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1.
Undersea Hyperb Med ; 46(5): 635-646, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31683362

RESUMO

We aimed to assess the effects of intermittent hyperbaric oxygenation (HBO2 at 2 bars for 120 minutes a day for four successive days) on acetylcholine-induced vasorelaxation (AChIR) in female Sprague-Dawley (SD) rats (N=80) that were randomized into four groups: healthy controls (CTR); diabetic rats (DM); and control and diabetic rats that underwent hyperbaric oxygenation (CTR+HBO and DM+HBO), respectively. AChIR was measured in vitro in aortic rings, with/without L-NAME, MS-PPOH, HET0016 or indomethacin. mRNA expression of eNOS, iNOS, COX-1, COX-2, thromboxane A synthase 1 (TBXAS1), CYP4A1, CYP4A3 and CYP2J3 was assessed by qPCR. Systemic oxidative stress and plasma antioxidative capacity were determined with the thiobarbituric acid-reactive substances (TBARS) and the ferric reducing ability of plasma (FRAP) assays, respectively. There was no significant difference in AChIR among experimental groups of rats. In CTR and DM group of rats, AChIR was mediated by NO and EETs pathway, while in the CTR+HBO and DM+HBO groups, NO-pathway prevailed. iNOS expression was upregulated in the DM group compared to CTR, while HBO2 upregulated eNOS in CTR group and TBXAS1 in DM group of rats. In both, CTR and DM group of rats, the sensitivity to ACh in the presence of L-NAME or in the presence of MSPPOH was significantly decreased compared to the response to ACh in the absence or presence of indomethacin or HET0016. DM and DM+HBO rats had increased TBARS compared to their respective controls. In conclusion, HBO2 presumably alters vasorelaxation in response to ACh from NO-EETs mediated pathways to solely NO-pathway, without affecting oxidative status of DM rats.


Assuntos
Acetilcolina/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Oxigenação Hiperbárica , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Análise de Variância , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Glicemia/análise , Peso Corporal , Sistema Enzimático do Citocromo P-450/fisiologia , Primers do DNA , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Oxigenação Hiperbárica/métodos , Estresse Oxidativo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina , Fatores de Tempo , Vasodilatação/fisiologia
2.
Life Sci ; 233: 116711, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31374233

RESUMO

AIMS: Insulin is a central peptide hormone required for carbohydrate metabolism; however, its role in diabetes-associated pulmonary disease is unknown. Here, we investigated the preventative effect of insulin against hyperglycemia-induced pulmonary vascular leakage and its molecular mechanism of action in the lungs of diabetic mice. MAIN METHODS: Vascular endothelial growth factor (VEGF) activated transglutaminase 2 (TGase2) by sequentially elevating intracellular Ca2+ and reactive oxygen species (ROS) levels in primary human pulmonary microvascular endothelial cells (HPMVECs). KEY FINDINGS: Insulin inhibited VEGF-induced TGase2 activation, but did not affect intracellular Ca2+ elevation and ROS generation. Insulin prevented VEGF-induced vascular leakage by inhibiting TGase2-mediated c-Src phosphorylation, disassembly of VE-cadherin and ß-catenin, and stress fiber formation. Insulin replacement therapy prevented hyperglycemia-induced TGase2 activation, but not ROS generation, in the lungs of diabetic mice. Insulin also prevented vascular leakage and cancer metastasis in the diabetic lung. Notably, vascular leakage was not detectable in the lungs of TGase2-null (Tgm2-/-) diabetic mice. SIGNIFICANCE: These findings demonstrate that insulin prevents hyperglycemia-induced pulmonary vascular leakage in diabetic mice by inhibiting VEGF-induced TGase2 activation rather than ROS generation.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Proteínas de Ligação ao GTP/antagonistas & inibidores , Hemorragia/prevenção & controle , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Pneumopatias/prevenção & controle , Transglutaminases/antagonistas & inibidores , Animais , Proteínas de Ligação ao GTP/fisiologia , Hemorragia/etiologia , Hemorragia/patologia , Humanos , Pneumopatias/etiologia , Pneumopatias/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Masculino , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Melanoma Experimental/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transglutaminases/fisiologia , Células Tumorais Cultivadas
3.
Yonsei Med J ; 60(7): 667-678, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31250581

