Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-32048199

RESUMO

Both diabetes mellitus (DM) and atrial fibrillation (AF) are usually associated with enhanced inflammatory response. The effect of the "NACHT, LRR and PYD domain containing protein 3" (NLRP3)-inflammasome/caspase-1/galectin-3 pathway and the potential benefits of NLRP3-inflammasome inhibitor glibenclamide (GLB) on atrial remodeling in the DM state are still unknown. Here, we demonstrated that higher AF inducibility and conduction inhomogeneity, slower epicardial conduction velocity, and increased amount of fibrosis in diabetic rabbits as against normal ones were markedly reduced by GLB. Atrial caspase-1 activity as well as serum IL-1ß and IL-18 levels were elevated in diabetic animals but suppressed by GLB. Moreover, GLB decreased the DM-induced protein expression enhancement of NLRP3, Gal-3, TGF-ß1, and CaV1.2 according to western blot analysis. Summarily, our findings indicate that the NLRP3-inflammasome/caspase-1/Gal-3 signaling pathway is related to the pathogenesis of AF in the diabetic state. NLRP3-inflammasome inhibitor GLB prevents AF inducibility and moderates atrial structural remodeling in DM.

2.
Nat Commun ; 10(1): 4530, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594940

RESUMO

A phase transition is often accompanied by the appearance of an order parameter and symmetry breaking. Certain magnetic materials exhibit exotic hidden-order phases, in which the order parameters are not directly accessible to conventional magnetic measurements. Thus, experimental identification and theoretical understanding of a hidden order are difficult. Here we combine neutron scattering and thermodynamic probes to study the newly discovered rare-earth triangular-lattice magnet TmMgGaO4. Clear magnetic Bragg peaks at K points are observed in the elastic neutron diffraction measurements. More interesting, however, is the observation of sharp and highly dispersive spin excitations that cannot be explained by a magnetic dipolar order, but instead is the direct consequence of the underlying multipolar order that is "hidden" in the neutron diffraction experiments. We demonstrate that the observed unusual spin correlations and thermodynamics can be accurately described by a transverse field Ising model on the triangular lattice with an intertwined dipolar and ferro-multipolar order.

3.
Int J Med Microbiol ; 309(8): 151340, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31494039

RESUMO

Chlamydia pneumoniae (C. pneumoniae) infection is associated with the initiation and progression of atherosclerosis. The migration of vascular smooth muscle cell (VSMC) from the media to the intima is a key event in the development of atherosclerosis. Interleukin-17C (IL-17C) could enhance cell migration ability. The aim of our study is to investigate the role of IL-17C in C. pneumoniae infection-promoted VSMC migration, thereby possibly accelerating atherosclerosis. We firstly demonstrated that C. pneumoniae infection significantly increased IL-17C expression in VSMCs in the atherosclerotic lesion area from ApoE deficient mice. Our in vitro study further showed that IL-17C is required for C. pneumoniae infection-promoted VSMC migration, and its expression could be regulated by c-Fos through phosphorylating extracellular signal-regulated kinase (ERK). Unexpectedly, in the present study, we also found that IL-17C is critical for C. pneumoniae infection-induced c-Fos activation. c-Fos expression and activation induced by the exposure to recombinant IL-17C were markedly suppressed in the presence of the ERK inhibitor PD98059. These results suggest a possible positive feedback between c-Fos and IL-17C after C. pneumoniae infection. Taken together, our results indicate that C. pneumoniae infection promotes VSMC migration via c-Fos/IL-17C signaling.

4.
Cardiovasc Diabetol ; 17(1): 160, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30591063

RESUMO

BACKGROUND: There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits. METHODS: A total of 30 rabbits were randomized into control group (CON, n = 10), alloxan-induced diabetic group (DM, n = 10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n = 10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-ß1, NF-κB p65 and mitochondrial biogenesis related proteins were determined by Western blotting. RESULTS: DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e' ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (- dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling pathway. CONCLUSIONS: The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Inibidores da Dipeptidil Peptidase IV/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Piperidinas/farmacologia , Uracila/análogos & derivados , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Diástole/efeitos dos fármacos , Fibrose , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Fator 1 Nuclear Respiratório/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Uracila/farmacologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Pressão Ventricular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
5.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 30(5): 416-421, 2018 May.
Artigo em Chinês | MEDLINE | ID: mdl-29764544

