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1.
Sci Rep ; 14(1): 15642, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977865

RESUMO

Oxidative stress plays an essential role in the progression of Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. Streptozotocin (STZ)-induced abnormal brain insulin signaling and oxidative stress play crucial roles in the progression of Alzheimer's disease (AD)-like pathology. Peroxiredoxins (Prxs) are associated with protection from neuronal death induced by oxidative stress. However, the molecular mechanisms underlying Prxs on STZ-induced progression of AD in the hippocampal neurons are not yet fully understood. Here, we evaluated whether Peroxiredoxin 1 (Prx1) affects STZ-induced AD-like pathology and cellular toxicity. Prx1 expression was increased by STZ treatment in the hippocampus cell line, HT-22 cells. We evaluated whether Prx1 affects STZ-induced HT-22 cells using overexpression. Prx1 successfully protected the forms of STZ-induced AD-like pathology, such as neuronal apoptosis, synaptic loss, and tau phosphorylation. Moreover, Prx1 suppressed the STZ-induced increase of mitochondrial dysfunction and fragmentation by down-regulating Drp1 phosphorylation and mitochondrial location. Prx1 plays a role in an upstream signal pathway of Drp1 phosphorylation, cyclin-dependent kinase 5 (Cdk5) by inhibiting the STZ-induced conversion of p35 to p25. We found that STZ-induced of intracellular Ca2+ accumulation was an important modulator of AD-like pathology progression by regulating Ca2+-mediated Calpain activation, and Prx1 down-regulated STZ-induced intracellular Ca2+ accumulation and Ca2+-mediated Calpain activation. Finally, we identified that Prx1 antioxidant capacity affected Ca2+/Calpain/Cdk5-mediated AD-like pathology progress. Therefore, these findings demonstrated that Prx1 is a key factor in STZ-induced hippocampal neuronal death through inhibition of Ca2+/Calpain/Cdk5-mediated mitochondrial dysfunction by protecting against oxidative stress.


Assuntos
Doença de Alzheimer , Cálcio , Calpaína , Quinase 5 Dependente de Ciclina , Hipocampo , Mitocôndrias , Neurônios , Peroxirredoxinas , Estreptozocina , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/etiologia , Quinase 5 Dependente de Ciclina/metabolismo , Quinase 5 Dependente de Ciclina/genética , Estreptozocina/toxicidade , Hipocampo/metabolismo , Hipocampo/patologia , Neurônios/metabolismo , Neurônios/patologia , Calpaína/metabolismo , Peroxirredoxinas/metabolismo , Peroxirredoxinas/genética , Mitocôndrias/metabolismo , Camundongos , Cálcio/metabolismo , Linhagem Celular , Estresse Oxidativo , Apoptose , Dinaminas/metabolismo , Dinaminas/genética , Fosforilação , Proteínas tau/metabolismo , Transdução de Sinais
2.
BMC Cardiovasc Disord ; 24(1): 333, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38961333

RESUMO

BACKGROUND: Oxidative stress may contribute to cardiac ryanodine receptor (RyR2) dysfunction in diabetic cardiomyopathy. Ginsenoside Rb1 (Rb1) is a major pharmacologically active component of ginseng to treat cardiovascular diseases. Whether Rb1 treat diabetes injured heart remains unknown. This study was to investigate the effect of Rb1 on diabetes injured cardiac muscle tissue and to further investigate its possible molecular pharmacology mechanisms. METHODS: Male Sprague-Dawley rats were injected streptozotocin solution for 2 weeks, followed 6 weeks Rb1 or insulin treatment. The activity of SOD, CAT, Gpx, and the levels of MDA was measured; histological and ultrastructure analyses, RyR2 activity and phosphorylated RyR2(Ser2808) protein expression analyses; and Tunel assay were performed. RESULTS: There was decreased activity of SOD, CAT, Gpx and increased levels of MDA in the diabetic group from control. Rb1 treatment increased activity of SOD, CAT, Gpx and decreased the levels of MDA as compared with diabetic rats. Neutralizing the RyR2 activity significantly decreased in diabetes from control, and increased in Rb1 treatment group from diabetic group. The expression of phosphorylation of RyR2 Ser2808 was increased in diabetic rats from control, and were attenuated with insulin and Rb1 treatment. Diabetes increased the apoptosis rate, and Rb1 treatment decreased the apoptosis rate. Rb1 and insulin ameliorated myocardial injury in diabetic rats. CONCLUSIONS: These data indicate that Rb1 could be useful for mitigating oxidative damage, reduced phosphorylation of RyR2 Ser2808 and decreased the apoptosis rate of cardiomyocytes in diabetic cardiomyopathy.


Assuntos
Antioxidantes , Apoptose , Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Ginsenosídeos , Miócitos Cardíacos , Estresse Oxidativo , Ratos Sprague-Dawley , Canal de Liberação de Cálcio do Receptor de Rianodina , Estreptozocina , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , Ginsenosídeos/farmacologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Apoptose/efeitos dos fármacos , Antioxidantes/farmacologia , Fosforilação , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismo , Miocárdio/patologia , Miocárdio/metabolismo , Insulina , Malondialdeído/metabolismo
3.
Nutrients ; 16(11)2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38892601

RESUMO

Type 2 diabetes mellitus (T2DM) is a major global public health concern, prompting the ongoing search for new treatment options. Medicinal plants have emerged as one such alternative. Our objective was to evaluate the antidiabetic effect of an extract from the leaves of Passiflora ligularis (P. ligularis). For this purpose, T2DM was first induced in mice using a high-fat diet and low doses of streptozotocin. Subsequently, an aqueous extract or an ethanolic extract of P. ligularis leaves was administered for 21 days. The following relevant results were found: fasting blood glucose levels were reduced by up to 41%, and by 29% after an oral glucose overload. The homeostasis model assessment of insulin resistance (HOMA-IR) was reduced by 59%. Histopathologically, better preservation of pancreatic tissue was observed. Regarding oxidative stress parameters, there was an increase of up to 48% in superoxide dismutase (SOD), an increase in catalase (CAT) activity by 35% to 80%, and a decrease in lipid peroxidation (MDA) by 35% to 80% in the liver, kidney, or pancreas. Lastly, regarding the lipid profile, triglycerides (TG) were reduced by up to 30%, total cholesterol (TC) by 35%, and low-density lipoproteins (LDL) by up to 32%, while treatments increased high-density lipoproteins (HDL) by up to 35%. With all the above, we can conclude that P. ligularis leaves showed antihyperglycemic, hypolipidemic, and antioxidant effects, making this species promising for the treatment of T2DM.


Assuntos
Glicemia , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica , Hipoglicemiantes , Passiflora , Extratos Vegetais , Folhas de Planta , Animais , Folhas de Planta/química , Diabetes Mellitus Experimental/tratamento farmacológico , Extratos Vegetais/farmacologia , Hipoglicemiantes/farmacologia , Dieta Hiperlipídica/efeitos adversos , Passiflora/química , Camundongos , Masculino , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Estreptozocina , Resistência à Insulina , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/metabolismo , Antioxidantes/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Lipídeos/sangue , Fitoterapia
4.
Nutrients ; 16(11)2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38892624

RESUMO

Probiotics have garnered increasing attention as a potential therapeutic approach for type 2 diabetes mellitus (T2DM). Previous studies have confirmed that Bifidobacterium animalis subsp. lactis MN-Gup (MN-Gup) could stimulate the secretion of glucagon-like peptide-1 (GLP-1) in NCI-H716 cells, but whether MN-Gup has a hypoglycemic effect on T2DM in vivo remains unclear. In this study, a T2DM mouse model was constructed, with a high-fat diet and streptozotocin in mice, to investigate the effect of MN-Gup on diabetes. Then, different doses of MN-Gup (2 × 109 CFU/kg, 1 × 1010 CFU/kg) were gavaged for 6 weeks to investigate the effect of MN-Gup on glucose metabolism and its potential mechanisms. The results showed that a high-dose of MN-Gup significantly reduced the fasting blood glucose (FBG) levels and homeostasis model assessment-insulin resistance (HOMA-IR) of T2DM mice compared to the other groups. In addition, there were significant increases in the short-chain fatty acids (SCFAs), especially acetate, and GLP-1 levels in the MN-Gup group. MN-Gup increased the relative abundance of Bifidobacterium and decreased the number of Escherichia-Shigella and Staphylococcus. Moreover, the correlation analysis revealed that Bifidobacterium demonstrated a significant positive correlation with GLP-1 and a negative correlation with the incremental AUC. In summary, this study demonstrates that Bifidobacterium animalis subsp. lactis MN-Gup has significant hypoglycemic effects in T2DM mice and can modulate the gut microbiota, promoting the secretion of SCFAs and GLP-1.


Assuntos
Bifidobacterium animalis , Glicemia , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Peptídeo 1 Semelhante ao Glucagon , Probióticos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Probióticos/farmacologia , Glicemia/metabolismo , Camundongos , Masculino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/sangue , Ácidos Graxos Voláteis/metabolismo , Resistência à Insulina , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Estreptozocina , Bifidobacterium
5.
J Enzyme Inhib Med Chem ; 39(1): 2367128, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38913598

RESUMO

Inhibition of α-glucosidase and α-amylase are key tactics for managing blood glucose levels. Currently, stronger, and more accessible inhibitors are needed to treat diabetes. Indeno[1,2-b] quinoxalines-carrying thiazole hybrids 1-17 were created and described using NMR. All analogues were tested for hypoglycaemic effect against STZ-induced diabetes in mice. Compounds 4, 6, 8, and 16 were the most potent among the synthesised analogues. These hybrids were examined for their effects on plasma insulin, urea, creatinine, GSH, MDA, ALT, AST, and total cholesterol. Moreover, these compounds were tested against α-glucosidase and α-amylase enzymes in vitro. The four hybrids 4, 6, 8, and 16 represented moderate to potent activity with IC50 values 0.982 ± 0.04, to 10.19 ± 0.21 for α-glucosidase inhibition and 17.58 ± 0.74 to 121.6 ± 5.14 µM for α-amylase inhibition when compared to the standard medication acarbose with IC50=0.316 ± 0.02 µM for α-glucosidase inhibition and 31.56 ± 1.33 µM for α-amylase inhibition. Docking studies as well as in silico ADMT were done.


Assuntos
Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes , Simulação de Acoplamento Molecular , Quinoxalinas , Tiazóis , alfa-Amilases , alfa-Glucosidases , Quinoxalinas/farmacologia , Quinoxalinas/química , Quinoxalinas/síntese química , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/síntese química , Animais , Camundongos , Relação Estrutura-Atividade , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Estrutura Molecular , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/síntese química , Diabetes Mellitus Experimental/tratamento farmacológico , Estreptozocina , Halogenação , Masculino , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química
6.
Food Funct ; 15(13): 7003-7016, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38855929

RESUMO

Food proteins are considered an ideal source for the identification of bioactive peptides with the potential to intervene in nutrition-related chronic diseases such as cardiovascular disease, obesity, and diabetes. Egg white-derived peptides (EWPs) have been shown to improve glucose tolerance in insulin-resistant rats. However, underlying mechanisms are to be elucidated. Therefore, we hypothesized that EWP exerts a hypoglycemic effect by regulating hepatic glucose homeostasis. Our results showed that 7 weeks of EWP treatment reduced the fasting blood glucose in T2DM mice and the inhibition of the liver gluconeogenic pathway was involved in the mechanisms of actions. Using the untargeted metabolomics technique, we found that EWP treatment also altered the hepatic metabolic profile in T2DM mice, in which, the role of fatty acid esters of hydroxy fatty acids in mediating the hypoglycemic effect of EWPs might be pivotal.


Assuntos
Glicemia , Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica , Gluconeogênese , Fígado , Peptídeos , Animais , Gluconeogênese/efeitos dos fármacos , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Masculino , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Peptídeos/farmacologia , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Estreptozocina , Diabetes Mellitus Experimental/metabolismo , Clara de Ovo/química , Metaboloma/efeitos dos fármacos
8.
Drug Des Devel Ther ; 18: 1981-1996, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38855535

RESUMO

Background: Polygonum capitatum Buch.-Ham. ex D. Don (P. capitatum), a traditional herb used in Miao medicine, is renowned for its heart-clearing properties. Davidiin, the primary bioactive component (approximately 1%), has been used to treat various conditions, including diabetes. Given its wide range of effects and the diverse biomolecular pathways involved in diabetes, there is a crucial need to study how davidiin interacts with these pathways to better understand its anti-diabetic properties. Materials and Methods: Diabetic rats were induced using a high-fat diet and streptozotocin (STZ) administered intraperitoneally at 35 mg/kg. Out of these, 24 rats with blood glucose levels ≥ 11.1 mmol/L and fasting blood glucose levels ≥ 7.0 mmol/L were selected for three experimental groups. These groups were then treated with either metformin (gavage, 140 mg/kg) or davidiin (gavage, 90 mg/kg) for four weeks. After the treatment period, we measured body weight, blood glucose levels, and conducted untargeted metabolic profiling using UPLC-QTOF-MS. Results: Davidiin has been shown to effectively treat diabetes by reducing blood glucose levels from 30.2 ± 2.6 mmol/L to 25.1 ± 2.4 mmol/L (P < 0.05). This effect appears stronger than that of metformin, which lowered glucose levels to 26.5 ± 2.6 mmol/L. The primary outcomes of serum metabolomics are significant changes in lipid and lipid-like molecular profiles. Firstly, davidiin may affect phosphatide metabolism by increasing levels of phosphatidylinositol and sphingosine-1-phosphate. Secondly, davidiin could influence cholesterol metabolism by reducing levels of glycocholic acid and glycochenodeoxycholic acid. Lastly, davidiin might impact steroid hormone metabolism by increasing hepoxilin B3 levels and decreasing prostaglandins. Conclusion: Our study demonstrates that davidiin modulates various lipid-related metabolic pathways to exert its anti-diabetic effects. These findings offer the first detailed metabolic profile of davidiin's action mechanism, contributing valuable insights to the field of Traditional Chinese Medicine in the context of diabetes treatment.


Assuntos
Diabetes Mellitus Experimental , Hipoglicemiantes , Metaboloma , Ratos Sprague-Dawley , Estreptozocina , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Ratos , Hipoglicemiantes/farmacologia , Masculino , Metaboloma/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica , Medicamentos de Ervas Chinesas/farmacologia
9.
Sci Rep ; 14(1): 12978, 2024 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-38839927

RESUMO

Diabetic cardiomyopathy is a specific type of cardiomyopathy. In DCM, glucose uptake and utilization are impaired due to insulin deficiency or resistance, and the heart relies more heavily on fatty acid oxidation for energy, resulting in myocardial lipid toxicity-related injury. MARK4 is a member of the AMPK-related kinase family, and improves ischaemic heart failure through microtubule detyrosination. However, the role of MARK4 in cardiac regulation of metabolism is unclear. In this study, after successful establishment of a diabetic cardiomyopathy model induced by streptozotocin and a high-fat diet, MARK4 expression was found to be significantly increased in STZ-induced DCM mice. After AAV9-shMARK4 was administered through the tail vein, decreased expression of MARK4 alleviated diabetic myocardial damage, reduced oxidative stress and apoptosis, and facilitated cardiomyocyte mitochondrial fusion, and promoted myocardial lipid oxidation metabolism. In addition, through the RNA-seq analysis of differentially expressed genes, we found that MARK4 deficiency promoted lipid decomposition and oxidative metabolism by downregulating the expression of ACSL4, thus reducing myocardial lipid accumulation in the STZ-induced DCM model.


Assuntos
Coenzima A Ligases , Cardiomiopatias Diabéticas , Metabolismo dos Lipídeos , Miocárdio , Animais , Masculino , Camundongos , Apoptose , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/etiologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Estreptozocina
10.
Pak J Pharm Sci ; 37(2(Special)): 459-462, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38822550

RESUMO

The purpose of this study was to examine the potential hypoglycemic effects of administering ginger (Zingiber officinale) and garlic (Allium sativum) to rats with induced type 2 diabetes. A total of forty-five male adult albino rats were randomly assigned to five groups. The groups were named Normal Control, Diabetic Control, Ginger group, Garlic group and a combination group of ginger and garlic. Diabetes was produced in all groups, except the normal control group, using an intraperitoneal injection of streptozotocin at a dosage of 60 mg/body weight. During the course of two months, rats were administered varying amounts of ginger and garlic powders as part of their treatment After the experiment concluded, measurements were taken for glycated hemoglobin, serum glucose, insulin, cholesterol, high density protein, low density protein and liver glycogen levels. These groups exhibited considerably greater serum insulin and high-density lipoprotein concentrations (P<0.05) compared to the diabetic control group. Conversely, body weight, fasting blood glucose, total cholesterol, low density lipoprotein, and glycated hemoglobin levels were significantly lower (P<0.05) in all groups compared to the diabetic control group. A statistically significant increase (P<0.05) increase shown in liver glycogen levels. This study proposes that the utilization of ginger and garlic powders improve the condition of type 2 diabetes and maybe reduce the risk of subsequent diabetic complications.


Assuntos
Glicemia , Diabetes Mellitus Experimental , Alho , Hipoglicemiantes , Insulina , Pós , Zingiber officinale , Animais , Alho/química , Zingiber officinale/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/sangue , Masculino , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Ratos , Insulina/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Hemoglobinas Glicadas/metabolismo , Extratos Vegetais/farmacologia , Fitoterapia , Glicogênio Hepático/metabolismo , Estreptozocina
11.
Food Res Int ; 188: 114508, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38823847

RESUMO

Procyanidins, which are oligomerized flavan-3-ols with a polyphenolic structure, are bioactive substances that exhibit various biological effects. However, the relationship between the degree of polymerization (DP) of procyanidins and their bioactivities remains largely unknown. In this study, the preventive effects of procyanidins with different DP (EC, PB2 and PC1) on glucose improvement and liver lipid deposition were investigated using a high-fat diet/streptozotocin-induced diabetes mouse model. The results demonstrated that all the procyanidins with different DP effectively reduced fasting blood glucose and glucose/insulin tolerance, decreased the lipid profile (total cholesterol, triglyceride, and low-density lipoprotein cholesterol content) in serum and liver tissue as well as the liver oil red staining, indicating the improvement of glucose metabolism, insulin sensitivity and hepatic lipid deposition in diabetic mice. Furthermore, the procyanidins down-regulated expression of glucose regulated 78-kDa protein (GRP78) and C/EBP homologous protein (CHOP), indicating a regulation role of endoplasmic reticulum (ER) stress. The inhibition of ER stress by tauroursodeoxycholic acid (TUDCA) treatment abolished the effects of procyanidins with different DP in PA-induced HepG2 cells, confirming that procyanidins alleviate liver hyperlipidemia through the modulation of ER stress. Molecular docking results showed that EC and PB2 could better bind GRP78 and CHOP. Collectively, our study reveals that the structure of procyanidins, particularly DP, is not directly correlated with the improvement of blood glucose and lipid deposition, while highlighting the important role of ER stress in the bioactivities of procyanidins.


Assuntos
Glicemia , Diabetes Mellitus Experimental , Dieta Hiperlipídica , Chaperona BiP do Retículo Endoplasmático , Metabolismo dos Lipídeos , Fígado , Proantocianidinas , Animais , Proantocianidinas/farmacologia , Dieta Hiperlipídica/efeitos adversos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Células Hep G2 , Humanos , Polimerização , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Simulação de Acoplamento Molecular , Biflavonoides/farmacologia , Camundongos Endogâmicos C57BL , Estreptozocina , Resistência à Insulina , Catequina/farmacologia
12.
Carbohydr Polym ; 339: 122275, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38823933

RESUMO

Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and few therapeutic options are available. The root of Achyranthis bidentatae (AB) is commonly used for DKD treatment in Traditional Chinese medicine. However, its mechanisms are still unclear. Here, a graminan type fructan ABPW1 with molecular weight of 3998 Da was purified from AB. It was composed of ß-1,2-linked Fruf, ß-2,6-linked-Fruf and ß-1,2,6-linked-Fruf backbone, and terminated with T-Glcp and 2-Fruf residues. ABPW1 protected against kidney injuries and intestinal barrier disruption in Streptozotocin (STZ)/High fat diet (HFD) mice. It could modulate gut microbiota composition, evidenced by a rise in the abundance of Bacteroide and decreases of Rikenella, Alistipes, Laedolimicola and Faecalibaculum. ABPW1 intervention promoted short chain fatty acids (SCFAs) production in STZ/HFD mice, especially propionate and isobutyric acid. Antibiotic treatment further demonstrated the key role of gut microbiota in the renal protective action of ABPW1. In addition, in vitro simulated digestion and fermentation together with in vivo fluorescent labeling studies demonstrated ABPW1 was indigestible in upper digestive tract but could reach the colon and be degraded into SCFAs by gut microbiota there. Overall, these data suggested ABPW1 has the potential application on DKD prevention.


Assuntos
Achyranthes , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Frutanos , Microbioma Gastrointestinal , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Achyranthes/química , Camundongos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Masculino , Frutanos/farmacologia , Frutanos/química , Camundongos Endogâmicos C57BL , Dieta Hiperlipídica/efeitos adversos , Estreptozocina , Rim/efeitos dos fármacos , Rim/patologia , Ácidos Graxos Voláteis/metabolismo
13.
Mol Biol Rep ; 51(1): 711, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824245

RESUMO

BACKGROUND: Diabetes is a chronic metabolic disease that affects many parts of the body. Considering diabetes as a beta cells' defect and loss, the focus is on finding mechanisms and compounds involved in stimulating the function and regeneration of pancreatic ß-cells. DNA methylation as an epigenetic mechanism plays a pivotal role in the ß-cells' function and development. Considering the regenerative and anti-diabetic effects of Rosa canina extract, this study aimed to assess the methylation levels of Pdx-1, Pax-4, and Ins-1 genes in diabetic rats treated with Rosa Canina extract. METHODS AND RESULTS: Streptozotocin-induced diabetic rats were used to evaluate the frequency of Pdx-1, Pax-4, and Ins-1 gene methylation. Treatment groups were exposed to Rosa canina as spray-dried and decoction extracts. Following blood glucose measurement, pancreatic DNA was extracted and bisulfited. Genes' methylation was measured using MSP-PCR and qRT-PCR techniques. Oral administration of Rosa canina extracts significantly reduced blood sugar levels in diabetic rats compared to the control group. The methylation levels of the Pdx-1, Pax-4, and Ins-1 genes promoter in streptozotocin-induced diabetic rats increased compared to the control rats while, the treatment of diabetic rats with Rosa canina extracts, spray-dried samples especially, led to a decreased methylation in these genes. CONCLUSION: The results of this study showed that Rosa canina extract as a spray-dried sample could be effective in treating diabetes by regulating the methylation of genes including Pdx-1, Pax-4, and Ins-1 involved in the activity and regeneration of pancreatic islet cells.


Assuntos
Glicemia , Metilação de DNA , Diabetes Mellitus Experimental , Extratos Vegetais , Rosa , Transativadores , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Rosa/química , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Ratos , Extratos Vegetais/farmacologia , Masculino , Transativadores/genética , Transativadores/metabolismo , Glicemia/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Estreptozocina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Insulina/metabolismo
14.
Metab Brain Dis ; 39(5): 661-678, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38842663

RESUMO

This study examines the effectiveness of lupeol and metformin in a mouse model of dementia generated by intracerebroventricular streptozotocin (i.c.v., STZ). Dementia was induced in Swiss mice with the i.c.v. administration of STZ at a dosage of 3 mg/kg on the first and third day. The assessment of dementia involved an examination of the Morris Water Maze (MWM) performance, as well as a number of biochemical and histological studies. STZ treatment resulted in significant decrease in MWM performance; various biochemical alterations (increase in brain acetyl cholinesterase (AChE) activity, thiobarbituric acid reactive species (TBARS), nitrite/nitrate, and reduction in nuclear factor erythroid 2 related factor-2 (Nrf-2), reduced glutathione (GSH) levels) and neuroinflammation [increased myeloperoxidase (MPO) activity & neutrophil infiltration]. The administration of Lupeol (50 mg/kg & 100 mg/kg; p.o.) and Metformin (150 mg/kg & 300 mg/kg; p.o.) demonstrated a considerable reduction in the behavioral, biochemical, and histological alterations produced by STZ. Low dose combination of lupeol (50 mg/kg; p.o.) and Metformin (150 mg/kg; p.o.) produced more pronounced effect than that of high doses of either agent alone. It is concluded that Lupeol and Metformin has shown efficacy in dementia with possible synergism between the two and can be explored as potential therapeutic agents for managing dementia of Alzheimer's disease (AD) type.


Assuntos
Demência , Modelos Animais de Doenças , Metformina , Triterpenos Pentacíclicos , Estreptozocina , Animais , Triterpenos Pentacíclicos/uso terapêutico , Triterpenos Pentacíclicos/farmacologia , Metformina/farmacologia , Metformina/uso terapêutico , Estreptozocina/toxicidade , Camundongos , Demência/tratamento farmacológico , Demência/induzido quimicamente , Masculino , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Glutationa/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Lupanos
15.
Drug Des Devel Ther ; 18: 2103-2124, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38882044

RESUMO

Introduction: Autologous stem cell transplantation has emerged as a promising strategy for bone repair. However, the osteogenic potential of mesenchymal stem cells derived from diabetic patients is compromised, possibly due to hyperglycemia-induced senescence. The objective of this study was to assess the preconditioning effects of extracellular vesicles derived from H2O2-stimulated adipose-derived stem cells (ADSCs) and non-modified ADSCs on the osteogenic potential of diabetic bone marrow mesenchymal stem cells (BMSCs). Methods: Sprague-Dawley (SD) rats were experimentally induced into a diabetic state through a high-fat diet followed by an injection of streptozotocin, and diabetic BMSCs were collected from the bone marrow of these rats. Extracellular vesicles (EVs) were isolated from the conditioned media of ADSCs, with or without hydrogen peroxide (H2O2) preconditioning, using density gradient centrifugation. The effects of H2O2 preconditioning on the morphology, marker expression, and particle size of the EVs were analyzed. Furthermore, the impact of EV-pretreatment on the viability, survivability, migration ability, osteogenesis, cellular senescence, and oxidative stress of diabetic BMSCs was examined. Moreover, the expression of the Nrf2/HO-1 pathway was also assessed to explore the underlying mechanism. Additionally, we transplanted EV-pretreated BMSCs into calvarial defects in diabetic rats to assess their in vivo bone formation and anti-senescence capabilities. Results: Our study demonstrated that pretreatment with EVs from ADSCs significantly improved the viability, senescence, and osteogenic differentiation potential of diabetic BMSCs. Moreover, in-vitro experiments revealed that diabetic BMSCs treated with H2O2-activated EVs exhibited increased viability, reduced senescence, and enhanced osteogenic differentiation compared to those treated with non-modified EVs. Furthermore, when transplanted into rat bone defects, diabetic BMSCs treated with H2O2-activated EVs showed improved bone regeneration potential and enhanced anti-senescence function t compared to those treated with non-modified EVs. Both H2O2-activated EVs and non-modified EVs upregulated the expression of the Nrf2/HO-1 pathway in diabetic BMSCs, however, the promoting effect of H2O2-activated EVs was more pronounced than that of non-modified EVs. Conclusion: Extracellular vesicles derived from H2O2-preconditioned ADSCs mitigated senescence in diabetic BMSCs and enhanced their bone regenerative functions via the activation of the Nrf2/HO-1 pathway.


Assuntos
Senescência Celular , Diabetes Mellitus Experimental , Vesículas Extracelulares , Peróxido de Hidrogênio , Células-Tronco Mesenquimais , Osteogênese , Ratos Sprague-Dawley , Animais , Peróxido de Hidrogênio/farmacologia , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Ratos , Osteogênese/efeitos dos fármacos , Diabetes Mellitus Experimental/terapia , Senescência Celular/efeitos dos fármacos , Masculino , Células Cultivadas , Tecido Adiposo/citologia , Estresse Oxidativo/efeitos dos fármacos , Estreptozocina
16.
PLoS One ; 19(6): e0306039, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38924022

RESUMO

BACKGROUND: Spilanthes filicaulis (Schumach. & Thonn.) C. D Adam is a shrubby plant of the Asteraceae family that has medicinal benefits for the pharmaceutical and cosmetic industries. PURPOSE: The purpose of this study was to assess the effectiveness of Spilanthes filicaulis leaf extract in a streptozotocin (STZ)-induced rat model and the associated signaling pathways. METHODS: A sample of 25 male Wistar rats was randomly assigned to groups I, II, III, IV, and V. Each group included five animals, i.e., control rats, diabetic control rats, diabetic rats treated with metformin, and diabetic rats treated with 150 mg/kg/bw and 300 mg/kg/bw of the methanolic extract of S. filicaulis leaves (MESFL). Treatment was administered for 15 successive days via oral gavage. After 15 days, the rats were evaluated for fasting blood glucose (FBG), glycated hemoglobin (HbA1c), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), lipid peroxidation (MDA), hexokinase, and glucose-6-phosphatase activities. Gene expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor gamma (PPAR-γ), kelch-like ECH-associated protein 1 (Keap1), protein tyrosine phosphatase 1B (PTP1B) and the antiapoptotic protein caspase-3 were examined. RESULTS: MESFL was administered to diabetic rats, and changes in body weight, fasting blood glucose (FBG) and HbA1c were restored. Furthermore, in diabetic rats, S. filicaulis significantly reduced the levels of triglycerides (TGs), total cholesterol (TC), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) and significantly increased HDL. S. filicaulis improved ALT, AST, and ALP enzyme activity in diabetic rats. MDA levels decreased considerably with increasing activity of antioxidant enzymes, such as GST, SOD, CAT and GSH, in diabetic liver rats treated with S. filicaulis. Diabetic rats treated with MESFL and metformin exhibited upregulated mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor gamma (PPAR-γ). Kelch-like ECH-associated protein 1 (Keap1) and protein tyrosine phosphatase 1B (PTP1B) mRNA expression in the liver was downregulated in diabetic rats treated with MESFL and metformin. In addition, MESFL downregulated the mRNA expression of caspase-3 in diabetic rats. CONCLUSION: It can be concluded from the data presented in this study that MESFL exerts a protective effect on diabetic rats due to its antidiabetic, antioxidant, antihyperlipidemic and antiapoptotic effects and may be considered a treatment for T2DM.


