RESUMO
A recent genome-wide association study conducted in Caucasians has identified glutaminyl-peptide cyclotransferase (QPCT) gene as a susceptibility gene for schizophrenia, as its common single nucleotide polymorphism (SNP) rs2373000 was significantly associated with the risk of this disease. To date, this finding has not been validated in other populations or ethnic groups. The aim of this study was to investigate the association of common SNPs spanning QPCT gene with the susceptibility of schizophrenia in a Han Chinese population comprising 440 schizophrenia patients and 450 control subjects. A total of 6 tagSNPs including rs2373000 was selected and then genotyped in our sample. Although the relation between rs2373000 and the risk of schizophrenia was not successfully replicated, we showed for the first time that the minor allele (C) of rs3770752 was associated with a reduced risk of schizophrenia (odds ratio (OR) = 0.645; 95 % confidence interval (CI) 0.486-0.855; P corrected = 0.012) in our cohorts. Meanwhile, this allele seemed to modify the schizophrenia risk through a dominant manner (CC + CT vs. TT, OR = 0.625; 95 % CI 0.457-0.854; P corrected = 0.03). In addition, we found that the minor allele (T) of rs3770748 remarkably reduced the schizophrenia risk via a recessive manner (TT vs. TC + CC, OR = 0.618; 95 % CI: 0.449-0.851; P corrected = 0.03). Taken together, these findings demonstrate a significant association between common SNPs within QPCT gene and schizophrenia risk in a Han Chinese population, suggesting QPCT gene may represent a susceptibility gene for this disease.
Assuntos
Aminoaciltransferases/genética , Povo Asiático/genética , Etnicidade/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/enzimologia , Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Frequência do Gene/genética , Humanos , Pessoa de Meia-Idade , Modelos Genéticos , Fatores de Risco , Adulto JovemRESUMO
t-SNARE domain containing 1 gene (TSNARE1) is located at human chromosome 8q24.3, and may play a crucial role in intracellular protein transport and synaptic transmission. Recently, a large-scale meta-analysis of genome-wide association study dataset identified that rs10098073 and rs4129585, two single nucleotide polymorphisms (SNPs) within TSNARE1, were closely associated with the risk of schizophrenia in Caucasians. However, this finding has not been validated in other populations or ethnic groups thus far. In the current study, we conducted a case-control study to confirm the association of these two SNPs with the schizophrenia risk in a Han Chinese population comprising 440 schizophrenia patients and 450 control subjects. According to the genotype data of Han Chinese from Beijing in 1,000 Genomes Project database, rs10098073 and rs4129585 were located in one haplotype block and were in almost complete linkage disequilibrium (D' = 1, r (2) ≥ 0.952). Therefore, only rs10098073 was selected for the subsequent analysis. We showed for the first time that the minor allele (A) of rs10098073 was associated with a reduced risk of schizophrenia (OR = 0.753; 95 % CI 0.613-0.924; P = 0.007). Furthermore, we found that the A allele of rs10098073 reduced the schizophrenia risk through a recessive manner (A/A vs. A/C + C/C, OR = 0.563; 95 % CI 0.357-0.89; P = 0.013, P Bonferroni corrected = 0.026) rather than a dominant manner (A/A + A/C vs. C/C, OR = 0.762; 95 % CI 0.586-0.992; P = 0.043, P Bonferroni corrected = 0.086). Taken together, these findings demonstrate a significant association between TSNARE1 polymorphisms and schizophrenia risk in a Han Chinese population, suggesting TSNARE1 may represent a susceptibility gene for this disease.
Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas SNARE/genética , Esquizofrenia/genética , Adulto , Idoso , Alelos , Povo Asiático/genética , Pequim , Estudos de Casos e Controles , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
A recent genome-wide association study indicated that rs11098403, a single nucleotide polymorphism in the vicinity of NDST3, was strongly associated with the risk of schizophrenia in Caucasians. However, this relation has not been validated in other populations or ethnic groups. Herein, we conducted a case-control study to investigate the association of rs11098403 polymorphism with the schizophrenia risk in a Han Chinese population comprising 440 schizophrenia patients and 450 control subjects. For the first time, we showed that the minor allele (G) of rs11098403 is closely associated with a reduced risk of schizophrenia (OR=0.614; 95% CI: 0.453-0.833; P=0.002; Power=0.832). Meanwhile, the G allele of rs11098403 seemed to reduce the schizophrenia risk via a dominant manner (GG+AG vs. AA, OR=0.526; 95% CI: 0.374-0.74; P<0.001). Furthermore, this association was further confirmed using an independent replication sample containing 267 schizophrenia patients and 400 control subjects with a Han Chinese descent (OR=0.652; 95% CI: 0.469-0.907; P=0.011; Power=0.772). Taken together, these findings demonstrate a significant association between rs11098403 and schizophrenia risk in Han Chinese, confirming the data that previously obtained from Caucasians.
Assuntos
Polimorfismo de Nucleotídeo Único , Esquizofrenia/etnologia , Esquizofrenia/genética , Sulfotransferases/genética , Adulto , Idoso , Povo Asiático , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
Triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for Alzheimer's disease (AD), as its low-frequency variants increase the risk of this disease with an odds ratio similar to that of an APOE É4 allele. To date, the expression and biologic functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was upregulated in microglia during disease progression. For the first time, we provided in vitro and in vivo evidence that this upregulation was attributed to the increased amyloid-ß (Aß)(1-42) levels in the brain. By knockdown and overexpression of TREM2 in cultured primary microglia, we revealed that TREM2 modulated microglial functions under AD context, as it facilitated Aß(1-42) phagocytosis and inhibited Aß(1-42)-triggered proinflammatory responses. Meanwhile, this modulation was dependent on DAP12, the adapter protein of TREM2. More importantly, overexpression of TREM2 in the brain of APPswe/PS1dE9 mice markedly ameliorated AD-related neuropathology including Aß deposition, neuroinflammation, and neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive functions. Taken together, our data suggest that the upregulation of TREM2 serves as a compensatory response to Aß(1-42) and subsequently protects against AD progression by modulation of microglia functions. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a potential therapeutic target for this disease.
Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Percepção Espacial/fisiologia , Regulação para Cima/fisiologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Claudinas/genética , Claudinas/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Mutação/genética , Fragmentos de Peptídeos/farmacologia , Fagocitose/efeitos dos fármacos , Fagocitose/genética , Presenilina-1/genética , Percepção Espacial/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Double-stranded RNA-dependent protein kinase (PKR) is revealed to participate in the development of insulin resistance in peripheral tissues in type 2 diabetes (T2DM). Meanwhile, PKR is also characterized as a critical regulator of cell proliferation. To date, no study has focused on the impact of PKR on the proliferation of pancreatic ß-cells. Here, we adopted insulinoma cell lines and mice islet ß-cells to investigate: (1) the effects of glucolipotoxicity and pro-inflammatory cytokines on PKR activation; (2) the effects of PKR on proliferation of pancreatic ß-cells and its underlying mechanisms; (3) the actions of PKR on pro-proliferative effects of IGF-I and its underlying pathway. Our results provided the first evidence that PKR can be activated by glucolipitoxicity and pro-inflammatory cytokines in pancreatic ß-cells, and activated PKR significantly inhibited cell proliferation by arresting cell cycle at G1 phase. Reductions in cyclin D1 and D2 as well as increases in p27 and p53 were associated with the anti-proliferative effects of PKR, and proteasome-dependent degradation took part in the reduction of cyclin D1 and D2. Besides, PKR activation abrogated the pro-proliferative effects of IGF-I by activating JNK and disrupting IRS1/PI3K/Akt signaling pathway. These findings indicate that the anti-proliferative actions of PKR on pancreatic ß-cells may contribute to the pathogenesis of T2DM.
Assuntos
Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/enzimologia , eIF-2 Quinase/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Ciclina D2/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Citocinas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Fase G1/genética , Glucose/toxicidade , Mediadores da Inflamação/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Lipídeos/toxicidade , Camundongos , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
As a major characteristic of aging process, neuroinflammation is involved in the pathogenesis of several aging-related diseases including Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a newly identified risk gene for AD, which regulates inflammatory process in peripheral tissues via modulating the release of inflammatory cytokines. However, the role of TREM2 in aging-related neuroinflammation, cognitive deficiency, and AD-like neuropathology is unclear so far. Here, we detected the protein levels of TREM2 in brain of 3-, 7-, and 11-month-old senescence-accelerated mouse prone 8 (SAMP8) mice and observed that TREM2 levels were increased during aging process. We then knocked down TREM2 expression in brain of SAMP8 mice by nonviral RNA interference and found a significant increase in proinflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-6, which was accompanied by a reduction in IL-10. Meanwhile, more obvious neuronal and synaptic losses and cognitive impairment were observed. These findings indicate that TREM2 may play a protective role against aging-related neuroinflammation and cognitive impairment.
Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Transtornos Cognitivos/genética , Técnicas de Silenciamento de Genes , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiologia , Receptores Imunológicos/genética , Receptores Imunológicos/fisiologia , Envelhecimento/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Transtornos Cognitivos/patologia , Citocinas/metabolismo , Progressão da Doença , Regulação para Baixo , Mediadores da Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Mutantes Neurológicos , Neurônios/patologia , RNA Interferente Pequeno , Receptores Imunológicos/metabolismo , Sinapses/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: To investigate the protective effect of H2S pretreatment after cerebral schemia/reperfusion injury and its mechanisms in rats. METHODS: The rat model of global cerebral ischemia/reperfusion injury was established by bilateral common carotid arteries occlusion combined with hemorrhagic hypotension.30 rats were randomly divided into four groups(1)sham group(n=5),in which rats received sham surgery only,with their bilateral vertebral artery and bilateral common carotid artery exposed but without ischemia treatment;(2)global cerebral ischemia/reperfusion model group(IR group,n=5),in which the global cerebral ischemia was induced by 10-min occlusion of bilateral common carotid arteries combined with hypotension;(3)H2S pretreatment group(n=15),in which H2S(12,24,48 Μmol/kg)was intraperitoneally injected before operation;(4)NaCl pretreatment group(n=5),in which the rats were intraperitoneally injected with saline 30 minutes before operation.The activities of superoxide dismutase(SOD)and the levels of malondialdeehyde(MDA)in brain were measured by spectrophotometry.Brain water content was detected.The expression of heat shock protein 70(HSP70) in the hippocampus was determined by Western blotting. RESULTS: The SOD activities were significant increased in groups pretreated with 12Μmol/kg H2S(P=0.042),24Μmol/kg H2S(P=0.002),and 48Μmol/kg H2S(P=0.000),and the SOD activity was significantly lower in the ischemia group than in the Sham group(P=0.003).The MDA activities in the 24Μmol/kg group(P=0.026)and the 48Μmol/kg group(P=0.015)groups were significantly lower than in the IR group.The brain water content was decreased in H2S pretreatment group(24Μmol/kg and 48 Μmol/kg)compared with IR group(P=0.018,P=0.008),and it was also significantly higher in the IR group than in the sham group(P=0.009).The expression of HSP70 were decreased in H2S pretreatment group(24 Μmol/kg)compared with the IR group(P=0.000),and the expression of HSP70 were significantly higher in the IR group than in HSP70 group(P=0.000).The expression of HSP70 also significantly differed between NaCl group and HSP70 group(P=0.000). CONCLUSION: H2S has protective effects on cerebral ischemia and reperfusion,which may be achieved by improving SOD activity,removing oxygen free radicals,inhibiting lipid peroxidation,and down-regulating the expression of HSP70 in the hippocampus.