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1.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445304

RESUMO

Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.


Assuntos
Processamento Alternativo/fisiologia , Diabetes Mellitus Tipo 2/genética , Ilhotas Pancreáticas/metabolismo , Processamento Alternativo/genética , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Suscetibilidade a Doenças , Secreção de Insulina/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Regulação para Cima/genética
2.
Nutrients ; 13(8)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445047

RESUMO

Sargassum fusiforme alginate (SF-Alg) possess many pharmacological activities, including hypoglycemic and hypolipidemic. However, the hypoglycemic mechanisms of SF-Alg remain unclear due to its low bioavailability. In this study, we evaluated the therapeutic effect of SF-Alg on high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetes (T2D) mice. SF-Alg intervention was found to significantly reduce fasting blood glucose (FBG), triglycerides (TG), and total cholesterol (TC), while increasing high-density lipoprotein cholesterol (HDL-c) and improving glucose tolerance. In addition, administrating SF-Alg to diabetic mice moderately attenuated pathological changes in adipose, hepatic, and heart tissues as well as skeletal muscle, and diminished oxidative stress. To probe the underlying mechanisms, we further analyzed the gut microbiota using 16S rRNA amplicon sequencing, as well as metabolites by non-targeted metabolomics. Here, SF-Alg significantly increased some benign bacteria (Lactobacillus, Bacteroides, Akkermansia Alloprevotella, Weissella and Enterorhabdus), and significantly decreased harmful bacteria (Turicibacter and Helicobacter). Meanwhile, SF-Alg dramatically decreased branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) in the colon of T2D mice, suggesting a positive benefit of SF-Alg as an adjvant agent for T2D.


Assuntos
Alginatos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Sargassum/química , Animais , Glicemia/efeitos dos fármacos , Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hiperglicemia/etiologia , Camundongos , Estreptozocina , Triglicerídeos/sangue
3.
Biomed Pharmacother ; 140: 111738, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34029949

RESUMO

BACKGROUND: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. METHODS: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. FINDINGS: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. INTERPRETATION: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Compostos Benzidrílicos/farmacologia , Glicemia/análise , Senescência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Dieta Ocidental , Modelos Animais de Doenças , Progressão da Doença , Glucosídeos/farmacologia , Hepatócitos/efeitos dos fármacos , Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/sangue , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/patologia , Receptor Tipo 4 de Melanocortina/genética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
4.
Molecules ; 26(7)2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800673

RESUMO

Coffea arabica pulp (CP) is a by-product of coffee processing. CP contains polyphenols that have exhibited beneficial effects, including antioxidant and lipid-lowering effects, as well as enhanced insulin sensitivity, in in vitro and in vivo models. How polyphenols, as found in CP aqueous extract (CPE), affect type 2 diabetes (T2D) has not been investigated. Thus, the present study examined the potential antidiabetic, antioxidant, and renoprotective effects of CPE-rich polyphenols, using an experimental model of T2D in rats induced by a high-fat diet and a single low dose of streptozotocin. The T2D rats received either 1000 mg/kg body weight (BW) of CPE, 30 mg/kg BW of metformin (Met), or a combination treatment (CPE + Met) for 3 months. Plasma parameters, kidney morphology and function, and renal organic transport were determined. Significant hyperglycemia, hypertriglyceridemia, insulin resistance, increased renal lipid content and lipid peroxidation, and morphological kidney changes related to T2D were restored by both CPE and CPE + Met treatments. Additionally, the renal uptake of organic cation, 3H-1-methyl-4-phenylpyridinium (MPP+), was reduced in T2D, while transport was restored by CPE and CPE + Met, through an up-regulation of antioxidant genes and protein kinase Cα deactivation. Thus, CPE has antidiabetic and antioxidant effects that potentially ameliorate kidney function in T2D by preserving renal organic cation transport through an oxidative stress pathway.