RESUMO

PURPOSE: The aim of this study was to investigate how type I diabetes mellitus (T1D) affects the folliculogenesis and oocyte development, fertilization, and embryo development. MATERIALS AND METHODS: A comparative animal study was conducted using two different mouse models of T1D, a genetic AKITA model and a streptozotocin-induced diabetes model. Ovarian function was assessed by gross observation, immunoblot, immunohistochemistry, oocyte counting, and ELISA for serum hormones (insulin, anti-Mullerian hormone, estradiol, testosterone, and progesterone). Maturation and developmental competence of metaphase II oocytes from control and T1D animals was evaluated by immunofluorescent and immunohistochemical detection of biomarkers and in vitro fertilization. RESULTS: Animals from both T1D models showed increased blood glucose levels, while only streptozotocin (STZ)-injected mice showed reduced body weight. Folliculogenesis, oogenesis, and preimplantation embryogenesis were impaired in both T1D mouse models. Interestingly, exogenous streptozotocin injection to induce T1D led to marked decreases in ovary size, expression of luteinizing hormone/chorionic gonadotropin receptor in the ovaries, the number of corpora lutea per ovary, oocyte maturation, and serum progesterone levels. Both T1D models exhibited significantly reduced pre-implantation embryo quality compared with controls. There was no significant difference in embryo quality between STZ-injected and AKITA diabetic mice. CONCLUSION: These results suggest that T1D affects folliculogenesis, oogenesis, and embryo development in mice. However, the physiological mechanisms underlying the observed reproductive effects of diabetes need to be further investigated.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Fertilidade , Hormônio Luteinizante/metabolismo , Oócitos/patologia , Ovário/patologia , Receptores do LH/metabolismo , Transdução de Sinais , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL
4.
Life Sci ; 235: 116553, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185237

RESUMO

AIMS: Dexmedetomidine (Dex) has been noted to have neuroprotective effect against cerebral ischemia-reperfusion (I/R) injury. However, the effect of Dex in diabetic hyperglycemia-exacerbated cerebral I/R injury and its underlying mechanism remain unclear. MAIN METHODS: The infarct volume and brain edema were evaluated by 2,3,5-triphenyltetrazolium chloride staining and standard wet-dry method. Modified neurological severity score was utilized to assess the neurological deficits. The oxidative stress and inflammation were evaluated by detecting reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor (TNF)-α and interleukin (IL)-1ß. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay and cell count kit-8 were applied to measure cell apoptosis and viability. KEY FINDINGS: Dex treatment reduced infarct volume, decreased brain water content and improved neurological deficit in middle cerebral artery occlusion/reperfusion (MCAO/R) mice. Dex treatment reduced the levels of ROS, MDA, TNF-α and IL-1ß in the entire middle cerebral artery territory of diabetic mice subjected to MCAO/R, as well as in primary culture of mouse hippocampal neurons stimulated with 50 mM glucose and oxygen glucose deprivation/reperfusion. Dex treatment inhibited neuronal apoptosis induced by diabetic hyperglycemia-exacerbated cerebral I/R injury. Dex upregulated nuclear factor of activated T-cells 5 (NFAT5) and Sirtuin 1 (SIRT1) expression, induced NF-E2-related factor 2 (Nrf2) translocation from cytoplasm to nucleus and inhibited the acetylation of Nrf2. However, these changes triggered by Dex treatment were abrogated by NFAT5 knockdown. SIGNIFICANCE: Dex protects against diabetic hyperglycemia-exacerbated cerebral I/R injury through attenuation of oxidative stress, inflammation and apoptosis. The underlying mechanism is at least the NFAT5/SIRT1/Nrf2 signaling pathway dependent.


Assuntos
Dexmedetomidina/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Hiperglicemia/complicações , Infarto da Artéria Cerebral Média/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Técnicas In Vitro , Infarto da Artéria Cerebral Média/etiologia , Infarto da Artéria Cerebral Média/patologia , Inflamação/etiologia , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais
5.
Int Braz J Urol ; 45(4): 815-824, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31184457

RESUMO

INTRODUCTION: Chronic hyperglycemia is caused by diabetes mellitus-committed genital morphophysiology, and oxidative stress is one of the main factors involved in this process. Alpha lipoic acid (ALA) can prevent metabolic and morphological changes in diabetic individuals. OBJECTIVES: In present study, we evaluated the effects of regular ALA consumption on the spermatogenesis and histoarchitecture in the male genital system of diabetic rats. MATERIALS AND METHODS: Thirty-two Wistar rats were divided into groups: Control (CG); Diabetic Control (DCG), receiving commercial diet: ALA Group (ALAG) and Diabetic ALA Group (DALAG), fed diets with added ALA (300 mg/Kg bw). The diabetic groups received a single injection of streptozotocin (60 mg/kg). After sixty days of the diet, the animals were euthanized, and semen, testis and epididymis samples were collected. A histomorphometric analysis was performed to determine the epithelial height, tubular and luminal diameter, tubular and luminal area of seminiferous tubules and each epididymal region. Sertoli cells were evidenced using the antivimentin antibody and were quantified. The results were statistically analyzed by the ANOVA test. RESULTS: At the end of the experiment, the DALAG glycemia was signifi cantly lower than DCG. The histomorphometric parameters of the seminiferous and epididymal tubules did not show improvement in the DALAG. However, there was an improvement in the DALAG in terms of the concentration, motility and percentage of spermatic pathologies, as well as in the number of Sertoli cells (p<0.001). CONCLUSIONS: The results demonstrated that supplementation with the ALA antioxidant retards testicular lesions and preserve the process of spermatogenesis in diabetes.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/patologia , Epididimo/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Ácido Tióctico/farmacologia , Animais , Diabetes Mellitus Experimental/fisiopatologia , Epididimo/patologia , Imuno-Histoquímica , Masculino , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos Testes , Células de Sertoli , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatogênese/fisiologia , Espermatozoides/fisiologia , Testículo/patologia , Testículo/fisiopatologia
6.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(2): 149-155, 2019 04 28.
Artigo em Chinês | MEDLINE | ID: mdl-31060667

