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1.
World J Gastroenterol ; 25(17): 2099-2109, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31114136

RESUMO

BACKGROUND: The methylated septin 9 (mSEPT9) assay was the first blood-based test approved by the United States Food and Drug Administration as a colorectal screening test. However, the diagnostic and prognostic role of preoperative mSEPT9 for colorectal cancer (CRC) in Chinese patients is still unknown. AIM: To improve the understanding of diagnostic and prognostic factors, serum mSEPT9 was detected in Chinese CRC patients. METHODS: A retrospective analysis of 354 cases, of which 300 had CRC and 54 were normal, was performed in China. Patients' characteristics, treatments, and laboratory data, including age, the date of surgery, Union for International Cancer Control (UICC) stages, distant metastasis (M), and so on, were collected. Methylation levels of SEPT9 were quantified by quantitative, methylation-specific polymerase chain reaction before surgery. In addition, the effects of mSEPT9 on the occurrence and prognosis of 330 CRC cases from The Cancer Genome Atlas (TCGA) database were evaluated using bioinformatics analyses. Potential prognostic factors for overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier univariate analysis. RESULTS: In Chinese CRC patients, positive mSEPT9 was strongly associated with advanced UICC stages, deeper invasion by the primary tumor, and more distant metastasis. Methylation levels of SEPT9 were stage-dependent and showed a stepwise increase in UICC stages (I-IV), primary tumor categories (T1-T4), regional node categories (N0-N2), and distant metastasis categories (M0-M1). The patients with positive mSEPT9 showed a tendency toward lower PFS. After analyzing TCGA clinical data, the high mSEPT9 group was found to be obviously correlated only with more distant metastasis. The patients with high mSEPT9 levels showed a tendency toward lower OS. Besides, nine meaningful mSEPT9 sites were found to provide guidance for the follow-up studies. CONCLUSION: MSEPT9 analysis may add valuable information to current tumor staging. Serum mSEPT9 in Chinese CRC patients appears to offer promising novel prognostic markers and might be considered for monitoring CRC recurrence.

2.
Pharmacol Res ; 142: 294-302, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30553824

RESUMO

Stress response refers to the systemic nonspecific response upon exposure to strong stimulation or chronic stress, such as severe trauma, shock, infection, burn, major surgery or improper environment, which disturb organisms and damage their physical and psychological health. However, the pathogenesis of stress induced disorder remains complicated and diverse under different stress exposure. Recently, studies have revealed a specific role of microRNAs (miRNAs) in regulating cellular function under different types of stress, suggesting a significant role in the treatment and prevention of stress-related diseases, such as stress ulcer, posttraumatic stress disorder, stress-induced cardiomyopathy and so on. This paper have reviewed the literature on microRNA related stress diseases in different databases including PubMed, Web of Science, and the MiRbase. It considers only peer-reviewed papers published in English between 2004 and 2018. This review summarizes new advances in principles and mechanisms of miRNAs regulating stress signalling pathway and the role of miRNAs in human stress diseases. This comprehensive review is to provide an integrated account of how different stresses affect miRNAs and how stress-miRNA pathways may, in turn, be linked with disease, which offers some potential strategies for stress disorder treatment. Furthermore, the limitation of current studies and challenges for clinical use are discussed.

3.
Oncol Lett ; 16(2): 2271-2278, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30008929

RESUMO

Castration-resistant prostate cancer (CRPC) is a leading cause of mortality among cases of prostate cancer (PCa). Current treatment options for CRPC are limited. Ethyl pyruvate (EP), a lipophilic derivative of pyruvic acid, has been reported to have antitumor activities. In the present study, the efficacy of EP against PCa was investigated using two human PCa cell lines and a mouse xenograft tumor model. PC3 and CWR22RV1 cells were treated with EP, and cytotoxicity was evaluated via Cell Counting Kit-8 and colony formation assays, while cell cycle distribution was assessed by flow cytometry. Changes in cell migration and invasion caused by EP treatment were also evaluated with Transwell and wound healing assays, and changes in the expression of intracellular signaling pathway components were detected by western blotting. EP treatment reduced cell viability, induced G1 arrest, and activated the intrinsic apoptosis pathway. Additionally, the in vivo experiments revealed that EP administration markedly inhibited tumor growth. EP also reversed epithelial-mesenchymal transition and suppressed cancer stem cell properties in part through negative regulation of AKT/nuclear factor-κB signaling. These results indicate that EP has anticancer activity in vitro and in vivo, and is therefore a promising therapeutic agent for the treatment of PCa.