Assuntos
Antioxidantes/farmacologia , Coffea/química , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Polifenóis/farmacologia , Animais , Antioxidantes/isolamento & purificação , Proteínas de Transporte/agonistas , Proteínas de Transporte/metabolismo , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , Combinação de Medicamentos , Sinergismo Farmacológico , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hipoglicemiantes/isolamento & purificação , Resistência à Insulina , Transporte de Íons/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Polifenóis/isolamento & purificação , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem
5.
Int J Mol Sci ; 22(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916315

RESUMO

Lipids are highly diverse in their composition, properties and distribution in different biological entities. We aim to establish the lipidomes of several insulin-sensitive tissues and to test their plasticity when divergent feeding regimens and lifestyles are imposed. Here, we report a proton nuclear magnetic resonance (1H-NMR) study of lipid abundance across 4 tissues of C57Bl6J male mice that includes the changes in the lipid profile after every lifestyle intervention. Every tissue analysed presented a specific lipid profile irrespective of interventions. Glycerolipids and fatty acids were most abundant in epididymal white adipose tissue (eWAT) followed by liver, whereas sterol lipids and phosphoglycerolipids were highly enriched in hypothalamus, and gastrocnemius had the lowest content in all lipid species compared to the other tissues. Both when subjected to a high-fat diet (HFD) and after a subsequent lifestyle intervention (INT), the lipidome of hypothalamus showed no changes. Gastrocnemius and liver revealed a pattern of increase in content in many lipid species after HFD followed by a regression to basal levels after INT, while eWAT lipidome was affected mainly by the fat composition of the administered diets and not their caloric density. Thus, the present study demonstrates a unique lipidome for each tissue modulated by caloric intake and dietary composition.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Lipidômica , Obesidade/dietoterapia , Obesidade/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Restrição Calórica , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Estilo de Vida Saudável , Hipotálamo/metabolismo , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Obesidade/complicações , Condicionamento Físico Animal
6.
FASEB J ; 35(5): e21374, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33835493

RESUMO

Inhibition of insulin-degrading enzyme (IDE) is a possible target for treating diabetes. However, it has not yet evolved into a medical intervention, mainly because most developed inhibitors target the zinc in IDE's catalytic site, potentially causing toxicity to other essential metalloproteases. Since IDE is a cellular receptor for the varicella-zoster virus (VZV), we constructed a VZV-based inhibitor. We computationally characterized its interaction site with IDE showing that the peptide specifically binds inside IDE's central cavity, however, not in close proximity to the zinc ion. We confirmed the peptide's effective inhibition on IDE activity in vitro and showed its efficacy in ameliorating insulin-related defects in types 1 and 2 diabetes mouse models. In addition, we suggest that inhibition of IDE may ameliorate the pro-inflammatory profile of CD4+ T-cells toward insulin. Together, we propose a potential role of a designed VZV-derived peptide to serve as a selectively-targeted and as an efficient diabetes therapy.


Assuntos
Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/terapia , Insulina/metabolismo , Insulisina/antagonistas & inibidores , Fragmentos de Peptídeos/administração & dosagem , Proteínas do Envelope Viral/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Inibidores Enzimáticos/administração & dosagem , Feminino , Herpesvirus Humano 3/fisiologia , Insulisina/genética , Insulisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout
7.
J Biol Chem ; 296: 100624, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33812996

RESUMO

The reduction of insulin resistance or improvement of insulin sensitivity is the most effective treatment for type 2 diabetes (T2D). We previously reported that Nogo-B receptor (NGBR), encoded by the NUS1 gene, is required for attenuating hepatic lipogenesis by blocking nuclear translocation of liver X receptor alpha, suggesting its important role in regulating hepatic lipid metabolism. Herein, we demonstrate that NGBR expression was decreased in the liver of obesity-associated T2D patients and db/db mice. NGBR knockout in mouse hepatocytes resulted in increased blood glucose, insulin resistance, and beta-cell loss. High-fat diet (HFD)/streptozotocin (STZ)-treated mice presented the T2D phenotype by showing increased nonesterified fatty acid (NEFA) and triglyceride (TG) in the liver and plasma and increased insulin resistance and beta-cell loss. AAV-mediated NGBR overexpression in the liver reduced NEFA and TG in the liver and circulation and improved liver functions. Consequently, HFD/STZ-treated mice with hepatic NGBR overexpression had increased insulin sensitivity and reduced beta-cell loss. Mechanistically, NGBR overexpression restored insulin signaling of AMPKα1-dependent phosphorylation of AKT and GSK3ß. NGBR overexpression also reduced expression of endoplasmic reticulum stress-associated genes in the liver and skeletal muscle to improve insulin sensitivity. Together, our results reveal that NGBR is required to ameliorate T2D in mice, providing new insight into the role of hepatic NGBR in insulin sensitivity and T2D treatment.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Resistência à Insulina , Secreção de Insulina , Metabolismo dos Lipídeos , Receptores de Superfície Celular/metabolismo , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Receptores de Superfície Celular/genética , Transdução de Sinais
8.
J Cell Mol Med ; 25(10): 4800-4813, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33742502