RESUMO

Objective To investigate diabetes-mediated changes in the neuromuscular pharmacodynamics of rocuronium in rats. Methods Diabetes mellitus was induced by a single injection of streptozotocin in rats.A total of 24 male SD rats were assigned to four groups using random number table:the normal control group,diabetic 2-week group,diabetic 4-week group,and diabetic 8-week group(6 rats per group).The sciatic nerve was stimulated in a rain-of-four(TOF)pattern,and the twitch tension changes in the tibialis anterior muscle were demonstrated by mechanomyography after intravenous injection of rocuronium in vivo.The time course characteristics of rocuronium,including onset time,and the recovery time from rocuronium injection to TOF ratio 75%(RT75%)and 90%(RT90%),were recorded,and half maximal inhibitory concentration(IC50)values of rocuronium were determined using a four-parameter dose response curve. Results Compared with the normal controls,the diabetic rats had significantly prolonged onset time of rocuronium,while the RT75% and RT90% were decreased at all rocuronium doses(P<0.001).The time course changes became increasingly significant as the duration of diabetes lengthened(P<0.001).The IC50 and 95% confidence interval values for rocuronium in the normal control group,diabetic 2-week group,diabetic 4-week group,and diabetic 8-week group were 0.37(0.35-0.38)mg/kg,0.44(0.43-0.46)mg/kg,0.59(0.57-0.61)mg/kg,and 0.64(0.61-0.66)mg/kg,respectively.IC50 values were significantly higher in the diabetic groups vs.normal control(P<0.001)and gradually increased as the duration of diabetes lengthened(P<0.001).Conclusion Diabetes is associated with the rat skeletal muscle hyposensitivity to rocuronium,which is featured by prolonged onset time of rocuronium,decreased RT 75% and RT 90%,and right shift of the cumulative dose-response curve of rocuronium.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Fármacos Neuromusculares não Despolarizantes/farmacologia , Rocurônio/farmacologia , Animais , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
7.
Mar Drugs ; 17(5)2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31083588

RESUMO

Refractory wound healing is one of the most common complications of diabetes. Excessive production of reactive oxygen species (ROS) can cause chronic inflammation and thus impair cutaneous wound healing. Scavenging these ROS in wound dressing may offer effective treatment for chronic wounds. Here, a nanocomposite hydrogel based on alginate and positively charged Eudragit nanoparticles containing edaravone, an efficient free radical scavenger, was developed for maximal ROS sequestration. Eudragit nanoparticles enhanced edaravone solubility and stability breaking the limitations in application. Furthermore, loading these Eudragit nanoparticles into an alginate hydrogel increased the protection and sustained the release of edaravone. The nanocomposite hydrogel is shown to promote wound healing in a dose-dependent way. A low dose of edaravone-loaded nanocomposite hydrogel accelerated wound healing in diabetic mice. On the contrary, a high dose of edaravone might hamper the healing. Those results indicated the dual role of ROS in chronic wounds. In addition, the discovery of this work pointed out that dose could be the key factor limiting the translational application of antioxidants in wound healing.


Assuntos
Alginatos/administração & dosagem , Hidrogéis/administração & dosagem , Nanocompostos/administração & dosagem , Nanopartículas/administração & dosagem , Cicatrização/efeitos dos fármacos , Alginatos/química , Animais , Materiais Biocompatíveis/administração & dosagem , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Hidrogéis/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanocompostos/química , Nanopartículas/química , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo
8.
Life Sci ; 231: 116422, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31059689

