RESUMO
Nucleotide-binding domain, leucine-rich repeat family with a caspase activation and recruitment domain 3 (NLRC3) participates in both immunity and cancer. The aim of this study was to determine the role of NLRC3 in human hepatocellular carcinoma (HCC) and the underlying mechanisms. We collected human liver tissues from nonalcoholic steatohepatitis (NASH), HCC, and adjacent normal tissues to characterize the pattern of NLRC3 expression by real-time quantitative polymerase chain reaction and immunohistochemistry. Then, we used the HCC cell line, HuH-7, transfected with small interfering RNA to silence the NLRC3 expression. 5-Ethynyl-2'-deoxyuridine assay, scratch assay, and transwell invasion assay were used for assessing proliferation, migration, and invasion, respectively. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were conducted to assess cell apoptosis. The expression of NLRC3 was reduced in human HCC tissues, compared with normal liver and nonalcoholic steatohepatitis tissues. After knocking down of NLRC3, the proliferation, migration, and invasion were increased in HuH-7 cells. And flow cytometry and TUNEL assay showed that HuH-7 cell apoptosis was suppressed after NLRC3 knockdown. As for the underlying mechanisms, knockdown of NLRC3 in HuH-7 cells was associated with the activation of Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway under interleukin-6 (IL-6) stimulation. NLRC3 expression was downregulated in human HCC tissues. NLRC3 silencing in HuH-7 cells can promote the proliferation, migration, and invasion of hepatocellular carcinoma cells. JAK2/STAT3 pathway activation induced by IL-6 may be the underlying mechanism for HCC when NLRC3 expression is silenced. And the invasion of HuH-7 cells was partially suppressed by the STAT3 specific inhibitor (cryptotanshinone). Therefore, NLRC3 may play a significant role in HCC and might be a therapeutic target for the treatment of HCC.
Assuntos
Carcinoma Hepatocelular , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Neoplasias Hepáticas , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Células THP-1RESUMO
Pathological cardiac hypertrophy is an independent risk factor of heart failure. However, we still lack effective methods to reverse cardiac hypertrophy. DUSP12 is a member of the dual specific phosphatase (DUSP) family, which is characterized by its DUSP activity to dephosphorylate both tyrosine and serine/threonine residues on one substrate. Some DUSPs have been identified as being involved in the regulation of cardiac hypertrophy. However, the role of DUSP12 during pathological cardiac hypertrophy is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in hypertrophic hearts and cardiomyocytes. Using a genetic loss-of-function murine model, we demonstrated that DUSP12 deficiency apparently aggravated pressure overload-induced cardiac hypertrophy and fibrosis as well as impaired cardiac function, whereas cardiac-specific overexpression of DUPS12 was capable of reversing this hypertrophic and fibrotic phenotype and improving contractile function. Furthermore, we demonstrated that JNK1/2 activity but neither ERK1/2 nor p38 activity was increased in the DUSP12 deficient group and decreased in the DUSP12 overexpression group both in vitro and in vivo under hypertrophic stress conditions. Pharmacological inhibition of JNK1/2 activity (SP600125) is capable of reversing the hypertrophic phenotype in DUSP12 knockout (KO) mice. DUSP12 protects against pathological cardiac hypertrophy and related pathologies. This regulatory role of DUSP12 is primarily through c-Jun N-terminal kinase (JNK) inhibition. DUSP12 could be a promising therapeutic target of pathological cardiac hypertrophy. DUSP12 is down-regulated in hypertrophic hearts. An absence of DUSP12 aggravated cardiac hypertrophy, whereas cardiomyocyte-specific DUSP12 overexpression can alleviate this hypertrophic phenotype with improved cardiac function. Further study demonstrated that DUSP12 inhibited JNK activity to attenuate pathological cardiac hypertrophy.