RESUMO

OBJECTIVE: To investigate the potential effects and mechanism on peroxisome proliferator-activated receptor γ-toll-like receptor 4-tumor necrosis factor-α (PPARγ-TLR4-TNF-α) targeted pathway on hyperglycemia induced myocardium inflammation and oxidative stress. METHODS: Thirty-two Japanese healthy adult rabbits were randomly divided into four groups with 8 rabbits in each group: normal control group (NC group), diabetes mellitus group (DM group), diabetes mellitus + pioglitazone 4 mg×kg-1×d-1 and 8 mg×kg-1×d-1 groups (DM+PGZ 4 mg and 8 mg groups). DM model was reproduced by alloxan of 150 mg/kg through auricular vein injection. On the same day of successful DM model reproduction, the diabetic rabbits were fed with corresponding dose of pioglitazone in DM+PGZ 4 mg and 8 mg groups, but the rabbits in NC group were not challenged. After 8 weeks of feeding, venous blood of left jugular vein bifurcation and myocardium tissue were harvested respectively for the determination of inflammation and oxidative stress parameters. TNF-α, interleukin-1 (IL-1), adiponectin (ADP), nitric oxide (NO) and total nitric oxide synthase (NOS) levels were determined by enzyme linked immunosorbent assay (ELISA), myeloperoxidase (MPO) activity was determined by colorimetric method, superoxide dismutase (SOD) activity was determined by hydroxylamine method, malondialdehyde (MDA) was determined by thiobarbituric acid colorimetric method, and catalase (CAT) activity was determined by UV spectrophotometry method. In addition, the mRNA expressions of TNF-α and TLR4 were determined by real-time quantitate reverse transcription-polymerase chain reaction (RT-qPCR). RESULTS: (1) IL-1 and TNF-α in serum and myocardium of model rabbits were significantly increased, ADP was significantly decreased, and the mRNA expressions of TNF-α and TLR4 in myocardium were significantly increased, indicating a significant inflammatory reaction. The inflammatory reaction in pioglitazone intervention groups was significantly reduced, TNF-α and IL-1 levels in serum and myocardium of DM+PGZ 4 mg and 8 mg groups were significantly decreased as compared with those of DM group [serum: TNF-α (ng/L) was 268.33±46.57, 261.34±33.73 vs. 331.40±69.05, myocardium: TNF-α (ng/L) was 144.72±26.90, 139.59±14.59 vs. 177.48±27.40; serum: IL-1 (ng/L) was 24.40±2.56, 23.35±3.13 vs. 30.08±5.44, myocardium: IL-1 (ng/L) was 21.26±2.85, 20.54±2.75 vs. 24.78±3.60, all P < 0.05], and ADP levels were significantly increased [serum (µg/L): 19.64±8.85, 20.54±7.47 vs. 15.45±3.06, myocardium (µg/L): 10.31±2.22, 11.49±3.42 vs. 7.76±1.77, all P < 0.05], and the mRNA expressions of TNF-α and TLR4 in myocardium were significantly decreased (TNF-α mRNA: 0.15±0.05, 0.14±0.06 vs. 0.25±0.09; TLR4 mRNA: 0.57±0.17, 0.40±0.18 vs. 0.75±0.35, all P < 0.05). (2) Oxidative stress in serum and myocardium of model rabbits was significantly increased, SOD, NO, and total NOS levels were significantly decreased while the serum CAT and MDA levels were significantly increased without effect on MPO. Compared with the DM group, SOD and NO levels in serum and myocardium were significantly increased in DM+PGZ 4 mg and 8 mg groups [serum: SOD (U/L) was 571.39±40.85, 609.28±54.47 vs. 535.10±37.08, myocardium: SOD (U/mg) was 55.74±8.12, 53.60±9.87 vs. 42.26±12.34; serum: NO (µmol/L) was 2.95±0.51, 2.99±0.43 vs. 2.03±0.78, myocardium: NO (nmol/mg) was 1.95±0.37, 2.11±0.26 vs. 1.56±0.33, all P < 0.05], the serum MDA levels were significantly decreased (µmol/L: 20.11±2.34, 19.70±2.02 vs. 23.07±3.06, both P < 0.05), while no significant effect on CAT. There was no significant difference in parameter of inflammatory and oxidative stress between the two pioglitazone intervention groups. CONCLUSIONS: 4 mg×kg-1×d-1 pioglitazone could activate PPARγ-TLR4-TNF-α targeted pathway, thus inhibit inflammatory and oxidative stress factors expression, and down-regulate hyperglycemia induced myocardium inflammatory and oxidative stress level, but the effect did not show a dose dependent manner.


