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1.
Einstein (Sao Paulo) ; 18: eAO4876, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31576909

RESUMO

OBJECTIVE: To investigate the effects of sericin extracted from silkworm Bombyx mori cocoon on morphophysiological parameters in mice with obesity induced by high-fat diet. METHODS: Male C57Bl6 mice aged 9 weeks were allocated to one of two groups - Control and Obese, and fed a standard or high-fat diet for 10 weeks, respectively. Mice were then further subdivided into four groups with seven mice each, as follows: Control, Control-Sericin, Obese, and Obese-Sericin. The standard or high fat diet was given for 4 more weeks; sericin (1,000mg/kg body weight) was given orally to mice in the Control-Sericin and Obese-Sericin Groups during this period. Weight gain, food intake, fecal weight, fecal lipid content, gut motility and glucose tolerance were monitored. At the end of experimental period, plasma was collected for biochemical analysis. Samples of white adipose tissue, liver and jejunum were collected and processed for light microscopy analysis; liver fragments were used for lipid content determination. RESULTS: Obese mice experienced significantly greater weight gain and fat accumulation and had higher total cholesterol and glucose levels compared to controls. Retroperitoneal and periepididymal adipocyte hypertrophy, development of hepatic steatosis, increased cholesterol and triglyceride levels and morphometric changes in the jejunal wall were observed. CONCLUSION: Physiological changes induced by obesity were not fully reverted by sericin; however, sericin treatment restored jejunal morphometry and increased lipid excretion in feces in obese mice, suggesting potential anti-obesity effects.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Dieta Hiperlipídica , Obesidade/tratamento farmacológico , Sericinas/uso terapêutico , Tecido Adiposo/patologia , Animais , Fármacos Antiobesidade/farmacologia , Peso Corporal/efeitos dos fármacos , Colesterol/análise , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Fígado Gorduroso/patologia , Trânsito Gastrointestinal/efeitos dos fármacos , Teste de Tolerância a Glucose , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/fisiopatologia , Reprodutibilidade dos Testes , Sericinas/farmacologia , Fatores de Tempo , Resultado do Tratamento , Triglicerídeos/análise , Ganho de Peso/efeitos dos fármacos
2.
Toxicol Lett ; 316: 183-193, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31437515

RESUMO

Olanzapine, a representative of antipsychotics, is a first-line drug for treatment of schizophrenia. However, olanzapine-induced liver steatosis limits its clinical utilization. This study is to explore the mechanism of liver steatosis induced by olanzapine based on the regulation of transporters involved in uptake and oxidation of fatty acids. Our results revealed that 12-week oral administration of olanzapine increased hepatic triglyceride(TG), caused liver steatosis. Our further studies showed that the expression of fatty acid transporter 2(FATP2) and fatty acid binding protein 1(FABP1) were up-regulated in liver of female mice after 12-week olanzapine exposure, as well as in primary mouse hepatocytes treated with olanzapine. Olanzapine treatment also reduced hepatic ß-hydroxybutyrate level (indicator of fatty acid ß-oxidation), meanwhile, the L-carnitine (L-Car) concentration in liver of olanzapine group was significantly lower than that in control group. Further study demonstrated that both mRNA and protein expression of hepatic OCTN2 (carnitine/organic cation transporter 2) were obviously down-regulated in male mice after 12-week olanzapine treatment. Also, olanzapine markedly inhibited L-Car uptake in MDCK-hOCTN2 cells (1.06 µM of IC50), HepG2 cells and primary mouse hepatocytes. Supplementation of L-Car attenuated hepatic TG rise and improved simple steatosis in olanzapine treatment mice. Taken together, up-regulation of FATP2/FABP1 and down-regulation/inhibition of hepatic OCTN2 probably contribute to olanzapine-induced liver steatosis. Supplementation of L-Car is a promising strategy to attenuate olanzapine-induced simple steatosis.