Assuntos
Cardiomegalia/enzimologia , Fosfatases de Especificidade Dupla/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Fosfatases de Especificidade Dupla/genética , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/enzimologia , Transdução de Sinais , Estresse FisiológicoRESUMO
BACKGROUND AND OBJECTIVE: Transradial access is an attractive approach for angiography or percutaneous coronary intervention. Different devices have been used to apply pressure locally at the site of arterial entry for achieving hemostasis. The aim of this study was to evaluate the effect of 2 different hemostatic devices on radial artery outcomes after transradial coronary intervention. SUBJECTS AND METHODS: This study included 600 patients who had undergone transradial coronary intervention who were randomized into 2 groups after the procedure: 300 were treated with a radial compression device (TR Band, Terumo Medical, Tokyo, Japan) (CD group) and the other 300 patients were treated using a chitosan-based pad (Anscare, Daxon, Taoyuan, Taiwan) (CS group). Compression time, major and minor access site bleeding complications, and incidence of radial artery occlusion were recorded. RESULTS: There were no statistical differences in the baseline clinical characteristics of the patients between the 2 groups. Compression time in the CS group was significantly shorter than that in the CD group (P < .001). Although no major access site bleeding complications were observed in either group, 6 patients in each group experienced minor access site bleeding complications. At the same time, 61 patients in the CD group and 21 patients in the CS group experienced errhysis (20% vs 7%, respectively; P < .001). Early radial artery occlusion (24 hours) occurred in 11.7% of the patients in the CD group and 5.4% of the patients in the CS group (P < .05). Chronic radial artery occlusion (30 days) occurred in 10% of the patients in the CD group and 5% of the patients in the CS group (P < .05). CONCLUSION: The application of the chitosan-based pad showed better hemostatic efficacy and a lower incidence of radial artery occlusion after transradial coronary intervention compared with the compression device.
Assuntos
Hemostasia Cirúrgica/instrumentação , Intervenção Coronária Percutânea , Artéria Radial , Dispositivos de Oclusão Vascular , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/etiologia , Quitosana/administração & dosagem , Feminino , Hemorragia/etiologia , Hemostasia , Hemostáticos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , UltrassonografiaRESUMO
BACKGROUND: Myeloid-related protein 8/14 (MRP8/14) is a stable heterodimer formed by two different calcium-binding proteins (MRP8 and MRP14). Studies have identified that MRP8/14 regulates vascular inflammation and serves as a novel marker of acute coronary syndrome. In this study, we evaluated the correlation between serum levels of MRP8/14, hsCRP, endogenous secretory receptor for advanced glycation end-products (esRAGE) and the occurrence of coronary artery disease (CAD), or carotid intima-media thickness (IMT) when CAD was not yet developed in diabetic patients. METHODS: Serum levels of MRP8/14, esRAGE and hsCRP were measured in 375 diabetic patients. Then the results of those who had CAD were compared against who had not. Also, we investigated the associations between above-mentioned indicators and IMT of subjects without CAD in both diabetic group and non-diabetic one. RESULTS: Serum MRP8/14 was significantly higher in CAD than in non-CAD group (9.7 ± 3.6 ug/ml vs. 8.2 ± 3.0 ug/ml, P < 0.001). It was associated with severity of CAD (r = 0.16, P = 0.026). In non-CAD group, MRP8/14 was associated with IMT in patients with (r = 0.30, P < 0.001) or without diabetes (r = 0.26, P = 0.015). The areas under the curves of receiver operating characteristic for CAD were 0.63 (95% CI 0.57-0.68) for MRP8/14, 0.76 (95% CI 0.71-0.81) for hsCRP and 0.62 (95% CI 0.56 -0.67) for esRAGE. CONCLUSION: In summary, we report that diabetic patients with CAD had elevated plasma MRP8/14 levels which were also positively correlated with the severity of CAD and carotid IMT in patients without clinically overt CAD.