RESUMO

This study was performed to evaluate the antidiabetic and wound healing activity of plumbagin in diabetic rats by macroscopical, biochemical, histological, immunohistochemical and molecular methods. Percentage of wound closure and contraction was delayed in diabetic rats when compared to non-diabetic group. There was significant reduction in period of epithelialization, collagen and protein content. Serum insulin level was significantly lowered together with increase in glucose level in diabetic rats. Lipid levels were increased significantly with concomitant decrease in HDL level. The mRNA levels of Nrf2, collagen-1, TGF-ß and α-SMA were significantly lowered whereas Keap-1 levels were increased in diabetic rats. The level of lipid peroxides was increased while the levels of antioxidants were lowered significantly. ELISA results reveal upregulated levels of inflammatory markers. Western blot result shows upregulated levels of CD68 and CD163 proteins in wound area of diabetic rats. Histopathological observation revealed increased inflammatory cells infiltration in diabetic control. Immunofluorescent staining and immunohistochemical analysis also displayed delayed wound healing in diabetic groups. Diabetic rats treated with 10% and 20% plumbagin showed increased epithelialization, collagen deposition, increased serum insulin level and increased antioxidant status. Lipid peroxides and lipid levels were lowered significantly with increase in HDL level. Inflammatory markers were lowered, and growth factors expressions were increased markedly. Thus, the results of the study indicated that plumbagin administration could improve wound healing activity and could serve as a potent antidiabetic and anti-inflammatory agent.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Naftoquinonas/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Colágeno/metabolismo , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Insulina/sangue , Masculino , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/metabolismo
9.
Pharm Biol ; 57(1): 250-254, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30957612

RESUMO

CONTEXT: In vitro and in vivo research has shown that curcumin can alleviate diabetes and the relevant complications. OBJECTIVE: To investigate the effect of curcumin on gestational diabetes (GD). MATERIALS AND METHODS: C57 BL/KsJdb/+(db/+) mice and C57 BL/KsJ+/+ mice (10-12 weeks old) were divided into four groups (n = 15): normal pregnancy (C57 BL/KsJ+/+), GD (C57 BL/KsJdb/+), GD plus low dose curcumin (50 mg/kg, orally gavage every day) and GD plus high dose curcumin (100 mg/kg, orally gavage every day). The tolerance of glucose and insulin were measured on gestation day 10. Body weight at birth and litter size of offspring were investigated, and the expression of oxidative stress factors [thiobarbituric acid reactive substance (TBARS), glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT)] and AMP-activated protein kinase (AMPK), phospho-AMPK, histone deacetylases 4 (HDAC4), pHDAC4 and glucose-6-phosphatase (G6Pase) in the livers were analyzed by ELISA and Western blot on gestation day 20. RESULTS: High dose curcumin could partly ameliorate the intolerance of glucose and insulin, and completely restore the litter size and the body weight of GD mice through decreased TBARS expression (p < 0.05) and increased GSH, SOD and CAT expression (p < 0.05). Enhanced AMPK activation, accompanied with decreased HDAC4 and G6Pase expression (p < 0.05) were partly contributed to the alleviation of GD mediated by curcumin. CONCLUSIONS: Although further detailed mechanism needs to be deciphered, curcumin can be considered as an alternative treatment for gestational diabetes.


Assuntos
Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Curcumina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Gestacional/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Western Blotting , Catalase/metabolismo , Curcumina/administração & dosagem , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Gestacional/fisiopatologia , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Glucose/metabolismo , Glutationa/metabolismo , Insulina/metabolismo , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Superóxido Dismutase/metabolismo
10.
Sci Data ; 6(1): 37, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31000708

RESUMO

A better understanding of the permittivity property of skeletal muscle is essential for the development of new diagnostic tools and approaches for neuromuscular evaluation. However, there remain important knowledge gaps in our understanding of this property in healthy and diseased skeletal muscle, which hinder its translation into clinical application. Here, we report the permittivity of gastrocnemius muscle in healthy wild type mice and murine models of spinal muscular atrophy, muscular dystrophy, diabetes, amyotrophic lateral sclerosis and in a model of myofiber hypertrophy. Data were measured ex vivo from 10 kHz to 1 MHz using the four-electrode impedance technique. Additional quantitative histology information were obtained. Ultimately, the normative data reported will offer the scientific community the opportunity to develop more accurate models for the validation and prediction of experimental observations in both pre-clinical and clinical neuromuscular disease research.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Músculo Esquelético/fisiologia , Atrofia Muscular Espinal/fisiopatologia , Distrofia Muscular Animal/fisiopatologia , Animais , Modelos Animais de Doenças , Capacitância Elétrica , Camundongos
11.
Environ Pollut ; 249: 822-830, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953944

RESUMO

Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants that have been shown to be related to the occurrence of type 2 diabetes mellitus (T2DM). Nevertheless, it is necessary to further explore the development of T2DM caused by PCBs and its underlying mechanisms. In the present study, 21-day-old C57BL/6 male mice were orally treated with Aroclor 1254 (0.5, 5, 50 or 500 µg kg-1) once every three days. After exposure for 66 d, the mice showed impaired glucose tolerance, 13% and 14% increased fasting serum insulin levels (FSIL), and 63% and 69% increases of the pancreatic ß-cell mass in the 50 and 500 µg kg-1 groups, respectively. After stopping exposure for 90 d, treated mice returned to normoglycemia and normal FSIL. After re-exposure of these recovered mice to Aroclor 1254 for 30 d, fasting plasma glucose showed 15%, 28% and 16% increase in the 5, 50 and 500 µg kg-1 treatments, FSIL exhibited 35%, 27%, 30% and 32% decrease in the 0.5, 5, 50 or 500 µg kg-1 groups respectively, and there was no change in pancreatic ß-cell mass. Transcription of the pancreatic insulin gene (Ins2) was significantly down-regulated in the 50 and 500 µg kg-1 groups, while DNA-methylation levels were simultaneously increased in the Ins2 promoter during the course of exposure, recovery and re-exposure. Reduced insulin levels were initially rescued by a compensative increase in ß-cell mass. However, ß-cell mass eventually failed to make sufficient levels of insulin, resulting in significant increases in fasting blood glucose, and indicating the development of T2DM.


Assuntos
Glicemia/efeitos dos fármacos , /toxicidade , Poluentes Ambientais/toxicidade , Homeostase/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Glicemia/metabolismo , /administração & dosagem , Metilação de DNA/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Poluentes Ambientais/administração & dosagem , Insulina/sangue , Insulina/genética , Células Secretoras de Insulina/patologia , Masculino , Camundongos Endogâmicos C57BL
12.
Life Sci ; 225: 79-87, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30946838

RESUMO

The different ailments of heart including myocardial infarction (MI) and ischemic heart diseases are the foremost trigger of high mortality across the world which is instigated by sedentary life style, chronic hyperglycaemia and atherosclerosis. Albeit strenuous exercise itself induces temporary hypoxia which causes myocardial damage and this vitiosus circulus is poorly understood and has been assumed difficult to break. Present investigation targets temporal dynamics of aerobic exercise treatment induced preconditioning against diabetes associated pre- and post- myocardial injury. The persisting high blood sugar level leads to several biochemical alterations at pre- and post-MI phase. Here, we present the assessment of temporal expression of cardiac biomarkers (CKMB, LDH, cTnI and serum nitrite/nitrate), oxidative stress (myocardial TBARS and reduced NBT), inflammatory cytokines (IL-6, TNF-α and IL-10), renal biomarkers (BUN, serum creatinine and microproteinuria) and structural alterations of cardio-renal tissue. Aerobic exercise preconditioning significantly downregulate the pathological events or biomarkers and upsurge the physiological biomarkers at both pre- and post-MI phase. The attenuation or returning of pathological makers to lowest level at different time points endorses the therapeutic management of aerobic exercise against diabetic MI. Furthermore, the temporal expression of various cardio-renal biomarkers pattern elucidates that aerobic exercise preconditioning boost the strength and consolidate the cardiac muscles to work under stress. Despite the presence of traditional knowledge about health benefits of aerobic exercise, it is yet to be brought into the clinical arena. In spite of few impending challenges subjected to additional investigations, aerobic exercise preconditioning shows a high degree of promise.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Experimental/fisiopatologia , Precondicionamento Isquêmico Miocárdico/métodos , Infarto do Miocárdio/complicações , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Condicionamento Físico Animal , Animais , Lipídeos/análise , Estresse Oxidativo , Ratos
13.
Malays J Pathol ; 41(1): 25-32, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31025634

RESUMO

INTRODUCTION: Experimental models are essential for clarifying the pathogenesis of atherosclerosis in the context of diabetes mellitus (DM). We aimed to evaluate the presence and the magnitude of several factors known to promote atherogenesis, and to assess the potential of a pro-atherogenic environment to stimulate the development of atherosclerotic lesions in a rat model of long-term type 1 DM. MATERIALS AND METHODS: Six control and five DM Wistar rats were evaluated. DM was induced at 11 weeks of age using streptozotocin (STZ; 60 mg/kg, intraperitoneal). Animals were monitored up to 38 weeks of age, when plasma glucose, lipid profile, and markers specific for systemic inflammation, endothelial dysfunction, and oxidative stress were measured. The amount of fat within the aortic wall was assessed semiquantitatively using Oil Red O staining. RESULTS: Diabetic rats presented significantly higher plasma glucose (p < 0.001), total cholesterol and triglycerides (both p = 0.02), high-sensitivity C-reactive protein (p = 0.01), and vascular endothelial growth factor (p = 0.04) levels, and significantly lower interleukin-10 (p = 0.04), superoxide dismutase (p < 0.01), and glutathione peroxidase (p = 0.01) levels than the control rats. Mild (grade 1) atherosclerotic lesions were observed in the aortic wall of 80% of the diabetic rats and in none of the control rats. CONCLUSIONS: This study presents a STZ-induced type 1 DM rat model with one of the longest follow-ups in the literature. In this model, long-term DM created a highly pro-atherogenic environment characterised by hyperglycemia, dyslipidemia, systemic inflammation, endothelial dysfunction, and oxidative stress that resulted in the development of early aortic atherosclerotic lesions.