4.
Pulm Pharmacol Ther ; 44: 70-77, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28315789

RESUMO

BACKGROUND AND OBJECTIVE: Diabetic pulmonary fibrosis is a severe disease that increases mortality risk of diabetes. However, the molecular mechanisms leading to pulmonary fibrosis in diabetes are poorly understood. This study investigated the roles of epithelial-mesenchymal transition (EMT) and the associated molecular mechanisms in streptozotocin (STZ)-induced rat pulmonary fibrosis. METHODS: The rat model of diabetic pulmonary fibrosis was established by intraperitoneal injection of a single dose of STZ (35 mg/kg). Typical lesions of diabetic pulmonary fibrosis were observed 8 weeks after STZ injection by hematoxylin-eosin (HE) and Masson staining. Human bronchial epithelial cells (HBECs) and A549 cells were treated by high glucose. Gene or protein expression was measured by real-time PCR, Western blot, immunohistochemistry or immunofluorescence. The knockdown of lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) or transforming growth factor-ß1 (TGF-ß1) was conducted by siRNA. RESULTS: Activation of EMT was observed in lung tissues of STZ-induced diabetic rats, exhibiting a loss in the epithelial cell marker E-cadherin and an increase in the mesenchymal marker Vimentin. The protein and mRNA levels of LOX-1, TGF-ß1 and krüppel-like factor 6 (KLF6) in the lung tissues were increased. Incubation of HBECs and A549 cells with high glucose activated EMT and induced an increase in LOX-1, TGF-ß1 and KLF-6 expression. LOX-1 siRNA inhibited high glucose-induced EMT in HBECs and A549 cells, which correlated with the reduction of TGF-ß1. TGF-ß1 siRNA decreased the expression of LOX-1 and KLF6. CONCLUSIONS: EMT was involved in the pathological process of diabetic pulmonary fibrosis, which was activated by LOX-1/TGF-ß1/KLF6 signaling pathway.


Assuntos
Diabetes Mellitus Experimental/complicações , Transição Epitelial-Mesenquimal/fisiologia , Pulmão/patologia , Fibrose Pulmonar/etiologia , Células A549 , Animais , Western Blotting , Caderinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Humanos , Fator 6 Semelhante a Kruppel/genética , Fator 6 Semelhante a Kruppel/metabolismo , Pulmão/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Receptores Depuradores Classe E/genética , Receptores Depuradores Classe E/metabolismo , Transdução de Sinais/fisiologia , Estreptozocina , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Vimentina/metabolismo
5.
Eur J Pharmacol ; 796: 190-206, 2017 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-27916556

RESUMO

MicroRNAs (miRNAs), a large family of small and highly conserved non-coding RNAs, regulate gene expression through translational repression or mRNA degradation. Aberrant expression of miRNAs underlies a spectrum of diseases including organ fibrosis. Recent evidence suggests that miRNAs contribute to organ fibrosis through mediating epithelial-mesenchymal transition (EMT). Alleviation of EMT has been proposed as a promising strategy against fibrotic diseases given the key role of EMT in fibrosis. miRNAs impact the expression of specific ligands, receptors, and signaling pathways, thus modulating EMT and consequently influencing fibrosis. This review summarizes the current knowledge concerning how miRNAs regulate EMT and highlights the specific roles that miRNAs-regulated EMT plays in fibrotic diseases as diverse as pulmonary fibrosis, hepatic fibrosis, renal fibrosis and cardiac fibrosis. It is desirable that a more comprehensive understanding of the functions of miRNAs-regulated EMT will facilitate the development of novel diagnostic and therapeutic strategies for various debilitating organ fibrosis.