Assuntos
Antipsicóticos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Coenzima A Ligases/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Fígado Gorduroso/induzido quimicamente , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Olanzapina/toxicidade , Membro 5 da Família 22 de Carreadores de Soluto/antagonistas & inibidores , Adulto , Animais , Carnitina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Coenzima A Ligases/genética , Cães , Proteínas de Ligação a Ácido Graxo/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos C57BL , Membro 5 da Família 22 de Carreadores de Soluto/genética , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Regulação para Cima
3.
Transplant Proc ; 51(6): 1679-1683, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31301860

RESUMO

BACKGROUND: Accurate assessment of steatosis in procured livers is crucial to reduce the poor outcome associated with high-grade steatosis and to optimize the utilization of donor grafts. Clinical examination and digital image analysis (DIA) have been used for steatosis evaluation, but the validity of these methods is debated. This study aimed to compare these methods with standard histology for assessment of steatosis severity in human livers and to evaluate a revised classification system for automated fat measurement. METHODS: Clinical assessment of liver steatosis at time of retrieval and automated measurement were compared with standard histology in paraffinized and hematoxylin and eosin-stained slides, using a 4-grade scale for ordinal data and percentages for numerical values. RESULTS: Analysis of 42 human livers that were retrieved but not transplanted showed that clinical examination was not reliable for assigning steatosis grades (κw, 0.12; 95% CI, -0.06 to 0.30), overestimated steatosis severity, and had an accuracy of 67% for discriminating low- and high-grade steatosis. Digital image analysis had a substantial agreement on absolute fat percentage (intraclass correlation coefficient, 0.76; 95% CI, 0.63-0.84) and steatosis grades (κw, 0.70; 95% CI, 0.57-0.82), with 88% accuracy using the revised classification system. CONCLUSIONS: Clinical assessment of steatosis is inaccurate, and relying on this method alone could result in unnecessary discard of livers. Digital image analysis is feasible with higher accuracy and reliability, but further clinical studies are required to evaluate its clinical validity.


Assuntos
Fígado Gorduroso/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/estatística & dados numéricos , Transplante de Fígado , Fígado/diagnóstico por imagem , Transplantes/diagnóstico por imagem , Fígado Gorduroso/patologia , Feminino , Humanos , Fígado/patologia , Masculino , Reprodutibilidade dos Testes , Transplantes/patologia
4.
Arch Virol ; 164(10): 2559-2563, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321587

RESUMO

Polymorphisms in the microsomal triglyceride transfer protein (MTTP) gene were genotyped in individuals who were chronically infected with hepatitis C virus (HCV). In the 236 patients, the frequencies of risk alleles of the -164T/C (rs1800804), -400A/T (rs1800803) and H297Q (rs2306985) polymorphisms were 0.30, 0.41 and 0.50, respectively. A significant association between the risk alleles of the -164T/C and -400A/T polymorphisms combined with HCV genotype 3 infection and the occurrence of steatosis was detected (p = 0.004 and p = 0.032), suggesting that a combination of host and viral factors can potentially be used to predict hepatic steatosis.


Assuntos
Proteínas de Transporte/genética , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Predisposição Genética para Doença , Hepacivirus/classificação , Hepatite C Crônica/complicações , Hepatite C Crônica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Genótipo , Técnicas de Genotipagem , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Histocitoquímica , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto Jovem
5.
Nat Commun ; 10(1): 2375, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147543

RESUMO

Human antigen R (HuR) is a member of the Hu family of RNA-binding proteins and is involved in many physiological processes. Obesity, as a worldwide healthcare problem, has attracted more and more attention. To investigate the role of adipose HuR, we generate adipose-specific HuR knockout (HuRAKO) mice. As compared with control mice, HuRAKO mice show obesity when induced with a high-fat diet, along with insulin resistance, glucose intolerance, hypercholesterolemia and increased inflammation in adipose tissue. The obesity of HuRAKO mice is attributed to adipocyte hypertrophy in white adipose tissue due to decreased expression of adipose triglyceride lipase (ATGL). HuR positively regulates ATGL expression by promoting the mRNA stability and translation of ATGL. Consistently, the expression of HuR in adipose tissue is reduced in obese humans. This study suggests that adipose HuR may be a critical regulator of ATGL expression and lipolysis and thereby controls obesity and metabolic syndrome.


Assuntos
Tecido Adiposo Branco/metabolismo , Proteína Semelhante a ELAV 1/genética , Intolerância à Glucose/genética , Hipercolesterolemia/genética , Resistência à Insulina/genética , Lipase/genética , Obesidade/genética , Adipócitos/patologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/imunologia , Animais , Crescimento Celular , Dieta Hiperlipídica , Proteína Semelhante a ELAV 1/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Intolerância à Glucose/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Hipertrofia , Inflamação/imunologia , Lipase/metabolismo , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Biossíntese de Proteínas , Estabilidade de RNA/genética , Gordura Subcutânea/metabolismo
6.
Acta Histochem ; 121(5): 646-656, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31153588

RESUMO

Obesity, type two diabetes mellitus and insulin resistance are associated with increased oxidative stress and inflammation. Unfermented green rooibos is an aspalathin rich variant of traditional fermented rooibos (Aspalathus linearis) and has a high polyphenol content. The present study aimed to determine the histologically observable effects of a commercially produced, aspalathin-rich green rooibos extract, Afriplex GRT™ (GRE) in a diet-induced obese rat model. Male Wistar rats (N = 28) were randomly assigned to four study groups (n = 7): control (C), green rooibos (GRT), high-fat diet (HFD) and experimental (HFD-GRT) group. Body mass was determined prior to euthanasia and liver mass was determined after death. The left lateral lobe of the liver was processed to wax and stained using haematoxylin and eosin (H & E), Masson's trichrome stain, Gordons and Sweet's reticulin impregnation and periodic acid-Schiff stain. Frozen liver tissue sections were used for Oil red O staining. Morphometric quantification of steatosis, semiquantitative pathology grading and scoring were performed and verified by a veterinary histopathologist. A significant increase in body and liver mass was observed in the HFD groups while co-treatment with green rooibos significantly reduced both. The volume and area of steatosis were significantly increased in the HFD groups while the area of steatosis significantly reduced with green rooibos co-treatment. The percentage, location and type of steatosis as well as presence of inflammation and hepatocellular injury were reduced in the HFD group co-treated with GRE. These findings suggest that a GRE has potential as an anti-steatotic, anti-inflammatory and weight reducing agent in vivo.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Aspalathus , Fígado/citologia , Fígado/patologia , Obesidade/tratamento farmacológico , Fitoterapia , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Fígado Gorduroso/patologia , Histocitoquímica , Masculino , Obesidade/etiologia , Obesidade/patologia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar
7.
Gen Physiol Biophys ; 38(4): 343-352, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31241045

RESUMO

Non-alcoholic fatty liver disease and its complications are frequent causes of liver-related morbidity and mortality. Incretin glucagon-like peptide-1 (GLP-1) affects liver functions and metabolism. Although GLP-1 analogues are widely used in clinical practice, information regarding their potential toxic effect on hepatocytes in vitro is missing. Therefore, we evaluated the effect of GLP-1 analogue liraglutide on activity of caspases 3/7, cell viability and oxidative stress in primary cultures of hepatocytes. Primary cultures isolated from male Wistar rats fed a standard (ST1-group, 10% energy from fat) or a high-fat diet (HF-group, 71% fat) for 10 weeks were incubated with liraglutide (0.1-1000 nmol/l) for 24 h. Activities of caspases 3/7 and cellular dehydrogenases (WST-1), lactate dehydrogenase (LDH) leakage and oxidative stress (malondialdehyde concentration and DCFDA assay) were evaluated. HF-groups vs. ST1-groups showed higher caspases activity, LDH leakage and MDA production (p < 0.001) and lower cellular dehydrogenases activity (p < 0.01). Liraglutide induced a dose-dependent decrease of caspases activity in both groups, reduction of oxidative stress in HF-animals and exerted no negative effects on other parameters. In conclusion, GLP-1 analogue liraglutide decreased activity of caspases 3/7, reduced ROS production and didn't exhibit negative effects on cell viability and oxidative stress in primary cultures of hepatocytes isolated from lean and steatotic livers.


Assuntos
Separação Celular , Fígado Gorduroso/patologia , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Liraglutida/farmacologia , Fígado/citologia , Animais , Células Cultivadas , Masculino , Ratos , Ratos Wistar
8.
Folia Histochem Cytobiol ; 57(2): 74-83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31187872

RESUMO

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease which becomes a rapidly growing health problem in the Western countries. The development of the disease is most often connected to obesity. NAFLD is also considered as the hepatic manifestation of metabolic syndrome. Transforming growth factor b1 (TGF-b1) plays an important role in the pathogenesis of liver fibrosis, being involved in activation of hepatic stellate cells, stimulation of collagen gene transcription, and suppression of matrix metalloproteinase expression. The objective of the study was to evaluate by immunohistochemistry the expression of TGF-b1 in the liver tissue of NAFLD patients and correlate it with anthropometric, biochemical and routine histological parameters. MATERIAL AND METHODS: The study group consisted of 48 patients with diagnosed NAFLD. Liver steatosis, NAFLD Activity Score (NAS) and METAVIR score of fibrosis were evaluated in liver biopsies. The immunoreactivity of TGF-b1 was evaluated semi-quantitatively separately in portal, septal, lobular hepatocytic and lobular sinu-soidal liver compartments. The results were analyzed in regard to patients' clinical and biochemical parameters. RESULTS: Neither steatosis nor NAS correlated with TGF-b1 expression in any liver compartment, whereas METAVIR score of fibrosis was associated with increased immunoreactivity of TGF-b1 in most of the studied liver compartments. TGF-b1 immunoreactivity showed positive correlation with patients' age and its expression in septal compartment disclosed positive correlation with body mass index, and waist and hip circumference. Hyaluronic acid serum level was positively and iron concentration was negatively associated with TGF-b1 ex-pression in the selected consecutive liver compartments. CONCLUSIONS: The immunohistochemical expression of TGF-b1 may be complementary to routine methods of liver fibrosis evaluation.


Assuntos
Cirrose Hepática/imunologia , Fígado/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Fator de Crescimento Transformador beta1/imunologia , Adulto , Peptídeo C/sangue , Fígado Gorduroso/patologia , Feminino , Hemoglobina A Glicada/análise , Haptoglobinas/análise , Humanos , Ácido Hialurônico/sangue , Imuno-Histoquímica , Ferro/sangue , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Fator de Crescimento Transformador beta1/sangue
9.
Molecules ; 24(11)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212585

RESUMO

AIM: To investigate the anti-diabetic activity of amentoflavone (AME) in diabetic mice, and to explore the potential mechanisms. METHODS: Diabetic mice induced by high fat diet and streptozotocin were administered with amentoflavone for 8 weeks. Biochemical indexes were tested to evaluate its anti-diabetic effect. Hepatic steatosis, the histopathology change of the pancreas was evaluated. The activity of glucose metabolic enzymes, the expression of Akt and pAkt, and the glucose transporter type 4 (GLUT4) immunoreactivity were detected. RESULTS: AME decreased the level of glucose, total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and glucagon, and increased the levels of high density lipoprotein cholesterol (HDL-C) and insulin. Additionally, AME increased the activity of glucokinase (GCK), phosphofructokinase-1 (PFK-1), and pyruvate kinase (PK), and inhibited the activity of glycogen synthase kinase-3 (GSK-3), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G-6-Pase). Mechanistically, AME increased superoxide dismutase (SOD), decreased malondialdehyde (MDA), activation of several key signaling molecules including pAkt (Ser473), and increased the translocation to the sedimenting membranes of GLUT4 in skeletal muscle tissue. CONCLUSIONS: AME exerted anti-diabetic effects by regulating glucose and lipid metabolism, perhaps via anti-oxidant effects and activating the PI3K/Akt pathway. Our study provided novel insight into the role and underlying mechanisms of AME in diabetes.


Assuntos
Biflavonoides/química , Biflavonoides/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Animais , Biomarcadores , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental , Jejum , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Glucagon/sangue , Glucose/metabolismo , Teste de Tolerância a Glucose , Insulina/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Lipoproteínas/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Oxirredução/efeitos dos fármacos , Fosforilação
10.
Medicine (Baltimore) ; 98(19): e15606, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083253

RESUMO

To evaluate the feasibility of computed tomography (CT) in the assessment of the change in hepatic steatosis (HS) in longitudinal follow-up by employing pathological HS as the reference standard.We retrospectively evaluated 38 living liver donor candidates (27 men and 11 women; mean age, 29.5 years) who underwent liver biopsy twice and had liver CT scans within 1 week of each biopsy. Four readers independently calculated CTL-S index by subtracting spleen attenuation from liver attenuation on non-enhanced CT images. The changes in pathological HS (ΔHS) and CTL-S (ΔCTL-S) between the 1st and 2nd examinations were assessed. The correlation between ΔHS and ΔCTL-S was assessed using the linear regression analysis. Inter-observer measurement error for ΔCTL-S among the 4 readers was assessed using the repeatability coefficient.ΔCTL-S showed a significant correlation with ΔHS in all readers (r = 0.571-0.65, P < .001). The inter-observer measurement error for ΔCTL-S was ±8.9. The ΔCTL-S values beyond the measurement error were associated with a consistent change in HS in 83.3% (13/15) to 100% (15/15), with sensitivities of 47.8 to 79.9% and specificities of 86.7 to 100% for detecting an absolute change of ≥10% in HS among the 4 readers. However, ΔCTL-S values within the measurement error were associated with a consistent change in HS in 43.5% (8/19) to 61.5% (16/26).The change in CTL-S roughly reflects the change in HS during longitudinal follow-up. A small change in CTL-S should not be considered meaningful, while a larger change in CTL-S beyond the measurement error strongly indicates a true change in HS.


Assuntos
Fígado Gorduroso/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Fígado Gorduroso/patologia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Interpretação de Imagem Assistida por Computador , Fígado/diagnóstico por imagem , Fígado/patologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Retrospectivos , Sensibilidade e Especificidade , Baço/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
11.
Sci Total Environ ; 659: 561-567, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096385

RESUMO

Severe pollution of organohalogen compounds (OHCs) including PBDEs, PCBs and DDTs is demonstrated in e-waste recycling sites and metropolis in South China, but relatively little is known of their impacts on wildlife that inhabits nature reserves in this region, especially those located at the neighborhood areas of e-waste recycling sites. In the present study, PBDEs, PCBs and DDTs as well as liver histological changes were examined in common kingfisher breeding at a nature reserve (Shimentai National Nature Reserve, SNNR) near a notorious e-waste recycling site in South China. Mean ∑PBDEs (84.9 ng/g lipid weight), ∑PCBs (397 ng/g) and ∑TEQs (total toxic equivalent of coplanar PCBs, 2.68 ng/g) concentrations in kingfishers from SNNR were approximately 2-, 5-, and 4-fold higher than those detected in a reference population, respectively; suggesting contamination of the e-waste-derived OHCs in SNNR. Mean ∑DDTs concentration (2150 ng/g) in kingfishers from SNNR was also higher (~2-fold) than that from the reference samples. While ∑DDTs dominated the composition of the OHCs at both sampling sites, ∑PCBs was also important in kingfishers from SNNR, averaging 15% of ∑OHCs. Histological examination of the liver showed steatosis occurred in 60% of the kingfishers from SNNR. Birds with hepatic steatosis had significantly (p = 0.03) higher ∑TEQs than those without steatosis. Similar trends were also found for ∑PCBs and ∑DDTs, although it is not statistically significant. It therefore seems likely that the hepatic steatosis were associated with the relatively high body-burden of OHCs, although the possibility of other factors resulting in hepatic steatosis cannot be ruled out.


Assuntos
Aves , Resíduo Eletrônico , Monitoramento Ambiental , Fígado Gorduroso/veterinária , Hidrocarbonetos Halogenados/análise , Instalações de Eliminação de Resíduos , Poluentes Químicos da Água/análise , Animais , China , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Reciclagem , Estações do Ano
12.
J Pediatr Endocrinol Metab ; 32(5): 537-541, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31075084

RESUMO

Hematopoietic stem cell transplantation (HSCT) has been newly identified as an etiology underlying acquired lipodystrophy (ALD). We report about two children with leukemia who underwent HSCT and later manifested aberrant fat distributions consistent with acquired partial lipodystrophy (APL). Both patients manifested graft-versus-host disease (GVHD), suggesting that GVHD may trigger lipodystrophy. The patients exhibited diabetic blood glucose patterns in the oral glucose tolerance test (OGTT) with high homeostasis model assessment ratios (HOMA-Rs), hypertriglyceridemia, fatty liver, and decreased serum leptin and adiponectin levels. Both patients were diagnosed with APL with metabolic disease. A review of the data of patients with ALD after HSCT revealed common clinical features, including aberrant fat distribution, impaired glucose tolerance (IGT) or diabetes and dyslipidemia. Based on previous reports and our two cases, we speculate that GVHD in the adipose tissue supports the development of ALD after HSCT. In conclusion, children may develop APL after HSCT. Therefore, evaluations of fat distribution and metabolic disease may be important during the long-term follow-up of these patients.


Assuntos
Fígado Gorduroso/etiologia , Intolerância à Glucose/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipertrigliceridemia/etiologia , Leucemia Mieloide Aguda/terapia , Lipodistrofia/etiologia , Doenças Metabólicas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Criança , Fígado Gorduroso/patologia , Feminino , Intolerância à Glucose/patologia , Humanos , Hipertrigliceridemia/patologia , Lactente , Leucemia Mieloide Aguda/patologia , Lipodistrofia/patologia , Doenças Metabólicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico
13.
Transl Res ; 210: 26-42, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31121128

RESUMO

Obesity is a major cause of metabolic syndrome and type II diabetes, and it presents with metabolic disorders, such as hyperglycemia, hyperlipidemia, and insulin resistance. Pigment epithelium-derived factor (PEDF), a protein isolated from retinal pigment epithelial cells, has multiple functions, including neuronal protection, antineoplastic effects, and anti-inflammatory activity. The aim of this study is to investigate the antiobesity effects of PEDF. The antiobesity effects of PEDF on fat accumulation, inflammation, energy expenditure, insulin resistance, and obesity-related physiological parameters and protein levels were assessed in high-fat diet (HFD)-induced obese mice in vivo and in 3T3-L1 adipocytes, palmitate (PA)-treated HepG2 cells, and C2C12 myotubes in vitro. In an in vivo assay, PEDF effectively decreased body weight gain, white adipose tissue mass, and inflammation and improved insulin resistance, dyslipidemia, and hyperglycemia in HFD-induced mice. In liver tissue, PEDF decreased lipid accumulation and fibrosis. In an in vitro assay, PEDF diminished the differentiation of 3T3-L1 preadipocytes. We also determined that PEDF promoted lipolysis and prolonged cell cycle progression, through the mTOR-S6K pathway and downstream transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein α (CEBP-α), and CEBP-ß. In addition, PEDF decreased reactive oxygen species production in PA-induced HepG2 cells and improved glucose uptake ability in PA-induced HepG2 cells and C2C12 myotubes. In the present study, PEDF protected against HFD-induced obesity and metabolic disorders in mice, inhibited adipogenesis, and improved insulin resistance. These results provide a new potential treatment for obesity in the future.


Assuntos
Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Proteínas do Olho/farmacologia , Doenças Metabólicas/patologia , Fatores de Crescimento Neural/farmacologia , Obesidade/patologia , Obesidade/prevenção & controle , Serpinas/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Clonais , Dieta Hiperlipídica , Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Fígado Gorduroso/patologia , Células Hep G2 , Humanos , Inflamação/patologia , Resistência à Insulina , Masculino , Doenças Metabólicas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Obesidade/sangue , Obesidade/complicações , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
14.
Int J Mol Sci ; 20(10)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121839

RESUMO

There is growing evidence that glucose metabolism in the liver is in part under the control of the endocannabinoid system (ECS) which is also supported by its presence in this organ. The ECS consists of its cannabinoid receptors (CBRs) and enzymes that are responsible for endocannabinoid production and metabolism. ECS is known to be differentially influenced by the hepatic glucose metabolism and insulin resistance, e.g., cannabinoid receptor type 1(CB1) antagonist can improve the glucose tolerance and insulin resistance. Interestingly, our own study shows that expression patterns of CBRs are influenced by the light/dark cycle, which is of significant physiological and clinical interest. The ECS system is highly upregulated during chronic liver disease and a growing number of studies suggest a mechanistic and therapeutic impact of ECS on the development of liver fibrosis, especially putting its receptors into focus. An opposing effect of the CBRs was exerted via the CB1 or CB2 receptor stimulation. An activation of CB1 promoted fibrogenesis, while CB2 activation improved antifibrogenic responses. However, underlying mechanisms are not yet clear. In the context of liver diseases, the ECS is considered as a possible mediator, which seems to be involved in the synthesis of fibrotic tissue, increase of intrahepatic vascular resistance and subsequently development of portal hypertension. Portal hypertension is the main event that leads to complications of the disease. The main complication is the development of variceal bleeding and ascites, which have prognostic relevance for the patients. The present review summarizes the current understanding and impact of the ECS on glucose metabolism in the liver, in association with the development of liver cirrhosis and hemodynamics in cirrhosis and its complication, to give perspectives for development of new therapeutic strategies.


Assuntos
Endocanabinoides/metabolismo , Fígado Gorduroso/metabolismo , Glucose/metabolismo , Cirrose Hepática/metabolismo , Fígado/metabolismo , Animais , Fígado Gorduroso/patologia , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Receptores de Canabinoides/metabolismo
15.
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
16.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083300

RESUMO

TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp-/- mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp-/- mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp-/- or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP's role as a repressor of AHR signaling, 3MC-treated Tiparp-/- mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp-/- mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp-/- mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp-/- mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC-Tiparp-/- mice. Our study reveals that Tiparp-/- mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome.


Assuntos
Ascite Quilosa/induzido quimicamente , Ascite Quilosa/enzimologia , Metilcolantreno/toxicidade , Poli(ADP-Ribose) Polimerases/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Compostos Azo/farmacologia , Ascite Quilosa/patologia , Citocinas/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Knockout , Poli(ADP-Ribose) Polimerases/genética , Pirazóis/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Análise de Sobrevida
17.
Artif Cells Nanomed Biotechnol ; 47(1): 1782-1787, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31062612

RESUMO

Hepatic steatosis is one of the most important features of the pathogenesis for non-alcoholic fatty liver disease. Fat deposition in liver cells can influence hepatic lipogenesis along with other metabolic pathways and further lead to the irreversible liver cirrhosis and injury. However, the underlying mechanism of steatosis remains largely unexplored. Our previous study revealed that AQP7 played an important role in liver steatosis. In this study, we determined that the transcriptional level of AQP7 was up-regulated by estrogen receptor alpha (ERα) upon 17ß-estradiol (E2) and oleic acids treated HepG2 cells. Furthermore, we identified long non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) as a potential hallmark which was down-regulated in ERα silencing HepG2 cells by RNA-Seq. Finally, we validated that the 3' terminal nucleotides of NEAT1 were contributed for the interaction with ERα to facilitate AQP7 transcription to suppress liver steatosis. Overall, our study gave evidence that NEAT1 played an important role in the activation of ERα to regulate AQP7-mediated hepatic steatosis.


Assuntos
Aquaporinas/genética , Receptor alfa de Estrogênio/metabolismo , Fígado Gorduroso/genética , Regulação da Expressão Gênica/genética , RNA Longo não Codificante/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Células Hep G2 , Humanos , RNA Longo não Codificante/metabolismo , Transcrição Genética/genética
18.
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
19.
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
20.
Life Sci ; 227: 201-211, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31002917

RESUMO

AIMS: Colorectal cancer syndrome has been one of the greatest concerns in the world. Although several epidemiological studies have shown that hepatic low lipoprotein lipase (LPL) mRNA expression may be associated with dyslipidemia and tumor progression, it is still not known whether the liver plays an essential role in hyperlipidemia of ApcMin/+ mice. MAIN METHODS: We measured the expression of metabolic enzymes that involved fatty acid uptake, de novo lipogenesis (DNL), ß-oxidation and investigated hepatic triglyceride production in the liver of wild-type and ApcMin/+ mice. KEY FINDINGS: We found that hepatic fatty acid uptake and DNL decreased, but there was no significant difference in fatty acid ß-oxidation. Interestingly, the production of hepatic very low-density lipoprotein-triglyceride (VLDL-TG) decreased at 20 weeks of age, but marked steatosis was observed in the livers of the ApcMin/+ mouse. To further explore hypertriglyceridemia, we assessed the function of hepatic glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) for the first time. GPIHBP1 is governed by the transcription factor octamer-binding transcription factor-1 (Oct-1) which are involved in the nuclear factor-κB (NF-κB) signaling pathway in the liver of ApcMin/+ mice. Importantly, it was also confirmed that sn50 (100 µg/mL, an inhibitor of the NF-κB) reversed the tumor necrosis factor α (TNFα)-induced Oct-1 and GPIHBP1 reduction in HepG2 cells. SIGNIFICANCE: Altogether, these findings highlighted a novel role of GPIHBP1 that might be responsible for hypertriglyceridemia in ApcMin/+ mice. Hypertriglyceridemia in these mice may be associated with their hepatic lipid metabolism development.


Assuntos
Fígado/metabolismo , Receptores de Lipoproteínas/fisiologia , Triglicerídeos/metabolismo , Animais , Caquexia/metabolismo , Caquexia/fisiopatologia , Neoplasias do Colo/fisiopatologia , Ácidos Graxos/metabolismo , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/genética , Células Hep G2 , Humanos , Hiperlipidemias/genética , Metabolismo dos Lipídeos/genética , Lipídeos/fisiologia , Lipogênese/fisiologia , Lipólise/fisiologia , Lipoproteínas VLDL/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 1 de Transcrição de Octâmero/fisiologia , Receptores de Lipoproteínas/genética , Receptores de Lipoproteínas/metabolismo , Triglicerídeos/genética , Fator de Necrose Tumoral alfa/fisiologia
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