Assuntos
Aterosclerose/etiologia , Diabetes Mellitus Tipo 1/complicações , Animais , Aterosclerose/fisiopatologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Dislipidemias/complicações , Hiperglicemia/complicações , Masculino , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar
14.
Biomed Pharmacother ; 112: 108722, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970521

RESUMO

Microvascular and macrovascular complications are major causes of disability and death in diabetic patients. High levels of blood glucose sabotage the integrity of blood vessels and induce endothelial dysfunction. Fenofibrate is an agonist of peroxisome proliferator-activated receptor α and can reduce the incidence of cardiovascular events in diabetic patients. This study tested the hypothesis that fenofibrate could ameliorate endothelium-dependent vasodilation in diabetic mice and relieve high glucose-induced endothelial dysfunction via activating endothelial nitric oxide synthase (eNOS) and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. A streptozotocin (STZ)-induced diabetic model was established by intraperitoneal injection of STZ (dissolved in sodium citrate buffer) at a dose of 60 mg/kg for 5 consecutive days. Mice were administered fenofibrate (100 mg/kg/d, i.g.) for 14 days. The endothelial function of extracted mouse aortae was examined by evaluating acetylcholine induced endothelium-dependent relaxation combined with phenylephrine-induced vasoconstriction and sodium nitroprusside-induced endothelium-independent relaxation. Superoxide onion (O2-) was determined using dihydroethidium staining of aortae. Functions of mouse aortic endothelial cells (MAECs) were assessed, and expression levels of eNOS and AMPK were determined by Western blotting. Fenofibrate ameliorated the impaired endothelium-dependent relaxation in diabetic mice and decreased the level of intracellular O2- in diabetic mouse aortae. In-vitro, fenofibrate treatment improved the impaired function of MAECs, increased nitric oxide production, and decreased the O2- level, as well as activated eNOS and AMPK phosphorylation in cultured MAECs by high glucose. Fenofibrate could ameliorate endothelium-dependent vasodilation in diabetic mice and relieve high glucose-induced endothelial dysfunction, which was possibly related to the activation of eNOS and AMPK phosphorylation.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Fenofibrato/uso terapêutico , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/fisiopatologia , Fenofibrato/farmacologia , Glucose/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , PPAR alfa/agonistas , Estreptozocina
15.
Sheng Li Xue Bao ; 71(2): 271-278, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31008486

RESUMO

More and more evidence suggests that microRNA is widely involved in the regulation of cardiovascular function. Our preliminary experiment showed that miR-494-3p was increased in heart of diabetic rats, and miR-494-3p was reported to be related to metabolism such as obesity and exercise. Therefore, this study was aimed to explore the role of miR-494-3p in diabetic myocardial insulin sensitivity and the related mechanism. The diabetic rat model was induced by high fat diet (45 kcal% fat, 12 weeks) combined with streptozotocin (STZ, 30 mg/kg), and cardiac tissue RNA was extracted for qPCR. The results showed that the level of miR-494-3p was significantly up-regulated in the myocardium of diabetic rats compared with the control (P < 0.05). The level of miR-494-3p in H9c2 cells cultured in high glucose and high fat medium (HGHF) was significantly increased (P < 0.01) with the increase of sodium palmitate concentration, whereas down-regulation of miR-494-3p in HGHF treated cells led to an increase in insulin-stimulated glucose uptake (P < 0.01) and the ratio of p-Akt/Akt (P < 0.05). Over-expression of miR-494-3p in H9c2 cell line significantly inhibited insulin-stimulated glucose uptake and phosphorylation of Akt (P < 0.01). Bioinformatics combined with Western blotting experiments confirmed insulin receptor substrate 1 (IRS1) as a target molecule of miR-494-3p. These results suggest that miR-494-3p reduces insulin sensitivity in diabetic cardiomyocytes by down-regulating IRS1.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Proteínas Substratos do Receptor de Insulina/fisiologia , Resistência à Insulina , MicroRNAs/genética , Miócitos Cardíacos/fisiologia , Animais , Regulação para Baixo , Insulina , Ratos
16.
Invest Ophthalmol Vis Sci ; 60(5): 1538-1546, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30994864