Assuntos
Transição Epitelial-Mesenquimal/genética , Fibrose/genética , Fibrose/patologia , MicroRNAs/genética , Animais , Humanos
6.
J Clin Neurosci ; 37: 6-14, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27816260

RESUMO

Several studies examined a possible link between multidrug resistance-associated protein 2 (ABCC2) gene variants and the risk of resistance to antiepileptic drugs (AEDs) in epilepsy, but the results were contradictory. In this study, a meta-analysis was conducted to assess the relevance of ABCC2 common variants (c.-24C>T, c.1249G>A, c.3972C>T) with the response risk of AEDs. We searched Embase, PubMed, the Cochrane Library and CNKI databases for case-control studies published through May 2016 that evaluated the role of ABCC2 gene variants in pharmacoresistance to AEDs. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated to assess the strength of associations between the ABCC2 c.-24C>T, c.1249G>A and c.3972C>T variants and the risk of resistance to AEDs using an allele frequency model, dominant model and recessive model. Subgroup analyses were performed by ethnicity and the definition of drug-resistance. A total of 13 published studies involving 4300 patients (2261 patients with drug-resistant epilepsy and 2039 controls with drug-responsive epilepsy) met the selection criteria. We observed that the variant c.-24C>T was associated with a significantly increased risk of AED resistance (TT+CT vs CC: OR=1.24, 95%CI=1.06-1.46, p=0.009; TT vs CT+CC: OR=1.90, 95%CI=1.31-2.76, p=0.0008; T vs C: OR=1.27, 95%CI=1.11-1.46, p=0.0006). However, we identified no significant association of the ABCC2 c.1249G>A, c.3972C>T variants and haplotypes with the response to anticonvulsant drug in the overall population. In summary, these observations suggest that the ABCC2 c.-24C>T polymorphism is a likely risk factor for resistance to AEDs.


Assuntos
Anticonvulsivantes/uso terapêutico , Resistência a Medicamentos/genética , Epilepsia/tratamento farmacológico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Polimorfismo de Nucleotídeo Único , Epilepsia/genética , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos
7.
Eur J Pharmacol ; 775: 67-77, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26872992

RESUMO

Non-muscle myosin regulatory light chain (nmMLC20) is reported to exert transcriptional function in regulation of gene expression, and NADPH oxidase (NOX)-derived reactive oxygen species contribute to vascular remodeling of pulmonary artery hypertension (PAH). This study aims to determine if nmMLC20 can promote endothelial progenitor cells (EPCs) senescence and dysfunction through up-regulation of NOX in PAH rats. The rats were exposed to10% hypoxia for 3 weeks to establish a PAH model, which showed an increase in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, and the accelerated senescence and impaired functions in EPCs, accompanied by an increase in Rho-kinase (ROCK) and NOX activities, p-nmMLC20 level, NOX expression and H2O2 content; these phenomena were reversed by fasudil, a selective inhibitor of ROCK. Next, normal EPCs were cultured under hypoxia to induce senescence in vitro. Consistent with the in vivo findings, hypoxia increased the senescence and dysfunction of EPCs concomitant with an increase in ROCK and NOX activities, p-nmMLC20 level, NOX expression and H2O2 content; these phenomena were reversed by fasudil. Knockdown of nmMLC20 showed similar results to that of fasudil except no effect on ROCK activity. Based on these observations, we conclude that nmMLC20 could promote the senescence and dysfunctions of EPCs in PAH through up-regulation of NOX in a phosphorylation-dependent manner.


Assuntos
Senescência Celular/fisiologia , Células Progenitoras Endoteliais/fisiologia , Hipertensão Pulmonar/metabolismo , Cadeias Leves de Miosina/fisiologia , NADPH Oxidases/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Masculino , Cadeias Leves de Miosina/genética , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley , Regulação para Cima , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo
8.
Zhongguo Dang Dai Er Ke Za Zhi ; 17(4): 414-9, 2015 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-25919567

RESUMO

Oxcarbazepine is a new antiepileptic drug. The results of clinical trials suggest that oxcarbazepine is well tolerated and has less drug interactions. It is being used more and more widely in clinical practice, but its adverse effects should not be ignored. The most common adverse effects of oxcarbazepine are usually related to the central nervous system and digestive system, including fatigue, drowsiness, diplopia, dizziness, nausea and vomit. The common skin adverse reaction is rash. Long-term use of oxcarbazepine may also cause hyponatremia. This article reviews the literature from China and overseas about the adverse effets of oxcarbazepine over the last 10 years in order to find information about rational clinical use of oxcarbazepine.