RESUMO

The two insulin receptor (IR) isoforms IR-A and IR-B are responsible for the pleiotropic actions of insulin and insulin-like growth factors. Consequently, changes in IR isoform expression and in the bioavailability of their ligands will impact on IR-mediated functions. Although alteration of IR isoform expression has been linked to insulin resistance, knowledge of IR isoform expression and mechanisms underlying tissue/cell-type-specific changes in metabolic disease are lacking. Using mouse models of obesity/diabetes and measuring the mRNA of the IR isoforms and mRNA/protein levels of total IR, we provide a data set of IR isoform expression pattern that documents changes in a tissue-dependent manner. Combining tissue fractionation and a new in situ mRNA hybridization technology to visualize the IR isoforms at cellular resolution, we explored the mechanism underlying the change in IR isoform expression in perigonadal adipose tissue, which is mainly caused by tissue remodelling, rather than by a shift in IR alternative splicing in a particular cell type, e.g. adipocytes.


Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Regulação da Expressão Gênica , Resistência à Insulina , Obesidade/complicações , Receptor de Insulina/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Processamento Alternativo , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Isoformas de Proteínas , Receptor de Insulina/genética , Transdução de Sinais
9.
Biosci Biotechnol Biochem ; 85(5): 1183-1193, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33704405

RESUMO

Obesity is one of the most critical risk factors for diabetes mellitus and plays a significant role in diabetic nephropathy (DN). The present investigation aimed to evaluate the possible mechanism of action of vitexin on obesity-induced DN in a high-fat diet (HFD)-fed experimental C57BL/6 mice model. Obesity was induced in male C57BL/6 mice by chronic administration of HFD, and mice were concomitantly treated with vitexin (15, 30, and 60 mg/kg, p.o.). HFD-induced increased renal oxido-nitrosative stress and proinflammatory cytokine levels were significantly inhibited by vitexin. The Western blot analysis suggested that alteration in renal NF-κB, IκBα, nephrin, AMPK, and ACC phosphorylation levels was effectively restored by vitexin treatment. Histological aberration induced in renal tissue after chronic administration of HFD was also reduced by vitexin. In conclusion, vitexin suppressed the progression of obesity-induced DN via modulation of NF-κB/IkBα and AMPK/ACC pathways in an experimental model of HFD-induced DN in C57BL/6J mice.


Assuntos
Fármacos Antiobesidade/farmacologia , Apigenina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/farmacologia , Obesidade/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Fármacos Antiobesidade/isolamento & purificação , Apigenina/isolamento & purificação , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica , Hipoglicemiantes/isolamento & purificação , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Masculino , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/patologia , Extratos Vegetais/química , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Trigonella/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Dev Cell ; 56(6): 747-760.e6, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33667344

RESUMO

Loss of insulin-secreting pancreatic ß cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains ß cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce ß cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. ß cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by ß cells. Loss of the serpin α1-antitrypsin from the extracellular space unleashes elastase, triggering the disruption of ß cell anchorage and subsequent cell death. Administration of α1-antitrypsin to mice with diabetes prevents ß cell death and metabolic abnormalities. These data uncover a pathway for ß cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome.


Assuntos
Apoptose , Núcleo Celular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Células Secretoras de Insulina/patologia , Proteínas do Tecido Nervoso/metabolismo , alfa 1-Antitripsina/química , Animais , Proteínas Reguladoras de Apoptose/fisiologia , Citoplasma/metabolismo , Proteínas do Citoesqueleto/genética , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Musculares/fisiologia , Proteínas do Tecido Nervoso/genética , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo
11.
Biomed Pharmacother ; 138: 111391, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33676309

RESUMO

Capparis spinosa (CS) is known as a hypoglycemic medication in many countries. This study was designed to reveal the protective effects of the hydro-ethanolic extract of CS (HECS) fruit against diabetes and oxidative stress in type 2 diabetic rats (T2D). T2D was induced in 4 groups of adult male Sprague Dawley rats, using high fat diet (HFD) and low dose of streptozotocin (STZ). The four groups of diabetic rats were orally gavaged with HECS (200 & 400 mg/kg), metformin (50 mg/kg) or vehicle for 28 days. Two non-diabetic groups were assigned as normal control and HECS treated ones (400 mg/kg). The glucose intolerance, HOMA-IR score, HbA1c level, antioxidative status and expression of genes involved in hepatic gluconeogenesis and lipogenesis were determined. Although HECS had no significant effect on decreasing of HOMA-IR score and HbA1c, it significantly decreased glucose intolerance as well as oxidative stress by reduction of hepatic lipid peroxidation and increase of antioxidant enzymes levels in diabetic rats. Also, HECS treated diabetic rats showed a significant enhanced dyslipidemia, increased weight gain and sera insulin level. In addition, HECS significantly decreased hepatic phosphoenolpyruvate carboxykinase (PEPCK), increased acetyl CoA carboxylase and non-significantly decreased hepatocyte nuclear factor-4α (HNF-4α) as a transactivator of PEPCK at mRNA expression level in diabetic rats. This study indicated the anti-oxidative and anti-diabetic effects of C. spinosa fruit extract and confirmed its traditional usage as a remedy for T2D.


Assuntos
Antioxidantes/uso terapêutico , Capparis , Diabetes Mellitus Experimental/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Hipoglicemiantes/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Frutas , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Masculino , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Estreptozocina
12.
Life Sci ; 274: 119313, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33667511

RESUMO

AIMS: To design and evaluate a novel AWRK6 peptide-based long-acting GLP-1 receptor agonist (GLP-1RA) conjugated a recombinant polyethylene glycol mimetic (XTEN protein) with significant therapeutic potential on type 2 diabetes mellitus (T2DM) alone as well as Herpes simplex virus type 2 (HSV-2) infection in combination with double shRNA. MAIN METHODS: First, four AWRK6 analogs (termed XA-1 to XA-4) were designed and produced by solid phase synthesis strategy. Further surface plasmon resonance (SPR) measurement and in vitro cAMP accumulation assay were performed to detect the GLP-1R binding affinities and GLP-1R activation, respectively. The in vivo efficacy evaluation including pharmacokinetic test, oral glucose tolerance test (OGTT), hypoglycemic duration test and chronic pharmacodynamics study in rodent animals were all carefully performed. KEY FINDINGS: Four XA peptides were synthesized with purity >99%. High binding affinity as well as activation potency of XA-4 for GLP-1R were demonstrated by SPR and cell-based luciferase reporter assay, respectively. Additionally, XA-4 exhibited the long-lasting antidiabetic effects in the multiple OGTTs, hypoglycemic duration test and chronic study in mice. Furthermore, combined treatment of XA-4 and double shRNA (D-shRNA) achieved potent antiviral effects in HSV-2 infected HEK293 cells. SIGNIFICANCE: XA-4 exhibited promising pharmaceutical potential to be a therapeutic drug for treating T2D, and also held potential to against the HSV-2 infection, which is really an accidental discovery. The strategy of recombinant XTENylation can also be applied to other peptides or small molecules for the development of long-acting therapeutic drugs.