Assuntos
Diabetes Mellitus Experimental , Proteína 1 Associada a ECH Semelhante a Kelch , Fígado , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , PPAR gama , Extratos Vegetais , Folhas de Planta , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Ratos Wistar , Transdução de Sinais , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Masculino , Extratos Vegetais/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/química , Transdução de Sinais/efeitos dos fármacos , Ratos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , PPAR gama/metabolismo , PPAR gama/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Asteraceae/química , Estreptozocina , Hipoglicemiantes/farmacologia
17.
Int J Biol Macromol ; 273(Pt 1): 133060, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38871107

RESUMO

Plant-derived polysaccharides are important components for biological functions. The objective of this study is to study the mechanisms by which polysaccharides from three Huanglian (Rhizome Coptidis, HL) of Coptis chinensis, C. deltoidea, and Coptis teeta affect type 2 diabetes mellitus (T2DM) by analyzing the gut microbiome and their metabolites. A long-term high-fat diet (HFD) combined with streptozocin (STZ) induction was used to construct the T2DM mice model. The histopathology of liver, pancreas, and colon, biochemical indexes related to mice were determined to assess the ameliorative effects of these three HL polysaccharides (HLPs) on T2DM. The results indicated that oral HLPs improved hyperglycemia, insulin resistance, blood lipid levels, and ß-cell function. Further, HLPs elevated the growth of advantageous beneficial bacteria within the gut microbiota and raised the concentrations of short-chain fatty acids (SCFAs), particularly butyric acid. Metabolic analyses showed that HLPs ameliorated the effects of T2DM on microbial-derived metabolites and related metabolic pathways, especially the biosynthetic pathways of phenylalanine, tyrosine, and tryptophan. In the combined analysis, many associations of T2DM-related biochemical indicators with gut microbes and their metabolites were extracted, which suggested the important role of gut microbiome and fecal metabolome in the amelioration of type 2 diabetes mellitus by HLPs.


Assuntos
Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica , Fezes , Microbioma Gastrointestinal , Metaboloma , Polissacarídeos , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Camundongos , Polissacarídeos/farmacologia , Polissacarídeos/química , Fezes/microbiologia , Metaboloma/efeitos dos fármacos , Masculino , Estreptozocina , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Coptis/química , Resistência à Insulina
18.
J Microbiol Biotechnol ; 34(6): 1307-1313, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38881175

RESUMO

This study investigates whether red pine (Pinus densiflora Sieb. et Zucc.) bark extract (PBE) can alleviate diabetes and abnormal apoptosis signaling pathways in the hippocampus of streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rats. Two dosages of PBE (15 and 30 mg/kg of body weight/day) were administered orally to STZ-induced diabetic SD rats for 20 days. Blood glucose level and body weight were measured once per week. After 20 days of oral administration of PBE, the rat hippocampus was collected, and the production of Akt, p-Akt, GSK-3ß, p-GSK-3ß, tau, p-tau, Bax, and Bcl-2 proteins were determined by western blot analysis. A decrease in blood glucose level and recovery of body weight were observed in PBE-treated diabetic rats. In the Akt/GSK-3ß/tau signaling pathway, PBE inhibited diabetes-induced Akt inactivation, GSK-3ß inactivation, and tau hyperphosphorylation. The protein production ratio of Bax/Bcl-2 was restored to the control group level. These results suggest that PBE, rich in phenolic compounds, can be used as a functional food ingredient to ameliorate neuronal apoptosis in diabetes mellitus.