Assuntos
Calgranulina A/sangue , Calgranulina B/sangue , Doenças das Artérias Carótidas/etiologia , Doença da Artéria Coronariana/etiologia , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Idoso , Biomarcadores/sangue , Proteína C-Reativa/análise , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico por imagem , Distribuição de Qui-Quadrado , China , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/diagnóstico , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/sangue , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , Ultrassonografia , Regulação para CimaRESUMO
BACKGROUND: Vaspin was a recently identified adipokine, playing a protective role in many metabolic diseases. The present study aimed to investigate the association between vaspin plasma level and stable angina pectoris (SAP) and unstable angina pectoris (UAP). METHODS: A total of 88 patients with angiographically-proved coronary artery disease (CAD) (SAP 47, UAP 41) and 103 control subjects without cardiovascular diseases were enrolled in this study. Circulating vaspin, mRNA expression of vaspin in peripheral blood mononuclear cells (PBMC), clinical parameters, lipid profile and high-sensitivity C-reactive protein (hsCRP) were assayed. The severity of CAD was also assessed according to the number of vessels diseased. RESULTS: There are significant differences in circulating vaspin levels and mRNA levels of PBMC between SAP and UAP groups (SAP 0.91±0.95 ng/mL and UAP 0.43±0.38 ng/mL, p<0.01 in circulating vaspin level; SAP 1.19±0.85 and UAP 0.82±0.56, p<0.05 in mRNA level of PBMC). An inverse correlation between the number of diseased vessels and plasma vaspin concentration was observed (r=-0.350, p<0.01) in the CAD group. Construction of receiver operating characteristic curves confirmed that vaspin plasma concentrations significantly differentiated CAD patients (area under the curve=0.684, p<0.001), as well as UAP (area under the curve=0.640, p<0.05). CONCLUSION: Decreased vaspin plasma levels and mRNA levels in PBMC were observed in patients with UAP. Low vaspin concentrations correlate with CAD severity. The findings suggested that vaspin could serve as a novel biomarker of CAD as well as UAP.
Assuntos
Angina Estável/sangue , Angina Estável/genética , Angina Instável/sangue , Angina Instável/genética , Regulação da Expressão Gênica , Serpinas/sangue , Serpinas/genética , Angina Estável/complicações , Angina Estável/patologia , Angina Instável/complicações , Angina Instável/patologia , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROCRESUMO
BACKGROUND: Tuberculosis (TB) is an important public health problem in China and environmental and genetic factors have an impact on its occurrence and development. We explored the relationship between environmental factors, genetic susceptibility genes and gene-environment interactions and the incidence of TB, as well as their high-risk combination, which can provide a scientific basis for prevention of the disease. METHODS: The 242 individuals, which included 82 TB patients, 67 family genetically related patients and 93 healthy controls, all of whom were of the Han population in Guangdong Province. The basic information of subjects was collected, including general conditions, behaviour habits, family environmental factors and blood samples. Two single nucleotides with potential functions (interleukin-10 [IL-10] rs1800896, interferon-γ [IFN-γ] rs2430561) were screened by bioinformatics tools and identified by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: We found that gender, education, TB exposure history, fitness activities, residential areas and indoor hygiene conditions were all associated with the occurrence of TB. In the dominant model, AG+GG of IL-10 and AA of IFN-γ are high-risk genotypes. Multifactor dimensionality reduction (MDR) analysis of TB-prone families shows that a combination of male sex, IL-10 AA and AG genotypes and smoking history are elements of high risk for TB infection (prediction accuracy 62.45%, cross-validation consistency 10/10). The MDR analysis of the TB patients group and the healthy control group showed that the combination of low education level, history of TB exposure, and IFN-γ AA genotype represented a higher risk of TB infection (prediction accuracy 80.34%, cross-validation consistency 10/10). CONCLUSIONS: The occurrence of TB in TB-prone families in the Han population of Guangdong Province is related to environmental factors as well as cytokines IL-10 and IFN-γ. We also found high-risk combinations of genes and environmental factors, providing clues for the timely detection of high-risk groups.