Assuntos
Diabetes Mellitus Experimental/terapia , Herpes Simples/terapia , Herpesvirus Humano 2/efeitos dos fármacos , Obesidade/complicações , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , RNA Interferente Pequeno/administração & dosagem , Animais , Terapia Combinada , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , Herpes Simples/genética , Herpes Simples/virologia , Herpesvirus Humano 2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Fragmentos de Peptídeos/química , Peptídeos/química , RNA Interferente Pequeno/genética
13.
Life Sci ; 276: 119374, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33745896

RESUMO

AIMS: Immunomodulation concurrent with the promotion of ß-cell function is a strategy used to develop innovative therapies for type 1 diabetes (T1D). Here, we assessed the therapeutic potential of co-administration of human clonal mesenchymal stem (stromal) cells (hBM-cMSCs) and liraglutide as a glucagon-like peptide-1 agonist in a non-human primate model with streptozotocin (STZ)-induced diabetes. MAIN METHODS: Diabetes was induced through intravenous (i.v.) multiple low-dose (MLD) infusions of STZ at a dose of 30 mg/kg body weight (b.w.) for five consecutive days, followed by two booster injections of 35 mg/kg on days 12 and 19. After 90 days, the diabetic animals were randomly allocated to two groups: The combination therapy group (n = 4) received injections of 1.5 × 106 hBM-cMSCs/kg b.w. through celiac artery by angiography on days 91 and 105 and daily subcutaneous injections of liraglutide (up to 1.8 mg/day) until day 160 while vehicle group received phosphate-buffered saline. The monkeys were assessed for functional, immunological, and histological analysis. KEY FINDINGS: The combined treatment group had continued reduction in FBG levels up to day 160, which was accompanied by increased b.w., C-peptide, and ß-cell function, and decreased HbA1c and fructosamine levels compared to vehicle group. The combined treatment increased Tregs, IL-4, IL-10, and TGF-ß1 and decreased IL-6 and IL-1ß. Stereological analysis of the pancreatic tissue exhibited more total volume of insulin-secreting islets in the combined treatment group compared to vehicle group. SIGNIFICANCE: Our findings demonstrated this combined treatment impaired the clinical symptoms of diabetes in this animal model through immunomodulation and ß-cell preservation.


Assuntos
Diabetes Mellitus Experimental/terapia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Inflamação/fisiopatologia , Liraglutida/farmacologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Animais , Terapia Combinada , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Feminino , Hipoglicemiantes/farmacologia , Macaca mulatta , Masculino
14.
Phytomedicine ; 83: 153478, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33567371

RESUMO

BACKGROUND: Protection of pancreatic islet cells against dysfunction or death by regulating autophagy is considered to be an effective method for treatment of type 2 diabetes mellitus (T2DM). Morus alba leaves (mulberry leaves), a popular herbal medicine, have been used for prevention of T2DM since ancient times. PURPOSE: This study aimed to clarify whether Morus alba leaves ethanol extract (MLE) could protect islet cells in vivo and in vitro by regulating autophagy in T2DM, and explore the possible mechanism of action. METHODS: The main chemical constituents in MLE were analyzed by HPLC. The T2DM rat model was induced via high-fat diet combined with peritoneal injection of low-dose streptozotocin, and MLE was administered by oral gavage. Fasting blood glucose (FBG) and plasma insulin were measured, and homeostatic model assessment of ß cell function (HOMA-ß) and insulin resistance (HOMA-IR) were determined. The histomorphology of pancreas islets was evaluated by haematoxylin and eosin staining. In palmitic acid (PA)-stressed INS-1 rat insulinoma cells, cell viability was assayed by an MTT method. Expression of the autophagy-related proteins LC3 I/II, p62, p-AMPK and p-mTOR in islet tissues and INS-1 cells was evaluated by western blotting or immunohistochemistry analysis. RESULTS: The four main chemical constituents in MLE were identified as chlorogenic acid, rutin, isoquercitrin and quercitrin. MLE ameliorated hyperglycemia, insulin resistance and dyslipidemia of T2DM rats with prominent therapeutic effect. Further study indicated that MLE observably improved islet function, alleviated islet injury of T2DM rats, and inhibited PA-induced INS-1 cell death. On the other hand, MLE significantly induced autophagy in islet cells both in vivo and in vitro, and autophagy inhibitors abolished its therapeutic effect on T2DM rats and protective effect on islet cells. Apart from this, MLE markedly activated the AMPK/mTOR pathway in INS-1 cells, and the AMPK inhibitor prevented the autophagy induction ability of MLE. CONCLUSION: Together, MLE could protect islet cells against dysfunction and death by inducing AMPK/mTOR-mediated autophagy in T2DM, and these findings provide a new perspective for understanding the treatment mechanism of Morus alba leaves against T2DM.


Assuntos
Autofagia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ilhotas Pancreáticas/efeitos dos fármacos , Morus/química , Extratos Vegetais/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Etanol/química , Hiperglicemia/tratamento farmacológico , Resistência à Insulina , Ilhotas Pancreáticas/patologia , Masculino , Extratos Vegetais/química , Folhas de Planta/química , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/metabolismo
15.
Biochem Biophys Res Commun ; 534: 680-686, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33208230

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease caused by destruction of insulin-producing ß cells. The response of autoreactive T cells to ß cell antigens plays a central role in the development of T1D. Recently, fusion peptides composed by insulin C-peptide fragments and other proteins were reported as ß cell target antigens for diabetogenic CD4+ T cells in non-obese diabetic (NOD) mice. In this study, we generated a T cell-receptor (TCR)-like monoclonal antibody (mAb) against a fusion peptide bound to major histocompatibility complex (MHC) class II component to elucidate the function of the fusion peptides in T1D. In addition, we developed a novel NFAT-GFP TCR reporter system to evaluate the TCR-like mAb. The NFAT-GFP reporter T cells expressing the diabetogenic TCR were specifically activated by the fusion peptide presented on the MHC class II molecules. By using the NFAT-GFP reporter T cells, we showed that the TCR-like mAb blocks the diabetogenic T cell response against the fusion peptide presented on the MHC class II molecules. Furthermore, the development of T1D was ameliorated when pre-diabetic NOD mice were treated with this mAb. These findings suggest that NFAT-GFP reporter T cells are useful to assess the function of specific TCR and the recognition of fusion peptides by T cells is crucial for the pathogenesis of T1D.


Assuntos
Anticorpos Monoclonais/farmacologia , Diabetes Mellitus Tipo 1/prevenção & controle , Proinsulina/antagonistas & inibidores , Proinsulina/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Peptídeo C/antagonistas & inibidores , Peptídeo C/genética , Peptídeo C/imunologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Camundongos , Camundongos Endogâmicos NOD , Proinsulina/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Linfócitos T/imunologia
16.
Biochim Biophys Acta Gen Subj ; 1865(3): 129811, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33309687

RESUMO

BACKGROUND: There is growing evidence to support beneficial effects of the hypothalamic synthesised hormone, oxytocin, on metabolism. However, the biological half-life of oxytocin is short and receptor activation profile unspecific. METHODS: We have characterised peptide-based oxytocin analogues with structural modifications aimed at improving half-life and receptor specificity. Following extensive in vitro and in vivo characterisation, antidiabetic efficacy of lead peptides was examined in high fat fed (HFF) mice. RESULTS: Following assessment of stability against enzymatic degradation, insulin secretory activity, receptor activation profile and in vivo bioactivity, analogues 2 N (Ac-C ˂YIQNC >PLG-NH2) and D7R ((d-C)YIQNCYLG-NH2) were selected as lead peptides. Twice daily injection of either peptide for 22 days reduced body weight, energy intake, plasma glucose and insulin and pancreatic glucagon content in HFF mice. In addition, both peptides reduced total- and LDL-cholesterol, with concomitant elevations of HDL-cholesterol, and D7R also decreased triglyceride levels. The two oxytocin analogues improved glucose tolerance and insulin responses to intraperitoneal, and particularly oral, glucose challenge on day 22. Both oxytocin analogues enhanced insulin sensitivity, reduced HOMA-IR and increased bone mineral density. In terms of pancreatic islet histology, D7R reversed high fat feeding induced elevations of islet and beta cell areas, which was associated with reductions in beta cell apoptosis. Islet insulin secretory responsiveness was improved by 2 N, and especially D7R, treatment. CONCLUSION: Novel, enzymatically stable oxytocin analogues exert beneficial antidiabetic effects in HFF mice. GENERAL SIGNIFICANCE: These observations emphasise the, yet untapped, therapeutic potential of long-acting oxytocin-based agents for obesity and type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Obesidade/tratamento farmacológico , Oligopeptídeos/farmacologia , Ocitocina/farmacologia , Animais , Glicemia/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Ingestão de Energia/genética , Feminino , Glucagon/sangue , Meia-Vida , Hipoglicemiantes/síntese química , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Obesidade/sangue , Obesidade/etiologia , Obesidade/patologia , Oligopeptídeos/síntese química , Ocitocina/análogos & derivados , Ocitocina/síntese química , Estabilidade Proteica , Triglicerídeos/sangue
17.
J Ethnopharmacol ; 269: 113692, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33321187

