Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 243
Filtrar
1.
J Immunol ; 204(6): 1674-1688, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32060138

RESUMO

Notch signaling is emerging as a critical regulator of T cell activation and function. However, there is no reliable cell surface indicator of Notch signaling across activated T cell subsets. In this study, we show that Notch signals induce upregulated expression of the Gcnt1 glycosyltransferase gene in T cells mediating graft-versus-host disease after allogeneic bone marrow transplantation in mice. To determine if Gcnt1-mediated O-glycosylation could be used as a Notch signaling reporter, we quantified the core-2 O-glycoform of CD43 in multiple T cell subsets during graft-versus-host disease. Pharmacological blockade of Delta-like Notch ligands abrogated core-2 O-glycosylation in a dose-dependent manner after allogeneic bone marrow transplantation, both in donor-derived CD4+ and CD8+ effector T cells and in Foxp3+ regulatory T cells. CD43 core-2 O-glycosylation depended on cell-intrinsic canonical Notch signals and identified CD4+ and CD8+ T cells with high cytokine-producing ability. Gcnt1-deficient T cells still drove lethal alloreactivity, showing that core-2 O-glycosylation predicted, but did not cause, Notch-dependent T cell pathogenicity. Using core-2 O-glycosylation as a marker of Notch signaling, we identified Ccl19-Cre+ fibroblastic stromal cells as critical sources of Delta-like ligands in graft-versus-host responses irrespective of conditioning intensity. Core-2 O-glycosylation also reported Notch signaling in CD8+ T cell responses to dendritic cell immunization, Listeria infection, and viral infection. Thus, we uncovered a role for Notch in controlling core-2 O-glycosylation and identified a cell surface marker to quantify Notch signals in multiple immunological contexts. Our findings will help refine our understanding of the regulation, cellular source, and timing of Notch signals in T cell immunity.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Linfócitos T CD8-Positivos/metabolismo , Doença Enxerto-Hospedeiro/imunologia , N-Acetilglucosaminiltransferases/metabolismo , Receptores Notch/metabolismo , Animais , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Citometria de Fluxo/métodos , Glicosilação/efeitos dos fármacos , Humanos , Leucossialina/metabolismo , Ligantes , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Sensibilidade e Especificidade , Sialomucinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Estromais/imunologia , Células Estromais/metabolismo , Transplante Homólogo/efeitos adversos , Regulação para Cima
2.
J Immunol ; 203(2): 557-568, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31182480

RESUMO

Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic cell transplantation. Notch signals delivered during the first 48 h after transplantation drive proinflammatory cytokine production in conventional T cells (Tconv) and inhibit the expansion of regulatory T cells (Tregs). Short-term Notch inhibition induces long-term GVHD protection. However, it remains unknown whether Notch blockade blunts GVHD through its effects on Tconv, Tregs, or both and what early Notch-regulated molecular events occur in alloantigen-specific T cells. To address these questions, we engineered T cell grafts to achieve selective Notch blockade in Tconv versus Tregs and evaluated their capacity to trigger GVHD in mice. Notch blockade in Tconv was essential for GVHD protection as GVHD severity was similar in the recipients of wild-type Tconv combined with Notch-deprived versus wild-type Tregs. To identify the impact of Notch signaling on the earliest steps of T cell activation in vivo, we established a new acute GVHD model mediated by clonal alloantigen-specific 4C CD4+ Tconv. Notch-deprived 4C T cells had preserved early steps of activation, IL-2 production, proliferation, and Th cell polarization. In contrast, Notch inhibition dampened IFN-γ and IL-17 production, diminished mTORC1 and ERK1/2 activation, and impaired transcription of a subset of Myc-regulated genes. The distinct Notch-regulated signature had minimal overlap with known Notch targets in T cell leukemia and developing T cells, highlighting the specific impact of Notch signaling in mature T cells. Our findings uncover a unique molecular program associated with the pathogenic effects of Notch in T cells at the earliest stages of GVHD.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Isoantígenos/imunologia , Receptores Notch/imunologia , Animais , Transplante de Medula Óssea/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Transplante Homólogo/efeitos adversos
3.
Blood ; 132(20): 2188-2200, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30181175