Assuntos
Estresse Oxidativo , Animais , Hiperglicemia , Inflamação , Miocárdio , PPAR gama , Coelhos , Receptor 4 Toll-Like , Fator de Necrose Tumoral alfa
6.
Cardiovasc Ther ; 35(5)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28665544

RESUMO

BACKGROUND/AIMS: Recent evidence indicates that peroxisome proliferator-activated receptor (PPAR)-γ activators exert anti-inflammatory and antioxidant actions. However, the underlying mechanisms by which these agents prevent atrial remodeling in diabetes are not completely elucidated. We sought to investigate the potential effects of pioglitazone, a PPAR-γ activator, on atrial remodeling and atrial fibrillation (AF) inducibility in diabetic rabbits. METHODS: Alloxan-induced diabetic rabbits were randomly divided into three groups: diabetes only, diabetes treated with low-dose pioglitazone (4 mg/day/kg), or diabetes treated with high-dose pioglitazone (8 mg/day/kg) (n=24 for each group). A total of 24 healthy rabbits served as controls. Eight weeks later, hemodynamic, echocardiographic, and electrophysiological parameters were recorded. Left atrial whole-cell patch-clamp studies, histological examination, and Western blot analysis were also performed. RESULTS: In the DM group (6/8 vs 1/8, P<.05), higher AF inducibility, increased amount of fibrosis, lower INa , and higher ICaL were observed in the DM group compared to controls. Western blot analysis showed that DM increased the expression of extracellular signal-regulated kinase 2 (ERK2), phosphorylation ERK, transforming growth factor beta-1, Toll-like receptor 4, nuclear factor-κB p50, and heat-shock protein 70. All of these electrophysiological, histological, ion current density, and protein expression changes were all reduced by pioglitazone. CONCLUSION: Pioglitazone attenuates diabetes-induced structural and electrophysiological remodeling in the atria, thereby reducing the vulnerability to AF.


Assuntos
Aloxano , Fibrilação Atrial/prevenção & controle , Remodelamento Atrial/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Fibrose , Proteínas de Choque Térmico HSP70/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , PPAR gama/metabolismo , Fosforilação , Pioglitazona , Coelhos , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
7.
Purinergic Signal ; 13(3): 339-346, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28497417

RESUMO

Osteoporosis (OP) is a major public health problem worldwide. Genetic factors are considered to be major contributors to the pathogenesis of OP. The purinergic P2X7 receptor (P2X7R) has been shown to play a role in the regulation of osteoblast and osteoclast activity and has been considered as an important candidate gene for OP. A case-control study was performed to investigate the associations of functional single nucleotide polymorphisms (SNPs) in the P2X7R gene (rs2393799, rs7958311, rs1718119, rs2230911, and rs3751143) with susceptibility to OP in 400 Chinese OP patients and 400 controls. Results showed that rs3751143 was associated with OP; in particular, carriers of the C allele and CC/(AC + CC) genotypes were at a higher risk of OP, but no significant association of rs2230911, rs7958311, rs1718119, and rs2393799 with OP risk was observed. Analysis of the haplotypes revealed one haplotype (rs1718119G-rs2230911G-rs3751143C) that appeared to be a significant "risk" haplotype with OP. The rs3751143 polymorphism was associated with osteoclast apoptosis; ATP-induced caspase-1 activity of osteoclasts with AC and CC genotypes is lower than that of osteoclasts with AA genotype in vitro. The findings suggest that the P2X7R rs3751143 functional polymorphism might contribute to OP susceptibility in Chinese postmenopausal women.


Assuntos
Predisposição Genética para Doença , Osteoporose/genética , Pós-Menopausa/genética , Receptores Purinérgicos P2X7/genética , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores Sexuais
8.
Nat Commun ; 7: 13833, 2016 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-27982036

RESUMO

Dirac materials exhibit intriguing low-energy carrier dynamics that offer a fertile ground for novel physics discovery. Of particular interest is the interplay of Dirac carriers with other quantum phenomena such as magnetism. Here we report on a two-magnon Raman scattering study of AMnBi2 (A=Ca, Sr), a prototypical magnetic Dirac system comprising alternating Dirac carrier and magnetic layers. We present the first accurate determination of the exchange energies in these compounds and, by comparison with the reference compound BaMn2Bi2, we show that the Dirac carrier layers in AMnBi2 significantly enhance the exchange coupling between the magnetic layers, which in turn drives a charge-gap opening along the Dirac locus. Our findings break new grounds in unveiling the fundamental physics of magnetic Dirac materials, which offer a novel platform for probing a distinct type of spin-Fermion interaction. The results also hold great promise for applications in magnetic Dirac devices.

9.
Oncotarget ; 7(51): 83850-83858, 2016 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-27863381

RESUMO

Diabetes mellitus (DM) increases the risk of developing atrial fibrillation (AF), but the molecular mechanisms of diabetes-induced atrial remodeling processes have not been fully characterized. The aim of this study was to examine the mechanisms underlying atrial ion channel remodeling in alloxan-induced diabetes model in rabbits. A total of 40 Japanese rabbits were randomly assigned to a control group (C), alloxan-induced diabetic group (DM), probucol-treated control group (Control-P), and probucol-treated diabetic group (DM-P). Using whole-cell voltage-clamp techniques, ICa,L, INa and action potential durations (APDs) were measured in cardiomyocytes isolated from the left atria in the four groups, respectively. In the DM group, increased Ica,L and decreased INa currents were reflected in prolonged APD90 and APD50 values. These changes were reversed in the DM-P group. In conclusion, probucol cured AF by alleviating the ion channel remodeling of atrial myocytes in the setting of diabetes and the promising therapeutic potential of anti-oxidative compounds in the treatment of AF warrants further study.


Assuntos
Aloxano , Antiarrítmicos/farmacologia , Antioxidantes/farmacologia , Fibrilação Atrial/prevenção & controle , Remodelamento Atrial/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Átrios do Coração/efeitos dos fármacos , Canais Iônicos/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Probucol/farmacologia , Potenciais de Ação , Animais , Fibrilação Atrial/sangue , Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Biomarcadores/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/diagnóstico , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Canais Iônicos/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Coelhos , Fatores de Tempo
10.
Auton Neurosci ; 201: 1-7, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27519467

RESUMO

Diabetic cardiac autonomic neuropathy (DCAN) is a serious and common complication in diabetes mellitus (DM). Long noncoding RNAs (lncRNAs), an important class of regulatory molecules in diverse biological processes, have attracted considerable interest in DCAN. Our previous study has indicated a lncRNA, NONRATT021972 (NONCODE ID), was enhanced in sympathetic neuronal-like PC12 cells in the setting of high glucose (HG) and high FFAs (HF); its silence was found to significantly alleviate HGHF-induced tumor necrosis factor-α (TNF-α) release in PC12 cells. Here we further explore the effects of NONRATT021972 small interference RNA (siRNA) on heart rate variability (HRV) mediated by superior cervical ganglia (SCG) in diabetic rats and the possible mechanism underlying. We found an increment of NONRATT021972 in SCG of DM rats. Treatment of NONRATT021972 siRNA in DM rats decreased the elevated expression of TNF-α, blocked serine phosphorylation of insulin receptor substrate (IRS) 1 and increased the down-regulated expression of IRS1 in SCG. Meanwhile, NONRATT021972 siRNA rescued decreased HRV in DM rats. Therefore, inhibition of NONRATT021972 may serve as a novel therapeutic strategy for preventing the development of DCAN.