Assuntos
Anticonvulsivantes/efeitos adversos , Carbamazepina/análogos & derivados , Carbamazepina/efeitos adversos , Exantema/induzido quimicamente , Humanos , Hiponatremia/induzido quimicamente , Oxcarbazepina
9.
Biochem Biophys Res Commun ; 458(4): 869-76, 2015 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-25701782

RESUMO

The risk of cardiovascular complications in diabetic patients is mainly associated with endothelial dysfunction. Reduced number of EPCs and impaired function of EPCs in diabetes result in imbalance of endothelial homeostasis and dysfunction of vessels. In patients with diabetes mellitus, plasma levels of asymmetric dimethylarginine (ADMA) were elevated, while the expression and activity of dimethylarginine dimethylaminohydrolase (DDAH) were reduced. In the present study, we investigated the role of the DDAH2/ADMA pathway in the senescence of EPCs in type 2 diabetic patients and cultured EPCs treated with high glucose. The results showed that the percentage of senescent EPCs increased while the expression of DDAH2 decreased concomitantly with an increase in the plasma levels of ADMA in patients with type 2 diabetes mellitus (T2DM). Similar results were seen in cultured EPCs treated with high glucose. Exogenous application of ADMA accelerated the senescence of EPCs in a dose-dependent manner, and overexpression of DDAH2 inhibited high glucose-induced EPCs senescence. In addition, it has also been reported that DDAH/ADMA pathway is regulated by silent information regulator 1 (SIRT1) in endothelial cell. In the present study, we found decreased expression of SIRT1 both in T2DM patients and EPCs pretreated with high glucose. And resveratrol (activating SIRT1) inhibited high glucose-induced EPCs senescence by upregulating the expression of DDAH2 and decreasing the levels of ADMA. Taken together, we concluded that DDAH2/ADMA is involved in the accelerated senescence of EPCs in diabetes, which is associated with the activation of SIRT1.


Assuntos
Amidoidrolases/metabolismo , Arginina/análogos & derivados , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/patologia , Células Progenitoras Endoteliais/patologia , Arginina/sangue , Arginina/metabolismo , Senescência Celular , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Células Progenitoras Endoteliais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sirtuína 1/metabolismo
11.
Tumour Biol ; 35(8): 8259-65, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24852429

RESUMO

This study aims to investigate the influence of ATP7B genetic polymorphism to platinum-based chemotherapy in Chinese Han lung cancer patients. A total of 338 Chinese Han lung cancer patients were enrolled in this study. All patients underwent at least two cycles of platinum-based chemotherapy. Four tag SNPs of ATP7B (rs1061472, rs9535826, rs7999812, and rs9535828) were selected to evaluate their impacts to platinum-based chemotherapy in these patients. ATP7B rs9535828 and rs9535826 were found to be associated with platinum resistance in Chinese Han lung cancer patients. Patients with A allele in ATP7B rs9535828 presented an increased susceptibility to platinum drugs (OR 1.96, 95 % CI 1.17-3.30, p < 0.01). Patients with G allele in ATP7B rs9535826 had the highest susceptibility to platinum drugs (OR 2.05, 95 % CI 1.19-3.52, p < 0.01). Our findings suggest that ATP7B genetic polymorphisms could affect the therapeutic efficacy of platinum-based chemotherapy, and ATP7B gene might be considered as predictive markers for the efficacy evaluation of platinum-based chemotherapy in Chinese Han lung cancer patients.


Assuntos
Adenosina Trifosfatases/genética , Proteínas de Transporte de Cátions/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , ATPases Transportadoras de Cobre , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Platina/uso terapêutico
12.
Clin Exp Pharmacol Physiol ; 41(8): 558-64, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24827774

RESUMO

The purpose of the present study was to clarify the association of eNOS 894G/T and ACE I/D genetic polymorphisms with the risk of coronary heart disease (CHD) and to explore the effects of these polymorphisms on the therapeutic efficacy of salvianolate injection in Chinese CHD patients. In all, 153 CHD patients and 198 healthy controls were enrolled in the study. We collected 5 mL peripheral blood for DNA extraction. Genetic diagnosis of eNOS 894G/T was determined by direct sequencing. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect ACE I/D genotypes. We observed significant differences in the frequency distribution of eNOS and ACE polymorphisms between CHD patients and healthy controls (P < 0.05). Binary logistic regression stepwise analysis revealed that the genotypes had an additive and dominant effect on patients' therapeutic responses (P < 0.05). These data suggest that the genetic polymorphisms of ACE I/D and eNOS 894G/T probably play a role in the development of CHD and these genetic polymorphisms may affect the response to salvianolate injection in Chinese CHD patients.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/genética , Óxido Nítrico Sintase Tipo III/genética , Peptidil Dipeptidase A/genética , Extratos Vegetais/uso terapêutico , Estudos de Casos e Controles , Doença das Coronárias/enzimologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco
13.
Clin Exp Pharmacol Physiol ; 39(5): 462-8, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22414228

RESUMO

The present study evaluated the effects of KCNQ1 rs2237892 and rs2237895 polymorphisms on repaglinide efficacy in Chinese patients with type 2 diabetes mellitus (T2DM). In all, 367 T2DM patients and 214 controls were genotyped. Forty of the T2DM patients were randomly selected to undergo 8 weeks repaglinide treatment. The frequency of the rs2237892 allele was lower in the T2DM patients than in the control group (P < 0.05). The frequency of the rs2237895 C allele was higher in T2DM patients than in healthy control subjects (P < 0.05). Diabetic patients with the rs2237892 risk C allele had lower fasting insulin levels (P < 0.01) and homeostasis model assessment of insulin resistance (HOMA-IR; P < 0.01) values than carriers of the T allele. Diabetic patients with the rs2237895 risk C allele had higher fasting plasma glucose (P < 0.01), postprandial plasma glucose (PPG) levels (P < 0.01) and HOMA-IR values (P < 0.01) than those with the A allele. Following repaglinide treatment, those T2DM patients with the rs2237892 T allele and rs2237895 C allele were more likely to have a positive response to repaglinide in terms of PPG levels (P < 0.05) than T2DM patients with the rs2237892 CC and rs2237895 AA genotypes. In conclusion, KCNQ1 rs2237892 and rs2237895 polymorphisms were found to be associated with the therapeutic efficacy of repaglinide in Chinese T2DM patients.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Carbamatos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Canal de Potássio KCNQ1/genética , Piperidinas/uso terapêutico , Polimorfismo Genético/genética , Adulto , Feminino , Frequência do Gene/efeitos dos fármacos , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/efeitos dos fármacos , Fatores de Risco , Resultado do Tratamento
14.
Br J Clin Pharmacol ; 74(3): 501-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22296034

RESUMO

AIMS: We aimed to determine whether NeuroD1/BETA2 and PAX4 polymorphisms were associated with the therapeutic efficacy of repaglinide in Chinese type 2 diabetes mellitus (T2DM) patients. METHODS: Three hundred and sixty-eight T2DM patients and 132 healthy control subjects were genotyped by restriction fragment length polymorphism. Forty-three patients with various genotypes were randomly selected to undergo 8 weeks of repaglinide treatment (3 mg day(-1)). Fasting plasma glucose, postprandial plasma glucose, glycated haemoglobin, fasting and postprandial serum insulin (FINS, PINS), homeostasis model assessment for insulin resistance, serum triglyceride, total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol were determined before and after repaglinide treatment. RESULTS: The allelic frequency of NeuroD1/BETA2 T45 was higher in T2DM patients than in the control subjects [13.45 vs. 6.82%, P < 0.01, odds ratios = 2.342 (1.365, 4.019), P= 0.002]. Type 2 diabetes mellitus patients with the mutated allele of NeuroD1/BETA2 A45T polymorphism showed higher FINS (13.46 ± 12.57 vs. 10.04 ± 7.09 mU l(-1) , P < 0.05) (11.67, 14.83 vs. 8.38, 11.37) and PINS (52.11 ± 40.93 vs. 68.66 ± 43.87 mU l(-1), P < 0.05) (44.89, 58.35 vs. 55.35, 88.87) than individuals with the T allele. The PAX4 R121W R allele carriers had higher PINS (52.11 ± 40.93 vs. 68.66 ± 43.87 mU l(-1), P < 0.05) (44.89, 58.35 vs. 55.35, 88.87) than subjects with the W allele. After repaglinide treatment, patients with the T allele of NeuroD1/BETA2 A45T polymorphisms had attenuated efficacy on fasting plasma glucose (-2.79 ± 2.14 vs.-0.99 ± 1.80 mmol l(-1), P < 0.01) (-3.53, -1.84 vs.-1.99, -0.13) and postprandial plasma glucose (-6.71 ± 5.90 vs.-2.54 ± 3.39 mmol l(-1), P < 0.01) (-9.28, -4.62 vs.-4.34, -0.84). Patients with the RR genotype of PAX4 R121W showed better efficacy with respect to the level of postprandial plasma glucose than R/W genotypes (-6.53 ± 6.52 vs.-2.95 ± 1.17 mmol l(-1), P < 0.05) (-8.20, -4.89 vs.-3.92, -1.20). CONCLUSIONS: The NeuroD1/BETA2 and PAX4 polymorphisms were substantially associated with plasma glucose level after repaglinide monotherapy.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carbamatos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteínas de Homeodomínio/genética , Fatores de Transcrição Box Pareados/genética , Piperidinas/farmacologia , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático , Glicemia/efeitos dos fármacos , Estudos de Casos e Controles , China , Diabetes Mellitus Tipo 2/genética , Feminino , Genótipo , Humanos , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição
15.
Auton Neurosci ; 167(1-2): 66-9, 2012 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-22093677