RESUMO

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) and remains an area of unmet clinical need with few treatment options available. Notch blockade prevents acute GVHD in multiple mouse models, but the impact of Notch signaling on cGVHD remains unknown. Using genetic and antibody-mediated strategies of Notch inhibition, we investigated the role of Notch signaling in complementary mouse cGVHD models that mimic several aspects of human cGVHD in search of candidate therapeutics. In the B10.D2→BALB/c model of sclerodermatous cGVHD, Delta-like ligand 4 (Dll4)-driven Notch signaling was essential for disease development. Antibody-mediated Dll4 inhibition conferred maximum benefits when pursued early in a preventative fashion, with anti-Dll1 enhancing early protection. Notch-deficient alloantigen-specific T cells showed no early defects in proliferation or helper polarization in vivo but subsequently exhibited markedly decreased cytokine secretion and enhanced accumulation of FoxP3+ regulatory T cells. In the B6→B10.BR major histocompatibility complex-mismatched model with multi-organ system cGVHD and prominent bronchiolitis obliterans (BO), but not skin manifestations, absence of Notch signaling in T cells provided long-lasting disease protection that was replicated by systemic targeting of Dll1, Dll4, or both Notch ligands, even during established disease. Notch inhibition decreased target organ damage and germinal center formation. Moreover, decreased BO-cGVHD was observed upon inactivation of Notch1 and/or Notch2 in T cells. Systemic targeting of Notch2 alone was safe and conferred therapeutic benefits. Altogether, Notch ligands and receptors regulate key pathogenic steps in cGVHD and emerge as novel druggable targets to prevent or treat different forms of cGVHD.


Assuntos
Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas de Membrana/imunologia , Receptores Notch/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/imunologia , Bronquiolite Obliterante/patologia , Proteínas de Ligação ao Cálcio , Doença Crônica , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Isoantígenos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia , Linfócitos T/patologia , Transplante Homólogo/efeitos adversos
4.
J Immunol ; 199(2): 643-655, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28615417

RESUMO

Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen but the cell signaling pathways that drive T cell responses regulating antifungal immunity are incompletely understood. Notch is a key signaling pathway regulating T cell development, and differentiation and functional responses of mature T cells in the periphery. The targeting of Notch signaling within T cells has been proposed as a potential treatment for alloimmune and autoimmune disorders, but it is unknown whether disturbances to T cell immunity may render these patients vulnerable to fungal infections. To elucidate the role of Notch signaling during fungal infections, we infected mice expressing the pan-Notch inhibitor dominant negative mastermind-like within mature T cells with C. neoformans Inhibition of T cell-restricted Notch signaling increased fungal burdens in the lungs and CNS, diminished pulmonary leukocyte recruitment, and simultaneously impaired Th1 and Th2 responses. Pulmonary leukocyte cultures from T cell Notch-deprived mice produced less IFN-γ, IL-5, and IL-13 than wild-type cells. This correlated with lower frequencies of IFN-γ-, IL-5-, and IL-13-producing CD4+ T cells, reduced expression of Th1 and Th2 associated transcription factors, Tbet and GATA3, and reduced production of IFN-γ by CD8+ T cells. In contrast, Th17 responses were largely unaffected by Notch signaling. The changes in T cell responses corresponded with impaired macrophage activation and reduced leukocyte accumulation, leading to diminished fungal control. These results identify Notch signaling as a previously unappreciated regulator of Th1 and Th2 immunity and an important element of antifungal defenses against cryptococcal infection and CNS dissemination.


Assuntos
Criptococose/imunologia , Cryptococcus neoformans/imunologia , Receptores Notch/metabolismo , Animais , Antígenos de Fungos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Sistema Nervoso Central/parasitologia , Criptococose/microbiologia , Fator de Transcrição GATA3/metabolismo , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-13/biossíntese , Interleucina-13/imunologia , Interleucina-5/biossíntese , Interleucina-5/imunologia , Pulmão/parasitologia , Ativação de Macrófagos , Camundongos , Receptores Notch/deficiência , Transdução de Sinais , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia
6.
J Immunol ; 194(6): 2899-908, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25687759

