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1.
An Acad Bras Cienc ; 93(suppl 3): e20201351, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34468491

RESUMO

Obesity is a major risk factor for type 2 diabetes mellitus development and is characterized by an abnormal expansion of adipose tissue and low-grade chronic inflammation that contribute to insulin resistance. Although there are multiple treatments, most therapies can produce undesirable side effects and therefore, new and effective treatments with fewer side effects are necessary. Previously, we demonstrated that a natural extract from the leaves of Eucalyptus tereticornis (OBE100) has anti-inflammatory, hypoglycemic and hypolipidemic activities. The major compounds identified in OBE100 were three pentacyclic triterpenoids, ursolic acid, oleanolic acid, and ursolic acid lactone. Triterpenoids have shown multiples biological activities. This current study compared the biological effect produced by OBE100 with five different reconstituted mixtures of these triterpenoids. Different cell lines were used to evaluate cytotoxicity, reactive oxygen species production, inflammatory cytokine expression, glucose uptake induction, leptin and adiponectin expression, and lipid accumulation. OBE100 treatment was the most efficacious and none of the formulated triterpenoid mixtures significantly improved on this. Moreover, OBE100 was less toxic and reduced reactive oxygen species production. Our study showed that the proven beneficial properties of triterpenoids may be enhanced due to the interaction with minor secondary metabolites present in the natural extract improving their anti-inflammatory properties.


Assuntos
Diabetes Mellitus Tipo 2 , Eucalyptus , Resistência à Insulina , Triterpenos , Extratos Vegetais/farmacologia , Triterpenos/farmacologia
2.
Molecules ; 26(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920841

RESUMO

Obesity has a strong relationship to insulin resistance and diabetes mellitus, a chronic metabolic disease that alters many physiological functions. Naturally derived drugs have aroused great interest in treating obesity, and triterpenoids are natural compounds with multiple biological activities and antidiabetic mechanisms. Here, we evaluated the bioactivity of ursolic acid lactone (UAL), a lesser-known triterpenoid, obtained from Eucalyptus tereticornis. We used different cell lines to show for the first time that this molecule exhibits anti-inflammatory properties in a macrophage model, increases glucose uptake in insulin-resistant muscle cells, and reduces triglyceride content in hepatocytes and adipocytes. In 3T3-L1 adipocytes, UAL inhibited the expression of genes involved in adipogenesis and lipogenesis, enhanced the expression of genes involved in fat oxidation, and increased AMP-activated protein kinase phosphorylation. The range of biological activities demonstrated in vitro indicates that UAL is a promising molecule for fighting diabetes.


Assuntos
Eucalyptus/química , Lactonas/química , Lactonas/farmacologia , Triterpenos/química , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Macrófagos , Camundongos , Células Musculares/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo , Triterpenos/farmacologia
3.
Molecules ; 26(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670502

RESUMO

Promising research over the past decades has shown that some types of pentacyclic triterpenes (PTs) are associated with the prevention of type 2 diabetes (T2D), especially those found in foods. The most abundant edible sources of PTs are those belonging to the ursane and oleanane scaffold. The principal finding is that Cecropia telenitida contains abundant oleanane and ursane PT types with similar oxygenation patterns to those found in food matrices. We studied the compositional profile of a rich PT fraction (DE16-R) and carried out a viability test over different cell lines. The biosynthetic pathway connected to the isolated PTs in C. telenitida offers a specific medicinal benefit related to the modulation of T2D. This current study suggests that this plant can assemble isobaric, positional isomers or epimeric PT. Ursane or oleanane scaffolds with the same oxygenation pattern are always shared by the PTs in C. telenitida, as demonstrated by its biosynthetic pathway. Local communities have long used this plant in traditional medicine, and humans have consumed ursane and oleanane PTs in fruits since ancient times, two key points we believe useful in considering the medicinal benefits of C. telenitida and explaining how a group of molecules sharing a closely related scaffold can express effectiveness.