Assuntos
Polimorfismo de Nucleotídeo Único , Tuberculose , Estudos de Casos e Controles , China/epidemiologia , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Tuberculose/epidemiologia , Tuberculose/genéticaRESUMO
Chemotherapy drugs exerts beneficial antitumor activity before and after cancer surgery. Post-injury complications are a potential hazard after surgical tumor resection. Inflammation caused by surgical stress is known to promote the progression of post-injury complications. Recent studies have found that chemotherapy drugs can promote post-injury inflammatory response, leading to increased post-injury complications. Imidazole derivatives have effective anticancer activity. However, the impact of post-operative inflammation caused by imidazole derivatives is unclear. In this study, two novel phenanthroimidazole derivatives (L082 and L142) were synthesized and characterized. These compounds showed significant inhibitory effects on different tumor cells. The compound L082 also inhibited liver cancer in vivo. In addition, L082 played a significant role in inhibiting the accumulation of inflammatory cells and promoting the elimination of inflammatory cells at the incision, which may be related to inhibiting the production of ROS and NO in oxidative and nitric stress. These results suggest that L082 can be used as a bifunctional drug to suppress tumors and reduce post-injury inflammation complications.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Fenantrenos/síntese química , Fenantrenos/uso terapêutico , Células A549 , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Células HeLa , Células Hep G2 , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Fenantrenos/farmacologia , Peixe-ZebraRESUMO
BACKGROUND: rs1333049 polymorphism on chromosome 9p21 has been shown to affect susceptibility to coronary artery disease (CAD) in Caucasians. This study examined the association of rs1333049 with myocardial infarction (MI), angiographic severity of CAD and clinical outcome after a first acute MI in Han Chinese. METHODS: rs1333049 polymorphism was genotyped in 520 patients with a first acute MI and in 560 controls. The number of angiographically documented diseased coronary arteries (luminal diameter stenosis > or = 50%), echocardiographic left ventricular ejection fraction (LVEF), and major adverse cardiac events (MACE) during follow-up (mean, 29+/-15 months) were recorded. RESULTS: Patients with MI had higher frequencies of the CC genotype (30.0% vs. 20.7%) or C allele (55.5% vs. 46.2%) compared with controls (all p<0.01). rs1333049 polymorphism was strongly associated with MI [odds ratio (OR) 1.48, 95% confidence interval (CI) 1.22-1.79] after adjusting for traditional risk factors. Although longer hospitalization stay was observed in patients with the rs1333049-C allele, this polymorphism was not related to angiographic severity of CAD, LVEF, and occurrence of MACE after MI. CONCLUSIONS: This study demonstrates an association of rs1333049 polymorphism locus on chromosome 9p21 with risk for MI, but not with post-MI prognosis in Han Chinese.
Assuntos
Povo Asiático/genética , Cromossomos Humanos Par 9/genética , Frequência do Gene/genética , Infarto do Miocárdio/genética , Idoso , Alelos , China/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Estimativa de Kaplan-Meier , Desequilíbrio de Ligação/genética , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/mortalidade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
This study aimed to characterize matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in relation to changes in left ventricle (LV) geometry and function in a porcine model with streptozotocin (STZ)-induced diabetes. In 15 Chinese Guizhou minipigs with STZ-induced diabetes (diabetic group) and 15 age-matched normal controls (control group), Doppler tissue imaging was performed at 6 months of diabetes. Serum MMP-2, -9, TIMP-1, -4 and B-type natriuretic peptide (BNP) were determined. Expression of MMPs, TIMPs, urokinase type-plasminogen activator (uPA), its receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) in aortic intima and LV myocardium was evaluated, with gelatinolytic activities of tissue MMP-2, -9 accessed by zymography. Left ventricle end-diastolic septum thickness (P < 0.05) and mass (P < 0.05) were increased, whereas peak systolic mitral annulus velocity (Sm, P < 0.001), LV systolic (P = 0.01) and diastolic strain (P < 0.001) were significantly decreased in diabetic group than in controls. Diabetic group showed higher expression of TIMP-1, -4 in aortic intima and LV myocardium (P < 0.01 or P < 0.05), with increased collagen content and elevated serum BNP level (P = 0.004) and lower gelatinolytic activities of tissue MMP-2, -9 (all P < 0.05). Semi-quantitative RT-PCR of those diabetic tissues revealed elevated mRNA levels of major TIMPs, uPA, uPAR and PAI-1. Reduction of serum MMP-2 and -9 levels was observed in diabetic group vs. control group (both P < 0.05). This study features elevated levels of TIMP-1, -4, uPA, uPAR and PAI-1, and decreased activities of MMP-2, -9 in aorta and myocardium in STZ-induced diabetic minipigs, indicating that MMP-TIMP dysregulation is associated with LV hypertrophy, cardiac dysfunction and increased cardiovascular fibrosis in diabetes.
Assuntos
Diabetes Mellitus Experimental/patologia , Metaloproteinases da Matriz/metabolismo , Inibidores Teciduais de Metaloproteinases/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Animais , Aorta/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Regulação da Expressão Gênica , Ventrículos do Coração/metabolismo , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/fisiologia , Peptídeo Natriurético Encefálico/sangue , RNA Mensageiro/genética , Suínos , Porco Miniatura , Técnicas de Cultura de Tecidos , Inibidores Teciduais de Metaloproteinases/genética , Inibidores Teciduais de Metaloproteinases/fisiologia , Túnica Íntima/metabolismo , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologiaRESUMO
Lesch-Nyhan disease (LND) is caused by deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT). The aim of the present study is to characterize the molecular deficiency of a clinical diagnosed Chinese patient with attenuated variant of LND. The coding region and the intron-exon boundaries of HPRT1 gene were sequenced by standard methods, and HPRT activity was assayed by HPLC method. Structure analysis was performed to estimate the consequence of the mutant of HPRT1 gene. A new mutation c.245T>G (p.Ile82Ser) was identified in this patient, and heterozygous mutation was found in the patient's mother. The activity of HPRT in the patient was completely undetectable. Structure study indicates that the mutation of p.Ile82Ser may lead to loss of hydrophobic side chain and disrupt its normal conformation of HPRT protein. It is helpful for diagnosis of LND that sequencing analysis of HPRT1 gene is performed in male infant and juvenile with hyperuricaemia and neurologic dysfunction in Chinese.
Assuntos
Hipoxantina Fosforribosiltransferase/química , Hipoxantina Fosforribosiltransferase/genética , Síndrome de Lesch-Nyhan/genética , Adulto , China , Humanos , Masculino , Modelos Moleculares , Mutação , Adulto JovemRESUMO
BACKGROUND: Visceral adipose tissue-derived serine protease inhibitor (vaspin) is a recently identified adipokine. Studies suggest it is involved in many diseases such as obesity, diabetes and coronary artery disease (CAD). This study is to investigate the association of single nucleotide polymorphisms (SNPs) in vaspin with CAD and its potential mechanisms. METHODS: A total of 1570 consecutive patients undergoing coronary angiography were enrolled and the genotypes were determined by TaqMan allelic discrimination. Serum vaspin concentrations and mRNA expression levels were determined by ELISA and RT-PCR, respectively. Reporter gene assay was performed to investigate the effect of polymorphism on vaspin promoter function. RESULTS: After multivariate analysis, allele A of rs2236242 was found as an independent determinant of CAD (OR=1.32, p=0.004). Rs35262691 in vaspin promoter was associated with serum vaspin concentration and mRNA expression in peripheral blood mononuclear cells (PBMC) though no association had been found with CAD. Reporter gene assay further confirmed that CC genotype of rs35262691 had 2.1±0.4-fold higher activities than TT genotype in facilitating gene expression. CONCLUSIONS: Our results show that the variants of vaspin gene are associated with serum vaspin levels and risk for CAD in Chinese population.
Assuntos
Povo Asiático , Doença das Coronárias/genética , Polimorfismo de Nucleotídeo Único , Serpinas/genética , Idoso , Alelos , Doença das Coronárias/etnologia , Doença das Coronárias/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Expressão Gênica , Genes Reporter , Genótipo , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Fibroblast growth factor 21 (FGF-21) is a new metabolic regulator with beneficial effects on lipid and glucose metabolism in animal models of diabetes mellitus. The aim of this study was to explore the relationship between FGF-21 and diabetic nephropathy in humans. Serum FGF-21 levels were determined in groups of control (n = 50) and type 2 diabetes mellitus (T2DM) patients with normoalbuminuria (n = 158), microalbuminuria (n = 68), and macroalbuminuria (n = 38) using enzyme-linked immunosorbent assay. Multiple linear regression models were used to analyze the associations between FGF-21 or other biomedical indices and urinary albumin excretion (UAE). Median serum FGF-21 levels were increased in T2DM patients compared with nondiabetic controls and were significantly higher in patients of higher UAE group. In groups of control and T2DM patients with normoalbuminuria, microalbuminuria, and macroalbuminuria, median serum (interquartile range) FGF-21 levels were 467.89 (294.59-519.56), 492.30 (354.59-640.42), 595.01 (480.49-792.31), and 665.20 (448.68-829.75) ng/L (P < .001), respectively. After adjustment for the confounders, FGF-21, fasting plasma glucose, and high-density lipoprotein cholesterol levels were found to be independently associated with UAE in diabetic patients. Serum FGF-21 level is independently correlated with UAE in T2DM patients, indicating that circulating FGF-21 may be involved in diabetic nephropathy.
Assuntos
Albuminúria/sangue , Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/sangue , Fatores de Crescimento de Fibroblastos/sangue , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Advanced glycation end-products (AGEs) exert inflammatory and oxidative stress insults to produce diabetic nephropathy mainly through the receptor for AGEs (RAGE). This study aimed to assess the effect of atorvastatin on diabetic nephropathy via soluble RAGE (sRAGE) and RAGE expressions in the rat kidney. METHODS: Thirty-two male Sprague-Dawley rats were divided into four groups based on the presence or absence of streptozotocin-induced diabetes with or without atorvastatin treatment (10 mg/kg for 24 weeks). Serum sRAGE and glycated albumin (GA) levels were measured with enzyme-linked immunosorbent assay (ELISA) and improved bromocresol purple methods. Renal AGEs, RAGE, endogenous secretory RAGE (esRAGE), and sRAGE were determined with reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: Mesangial expansion and microalbuminuria were aggravated in diabetic rats, and improved with atorvastatin treatment. Serum sRAGE levels were lower in diabetic than in normal rats. After atorvastatin treatment, serum and renal sRAGE levels were up-regulated, while renal RAGE expression was decreased in diabetic rats, associated with a reduction in accumulation of AGEs, though renal esRAGE mRNA expression was not significantly increased. CONCLUSIONS: Atorvastatin exerted a beneficial effect on diabetic nephropathy with reduced AGE accumulation, down-regulating RAGE expression and up-regulating sRAGE in the kidney.
Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Regulação da Expressão Gênica , Ácidos Heptanoicos/farmacologia , Pirróis/farmacologia , Receptores Imunológicos/biossíntese , Animais , Atorvastatina , Western Blotting , Diabetes Mellitus Experimental , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Rim/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Estreptozocina/farmacologiaRESUMO
BACKGROUND: Susceptibility to coronary artery disease (CAD) and diabetes is encoded by distinct, tightly-linked single nucleotide polymorphisms on chromosome 9p21. This study aimed to examine the association of variant rs1333049 on chromosome 9p21.3 with early-onset and severity of CAD in Chinese patients with and without type 2 diabetes, and to determine the possible impact of rs1333049 on glucose metabolism and inflammation pathways. METHODS: Genotyping of variant rs1333049 on chromosome 9p21.3 was performed in 2387 patients with and without diabetes who were undergoing coronary angiography to evaluate suspected or established CAD. Serum levels of glucose, glycosylated hemoglobin A(1c) (HbA(1c)), insulin, high-sensitivity C-reactive protein, tumor necrosis factor-α, and interleukin-6 were also measured, and compared with each patient's genotype. RESULTS: The homozygous CC genotype of rs1333049 was significantly associated with CAD in diabetic (OR: 1.270, P = 0.044) and non-diabetic (OR: 1.369, P = 0.011) patients after adjusting for traditional risk factors. There was an association between CC genotype and number of diseased vessels in diabetics (P = 0.019), but not in non-diabetics (P = 0.126). Among diabetic patients, CC genotype carriers had an increased risk of early-onset CAD (OR: 2.367, P = 0.008) and greater cumulative atherosclerotic burden compared with non-CC genotype carriers (Gensini score: 31.80 ± 17.20 vs. 23.09 ± 21.63, P = 0.039). No significant differences were observed between genotypes of rs1333049 in serum levels of glucose, insulin, HbA(1c), or inflammatory cytokines for diabetic or non-diabetic patients with CAD. CONCLUSIONS: This study demonstrated a significant association of rs1333049 polymorphism on chromosome 9p21.3 with CAD in Chinese diabetic and non-diabetic patients. The homozygous CC genotype of rs1333049 confers a magnified risk of early-onset and more severe CAD in diabetic patients through a novel biological pathway unrelated to glucose metabolism or inflammation.
Assuntos
Cromossomos Humanos Par 9/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Idoso , Proteína C-Reativa/metabolismo , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Predisposição Genética para Doença/genética , Genótipo , Hemoglobinas Glicadas/metabolismo , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: The transradial approach is regarded as a useful vascular site for coronary procedures. The aim of this study was to test whether 4Fr catheters assisted by ACIST variable rate injector system can produce comparable angiographic quality and reduce the risk of radial artery injury compared to hand manifold 6 Fr catheters. METHODS: A total of 1816 patients were studied consecutively, among whom 856 patients received coronary angiography by 4 Fr catheters (4Fr group) and 960 patients by 6 Fr catheters (6Fr group). Angiographic and procedural characteristics were observed and recorded. The luminal inner radial arterial diameter before and after the procedure were collected. RESULTS: The baseline clinical characteristics were similar in both groups. There were no significant differences in procedure time, radiation dose and quality scores in both groups (P > 0.05), but more contrast media was delivered in the 6Fr group (P < 0.001). The mean radial arterial diameter six months after the procedure in the 6Fr group reduced significantly compared to that measured one day prior to the procedure (P < 0.001). CONCLUSIONS: Coronary angiography using the 4Fr catheters with Acist power injection system can achieve an acceptable diagnostic quality while at the same time minimizing radial artery injury and contrast media consumption.
Assuntos
Cateterismo Cardíaco/instrumentação , Angiografia Coronária/instrumentação , Angiografia Coronária/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Radial/diagnóstico por imagem , UltrassonografiaRESUMO
BACKGROUND AND AIMS: Engagement of the receptor for advanced glycation end products (RAGE) with advanced glycation end products and subsequent signaling play an important role in the development of diabetic complications. This pathophysiological effect was mitigated partially by endogenous secretory RAGE (esRAGE). The present study aimed to explore the possible association of RAGE polymorphism with serum esRAGE level and coronary artery disease (CAD) in Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 740 consecutive patients with T2DM undergoing coronary angiography were enrolled. The severity of coronary atherosclerosis was defined as the number of diseased vessels; 69 bp insertion/deletion was determined by polymerase chain reactions, and -429 T/C, -374A/T and G82S variants were assessed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Patients with genotypes carrying C allele of -429 T/C and G allele of G82S had significantly higher esRAGE levels. 82S allele was also associated with increased tumor necrosis factor-alpha and interleukin-6 levels in diabetic patients with CAD (all p <0.05), but none of the polymorphisms or haplotypes was related to the presence and severity of CAD. CONCLUSIONS: G82S and -429 T/C polymorphisms of RAGE were associated with the circulating levels of esRAGE but not with CAD in Chinese patients with T2DM.
Assuntos
Doença da Artéria Coronariana/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Idoso , Alelos , Proteína C-Reativa/metabolismo , China , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Feminino , Genótipo , Haplótipos/genética , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVE: This cross-sectional study tested the hypothesis that increased serum level of high mobility group box-1 protein (HMGB1), a pro-inflammatory ligand of receptor for advanced glycation end products (RAGE), is associated with coronary artery disease (CAD) in nondiabetic and type 2 diabetic patients. METHODS: Serum levels of HMGB1, endogenous secretory RAGE (esRAGE), soluble RAGE (sRAGE) and inflammatory cytokines were determined in 512 patients categorized as Group I (n=132, without diabetes and CAD), Group II (n=149, with CAD but no diabetes), Group III (n=80, with diabetes but no CAD) and Group IV (n=151, with diabetes and CAD). RESULTS: Serum levels of HMGB1 and hsCRP were higher in Group II than in Group I, and in Group IV than in Group III (all P<0.001). HMGB1 was positively related to hsCRP, TNF-alpha and IL-6 levels in the whole subjects (all P<0.01). Group II patients had lower sRAGE (P=0.058) and esRAGE (P<0.001) levels versus those in Group I. However, in the diabetic patients, those in Group IV had lower esRAGE (P<0.001) but higher sRAGE (P=0.002) levels compared to those in Group III. In multivariable regression analysis, HMGB1, esRAGE and conventional risk factors (age, smoking, hypertension, HDL-C, hsCRP, TNF-alpha) were independent determinants of CAD in nondiabetic patients. Moreover, HMGB1 and esRAGE consistently remained to be independently associated with CAD in diabetic patients, so did other major conventional risk factors. CONCLUSION: This study demonstrates that increased serum HMGB1 level is associated with CAD in nondiabetic and type 2 diabetic patients.
Assuntos
Doença da Artéria Coronariana/sangue , Diabetes Mellitus Tipo 2/sangue , Proteína HMGB1/sangue , Idoso , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico , Estudos Transversais , Citocinas/metabolismo , Complicações do Diabetes/sangue , Complicações do Diabetes/diagnóstico , Feminino , Humanos , Inflamação , Ligantes , Masculino , Pessoa de Meia-Idade , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/metabolismo , Fatores de RiscoRESUMO
BACKGROUND: This study examined whether genetic variants of matrix metallopeptidases (MMPs) and their tissue inhibitors (TIMPs) were associated with angiographic coronary plaque progression (PP) in type 2 diabetic and non-diabetic patients. METHODS: Four hundred and ninety-nine patients were grouped, who underwent coronary angiography and received repeat examinations after 1-y follow-up. Twelve functional polymorphisms of MMPs and TIMPs were characterized. RESULTS: Genotype distribution and allele frequency of -1612 5A/6A MMP-3 and 3'UTR C/T TIMP-4 differed between patients with PP and those without in both diabetic and non-diabetic groups after Bonferroni's correction (all P<0.0041667, except for allele frequency of MMP-3 [P=0.007] and genotype/allele frequency of TIMP-4 [P=0.04 and P=0.016, respectively] in diabetes). MMP-3 and TIMP-4 polymorphisms were associated with changes in percent diameter stenosis and minimal lumen diameter in diabetic patients, and changes in cumulative coronary obstruction in both diabetic and non-diabetic patients (all P<0.05). Multivariable regression analysis revealed that hypertension, low HDL-C and genotypes of MMP-3 and TIMP-4 were independent determinants of PP in the whole patients, with these 2 genetic factors being associated with PP in diabetic and non-diabetic subgroups. CONCLUSION: This study demonstrated that MMP-3 and TIMP-4 polymorphisms affect angiographic coronary PP in type 2 diabetic and non-diabetic patients.
Assuntos
Oclusão Coronária/enzimologia , Oclusão Coronária/patologia , Diabetes Mellitus Tipo 2/complicações , Metaloproteinase 3 da Matriz/genética , Polimorfismo Genético/genética , Inibidores Teciduais de Metaloproteinases/genética , Idoso , Alelos , Angiografia Coronária , Oclusão Coronária/complicações , Oclusão Coronária/genética , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Progressão da Doença , Feminino , Genótipo , Humanos , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Inibidores Teciduais de Metaloproteinases/metabolismo , Inibidor Tecidual 4 de MetaloproteinaseRESUMO
OBJECTIVE: This study evaluated the relationship between serum levels of endogenous secretory receptor for advanced glycation endproducts (esRAGE) and coronary plaque progression in diabetic and nondiabetic patients. DESIGN AND METHODS: Serum esRAGE level was measured and quantitative coronary angiography (QCA) was performed in 265 consecutive patients at baseline and 1-year follow-up. RESULTS: Comparing to baseline, serum esRAGE level was significantly increased during follow-up in nondiabetic patients without plaque progression (p=0.014), unchanged in nondiabetic patients with plaque progression and diabetic patients without plaque progression, and decreased in diabetic patients with plaque progression (p=0.011). Moreover, change of esRAGE levels correlated with change of QCA measurements. Multivariable regression analyses revealed that high-density lipoprotein cholesterol (OR=0.214, p=0.037), hypertension (OR=2.755, p=0.011), high-sensitivity C-reactive protein (OR=1.083, p<0.001) and change of esRAGE (OR=23.477, p<0.001) were independent risk factors for plaque progression in diabetic patients. CONCLUSIONS: This study demonstrated an association of decreased serum esRAGE level with coronary plaque progression in patients with diabetes.