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Type 2 diabetes mellitus (DM) is a complicated metabolic disorder with no definite treatment. Different species of the genus Tamarix (tamarisk) are used by local people to treat DM. Tamarix stricta Boiss. is an endemic species to Iran with several traditional therapeutic uses in Persian Medicine. This study aimed to assess the antidiabetic activity of T. stricta. MATERIALS AND METHODS: Hydroethanolic extract of the plant was prepared and analyzed by High-performance liquid chromatography (HPLC). The protective effect of the extract was evaluated in streptozotocin (STZ)-induced toxicity and markers of autophagy in pancreatic RIN-5F cells. The effect of intragastric 10 or 20 mg/kg of the extract was compared with negative control (water) or positive control (metformin) treatment during four weeks of administration in high-fat diet + STZ-induced DM in Balb/c mice. RESULTS: Results showed the presence of 8.436 mg of gallic acid in each gram of the extract. A significant cytoprotective effect was observed by T. stricta in STZ-induced toxicity in RIN-5F cells, partially due to the modulation of autophagy. Also, animals treated with the extract showed a significant improvement in glycemic and lipid profiles, liver function, and histopathologic features of pancreas and liver compared with the negative control. CONCLUSION: T. stricta demonstrated beneficial effects in animal model of DM; though, further studies are recommended to confirm the clinical use of this plant in DM.


Assuntos
Autofagia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Extratos Vegetais/uso terapêutico , Tamaricaceae , Animais , Autofagia/fisiologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ratos , Estreptozocina
18.
Diab Vasc Dis Res ; 17(6): 1479164120966998, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33280417

RESUMO

AIMS: The objective of this study was to explore the effects of epigallocatechin-3-gallate (EGCG) on type 2 diabetes mellitus (T2DM). MAIN METHODS: Male Sprague-Dawley rats were allocated into six groups. The control group received a conventional diet. The diabetic group received a high-sucrose high-fat (HSHF) diet for 4 weeks and then was fasted and injected with streptozotocin (STZ); subsequently, the rats received a HSHF diet for another 4 weeks to develop diabetes. The four treatment groups were diabetic rats that received intragastric metformin (500 mg/kg/day) or EGCG (25, 50, and 100 mg/kg/day) for 10 weeks. All groups except the control group received a HSHF diet throughout the experiment. Several biochemical parameters such as fasting blood glucose (FBG), postprandial blood glucose (PBG), liver glycogen, muscle glycogen, fasting serum insulin (FSI), homeostasis model of insulin resistance (HOMA-IR), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), free fatty acids (FFA), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured to assess the effects of EGCG on glycemic control, insulin resistance, lipid profile, and oxidative stress. Furthermore, oxidative stress in pancreatic islet ß cells was detected by dihydroethidium staining. KEY FINDINGS: A HSHF diet and STZ injection induced T2DM, as indicated by changed blood glucose and body weight, which was accompanied by insulin resistance, an altered lipid profile, and oxidative stress. Interestingly, EGCG treatment dose-dependently recovered these indexes. SIGNIFICANCE: EGCG successfully ameliorated glycemic control and insulin sensitivity while reducing the lipid profile and oxidative stress in a T2DM rat model.


