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1.
Medicine (Baltimore) ; 99(31): e20960, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756082

RESUMO

BACKGROUND: The number of children with nonalcoholic fatty liver disease (NAFLD) is proliferating. However, currently, there are no drugs approved for the management of NAFLD. There have been some studies on vitamin D and NAFLD in children. However, the effectiveness of vitamin D in children with NAFLD has not been systematically evaluated. The objective of this systematic review will be to evaluate the effectiveness of vitamin D in children with NAFLD. METHODS: We will search through PubMed, Google Scholar, Cochrane Library, Web of Science, and the ClinicalTrials.gov website without restriction on publishing status. To supplement our search strategy, we will scan the reference lists of the identified studies for detailed evaluation for additional possible eligible studies, and we will also search conference proceedings related to this topic. All databases were searched from inception to present. Any clinical randomized controlled trials related to vitamin D supplement for treating NAFLD (simple steatosis/NAFL and NASH) in children will be included. NAFLD had to be diagnosed by liver histology, imaging (ultrasound, computer tomography, magnetic resonance imaging). The primary outcomes will be changes in liver fibrosis and liver enzymes. The variations in serum vitamin D level, BMI, insulin levels, lipid profiles, liver fat content will also be assessed. All statistical analyses will be carried out using RevMan, version 5.3, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. RESULTS: This study will provide a comprehensive high-quality synthesis to evaluate the effectiveness of vitamin D supplementation in children with NAFLD. CONCLUSION: This systematic review and meta-analysis will provide evidence to judge whether vitamin D supplementation is an effective intervention for children with NAFLD. REGISTRATION NUMBER: INPLASY202050049.


Assuntos
Suplementos Nutricionais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Criança , Humanos , Resultado do Tratamento
2.
Medicine (Baltimore) ; 99(32): e21568, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769900

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries, and strongly associated with type 2 diabetes mellitus (T2DM). Several studies have shown that hypoglycemic agents are effective for NAFLD combined with T2DM. However, there is still controversy over which hypoglycemic agent is the best for NAFLD combined with T2DM patients. OBJECTIVE: To systematically evaluate the efficacy and safety of hypoglycemic agents in NAFLD combined with T2DM patients. METHODS: A comprehensive electronic search will be conducted by searching Web of Science, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Clinical Trials and Chinese Biomedical Medicine. All randomized controlled trials of hypoglycemic agents interventions for NAFLD combined with T2DM will be identified. Two reviewers independently screened and evaluated each included study and extracted the outcome indexes. ADDIS 1.16.8 software will be used for the network meta-analysis and STATA 14 software will be used for drawing network evidence plots and funnel plots. CONCLUSION: This network meta-analysis will provide stronger evidence for the efficacy and safety of hypoglycemic agents in the treatment of NAFLD combined with T2DM, and provide a reference for clinical application. PROTOCOL REGISTRATION NUMBER: INPLASY202070016.


Assuntos
Protocolos Clínicos , Hipoglicemiantes/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Metanálise como Assunto , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Revisões Sistemáticas como Assunto
3.
Nat Commun ; 11(1): 3360, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620763

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is considered the next major health epidemic with an estimated 25% worldwide prevalence. No drugs have yet been approved and NAFLD remains a major unmet need. Here, we identify MCJ (Methylation-Controlled J protein) as a target for non-alcoholic steatohepatitis (NASH), an advanced phase of NAFLD. MCJ is an endogenous negative regulator of the respiratory chain Complex I that acts to restrain mitochondrial respiration. We show that therapeutic targeting of MCJ in the liver with nanoparticle- and GalNAc-formulated siRNA efficiently reduces liver lipid accumulation and fibrosis in multiple NASH mouse models. Decreasing MCJ expression enhances the capacity of hepatocytes to mediate ß-oxidation of fatty acids and minimizes lipid accumulation, which results in reduced hepatocyte damage and fibrosis. Moreover, MCJ levels in the liver of NAFLD patients are elevated relative to healthy subjects. Thus, inhibition of MCJ emerges as an alternative approach to treat NAFLD.