RESUMO

In the present study, we explored the association of catecholamines with insulin sensitivity in "metabolically healthy but obese" (MHO) individuals, by examining the metabolic characteristics and plasma catecholamine levels in 100 obese, sedentary postmenopausal women. Subjects were classified as MHO (n=25) or at-risk (n=25) based on the upper and lower quartiles of insulin sensitivity as measured by the hyperinsulinemic-euglycemic clamp technique. The MHO group presented a significantly higher range of plasma epinephrine levels (73 ± 21 pg/mL) than the at-risk group (39 ± 20 pg/mL) (P<0.05), though both within the normal basal range of plasma epinephrine (56 ± 30 pg/mL). Multivariate regression analysis showed that high-sensitivity C-reactive protein, plasma epinephrine, triglycerides and lean body mass index were independent predictors of glucose disposal. The plasma epinephrine level was positively correlated with the glucose disposal rate, insulin sensitivity and the HDL-cholesterol level, and negatively correlated with the triglycerides level (P<0.05). In conclusion, this study for the first time demonstrates a positive association between plasma epinephrine level and insulin sensitivity in MHO individuals.


Assuntos
Epinefrina/sangue , Resistência à Insulina/fisiologia , Obesidade/sangue , Obesidade/fisiopatologia , Absorciometria de Fóton , Idoso , Biomarcadores/sangue , Composição Corporal/fisiologia , Índice de Massa Corporal , Proteína C-Reativa/análise , Catecolaminas/sangue , HDL-Colesterol/sangue , Feminino , Técnica Clamp de Glucose , Humanos , Inflamação/sangue , Lipídeos/sangue , Pessoa de Meia-Idade , Pós-Menopausa/fisiologia , Análise de Regressão , Triglicerídeos/sangue
16.
Clin Exp Pharmacol Physiol ; 38(12): 824-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21933224

RESUMO

1. The aim of this study was to investigate the association of the serine racemase (SRR) rs391300 G/A polymorphism with the risk of diabetes mellitus type 2 (T2DM) and to assess the impacts of the polymorphism on the therapeutic efficacy of metformin in Chinese patients. 2. A case-control study of 402 patients with T2DM and 171 healthy controls was conducted. The SRR rs391300 polymorphism was genotyped in all participants using the ABI 3700 automated sequencer. Forty-four recent-onset T2DM patients with different rs391300 genotypes were selected to receive 500 mg metformin orally daily for 12 consecutive weeks as monotherapy. Serum fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated haemoglobin (HbA1c), fasting serum insulin (FINS), postprandial serum insulin (PINS), triglycerol (TG), cholesterol (CHO), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), homeostasis model assessment for insulin resistance (HOMA-IR), and body mass index (BMI) were determined before and after metformin treatment. 3. The distribution frequencies of rs391300 were in agreement with Hardy-Weinberg equilibrium (P > 0.05). After treatment with metformin, the values of BMI, FPG, PPG, PINS, HbA1c, CHO, and TG decreased significantly (P < 0.01), whereas FINS increased (P < 0.001), in patients with T2DM. Patients with the GA or AA genotype of rs391300 showed better improvements in the levels of FPG, PPG, and CHO (P < 0.05) than individuals with the GG genotype. 4. The SRR rs391300 polymorphism was associated with the therapeutic efficacy of metformin in Chinese patients with T2DM.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Polimorfismo Genético , Racemases e Epimerases/genética , Adulto , Idoso , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Feminino , Estudos de Associação Genética , Hemoglobina A Glicada/análise , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Eur J Clin Pharmacol ; 66(12): 1207-15, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20809084