RESUMO

Rejection remains a major clinical challenge limiting allograft survival after solid organ transplantation. Both cellular and humoral immunity contribute to this complication, with increased recognition of Ab-mediated damage during acute and chronic rejection. Using a mouse model of MHC-mismatched heart transplantation, we report markedly protective effects of Notch inhibition, dampening both T cell and Ab-driven rejection. T cell-specific pan-Notch blockade prolonged heart allograft survival and decreased IFN-γ and IL-4 production by alloreactive T cells, especially when combined with depletion of recipient CD8(+) T cells. These effects were associated with decreased infiltration by conventional T cells and an increased proportion of regulatory T cells in the graft. Transient administration of neutralizing Abs specific for delta-like (Dll)1/4 Notch ligands in the peritransplant period led to prolonged acceptance of allogeneic hearts, with superior outcome over Notch inhibition only in T cells. Systemic Dll1/4 inhibition decreased T cell cytokines and graft infiltration, germinal center B cell and plasmablast numbers, as well as production of donor-specific alloantibodies and complement deposition in the transplanted hearts. Dll1 or Dll4 inhibition alone provided partial protection. Thus, pathogenic signals delivered by Dll1/4 Notch ligands early after transplantation promote organ rejection through several complementary mechanisms. Transient interruption of these signals represents an attractive new therapeutic strategy to enhance long-term allograft survival.


Assuntos
Anticorpos Neutralizantes/imunologia , Rejeição de Enxerto/imunologia , Transplante de Coração/métodos , Imunidade/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas de Membrana/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Anticorpos Neutralizantes/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proteínas de Ligação ao Cálcio , Citometria de Fluxo , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores Notch/antagonistas & inibidores , Receptores Notch/imunologia , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Transplante Homólogo
7.
Med Sci Monit ; 23: 2104-2110, 2017 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-28465500

RESUMO

BACKGROUND The relationship between alcohol consumption and metabolic syndrome (MetS) remains controversial. This study investigated the relationship between alcohol consumption and MetS components and prevalence. MATERIAL AND METHODS We analyzed 10 037 subjects (3076 MetS and 6961 non-MetS) in a community-based cohort. MetS was defined according to the ATP III Guidelines. Subjects were divided according to amount of alcohol consumption; non-drinker, very light (0.1-5.0 g/day), light (5.1-15.0 g/day), moderate (15.1-30.0 g/day), and heavy drinker (>30 g/day). Multiple logistic regression models were performed to estimate odds ratios (ORs) and confidence intervals (CIs). The analyses were performed in men and women separately. SPSS statistical software was used for analyses. RESULTS The prevalence of MetS in both males and females was associated with alcohol drinking status (p<0.0001). Amount of alcohol consumption (0.1-5.0 g/day) was significantly associated with lower prevalence of MetS in both genders compared to non-drinkers. Amount of alcohol consumption (>30.0 g/day) did not show a significant association with prevalence of MetS. However, alcohol consumption (>30.0 g/day) showed an association with glucose and HDL cholesterol among the components of MetS. CONCLUSIONS Our results indicate that alcohol drinking (0.1-5.0 g/day) contributed to decrease prevalence of MetS and components, including triglyceride and HDL cholesterol.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Síndrome Metabólica/epidemiologia , Adulto , Consumo de Bebidas Alcoólicas/metabolismo , Pressão Sanguínea , HDL-Colesterol , Estudos de Coortes , Pesquisa Participativa Baseada na Comunidade , Estudos Transversais , Etanol/metabolismo , Feminino , Humanos , Modelos Logísticos , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Razão de Chances , Prevalência , República da Coreia , Fatores de Risco , Triglicerídeos
8.
Med Sci Monit ; 23: 1880-1885, 2017 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-28422086

RESUMO

BACKGROUND Secretoglobin family 3A member 2 (SCGB3A2) plays an important role in secreting lung surfactant protein, which is a downstream target of thyroid transcription factor. MATERIAL AND METHODS We investigated whether single-nucleotide polymorphisms (SNPs) of SCGB3A2 gene contribute to susceptibility to asthma. To explore this possible association, 2 promoter SNPs (rs6882292, 659 G/A and rs1368408, -112 G/A) and missense SNP (rs151333009, stop codon) were tested in SCGB3A2 gene in 101 asthma patients and 377 healthy control subjects. SNPStats was used to obtain odds ratio (OR), 95% confidence intervals (CI), and P value adjusted for age and sex as covariables. Logistic regression method in each model (dominant, recessive, and log-additive) was applied to analyze genetic data. RESULTS rs151333009 SNP showed a monomorphic genotype. Two promoter SNPs (rs6882292, -659 G/A and rs1368408, -112 G/A) showed significant association with asthma (rs6882292, OR=2.66, 95% CI=1.42-5.01, p=0.0033 in dominant model, OR=2.45, 95% CI=1.33-4.54, p=0.0055 in log-additive model; rs1368408, OR=1.59, 95% CI=1.02-2.49, p=0.041 in dominant model, OR=3.02, 95% CI=1.15-7.90, p=0.03 in recessive model, OR=1.63, 95% CI=1.63, 95% CI=1.12-2.37, p=0.012 in log-additive model). CONCLUSIONS These results suggest that the promoter SNPs (rs6882292 and rs1368408) of SCGB3A2 gene may contribute to susceptibility to asthma in a Korean population.


Assuntos
Asma/genética , Secretoglobinas/genética , Adulto , Povo Asiático/genética , Asma/metabolismo , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , República da Coreia , Secretoglobinas/metabolismo
9.
Dev Biol ; 402(1): 98-108, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25835502

RESUMO

The Notch signaling pathway regulates intestinal epithelial cell homeostasis, including stem cell maintenance, progenitor cell proliferation and differentiation. Notch1 and Notch2 receptors are expressed in the epithelium, but individual contributions to these functions are unclear. We used genetic deletion to define receptor roles on stem cell function, cell proliferation/differentiation, and repair after injury. Loss of Notch1 induced a transient secretory cell hyperplasia that spontaneously resolved over time. In contrast, deletion of Notch2 had no secretory cell effect. Compound deletions of Notch1 and Notch2 resulted in a more severe secretory cell hyperplasia than deletion of Notch1 alone. Furthermore, only double deletion of Notch1 and Notch2 decreased cell proliferation, suggesting a low threshold for maintenance of proliferation compared to differentiation. Stem cells were affected by deletion of Notch1, with reduced expression of Olfm4 and fewer LGR5(+) stem cells. Deletion of Notch2 had no apparent affect on stem cell homeostasis. However, we observed impaired crypt regeneration after radiation in both Notch1- and Notch2-deleted intestine, suggesting that higher Notch activity is required post-injury. These findings suggest that Notch1 is the primary receptor regulating intestinal stem cell function and that Notch1 and Notch2 together regulate epithelial cell proliferation, cell fate determination, and post-injury regeneration.


Assuntos
Deleção de Genes , Regulação da Expressão Gênica , Mucosa Intestinal/metabolismo , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Células-Tronco/citologia , Animais , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Cruzamentos Genéticos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Homeostase , Hiperplasia/metabolismo , Intestinos/citologia , Intestinos/embriologia , Camundongos , Camundongos Endogâmicos C57BL
10.
Neurol Sci ; 37(6): 983-5, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26846416

RESUMO

Cytokines and their receptors are involved in the development of intracerebral hemorrhage (ICH). Interleukin 23 receptor (IL23R) has been implicated in numerous inflammatory and immune diseases. In this study, we investigated whether single nucleotide polymorphisms (SNPs) of IL23R were associated with the susceptibility of ICH in Korean population. Two coding region SNPs (cSNPs) [rs1884444 (Gln3His), and rs7530511 (Leu310Pro)] were selected, and genotyped in 167 ICH patients and 377 control subjects using direct sequencing. Of two cSNPs, only rs7530511 showed a significant association with ICH in codominant model (C/T vs. C/C, P = 0.017, odds ratio (OR) 4.15, 95 % confidential interval (CI) 1.27-13.58). Allele frequency analysis also revealed that rs7530511 was associated with ICH (P = 0.023, OR 3.68, 95 % CI 1.19-11.32). The frequency of the T allele was increased in the ICH patients, compared to the control subjects. These results suggest that IL23R may contribute to the development of ICH.


Assuntos
Hemorragia Cerebral/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina/genética , Adulto , Idoso , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , República da Coreia
11.
Med Sci Monit ; 22: 4345-4353, 2016 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-27840402

RESUMO

BACKGROUND Ischemic stroke and myocardial infarction are fatal diseases and are among the top 10 causes of death in Korea, including arterial thromboembolic events. Many previous studies have described the function of interleukin-6 (IL-6) in arterial thromboembolic events and the association between promoter single-nucleotide polymorphism (SNP) (rs1800795; -174, G/C) of the IL-6 gene. However, these results were controversial. Therefore, we performed a meta-analysis to more precisely assess the association between the SNP of the IL-6 gene and susceptibility to arterial thromboembolic events. MATERIAL AND METHODS We used PubMed, Embase, Google Scholar, and Korean Studies Information Service System (KISS) electronic databases. Comprehensive Meta-analysis software (Corporation, NJ) was used to evaluate the relationship between rs1800795 SNP of IL-6 gene and risk of arterial thromboembolic events. Odds ratio (OR), 95% confidence interval (CI), and P value were also calculated. The 13 eligible studies were analyzed in the meta-analysis. RESULTS The present meta-analysis found that rs1800795 SNP of IL-6 gene is not significantly associated with susceptibility to arterial thromboembolic events (C allele vs. G allele, OR=1.04, 95% CI=0.91-1.19, P=0.619; CC vs. CG+GG, OR=1.09, 95% CI=0.91-1.31, P=0.364; CC+CG vs. GG, OR=0.97, 95% CI=0.78-1.21, P=0.763, respectively), and the SNP of IL-6 gene also did not show any significant association with ischemic stroke or myocardial infarction (P>0.05 in each model). CONCLUSIONS We found that rs1800795 SNP of IL-6 gene was not related to arterial thromboembolic events. However, further study will be needed to confirm these results.


Assuntos
Interleucina-6/genética , Infarto do Miocárdio/genética , Tromboembolia/genética , Alelos , Predisposição Genética para Doença , Humanos , Interleucina-6/metabolismo , Infarto do Miocárdio/metabolismo , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Tromboembolia/metabolismo
12.
J Korean Med Sci ; 31(3): 430-4, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26955245

RESUMO

To investigate the contribution of the interleukin-6 receptor (IL-6R) gene single nucleotide polymorphisms (SNPs) to the neurological status of Korean patients with ischemic stroke (IS), two SNPs of the IL-6R gene (rs4845617, 5 UTR; rs2228144, Ala31Ala) were selected. IS patients were classified into clinical phenotypes according to two well-defined scores: the National Institutes of Health Stroke Survey (NIHSS) and the Modified Barthel Index scores. There were 121 IS patients and 291 control subjects. The SNP rs4845617 significantly contributed to the neurological status of patients with IS (P = 0.011 in codominant model 2, P = 0.006 in recessive model, and P = 0.008 in log-additive model). Allele frequencies of rs4845617 and rs2228144 demonstrated no significant difference in IS patients and controls. The AG and GG haplotypes differed between the NIHSS 1 (NIHSS scores < 6) group and the NIHSS 2 (NIHSS scores ≥ 6) group in patients with IS (P = 0.014, P = 0.0024). These results suggest that rs4845617 of the IL-6R gene is associated with the neurologic status of Korean patients with IS.


Assuntos
Povo Asiático/genética , Receptores de Interleucina-6/genética , Acidente Vascular Cerebral/genética , Idoso , Alelos , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único , República da Coreia , Índice de Gravidade de Doença , Acidente Vascular Cerebral/patologia
13.
Int J Mol Sci ; 17(8)2016 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-27483248

RESUMO

The insulin-like growth factor (IGF) pathway is thought to play an important role in brain development. Altered levels of IGFs and their signaling regulators have been shown in autism spectrum disorder (ASD) patients. In this study, we investigated whether coding region single-nucleotide polymorphisms (cSNPs) of the insulin receptor substrates (IRS1 and IRS2), key mediators of the IGF pathway, were associated with ASD in Korean males. Two cSNPs (rs1801123 of IRS1, and rs4773092 of IRS2) were genotyped using direct sequencing in 180 male ASD patients and 147 male control subjects. A significant association between rs1801123 of IRS1 and ASD was shown in additive (p = 0.022, odds ratio (OR) = 0.66, 95% confidence interval (CI) = 0.46-0.95) and dominant models (p = 0.013, OR = 0.57, 95% CI = 0.37-0.89). Allele frequency analysis also showed an association between rs1801123 and ASD (p = 0.022, OR = 0.66, 95% CI = 0.46-0.94). These results suggest that IRS1 may contribute to the susceptibility of ASD in Korean males.


Assuntos
Transtorno do Espectro Autista/genética , Proteínas Substratos do Receptor de Insulina/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Povo Asiático/genética , Estudos de Casos e Controles , Humanos , Masculino , Projetos Piloto , Prognóstico
14.
Cytokine ; 71(2): 283-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25484349

RESUMO

BACKGROUND: Although numerous recent studies have implicated a role for interleukin 17(IL17) in tumor development, the mechanisms of IL17 involvement are still uncharacterized. The aims of this study were to determine whether single nucleotide polymorphisms (SNPs) in IL17 and IL17R contribute to the development of papillary thyroid cancer (PTC) and to assess the relationship between IL17 and IL17R SNPs and the clinicopathologic characteristics of PTC. MATERIALS AND METHODS: Eight SNPs located within the IL17A, IL17RA, and IL17RB genes were genotyped using direct sequencing in 94 patients with PTC and 260 patients without PTC (controls). Genetic data were analyzed using commercially available software. Statistical analyses were then performed to examine the relationships between these SNPs and the clinicopathologic characteristics of PTC. RESULTS: Genotyping analysis demonstrated that the IL17RA SNP rs4819554 (codominant model 1, odds ratio (OR)=0.39, P=0.001) and the IL17RB SNP rs1025689 (dominant model, OR=0.59, P=0.043) were significantly associated with lack of PTC. Interestingly, the IL17A SNP rs2275913 (codominant model 2, OR=0.19, P=0.034) was significantly associated with lack of multifocality. Furthermore, the IL17RA SNP rs4819554 (dominant model, OR=0.25, P=0.010) was significantly associated with lack of cancer bilaterality. CONCLUSION: In this study of SNPs in the IL17 and IL17R genes in patients with PTC, we demonstrated that IL17RA polymorphisms can influence both the development and the bilaterality of PTC.


Assuntos
Interleucina-17/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-17/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Idoso , Alelos , Sequência de Bases , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Razão de Chances , República da Coreia , Software , Neoplasias da Glândula Tireoide/etnologia
15.
J Immunol ; 190(11): 5818-28, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23636056

RESUMO

Graft-versus-host disease (GVHD) induced by donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). We previously reported that the pan-Notch inhibitor dominant-negative form of Mastermind-like 1 (DNMAML) markedly decreased the severity and mortality of acute GVHD mediated by CD4(+) T cells in mice. To elucidate the mechanisms of Notch action in GVHD and its role in CD8(+) T cells, we studied the effects of Notch inhibition in alloreactive CD4(+) and CD8(+) T cells using mouse models of allo-BMT. DNMAML blocked GVHD induced by either CD4(+) or CD8(+) T cells. Both CD4(+) and CD8(+) Notch-deprived T cells had preserved expansion in lymphoid organs of recipients, but profoundly decreased IFN-γ production despite normal T-bet and enhanced Eomesodermin expression. Alloreactive DNMAML T cells exhibited decreased Ras/MAPK and NF-κB activity upon ex vivo restimulation through the TCR. In addition, alloreactive T cells primed in the absence of Notch signaling had increased expression of several negative regulators of T cell activation, including Dgka, Cblb, and Pdcd1. DNMAML expression had modest effects on in vivo proliferation but preserved overall alloreactive T cell expansion while enhancing accumulation of pre-existing natural regulatory T cells. Overall, DNMAML T cells acquired a hyporesponsive phenotype that blocked cytokine production but maintained their expansion in irradiated allo-BMT recipients, as well as their in vivo and ex vivo cytotoxic potential. Our results reveal parallel roles for Notch signaling in alloreactive CD4(+) and CD8(+) T cells that differ from past reports of Notch action and highlight the therapeutic potential of Notch inhibition in GVHD.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Receptores Notch/antagonistas & inibidores , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citotoxicidade Imunológica , Ativação Enzimática , Regulação da Expressão Gênica , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/metabolismo , Interferon gama/biossíntese , Ativação Linfocitária , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores Notch/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
16.
BMC Complement Altern Med ; 15: 380, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26490686

RESUMO

BACKGROUND: Benign prostatic hyperplasia (BPH) is one of the common male diseases, which is provoked by dihydrotestosterone (DHT) and androgen signals. Several studies showed that curcumin has various effects of prevention and treatment to diseases. We investigated whether curcumin may repress the development of BPH in male Wistar rats. METHODS: Seven weeks male Wistar rats were and divided into 4 groups (normal group, BPH group, finasteride group, curcumin group; n = 8 for each group). In order to induce BPH in rats, rats were castrated and testosterone was injected subcutaneously everyday (s.c., 20 mg/kg). Rats in the curcumin group were treated 50 mg/kg, administered orally for 4 weeks. After 4 weeks, all rats were sacrificed and their prostate and serum were analyzed. RESULTS: Compared to the finasteride group as positive group, the curcumin group showed similarly protective effect on BPH in histopathologic morphology, prostate volume. Results of immunohistochemistry and western-blot showed decreased expressions of VEGF, TGF-ß1, and IGF1 were also decreased in the curcumin group. CONCLUSIONS: These results suggested that curcumin inhibited the development of BPH and might a useful herbal treatment or functional food for BPH.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Curcumina/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Análise de Variância , Animais , Biomarcadores/metabolismo , Glicemia/efeitos dos fármacos , Western Blotting , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Imuno-Histoquímica , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Ratos , Ratos Wistar , Testosterona/sangue , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Int J Mol Sci ; 16(8): 19602-11, 2015 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-26295386

RESUMO

The association between polymorphisms of glutathione-related enzyme (GST) genes and the risk of schizophrenia has been investigated in many published studies. However, their results were inconclusive. Therefore, we performed a meta-analysis to explore the association between the GSTM1, GSTT1, and GSTP1 polymorphisms and the risk of schizophrenia. Twelve case-control studies were included in this meta-analysis. The odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Our meta-analysis results revealed that GSTM1, GSTT1, and GSTP1 polymorphisms were not related to risk of schizophrenia (p > 0.05 in each model). Further analyses based on ethnicity, GSTM polymorphism showed weak association with schizophrenia in East Asian population (OR = 1.314, 95% CI = 1.025-1.684, p = 0.031). In conclusion, our meta-analysis indicated the GSTM1 polymorphism may be the only genetic risk factor for schizophrenia in East Asian population. However, more meta-analysis with a larger sample size were needed to provide more precise evidence.


Assuntos
Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Polimorfismo Genético , Esquizofrenia/genética , Povo Asiático/etnologia , Povo Asiático/genética , Ásia Oriental , Predisposição Genética para Doença , Humanos , Esquizofrenia/etnologia
18.
Clin Transplant ; 28(6): 707-12, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24654912

RESUMO

Recent studies have shown that single-nucleotide polymorphisms (SNPs) are associated with allograft rejection in kidney transplantation recipients. We evaluated the possible association between SNPs of the cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1) gene, and acute rejection (AR) among renal transplant patients in a Korean population. We conducted a case-control association study in 63 AR and 284 non-AR kidney transplant recipients. The SNPs of CYP2E1 were genotyped by direct sequencing. Recipient sex (p = 0.023) and the use of tacrolimus (p = 0.017) were significantly different between the two groups. The use of mycophenolate mofetil (MMF) and antibody induction therapy was significantly lower in the AR group. Multiple logistic regression models (codominant, dominant, recessive, and log-additive models) adjusted by sex and type of immunosuppressive regimens were applied to determine the odds ratios (ORs), 95% confidence intervals (CIs), and p-values. The rs2515641 of CYP2E1 showed significant differences between the AR patient group and non-AR group (p = 0.003, OR = 2.55, 95% CI = 1.37-4.75 in the codominant 1 model; p = 0.002, OR = 2.61, 95% CI = 1.43-4.77 in the dominant model; p = 0.0035, OR = 2.13, 95% CI = 1.29-3.50 in the log-additive model). The allele of the rs2515641 SNP also showed a significant association (p = 0.004, OR = 1.99, 95% CI = 1.24-3.21). This study suggests that the CYP2E1 polymorphism may be related to the development of AR in Korean kidney transplantation recipients.


Assuntos
Citocromo P-450 CYP2E1/genética , Estudos de Associação Genética , Rejeição de Enxerto/genética , Haplótipos/genética , Transplante de Rim , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/cirurgia , Testes de Função Renal , Desequilíbrio de Ligação , Masculino , Prognóstico , Fatores de Risco
19.
Immunol Invest ; 43(3): 212-23, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24303776

RESUMO

The heat shock 70 kDa protein 1B (HSPA1B), which has been well-studied among the famous heat shock proteins HSPA1A/B/L, is related to autoimmune diseases, including Alopecia Areata (AA). In this study, the association of a 5'-untranslated region (5'UTR) SNP rs6457452 and a promoter SNP rs2763979 (-1140C > T) of HSPA1B with AA was investigated in 236 controls and 228 AA patients. Statistical analyses using the multiple logistic models were done, according to the onset and the clinical features of AA, including the age of onset, family history, type of AA lesion, nail involvement and body hair involvement. The results showed that rs6457452 was associated with the onset of AA (p < 0.002). In the analysis of clinical features of AA, rs6457452 was weakly related to the age of onset (p ≤ 0.04) and that rs2763979 was only weakly related to the type of AA lesion (p = 0.041). In conclusion, we suggest that the 5'UTR SNP rs6457452 of HSPA1B may be associated with the onset of AA and the T allele of rs6457452 may confer the reduced susceptibility to AA in the Korean population.


Assuntos
Alopecia em Áreas/epidemiologia , Alopecia em Áreas/genética , Proteínas de Choque Térmico HSP70/genética , Regiões 5' não Traduzidas/genética , Adolescente , Adulto , Idade de Início , Alopecia em Áreas/imunologia , Análise Mutacional de DNA , Progressão da Doença , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Adulto Jovem
20.
Mol Biol Rep ; 41(5): 3457-64, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24510409

RESUMO

Monoamine oxidase A (MAOA) catalyzes monoamine neurotransmitters including dopamine, 5-hydroxytryptamine (5-HT, serotonin), and norepinephrine. MAOA also plays a key role in emotional regulation. The aim of this study was to investigate the associations between the exonic single nucleotide polymorphisms (SNPs) of the MAOA gene located on the X chromosome and schizophrenia. We also analyzed the relationships between these SNPs and the common clinical symptoms of schizophrenia such as persecutory delusion, auditory hallucinations, affective disturbances, and poor concentration. Two hundred seventy five Korean schizophrenia patients and 289 control subjects were recruited. Three SNPs [rs6323 (Arg294Arg), rs1137070 (Asp470Asp), and rs3027407 (3'-untranslated region)] of the MAOA gene were selected and genotyped by direct sequencing. The common clinical symptoms of schizophrenia according to the Operation Criteria Checklist were analyzed. Three examined SNPs showed no associations with male and female schizophrenia, respectively (p>0.05). In the analysis of the common clinical symptoms of schizophrenia patients, three examined SNPs were associated with affective disturbances, especially restricted affect and blunted affect in male schizophrenia, respectively (restricted affect, p=0.002, OR=2.71, 95% CI 1.45-5.00; blunted affect, p=0.009, OR 2.25, 95% CI 1.22-4.12). The SNPs were not associated with other clinical symptoms of schizophrenia (persecutory delusion, auditory hallucinations, and poor concentration). These results suggest that exonic SNPs (rs6323, rs1137070, and rs3027407) of the MAOA gene may be contributed to affective disturbances of Korean males schizophrenia, especially restricted affect and blunted affect.


Assuntos
Monoaminoxidase/genética , Polimorfismo Genético , Esquizofrenia/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , República da Coreia , Esquizofrenia/diagnóstico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA