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1.
Environ Pollut ; 256: 113342, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31676093

RESUMO

PM2.5 exposure aggravates type 2 diabetes, in which inflammatory factors play an important role. In this study, we aimed to explore the mechanisms responsible for aggravating diabetes after PM2.5 exposure, and study the roles of inflammatory factors in insulin-resistant type 2 diabetes. Our study indicated that short-time PM2.5 exposure enhances insulin resistance in type 2 diabetic rats and significantly raises inflammatory factors, including IL-6, TNF-α, and MCP-1, in lungs. However, we found that of these inflammatory factors only IL-6 levels are elevated in blood, liver, adipose tissue, and macrophages, but not in skeletal muscle. IL-6 induced activation of the STAT3/SOCS3 pathway in liver, but not other downstream pathways including STAT1, ERK1/2, and PI3K. Both STAT3 inhibition and IL-6 neutralization effectively alleviated the disorders of glucose metabolism after PM2.5 exposure. Taken together, this suggests that the systemic increase in IL-6 may play an important role in the deterioration of the type 2 diabetes via IL-6/STAT3/SOCS3 pathway in liver after short-time exposure to PM2.5. Besides, we unexpectedly found a stronger resistance to the PM2.5 exposure-induced increase in IL-6 in skeleton muscle than those of many other tissues.


Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Interleucina-6/sangue , Material Particulado/toxicidade , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/imunologia , Material Particulado/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais
2.
J Surg Res ; 246: 213-223, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31606511

RESUMO

BACKGROUND: For patients with diabetes mellitus, excessive and long-lasting inflammatory reactions at the wound site commonly lead to the delayed refractory wound healing. The polarization of macrophages in terms of M1 and M2 phenotypes is closely related to the production of inflammatory cytokines. Quercetin is traditionally recognized to have anti-inflammatory effect; however, whether quercetin modulates macrophage polarization from M1 to M2 and thus promotes diabetic wound healing remain unknown. MATERIALS AND METHODS: Wounded male diabetic rats were equally divided into five groups: model group, solvent control group (10% DMSO), and three drug groups treated with quercetin (Q) at concentrations of 10 mg/mL (Q-LD [low dose]), 20 mg/mL (Q-MD [medium dose]), and 40 mg/mL (Q-HD [high dose]), respectively. The anti-inflammatory effect of quercetin on diabetic wounds was observed. Immunohistochemistry and quantificational real-time polymerase chain reaction were applied to test the changes in macrophage polarization and inflammatory responses. RESULTS: The wound contraction was fastest in Q-HD group. Hematoxylin and eosin (H&E) and Masson's trichrome staining revealed that fibroblast distribution and collagen deposition in quercetin-treated groups were significantly higher than those in the model group. Immunohistochemistry tests showed more CD206-positive cells and less iNOS-positive cells in quercetin-treated groups. Furthermore, the levels of proinflammatory factors in quercetin-treated groups were lower than those in the model group, whereas the levels of the anti-inflammatory factors and angiogenesis-related factors were relatively higher. CONCLUSIONS: In short, quercetin inhibits inflammatory reactions via modulating macrophage polarization switching from M1 to M2 phenotype, thereby accelerating the diabetic wound repair.


Assuntos
Diabetes Mellitus Experimental/complicações , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Quercetina/administração & dosagem , Pele/lesões , Cicatrização/efeitos dos fármacos , Administração Cutânea , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/imunologia , Relação Dose-Resposta a Droga , Humanos , Inflamação/imunologia , Inflamação/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Ratos , Pele/imunologia , Pele/patologia , Estreptozocina/toxicidade , Resultado do Tratamento , Cicatrização/imunologia
3.
Nat Biotechnol ; 37(12): 1446-1451, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31712773

RESUMO

Vagus nerve stimulation can ameliorate autoimmune diseases such as rheumatoid arthritis by modulation of the immune system. Its efficacy for the treatment of type 1 diabetes has not been explored, in part because the nerves projecting to the pancreatic lymph nodes (pLNs) in mice are unmapped. Here, we map the nerve projecting to the pancreas and pLNs in mice and use a minimally invasive surgical procedure to implant micro-cuff electrodes onto the nerve. Pancreatic nerve electrical stimulation (PNES) resulted in ß-adrenergic receptor-mediated-accumulation of B and T cells in pLNs and reduced production of pro-inflammatory cytokines following lipopolysaccharide stimulation. Autoreactive T cells showed reduced proliferation in pLNs of mice receiving PNES as compared to sham controls. In a spontaneous mouse model of autoimmune diabetes, PNES inhibited disease progression in diabetic mice.


Assuntos
Diabetes Mellitus Tipo 1 , Terapia por Estimulação Elétrica , Pâncreas , Animais , Linfócitos B/imunologia , Glicemia/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Feminino , Insulina/metabolismo , Linfonodos/citologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Pâncreas/imunologia , Pâncreas/inervação , Pâncreas/metabolismo , Linfócitos T/imunologia
4.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(12): 158532, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31647995

RESUMO

Exosomes have been demonstrated to be one of the mechanisms mediating the release of intracellular signaling molecules to conduct cell-to-cell communication. However, it remains unknown whether and how exosomes mediate the release of NOD-like receptor pyrin domain 3 (NLRP3) inflammasome products such as interleukin-1 beta (IL-1ß) from endothelial cells. The present study hypothesized that lysosomal acid ceramidase (AC) determines the fate of multivesicular bodies (MVBs) to control the exosome-mediated release of NLRP3 inflammasome products during hyperglycemia. Using a streptozotocin (STZ)-induced diabetes mouse model, we found that endothelium-specific AC gene knockout mice (Asah1fl/fl/ECcre) significantly enhanced the formation and activation of NLRP3 inflammasomes in coronary arterial ECs (CECs). These mice also had increased thickening of the coronary arterial wall and reduced expression of tight junction protein compared to wild-type (WT/WT) littermates. We also observed the expression of exosome markers such as CD63 and alkaline phosphatase (ALP) was augmented in STZ-treated Asah1fl/fl/ECcre mice compared to WT/WT mice, which was accompanied by an increased IL-1ß release of exosomes. In the primary cultures of CECs, we demonstrated that AC deficiency markedly enhanced the formation and activation of NLRP3 inflammasomes, but significantly down-regulated tight junction proteins when these cells were exposed to high levels of glucose. The CECs from Asah1fl/fl/ECcre mice had decreased MVB-lysosome interaction and increased IL-1ß-containing exosome release in response to high glucose stimulation. Together, these results suggest that AC importantly controls exosome-mediated release of NLRP3 inflammasome products in CECs, which is enhanced by AC deficiency leading to aggravated arterial inflammatory response during hyperglycemia.


Assuntos
Ceramidase Ácida/imunologia , Células Endoteliais/imunologia , Hiperglicemia/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Ceramidase Ácida/genética , Animais , Vasos Coronários/imunologia , Vasos Coronários/patologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Células Endoteliais/patologia , Exossomos/imunologia , Exossomos/patologia , Feminino , Deleção de Genes , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , Camundongos , Camundongos Knockout
5.
Artif Cells Nanomed Biotechnol ; 47(1): 3793-3803, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31556314

RESUMO

Chronic, subclinical inflammation was often observed in the diabetic wound area, causing inadequate and delayed wound-healing effects by failing to initiate cell migration, proliferation, and extracellular matrix deposition. Therefore, we presented macrophage-derived exosomes (Exos) and explored their potential for inhibiting inflammation and accelerating diabetic wound healing in a skin defect, diabetic rat model. A thorough investigation demonstrated that Exos exerted anti-inflammatory effects by inhibiting the secretion of pro-inflammatory enzymes and cytokines. Furthermore, they accelerated the wound-healing process by inducing endothelial cell proliferation and migration to improve angiogenesis and re-epithelialization in diabetic wounds.


Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Exossomos/metabolismo , Macrófagos/citologia , Cicatrização , Animais , Movimento Celular , Proliferação de Células , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/fisiopatologia , Camundongos , Células RAW 264.7 , Ratos
6.
Biomed Pharmacother ; 118: 109131, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545226

RESUMO

Berberine and metformin, both established pharmaceutical agents with herbal origins, have incidental beneficial effects on multiple diseases, including diabetes. These effects have been speculated to occur via the gut microbiome. In this study, we administered either berberine or metformin to db/db mice and investigated changes in body weight, food intake, and blood glucose levels. Fresh stool samples were analyzed using 16 s rDNA high-throughput sequencing to evaluate the gut microbiome. Short-chain fatty acids (SCFA) in the stool were quantified using gas chromatography. The expression of NF-κB signaling pathway and tight junction (ZO1 and occludin) proteins in the intestinal epithelium was determined using qPCR and western blotting. The intestinal barrier structure was examined using transmission electron microscopy and serum lipopolysaccharide (LPS) was measured using a commercial kit. Both berberine and metformin reduced food intake, body weight, and blood glucose and HbA1c levels. Both treatments effectively restored the intestinal SCFA content, reduced the level of serum LPS, relieved intestinal inflammation, and repaired intestinal barrier structure. Intervention with metformin or berberine modified the gut microbiome in db/db mice, increasing the number of SCFA-producing bacteria (e.g., Butyricimonas, Coprococcus, Ruminococcus) and reducing opportunistic pathogens (e.g., Prevotella, Proteus). An increased abundance of other probiotics including Lactobacillus and Akkermansia was also observed. Berberine and metformin can modulate the composition of the gut microbiome and reduce body weight, blood glucose levels, and intestinal inflammation in db/db mice, which demonstrates their effectiveness in the reduction of diabetic complications in this model.