Assuntos
Vias Biossintéticas , Cecropia (Planta)/química , Suplementos Nutricionais , Triterpenos Pentacíclicos/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fracionamento Químico , Cromatografia Líquida de Alta Pressão , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/farmacologia
4.
J Ethnopharmacol ; 265: 113298, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32860892

RESUMO

ETNOPHARMACOLOGICAL RELEVANCE: Eucalyptus tereticornis Sm. (Eu) is a plant species used in traditional medicine to treat diabetes mellitus. Eu leaf extracts have been shown to regulate immuno-metabolic activities that are associated with obesity and insulin resistance. OBE100 and OBE104 are two natural Eu extracts that are rich in pentacyclic triterpenes. The major compounds identified in OBE100 are ursolic acid (UA), oleanolic acid (OA), and ursolic acid lactone (UAL), and the major compounds identified in OBE104 are UA and OA. AIM OF THE STUDY: This study aimed to investigate the effects of two extracts from Eu leaves with different triterpene composition in a nutritional animal model of prediabetes. METHODS: A mouse model of diet-induced obesity was used to analyze the effects of the OBE100 and OBE104 treatments on metabolic markers and gene expression in liver and visceral adipose tissue. RESULTS: Treating the prediabetic mouse model with OBE100 and OBE104 increased glucose tolerance. However, only the Eu extract that contained three triterpenes reduced mouse body weight, hepatic and adipose fat content, and plasma lipid levels. OBE100 treatment also led to decreased hepatic mRNA levels of PPARA, CPT1A, and SERBP1. In visceral adipose tissue, OBE100 treatment reduced expression of PPARA and ACACA and increased UCP1 expression. CONCLUSIONS: These results suggest that developing a new multitargeting bioactive compound from the natural extract from Eu may help combat obesity and diabetes. Treatment with OBE100 had better effects than OBE104 in a diet-induced obesity mouse model, suggesting that the OBE100 extract, which contains three triterpenes, may be beneficial in combating obesity.


Assuntos
Eucalyptus/química , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Estado Pré-Diabético/tratamento farmacológico , Triterpenos/farmacologia , Animais , Dieta , Modelos Animais de Doenças , Resistência à Insulina , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/fisiopatologia , Extratos Vegetais/química , Triterpenos/isolamento & purificação
5.
Pharm Res ; 37(8): 152, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32700034

RESUMO

PURPOSE: Anthocyanins (ACNs) are polyphenols that might reduce pathological processes associated with type 2 diabetes mellitus and other chronic diseases, but their bioavailability is still controversial. In this study, the metabolic activity of oral delivery of ACN-loaded niosomes was investigated and evaluated in a diet-induced obesity (DIO) mice model. METHODS: ACNs extracted from Vaccinium Meridionale by the supercritical fluid extraction method were loaded in niosomes. The niosomal formulation was physically characterized and further administrated in drinking water to obese, insulin resistant mouse. We evaluated the effect of ACN loaded niosomes on hyperglycemia, glucose and insulin intolerance and insulin blood levels in C57BL/6 J mice fed with a high-fat diet. RESULTS: The ACN-loaded particles were moderately monodisperse, showed a negative surface charge and 57% encapsulation efficiency. The ACN-loaded niosomes ameliorated the insulin resistance and glucose intolerance in the DIO mice model. Additionally, they reduced animal weight and plasma insulin, glucose, leptin and total cholesterol levels in obese mice. CONCLUSION: ACN-loaded niosomes administration, as a functional drink, had a beneficial effect on the reversal of metabolic abnormalities associated with obesity.