RESUMO

Purpose: Recent evidence suggests that retinal photoreceptor cells have an important role in the pathogenesis of retinal microvascular lesions in diabetes. We investigated the role of rod cell phototransduction on the pathogenesis of early diabetic retinopathy (DR) using Gnat1-/- mice (which causes permanent inhibition of phototransduction in rod cells without degeneration). Methods: Retinal thickness, oxidative stress, expression of inflammatory proteins, electroretinograms (ERG) and optokinetic responses, and capillary permeability and degeneration were evaluated at up to 8 months of diabetes. Results: The diabetes-induced degeneration of retinal capillaries was significantly inhibited in the Gnat1-/- diabetics. The effect of the Gnat1 deletion on the diabetes-induced increase in permeability showed a nonuniform accumulation of albumin in the neural retina; the defect was inhibited in diabetic Gnat1-/- mice in the inner plexiform layer (IPL), but neither in the outer plexiform (OPL) nor inner nuclear (INL) layers. In Gnat1-deficient animals, the diabetes-induced increase in expression of inflammatory associated proteins (iNOS and ICAM-1, and phosphorylation of IĸB) in the retina, and the leukocyte mediated killing of retinal endothelial cells were inhibited, however the diabetes-mediated induction of oxidative stress was not inhibited. Conclusions: In conclusion, deletion of transducin1 (and the resulting inhibition of phototransduction in rod cells) inhibits the development of retinal vascular pathology in early DR.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Retinopatia Diabética/etiologia , Retinopatia Diabética/fisiopatologia , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Deleção de Genes , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Transducina/genética , Visão Ocular/fisiologia , Animais , Permeabilidade Capilar , Retinopatia Diabética/metabolismo , Eletrorretinografia , Proteínas I-kappa B/metabolismo , Immunoblotting , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Óxido Nítrico Sintase Tipo II/metabolismo , Nistagmo Optocinético/fisiologia , Estresse Oxidativo , Fosforilação , Vasos Retinianos/patologia , Estreptozocina , Tomografia de Coerência Óptica
17.
Ann Clin Lab Sci ; 49(1): 97-104, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30814084

RESUMO

PURPOSE: The objective of this research was to explore the effect of dioscin on myocardium in streptozotocin (STZ)-induced diabetic rats and the underlying mechanisms. METHODS: Diabetic rat model was established by a single intravenous injection of streptozocin (STZ). The rats were divided into 5 groups: control group, control+dioscin group, model group (diabetes), DDL group (diabetic rats treated with 100 µg/kg/day dioscin) and DDH group (diabetic rats treated with 200 µg/kg/day dioscin). Each group was continuously intervened for 6 weeks. Hemodynamic parameters were detected and pathological alterations of myocardium were observed by hematoxylin-eosin (HE) staining. Inflammatory response and related proteins in the NO-sGC-cGMP-PKG pathway were detected by western blot. RESULTS: Dioscin treatment can increase ejection fraction (EF) and decrease left ventricular end-diastolic pressure (LVEDP) as well as time constant of left ventricular pressure decay (Tau) parameters in diabetic rats, suggesting the improvement of left ventricular function. By histopathology observation, we found that dioscin treatment can also improve myocardial histological lesions caused by diabetes. In addition, the levels of inflammatory cytokines TGF-ß1, TNF-α and IL-1ß of the model group were remarkably higher than those in the control group (p<0.01), while after being treated with dioscin these cytokines were obviously decreased (p<0.05). The levels of PDE-5, PKG and p-VASP in the diabetic rats were significantly declined after being treated by dioscin in a dose-dependent manner (p<0.05). CONCLUSION: Dioscin may prevent the myocardial injury in diabetic rats by up-regulating NO-sGC-cGMP-PKG pathway.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/prevenção & controle , Diosgenina/análogos & derivados , Guanilato Ciclase/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Diosgenina/farmacologia , Modelos Animais de Doenças , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/prevenção & controle , Ratos , Ratos Sprague-Dawley
18.
Neurol Res ; 41(6): 544-553, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30822229

RESUMO

OBJECTIVES: Neuropathic pain reduces the life qualities of patients with Diabetes mellitus. Clinical guidelines recommend relief in diabetic neuropathic pain through the use of some antidepressants, anticonvulsants, opioids as well as capsaicin cream or lidocaine patches. However, since the majority of patients do not or partially respond to current treatments, there is a growing necessity for new drugs increasing the pain relief in patients with diabetes. Therefore, based on the therapeutic potential of antidepressants on neuropathic pain, we investigated the promising antihyperalgesic effect of mirtazapine (MRT) in painful diabetic neuropathy. METHODS: Experimental diabetes was induced in rats by single intraperitoneal injection of 55 mg/kg dose of streptozocin (STZ). After 4 weeks of injection of STZ, MRT was administrated for 14 days at 40 mg/kg dose. Randall-Selitto and Hargreaves tests were applied for paw-withdrawal threshold and paw-withdrawal latency measurement. TRPV1 and ASIC1 expressions measured by Western blot in dorsal root ganglion and spinal cord. RESULTS: Administration of MRT significantly improved both of the decreased paw-withdrawal threshold and shortened the paw-withdrawal latency of diabetic rats, respectively. Besides, increased levels of TRPV1 and ASIC1 channels in dorsal root ganglion and spinal cord of diabetic rats, evaluated by Western blot method, were decreased following the MRT treatment. DISCUSSION: These data show, for the first time, that MRT has beneficial effects against diabetes-induced hyperalgesia, and that suppressive effect of this drug on TRPV1 and ASIC1 levels, which are increased in diabetic rats, may be some of the pharmacological mechanisms underlying the exhibited antihyperalgesic effect of MRT.