RESUMO

OBJECTIVE: Genome-wide association studies (GWASs) identified that SLC30A8 genetic polymorphism was a risk of type 2 diabetes mellitus (T2DM) in several populations. This study aimed to investigate whether the SLC30A8 rs13266634 and rs16889462 polymorphisms were associated with T2DM susceptibility and repaglinide therapeutic efficacy in Chinese T2DM patients. METHODS: We conducted a case-control study of 443 T2DM patients and 229 healthy volunteers to identify SLC30A8 rs13266634 and rs16889462 genotypes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Forty-eight patients were randomly selected and underwent an 8-week repaglinide treatment (3 mg/d). Fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin (HbAlc), fasting serum insulin (FINS), postprandial serum insulin (PINS), homeostasis model assessment for insulin resistance (HOMA-IR), serum triglyceride, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c) and high-density lipoprotein-cholesterol (HDL-c) were determined before and after repaglinide treatment. RESULTS: SLC30A8 rs13266634 risk C allele frequency was higher in T2DM patients than in healthy controls (P < 0.05). There was a better repaglinide response on FINS (P < 0.05) and PINS (P < 0.01) in patients with rs13266634 CT+TT genotypes compared with CC genotype carriers. Patients with rs16889462 GA genotype showed an enhanced repaglinide efficacy on FPG (P < 0.01), PPG (P < 0.01) and HbAlc (P < 0.05) compared with GG genotype individuals. CONCLUSIONS: SLC30A8 rs13266634 and rs16889462 polymorphisms were associated with repaglinide therapeutic efficacy in Chinese T2DM patients.


Assuntos
Carbamatos/uso terapêutico , Diabetes Mellitus Tipo 2/genética , Hipoglicemiantes/uso terapêutico , Piperidinas/uso terapêutico , Polimorfismo Genético , Adulto , Idoso , Sequência de Bases , Estudos de Casos e Controles , Proteínas de Transporte de Cátions , China , Primers do DNA , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Transportador 8 de Zinco
18.
Clin Chim Acta ; 408(1-2): 98-104, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19682446

RESUMO

OBJECTIVES: The aims of this study were to investigate the effects of clozapine on adipocyte differentiation and its regulation for fat-cell derived factors. MATERIALS AND METHODS: 3T3-L1 preadipocytes were induced into differentiated adipocytes by the addition of 5 microg/ml of insulin, 1 micromol/l dexamethasone, 10 mmol/l IBMX, 1% DMSO, and 10% FBS in DMEM medium. The semi-quantitative RT-PCR was performed to determine the mRNA levels of PPAR gamma, C/EBP alpha, ADD1/SREBP(1C), LPL, and DGAT1. The expression levels of LPL and DGAT1 proteins in the adipocytes treated with clozapine or rosiglitazone were determined by Western blot analysis. The triglyceride concentration was determined by use of GPO-POD assay Kit. RESULTS: Clozapine enhanced the expression level of ADD1/SREBP(1C) mRNA and triglyceride concentration in the differentiated adipocytes. Clozapine significantly suppressed the expression levels of LPL mRNA and LPL protein with a dose-dependent and time-dependent manner, respectively. CONCLUSION: These data suggest that clozapine might play an important role in inducing adipocyte differentiation and the regulation of fat-cell derived factors.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Clozapina/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/enzimologia , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triglicerídeos/metabolismo
19.
Br J Clin Pharmacol ; 65(6): 917-26, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18429970

RESUMO

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Rosiglitazone is able to increase serum adiponectin levels significantly in Type 2 diabetic patients. :The role of genetic factors that determine the marked interindividual variability in glucose-lowering efficacy of rosiglitazone in Chinese patients is not known. The current study was designed to evaluate the impact of the adiponectin common allele 45T/G and -11377C/G polymorphisms on the response to rosiglitazone monotherapy in Chinese patients with Type 2 diabetes (T2D). WHAT THIS STUDY ADDS: The genetic polymorphisms of adiponectin alleles 45T/G and -11377C/G as well as their common diplotypes are significantly associated with an attenuated fasting plasma glucose, postprandial plasma glucose and homeostasis model assessment for insulin resistance as well as an enhanced adiponectin concentration in Chinese patients with T2D after rosiglitazone treatment. AIMS The aim of the present study was to evaluate the impact of adiponectin allele T45G and C-11377G genetic polymorphisms on efficacy of rosiglitazone in Chinese patients with type 2 diabetes (T2D). METHODS: Patients with T2D (n = 255) and 120 healthy volunteers were enrolled to identify 45T/G and -11377C/G genotypes by polymerase chain reaction-restriction fragment length polymorphism assay. Forty-two T2D patients with different 45T/G or -11377C/G genotypes received orally rosiglitazone as a single-dose therapy (4 mg day-1 p.o.) for 12 weeks. Serum triglyceride, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin, fasting serum insulin, postprandial serum insulin, total cholesterol, homeostasis model assessment for insulin resistance (HOMA-IR), low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol (HDL-c) and adiponectin concentration were determined before and after rosiglitazone treatment. RESULTS: We showed an attenuated rosiglitazone effect in patients with -11377CG+GG heterozygote genotype on FPG, PPG, HOMA-IR compared with -11377CC homozygote genotype. However, we found an enhanced rosiglitazone effect on serum adiponectin concentration in patients with -11377CC homozygote genotype compared with -11377CG+GG heterozygote genotype (P = 0.000) and in patients with 45TG + GG heterozygote genotype compared with 45TT homozygote genotype (P = 0.018). Finally, our results showed that there was an enhanced effect in patients with -11377/45 CGTT diplotype compared with other discovered diplotypes on FPG (P = 0.001) and PPG (P = 0.003) after rosiglitazone treatment. CONCLUSIONS: These data suggest that the adiponectin allele 45T/G and -11377C/G polymorphisms are significantly associated with the therapeutic efficacy of multiple-dose rosiglitazone in Chinese patients with T2D.


Assuntos
Adiponectina/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Tiazolidinedionas/farmacocinética , Adiponectina/sangue , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Rosiglitazona
20.
Eur J Clin Pharmacol ; 64(7): 663-71, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18438653

RESUMO

BACKGROUND: Leptin and tumor necrosis factor-alpha (TNF-alpha) play important role in homeostasis and insulin resistance in the treatment of Type 2 diabetes (T2DM). The aims of the present study were to investigate the association between leptin G-2548A and TNF-alpha G-308A polymorphisms and rosiglitazone response in T2DM patients. MATERIALS: 245 patients with T2D and 122 health volunteers were enrolled to identify leptin G-2548A and TNF-alpha G-308A genotypes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Forty-two T2D patients with different leptin G-2548A and TNF-alpha G-308A genotypes received orally rosiglitazone as a single-agent therapy (4 mg day(-1) p.o.) for 12 weeks. Serum triglyceride (TG), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting serum insulin (FINs), glycated hemoglobin (HbAlc), postprandial serum insulin (PINS), homeostasis model assessment for insulin resistance (HOMA-IR), low-density lipoprotein-cholesterol (LDL-c), and high-density lipoprotein-cholesterol (HDL-c) were determined before and after rosiglitazone treatment. RESULTS: A significant association between the variation of G-2548A allele with body mass index (BMI), serum leptin levels and FPG was observed in T2DM patients. Moreover, patients with G allele of leptin G-2548A had lower BMI and serum leptin concertration as well as bigger FPG than that in AA genotypes (P < 0.05). Moreover, we found an enhanced rosiglitazone effect in patients with AA genotype of leptin G-2548A on FINS and PINS compared with GG+GA genotype (P < 0.05). Finally, our results showed an attenuated rosiglitazone effect in patients with GA+AA genotype of TNF-alpha G-308A on FINS compared with GG genotype (P < 0.05). CONCLUSIONS: These data suggest there were not significantly differences in the frequencies of leptin G-2548A and TNF-alpha G-308A between patients with T2DM and health control. TNF-alpha G-308A polymorphism might be associated with the therapeutic efficacy of rosiglitazone in T2DM patients.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Leptina/genética , Polimorfismo Genético , Tiazolidinedionas/uso terapêutico , Fator de Necrose Tumoral alfa/genética , Adulto , Idoso , Glicemia/análise , China , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Rosiglitazona , Triglicerídeos/sangue
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