Assuntos
Apoptose , Glicemia , Diabetes Mellitus Experimental , Glicogênio Sintase Quinase 3 beta , Hipocampo , Pinus , Casca de Planta , Extratos Vegetais , Proteínas Proto-Oncogênicas c-akt , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Casca de Planta/química , Ratos , Masculino , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Pinus/química , Apoptose/efeitos dos fármacos , Estreptozocina , Proteínas tau/metabolismo , Peso Corporal/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
19.
Sci Rep ; 14(1): 13016, 2024 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844763

RESUMO

Diabetes mellitus (DM) is a complex metabolic condition that causes organ dysfunction. The current experiment sought to determine the effect of thymoquinone (TQ) on hyperglycemia, hyperlipidemia, oxidative/nitrosative stress, inflammation, and apoptosis in diabetic rats prompted by streptozotocin (STZ) (55 mg/kg body weight i/p). The animals were allocated into control, TQ (50 mg/kg B.W. orally administered for 4 succeeding weeks), Diabetic, and Diabetic + TQ groups. This study confirmed that TQ preserves the levels of insulin, fasting blood glucose, HOMA ß-cell indices, HbA1c %, body weight, and lipid profile substantially relative to the DC group. Furthermore, hepatic antioxidant (CAT, GSH, and T-SOD) values were reduced. Conversely, the enzymatic activity of liver functions (AST, ALT, ALP, cytochrome P450, and hepatic glucose-6-phosphatase), lipid peroxidation (MDA), pro-inflammatory cytokines (IL-1ß, TNF-α, and IL-6), nitric oxide (NO) and inflammatory marker (CRP) enhanced with STZ administration, which is substantially restored after TQ treatment. Relative to the diabetic rats, TQ reestablished the hepatic architectural changes and collagen fibers. Additionally, TQ downregulated the intensity of the immunohistochemical staining of pro-apoptotic marker (caspase-3), p53, and tumor necrosis factor-alpha (TNF-α) proteins in hepatic tissues. Furthermore, TQ displayed abilities to interact and inhibit the binding site of caspase-3, interleukin-6 receptor, interleukin-1 receptor type 1, TNF receptor superfamily member 1A, and TNF receptor superfamily member 1B in rats following the molecular docking modeling. All these data re-establish the liver functions, antioxidant enzymes, anti-inflammatory markers, and anti-apoptotic proteins impacts of TQ in STZ-induced DM rats. Founded on these outcomes, the experiment proposes that TQ is a novel natural supplement with various clinical applications, including managing DM, which in turn is recommended to play a pivotal role in preventing the progression of diabetes mellitus.


Assuntos
Apoptose , Benzoquinonas , Diabetes Mellitus Experimental , Fígado , Simulação de Acoplamento Molecular , Estresse Nitrosativo , Estresse Oxidativo , Animais , Benzoquinonas/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Ratos , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Masculino , Estresse Nitrosativo/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Glicemia/metabolismo , Ratos Wistar , Estreptozocina
20.
Sci Rep ; 14(1): 13559, 2024 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866877

RESUMO

Naringenin (NAR) has various biological activities but low bioavailability. The current study examines the effect of Naringenin-loaded hybridized nanoparticles (NAR-HNPs) and NAR on depression induced by streptozotocin (STZ) in rats. NAR-HNPs formula with the highest in vitro NAR released profile, lowest polydispersity index value (0.21 ± 0.02), highest entrapment efficiency (98.7 ± 2.01%), as well as an acceptable particle size and zeta potential of 415.2 ± 9.54 nm and 52.8 ± 1.04 mV, respectively, was considered the optimum formulation. It was characterized by differential scanning calorimetry, examined using a transmission electron microscope, and a stability study was conducted at different temperatures to monitor its stability efficiency showing that NAR-HNP formulation maintains stability at 4 °C. The selected formulation was subjected to an acute toxicological test, a pharmacokinetic analysis, and a Diabetes mellitus (DM) experimental model. STZ (50 mg/kg) given as a single i.p. rendered rats diabetic. Diabetic rat groups were allocated into 4 groups: one group received no treatment, while the remaining three received oral doses of unloaded HNPs, NAR (50 mg/kg), NAR-HNPs (50 mg/kg) and NAR (50 mg/kg) + peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist, GW9662 (1mg/kg, i.p.) for three weeks. Additional four non-diabetic rat groups received: distilled water (normal), free NAR, and NAR-HNPs, respectively for three weeks. NAR and NAR-HNPs reduced immobility time in forced swimming test and serum blood glucose while increasing serum insulin level. They also reduced cortical and hippocampal 5-hydroxyindoeacetic acid, 3,4-Dihydroxy-phenylacetic acid, malondialdehyde, NLR family pyrin domain containing-3 (NLRP3) and interleukin-1beta content while raised serotonin, nor-epinephrine, dopamine and glutathione level. PPAR-γ gene expression was elevated too. So, NAR and NAR-HNPs reduced DM-induced depression by influencing brain neurotransmitters and exhibiting anti-oxidant and anti-inflammatory effects through the activation PPAR-γ/ NLRP3 pathway. NAR-HNPs showed the best pharmacokinetic and therapeutic results.


Assuntos
Antidepressivos , Diabetes Mellitus Experimental , Flavanonas , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nanopartículas , PPAR gama , Animais , Flavanonas/farmacologia , Flavanonas/administração & dosagem , Flavanonas/química , PPAR gama/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nanopartículas/química , Ratos , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina , Ratos Wistar , Anilidas
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