Assuntos
Hiperalgesia/tratamento farmacológico , Mirtazapina/farmacologia , Estreptozocina/farmacologia , Canais de Cátion TRPV/efeitos dos fármacos , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Capsaicina/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/induzido quimicamente , Ratos , Canais de Cátion TRPV/metabolismo
19.
Biomed Pharmacother ; 113: 108667, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30852419

RESUMO

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) showed protective effects on endothelium-dependent dilatation. Since endothelial barrier dysfunction also plays a pivotal role in atherosclerosis, this study was designed to investigate the effects of GLP-1 on endothelial barrier function in diabetic aortic endothelium and explore the underlying mechanism. METHODS: For in vivo studies, diabetic rats were established and subjected to 12- and 24-week treatment of exenatide. The morphological changes of aortic endothelium were observed with transmission electron microscope. A permeability assay of aortic endothelium was performed using the surface biotinylation technique. Protein expression was detected by immunohistochemical analysis and Western blots. For in vitro studies, human umbilical vein endothelial cells (HUVECs) were cultured in medium enriched with advanced glycation end products (AGEs) or AGEs plus GLP-1 and other reagents. The integrity of endothelium was evaluated by endothelial monolayer permeability assay and transendothelial resistance. The in vitro expressions of relevant proteins in signaling pathways were also detected by immunofluorescence and Western blots. RESULTS: In vivo, the enhanced aortic endothelial permeability in diabetic aortas were attenuated by exenatide treatment. Additionally, myosin light chain (MLC) phosphorylation, related to actomyosin contractility, and activation of its upstream targets in diabetic aorta were inhibited after administration of exenatide. In vitro, the endothelial monolayer permeability and the assembly of stress fibers were reduced by GLP-1 intervention under diabetic condition. Meanwhile, AGE-induced MLC phosphorylation mediating ECs contractility was inhibited by GLP-1. Furthermore, GLP-1 down-regulated the upstream targets of MLC phosphorylation, including RAGE, Rho/ROCK and MAPK signaling pathways. Intriguingly, the effects of GLP-1 elicited on ECs contractility and barrier function in diabetes were blunted by inhibition of GLP-1R, cAMP or PKA and stimulation of Rho/ROCK and MAPK signaling pathways. CONCLUSION: The findings of this study suggest that the stabilizing effect of GLP-1 on the endothelial barrier and contraction of AGE-treated ECs is caused by GLP-1R/cAMP/PKA activation and the subsequent inactivation of RAGE/Rho/ROCK as well as MAPK signaling pathways.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Endotélio Vascular/fisiopatologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Células Cultivadas , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Regulação para Baixo , Endotélio Vascular/efeitos dos fármacos , Exenatida/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Masculino , Cadeias Leves de Miosina/metabolismo , Permeabilidade , Fosforilação , Ratos Sprague-Dawley
20.
Eur J Pharmacol ; 853: 33-40, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30876977

RESUMO

Hydrogen sulfide (H2S) is a potential endothelium-derived hyperpolarizing factor (EDHF) and adventitium- or adipocyte-derived relaxing factor (ADRF) which vasorelaxant action is mediated by potassium channels. H2S could also play an important role in the pathophysiology of diabetic cardiovascular complications. The present study has investigated the influence of alloxan-induced diabetes on the role of potassium channels mediating the relaxant response of the rabbit carotid artery to NaHS, a donor of H2S. NaHS (10-8-3 × 10-5 M) relaxed phenylephrine-precontracted carotid arteries, with higher potency in diabetic than in control rabbits. The selective blockers of potassium channels charybdotoxin, 4-amynopiridine and glibenclamide significantly inhibited the relaxant action of NaHS in diabetic rabbits, but not in control rabbits. When compared to control rabbits, carotid arteries from diabetic rabbits showed significantly reduced expression of big conductance Ca+2-activated potassium channels (BKCa), significantly enhanced expression of intermediate conductance Ca+2-activated potassium channels (IKCa) and not significant different expression of voltage-sensitive potassium channels (KV) and ATP-sensitive potassium channels (KATP). These results suggest that an enhanced role of IKCa, KV and KATP potassium channels could be involved in the increased sensitivity of the rabbit carotid artery to H2S in diabetes.


Assuntos
Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiopatologia , Diabetes Mellitus Experimental/metabolismo , Sulfeto de Hidrogênio/farmacologia , Canais de Potássio/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Artérias Carótidas/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Relação Dose-Resposta a Droga , Masculino , Coelhos
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