Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Invest Dermatol ; 141(5): 1254-1263.e6, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33069728

RESUMO

Genetic factors play a key role in the pathogenesis of autoimmune diseases, whereas the disease-causing variants remain largely unknown. Herein, we performed an exome-wide association study of systemic sclerosis in a Han Chinese population. In the discovery stage, 527 patients with systemic sclerosis and 5,024 controls were recruited and genotyped. In the validation study, an independent sample set of 479 patients and 1,096 controls were examined. In total, we found that four independent signals reached genome-wide significance. Among them, rs7574865 (Pcombined = 3.87 × 10-12) located within signal transducer and activator of transcription 4 gene was identified previously using samples of European ancestry. Additionally, another signal including three SNPs in linkage disequilibrium might be unreported susceptibility loci located in the epidermis differentiation complex region. Furthermore, two SNPs located within exon 3 of IGHM (rs45471499, Pcombined = 1.15 × 10-9) and upstream of LRP2BP (rs4317244, Pcombined = 4.17 × 10-8) were found. Moreover, rs4317244 was identified as an expression quantitative trait locus for LRP2BP that regulates tight junctions, cell cycle, and apoptosis in endothelial cell lines. Collectively, our results revealed three signals associated with systemic sclerosis in Han Chinese and suggested the importance of LRP2BP in systemic sclerosis pathogenesis. Given the limited sample size and discrepancies between previous results and our study, further studies in multiethnic populations are required for verification.

2.
Int J Clin Exp Pathol ; 13(7): 1662-1668, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32782686

RESUMO

OBJECTIVE: The aim of this study was to use cerebrospinal fluid (CSF) cytology to give undiagnosed patients admitted to the hospital with severe neurological symptoms and without any anti-tumor treatment history a definitive diagnosis. Further, the aim was to explore the relationship between the frequency of gene mutations and mortality on the incidence of CSF metastasis in advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: 30 patients diagnosed with NSCLC through CSF cytology were retrospectively analyzed. We analyzed 30 CSF metastasis patients and a control group of 20 advanced NSCLC patients without CSF metastasis. RESULTS: 30 patients were diagnosed with CSF metastasis using CSF cytology and immunocytopathology. The frequencies of EGFR mutations and ALK fusion in the CSF metastasis group were higher than they were in the non-CSF metastasis group (80% and 50% respectively, P<0.05). The incidence of CSF metastasis with gene mutations was higher than it was with wild-type genes (70.6% and 37.5%, P<0.05), OR 4.0 (95% CI 1.14~13.99). The median survival time of the CSF metastasis group was 4.8 months (95% CI 4.2~5.3). However, the median survival time in the non-CSF metastasis group was 9.2 months (95% CI 3.3~15.1). The mortality of the CSF metastasis group (n=13, 43.3%) was significantly higher than it was in the non-CSF metastasis group (n=6, 30%). CONCLUSIONS: CSF metastasis in NSCLC patients has a higher frequency of gene mutations and mortality. EGFR mutation and ALK fusion patients have a higher incidence of CSF metastasis. EGFR mutations and ALK fusion may promote CSF metastasis and may be a predictor of prognosis in NSCLC patients.

3.
J Dermatol Sci ; 99(1): 44-52, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32571632

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease characterized by inflammation and fibrosis. Our previous research found Disabled-2 (DAB2) expression was significantly downregulated by salvianolic acid B, a small molecular medicine which attenuated experimental skin fibrosis of SSc. These suggest that DAB2 plays an important role in SSc skin fibrosis, but the role of DAB2 in SSc remains unclear. OBJECTIVES: To investigate the role of DAB2 in SSc. METHODS: DAB2 expression level was detected in the skin and peripheral blood mononuclear cells of SSc patients. Bleomycin (BLM)-induced SSc mice and primary SSc skin fibroblasts were used to investigate the effect of DAB2 downregulation on fibrosis. RNA-seq transcriptome analysis was performed to underlie the mechanism of DAB2 in fibroblasts. RESULTS: DAB2 expression was enhanced in SSc lesion skin and was positively correlated with fibrotic genes, such as α-SMA and PAI-1. The in vivo study revealed that DAB2 downregulation alleviated skin fibrosis, alleviating skin thickness and reducing collagen deposition, and DAB2 knockdown ameliorated the inflammatory cell infiltration. The in vitro study showed that DAB2 knockdown reduced extracellular matrix genes and proteins expression. Moreover, Transcriptome analysis revealed TGF-ß and focal adhesion signaling pathways were the main downregulated pathways involved in DAB2 siRNA treated fibroblasts. CONCLUSIONS: Taken together, our results revealed that DAB2 was increased in SSc skin, and DAB2 downregulation inhibited BLM-induced mouse skin fibrosis and SSc skin fibroblasts activation. DAB2 played an important role in the pathogenesis of SSc and DAB2 modulation may represent a potential therapeutic method for SSc.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Escleroderma Sistêmico/patologia , Pele/patologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Bleomicina/administração & dosagem , Bleomicina/toxicidade , Estudos de Casos e Controles , Células Cultivadas , Fármacos Dermatológicos/farmacologia , Fármacos Dermatológicos/uso terapêutico , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Feminino , Fibroblastos , Fibrose , Adesões Focais/metabolismo , Técnicas de Silenciamento de Genes , Voluntários Saudáveis , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Cultura Primária de Células , RNA-Seq , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/tratamento farmacológico , Pele/citologia , Pele/efeitos dos fármacos
4.
Exp Dermatol ; 28(11): 1313-1320, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31505074

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease mainly characterized by persistent inflammation and fibrosis. The receptor tyrosine kinase (RTK) signal pathway plays an important role in the process of SSc, and Grb2-associated binding protein (GAB) is crucial in activating RTK signalling. A previous study found elevated levels of GAB1 in bleomycin (BLM)-induced fibrotic lungs, but the effects of GAB1 in SSc remain unclear. Our aim was to investigate whether GAB1 was dysregulated and its potential role in SSc. Compared with healthy donors, we found GAB1 expression was 1.6-fold higher in peripheral blood mononuclear cells (PBMC), 2.5-fold higher in CD4 + T cells, and 2-fold higher in skin from of SSc patients (P < .01). At the same time, the levels of type one collagen (COLI) were also significantly increased (1.8-fold higher) in SSc skin. Additionally, BLM-induced SSc mice showed mRNA levels of Gab1 2-fold higher than saline-treated controls, and Gab1 expression correlated positively with collagen content. A further in vitro study showed silencing of GAB1 suppressed inflammatory gene expression in TNF-α induced fibroblasts. Additionally, GAB1 deficiency prominently inhibited cell proliferation and reduced COLI protein levels in TGF-ß induced fibroblasts. Taken together, these data suggest that GAB1 has a relatively high expression rate in SSc, and knockdown of GAB1 may attenuate SSc by stimulating inflammatory and fibrotic processes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Inflamação/metabolismo , Escleroderma Sistêmico/metabolismo , Animais , Estudos de Casos e Controles , Linhagem Celular , Colágeno/metabolismo , Fibroblastos/fisiologia , Fibrose , Camundongos , Cultura Primária de Células , Escleroderma Sistêmico/patologia , Pele/patologia
5.
Med Sci Monit ; 25: 532-539, 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30657743

RESUMO

BACKGROUND Brain microvessel endothelial cells constitute an important component in the blood-brain barrier. Cell-culture-based models of the blood-brain barrier (BBB) have been extensively applied in pharmacology, pathology and physiology. This study investigated effects of anti-N-methyl-D-aspartic acid receptor 2 (anti-NR2), N-methyl-D-aspartic acid (NMDA) receptor antibodies, NMDA receptor antagonists, and NMDA receptor agonists on brain microvessel endothelial cell models, and verified the effect of anti-NR2 antibody on the BBB as a receptor agonist. MATERIAL AND METHODS The primary brain microvessel endothelial cells were isolated and cultured, and an in vitro BBB model was established based on microvessel endothelial cells. Anti-NR2 antibody, glutamic acid, ifenprodil, and memantine were added in the BBB model to analyze changes in transepithelial electrical resistance (TEER) and to examine the permeability of the brain microvessel endothelial cell model. RESULTS The results showed that TEER values were significantly decreased by the addition of anti-NR2 antibody and glutamate, but were significantly increased by the addition of ifenprodil and memantine. TEER values showed no changes when treated by anti-NR2 antibody and ifenprodil, as well as anti-NR2 antibody and memantine. When dexamethasone was added, the TEER values increased by 23.8%, 39.4%, and 29.6% by treating with anti-NR2 antibody, positive cerebrospinal fluid, and positive serum, respectively. CONCLUSIONS Our findings show that anti-NR2 antibody in neuropsychiatric lupus serum can damage the BBB and enter the brain.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Animais , Autoanticorpos/imunologia , Transporte Biológico , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/metabolismo , China , Modelos Animais de Doenças , Impedância Elétrica , Células Endoteliais/metabolismo , Espaço Extracelular/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Vasculite Associada ao Lúpus do Sistema Nervoso Central/fisiopatologia , Masculino , Microvasos/metabolismo , N-Metilaspartato/metabolismo , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo
6.
Cell Biochem Biophys ; 70(2): 1005-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24845150

RESUMO

The objective is to explore the clinical curative effects of methylprednisolone combined with MTX and DXM intrathecal injection in treating neuropsychiatric systemic lupus erythematosus (NPSLE) and its effects on autoantibody level and anti-N-methyl-D-aspartate receptor subtype NR2a/2b antibody (anti-NR2 antibody) level. Thirty six admitted NPSLE patients were treated by methylprednisolone combined with MTX and DXM intrathecal injection. Thirty six SLE patients without neuropsychiatric symptoms were selected as non-NPSLE group. Clinical indexes including SLE activity index, erythrocyte sedimentation rate (ESR), cerebrospinal fluid pressure (CSFP), cerebrospinal fluid protein were observed before and after treatment. Autoantibodies including anti-nuclear antibody (ANA), anti-double stranded DNA antibody (anti-dsDNA antibody), anti-extractable nuclear antigen antibody (ENA-Ab) were detected before and after treatment. Enzyme linked immunosorbent assay was used to detect NR2 antibody level before and after treatment in two groups. Upon treatment of methylprednisolone combined with MTX and DXM intrathecal injection, SLE activity index, ESR, CSFP, cerebrospinal fluid protein of 36 NPSLE patients were significantly decreased. Before treatment, positive rates of ANA, anti-dsDNA antibody, and anti-ENA antibody in both NPSLE group and non-NPSLE group had no significant difference. However, positive rate of anti-NR2 antibody in NPSLE group was significantly higher than that of non-NPSLE group. After treatment, positive rates of autoantibodies and anti-NR2 antibody in both NPSLE and non-NPSLE group were significantly decreased. Anti-NR2 antibody can be a screening index of NPSLE, and methylprednisolone combined with MTX and DXM intrathecal injection has significant curative effects and can effectively decrease autoantibody level and anti-NR2 antibody level.


Assuntos
Autoanticorpos/metabolismo , Dextrometorfano/farmacologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/tratamento farmacológico , Metotrexato/farmacologia , Metilprednisolona/farmacologia , Receptores de N-Metil-D-Aspartato/imunologia , Adulto , Autoanticorpos/imunologia , Dextrometorfano/administração & dosagem , Dextrometorfano/uso terapêutico , Interações Medicamentosas , Feminino , Humanos , Injeções Espinhais , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Metilprednisolona/uso terapêutico , Resultado do Tratamento
7.
Gene ; 533(1): 385-8, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24004541

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease, with multiple genetic and environmental factors involving in its etiology. The toll-like receptor 9 (TLR9) gene has been reported to have important roles in the development and progression of SLE. We performed a case-control study to investigate the effects of 4 SNPs in the TLR9 gene in the development of SLE in Northern Chinese population. METHODS: Four SNPs including rs187084, rs5743836, rs352139 and rs352140 were genotyped using the SNaPshot® method. A group of 430 SLE patients were compared to 424 normal controls. Data were analyzed by SPSS 17.0 and HaploView v 4.1 software. RESULTS: The frequency distributions of SNP rs351240 and haplotype H2 (TGCT) and H3 (CATT) were found to differ significantly between patient and control groups (p<0.05), while other SNPs and haplotypes showed no significant difference between the two cohorts (p>0.05). CONCLUSION: The results revealed that variations in the TLR9 gene are associated with SLE, indicating that TLR9 may play an important role in the pathogenesis of SLE in the northern Chinese Han population.


Assuntos
Grupos Étnicos/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Receptor Toll-Like 9/genética , Adulto , Estudos de Casos e Controles , China , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
8.
Arthritis Rheum ; 61(7): 979-87, 2009 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-19565542

RESUMO

OBJECTIVE: To assess the efficacy and safety of T-614 versus methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: In this multicenter, double-blind trial, 489 patients randomly received either T-614 25 mg/day for the first 4 weeks and 50 mg/day for the subsequent 20 weeks (group 1, n = 163), T-614 50 mg/day for 24 weeks (group 2, n = 163), or MTX 10 mg/week for the first 4 weeks and 15 mg/week for the subsequent 20 weeks (n = 163). Clinical and laboratory parameters were analyzed at baseline and at 4, 10, 17, and 24 weeks. RESULTS: After 24 weeks of treatment, the American College of Rheumatology 20% improvement criteria response rate for patients in T-614 group 2 (63.8%) was not statistically significantly different from that for patients receiving MTX treatment (62.0%), and was superior to that for patients in T-614 group 1 (50.9%). The result of the noninferiority analysis indicated that the efficacy of T-614 (50 mg/day) was not lower than that of MTX by <10%. Rheumatoid factor and IgA, IgG, and IgM demonstrated a statistically significant decrease in all groups. Frequently reported adverse events included hematologic disorder, skin reactions, gastrointestinal symptoms, and transient liver enzyme elevations in the T-614 therapy groups. Side effects in the T-614 groups were generally fewer and milder than in the MTX group, except for skin reactions. There were no prominent cardiovascular adverse events and gastrointestinal ulcers found in the T-614 groups. CONCLUSION: Results indicate that T-614 therapy 50 mg/day is effective and well tolerated, and represents a new option for the treatment of patients with active RA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Benzopiranos/uso terapêutico , Metotrexato/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Adulto , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Benzopiranos/administração & dosagem , Benzopiranos/efeitos adversos , China , Método Duplo-Cego , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...