Assuntos
Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Catequina/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Lipídeos/sangue , Estresse Oxidativo/efeitos dos fármacos , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Catequina/farmacologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Sacarose na Dieta , Resistência à Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos Sprague-Dawley , Estreptozocina
19.
Front Endocrinol (Lausanne) ; 11: 601594, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362717

RESUMO

Objective: A low-carbohydrate diet (LC) can be beneficial to obese subjects with type2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 inhibitor (SGLT2i) presents prompt glucose-lowering effects in subjects with T2DM. We investigated how LC and SGLT2i could similarly or differently influence on the metabolic changes, including glucose, lipid, and ketone metabolism in lean insulinopenic Akita mice. We also examined the impacts of the combination. Methods: Male Akita mice were fed ad libitum normal-carbohydrate diet (NC) as a control or low-carbohydrate diet (LC) as an intervention for 8 weeks with or without SGLT2i treatment. Body weight and casual bold glucose levels were monitored during the study, in addition to measuring TG, NEFA, and ketone levels. We quantified gene expressions involved in gluconeogenesis, lipid metabolism and ketogenesis in the liver and the kidney. We also investigated the immunostaining analysis of pancreatic islets to assess the effect of islet protection. Results: Both LC and SGLT2i treatment reduced chronic hyperglycemia. Moreover, the combination therapy additionally ameliorated glycemic levels and preserved the islet morphology in part. LC but not SGLT2i increased body weight accompanied by epididymal fat accumulation. In contrast, SGLT2i, not LC potentiated four-fold ketone production with higher ketogenic gene expression, in comparison with the non-treated Akita mice. Besides, the combination did not enhance further ketone production compared to the SGLT2i alone. Conclusions: Our results indicated that both LC and SGLT2i reduced chronic hyperglycemia, and the combination presented synergistic favorable effects concomitantly with amelioration of islet morphology, while the combination did not enhance further ketosis in Akita mice.


Assuntos
Diabetes Mellitus Experimental/terapia , Nefropatias Diabéticas/prevenção & controle , Dieta com Restrição de Carboidratos/métodos , Hiperglicemia/terapia , Obesidade/complicações , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Magreza/complicações , Animais , Terapia Combinada , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Gluconeogênese , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
20.
Exp Cell Res ; 397(2): 112344, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33164862

RESUMO

High glucose (HG)-induced oxidative stress contributes significantly to the pathogenesis of diabetic retinopathy. Pleckstrin homology domain and leucine rich repeat protein phosphatase 1 (PHLPP1) has emerged as a key regulator of oxidative stress implicated in various pathological processes. However, whether PHLPP1 participates in the regulation of HG-induced oxidative stress injury of retinal ganglion cells (RGCs) in diabetic retinopathy is undetermined. The purpose of this study was to explore the potential role and molecular mechanism of PHLPP1 in regulating HG-induced injury of RGCs. Our data showed that PHLPP1 expression was markedly elevated in RGCs from diabetic rats and HG-exposed RGCs. Our functional assay elucidated that knockdown of PHLPP1 improved cell viability and decreased cell apoptosis and reactive oxygen species (ROS) production in HG-exposed RGCs. Additionally, upregulation of PHLPP1 lowered cell viability and increased cell apoptosis and ROS production in HG-exposed RGCs. Mechanistically, knockdown of PHLPP1 resulted in an increase in nuclear factor erythroid-2 related factor 2 (Nrf2) nuclear expression and Nrf2/antioxidant response element (ARE)-mediated transcription associated with upregulation of glycogen synthase kinase-3ß (GSK-3ß) phosphorylation. Moreover, inhibition of GSK-3ß significantly reversed the suppressive effect of PHLPP1 overexpression on Nrf2/ARE activation. Notably, the protective effect of PHLPP1 knockdown on HG-induced injury in RGCs was markedly abolished by Nrf2 inhibition. In conclusion, Our findings demonstrate that downregulation of PHLPP1 activates Nrf2/ARE signaling to protect RGCs from HG-induced apoptosis and oxidative stress. This study indicates a potential role of PHLPP1 in regulating HG-induced injury of RGCs during the development and progression of diabetic retinopathy.


Assuntos
Apoptose , Diabetes Mellitus Experimental/terapia , Glucose/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Estresse Oxidativo , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Substâncias Protetoras , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Transdução de Sinais
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