Assuntos
Arritmias Cardíacas/terapia , Diabetes Mellitus Experimental/terapia , Cardiomiopatias Diabéticas/terapia , Gânglios Espinais/metabolismo , RNA Longo não Codificante/metabolismo , Terapêutica com RNAi , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Vértebras Cervicais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Gânglios Espinais/patologia , Frequência Cardíaca/fisiologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , RNA Longo não Codificante/genética , RNA Interferente Pequeno/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
11.
Purinergic Signal ; 12(2): 259-68, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26865268

RESUMO

Diabetic neuropathy (DNP) is a frequent chronic complication of diabetes mellitus with potentially life-threatening outcomes. High glucose and elevated free fatty acids (FFAs) have been recently recognized as major causes of nervous system damage in diabetes. Our previous study has indicated extracellular stimuli, such as high glucose and/or FFA stress, may activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway and induce a p38 MAPK-dependent sensitization of the P2X7 receptor and release of inflammatory factors in PC12 cells, while the mechanisms underlying remain to be elucidated. Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes, including activation of a series of pathway signalings. Here, we showed combined high D-glucose and FFAs (HGHF) induced an increment of lncRNA-NONRATT021972 (NONCODE ID, nc021972) in PC12 cells. Nc021972 small interference RNA (siRNA) alleviated HGHF-induced activation of p38 MAPK, expression of the P2X7 receptor, and [Ca(2+)]i increment upon P2X7 receptor activation. Further experiments showed that there existed a crosstalk between nc021972 and the p38 MAPK signaling pathway. Inhibition of p38 MAPK signaling decreased nc021972-induced expression of the P2X7 receptor and [Ca(2+)]i increment upon P2X7 receptor activation. Also, nc021972 siRNA inhibited HGHF-induced PC12 release of TNF-α and IL-6 and rescued decreased cell viability mediated by the P2X7 receptor. Therefore, inhibition of nc021972 may serve as a novel therapeutic strategy for diabetes complicated with nervous inflammatory diseases.


Assuntos
Citocinas/biossíntese , Neuropatias Diabéticas/metabolismo , Regulação da Expressão Gênica/genética , RNA Longo não Codificante/metabolismo , Receptores Purinérgicos P2X7/biossíntese , Animais , Western Blotting , Ácidos Graxos não Esterificados/toxicidade , Técnicas de Silenciamento de Genes , Glucose/toxicidade , Imunoensaio , Células PC12 , RNA Interferente Pequeno , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
J Cardiovasc Electrophysiol ; 26(2): 211-22, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25199622

RESUMO

INTRODUCTION: Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). However, the underlying mechanisms for the increased propensity for AF in the setting of DM and the potential effects of probucol on atrial remodeling remain unclear. METHODS AND RESULTS: Eighty Japanese rabbits were randomly assigned to normal/control group (Control, n = 20), alloxan-induced diabetic group (DM, n = 20), probucol-treated group (Control-P, n = 20), and probucol-treated diabetic group (DM-P, n = 20). Rabbits in the DPR and CPR groups were orally administered probucol (1,000 mg/day) for 8 weeks. Serum and left atrial tissue malonaldehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), and catalase (CAT) levels were assessed. Isolated Langendorff perfused rabbit hearts were prepared to evaluate atrial refractory effective period (AERP) and its dispersion (AERPD), interatrial conduction time (IACT), and vulnerability to AF. Atrial interstitial fibrosis was also evaluated. The mRNA expression levels of TNF-α and TLR4 were analyzed. The protein expressions of NF-κB, HSP70, TGF-ß, and ERK in left atrial tissue were analyzed by Western blot. Probucol administration decreased the inducibility of AF in diabetic rabbits and attenuated atrial interstitial fibrosis. The DM-P rabbits exhibited significant alleviation of oxidative stress, evidenced by reduced serum and tissue MDA, compared with diabetic rabbits. Moreover, NF-κB, TGF-ß, and HSP70 protein expression and TNF-α mRNA expression were significantly downregulated by probucol treatment in alloxan-induced diabetic rabbits. CONCLUSIONS: Probucol prevents atrial remodeling and suppresses AF development in alloxan-induced diabetic rabbits. Its inhibitory effects on oxidative stress, NF-κB, TGF-ß, and TNF-α overexpression may contribute to its antiremodeling effects.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Fibrilação Atrial/prevenção & controle , Remodelamento Atrial/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Átrios do Coração/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Probucol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Biomarcadores/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Fibrose , Regulação da Expressão Gênica , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , RNA Mensageiro/metabolismo , Coelhos , Fator de Crescimento Transformador beta/genética
13.
Inflammation ; 38(1): 327-37, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25348860

RESUMO

Diabetic neuropathy (DNP) is the most common chronic complication of diabetes. Elevated free fatty acids (FFAs) have been recently recognized as major causes of inflammation and are relevant to the functional changes of nerve system in diabetes. Trans-resveratrol (RESV), a polyphenolic natural compound, has long been acknowledged to have anti-inflammation properties and may exert a neuroprotective effect on neuronal damage in diabetes, while the mechanisms underlying are largely unknown. Our previous study on differential PC12 cells cultured with high FFAs has shown chronic FFAs overload increased PC12 interleukin (IL)-6 release mediated by P2X7 receptor, a ligand-gated cation channel activated by extracellular adenosine triphosphate (ATP); a high FFA-induced activation of P38 mitogen-activated protein kinase (MAPK) pathway was pointed to be a potential underlying mechanism. Data from this study indicated that RESV, in a dose-dependent manner, reduced high FFA-induced IL-6 release by impeding the activation of P2X7 receptor, as shown by the results that both high FFA-elevated P2X7 receptor messenger RNA (mRNA) and protein expression as well as high FFA-evoked [Ca(2+)]i in response to 3'-O-(4-benzoyl) benzoyl-ATP (a selective P2X7 receptor agonist) were significantly attenuated. Meanwhile, high FFA-induced activation of P38 MAPK, an essential prerequisite for high FFA-activated P2X7 receptor and subsequent IL-6 release, was also dose-dependently abrogated by RESV. Furthermore, RESV may hamper the activation of P38a MAPK (one paramount P38 isoform) via forming hydrogen bonding with Thr175 residue, surrounding the two residues (Thy180 and Tyr182) essential for canonical activation of P38a MAPK. Taken together, RESV could inhibit high FFA-induced inflammatory IL-6 release mediated by P2X7 receptor through deactivation of P38 MAPK signaling pathway. All these results outline the potential mechanisms involved in the neuroprotective roles of RESV and highlight the clinical application of RESV in treatment of inflammation in relation to DNP.


Assuntos
Ácidos Graxos não Esterificados/toxicidade , Interleucina-6/metabolismo , Receptores Purinérgicos P2X7/biossíntese , Estilbenos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Células PC12 , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ratos , Resveratrol , Estilbenos/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
14.
Ann Hum Biol ; 42(5): 455-60, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25353278

RESUMO

BACKGROUND: Fasting plasma glucose (FPG) levels are usually tightly regulated within a narrow physiologic range. Variation of FPG levels is clinically important and is strongly heritable. Several lines of evidence suggest the importance of the oestrogen receptor α (ER-α) and osteocalcin (also known as BGP, for bone Gla protein) in determining FPG; however, whether their polymorphisms are associated with FPG variation is not well understood. AIM: To investigate whether ER-a PvuII and BGP HindIII genetic polymorphisms and their potential interaction are associated with FPG variation. SUBJECTS AND METHODS: The study subjects were 328 unrelated pre-menopausal Chinese women aged 21 years and over (mean age ± SD, 33.2 ± 5.9 years), with an average FPG of 4.92 (SD = 0.81). All subjects were genotyped at the ER-α PvuII and BGP HindIII loci using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). RESULTS: The ER-α PvuII genotypes were significantly associated with FPG (p = 0.007). In addition, a significant interaction was observed of the ER-α PvuII polymorphism with BGP HindIII polymorphism on FPG variation (p = 0.013), although the BGP HindIII polymorphism was not shown to be individually associated with FPG. CONCLUSION: The PvuII polymorphism of the ER-α gene and its potential interaction with the HindIII polymorphism of the BGP gene were associated with FPG in pre-menopausal Chinese women.