Assuntos
Antocianinas/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/química , Lipossomos/química , Nanocápsulas/química , Extratos Vegetais/química , Estreptófitas/química , Animais , Antocianinas/administração & dosagem , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Colesterol/metabolismo , Diabetes Mellitus Experimental , Dieta Hiperlipídica , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/sangue , Insulina/metabolismo , Insulina/farmacologia , Resistência à Insulina , Leptina/sangue , Leptina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem
6.
Molecules ; 25(7)2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32218297

RESUMO

Plant extracts from Cecropia genus have been used by Latin-American traditional medicine to treat metabolic disorders and diabetes. Previous reports have shown that roots of Cecropia telenitida that contains serjanic acid as one of the most prominent and representative pentacyclic triterpenes. The study aimed to isolate serjanic acid and evaluate its effect in a prediabetic murine model by oral administration. A semi-pilot scale extraction was established and serjanic acid purification was followed using direct MALDI-TOF analysis. A diet induced obesity mouse model was used to determine the impact of serjanic acid over selected immunometabolic markers. Mice treated with serjanic acid showed decreased levels of cholesterol and triacylglycerols, increased blood insulin levels, decreased fasting blood glucose and improved glucose tolerance, and insulin sensitivity. At transcriptional level, the reduction of inflammation markers related to adipocyte differentiation is reported.


Assuntos
Biomarcadores/metabolismo , Obesidade/imunologia , Obesidade/metabolismo , Triterpenos/uso terapêutico , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Metabolismo dos Carboidratos/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Secreção de Insulina/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Obesidade/sangue , Obesidade/tratamento farmacológico , Tamanho do Órgão/efeitos dos fármacos , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia
7.
Nutr Neurosci ; : 1-15, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32116157

RESUMO

Objectives: Cerebral ischemia is caused by a reduction of the blood flow in a specific area in the brain, triggering cellular cascades in the tissue that result in neuronal death. This phenomenon leads to neurological decline in patients with stroke. The extent of the injury after stroke could be related to the condition of obesity. Thus, we aim to analyze the effect of obesity induced by a high fructose diet (HFD) on the brain after cerebral ischemia in rats.Methods: We induced the obesity model in female Wistar rats with 20% fructose in water for 11 weeks. We then performed cerebral ischemia surgery (2-vessel occlusion), carried out the neurological test 6, 24 and 48 h post-ischemia and analyzed the histological markers.Results: The HFD induced an obese phenotype without insulin resistance. The obese rats exhibited worse neurological performance at 6 h post-ischemia and showed neuronal loss and astroglial and microglial immunoreactivity changes in the caudate putamen, motor cortex, amygdala and hippocampus at 48 h post-ischemia. However, the most commonly affected area was the hippocampus, where we found an increase in interleukin 1ß in the blood vessels of the dentate gyrus, a remarkable disruption of MAP-2+ dendrites, a loss of brain-derived neurotrophic factor and the presence of PHF-tau. In conclusion, a HFD induces an obese phenotype and worsens the neuronal loss, inflammation and plasticity impairment in the hippocampus after cerebral ischemia.

8.
Phytomedicine ; 50: 109-117, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30466969

RESUMO

BACKGROUND: Eucalyptus tereticornis Sm (Myrtaceae) is a plant used in traditional medicine to control obesity, insulin resistance and diabetes. Chronic adipose tissue inflammation is involved in generating insulin resistance, the greatest risk factor in developing type 2 diabetes mellitus and cardiovascular disease. In the present study, a mixture of triterpenes, as obtained from the starting plant material, was evaluated in inflamed adipose tissue cells models. AIM: Our goal is to advance into the understanding, at the cellular level, of the immunometabolic effects of the triterpene mixes from Eucalyptus tereticornis in in vitro models of mouse and human adipose tissues. METHODS: Triterpene mixes were obtained from Eucalyptus tereticornis leaves by organic extraction. The major compounds of these mixes were identified by 1H NMR and 13C NMR in addition to HPLC using primary and secondary standards of ursolic acid, oleanolic acid and ursolic acid lactone. To provide an approach for evaluating the cellular and molecular mechanisms through which triterpene mixes act to modify the metabolic processes associated with obesity, mouse macrophage and adipocyte cell lines, human macrophage cell line and primary culture of human adipocytes were used as models. RESULTS: Adipocytes treated with the two natural chemically characterized triterpene mixes partially reduce lipogenesis and leptin expression. Additionally, an increase in the transcriptional expression of PPARγ, and C/EBPα is observed. In macrophages, these triterpene mixes, decrease the transcriptional and translational expression of pro-inflammatory cytokines, such as interleukin-6 (IL-6), interleukin 1ß (IL-1ß) and tumoral necrosis factor α (TNFα). Conditioned medium of 3T3-L1 adipocytes treated with the triterpene mix shows a stronger anti-inflammatory response on activated J774A.1 macrophages. CONCLUSION: The mixtures of the three triterpenes in the proportions obtained from the plant material may act on different components of the cell, generating a different response, which, in some cases, is more powerful than that seen when exposure to only two triterpenes. It makes this three triterpenes mix a good phytotherapeutic prototype for pathologies as complex as those associated with obesity.


Assuntos
Adipócitos/efeitos dos fármacos , Eucalyptus/química , Triterpenos/farmacologia , Células 3T3 , Adipócitos/metabolismo , Adipocinas/metabolismo , Tecido Adiposo/citologia , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 2 , Humanos , Inflamação/metabolismo , Resistência à Insulina , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Obesidade , Folhas de Planta/química , Células U937
9.
Diabetes Metab J ; 41(4): 303-315, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28868828

RESUMO

BACKGROUND: The increase in circulating free fatty acid (FFA) levels is a major factor that induces malfunction in pancreatic ß-cells. We evaluated the effect of FFAs reconstituted according to the profile of circulating fatty acids found in obese adolescents on the viability and function of the murine insulinoma cell line (mouse insulinoma [MIN6]). METHODS: From fatty acids obtained commercially, plasma-FFA profiles of three different youth populations were reconstituted: obese with metabolic syndrome; obese without metabolic syndrome; and normal weight without metabolic syndrome. MIN6 cells were treated for 24 or 48 hours with the three FFA profiles, and glucose-stimulated insulin secretion, cell viability, mitochondrial function and antioxidant activity were evaluated. RESULTS: The high FFA content and high polyunsaturated ω6/ω3 ratio, present in plasma of obese adolescents with metabolic syndrome had a toxic effect on MIN6 cell viability and function, increasing oxidative stress and decreasing glucose-dependent insulin secretion. CONCLUSION: These results could help to guide nutritional management of obese young individuals, encouraging the increase of ω-3-rich food consumption in order to reduce the likelihood of deterioration of ß-cells and the possible development of type 2 diabetes mellitus.

10.
Am J Reprod Immunol ; 77(4)2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28132398

RESUMO

PROBLEM: Women with antiphospholipid antibodies (aPLs) present a risk of pregnancy morbidity (PM), vascular thrombosis (VT), or both (PM/VT). aPLs affect trophoblast function, and the aim of this study was to determine the modulation of this aPL-induced damage by different drugs. METHOD OF STUDY: IgG was obtained from women with PM and PM/VT positive to aPLs. Binding of IgG to trophoblastic cells, proliferation, mitochondrial membrane integrity, and trophoblast invasion were assessed. The effect of enoxaparin, aspirin, and aspirin-triggered lipoxin (ATL) were evaluated as well as signal transducer and activator of transcription 3 (STAT3) phosphorylation. RESULTS: IgG from women with aPLs strongly binds to trophoblastic cells. Integrity of mitochondrial membrane was reduced, and proliferation was increased by IgG-PM/VT. Both IgG-PM and IgG-PM/VT decreased trophoblast invasion, which was restored by enoxaparin, aspirin, and ATL. IgG-PM triggered reduction in STAT3 phosphorylation. CONCLUSION: Some drugs used to prevent aPL-induced PM modulated the alteration of trophoblast function.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/complicações , Complicações na Gravidez/imunologia , Trofoblastos/imunologia , Adulto , Anticoagulantes/farmacologia , Síndrome Antifosfolipídica/imunologia , Aspirina/farmacologia , Western Blotting , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/imunologia , Imuno-Histoquímica , Lipoxinas/farmacologia , Gravidez , Trofoblastos/efeitos dos fármacos , Trofoblastos/patologia
11.
Adv Pharmacol Sci ; 2015: 418673, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26366171

RESUMO

Eucalyptus tereticornis is a plant used in traditional medicine to control diabetes, but this effect has not been proved scientifically. Here, we demonstrated through in vitro assays that E. tereticornis extracts increase glucose uptake and inhibit their production in insulin-resistant C2C12 and HepG2 cells, respectively. Furthermore, in a nutritional model using diabetic mice, the administration of ethyl acetate extract of E. tereticornis reduced fasting glycaemia, improved tolerance to glucose, and reduced resistance to insulin. Likewise, this extract had anti-inflammatory effects in adipose tissue when compared to control diabetic mice. Via bioguided assays and sequential purification of the crude extract, a triterpenoid-rich fraction from ethyl acetate extracts was shown to be responsible for the biological activity. Similarly, we identified the main compound responsible for the antihyperglycemic activity in this extract. This study shows that triterpenes found in E. tereticornis extracts act as hypoglycemic/antidiabetic compounds and contribute to the understanding of their use in traditional medicine.

12.
Molecules ; 20(4): 6181-93, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25859777

RESUMO

Jatropha gossypifolia L. (Euphorbiaceae) is a plant widely used in the treatment of type 2 diabetes mellitus (T2DM), but there are few scientific reports validating its activity in this area. In this work and through a bioguided assay, a crude extract stimulated glucose uptake in C2C12 myotubes up to 30%, thereby reducing insulin resistance induced by fatty acids compared to the basal control. A chromatographic fraction applied intraperitoneally (IP) in mice reduced glucose by 42% in a mouse model of T2DM, after administration of 10 doses during 20 days. A flavanone was purified from this active fraction and its structure was assigned by 1H- and 13C-NMR (1D and 2D) and MS. This compound retains the previously reported activity, stimulating in vitro the glucose uptake in a concentration-dependent manner. This study indicates that Jatropha gossypifolia L. extracts enhance glucose uptake in cultured myotubes and adipocytes and also improving glucose tolerance in an in vivo model.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Flavonoides/administração & dosagem , Hipoglicemiantes/administração & dosagem , Extratos Vegetais/administração & dosagem , Animais , Glicemia , Diabetes Mellitus Tipo 2/patologia , Flavonoides/química , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/química , Jatropha/química , Camundongos , Extratos Vegetais/química
13.
Diabetes ; 59(10): 2390-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20622167

RESUMO

OBJECTIVE: The purpose of this study was to evaluate the role of the S6K arm of mammalian target of rapamycin complex 1 (mTORC1) signaling in regulation of ß-cell mass and function. Additionally, we aimed to delineate the importance of in vivo S6K activation in the regulation of insulin signaling and the extent to which alteration of insulin receptor substrate (IRS) signaling modulates ß-cell mass and function. RESEARCH DESIGN AND METHODS: The current experiments describe the phenotype of transgenic mice overexpressing a constitutively active form of S6K under the control of the rat insulin promoter. RESULTS: Activation of S6K signaling in these mice improved insulin secretion in the absence of changes in ß-cell mass. The lack of ß-cell mass expansion resulted from decreased G(1)-S progression and increased apoptosis. This phenotype was associated with increased p16 and p27 and decreased Cdk2 levels. The changes in cell cycle were accompanied by diminished survival signals because of impaired IRS/Akt signaling. CONCLUSIONS: This work defines the importance of S6K in regulation of ß-cell cycle, cell size, function, and survival. These experiments also demonstrate that in vivo downregulation of IRS signaling by TORC1/S6K induces ß-cell insulin resistance, and that this mechanism could explain some of the abnormalities that ultimately result in ß-cell failure and diabetes in conditions of nutrient overload.


Assuntos
Células Secretoras de Insulina/citologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Animais , Apoptose , Ciclo Celular , Divisão Celular , Tamanho Celular , Glucose/farmacologia , Teste de Tolerância a Glucose , Insulina/genética , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/enzimologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Transgênicos , Complexos Multiproteicos , Regiões Promotoras Genéticas , Proteínas , Ratos , Transdução de Sinais , Serina-Treonina Quinases TOR , Fatores de Transcrição/metabolismo
14.
J Biol Chem ; 284(12): 7832-42, 2009 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-19144649

RESUMO

Growth factors, insulin signaling, and nutrients are important regulators of beta-cell mass and function. The events linking these signals to the regulation of beta-cell mass are not completely understood. The mTOR pathway integrates signals from growth factors and nutrients. Here, we evaluated the role of the mTOR/raptor (mTORC1) signaling in proliferative conditions induced by controlled activation of Akt signaling. These experiments show that the mTORC1 is a major regulator of beta-cell cycle progression by modulation of cyclin D2, D3, and Cdk4 activity. The regulation of cell cycle progression by mTORC1 signaling resulted from modulation of the synthesis and stability of cyclin D2, a critical regulator of beta-cell cycle, proliferation, and mass. These studies provide novel insights into the regulation of cell cycle by the mTORC1, provide a mechanism for the antiproliferative effects of rapamycin, and imply that the use of rapamycin could negatively impact the success of islet transplantation and the adaptation of beta-cells to insulin resistance.


Assuntos
Ciclinas/biossíntese , Células Secretoras de Insulina/metabolismo , Biossíntese de Proteínas/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Animais , Ciclo Celular , Linhagem Celular , Tamanho Celular , Ciclina D2 , Ciclina D3 , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Ciclinas/genética , Ciclinas/metabolismo , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Resistência à Insulina/genética , Células Secretoras de Insulina/citologia , Transplante das Ilhotas Pancreáticas , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Transgênicos , Complexos Multiproteicos , Biossíntese de Proteínas/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteínas , Transdução de Sinais/efeitos dos fármacos , Sirolimo/efeitos adversos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Fatores de Transcrição/genética
15.
Proc Natl Acad Sci U S A ; 105(27): 9250-5, 2008 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-18587048

RESUMO

Regulation of pancreatic beta cell mass and function is a major determinant for the development of diabetes. Growth factors and nutrients are important regulators of beta cell mass and function. The signaling pathways by which these growth signals modulate these processes have not been completely elucidated. Tsc2 is an attractive candidate to modulate these processes, because it is a converging point for growth factor and nutrient signals. In these experiments, we generated mice with conditional deletion of Tsc2 in beta cells (betaTsc2(-/-)). These mice exhibited decreased glucose levels and hyperinsulinemia in the fasting and fed state. Improved glucose tolerance in these mice was observed as early as 4 weeks of age and was still present in 52-week-old mice. Deletion of Tsc2 in beta cells induced expansion of beta cell mass by increased proliferation and cell size. Rapamycin treatment reversed the metabolic changes in betaTsc2(-/-) mice by induction of insulin resistance and reduction of beta cell mass. The reduction of beta cell mass in betaTsc2(-/-) mice by inhibition of the mTOR/Raptor (TORC1) complex with rapamycin treatment suggests that TORC1 mediates proliferative and growth signals induced by deletion of Tsc2 in beta cells. These studies uncover a critical role for the Tsc2/mTOR pathway in regulation of beta cell mass and carbohydrate metabolism in vivo.


Assuntos
Glucose/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Metabolismo dos Carboidratos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Deleção de Genes , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos , Camundongos Knockout , Fenótipo , Proteínas Quinases/metabolismo , Ratos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/deficiência
16.
Diabetes ; 55(12): 3520-8, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17130500

RESUMO

beta-Cell cycle progression and proliferation are critical to maintain beta-cell mass in adult mice. Of the cell cycle inhibitors, p27Kip1 is thought to be the primary modulator of the proliferative status in most cell types. p27 plays a role in beta-cell adaptation in genetic models of insulin resistance. To study the role of p27 in beta-cells during physiological conditions and at different stages of beta-cell differentiation, we studied mice deficient of or overexpressing p27. Experiments in p27-deficient mice showed improved glucose tolerance and hyperinsulinemia. These changes were associated with increased islet mass and proliferation. The experiments overexpressing p27 in beta-cells were performed using a doxycycline-inducible model. Interestingly, overexpression of p27 for 16 weeks in beta-cells from adult mice had no effect on glucose tolerance, beta-cell mass, or proliferation. In contrast, induction of p27 expression during beta-cell development or early neonatal period resulted in severe glucose intolerance and reduced beta-cell mass by decreased proliferation. These changes were reversible upon discontinuation of doxycycline. These experiments suggest that p27 is a critical molecule for beta-cell proliferation during beta-cell development and early postnatal life but not for maintenance of adult mass.


Assuntos
Glicemia/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/fisiologia , Células Secretoras de Insulina/citologia , Ilhotas Pancreáticas/anatomia & histologia , Animais , Animais Recém-Nascidos , Divisão Celular , Inibidor de Quinase Dependente de Ciclina p27/deficiência , Inibidor de Quinase Dependente de Ciclina p27/genética , Homeostase , Ilhotas Pancreáticas/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
17.
Biomedica ; 26(2): 194-205, 2006 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-16925092

RESUMO

INTRODUCTION: Hepatitis C virus is associated with diverse liver diseases including acute and chronic hepatitis, steatosis, cirrhosis and hepatocellular carcinoma. Several studies have explored viral mechanisms involved in the establishment of persistent infection and oncogenic Hepatitis C virus. Expression assays of Hepatitis C virus core protein suggest that this protein has transforming and carcinogenic properties with multifunctional activities in host cells. Characterization of expressed genes in cells expressing Core protein is important in order to identify candidate genes responsible for these pathogenic alterations. OBJECTIVE: To compare and identify gene expression profiles in the human hepatocarcinoma derived cell line, HepG2, with transient expression of Hepatitis C virus Core protein. MATERIALS AND METHODS: We have used comparative PCR-mediated differential display of mRNA from HepG2 hepatocarcinoma with and without transient expression of HCV Core protein or green fluorescent protein, previously obtained using the Semliki Forest Virus-based expression, through transduction of recombinant particles, rSFV-Core and rSFV-GFP, respectively. RESULTS: We observed differences in band intensities of mRNA in HepG2 cells transduced with rSFV-Core compared with those detected in cells without transduction, and transduced with rSFV-GFP. Cloning and sequencing of a gene fragment (258 bp) that was expressed differentially in HepG2 cells transduced with rSFV-Core, was identified as selenocystein lyase. CONCLUSION: The results confirm that HCV Core protein expressed in HepG2 is associated with specific changes in mRNA expression, including the gene for selenocystein lyase. This gene may be involved in the pathophysiology of hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Liases/genética , RNA Mensageiro/metabolismo , Proteínas do Core Viral/metabolismo , Sequência de Bases , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Liases/metabolismo , Dados de Sequência Molecular , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução Genética , Proteínas do Core Viral/genética
18.
Biomédica (Bogotá) ; 26(2): 194-205, jun. 2006. ilus
Artigo em Espanhol | LILACS | ID: lil-434539

RESUMO

Introducción. El virus de la hepatitis C se asocia a diversas hepatopatías como hepatitis aguda, hepatitis crónica, esteatosis, cirrosis y carcinoma hepatocelular. Numerosos estudios han explorado mecanismos virales implicados en el establecimiento de la infección persistente y en las propiedades oncogénicas e inmunomoduladoras de la proteína core del virus de la hepatitis C. Las investigaciones orientadas a evaluar los cambios en la expresión de genes celulares endógenos inducidos por la proteína core son importantes para identificar genes candidatos responsables de los mecanismos de patogenicidad del virus de la hepatitis C. Objetivos. Comparar perfiles de expresión e identificar genes celulares endógenos en la línea celular derivada de carcinoma hepatocelular humano, HepG2, con expresión transitoria de la proteína core del virus de la hepatitis C. Materiales y métodos. Se utilizó la técnica de presentación diferencial de ARN mensajero por RT-PCR en células HepG2 con y sin expresión transitoria de la proteína core del virus de la hepatitis C o de la proteína verde fluorescente, obtenidas previamente con el sistema de expresión del Semliki Forest Virus, mediante transducción de partículas recombinantes rSFV-Core o rSFV-GFP. Resultados. Se observaron diferencias en las intensidades de las bandas de ARNm expresadas en células HepG2 transducidas con rSFV-Core comparadas con células sin transducir y trasducidas con rSFV-GFP. Un ARNm de 258 pb expresado diferencialmente en células HepG2 transducidas con rSFV-Core fue clonado e identificado como selenocisteína liasa. Conclusión. Los resultados confirman que la expresión de la proteína core del virus de la hepatitis C se asocia con cambios en la expresión de ARN mensajeros específicos, incluido al gen selenocisteina liasa, el cual puede estar involucrado en la fisiopatología del carcinoma hepatocelular


Assuntos
Carcinoma , Carcinoma Hepatocelular , Expressão Gênica , Hepatite C , RNA Mensageiro , Selenocisteína , Hepacivirus
19.
Diabetes ; 55(2): 318-25, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16443763

RESUMO

Proliferation is the major component for maintenance of beta-cell mass in adult animals. Activation of phosphoinositide 3-kinase/Akt-kinase pathway is a critical regulator of beta-cell mass. Pancreatic beta-cell overexpression of constitutively active Akt in mice (caAkt(Tg)) resulted in marked expansion of beta-cell mass by increase in beta-cell proliferation and size. The current studies provide new insights into the molecular mechanisms involved in beta-cell proliferation by Akt. Proliferation of beta-cells in caAkt(Tg) was associated with increased cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 (cdk4) activity. To determine the role of cdk4 in beta-cell proliferation induced by Akt, we generated caAkt(Tg) mice that were homozygous, heterozygous, or nullizygous for cdk4. The results of these studies showed that deletion of one cdk4 allele significantly reduced beta-cell expansion in caAkt(Tg) mice by decreased proliferation. CaAkt(Tg) mice deficient in cdk4 developed beta-cell failure and diabetes. These experiments suggest that Akt induces beta-cell proliferation in a cdk4-dependent manner by regulation of cyclin D1, cyclin D2, and p21 levels. These data also indicate that alteration in levels of these cell cycle components could affect the maintenance of beta-cell mass in basal states and the adaptation of beta-cells to pathological states resulting in diabetes.


Assuntos
Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Ciclinas/metabolismo , Células Secretoras de Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Animais Recém-Nascidos/metabolismo , Proliferação de Células , Ciclina D2 , Quinase 4 Dependente de Ciclina/genética , Feminino , Deleção de Genes , Regulação Enzimológica da Expressão Gênica , Glucose/metabolismo , Células Secretoras de Insulina/citologia , Masculino , Camundongos , Camundongos Transgênicos , Transdução de Sinais
20.
Int J Biochem Cell Biol ; 38(2): 157-63, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16213777

RESUMO

The serine-threonine kinase Akt also known as protein kinase B is one of the most studied molecules. In addition to the important role in carcinogenesis, Akt is a major regulator of carbohydrate metabolism. Akt mediates insulin-dependent glucose uptake in insulin-sensitive tissues. Recent evidence underscores the importance of Akt for regulation of beta-cell mass and function. This review summarizes current findings concerning the molecular mechanisms, downstream signaling pathways, and critical components involved in regulation of beta-cell mass and function by Akt. The results of these observations suggest that elucidation of critical downstream effectors of this signaling pathway could generate promising molecules as a potential target to induce proliferation and survival of beta-cells.


Assuntos
Células Secretoras de Insulina/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Animais , Apoptose , Proliferação de Células , Ativação Enzimática , Humanos , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/citologia , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/química , Proteínas Proto-Oncogênicas c-akt/genética
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