Assuntos
Berberina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gastroenterite/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/microbiologia , Ingestão de Alimentos/efeitos dos fármacos , Gastroenterite/microbiologia , Hemoglobina A Glicada/análise , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Obesidade/imunologia , Obesidade/microbiologia , Obesidade/prevenção & controle , Permeabilidade
7.
Mediators Inflamm ; 2019: 4315038, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396018

RESUMO

Patients with diabetes mellitus (DM) showed an increased risk of anxiety. High anxiety levels are also shown to increase stress of diabetic patients, which may contribute to poor clinical outcomes. The mechanisms underlying the development of anxiety disorders in diabetic patients remain unknown. As a result, there are no available treatments yet. Here, we tested the hypothesis that glial cells in the hippocampal area of DM mice might be responsible for their anxiety-like behaviors. Furthermore, we postulated that treatment with antidepressant, fluoxetine, could reduce anxiety behaviors and prevent the dysregulation of glial cells (oligodendrocyte and astrocyte) in DM mice. Diabetic mice were administered a single injection of streptozotocin (STZ), followed by treatment with fluoxetine. Mice were then tested on Y maze, open field, dark and light transition, and elevated plus maze tests to measure the status of anxiety and cognition. After completing these behavioral tests, mice were sacrificed and western blot was used to detect the oligodendrocyte and astrocyte maker proteins in hippocampal tissues. Emphasis was directed towards adult oligodendrocyte precursor cells (OPCs) and their marker protein to measure their proliferation and differentiation. We found that fluoxetine could effectively mitigate the level of anxiety and attenuate the cognitive dysfunction in diabetic mice. Meanwhile, fluoxetine inhibited astrocyte activation in mice exposed to STZ, prevented the loss of myelin basic protein (MBP), and affected the function of OPCs in these diabetic mice. The results suggested that the changes of these glial cells in the brains of diabetic mice might be related to the high anxiety levels and cognitive deficit in DM mice. Fluoxetine could ameliorate the high anxiety level and prevent cognitive deficit via inhibiting astrocyte activation and repairing the oligodendrocyte damage.


Assuntos
Ansiedade/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Fluoxetina/uso terapêutico , Inflamação/tratamento farmacológico , Animais , Antidepressivos/uso terapêutico , Ansiedade/imunologia , Western Blotting , Diabetes Mellitus Experimental/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/imunologia , Interleucina-6/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL
8.
Life Sci ; 234: 116773, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31422095

RESUMO

AIMS: NLRP3 inflammasome activation is essential for the development and prognosis of diabetic cardiomyopathy (DCM). The anti-aging protein Klotho is suggested to modulate tissue inflammatory responses. The aim of the present study was to examine the protective effects of Klotho on DCM. MAIN METHODS: A streptozotocin-induced diabetes mouse model was established to assess the effects of Klotho in vivo, which was administered for 12 weeks. The characteristics of type 1 DCM were evaluated by general status, echocardiography, and histopathology. The expression of associated factors was determined by RT-qPCR and western blotting. Parallel experiments to determine the molecular mechanism through which Klotho prevents DCM were performed using H9C2 cells exposed to high glucose (35 mM). KEY FINDINGS: Diabetes-induced increases in serum creatine kinase-muscle/brain and lactate dehydrogenase levels, cardiac fibrosis, cardiomyocyte apoptosis, and cardiac dysfunction were ameliorated by Klotho. Additionally, Klotho suppressed TXNIP expression, NLRP3 inflammasome activation, and expression of the inflammatory cytokines tumor necrosis factor ɑ, interleukin-1ß, and interleukin-18 in vivo. In high glucose-cultured cardiomyocytes, Klotho and N-acetylcysteine significantly downregulated intracellular reactive oxygen species generation and TXNIP/NLRP3 inflammasome activation. Pretreatment of H9C2 cells with NLRP3 siRNA or Klotho prevented high glucose-induced inflammation and apoptosis in H9C2 cells. SIGNIFICANCE: Our results demonstrate that the protective effect of Klotho on diabetes-induced cardiac injury is associated with inhibition of the NLRP3 inflammasome pathway, suggesting its therapeutic potential for DCM.


Assuntos
Diabetes Mellitus Experimental/imunologia , Cardiomiopatias Diabéticas/imunologia , Glucuronidase/imunologia , Inflamassomos/imunologia , Inflamação/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/uso terapêutico , Cardiotônicos/imunologia , Cardiotônicos/uso terapêutico , Linhagem Celular , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/patologia , Glucuronidase/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Ratos , Espécies Reativas de Oxigênio/imunologia
9.
Egypt J Immunol ; 26(1): 55-67, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31332996

RESUMO

Diabetes Mellitus (D.M.) is a disease with a high and increasing prevalence. The Insulin- producing Cells (IPCs) derived from the Wharton's jelly of human umbilical cord transplantation was thought to be the most promising strategy for treating Diabetes. This study aimed to evaluate IPCs immune modulatory changes occurred after transplanted through two different routes and the effect of these changes on their therapeutic efficiency in relation to transplantation microenvironment. Insulin Producing Cells was induced to differentiate from human Umbilical Cord-Mesenchymal Stem Cells and characterized by morphology under phase contrast inverted microscope and staining of secretory granules by DTZ (diphenylthiocarbonazone) stain, then therapeutic effect was evaluated both in vitro and in vivo through glucose challenge test and hyperglycemia correction in STZ (streptozotocin)- induced diabetic rats. Immune-modulatory changes evaluated by cell- mediated lysis assay and Syber green quantification of immune inflammatory cytokines (IFN- , TGF- ß and IL-10) gene expression by real-time PCR. We observed that in spite of the weak immunogenicity of induced IPCs derived from HUC-MSCs in vitro, but when transplanted in vivo especially through the intra portal vein they could induce an immune response when interact with the disease microenvironment resulting in different degree of inflammatory response. Therefore, the relationship between disease microenvironment and immune alteration should be examined before transplantation therapy.


Assuntos
Diabetes Mellitus Experimental/imunologia , Insulinas , Transplante de Células-Tronco Mesenquimais , Geleia de Wharton/citologia , Animais , Diferenciação Celular , Citocinas/imunologia , Diabetes Mellitus Experimental/terapia , Humanos , Células-Tronco Mesenquimais/citologia , Ratos , Cordão Umbilical/citologia
10.
Mol Immunol ; 112: 322-329, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31238287

RESUMO

OBJECTIVE: The morbidity and prevalence of type 2 diabetes mellitus (DM) are increasing in the elderly population. Interleukin 37 (IL-37) play important roles in anti-inflammatory and anti-bacteria immune responses, but its role in the development of type 2 DM in the elderly is unclear. Therefore, we investigated whether IL-37 is associated with type 2 DM in the elderly and the underlying mechanism. METHODS: Hospitalized patients (aged 65-95 years) with recently diagnosed type 2 diabetes mellitus were studied retrospectively and compared with healthy subjects without glucose metabolism abnormalities. A diabetic mouse model was established by feeding ob/ob mice (C57BL/6) a high-fat, carbohydrate-free diet. Plasma glucose and insulin levels were determined by glucose oxidase assay and radioimmunoassay, respectively. The IL-37 expression level was determined by real-time PCR, western blot and ELISA (Enzyme-linked immunoassay). RESULTS: Statistic analysis showed that the IL-37 level was significantly associated with type 2 DM and insulin resistance in the elderly. The patients were then divided into insulin therapy sensitive and resistant group according to their response to insulin therapy. Data showed that the IL-37 was highly expressed in the insulin therapy sensitive group. And this was related to the less severe gut microbiota dysbiosis. In the mice model, overexpressing the IL-37 could suppress the gut microbiota dysbiosis and also the diabetes development. CONCLUSION: Thus our results showed that higher IL-37 was associated with increased insulin sensitive in elderly type 2 DM patients through suppressing the gut microbiota dysbiosis.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Interleucina-1/imunologia , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/microbiologia , Dieta Hiperlipídica/efeitos adversos , Disbiose/microbiologia , Feminino , Células HEK293 , Humanos , Resistência à Insulina/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
Int J Nanomedicine ; 14: 2383-2395, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040663

RESUMO

Background: The inflammatory basis of diabetes mellitus directed the researchers' attention to the immune system for better management and prevention of complications. Metoclopramide (MCA; the only US Food and Drug Administration-approved for gastroparesis) has the ability to restore immune function through increasing prolactin secretion. This study aimed to test the effect of BSA/MCA nanoparticles (NPs) on modulating immune response. Methods: BSA/MCA NPs were fabricated by desolvation and evaluated in vitro via measuring loading efficiency, particle size, and surface charge. The selected formula was further evaluated via differential scanning calorimetry and release behavior. Then, NPs were injected into rats (25 mg MCA/kg/week) for 3 weeks to be evaluated histopathologically and immunologically via measuring proinflammatory cytokines, such as IL1ß, IL6, and TNFα, in addition to measuring regulatory T-cell frequency. Results: MCA was successfully loaded on BSA, achieving high encapsulation efficiency reaching 63±2%, particles size of 120-130 nm with good polydispersity, and a negative surface charge indicating that entire positively charged drug was encapsulated inside NPs. Differential scanning calorimetry thermography of selected NPs showed an obvious interaction between components and cross-linking of BSA molecules using glutaraldehyde, resulting in sustained release of MCA (around 50% within 3 days). MCA NPs significantly restored the immune response via decreasing proinflammatory cytokines and increasing regulatory T-cell frequency when compared to control and free MCA (drug not loaded in NPs)-treated groups. Histopathological examination of this MCA NPs-treated group did not show the characteristic lesions of diabetes, and apoptosis nearly disappeared. Conclusion: BSA/MCA NPs could be considered a new modality for treatment of gastro-paresis, in addition to management of diabetes itself and preventing its complications via an MCA-immunomodulatory effect.