Assuntos
Glicemia/fisiologia , Receptor alfa de Estrogênio/metabolismo , Osteocalcina/metabolismo , Pré-Menopausa/fisiologia , Adulto , Grupo com Ancestrais do Continente Asiático , China , Receptor alfa de Estrogênio/genética , Feminino , Estudos de Associação Genética , Humanos , Osteocalcina/genética , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição/genética , Adulto Jovem
15.
Cardiol J ; 20(1): 59-67, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23558812

RESUMO

BACKGROUND: Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). However, the underlying mechanisms are still not clearly elucidated. The aim of this study was to evaluate the atrial electromechanical function, atrial electrophysiological changes and AF inducibility in alloxan-induced diabetic rabbits. METHODS: In 8 alloxan-induced diabetic rabbits and 8 controls, we evaluated atrial electromechanical function by tissue Doppler imaging. Isolated Langendorff-perfused rabbit hearts were prepared to measure atrial refractory effective period (AERP) and its dispersion (AERPD), interatrial conduction time (IACT) and vulnerability to AF. Atrial interstitial fibrosis was evaluated by Sirius-Red staining. RESULTS: Compared with controls, left atrial lateral wall Pa'-start interval (Pastart) and right atrial wall Pastart were increased in diabetic rabbits. AERPD was increased and IACT was prolonged in diabetic rabbits. Inducibility of AF in diabetic group was significant higher than controls (6/8 vs. 1/8, p < 0.05). Extensive interstitial fibrosis was observed in the DM group (p < 0.01). Correlation analysis showed that right atrial wall Pastart, Pa'-peak interval (Papeak) and total electromechanical activity (TEMA); left atrial lateral wall Papeak and TEMA, left atrial posterior wall TEMA, and IACT were correlated with atrial areas of fibrosis. CONCLUSIONS: Atrial electromechanical function is impaired in diabetic rabbits, and is associated with atrial fibrosis and interatrial electrical conduction delay.


Assuntos
Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Animais , Fibrilação Atrial/diagnóstico por imagem , Função Atrial/fisiologia , Ecocardiografia Doppler , Feminino , Fibrose/diagnóstico por imagem , Fibrose/etiologia , Fibrose/fisiopatologia , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Hemodinâmica/fisiologia , Masculino , Miocárdio/patologia , Perfusão , Coelhos
17.
Anadolu Kardiyol Derg ; 12(7): 543-50, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22877897

RESUMO

OBJECTIVE: The purpose of this study was to investigate the effects of hyperglycemia on atrial interstitial fibrosis, ionic remodeling and vulnerability to atrial fibrillation (AF) in alloxan-induced diabetic rabbits. METHODS: Sixty Japanese rabbits were randomly assigned to alloxan-induced diabetic group (n=30) and control group (n=30). Ten rabbits in each group were respectively used to electrophysiological and histological study, patch-clamp study and Western blotting analysis. Langendorff perfusion was used to record inter-atrial conduction time (IACT), atrial effective refractory period (AERP) and dispersion (AERPD) and vulnerability to AF. Histological study was measured by Sirius-red stain. Patch-clamp technique was used to measure action potential duration (APD) and atrial ionic currents (INa and ICaL). Western blotting was applied to assess atrial protein expression of transforming growth factor beta 1 (TGFß1). RESULTS: Compared with control group, electrophysiological studies showed IACT was prolonged (37.91±6.81 vs. 27.43±1.63ms, p<0.01), AERPD was increased (30.37±8.33 vs. 14.70±5.16ms, p<0.01) in diabetic group. Inducibility of AF in diabetic group was significantly higher than in controls (8/10 vs. 1/10 of animals, p<0.01). Collagen volume fraction was increased (6.20±0.64% vs. 2.15±0.21%, p<0.01) in diabetic group. Patch-clamp studies demonstrated APD90 and APD50 were prolonged in diabetic rabbits (p<0.05 vs. control). The densities of INa were reduced and the densities of ICaL were increased (p<0.01 vs. control). Protein expression of TGFß1 was increased in diabetic group (p<0.001 vs. control). CONCLUSION: Our study suggests that hyperglycemia contributes to atrial interstitial fibrosis, ionic remodeling and vulnerability to AF in diabetic rabbits, resulting in atrial structural remodeling and electrical remodeling for the development and perpetuation of AF.


Assuntos
Fibrilação Atrial/fisiopatologia , Diabetes Mellitus Experimental , Hiperglicemia/fisiopatologia , Aloxano/farmacologia , Animais , Fibrilação Atrial/complicações , Remodelamento Atrial , Modelos Animais de Doenças , Eletrocardiografia , Feminino , Fibrose/fisiopatologia , Átrios do Coração/fisiopatologia , Hiperglicemia/complicações , Masculino , Coelhos , Distribuição Aleatória , Fator de Crescimento Transformador beta1/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA