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1.
Eur J Nutr ; 60(8): 4345-4355, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34041583

RESUMO

PURPOSE: Atherosclerosis and its related clinical complications are the leading cause of death. MicroRNA (miR)-92a in the inflammatory endothelial dysfunction leads to atherosclerosis. Krüppel-like factor 2 (KLF2) is required for vascular integrity and endothelial function maintenance. Flavonoids possess many biological properties. This study investigated the vascular protective effects of chrysin in balloon-injured carotid arteries. MATERIALS AND METHODS: Exosomes were extracted from human coronary artery endothelial cell (HCAEC) culture media. Herb flavonoids and chrysin were the treatments in these atheroprotective models. Western blotting and real-time PCRs were performed. In situ hybridization, immunohistochemistry, and immunofluorescence analyses were employed. RESULTS: MiR-92a increased after balloon injury and was present in HCAEC culture media. Chrysin was treated, and significantly attenuated the miR-92a levels after balloon injury, and similar results were obtained in HCAEC cultures in vitro. Balloon injury-induced miR-92a expression, and attenuated KLF2 expression. Chrysin increased the KLF2 but reduced exosomal miR-92a secretion. The addition of chrysin and antagomir-92a, neointimal formation was reduced by 44.8 and 49.0% compared with balloon injury after 14 days, respectively. CONCLUSION: Chrysin upregulated KLF2 expression in atheroprotection and attenuated endothelial cell-derived miR-92a-containing exosomes. The suppressive effect of miR-92a suggests that chrysin plays an atheroprotective role. Proposed pathway for human coronary artery endothelial cell (HCAEC)-derived exosomes induced by chrysin to suppress microRNA (miR)-92a expression and counteract the inhibitory effect of miR-92a on KLF2 expression in HCAECs. This provides an outline of the critical role of the herbal flavonoid chrysin, which may serve as a valuable therapeutic supplement for atheroprotection.


Assuntos
MicroRNAs , Células Endoteliais , Flavonoides/farmacologia , Humanos , Fatores de Transcrição Kruppel-Like/genética , MicroRNAs/genética
2.
J Cell Mol Med ; 24(22): 12945-12954, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32939962

RESUMO

Hyperbaric oxygen (HBO) improves angiogenesis. The effect of HBO on metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a pro-angiogenic long non-coding RNA, in cardiac myocyte-derived exosomes and acute myocardial infarction (AMI) is unknown. We aimed to investigate whether MALAT1 is altered in cardiac myocyte-derived exosomes in response to HBO as well as the molecular regulatory mechanisms of MALAT1 in cardiac myocytes treated with HBO. Cardiac myocytes were cultured, and HBO was applied at 2.5 atmosphere absolute in a hyperbaric chamber. Exosomes were extracted from the culture media. A rat model of AMI generated by the ligation of the left anterior descending artery was used. HBO significantly increased MALAT1 expression in cardiac myocytes and HBO-induced MALAT1 and exosomes attenuated miR-92a expression after myocardial infarction. Expression of krüppel-like factor 2 (KLF2) and CD31 was significantly decreased after infarction and HBO-induced exosomes significantly reversed the expression. Silencing of MALAT1 using MALAT1-locked nucleic acid GapmeR significantly attenuated KLF2 and CD31 protein expression after infarction induced by HBO-induced exosomes. HBO-induced exosomes also decreased infarct size significantly. HBO-induced exosomes from cardiac myocytes up-regulate MALAT1 to suppress miR-92a expression and counteract the inhibitory effect of miR-92a on KLF2 and CD31 expression in left ventricular myocardium after myocardial infarction to enhance neovascularization.


Assuntos
Oxigenação Hiperbárica/métodos , MicroRNAs/metabolismo , Infarto do Miocárdio/genética , RNA Longo não Codificante/genética , Animais , Modelos Animais de Doenças , Ecocardiografia , Exossomos/metabolismo , Perfilação da Expressão Gênica , Hemodinâmica , Hipóxia , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/citologia , Neovascularização Patológica , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos , Ratos Wistar
3.
Am J Chin Med ; 48(2): 341-356, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32138537

RESUMO

MicroRNA 145 (miR-145) is a critical modulator of cardiovascular diseases. The downregulation of myocardial miR-145 is followed by an increase in disabled-2 (Dab2) expression in cardiomyocytes. (-)-epigallocatechin gallate (EGCG) is a flavonoid that has been evaluated extensively due to its diverse pharmacological properties including anti-inflammatory effects. The aim of this study was to investigate the cardioprotective effects of EGCG under hypoxia-induced stress in vitro and in vivo. The hypoxic insult led to the suppression of miR-145 expression in cultured rat cardiomyocytes in a concentration-dependent manner. Western blotting and real-time PCR were performed. In rat myocardial infarction study, in situ hybridization, and immunofluorescent analyses were adopted. The western blot and real-time PCR data revealed that hypoxic stress with 2.5% O2 suppressed the expression of miR-145 and Wnt3a/ß-catenin in cultured rat cardiomyocytes but augmented Dab2. Treatment with EGCG attenuated Dab2 expression, but increased Wnt3a and ß-catenin in hypoxic cultured cardiomyocytes. Following in vivo myocardial infarction (MI) study, the data revealed the myocardial infarct area reduced by 48.5%, 44.6%, and 48.5% in EGCG (50mg/kg) or miR-145 dominant or Dab2 siRNA groups after myocardial infarction for 28 days, respectively. This study demonstrated that EGCG increased miR-145, Wnt3a, and ß-catenin expression but attenuated Dab2 expression. Moreover, EGCG ameliorated myocardial ischemia in vivo. The novel suppressive effect was mediated through the miR-145 and Dab2/Wnt3a/ß-catenin pathways.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Catequina/análogos & derivados , Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , MicroRNAs/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/genética , Miócitos Cardíacos/metabolismo , Fitoterapia , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Animais , Catequina/farmacologia , Catequina/uso terapêutico , Células Cultivadas , Relação Dose-Resposta a Droga , Ratos
4.
Planta Med ; 85(5): 406-411, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30609436

RESUMO

Catalpol, an iridoid glycoside, is an isolated natural product of Rehmannia glutinosa, which has been reported to have antidiabetic properties. This study investigated the vascular protective effects of catalpol in hyperglycemic rats with balloon-injured carotid arteries. Balloon injury stress led to the upregulation of monocyte chemoattractant protein-1 expression in rats with streptozotocin-induced diabetes. Western blotting and real-time PCR were performed. In situ hybridization, immunohistochemistry, and confocal analyses were employed. Monocyte chemoattractant protein-1 levels were increased through streptozotocin induction or balloon injury. After treatment with catalpol, the neointimal hyperplasia area was reduced 2 weeks after balloon injury in hyperglycemic rats. Real-time PCR and immunohistochemical analysis demonstrated reduced levels of monocyte chemoattractant protein-1 2 weeks after the balloon injury. Monocyte chemoattractant protein-1 expression was significantly increased in balloon-injured rats compared with the control groups. Thus, treatment with catalpol affected monocyte chemoattractant protein-1 expression. This study demonstrated that catalpol downregulated monocyte chemoattractant protein-1 expression in carotid arteries and ameliorated neointimal hyperplasia in hyperglycemic rats. The suppressive effect of monocyte chemoattractant protein-1 suggests that it plays a key role in neointimal hyperplasia. The results imply that catalpol is potentially effective for preventing hyperglycemia-related ischemic cardiac diseases.


Assuntos
Quimiocina CCL2/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Hipoglicemiantes/farmacologia , Glucosídeos Iridoides/farmacologia , Neointima/patologia , Rehmannia/química , Animais , Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/tratamento farmacológico , Lesões das Artérias Carótidas/patologia , Quimiocina CCL2/efeitos dos fármacos , Quimiocina CCL2/genética , Modelos Animais de Doenças , Hiperglicemia/complicações , Hiperplasia/tratamento farmacológico , Masculino , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/prevenção & controle , Ratos , Ratos Wistar , Estreptozocina
5.
Int J Cardiol ; 274: 271-278, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30301563

RESUMO

BACKGROUND: Hyperbaric oxygen (HBO) could improve wound healing by enhancement of angiogenesis. The effect of HBO on metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a proangiogenic long noncoding RNA, and on endothelial cell-derived exosome is unknown. We aim to investigate both whether MALAT1 is altered in human coronary artery endothelial cells (HCAECs)-derived exosomes in response to HBO as well as the molecular regulatory mechanisms of MALAT1 in HCAECs under HBO treatment. METHODS AND RESULTS: HCAECs were cultured and HBO was applied at 2.5 atmosphere absolute (ATA) in a hyperbaric chamber. Exosomes were extracted from culture media. A rat model of hind-limb ischemia was performed by ligation of the right femoral artery. HBO at 2.5 ATA significantly increased MALAT1 expression in HCAECs and HCAECs-derived exosomes. MALAT1 suppressed miR-92a expression in HCAEC-derived exosomes under HBO. Silencing MALAT1 by MALAT1 siRNA significantly inhibited KLF2 mRNA expression induced by HBO, as did MiR-92a. MiR-92a significantly decreased KLF2 luciferase activity in HCAECs under HBO. HBO and HBO-induced exosomes significantly increased cell proliferation and the capillary-like network formation of HCAECs. MALAT1 siRNA and miR-92a overexpression significantly attenuated the cell proliferation and tube formation caused by HBO-induced exosome. HBO and HBO-induced exosomes significantly improved neovascularization in a rat model of hind-limb ischemia. CONCLUSIONS: HBO upregulates MALAT1 to suppress miR-92a expression and counteracts the inhibitory effect of miR-92a on KLF2 expression in HCAECs to enhance neovascularization. HBO-induced derivation of exosomes from HCAECs enhances angiogenesis. Exosomes containing MALAT1 might serve as a valuable therapeutic tool for neovascularization by HBO.


Assuntos
Vasos Coronários/metabolismo , Endotélio Vascular/metabolismo , Oxigenação Hiperbárica/métodos , MicroRNAs/genética , Isquemia Miocárdica/genética , RNA Longo não Codificante/genética , Animais , Western Blotting , Proliferação de Células , Células Cultivadas , Vasos Coronários/patologia , Modelos Animais de Doenças , Endotélio Vascular/patologia , Exossomos/metabolismo , Humanos , Masculino , MicroRNAs/biossíntese , Isquemia Miocárdica/patologia , Isquemia Miocárdica/terapia , Neovascularização Fisiológica/genética , RNA/genética , RNA Longo não Codificante/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
6.
J Nutr Biochem ; 52: 27-35, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29127880

RESUMO

MicroRNA 145 (miR-145) is a critical modulator of vascular smooth muscle cell (VSMC) phenotyping and proliferation. Flavonoids have been studied extensively due to their diverse pharmacological properties, including anti-inflammatory effects. The aims of this study is designed to evaluate the atheroprotective effects on angiotensin II (Ang II)-induced miR-145 and Klf4/myocardin expression in vitro and in vivo of flavonoids, including (-)-epigallocatechin gallate (EGCG), chrysin, wogonin, silibinin, and ferulic acid. Ang II significantly reduced the miR-145 compared with the control VSMC groups; all the tested flavonoids increased miR-145 in the 100 nM concentration. Among the test compounds, EGCG showed the strongest augmenting effect on miR-145 and myocardin, however, it also abolished Ang II-induced Klf4. A [3H]-thymidine incorporation proliferation assay demonstrated that EGCG inhibited Ang II-induced VSMC proliferation, and Klf4 siRNA presented with the similar results. Immunohistochemical analysis and confocal microscopy demonstrated increased Klf4 expression and the arterial lumen was narrowed after balloon injury 14 days. With the addition of EGCG (50 mg/kg) and Klf4 siRNA, neointimal formation was reduced by 40.7% and 50.5% compared with balloon injury 14 days; Klf4 expression also was attenuated. This study demonstrated EGCG increased miR-145 and attenuated Klf4, and ameliorated neointimal formation in vitro and in vivo. The novel suppressive effect was mediated through the miR-145 and Klf4/myocardin pathways.


Assuntos
Flavonoides/farmacologia , Fatores de Transcrição Kruppel-Like/genética , MicroRNAs/genética , Neointima/tratamento farmacológico , Proteínas Nucleares/genética , Transativadores/genética , Angioplastia com Balão/efeitos adversos , Angiotensina II/farmacologia , Animais , Artérias Carótidas/cirurgia , Lesões das Artérias Carótidas/tratamento farmacológico , Catequina/análogos & derivados , Catequina/farmacologia , Células Cultivadas , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Neointima/genética , Proteínas Nucleares/metabolismo , RNA Interferente Pequeno , Ratos Wistar , Reprodutibilidade dos Testes , Transativadores/metabolismo
7.
EBioMedicine ; 2(6): 583-90, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26288819

RESUMO

Air pollution has been classified as Group 1 carcinogenic to humans, but the underlying tumorigenesis remains unclear. In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China attributed to severe air pollution generated by combustion of smoky coal, providing a unique opportunity to dissect lung carcinogenesis of air pollution. Here we analyzed the somatic mutations of 164 non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used. Whole genome sequencing revealed a mean of 289 somatic exonic mutations per tumor and the frequent C:G â†’ A:T nucleotide substitutions in Xuanwei NSCLCs. Exome sequencing of 2010 genes showed that Xuanwei and CR NSCLCs had a mean of 68 and 22 mutated genes per tumor, respectively (p < 0.0001). We found 167 genes (including TP53, RYR2, KRAS, CACNA1E) which had significantly higher mutation frequencies in Xuanwei than CR patients, and mutations in most genes in Xuanwei NSCLCs differed from those in CR cases. The mutation rates of 70 genes (e.g., RYR2, MYH3, GPR144, CACNA1E) were associated with patients' lifetime benzo(a)pyrene exposure. This study uncovers the mutation spectrum of air pollution-related lung cancers, and provides evidence for pollution exposure-genomic mutation relationship at a large scale.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Benzo(a)pireno/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Idoso , Sequência de Bases , Carcinoma Pulmonar de Células não Pequenas/induzido quimicamente , Transformação Celular Neoplásica , Carvão Mineral/efeitos adversos , Exposição Ambiental/efeitos adversos , Feminino , Frequência do Gene/genética , Genoma/genética , Humanos , Neoplasias Pulmonares/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Mutação/genética , Taxa de Mutação , Análise de Sequência de DNA , Fumaça/efeitos adversos
8.
Nat Genet ; 47(9): 1061-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26192917

RESUMO

Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56(+) and cytoCD3(+) lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.


Assuntos
RNA Helicases DEAD-box/genética , Exoma , Linfoma de Células T/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Ciclo Celular , Análise Mutacional de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células T/mortalidade , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Prognóstico , Transdução de Sinais , Dissomia Uniparental/genética , Adulto Jovem
9.
EBioMedicine ; 2(11): 1718-24, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26870797

RESUMO

Adipokines such as leptin play important roles in the regulation of energy metabolism, particularly in the control of appetite. Here, we describe a hormone, mimecan, which is abundantly expressed in adipose tissue. Mimecan was observed to inhibit food intake and reduce body weight in mice. Intraperitoneal injection of a mimecan-maltose binding protein (-MBP) complex inhibited food intake in C57BL/6J mice, which was attenuated by pretreatment with polyclonal antibody against mimecan. Notably, mimecan-MBP also induced anorexia in A(y)/a and db/db mice. Furthermore, the expression of interleukin (IL)-1ß and IL-6 was up-regulated in the hypothalamus by mimecan-MBP, as well as in N9 microglia cells by recombinant mouse mimecan. Taken together, the results suggest that mimecan is a satiety hormone in adipose tissue, and that mimecan inhibits food intake independently of leptin signaling by inducing IL-1ß and IL-6 expression in the hypothalamus.


Assuntos
Tecido Adiposo/metabolismo , Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Leptina/metabolismo , Transdução de Sinais , Animais , Peso Corporal , Ingestão de Alimentos , Humanos , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Leptina/genética , Camundongos , Camundongos Knockout , Microglia/metabolismo , Ratos
10.
Hum Mol Genet ; 23(20): 5505-17, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24852370

RESUMO

Thyroid-stimulating hormone (TSH) is a sensitive indicator of thyroid function. High and low TSH levels reflect hypothyroidism and hyperthyroidism, respectively. Even within the normal range, small differences in TSH levels, on the order of 0.5-1.0 mU/l, are associated with significant differences in blood pressure, BMI, dyslipidemia, risk of atrial fibrillation and atherosclerosis. Most of the variance in TSH levels is thought to be genetically influenced. We conducted a genome-wide association study of TSH levels in 1346 Chinese Han individuals. In the replication study, we genotyped four candidate SNPs with the top association signals in an independent isolated Chinese She cohort (n = 3235). We identified a novel serum TSH susceptibility locus within XKR4 at 8q12.1 (rs2622590, Pcombined = 2.21 × 10(-10)), and we confirmed two previously reported TSH susceptibility loci near FOXE1 at 9q22.33 and near CAPZB at 1p36.13, respectively. The rs2622590_T allele at XKR4 and the rs925489_C allele near FOXE1 were correlated with low TSH levels and were found to be nominally associated to patients with papillary thyroid carcinoma (PTC) (OR = 1.41, P= 0.014 for rs2622590_T, and OR = 1.61, P= 0.030 for rs925489_C). The rs2622590 and rs925489 genotypes were also correlated with the expression levels of FOXE1 and XKR4, respectively, in PTC tissues (P = 2.41 × 10(-4) and P= 0.02). Our findings suggest that the SNPs in XKR4 and near FOXE1 are involved in the regulation of TSH levels.


Assuntos
Carcinoma/genética , Fatores de Transcrição Forkhead/genética , Hipotireoidismo/genética , Proteínas de Membrana Transportadoras/genética , Neoplasias da Glândula Tireoide/genética , Tireotropina/sangue , Proteínas Reguladoras de Apoptose , Grupo com Ancestrais do Continente Asiático/genética , Proteína de Capeamento de Actina CapZ/genética , Carcinoma Papilar , China , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 9/genética , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana , Polimorfismo de Nucleotídeo Único , Câncer Papilífero da Tireoide , Tireotropina/genética
11.
Proc Natl Acad Sci U S A ; 111(23): 8589-94, 2014 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24850867

RESUMO

Myelodysplastic syndrome (MDS) includes a group of diseases characterized by dysplasia of bone marrow myeloid lineages with ineffective hematopoiesis and frequent evolution to acute myeloid leukemia (AML). Whole-genome sequencing was performed in CD34(+) hematopoietic stem/progenitor cells (HSPCs) from eight cases of refractory anemia with excess blasts (RAEB), the high-risk subtype of MDS. The nucleotide substitution patterns were found similar to those reported in AML, and mutations of 96 protein-coding genes were identified. Clonal architecture analysis revealed the presence of subclones in six of eight cases, whereas mutation detection of CD34(+) versus CD34(-) cells revealed heterogeneity of HSPC expansion status. With 39 marker genes belonging to eight functional categories, mutations were analyzed in 196 MDS cases including mostly RAEB (n = 89) and refractory cytopenia with multilineage dysplasia (RCMD) (n = 95). At least one gene mutation was detected in 91.0% of RAEB, contrary to that in RCMD (55.8%), suggesting a higher mutational burden in the former group. Gene abnormality patterns differed between MDS and AML, with mutations of activated signaling molecules and NPM1 being rare, whereas those of spliceosome more common, in MDS. Finally, gene mutation profiles also bore prognostic value in terms of overall survival and progression free survival.


Assuntos
Genoma Humano/genética , Genômica/métodos , Células-Tronco Hematopoéticas/metabolismo , Mutação , Síndromes Mielodisplásicas/genética , Antígenos CD34/metabolismo , Biomarcadores Tumorais/genética , Diferenciação Celular/genética , Proliferação de Células , Evolução Clonal , Feminino , Humanos , Estimativa de Kaplan-Meier , Cariotipagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/diagnóstico , Prognóstico , Análise de Sequência de DNA/métodos
12.
Hum Genet ; 133(5): 661-71, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24346624

RESUMO

The BACH2 gene regulates B cell differentiation and function and has been reported to be a shared susceptibility gene for several autoimmune diseases. Our previous genome-wide association study (GWAS) indicated that several single nucleotide polymorphisms (SNPs) in the BACH2 gene are associated with Graves' disease (GD) in the Chinese Han population; however, the association did not achieve genome-wide significance levels. Recently, this association of BACH2 with GD was confirmed in Caucasians in the UK population, but fine mapping in this region has not yet been reported. Here, we provide a refined analysis of a 331-kb region in the BACH2 gene, which harbors 359 SNPs, using GWAS data from 1,442 GD patients and 1,468 controls. The SNPs rs2474619 and rs9344996 were implied as the independent variants associated with GD by forward and two-locus logistic regression analysis. We genotyped eight out of 10 tagSNPs with P < 1 × 10(-3) in 3,508 GD patients and 3,209 controls, the results also showed that rs2474619 was independently associated with GD in the combined population from GWAS and the second stage (P = 1.81 × 10(-5)). The rs2474619 and rs9344996 were further genotyped in the third stage cohorts, and rs2474619 showed evidence of association with GD at genome-wide significance levels in the combined population (P = 3.28 × 10(-8), odds ratio = 1.13). The association of rs9344996 with GD can be explained by its linkage to rs2474619 in the combined population. Our study clearly demonstrated that BACH2 is a susceptibility gene for GD in the Chinese Han population and further supported rs2474619, in intron 2 of BACH2, is the best association signal with GD. However, the mechanism by which BACH2 confers increased risk of GD requires further study.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Grupos Étnicos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença de Graves/genética , Doenças Autoimunes/genética , Sequência de Bases , China , Primers do DNA , Humanos , Modelos Logísticos , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real
13.
Eur J Endocrinol ; 170(1): 109-19, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24144966

RESUMO

BACKGROUND: Convincing evidence has demonstrated the association of TSH receptor (TSHR) with Graves' disease (GD) in the Chinese Han population. OBJECTIVE: The aim of this study was to identify the causal variants for GD in the region encompassing TSHR by a refining association study. DESIGN AND METHODS: GD patients (1536) and 1516 sex-matched controls were recruited in the first stage, and an additional 3832 GD patients and 3426 sex-matched controls were recruited in the replication stage. Genotyping was performed using Illumina Human660-Quad BeadChips or TaqMan single nucleotide polymorphism (SNP) Genotyping Assays and the Fluidigm EP1 platform. RESULTS: When the results of regression analysis for 74 genotyped SNPs and 922 imputed SNPs in the first-stage cohort were combined, rs179243 and rs3783949 were the probable susceptibility SNPs associated with GD in TSHR. Eleven SNPs, including rs179243 and rs3783949, were selected to further refine the association in the replication study. Finally, rs12101261 and rs179243 were confirmed as independent GD susceptibility variants in the replication and combined populations. Further, we also found that the rate of persistent TSHR autoantibody positivity (pTRAb+) was significantly higher in the GD patients with the susceptible genotypes rs12101261 or rs179243 than in the GD patients carrying the protective genotypes, after the GD patients had been treated for more than 1 year. CONCLUSIONS: These findings indicate that rs12101261 and rs179243 are the possible causal SNPs for GD susceptibility in the TSHR gene and could serve as genetic markers to predict the outcome of pTRAb+ in GD patients.


Assuntos
Predisposição Genética para Doença , Doença de Graves/genética , Polimorfismo de Nucleotídeo Único , Receptores da Tireotropina/genética , Antitireóideos/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China , Estudos de Coortes , Terapia Combinada , Resistência a Medicamentos , Feminino , Estudos de Associação Genética , Loci Gênicos , Doença de Graves/imunologia , Doença de Graves/metabolismo , Doença de Graves/terapia , Humanos , Imunoglobulinas Glândula Tireoide-Estimulantes/análise , Radioisótopos do Iodo/uso terapêutico , Masculino , Compostos Radiofarmacêuticos/uso terapêutico , Receptores da Tireotropina/antagonistas & inibidores , Receptores da Tireotropina/metabolismo , Reprodutibilidade dos Testes
14.
Chin Med J (Engl) ; 126(23): 4403-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24286397

RESUMO

BACKGROUND: Interleukin-13 (IL-13) has been implicated to be responsible for recruitment of inflammatory cells from the blood to the lung, regulation of matrix metalloproteinase and induction of mucin production and secretion in chronic obstructive pulmonary disease (COPD). We determined plasma IL-13 levels in patients with COPD and investigated its association with common polymorphisms of IL-13 gene in a case-control study. METHODS: We genotyped 160 cases and 175 control subjects in a local hospital using Mass-Array(TM) Technology Platform then tested the association of four SNPs in IL-13 (rs1295685, rs1800925, rs1881457, rs20541) with COPD, and then determined plasma IL-13 levels in patients with COPD and controls. RESULTS: Association was found between IL-13 gene SNPs (rs20541 and rs1800925) and an increased risk of COPD. By linkage disequilibrium (LD) analysis, two blocks (rs1881457 and rs1800925; rs20541 and rs1295685) were found. The risk of COPD was found associated with the IL-13 gene polymorphism among southern Chinese Han population. Plasma IL-13 level was increased in COPD patients compared with controls. CONCLUSIONS: The polymorphism of the IL-13 gene is associated with an increased risk of COPD in southern Chinese Han population. Plasma IL-13 levels were found elevated in patients with COPD.


Assuntos
Interleucina-13/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
15.
Int J Oncol ; 43(3): 755-64, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23799614

RESUMO

Squamous cell lung cancer is a major histotype of non-small cell lung cancer (NSCLC) that is distinct from lung adenocarcinoma. We used whole-exome sequencing to identify novel non-synonymous somatic mutations in squamous cell lung cancer. We identified 101 single-nucleotide variants (SNVs) including 77 non-synonymous SNVs (67 missense and 10 nonsense mutations) and 11 INDELs causing frameshifts. We also found four SNVs located within splicing sites. We verified 62 of the SNVs (51 missense, 10 nonsense and 1 splicing-site mutation) and 10 of the INDELs as somatic mutations in lung cancer tissue. Sixteen of the mutated genes were also mutated in at least one patient with a different type of lung cancer in the Catalogue of Somatic Mutation in Cancer (COSMIC) database. Four genes (LPHN2, TP53, MYH2 and TGM2) were mutated in approximately 10% of the samples in the COSMIC database. We identified two missense mutations in C10orf137 and MS4A3 that also occurred in other solid-tumor tissues in the COSMIC database. We found another somatic mutation in EP300 that was mutated in 4.2% of the 2,020 solid-tumor samples in the COSMIC database. Taken together, our results implicate TP53, EP300, LPHN2, C10orf137, MYH2, TGM2 and MS4A3 as potential driver genes of squamous cell lung cancer.


Assuntos
Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Exoma , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Sítios de Splice de RNA/genética , Análise de Sequência de DNA/métodos
16.
J Mol Endocrinol ; 51(1): 37-48, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23549407

RESUMO

There is a high incidence of metabolic syndrome among patients with primary aldosteronism (PA), which has recently been associated with an unfavorable cardiometabolic profile. However, the underlying mechanisms have not been clarified in detail. Characterizing aldosterone (Ald) target genes in adipocytes will help us to elucidate the deleterious effects associated with excess Ald. Apelin, a novel adipokine, exerts beneficial effects on obesity-associated disorders and cardiovascular homeostasis. The objective of this study was to investigate the effects of high Ald levels on apelin expression and secretion and the underlying mechanisms involved in adipocytes. In vivo, a single-dose Ald injection acutely decreased apelin serum levels and adipose tissue apelin production, which demonstrates a clear inverse relationship between the levels of plasma Ald and plasma apelin. Experiments using 3T3-L1 adipocytes showed that Ald decreased apelin expression and secretion in a time- and dose-dependent manner. This effect was reversed by glucocorticoid receptor (GR) antagonists or GR (NR3C1) knockdown; furthermore, putative HREs were identified in the apelin promoter. Subsequently, we verified that both glucocorticoids and mineralocorticoids regulated apelin expression through GR activation, although no synergistic effect was observed. Additionally, detailed potential mechanisms involved a p38 MAPK signaling pathway. In conclusion, our findings strengthen the fact that there is a direct interaction between Ald and apelin in adipocytes, which has important implications for hyperaldosteronism or PA-associated cardiometabolic syndrome and hoists apelin on the list of potent therapeutic targets for PA.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Aldosterona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células 3T3-L1 , Adipocinas , Aldosterona/administração & dosagem , Animais , Apelina , Relação Dose-Resposta a Droga , Glucocorticoides/farmacologia , Masculino , Camundongos , Mineralocorticoides/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Hum Mol Genet ; 22(16): 3347-62, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23612905

RESUMO

Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identify new risk loci for GD and found genome-wide significant associations in the overall populations for five novel susceptibility loci: the GPR174-ITM2A at Xq21.1, C1QTNF6-RAC2 at 22q12.3-13.1, SLAMF6 at 1q23.2, ABO at 9q34.2 and an intergenic region harboring two non-coding RNAs at 14q32.2 and one previous indefinite locus, TG at 8q24.22 (Pcombined < 5 × 10(-8)). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number of GD loci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD.


Assuntos
Predisposição Genética para Doença , Doença de Graves/genética , RNA não Traduzido/genética , Fatores de Necrose Tumoral/genética , Sistema ABO de Grupos Sanguíneos/genética , Adulto , Antígenos CD/genética , Sequência de Bases , Estudos de Casos e Controles , Colágeno , DNA Intergênico , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas G/genética , Família de Moléculas de Sinalização da Ativação Linfocitária , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária
18.
PLoS One ; 8(3): e57758, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23505439

RESUMO

To pinpoint the exact location of the etiological variant/s present at 1q21.1 harboring FCRL1-5 and CD5L genes, we carried out a refined association study in the entire FCRL region in 1,536 patients with Graves' disease (GD) and 1,516 sex-matched controls by imputation analysis, logistic regression, and cis-eQTL analysis. Among 516 SNPs with P<0.05 in the initial GWAS scan, the strongest signals associated with GD and correlated to FCRL3 expression were located at a cluster of SNPs including rs7528684 and rs3761959. And the allele-specific effects for rs3761959 and rs7528684 on FCRL3 expression level revealed that the risk alleles A of rs3761959 and C of rs7528684 were correlated with the elevated expression level of FCRL3 whether in PBMCs or its subsets, especially in CD19(+) B cells and CD8(+) T subsets. Next, the combined analysis with 5,300 GD cases and 4,916 control individuals confirmed FCRL3 was a susceptibility gene of GD in Chinese Han populations, and rs3761959 and rs7528684 met the genome-wide association significance level (P(combined) = 2.27×10(-12) and 7.11×10(-13), respectively). Moreover, the haplotypes with the risk allele A of rs3761959 and risk allele C of rs7528684 were associated with GD risk. Finally, our epigenetic analysis suggested the disease-associated C allele of rs7528684 increased affinity for NF-KB transcription factor. Above data indicated that FCRL3 gene and its proxy SNP rs7528684 may be involved in the pathogenesis of GD by excessive inhibiting B cell receptor signaling and the impairment of suppressing function of Tregs.


Assuntos
Estudo de Associação Genômica Ampla , Doença de Graves/genética , Receptores Fc/genética , Cromossomos Humanos Par 1 , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
19.
Gene ; 516(2): 345-50, 2013 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-23291414

RESUMO

Mutations of CYP17A1 gene could cause complete or partial, combined or isolated 17α-hydroxylase/17,20-lyase enzyme deficiencies (17OHD). We intended to investigate the CYP17A1 mutation in five unrelated patients and analyze its possible influence on phenotype of an atypical 17OHD patient presented with micropenis, hypertension and intermittent hypokalemia. Steroid hormones were assayed in these patients. A novel missense mutation (c.1169C>G, p. Thr390Arg) located in exon 7 was detected in one of the patients. Homozygous c. 985_987delinsAA, p. Tyr329fs mutation was found in two patients, while compound heterozygous mutations (c. 985_987delinsAA, p. Tyr329fs/c. 932-939 del, p. Val311fs and c. 287G>A, p. Arg96Gln/c. 985_987delinsAA, p. Tyr329fs) were found in two other patients, respectively. Then, steric model analysis of CYP17A1 showed that the novel mutation T390R changed the local structure as well as the electrostatic potential of the nearby beta sheet. Finally, site-directed mutagenesis and in vitro expression were used to analyze the activity of novel mutant CYP17A1. It indicated the T390R mutant retained part of enzyme activity, which was consistent to the clinical features. In conclusion, we identified a novel missense mutation of CYP17A1 gene from a patient with micropenis, hypertension and intermittent hypokalemia, which varied from other four patients. It also expanded our understanding of genotype-phenotype correlation of the disease.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Grupo com Ancestrais do Continente Asiático/genética , Mutação de Sentido Incorreto , Esteroide 17-alfa-Hidroxilase/genética , Adolescente , Hiperplasia Suprarrenal Congênita/etnologia , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Consanguinidade , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Mutação de Sentido Incorreto/fisiologia , Esteroide 17-alfa-Hidroxilase/química , Adulto Jovem
20.
Clin Endocrinol (Oxf) ; 79(2): 267-74, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23170961

RESUMO

OBJECTIVE: Associations between IL2RA and various autoimmune diseases have been reported in Caucasians. We investigated whether genetic polymorphisms at the IL2RA locus were associated with Graves' disease (GD) in the Chinese Han population. DESIGN: We performed a genome-wide association study (GWAS) in 1 536 GD patients and 1 516 controls. The 1000 Genomes Project data were adopted as references for imputation analysis. After forward and conditional logistic regressions, we found that rs11256313 was the major risk variant in the CD25/IL2RA region. Thus, we further genotyped rs11256313 in a replication cohort with 3 694 GD patients and 3 510 controls using ABI 7900HT TaqMan Real-Time PCR System. RESULTS: Nine single nucleotide polymorphisms (SNPs) in the IL2RA block were nominally associated with GD in our GWAS (0·01 < P < 0·05). After imputation analysis, 13 imputed SNPs in the IL2RA block were weakly associated with GD (P ≤ 0·05). Logistic regression analysis suggested that the imputed rs11256313 could represent the IL2RA block (P = 0·003). However, we failed to replicate the association of rs11256313 in a larger cohort (P = 0·145). A subphenotype analysis of rs11256313 on thyroid hormone receptor antibody (TRAb) and gender showed that there was no association in any of the subphenotype groups (P > 0·05). CONCLUSIONS: The results suggested that common genetic polymorphisms at IL2RA do not exert a significant genetic effect on the development of GD in the Chinese Han population. Previously reported associations between CD25/IL2RA and autoimmune diseases including GD in Caucasians again imply that heterogeneity exists in different ethnic populations.


Assuntos
Doença de Graves/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Grupo com Ancestrais do Continente Asiático/genética , China/epidemiologia , Grupos Étnicos/genética , Estudo de Associação Genômica Ampla , Genótipo , Doença de Graves/epidemiologia , Humanos , Polimorfismo de Nucleotídeo Único
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