Assuntos
Ácidos Graxos/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Fígado/patologia , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Chaperonas Moleculares/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Adulto , Idoso , Animais , Conjuntos de Dados como Assunto , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Proteínas de Choque Térmico HSP40/antagonistas & inibidores , Proteínas de Choque Térmico HSP40/genética , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/genética , Chaperonas Moleculares/antagonistas & inibidores , Chaperonas Moleculares/genética , Nanopartículas/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredução/efeitos dos fármacos , Cultura Primária de Células , RNA Interferente Pequeno/administração & dosagem , RNA-Seq
4.
Life Sci ; 257: 118090, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679144

RESUMO

AIMS: This study aimed to investigate oxymatrine via regulating miR-182 improved the hepatic lipid accumulation in non-alcoholic fatty liver disease (NAFLD) model. MATERIALS AND METHODS: Wistar rats were fed high-fat and high-fructose diet (HFDHFr group) for 4 weeks and HepG2 cells were treated with palmitic acid (PA group), and then were given oxymatrine intervention. The expression profiles of miRNAs were accessed by RNA sequencing (RNA-Seq). Hematoxylin-eosin (HE) staining and Oil Red O staining were used to observe the inflammation and lipid accumulation in liver. The levels of sterol regulatory element binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty-acid synthase (FAS) and carnitine palmitoyltransferase 1A (CPT-1A) were detected by RT-qPCR and Western blotting, respectively. Cell viability was detected by Cell Counting Kit-8 (CCK-8). KEY FINDINGS: miR-182 was down-regulated in the HFDHFr group and PA group. Oxymatrine reduced body weight, and improved glucose tolerance and insulin resistance in the HFDHFr + OMT group compared with HFDHFr group. In addition, oxymatrine reduced the ratio (liver weight/body weight), the content of triglycerides (TG), hepatic lipid accumulation and steatosis. The levels of SREBP-1c, ACC, and FAS were significantly decreased, while the CPT-1A level was obviously elevated after oxymatrine intervention (P < 0.05). In vivo, miR-182 knockdown increased the levels of SREBP-1c, ACC and FAS, while reduced the CPT-1A level. Additionally, oxymatrine attenuated the effects of miR-182 inhibitor on lipid accumulation. SIGNIFICANCE: We presented a possible mechanism that oxymatrine alleviated hepatic lipid metabolism via regulating miR-182 in NAFLD model.


Assuntos
Alcaloides/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Quinolizinas/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Ácido Palmítico/administração & dosagem , Ratos , Ratos Wistar
5.
Medicine (Baltimore) ; 99(27): e20695, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629641

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is seriously affecting the general health due to its high prevalence and associated risk of liver-related consequences and extrahepatic chronic complications. New drugs are urgently needed for the treatment of NAFLD. The purpose of this meta-analysis is to assess the efficacy of incretin-based therapies in patients with NAFLD. METHODS: We will search 4 databases for relative studies: PubMed, Cochrane Library, Embase, and Web of Science databases and identified all reports of randomized controlled trials (RCTs) published from inception to July 2020. Two authors will independently scan the searched articles, extract the data from included articles, and assess the risk of bias by Cochrane tool of risk of bias. Disagreements will be resolved by discussion among authors. All analysis will be performed based on the Cochrane Handbook for Systematic Reviews of Interventions. Fixed-effects model or random-effects model will be used to calculate pooled estimates of weighted mean difference (WMD) with 95% confidence intervals (CIs) or odds ratio (OR) with 95% CIs. RESULTS: This systematic review aims to examine the effect of incretin-based therapies on liver histology, liver fat content, liver enzymes, and adverse events in patients with NAFLD. CONCLUSIONS: These findings will provide guidance to clinicians and patients on the use of incretin-based therapies for NAFLD.


Assuntos
Incretinas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto
6.
Arch Biochem Biophys ; 690: 108505, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679195

RESUMO

Obesity has major adverse consequences on human health contributing to the development of, among others, insulin resistance and type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, altered behavior and cognition, and cancer. Changes in dietary habits and lifestyle could contribute to mitigate the development and/or progression of these pathologies. This review will discuss current evidence on the beneficial actions of the flavan-3-ol (-)-epicatechin (EC) on obesity-associated comorbidities. These benefits can be in part explained through EC's capacity to mitigate several common events underlying the development of these pathologies, including: i) high circulating levels of glucose, lipids and endotoxins; ii) chronic systemic inflammation; iii) tissue endoplasmic reticulum and oxidative stress; iv) insulin resistance; v) mitochondria dysfunction and vi) dysbiosis. The currently known underlying mechanisms and cellular targets of EC's beneficial effects are discussed. While, there is limited evidence from human studies supplementing with pure EC, other studies involving cocoa supplementation in humans, pure EC in rodents and in vitro studies, support a potential beneficial action of EC on obesity-associated comorbidities. This evidence also stresses the need of further research in the field, which would contribute to the development of human dietary strategies to mitigate the adverse consequences of obesity.


Assuntos
Catequina/farmacologia , Obesidade/tratamento farmacológico , Animais , Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Comorbidade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Disbiose/metabolismo , Dislipidemias/metabolismo , Retículo Endoplasmático/metabolismo , Endotoxinas/metabolismo , Flavonoides/farmacologia , Humanos , Inflamação/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Transtornos Mentais/complicações , Transtornos Mentais/tratamento farmacológico , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Estresse Oxidativo
7.
Eur J Endocrinol ; 183(3): R57-R73, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32508312

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem with a global prevalence of over 25% and prevalence rates of over 60% in high-risk populations. It is considered the hepatic component of the metabolic syndrome and is associated with an increased risk of the development of various liver-associated and cardiometabolic complications. Given the complexity of NAFLD and associated comorbidities and complications, treatment requires interventions from a variety of different healthcare specialties. However, many clinicians are currently insufficiently aware of the potential harm and severity of NAFLD and associated comorbidities, complications and the steps that should be taken when NAFLD is suspected. Recognizing which patients suffer from non-progressive simple steatosis, metabolically active NASH with high risk of developing cardiovascular disease and which patients have a high risk of developing cirrhosis and hepatocellular carcinoma is important. Unfortunately, this can be difficult and guidelines towards the optimal diagnostic and therapeutic approach are ambivalent. Here we review the pathogenesis, diagnostics and treatment of NAFLD and discuss how multidisciplinary care path development could move forward.


Assuntos
Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/patologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/cirurgia , Humanos , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/cirurgia
8.
Expert Opin Pharmacother ; 21(13): 1637-1650, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32543284

RESUMO

INTRODUCTION: Chronic liver disease is due to various causes of persistent liver damage and will eventually lead to the development of liver fibrosis. If no treatment is initiated, this condition may progress to cirrhosis and hepatocellular carcinoma. Current treatments comprise the elimination of the cause of injury, such as by lifestyle changes, alcohol abstinence, and antiviral agents. However, such etiology-driven therapy is often insufficient in patients with late-stage fibrosis/cirrhosis, therefore maintaining the need for efficient antifibrotic pharmacotherapeutic interventions. AREAS COVERED: The authors discuss the recent advances in the development of antifibrotic drugs, which target various pathways of the fibrogenesis process, including cell death, inflammation, gut-liver axis, and myofibroblast activation. Due to the significant burden of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), various agents which specifically target metabolic pathways and their related receptors/ligands have been developed. For some of them, e.g., obeticholic acid, advanced stage clinical trials indicate antifibrotic efficacy in NAFLD and NASH. EXPERT OPINION: Significant advances have been made in the development of novel antifibrotic pharmacotherapeutics. The authors expect that the development of combinatorial therapies, which combine compounds that target various pathways of fibrosis progression, will have a major impact as future etiology-independent therapies.


Assuntos
Cirrose Hepática/tratamento farmacológico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Ensaios Clínicos como Assunto , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
9.
Lancet Gastroenterol Hepatol ; 5(9): 829-838, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32553151

RESUMO

BACKGROUND: Diacylglycerol-O-acyltransferase 2 (DGAT2) is one of two enzyme isoforms that catalyse the final step in the synthesis of triglycerides. IONIS-DGAT2Rx is an antisense oligonucleotide inhibitor of DGAT2 that is under clinical investigation for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The aim of this trial was to examine the safety, tolerability, and efficacy of IONIS-DGAT2Rx versus placebo in reducing liver fat in patients with type 2 diabetes and NAFLD. METHODS: This double-blind, randomised, placebo-controlled, phase 2 study consisted of a 2-week screening period, a run-in period of up to 4 weeks, a 13-week treatment period of once-weekly dosing, and a 13-week post-treatment follow-up period. The study was done at 16 clinical research sites in Canada, Poland, and Hungary. Eligible participants were aged 18-75 years, had a body-mass index at screening between 27 kg/m2 and 39 kg/m2, haemoglobin A1c (HbA1c) levels from 7·3% to 9·5%, and liver fat content 10% or greater before randomisation, and agreed to maintain a stable diet and exercise routine throughout the study. Enrolled participants were stratified on the basis of liver fat content during the run-in period (<20% or ≥20%) and then centrally randomised (2:1) to receive once weekly subcutaneous injection of 250 mg IONIS-DGAT2Rx or placebo for 13 weeks. Participants, investigators, funder personnel, and the clinical research organisation staff, including central readers of MRI scans, were all masked to treatment identity. The primary endpoints were the safety, tolerability, and pharmacodynamic effect of IONIS-DGAT2Rx on hepatic steatosis, according to absolute reduction from baseline in liver fat percentage as quantified by MRI-estimated proton density fat fraction and assessed in the per-protocol population. Pharmacodynamic performance was determined in the per-protocol population by the change in liver fat content from baseline to 2 weeks after the last dose. The per-protocol population included all randomised participants who received at least ten doses of study drug, with the first four doses administered in the first 5 weeks, did not miss more than three consecutive weekly doses, and who had no protocol deviations that might affect efficacy. All randomised participants who received at least one dose of study drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT03334214. FINDINGS: Between Nov 3, 2017, and Nov 28, 2018, we screened 173 people for eligibility. 44 were enrolled and randomly assigned to receive either IONIS-DGAT2Rx (29 participants) or placebo (15 participants). After 13 weeks of treatment, the mean absolute reduction from baseline was -5·2% (SD 5·4) in the IONIS-DGAT2Rx group compared with -0·6% (6·1) in the placebo group (treatment difference -4·2%, 95% CI -7·8 to -0·5, p=0·026). Reductions in liver fat were not accompanied by hyperlipidaemia, elevations in serum aminotransferases or plasma glucose, changes in bodyweight, or gastrointestinal side-effects compared with placebo. Six serious adverse events occurred in four patients treated with IONIS-DGAT2Rx. No serious adverse events were reported in the placebo group. One of four patients reported three serious adverse events: acute exacerbation of chronic obstructive pulmonary disease, cardiac arrest, and ischaemic cerebral infarction, each considered severe and not related to study drug. Three of four patients reported one serious adverse event of increased blood triglycerides (severe, unrelated to study drug), deep-vein thrombosis (severe, unlikely to be related to study drug), and acute pancreatitis (mild, unrelated to study drug). INTERPRETATION: Our results suggest that DGAT2 antisense inhibition could be a safe and efficacious strategy for treatment of NAFLD and support further investigation in patients with biopsy-proven NASH. Based on the pharmacological target, the response to treatment observed in this study population could extend to the broader population of patients with NAFLD. FUNDING: Ionis Pharmaceuticals.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Oligonucleotídeos Antissenso/antagonistas & inibidores , Idoso , Índice de Massa Corporal , Canadá/epidemiologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diacilglicerol O-Aciltransferase/administração & dosagem , Diacilglicerol O-Aciltransferase/efeitos adversos , Diacilglicerol O-Aciltransferase/farmacologia , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Humanos , Hungria/epidemiologia , Injeções Subcutâneas , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/efeitos dos fármacos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/farmacologia , Placebos/administração & dosagem , Polônia/epidemiologia , Segurança , Resultado do Tratamento
10.
Medicine (Baltimore) ; 99(24): e20624, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541499

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), especially non-alcoholic steatohepatitis, which is considered as the hepatic manifestation of metabolic syndrome, has a great prevalence all over the world. New drugs are urgently needed for the treatment of NAFLD. This review will be to assess the efficacy and safety of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on liver-related outcomes (liver histology and liver enzymes) in patients with NAFLD. METHODS: We will search 5 databases for relative studies: Medline, the Cochrane Library, EMBASE, Web of Science, and ClinicalTrials.gov and identified all reports of randomized controlled trials published prior to July 2020. Two authors will independently scan the articles searched, extract the data from articles included, and assess the risk of bias by Cochrane tool of risk of bias. Disagreements will be resolved by discussion among authors. All analysis will be performed based on the Cochrane Handbook for Systematic Reviews of Interventions. Fixed-effects model or random-effects model will be used to calculate pooled estimates of weighted mean difference with 95% confidence intervals. RESULTS: This systematic review aims to examine the effect of n-3 PUFAs on liver histology and liver enzymes in patients with NAFLD. CONCLUSIONS: These findings will provide guidance to clinicians and patients on the use of n-3 PUFAs for NAFLD. ETHICS AND DISSEMINATION: This study is a protocol for a systematic review of n-3 PUFAs as a treatment of NAFLD patients. This review will be published in a journal and disseminated in print by peer-review. SYSTEMATIC REVIEW REGISTRATION: INPLASY202050008.


Assuntos
Ácidos Graxos Ômega-3/uso terapêutico , Metanálise como Assunto , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Ácidos Graxos Ômega-3/efeitos adversos , Humanos , Fígado/enzimologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
11.
Toxicol Appl Pharmacol ; 401: 115101, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512072

RESUMO

Non-alcoholic steatohepatitis (NASH) is becoming of increasing significance due to its growing global prevalence and risk of progression to end-stage liver disease. This study was carried out to investigate the potential anti-inflammatory, insulin sensitizing, and antifibrotic effects of diosmin in an experimental model of NASH induced in rats using high-fat diet (HFD) and 30 mg/kg streptozotocin (STZ). Diosmin was administered orally at dose of 100 mg/kg for 8 weeks. Stained tissue sections were examined for histopathological signs of NASH, collagen deposition, and alpha smooth muscle actin (α-SMA) expression. In addition, insulin resistance, dyslipidemia, inflammation, and fibrosis markers were assessed. HFD/STZ successfully induced different NASH features such as insulin resistance seen by elevated fasting blood glucose levels and homeostasis model assessment for insulin resistance. Moreover, induced rats demonstrated dyslipidemia, a significant elevation in tumor necrosis factor alpha (TNF-α) and interleukin-6 levels, and an imbalance in the oxidative status of the liver. Those events altogether precipitated initiation of liver fibrosis as confirmed by elevated transforming growth factor beta (TGF-ß) levels. Treatment with diosmin demonstrated multiple beneficial effects as it significantly ameliorated histopathological NASH findings, lowered TNF-α, interleukin-6, and malondialdehyde levels, improved lipid and glucose metabolism, and lowered hepatic TGF-ß, α-SMA, and collagen content compared to untreated rats. The present study represents a drug repositioning scenario as diosmin is widely used for management of blood vessel disorders and is known to be well tolerated. This encourages the extension of our study to the clinical setting to explore diosmin effects in NASH patients.


Assuntos
Diosmina/uso terapêutico , Resistência à Insulina/fisiologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Diosmina/farmacologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Cirrose Hepática/etiologia , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
12.
Am J Physiol Gastrointest Liver Physiol ; 319(1): G87-G96, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32475129

RESUMO

Hydroxysteroid sulfotransferase 2B1b (SULT2B1b) plays a critical role in hepatic energy homeostasis. Liver X receptors (LXRs) are implicated in multiple physiological functions, including the inhibition of hepatocyte proliferation and regulation of fatty acid and cholesterol metabolism. We have previously reported that SULT2B1b promotes hepatocyte proliferation by inactivating LXR signaling in vivo and in vitro, leading to our hypothesis that SULT2B1b promotes fatty liver regeneration. In the present study, female C57BL/6 and S129 mice were fed a high-fat diet for 8 wk to establish a nonalcoholic fatty liver disease (NAFLD) mouse model. 70% partial hepatectomy (PH) was performed to induce liver regeneration. Our experiments revealed that the SULT2B1b overexpression significantly promotes the regeneration of hepatocytes in NAFLD C57BL/6 mice after PH, increasing liver regrowth by 11% within 1 day, and then by 21%, 33%, and 24% by 2, 3, and 5 days post-PH, respectively. Compared with the wild-type NAFLD S129 mice, SULT2B1 deletion NAFLD S129 mice presented reduced hepatocyte regeneration at postoperative day 2, as verified by decreased liver regrowth (37.4% vs. 46.1%, P < 0.05) and the results of immunohistochemical staining, quantitative real-time polymerase chain reaction, and Western blot analysis. Moreover, LXRα signaling and SULT2B1b expression are highly correlated in the regeneration of NAFLD mouse liver; SULT2B1b overexpression suppresses LXRα signaling, while the LXRα-signaling agonist T0901317 blocks SULT2B1b-induced hepatocyte regeneration in NAFLD mouse liver. Thus, the upregulation of SULT2B1b may promote hepatocyte regeneration via the suppression of LXRα activation in NAFLD mice, providing a potential strategy for improving hepatic-steatosis-related liver regeneration disorders.NEW & NOTEWORTHY This study demonstrates for the first time that hydroxysteroid sulfotransferase 2B1b (SULT2B1b) overexpression promotes the regeneration of fatty liver after partial hepatectomy in mice with nonalcoholic fatty liver disease, while reducing triglyceride accumulation in the regenerative fatty liver. Liver X receptor signaling may be crucial in the SULT2B1b-mediated regeneration of fatty liver. Thus, SULT2B1b may be a potential target for treating hepatic steatosis-related liver regeneration disorders.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Regeneração Hepática/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Hepatectomia/métodos , Hidrocarbonetos Fluorados/farmacologia , Metabolismo dos Lipídeos/fisiologia , Receptores X do Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Sulfonamidas/farmacologia
13.
PLoS One ; 15(5): e0232630, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32357187

RESUMO

Inflammation plays an essential role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Berberine (BBR), an isoquinoline alkaloid isolated from Chinese medicinal herbs, has been widely used to treat various diseases, including liver diseases for hundreds of years. The previous studies have shown that BBR inhibits high fat-diet-induced steatosis and inflammation in rodent models of NAFLD. However, the underlying molecular mechanisms remain unclear. This study is aimed to identify the potential mechanisms by which BBR inhibits free fatty acid (FFA) and LPS-induced inflammatory response in mouse macrophages and hepatocytes. Mouse RAW264.7 macrophages and primary mouse hepatocytes were treated with palmitic acid (PA) or LPS or both with or without BBR (0-10 µM) for different periods (0-24 h). The mRNA and protein levels of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, MCP-1) and ER stress genes (CHOP, ATF4, XBP-1) were detected by real-time RT-PCR, Western blot and ELISA, respectively. The results indicated that BBR significantly inhibited PA and LPS-induced activation of ER stress and expression of proinflammatory cytokines in macrophages and hepatocytes. PA/LPS-mediated activation of ERK1/2 was inhibited by BBR in a dose-dependent manner. In summary, BBR inhibits PA/LPS-induced inflammatory responses through modulating ER stress-mediated ERK1/2 activation in macrophages and hepatocytes.


Assuntos
Berberina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Berberina/uso terapêutico , Citocinas/metabolismo , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ácido Palmítico/toxicidade , Células RAW 264.7
14.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(3): 228-235, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32389170

RESUMO

Objective To investigate the effect of inulin on monocytic myeloid-derived suppressor cells (M-MDSCs) and plasma inflammatory cytokines in mouse models with non-alcoholic fatty liver disease (NAFLD). Methods C57BL/6 mice were randomly divided into 4 groups: normal diet group, inulin-treated control group, NAFLD model group and inulin-treated NAFLD model group. The normal diet group and inulin-treated control group were given normal diet daily, while the other two groups were fed high-fat diet (60% fat) instead. Meanwhile, the mice in the two inulin-treated groups were administrated dietary inulin (5 g/kg). After 14 weeks of feeding, the mice were sacrificed and their peripheral blood, liver and spleen cells were collected. The proportion of M-MDSCs in the peripheral blood, spleen and liver cells were separately detected by flow cytometry. Concentrations of plasma inflammatory cytokines including tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) were determined by flow cytometry CBA. Statistical Pearson was used to analyze the correlation between the proportion of M-MDSCs and plasma inflammatory cytokines. Results Compared with the normal diet group, the proportion of M-MDSCs in the peripheral blood, liver and spleen of the NAFLD model group significantly increased, plasma TNF-α level also dramatically increased, but IL-10 concentration showed no significant difference from that of the normal diet group. Conversely, INU treatment, compared with the NAFLD model group without INU treatment, increased the proportion of M-MDSCs in the peripheral blood, liver and spleen notably, decreased plasma TNF-α level, and increased plasma IL-10 concentration. The proportion of M-MDSCs in the peripheral blood, liver and spleen cells of NAFLD mice were negatively correlated with plasma TNF-α level, but positively correlated with plasma IL-10 concentration. Conclusion INU may alleviate the progression of NAFLD via recruiting M-MDSCs in the peripheral blood, liver and spleen and reducing inflammation in mice.


Assuntos
Citocinas/sangue , Inulina/farmacologia , Células Supressoras Mieloides/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Baço/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Células Supressoras Mieloides/citologia , Distribuição Aleatória , Baço/metabolismo
15.
Zhonghua Gan Zang Bing Za Zhi ; 28(4): 338-344, 2020 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-32403887

RESUMO

Objective: To observe the curative effects of berberine in rats with high-fat diet induced non-alcoholic fatty liver and to further explore its possible mechanism. Methods: Twenty-six Sprague-Dawley rats (120-160 g) were randomly divided into 3 groups: control group (n = 8), model group (n = 10) and treatment group (n = 8). Rats in the control group were fed with regular diet, and the model group and the treatment group were fed a high-fat diet. At the 12th week, two rats in the in the model group were sacrificed to verify whether model was successful established. Subsequently, treatment group rats were given a gavage of berberine at a dose of 150 mg·kg(-1)·d(-1) for 4 weeks, and the control and the model group rats were given the same dose of normal saline. Rats were sacrificed at week 16th. HE staining was used to observe the changes in the intestinal mucosa of rats. Sudan black B staining was used to observe the fatty changes in liver. Immunohistochemical staining was used to observe the expression level of occludin protein in the intestinal epithelium. A real-time 16S rDNA PCR method was used to measure the number of escherichia coli, bacteroides and faecalibacterium prausnitzii in the feces of rats. Results: Model group had a higher serum levels of endotoxin (0.288 ± 0.045) and tumor necrosis factor (TNF)-α (1.07 ± 0.11) than the control group (0.192 ± 0.049, 0.94 ± 0.07) (P < 0.05). Berberine intervention had significantly reduced endotoxin (0.213 ± 0.025) and TNF-α level (0.93 ± 0.07) (P < 0.05). The expression level of occludin protein was significantly lower in the intestinal mucosa of model group than that of control group (0.166 ± 0.014), and berberine had promoted the expression of occludin protein in intestinal mucosa (0.055 ± 0.009), but the difference was not statistically significant (P > 0.05). At the same time, compared with the model group (7.29 ± 0.47), the number of bacteroidetes in the control group (9.49 ± 0.59) was decreased, while the number of bacteroidetes in the treatment group was increased (9.77 ± 0.87). The number of escherichia coli (6.92 ± 0.77) and faecalibacterium prausnitzii (8.70 ± 0.62) in the model group were increased than control group (5.42 ± 0.63, 9.49 ± 0.59), while the number of escherichia coli (6.34 ± 0.71) and faecalibacterium prausnitzii (9.77 ± 0.87) (P < 0.05) was reduced with the intervention of berberine. Conclusion: Berberine could effectively protect the intestinal barrier function in rats with NAFLD and the possible mechanism of action behind it may be the regulation of intestinal flora.


Assuntos
Berberina/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Dieta Hiperlipídica , Fígado , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
16.
Medicine (Baltimore) ; 99(19): e20148, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384501

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM), and low vitamin D levels are positively associated with NAFLD and T2DM. But there is absence of convincing evidence-based medicine to confirm the efficacy of vitamin D supplementation for T2DM with NAFLD. Thus, we aimed to conduct this meta-analysis to summarize the efficacy of vitamin D supplementation for T2DM combined with NAFLD, and help to further clarify its beneficial action on diabetic patients with NAFLD. METHODS: The study only selects clinical randomized controlled trials of vitamin D supplementation for T2DM combined with NAFLD. We will search each database from the built-in until July 2020. The English literature mainly searches Cochrane Library, Pubmed, EMBASE, and Web of Science. While the Chinese literature comes from CNKI, CBM, VIP, and Wangfang database. Meanwhile, we will retrieve clinical trial registries and grey literature. Two researchers worked independently on literature selection, data extraction, and quality assessment. The dichotomous data is represented by relative risk (RR), and the continuous is expressed by mean difference (MD) or standard mean difference (SMD), eventually the data is synthesized using a fixed effect model (FEM) or a random effect model (REM) depending on the heterogeneity. The imaging markers of liver, biomarkers of hepatic steatosis, serological indexes of hepatic fibrosis, serum NAFLD liver fat score were evaluated as the main outcomes. While several secondary outcomes were also evaluated in this study. The statistical analysis of this meta-analysis was conducted by RevMan software version 5.3. RESULTS: This meta-analysis will further determine the beneficial efficacy of vitamin D supplementation for T2DM combined with NAFLD. CONCLUSION: This study determines the positive efficacy of vitamin D supplementation for diabetic patients with NAFLD.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Suplementos Nutricionais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Vitamina D/uso terapêutico , Biomarcadores , Humanos , Testes de Função Hepática , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
17.
Internist (Berl) ; 61(7): 759-765, 2020 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-32409850

RESUMO

The prevalence of nonalcoholic fatty liver disease (NAFLD) continues to increase worldwide, presently affecting 25% of the adult population, and is associated with an elevated risk of total and liver-specific mortality. NAFLD is a chronic disease and results from a combination of genetic, environmental and predominantly lifestyle-related causes. Therefore, NAFLD, similarly to cardiovascular disease, type 2 diabetes and many different types of cancer, can be considered a noncommunicable disease. Consequently, lifestyle intervention, particularly if associated with a large amount of weight loss, is considered highly effective and safe to treat NAFLD. For patients with advanced-stage NAFLD or that cannot lose weight, metabolically-based pharmacotherapy is effective to improve liver histology and cardiometabolic risk profile. If a moderate or advanced stage of liver fibrosis is present, additional antifibrotic therapy is necessary to halt the progression of the disease.


Assuntos
Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Adulto , Diabetes Mellitus Tipo 2 , Suplementos Nutricionais , Humanos , Hipolipemiantes/uso terapêutico , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica/metabolismo , Resultado do Tratamento
18.
J Pharmacol Sci ; 143(3): 188-198, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32414691

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease that causes morbidity associated with metabolic syndrome. NAFLD is a worldwide problem and represents a major cause of liver injury, which can lead to liver cell death. We investigated the effects of nonivamide (pelargonic acid vanillylamide, PAVA; 1 mg/kg) and rosuvastatin (RSV; 10 mg/kg) on hepatic steatosis induced by a high-fat diet (HFD). Male Sprague-Dawley rats were fed a HFD for 16 weeks then received PAVA or RSV for 4 additional weeks. We examined the metabolic parameters, function, fat content, histological alterations, reactive oxygen species production, and apoptotic cell death of the liver, in addition to the expression of the following important molecules: transient receptor potential cation channel subfamily V member 1 (TRPV1) phosphorylation of sterol regulatory element binding protein (pSREBP-1c/SREBP-1c), total and membrane glucose transporter 2 (GLUT2), 4-hydroxynonenal (4-HNE), and cleaved caspase-3. HFD-induced hepatic steatosis was associated with significantly increased morphological disorganization, injury markers, oxidative stress, lipid peroxidation, and apoptosis. However, metabolic dysfunction and hepatic injury were reduced by RSV and PAVA treatment. PAVA regulated lipid deposition, improved insulin resistance, and decreased oxidative stress and apoptotic cell death. Therefore, PAVA represents a promising therapeutic approach for treating metabolic disorders in patients with NAFLD.


