RESUMO
Understanding mechanisms of immune regulation is key to developing immunotherapies for autoimmunity and cancer. We examined the role of mononuclear phagocytes during peripheral T cell regulation in type 1 diabetes and melanoma. MERTK expression and activity in mononuclear phagocytes in the pancreatic islets promoted islet T cell regulation, resulting in reduced sensitivity of T cell scanning for cognate antigen in prediabetic islets. MERTK-dependent regulation led to reduced T cell activation and effector function at the disease site in islets and prevented rapid progression of type 1 diabetes. In human islets, MERTK-expressing cells were increased in remaining insulin-containing islets of type 1 diabetic patients, suggesting that MERTK protects islets from autoimmune destruction. MERTK also regulated T cell arrest in melanoma tumors. These data indicate that MERTK signaling in mononuclear phagocytes drives T cell regulation at inflammatory disease sites in peripheral tissues through a mechanism that reduces the sensitivity of scanning for antigen leading to reduced responsiveness to antigen.
Assuntos
Autoimunidade/fisiologia , Ilhotas Pancreáticas/enzimologia , Fagócitos/fisiologia , Linfócitos T/imunologia , c-Mer Tirosina Quinase/imunologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Antígenos/metabolismo , Antígenos CD11/metabolismo , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/patologia , Feminino , Humanos , Ilhotas Pancreáticas/imunologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Neoplasias Experimentais/enzimologia , Neoplasias Experimentais/imunologia , Fagócitos/imunologia , Piperazinas/farmacologia , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismoRESUMO
Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by insulin-producing pancreatic ß-cell destruction and hyperglycemia. While monocytes and NOD-like receptor family-pyrin domain containing 3 (NLRP3) are associated with T1D onset and development, the specific receptors and factors involved in NLRP3 inflammasome activation remain unknown. Herein, we evaluated the inflammatory state of resident peritoneal macrophages (PMs) from genetically modified non-obese diabetic (NOD), NLRP3-KO, wild-type (WT) mice and in peripheral blood mononuclear cells (PBMCs) from human T1D patients. We also assessed the effect of docosahexaenoic acid (DHA) on the inflammatory status. Macrophages from STZ-induced T1D mice exhibited increased inflammatory cytokine/chemokine levels, nitric oxide (NO) secretion, NLRP3 and iNOS protein levels, and augmented glycolytic activity compared to control animals. In PMs from NOD and STZ-induced T1D mice, DHA reduced NO production and attenuated the inflammatory state. Furthermore, iNOS and IL-1ß protein expression levels and NO production were lower in the PMs from diabetic NLRP3-KO mice than from WT mice. We also observed increased IL-1ß secretion in PBMCs from T1D patients and immortalized murine macrophages treated with advanced glycation end products and palmitic acid. The present study demonstrated that the resident PMs are in a proinflammatory state characterized by increased NLRP3/iNOS pathway-mediated NO production, up-regulated proinflammatory cytokine/chemokine receptor expression and altered glycolytic activity. Notably, ex vivo treatment with DHA reverted the diabetes-induced changes and attenuated the macrophage inflammatory state. It is plausible that DHA supplementation could be employed as adjuvant therapy for treating individuals with T1D.
Assuntos
Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/tratamento farmacológico , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Adulto , Animais , Células Cultivadas , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/enzimologia , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Macrófagos Peritoneais/enzimologia , Macrófagos Peritoneais/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Gravidez , Transdução de Sinais , EstreptozocinaRESUMO
Diabetic nephropathy (DN) is the main cause of end-stage renal disease, which remains incurable. The progression of DN is associated with progressive and irreversible renal fibrosis and also high levels of adenosine. Our aim was to evaluate the effects of ADORA3 antagonism on renal injury in streptozotocin-induced diabetic rats. An ADORA3 antagonist that was administered in diabetic rats greatly inhibited the levels of inflammatory interleukins IL-1ß and IL-18, meanwhile when adenosine deaminase was administered, there was a non-selective attenuation of the inflammatory mediators IL-1ß, IL-18, IL-6, and induction of IL-10. The ADORA3 antagonist attenuated the high glucose-induced activation of caspase 1 in HK2 cells in vitro. Additionally, ADORA3 antagonisms blocked the increase in caspase 1 and the nuclear localization of NFκB in the renal tubular epithelium of diabetic rats, both events that are involved in regulating the production and activation of IL-1ß and IL-18. The effects of the A3 receptor antagonist resulted in the attenuation of kidney injury, as evidenced by decreased levels of the pro-fibrotic marker α-SMA at histological levels and the restoration of proteinuria in diabetic rats. We conclude that ADORA3 antagonism represents a potential therapeutic target that mechanistically works through the selective blockade of the NLRP3 inflammasome.
Assuntos
Antagonistas do Receptor A3 de Adenosina/administração & dosagem , Caspase 1/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Antagonistas do Receptor A3 de Adenosina/farmacologia , Adenosina Desaminase/efeitos adversos , Animais , Linhagem Celular , Diabetes Mellitus Experimental/enzimologia , Nefropatias Diabéticas/induzido quimicamente , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções Intraperitoneais , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/enzimologia , Masculino , Ratos , EstreptozocinaRESUMO
BACKGROUND/AIM: Amaranth is a source of several bioactive compounds, among which peptides with inhibitory activity upon dipeptidyl peptidase IV (DPP-IV) have been reported. However, there is no information about the action of amaranth DPP-IV-inhibitory peptides using in vivo models. The aim of this work was to evaluate the effect of amaranth consumption on plasma and kidney DPP-IV activity as well the changes in plasma proteome profile of streptozotocin (STZ)-induced hyperglycemic rats. METHODS: Rats were fed for 12 weeks with a diet containing 20% popped amaranth grain. Kidneys and blood samples were collected for lipid profile, DPP-IV activity and expression, and proteomic analysis. RESULTS: Total cholesterol and DPP-IV activity in plasma was increased in hyperglycemic rats, but this effect was reverted by amaranth consumption. Triacylglycerols were increased in the hyperglycemic group fed amaranth, and the highest levels of high-density lipoproteins were also observed in this group. These data correlated with the accumulation of apolipoprotein A-II in plasma. Accumulation of the antioxidant protein paraoxonase/arylesterase 1 in STZ-induced hyperglycemic rats was observed when amaranth was supplied in the diet. CONCLUSION: This study provides new insights into the molecular mechanisms by which amaranth exerts its beneficial health action in a hyperglycemic state.
Assuntos
Amaranthus , Arildialquilfosfatase/sangue , Hidrolases de Éster Carboxílico/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/dietoterapia , Dipeptidil Peptidase 4/sangue , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Experimental/enzimologia , Dipeptidil Peptidase 4/metabolismo , Alimento Funcional , Rim/enzimologia , Lipídeos/sangue , Masculino , Nutrigenômica , Proteoma/metabolismo , Ratos , Ratos WistarRESUMO
Gestational diabetes mellitus (GDM) has increased in recent years. Although the cellular and molecular mechanisms involved in GDM-increased risk factors to offspring remained poorly understood, some studies suggested an association between an increase in oxidative stress induced by maternal hyperglycemia and complications for both mothers and newborns. Here, we investigated the impact of maternal hyperglycemia followed by maternal insulin replacement during lactation on the expression of antioxidant enzymes and mast cell number in offspring ventral prostate (VP) at puberty. Pregnant rats were divided into three groups: control (CT); streptozotocin-induced maternal hyperglycemia (MH); and MH plus maternal insulin replacement during lactation (MHI). Male offspring were euthanized at postnatal day (PND) 60 and the VP was removed and processed for histology and Western blotting analyses. Maternal hyperglycemia delayed prostate maturation, and increased mast cell number catalase (CAT), superoxide dismutase (SOD), glutatione-s-transferase (GST-pi), and cyclooxygenase-2 (Cox-2) expression in the offspring of hyperglycemic dams. Maternal insulin replacement restored VP structure, mast cell number and antioxidant protein expression, except for Cox-2, which remained higher in the MHI group. Thus, an increase in oxidative stress induced by intrauterine hyperglycemia impacts prostate development and maturation, which persists until puberty. The overall improvement of maternal metabolism after insulin administration contributes to the restoration of prostate antioxidant enzymes and secretory function. Taken together, our results highlighted that imbalanced physiological maternal-fetal interaction contributes to the impairment of reproductive performance of the offspring from diabetic mothers. Anat Rec, 300:291-299, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Gestacional/metabolismo , Mastócitos/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Próstata/metabolismo , Animais , Glicemia/metabolismo , Contagem de Células , Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Diabetes Gestacional/tratamento farmacológico , Diabetes Gestacional/enzimologia , Diabetes Gestacional/patologia , Feminino , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/farmacologia , Insulina/uso terapêutico , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/enzimologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Próstata/efeitos dos fármacos , Próstata/enzimologia , Próstata/patologia , Ratos , Ratos WistarRESUMO
Diabetes mellitus (DM) is characterised by hyperglycaemia associated with the increase of oxidative stress. Gallic acid has potent antioxidant properties. The aim of this study was to evaluate the effect of gallic acid on the biochemical, histological and oxidative stress parameters in the liver and kidney of diabetic rats. Male rats were divided in groups: control, gallic acid, diabetic and diabetic plus gallic acid. DM was induced in the animals by intraperitoneal injection of streptozotocin (65mg/kg). Gallic acid (30mg/kg) was administered orally for 21days. Our results showed an increase in reactive species levels and lipid peroxidation, and a decrease in activity of the enzymes superoxide dismutase and delta-aminolevulinic acid dehydratase in the liver and kidney of the diabetic animals (P<0.05). Gallic acid treatment showed protective effects in these parameters evaluated, and also prevented a decrease in the activity of catalase and glutathione S-transferase, and vitamin C levels in the liver of diabetic rats. In addition, gallic acid reduced the number of nuclei and increased the area of the core in hepatic tissue, and increased the glomerular area in renal tissue. These results indicate that gallic acid can protect against oxidative stress-induced damage in the diabetic state.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Ácido Gálico/uso terapêutico , Rim/patologia , Fígado/patologia , Estresse Oxidativo , Sintase do Porfobilinogênio/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Ácido Gálico/química , Ácido Gálico/farmacologia , Glutationa Transferase/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Rim/efeitos dos fármacos , Rim/enzimologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Glutaredoxin 1 (Grx1) has been found to be an important endogenous antioxidant enzyme closely related to the pathogenesis of diabetes and cardiovascular diseases caused by oxidative stress. In this study, the functional changes of the Grx1 redox system in blood of hyperglycemic patients were examined. Furthermore, using a rat model of streptozotocin (STZ)- and high-fat-diet-induced type 2 diabetes, we explored the correlation between functional changes of the Grx1 redox system in the left ventricular tissue and blood of the diabetic rats. Moreover, we studied the protective effect of Grx1 against cardiac toxicity caused by the high-glucose-induced expression of cardiac matrix metalloproteinases (MMPs) in primary cultured cardiac fibroblasts. Finally, we investigated the protective effects and signaling regulatory mechanism of Grx1 against diabetic cardiomyopathy (DCM) in terms of oxidative stress and NF-kB-mediated fibrosis-associated signaling pathways. In the serum of hyperglycemic patients, Grx1 levels were elevated, total/protein thiol or sulfhydryl (Total-SH/P-SH) levels were decreased, glutathione was downregulated, and oxidized glutathione was upregulated. In addition, in the left ventricular myocardium and blood of the diabetic rats, Grx1 levels were significantly increased and glutathione reductase and P-SH levels were decreased. Moreover, endogenous Grx1 was highly expressed in cardiac fibroblasts during high-glucose treatment, and exogenous Grx1 can prevent DCM by controlling oxidative damage and MMP expression. These findings are suggestive of changes in the Grx1 redox system, and Grx1-regulated protein oxidative modifications may serve as molecular markers for diabetes caused by high-glucose-induced oxidative stress.
Assuntos
Cardiomiopatias Diabéticas/enzimologia , Glutarredoxinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/patologia , Glutarredoxinas/sangue , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Coração/fisiopatologia , Humanos , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Metaloproteinases da Matriz/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Estresse Oxidativo/fisiologia , Cultura Primária de Células , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The present study investigated the protective effect of quercetin (Querc) on memory, anxiety-like behavior and impairment of ectonucleotidases and acetylcholinesterase (AChE) activities in brain of streptozotocin-induced diabetic rats (STZ-diabetes). The type 1 diabetes mellitus was induced by an intraperitoneal injection of 70mg/kg of streptozotocin (STZ), diluted in 0.1M sodium-citrate buffer (pH 4.5). Querc was dissolved in 25% ethanol and administered by gavage at the doses of 5, 25 and 50mg/kg once a day during 40days. The animals were distributed in eight groups of ten animals as follows: vehicle, Querc 5mg/kg, Querc 25mg/kg, Querc 50mg/kg, diabetes, diabetes plus Querc 5mg/kg, diabetes plus Querc 25mg/kg and diabetes plus Querc 50mg/kg. Querc was able to prevent the impairment of memory and the anxiogenic-like behavior induced by STZ-diabetes. In addition, Querc prevents the decrease in the NTPDase and increase in the adenosine deaminase (ADA) activities in SN from cerebral cortex of STZ-diabetes. STZ-diabetes increased the AChE activity in SN from cerebral cortex and hippocampus. Querc 50mg/kg was more effective to prevent the increase in AChE activity in the brain of STZ-diabetes. Querc also prevented an increase in the malondialdehyde levels in all the brain structures. In conclusion, the present findings showed that Querc could prevent the impairment of the enzymes that regulate the purinergic and cholinergic extracellular signaling and improve the memory and anxiety-like behavior induced by STZ-diabetes.
Assuntos
5'-Nucleotidase/metabolismo , Acetilcolinesterase/metabolismo , Adenosina Desaminase/metabolismo , Ansiedade/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Transtornos da Memória/prevenção & controle , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Quercetina/farmacologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/enzimologia , Ansiedade/psicologia , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/psicologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/psicologia , Relação Dose-Resposta a Droga , Proteínas Ligadas por GPI/metabolismo , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/enzimologia , Transtornos da Memória/psicologia , Atividade Motora/efeitos dos fármacos , Ratos Wistar , EstreptozocinaRESUMO
Six derivatives (1-6) of moronic acid were semi-synthesized and their in vitro protein tyrosine phosphatase 1B (PTP-1B) inhibition activity assessed. Derivatives 2 (IC50=10.8 ± 0.5 µM) and 6 (IC50=7.5 ± 0.1 µM) displayed the most potent inhibitory activity. Therefore, they (50mg/Kg) were tested for their antidiabetic effect in vivo using a non-insulin dependent diabetes mellitus rat model. The results indicated that they decrease plasma glucose levels during all the experiment (p <0.05). Docking analysis of 2 and 6 with PTP-1B orthosteric site A and allosteric site B, showed that 2 had polar and Van der Waals interactions in both sites with Val49, Gln262, Met258, Phe182, Ala217, Ile219 and Gly259, displaying more affinity for site A. Compound 6 showed polar interaction with Gln262 and Van der Waals with Val49, Ile219, Gly259, Arg254, Ala27, Phe52, Met258, Asp48 and Phe182, suggesting that the potential binding site is localized in site B, close to the catalytic site A. Therefore, derivatives 2 and 6 have potential for the development of antidiabetic agents.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Ácido Oleanólico/análogos & derivados , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Glicemia/efeitos dos fármacos , Simulação por Computador , Relação Dose-Resposta a Droga , Hipoglicemiantes/síntese química , Simulação de Acoplamento Molecular , Estrutura Molecular , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
This study was designed to evaluate the effects of Bauhinia forficata Link subsp. pruinosa (BF) tea on oxidative stress and liver damage in streptozotocin (STZ)-induced diabetic mice. Diabetic male mice have remained 30 days without any treatment. BF treatment started on day 31 and continued for 21 days as a drinking-water substitute. We evaluated (1) BF chemical composition; (2) glucose levels; (3) liver/body weight ratio and liver transaminases; (4) reactive oxygen species (ROS), lipid peroxidation, and protein carbonylation in liver; (5) superoxide dismutase (SOD) and catalase (CAT) activities in liver; (6) δ-aminolevulinate dehydratase (δ-ALA-D) and nonprotein thiols (NPSH) in liver; (7) Nrf2, NQO-1, and HSP70 levels in liver and pancreas. Phytochemical analyses identified four phenols compounds. Diabetic mice present high levels of NQO-1 in pancreas, increased levels of ROS and lipid peroxidation in liver, and decrease in CAT activity. BF treatment normalized all these parameters. BF did not normalize hyperglycemia, liver/body weight ratio, aspartate aminotransferase, protein carbonyl, NPSH levels, and δ-ALA-D activity. The raised oxidative stress seems to be a potential mechanism involved in liver damage in hyperglycemic conditions. Our results indicated that BF protective effect could be attributed to its antioxidant capacity, more than a hypoglycemic potential.