pathway. Fecal transplantation experiments definitely confirmed the causative role of gut microbiota in mediating the benefits of WIP. It is the first report that the water insoluble polysaccharide from the sclerotium of P. cocos modulates gut microbiota to improve hyperglycemia and hyperlipidemia. Thereby, WIP from P. cocos, as a prebiotic, has the potential for the prevention or cure of metabolic diseases and may elucidate new mechanism for the efficacies of this traditional herbal medicine on the regulation of lipid and glucose metabolism.


Assuntos
Polissacarídeos Fúngicos/farmacologia , Polissacarídeos Fúngicos/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Wolfiporia/química , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Butiratos/metabolismo , Fígado Gorduroso/tratamento farmacológico , Polissacarídeos Fúngicos/química , Microbioma Gastrointestinal/genética , Hiperglicemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Obesos , Prebióticos
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