Assuntos
Capsaicina/análogos & derivados , Capsicum/química , Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Fitoterapia , Aldeídos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Capsaicina/administração & dosagem , Capsaicina/isolamento & purificação , Capsaicina/farmacologia , Caspase 3/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Canais de Cátion TRPV/metabolismo
19.
Life Sci ; 253: 117725, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32348835

RESUMO

AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease. This study aimed to evaluate the role of exenatide compared with metformin in halting the progression of fatty liver stimulated by a high-fat diet (HiFD) in rats. MAIN METHODS: Thirty male Wistar rats were allocated into 6 groups, 5 rats per each group. Group I: maintained on normal diet (normal group) for fourteen weeks. The other five groups were kept on HiFD throughout the experiment, HiFD was administered beside pharmacological treatments/or vehicle. Group II: (NAFLD control group), group III: received metformin (60 mg/kg/day, P.O.), group IV-VI: received exenatide (10, 20, and 40 µg/kg/day, S.C.) respectively for 7 weeks. At the end of the therapeutic period, fasting blood glucose was determined, and body weight was registered. Rats were sacrificed, and blood samples were taken to measure serum insulin, lipids, and liver enzymes. The liver index and homeostasis model of insulin resistance (HOMA-IR) index were calculated. Further, livers were dissected for histopathological examination and Western blot analysis. KEY FINDINGS: NAFLD control group showed hyperglycemia, hyperinsulinemia, increased liver enzymes, hypertriglyceridemia, elevated hepatic lipid peroxides, and inflammatory mediators (interlukin 6, nuclear factor-κB, tumor necrosis factor-α and Toll-like receptor4) in addition to hepatic fatty degeneration. In a dose-dependent manner, exenatide significantly improved most of the above mentioned markers in comparsion with NAFLD at P≤0.05. SIGNIFICANCE: The current results suggest that exenatide is equivalent to metformin in controlling insulin resistance, body weight gain, improving liver function, suppressing inflammation, and attenuating NAFLD progression in male rats.


Assuntos
Exenatida/farmacologia , Hipoglicemiantes/farmacologia , Inflamação/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Progressão da Doença , Relação Dose-Resposta a Droga , Exenatida/administração & dosagem , Hipoglicemiantes/administração & dosagem , Inflamação/patologia , Resistência à Insulina , Masculino , Metformina/farmacologia , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
20.
Expert Opin Pharmacother ; 21(8): 953-967, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32237916

RESUMO

INTRODUCTION: There is an unmet medical need for an effective anti-fibrotic treatment for NASH with advanced fibrosis. AREAS COVERED: The authors review the current and novel agents for the treatment of NASH with fibrosis. They also consider the potential future strategies of combination therapies. EXPERT OPINION: Farnesoid X receptor (FXR) agonist (obeticholic acid [OCA]) significantly ameliorated hepatic fibrosis in NASH stage 2/3 fibrosis in an interim analysis of phase 3 trial. Because OCA has several drawbacks such as itching and elevated low-density lipoprotein-cholesterol (LDL-C), non-bile acid FXR agonists are now under development. Selonsertib (apoptosis signaling kinase 1 inhibitor), emricasan (an irreversible pan-caspase inhibitor), and simtsuzumab (a monoclonal antibody against lysyl oxidase-like 2) were discontinued because of no efficacy over placebo. Peroxisome proliferator-activator receptor α/δ agonists, C-C motif chemokine receptor-2/5 antagonists, and thyroid ß receptor agonist are ongoing in phase 3 trials. A variety of agents including fibroblast growth factor (FGF)-21 and FGF-19 agonists, as well as acetyl-CoA carboxylase inhibitors, are also expected. Among antidiabetic agents, semaglutide, a novel GLP-1 RA, is ongoing for NASH stage 1-3 fibrosis in a phase 2 trial. Furthermore, the combination of GLP-RA/glucagon receptor agonist and GLP-RA/gastrointestinal peptide agonist are promising future options.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pioglitazona/uso terapêutico , Vitamina E/uso terapêutico , Ácido Quenodesoxicólico/administração & dosagem , Ácido Quenodesoxicólico/uso terapêutico , Ensaios Clínicos como Assunto , Fatores de Crescimento de Fibroblastos/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Pioglitazona/administração & dosagem , Receptores Citoplasmáticos e Nucleares/agonistas , Resultado do Tratamento , Vitamina E/administração & dosagem
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