Assuntos
Citocinas/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/imunologia , Fatores Imunológicos/farmacologia , Mediadores da Inflamação/metabolismo , Metoclopramida/farmacologia , Nanopartículas/química , Linfócitos T Reguladores/imunologia , Animais , Apoptose/efeitos dos fármacos , Varredura Diferencial de Calorimetria , Citocinas/sangue , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Masculino , Nanopartículas/ultraestrutura , Tamanho da Partícula , Ratos Wistar , Soroalbumina Bovina/química , Eletricidade Estática , Linfócitos T Reguladores/efeitos dos fármacos
12.
J Immunol Res ; 2019: 5087847, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31073533

RESUMO

Diabetes currently affects over twenty-five million Americans. Annual health care cost of diabetes exceeds $254 billion and is associated with a distinct set of diabetic complications that include delayed wound healing and diabetic ulcers. Interleukin 6 (IL-6) plays an important role in wound healing and is known to be elevated in the serum of both type I and type II diabetes patients. This study assesses the expression and function of IL-6 in the hyperglycemic epidermis and keratinocyte culture. Streptozotocin-treated mice were wounded six weeks after induction of hyperglycemia. Wound closure, protein, and mRNA expression were assessed up to 13 days of postwounding. Wound closure was delayed 4-5 days in hyperglycemic animals. Hyperglycemic wounds displayed greater IL-6 and IL-6Rα protein expression at 1, 7, and 10 days of postwounding compared to euglycemic control. However, IL-6Rα mRNA expression was reduced at all time points beyond day 1, while IL-6 mRNA expression did not significantly differ at any time point. SOCS3 mRNA expression was higher in the hyperglycemic skin at every time point. Imaging of fluorescent immunohistology also revealed significantly lower expression of SOCS3, but higher nuclear pSTAT3 in the epidermis of the hyperglycemic skin. Primary mouse keratinocytes cultured in high glucose for 7 days displayed 2-fold higher IL-6Rα mRNA and higher rmIL-6-induced nuclear pSTAT3, but lower SOCS3 basal levels compared to normal glucose-cultured cells. Thus, it appears that delayed diabetic skin wound healing is associated with increased induction and expression of IL-6 and its receptor, but its function in epidermal keratinocytes may be impaired.


Assuntos
Hiperglicemia/imunologia , Interleucina-6/genética , Queratinócitos/imunologia , Pele/imunologia , Cicatrização/imunologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/imunologia , Epiderme/imunologia , Glucose/farmacologia , Hiperglicemia/induzido quimicamente , Interleucina-6/imunologia , Queratinócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Pele/patologia , Estreptozocina , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/imunologia
13.
Mol Med Rep ; 19(6): 5377-5385, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059096

RESUMO

Hyperglycemia promotes the growth and reproduction of bacteria, thereby increasing the probability of infection, which also causes rebound hyperglycemia. Therefore, the interactions of infection and hyperglycemia lead to the progression and deterioration of these diseases. Type 1 diabetes mellitus (T1DM) is an autoimmune disease. Studies have shown that regulatory T cells (Tregs) play a key role in maintaining islet­specific tolerance. Treg deficiency may lead to the development of early pancreatitis and T1DM, and sufficient amounts of Tregs can restore this tolerance, thereby inhibiting the occurrence of T1DM. Moreover, different subpopulations of dendritic cells (DCs) play an important role in activating autoreactive T cells and inducing autoimmune tolerance to autoantigens, which are closely related to the functional diversity caused by different phenotypes, maturation status, and the immune microenvironment of DC subpopulations. In the present study, we used streptozotocin­induced hyperglycemic mice to model T1DM and induced a Salmonella infection in the mouse model, leading to aggravated inflammation, which resulted in an elevated proportion of CD103+CD11b+ DCs and a significantly elevated proportion of CD4+FoxP3+ Tregs in the intestinal lamina propria. After co­culturing CD4+ T cells and DCs, we found that CD103+CD11b+ DCs could significantly promote the proliferation of CD4+ T cells. The elevated proportions of CD4+FoxP3+ Tregs were considered to be correlated with the increased number of CD103+CD11b+ DCs.


Assuntos
Infecções por Salmonella/patologia , Linfócitos T Reguladores/metabolismo , Animais , Antígenos CD/metabolismo , Antígeno CD11b/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Técnicas de Cocultura , Citocinas/sangue , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Inflamação , Cadeias alfa de Integrinas/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/patologia , Salmonella/patogenicidade , Infecções por Salmonella/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia
14.
Int J Mol Med ; 43(6): 2440-2450, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017263

RESUMO

Inflammatory response serves an important role in diabetic nephropathy (DN); however, the mechanism of inflammatory response results in renal damage is not yet clear. The aim of the present study was to investigate the role of the thioredoxin interacting protein (TXNIP)/NOD­like receptor protein 3 (NLRP3) axis­mediated activation of NLRP3 inflammasome in DN. A diabetic rat model was induced by streptozotocin injection. Hematoxylin and eosin (H&E) staining and streptavidin­peroxidase staining were then used to examine the kidney tissue morphology, and TXNIP and NLRP3 protein expression levels, respectively. Furthermore, RNA interference technology was applied to silence the TXNIP gene. TXNIP and NLRP3 inflammasome activation­associated proteins and mRNAs were detected by western blot analysis and RT­qPCR, respectively. Enzyme­linked immunosorbent assay was also used to examine interleukin (IL)­1 and IL­18 expression, while flow cytometry was performed to detect reactive oxygen species production. The data revealed that TXNIP and NLRP3 were overexpressed in kidney tissue of DN rats, and the level of antioxidant genes was downregulated. It was also observed that glucose promoted TXNIP expression and activation of NLRP3 inflammasome in a time­dependent and dose­dependent manner, therefore promoting inflammatory responses. Silencing of TXNIP gene resulted in the downregulation of NLRP3 inflammasome activation, and inhibited the expression levels of IL­1 and IL­18 in a high­glucose environment. Furthermore, low expression of TXNIP promoted the levels of antioxidant genes and reduced the ROS levels. Taken together, the high­glucose environment was able to upregulated the level of inflammatory factors by promoting the expression of TXNIP and the activation of NLRP3 inflammasome, consequently participating in DN.


Assuntos
Proteínas de Transporte/imunologia , Diabetes Mellitus Experimental/imunologia , Nefropatias Diabéticas/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Proteínas de Transporte/análise , Proteínas de Ciclo Celular , Linhagem Celular , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Glucose/imunologia , Humanos , Inflamassomos/análise , Inflamação/imunologia , Inflamação/patologia , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/análise , Estresse Oxidativo , Ratos Sprague-Dawley
15.
Prostate ; 79(9): 980-993, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30999385

RESUMO

BACKGROUND: Prostatic inflammation and various proinflammatory systemic comorbidities, such as diabetes and obesity are associated with human benign prostatic hyperplasia (BPH). There is a paucity of in vivo models reflecting specific aspects of BPH pathogenesis. Our aim was to investigate the nonobese diabetic (NOD) mouse as a potential model for subsequent intervention studies. MATERIALS AND METHODS: We used the NOD mouse, a model of autoimmune inflammation leading to type 1 diabetes to examine the effects of systemic inflammation and diabetes on the prostate. We assessed changes in prostatic histology, infiltrating leukocytes, and gene expression associated with aging and diabetic status. RESULTS: Both stromal expansion and epithelial hyperplasia were observed in the prostates. Regardless of diabetic status, the degree of prostatic hyperplasia varied. Local inflammation was associated with a more severe prostatic phenotype in both diabetic and nondiabetic mice. Testicular atrophy was noted in diabetic mice, but prostate glands showed persistent focal cell proliferation. In addition, a prostatic intraepithelial neoplasia (PIN)-like phenotype was seen in several diabetic animals with an associated increase in c-Myc and MMP-2 expression. To examine changes in gene and cytokine expression we performed microarray and cytokine array analysis comparing the prostates of diabetic and nondiabetic animals. Microarray analysis revealed several differentially expressed genes including CCL3, CCL12, and TNFS10. Cytokine array analysis revealed increased expression of cytokines and proteases such as LDLR, IL28 A/B, and MMP-2 in diabetic mice. CONCLUSION: Overall, NOD mice provide a model to examine the effects of hyperglycemia and chronic inflammation on the prostate, demonstrating relevance to some of the mechanisms present underlying BPH and potentially the initiation of prostate cancer.


Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/imunologia , Hiperglicemia/imunologia , Hiperplasia Prostática/sangue , Hiperplasia Prostática/imunologia , Linfócitos T/imunologia , Animais , Citocinas/imunologia , Diabetes Mellitus Experimental/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Hiperglicemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Hiperplasia Prostática/patologia , Neoplasia Prostática Intraepitelial/sangue , Neoplasia Prostática Intraepitelial/imunologia , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Células Estromais/imunologia , Células Estromais/patologia , Linfócitos T/patologia , Testículo/patologia
16.
Int J Mol Med ; 43(6): 2481-2490, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942391

RESUMO

Diabetic cardiomyopathy (DCM) is a leading contributor to the increased morbidity and mortality rates associated with diabetes. Persistent inflammation has previously been reported to be involved in the pathogenesis of DCM. However, the exact underlying molecular mechanisms remain to be fully elucidated. In the present study, the role of spleen tyrosine kinase (Syk) and c­Jun N­terminal kinase (JNK) in NLR family pyrin domain­containing 3 (NLRP3 inflammasome) activation in DCM were investigated in vivo and in vitro. Streptozotocin (65 mg/kg) was injected intraperitoneally into Sprague­Dawley rats to induce a rat model of diabetes. Neonatal rat cardiomyocytes and H9c2 cells were cultured to detect the expression of JNK, NLRP3 and its associated downstream molecules, following treatment with Syk/JNK inhibitor or Syk/JNK­small interfering (si)RNA in high glucose (HG) conditions. It was revealed that the protein and mRNA expression levels of phospho (p)­Syk, p­JNK, NLRP3 and its associated downstream molecules, including interleukin (IL)­1ß, were upregulated in vivo and in vitro. The JNK inhibitor significantly decreased the expression of NLRP3 and its downstream molecules in neonatal rat cardiomyocytes and H9c2 cells treated with HG. Furthermore, Syk­siRNA and the Syk inhibitor markedly inhibited the HG­induced activation of JNK, followed by the downregulation of NLRP3 and its downstream molecules at the mRNA and protein levels in cells. Therefore, it was demonstrated that the HG­induced activation of NLRP3 was mediated by the activation of Syk/JNK, which subsequently increased the protein expression levels of mature IL­1ß, suggesting that the Syk/JNK/NLRP3 signaling pathway serves a critical role in the pathogenesis of DCM.


Assuntos
Diabetes Mellitus Experimental/imunologia , Cardiomiopatias Diabéticas/imunologia , Inflamassomos/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Quinase Syk/imunologia , Animais , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/patologia , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Masculino , Ratos Sprague-Dawley
17.
Tuberculosis (Edinb) ; 115: 113-120, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30948165

RESUMO

Diabetes is one of the major co-morbidities contributing to the high global burden of tuberculosis (TB). The increased susceptibility of individuals with type 2 diabetes (T2D) to TB is multifactorial and may influence the efficacy of vaccines. This study was undertaken to determine the early immune responses that occur following infection with Mycobacterium bovis Bacille Calmette-Guérin (BCG) in a diet-induced murine model of T2D. The phagocytic capabilities of alveolar (AM) and resident peritoneal macrophages (RPM) were assessed using ex vivo assays. Compared to macrophages from non-diabetic mice, macrophages from diabetic animals showed decreased BCG uptake and killing and inflammatory cytokine production (TNF-α, MCP-1, IL-6, IL-1ß). In vivo susceptibility to BCG was determined following intravenous infection and diabetic mice showed a trend towards increased mortality, higher bacterial burden in the lung, liver and spleen and increased inflammatory lesions compared to controls. Differences between tissue cytokines were observed as early as one day post-infection and by days 14 and 35, lung and liver TNF-α and IFN-γ levels were decreased in diabetic mice compared to controls. These results suggest that early dysregulated immune responses may influence the susceptibility of T2D mice to BCG infection.


Assuntos
Citocinas/metabolismo , Diabetes Mellitus Tipo 2/imunologia , Mycobacterium bovis/imunologia , Tuberculose/imunologia , Animais , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Imunidade Celular/imunologia , Fígado/química , Pulmão/química , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Fagocitose/imunologia , Tuberculose/patologia
18.
Pharmacol Res ; 142: 237-250, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30818045

RESUMO

Diabetes increases the risk and worsens the progression of cognitive impairment via the greater occurrence of small vessel disease and stroke. Yet, the underlying mechanisms are not fully understood. It is now accepted that cardiovascular health is critical for brain health and any neurorestorative approaches to prevent/delay cognitive deficits should target the conceptual neurovascular unit (NVU) rather than neurons alone. We have recently shown that there is augmented hippocampal NVU remodeling after a remote ischemic injury in diabetes. NLRP3 inflammasome signaling has been implicated in the development of diabetes and neurodegenerative diseases, but little is known about the impact of NLRP3 activation on functional and structural interaction within the NVU of hippocampus, a critical part of the brain that is involved in forming, organizing, and storing memories. Endothelial cells are at the center of the NVU and produce trophic factors such as brain derived neurotrophic factor (BDNF) contributing to neuronal survival, known as vasotrophic coupling. Therefore, the aims of this study focused on two hypotheses: 1) diabetes negatively impacts hippocampal NVU remodeling and worsens cognitive outcome after stroke, and 2) NLRP3 inhibition with MCC950 will improve NVU remodeling and cognitive outcome following stroke via vasotrophic (un)coupling between endothelial cells and hippocampal neurons. Stroke was induced through a 90-min transient middle cerebral artery occlusion (MCAO) in control and high-fat diet/streptozotocin-induced (HFD/STZ) diabetic male Wistar rats. Saline or MCC950 (3 mg/kg), an inhibitor of NLRP3, was injected at 1 and 3 h after reperfusion. Cognition was assessed over time and neuronal density, blood-brain barrier (BBB) permeability as well as NVU remodeling (aquaporin-4 [AQP4] polarity) was measured on day 14 after stroke. BDNF was measured in endothelial and hippocampal neuronal cultures under hypoxic and diabetes-mimicking condition with and without NLRP3 inhibition. Diabetes increased neuronal degeneration and BBB permeability, disrupted AQP4 polarity, impaired cognitive function and amplified NLRP3 activation after ischemia. Inhibition with MCC950 improved cognitive function and vascular integrity after stroke in diabetic animals and prevented hypoxia-mediated decrease in BDNF secretion. These results are the first to provide essential data showing MCC950 has the potential to become a therapeutic to prevent neurovascular remodeling and worsened cognitive decline in diabetic patients following stroke.


Assuntos
Disfunção Cognitiva/imunologia , Diabetes Mellitus Experimental/imunologia , Furanos/farmacologia , Infarto da Artéria Cerebral Média/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fármacos Neuroprotetores/farmacologia , Sulfonamidas/farmacologia , Animais , Linhagem Celular , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Furanos/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Hipocampo/patologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Ratos Wistar , Sulfonamidas/uso terapêutico
19.
J Immunol ; 202(9): 2616-2627, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30910863

RESUMO

Appropriate T cell responses are controlled by strict balance between activatory and inhibitory pathways downstream of TCR. Although mice or humans with impaired TCR signaling develop autoimmunity, the precise molecular mechanisms linking reduced TCR signaling to autoimmunity are not fully understood. Engagement of TCR activates Ca2+ signaling mainly through store-operated Ca2+ entry activated by stromal interaction molecule (Stim) 1 and Stim2. Despite defective T cell activation, mice deficient in both Stim1 and Stim2 in T cells (conditional double knockout [cDKO]) developed lymphoproliferative disorders and skin inflammation with a concomitant increase in serum IgG1 and IgE levels. In cDKO mice, follicular helper T (Tfh) cells were dramatically increased in number, and they produced IL-4 spontaneously. These inflammatory symptoms were abolished by the deletion of IL-4 in cDKO mice. Tfh development and inflammatory symptoms in cDKO mice were abrogated by further deletion of NFAT2 in T cells. These findings suggest that Tfh cells spontaneously developed in the absence of Ca2+ signaling and caused unregulated type 2 responses.


Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Doenças do Sistema Imunitário/imunologia , Molécula 1 de Interação Estromal/deficiência , Molécula 2 de Interação Estromal/deficiência , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Sinalização do Cálcio/genética , Sinalização do Cálcio/imunologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Camundongos , Camundongos Knockout , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologia , Dermatopatias/genética , Dermatopatias/imunologia , Dermatopatias/patologia , Linfócitos T Auxiliares-Indutores/patologia
20.
Food Chem Toxicol ; 126: 192-198, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30802477

RESUMO

The purpose of present HUVE cells and mice study was to investigate the combined effects of carnosine and asiatic acid (AA) against diabetic progression. In HUVE cells, high glucose decreased cell viability, reduced Bcl-2 mRNA expression and increased Bax mRNA expression. The co-treatment of 0.5 µM carnosine plus 0.5 µM AA led to greater cell viability and Bcl-2 mRNA expression than 1 µM carnosine or 1 µM AA treatment alone. This combination more significantly decreased the production of DNA fragmentation, tumor necrosis factor (TNF)-alpha, reactive oxygen species (ROS), and nuclear factor kappa B binding activity than carnosine or AA treatment alone. In diabetic mice, the combination of 0.25% carnosine plus 0.25% AA in diet resulted in higher final body weight, and lower levels of plasma glucose and triglyceride than 0.5% carnosine or 0.5% AA treatment alone. Carnosine and AA combination caused more reduction in renal levels of leukin-6, TNF-alpha and ROS than carnosine or AA treatment alone. This combination also more significantly limited renal cyclooxygenase-2 activity and p-p38 phosphorylation than carnosine or AA treatment alone. These novel findings support that this combination is a more powerful remedy for diabetic control.


Assuntos
Anti-Inflamatórios/administração & dosagem , Carnosina/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Triterpenos Pentacíclicos/administração & dosagem , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Sinergismo Farmacológico , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/genética , NF-kappa B/imunologia , Espécies Reativas de Oxigênio/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
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