RESUMEN
Humanin (HN) is a 24-residue peptide identified from the brain of a patient with Alzheimer's disease (AD). HN has been found to protect against neuronal insult caused by Aß peptides or transfection of familial AD mutant genes. In order to elucidate the molecular mechanisms of HN neuroprotection, we explored the effects of HN on the association of Bax or Bid with lipid bilayers and their oligomerization in the membrane. By using single-molecule fluorescence and Förster resonance energy transfer techniques, we showed that Bax was mainly present as monomers, dimers and tetramers in lipid bilayers, while truncated Bid (tBid) enhanced the membrane association and tetramerization of Bax. HN (100 nmol/L) inhibited the self-association and tBid-activated association of Bax with the bilayers, and significantly decreased the proportion of Bax in tetramers. Furthermore, HN inhibited Bid translocation to lipid bilayers. HN could bind with Bax and Bid either in solution or in the membrane. However, HN could not pull the proteins out of the membrane. Based on these results, we propose that HN binds to Bax and cBid in solution and inhibits their translocation to the membrane. Meanwhile, HN interacts with the membrane-bound Bax and tBid, preventing the recruitment of cytosolic Bax and its oligomerization in the membrane. In this way, HN inhibits Bax pore formation in mitochondrial outer membrane and suppresses cytochrome c release and mitochondria-dependent apoptosis.
Asunto(s)
Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Péptidos y Proteínas de Señalización Intracelular/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Membranas Mitocondriales/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Proteína X Asociada a bcl-2/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/genética , Citocromos c/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Membrana Dobles de Lípidos , Membranas Mitocondriales/metabolismo , Fármacos Neuroprotectores/metabolismo , Unión Proteica , Multimerización de Proteína , Transporte de Proteínas , Imagen Individual de Molécula , Proteína X Asociada a bcl-2/genéticaRESUMEN
Although gender differences in self-efficacy and subjective well-being have been reported in previous studies, little published research has investigated the interrelationships between these variables in adolescents. 648 Chinese adolescents were administered a series of questionnaires to test the hypothesis that self-efficacy mediates the relationship between gender and subjective well-being. The results indicated that adolescent girls had lower general self-efficacy than adolescent boys, which explained girls' lower subjective well-being. The theoretical and practical implications may help parents and educators to strengthen adolescents' happiness.
Asunto(s)
Desarrollo del Adolescente , Satisfacción Personal , Autoeficacia , Adolescente , China/etnología , Femenino , Humanos , Masculino , Factores SexualesRESUMEN
SIRT1 exerts protective effects against endothelial cells dysfunction, inflammation and atherosclerosis, indicating an important role on myocardial infarction (MI) pathogenesis. Nonetheless, the effects of SIRT1 variants on MI risk remain poorly understood. Here we aimed to investigate the influence of SIRT1 polymorphisms on individual susceptibility to MI. Genotyping of three tagSNPs (rs7069102, rs3818292 and rs4746720) in SIRT1 gene was performed in a Chinese Han population, consisting of 287 MI cases and 654 control subjects. In a logistic regression analysis, we found that G allele of rs7069102 had increased MI risk with odds ratio (OR) of 1.57 [95% confidence interval (CI) = 1.15-2.16, Bonferroni corrected P (Pc) = 0.015] after adjustment for conventional risk factors compared to C allele. Similarly, the combined CG/GG genotypes was associated with the increased MI risk (OR = 1.64, 95% CI = 1.14-2.35, Pc = 0.021) compared to the CC genotype. Further stratified analysis revealed a more significant association with MI risk among younger subjects (≤ 55 years old). Consistent with these results, the haplotype rs7069102G-rs3818292A-rs4746720T containing the rs7069102 G allele was also associated with the increased MI risk (OR = 1.41, 95% CI = 1.09-1.84, Pc = 0.040). However, we did not detect any association of rs3818292 and rs4746720 with MI risk. Our study provides the first evidence that the tagSNP rs7069102 and haplotype rs7069102G-rs3818292A-rs4746720T in SIRT1 gene confer susceptibility to MI in the Chinese Han population.
Asunto(s)
Predisposición Genética a la Enfermedad , Infarto del Miocardio/genética , Polimorfismo de Nucleótido Simple , Sirtuina 1/genética , Anciano , Alelos , Pueblo Asiatico/genética , China , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Abnormal lipids is one of the critical risk factors for myocardial infarction (MI), however the role of genetic variants in lipid metabolism-related genes on MI pathogenesis still requires further investigation. We herein genotyped three SNPs (LRP6 rs2302685, LDLRAP1 rs6687605, SOAT1 rs13306731) in lipid metabolism-related genes, aimed to shed light on the influence of these SNPs on individual susceptibility to MI. METHODS: Genotyping of the three SNPs (rs2302685, rs6687605 and rs13306731) was performed in 285 MI cases and 650 control subjects using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. The association of these SNPs with MI and lipid profiles was performed with SPSS software. RESULTS: Multivariate logistic regression analysis showed that C allele (OR = 1.62, P = 0.039) and the combined CT/CC genotype (OR = 1.67, P = 0.035) of LRP6 rs2302685 were associated with increased MI risk, while the other two SNPs had no significant effect. Further stratified analysis uncovered a more evident association with MI risk among younger subjects (≤60 years old). Fascinatingly, CT/CC genotype of rs2302685 conferred increased LDL-C levels compared to TT genotype (3.0 mmol/L vs 2.72 mmol/L) in younger subjects. CONCLUSIONS: Our data provides the first evidence that LRP6 rs2302685 polymorphism is associated with an increased risk of MI in Chinese subjects, and the association is more evident among younger individuals, which probably due to the elevated LDL-C levels.