5-羟色胺受体基因多态性位点与海洛因依赖的关联性研究

目的：5-HT（5-hydroxytryptamine,5-HT）参与了多种中枢神经活动的生理过程,其功能异常可以影响很多行为障碍,已有研究显示,5-HT水平与多种精神疾病密切相关。5-HT受体及其转运体基因在海洛因依赖发生发展中起到了重要的作用,是海洛因依赖的主要候选基因。探讨5羟色胺2A受体（Serotonin 2A receptor,HTR2A）基因启动子区-1438A/G（rs6311）、外显子区102T/C（rs6313）与5羟色胺1B受体（Serotonin 1B receptor,HTR1B）基因外显子区861G/C（rs6296）3个单核苷酸多态性和海洛因依赖的关联性分析。方法：严格按照诊断标准,选取无亲缘关系的海洛因依赖个体616例及健康个体600例提取基因组DNA,采用PCR-RFLP方法检测rs6311、rs6313和rs6296 3个SNPs位点的基因型频率,采用SPSS16.0软件分析各位点等位基因、基因型频率在病例-对照组间差异。结果：HTR2A基因rs6311和HTR1B基因rs6296位点的等位基因及基因型频率分布在2组间存在统计学差异（P〈0.05）,病例组rs6311位点的等位基因A频率显著高于对照组（X2=5.436,P=0.020,OR=1.208,CI=1.031~1.417）,rs6296位点的等位基因C频率显著高于对照组（X2=12.116,P=0.000,OR=1.329,CI=1.132~1.560）。连锁不平衡检验结果显示,HTR2A基因rs6311、rs6313位点处于不连锁状态,D＇〈0.5。结论：HTR2A基因rs6311和HTR1B基因rs6296多态性可能与海洛因成瘾有关,携带有rs6311 A等位基因与rs6296 C等位基因的人可能更容易对海洛因产生依赖。我们的研究为海洛因依赖易感人群筛选及药物靶向治疗提供了理论依据。     

A set of Arabidopsis thaliana miRNAs involve shoot regeneration in vitro

Plant miRNAs, the critical regulator of gene expression, involve many development processes in vivo. However, the roles of miRNAs in plant cell proliferation and redifferntiation in vitro remain unknown. To determine better the molecular mechanism of these processes, we have recently reported that a set of miRNAs with different expression patterns between cells of totipotent and non-totipotent Arabidopsis calli. Some of these were specifically up- or downregulated during callus formation or shoot regeneration, and other development. Among them, miR160, and one of its target genes, ARF10, regulated Arabidopsis in vitro shoot regeneration via WUS, CLV3 and CUC1/2. The miR160-overexpressing, 35S transgenic lines, exhibited reduced shoot regeneration efficiency. The mARF10, a miR160-resistant form of ARF10, showed a high level of shoot regeneration ability. In the transgenic, expression of the above shoot meristem-specific genes was elevated, which is consistent with the improved shoot regeneration. In contrast, the ARF10 deficient knockout mutant produced fewer regenerated shoot. However, overexpressors of ARF10 were only marginally more efficient than the wild type with the respect to shoot regeneration. Our observation strongly supports that proper shoot regeneration from in vitro cultured cells requires the miR160-directed negative influence of ARF10. The enhanced expression of ARF10 is likely to have contributed to the improved regeneration ability.     

Developmental expression of P2X5 receptors in the mouse prenatal central and peripheral nervous systems

The functions of P2X purinoceptors (P2X1-7) in the nervous system of adults have been widely studied. However, little is known about their roles during embryonic development. Our previous work has reported an extensive expression of P2X5 receptors in the adult mouse central nervous system. In the present study, we have examined the expression pattern of P2X5 receptor mRNA and protein during prenatal development of the mouse nervous system (from embryonic day E8 to E17). P2X5 receptors appeared in the neural tube as early as E8 and were gradually confined to new-born neurons in the cortical plate and ventral horn of the spinal cord. Heavy signals for P2X5 receptors were also found in dorsal root ganglia (DRG), retina, olfactory epithelium, and nerve fibers in skeletal muscles. In conclusion, P2X5 receptors were strongly represented in the developing mouse nervous system. The transient high expression pattern of P2X5 receptors in epithelium-like structures suggests a role during early neurogenesis.     

Block of P2X7 receptors could partly reverse the delayed neuronal death in area CA1 of the hippocampus after transient global cerebral ischemia

Transient global ischemia (which closely resembles clinical situations such as cardiac arrest, near drowning or severe systemic hypotension during surgical procedures), often induces delayed neuronal death in the brain, especially in the hippocampal CA1 region. The mechanism of ischemia/reperfusion (I/R) injury is not fully understood. In this study, we have shown that the P2X7 receptor antagonist, BBG, reduced delayed neuronal death in the hippocampal CA1 region after I/R injury; P2X7 receptor expression levels increased before delayed neuronal death after I/R injury; inhibition of the P2X7 receptor reduced I/R-induced microglial microvesicle-like components, IL-1β expression, P38 phosphorylation, and glial activation in hippocampal CA1 region after I/R injury. These results indicate that antagonism of the P2X7 receptor and signaling pathways of microglial MV shedding, such as src-protein tyrosine kinase, P38 MAP kinase and A-SMase, might be a promising therapeutic strategy for clinical treatment of transient global cerebral I/R injury.     

Genome-Wide Association Analysis with Gray Matter Volume as a Quantitative Phenotype in First-Episode Treatment-Na?ve Patients with Schizophrenia

Reduced Gray matter (GM) volume is a core feature of schizophrenia. Mapping genes that is associated with the heritable disease-related phenotypes may be conducive to elucidate the pathogenesis of schizophrenia. This study aims to identify the common genetic variants that underlie the deficits of GM volume in schizophrenia. High-resolution T1 images and whole genome genotyping data were obtained from 74 first-episode treatment-naïve patients with schizophrenia and 51 healthy controls in the Mental Health Centre of the West China Hospital, Sichuan University. All participants were scanned using a 3T MR imaging system and were genotyped using the HumanHap660 Bead Array. Reduced GM volumes in three brain areas including left hOC3v in the collateral sulcus of visual cortex (hOC3vL), left cerebellar vermis lobule 10 (vermisL10) and right cerebellar vermis lobule 10 (vermisR10) were found in patients with schizophrenia. There was a group by genotype interaction when genotypes from genome-wide scan were subsequently considered in the case-control analyses. SNPs from three genes or chromosomal regions (TBXAS1, PIK3C2G and HS3ST5) were identified to predict the changes of GM volume in hOC3vL, vermisL10 and vermisR10. These results also highlighted the usefulness of endophenotype in exploring the pathogenesis of neuropsychiatric diseases such as schizophrenia although further independent replication studies are needed in the future.     

Estimation of Short-Term Effects of Air Pollution on Stroke Hospital Admissions in Wuhan,China

Background and Objective

High concentrations of air pollutants have been linked to increased incidence of stroke in North America and Europe but not yet assessed in mainland China. The aim of this study is to evaluate the association between stroke hospitalization and short-term elevation of air pollutants in Wuhan, China.

Methods

Daily mean NO₂, SO₂ and PM₁₀ levels, temperature and humidity were obtained from 2006 through 2008. Data on stroke hospitalizations (ICD 10: I60–I69) at four hospitals in Wuhan were obtained for the same period. A time-stratified case-crossover design was performed by season (April-September and October-March) to assess effects of pollutants on stroke hospital admissions.

Results

Pollution levels were higher in October-March with averages of 136.1 µg/m³ for PM₁₀, 63.6 µg/m³ for NO₂ and 71.0 µg/m³ for SO₂ than in April-September when averages were 102.0 µg/m³, 41.7 µg/m³ and 41.7 µg/m³, respectively (p<.001). During the cold season, every 10 µg/m³ increase in NO₂ was associated with a 2.9% (95%C.I. 1.2%–4.6%) increase in stroke admissions on the same day. Every 10 ug/m³ increase in PM₁₀ daily concentration was significantly associated with an approximate 1% (95% C.I. 0.1%–1.4%) increase in stroke hospitalization. A two-pollutant model indicated that NO₂ was associated with stroke admissions when controlling for PM₁₀. During the warm season, no significant associations were noted for any of the pollutants.

Conclusions

Exposure to NO₂ is significantly associated with stroke hospitalizations during the cold season in Wuhan, China when pollution levels are 50% greater than in the warm season. Larger and multi-center studies in Chinese cities are warranted to validate our findings.     

The Leptin Gene Family and Colorectal Cancer: Interaction with Smoking Behavior and Family History of Cancer

Background

Pathologic condition associated with metabolic syndrome traits seems to increase the risk of colorectal cancer. One mechanism underlying this relationship may involve the growth-promoting effects of the circulation hormones associated with obesity and insulin resistance, such as leptin.

Methodology/Principal Findings

A two-stage case-control study was used to explore the role of polymorphisms of Leptin (LEP) and Leptin receptor (LEPR), either alone or in combination with environmental factors in colorectal carcinogenesis. In stage 1, 20 single nucleotide polymorphisms (SNPs) that tag common SNPs in these two genes were genotyped among 470 cases and 458 controls. In stage 2, another population with 314 cases and 355 controls were genotyped for the two most promising SNPs from stage 1. LEPR rs12037879 only presented modestly increased colorectal cancer risk, with odds ratios of 1.41 (95% confidence interval [CI] 1.13–1.76) and 1.74 (95%CI 1.08–2.81) for GA and AA genotype when compared with GG genotype in combined population. Smokers carrying LEPR rs12037879 A allele presented 1.67-fold (95%CI 1.39-fold to 2.01-fold) increased colorectal cancer risk when compared with non-smokers carrying GG genotype in combined analysis. Individuals with family history of cancer harboring LEPR rs12037879 A allele showed 1.52-fold (95%CI: 1.24-fold to 1.86-fold) increased colorectal cancer risk, compared with individuals without family history of cancer harboring GG genotype. Multifactor gene-environment interaction analysis revealed significant interactions among LEPR rs12037879, LEPR rs6690625, smoking status and family history of cancer, exhibiting a gradient of increased colorectal cancer risk along with the increasing number of risk factors (P = 9.82×10⁻¹⁰).

Conclusions/Significance

Our research supports that polymorphisms in LEPR may be associated with marginal increase in the risk for colorectal cancer. Moreover, this association could be strengthened by cigarette smoking and family history of cancer.     

SPLUNC1 Regulates Cell Progression and Apoptosis through the miR-141-PTEN/p27 Pathway,but Is Hindered by LMP1

Little is known about the role of the host defensive protein short palate, lung and nasal epithelium clone 1 (SPLUNC1) in the carcinogenesis of nasopharyngeal carcinoma (NPC). Here we report that SPLUNC1 plays a role at a very early stage of NPC carcinogenesis. SPLUNC1 regulates NPC cell proliferation, differentiation and apoptosis through miR-141, which in turn regulates PTEN and p27 expression. This signaling axis is negatively regulated by the EBV-coded gene LMP1. Therefore we propose that SPLUNC1 suppresses NPC tumor formation and its inhibition by LMP1 provides a route for NPC tumorigenesis.     

Genetic Variation in BCL2 3′-UTR Was Associated with Lung Cancer Risk and Prognosis in Male Chinese Population

Objectives

Bcl-2 is a critical apoptosis inhibitor with established carcinogenic potential, and can confer cancer cell resistance to therapeutic treatments by activating anti-apoptotic cellular defense. We hypothesized that genetic variants of BCL2 gene may be associated with lung cancer susceptibility and prognosis.

Methods

Three selected tagSNPs of BCL2 (rs2279115, rs1801018, and rs1564483) were genotyped in 1017 paired male Chinese lung cancer cases and controls by TaqMan assay. The associations of these variants with risk of lung cancer and overall survival of 242 male advanced non-small-cell lung cancer (NSCLC) patients were separately investigated.

Results

Compared with the BCL2 3′UTR rs1564483GG genotype, the rs1564483GA, AA, and GA+AA genotypes were associated with significantly decreased susceptibilities of lung cancer in male Chinese (adjusted OR = 0.78, 0.73, and 0.76, P = 0.016, 0.038, and 0.007, respectively), while rs1564483A allele has a inverse dose-response relationship with lung cancer risk (P _trend = 0.010). These effects were more evident in the elders, smokers, and subjects without family history of cancer (P _trend = 0.017, 0.043 and 0.005, respectively). Furthermore, advanced NSCLC males carrying BCL2 rs1564483 GA+AA genotypes had significantly longer median survival time (Long-rank P = 0.036) and decreased death risk (adjusted HR = 0.69, P = 0.027) than patients with rs1564483GG genotype. These effects were more obvious in patients with smoking, stage IIIA, and in patients without surgery but underwent chemotherapy or radiotherapy (adjusted HR = 0.68, 0.49, 0.67, 0.69, 0.50, respectively, all P<0.05).

Conclusion

The BCL2 3′UTR rs1564483A allele was associated with a decreased lung cancer risk and better survival for advanced NSCLC in male Chinese, which may offer a novel biomarker for identifying high-risk population and predicting clinical outcomes.     

Nitric Oxide Mediates Root K+/Na+ Balance in a Mangrove Plant,Kandelia obovata,by Enhancing the Expression of AKT1-Type K+ Channel and Na+/H+ Antiporter under High Salinity

It is well known that nitric oxide (NO) enhances salt tolerance of glycophytes. However, the effect of NO on modulating ionic balance in halophytes is not very clear. This study focuses on the role of NO in mediating K⁺/Na⁺ balance in a mangrove species, Kandelia obovata Sheue, Liu and Yong. We first analyzed the effects of sodium nitroprusside (SNP), an NO donor, on ion content and ion flux in the roots of K. obovata under high salinity. The results showed that 100 μM SNP significantly increased K⁺ content and Na⁺ efflux, but decreased Na⁺ content and K⁺ efflux. These effects of NO were reversed by specific NO synthesis inhibitor and scavenger, which confirmed the role of NO in retaining K⁺ and reducing Na⁺ in K. obovata roots. Using western-blot analysis, we found that NO increased the protein expression of plasma membrane (PM) H⁺-ATPase and vacuolar Na⁺/H⁺ antiporter, which were crucial proteins for ionic balance. To further clarify the molecular mechanism of NO-modulated K⁺/Na⁺ balance, partial cDNA fragments of inward-rectifying K⁺ channel, PM Na⁺/H⁺ antiporter, PM H⁺-ATPase, vacuolar Na⁺/H⁺ antiporter and vacuolar H⁺-ATPase subunit c were isolated. Results of quantitative real-time PCR showed that NO increased the relative expression levels of these genes, while this increase was blocked by NO synthesis inhibitors and scavenger. Above results indicate that NO greatly contribute to K⁺/Na⁺ balance in high salinity-treated K. obovata roots, by activating AKT1-type K⁺ channel and Na⁺/H⁺ antiporter, which are the critical components in K⁺/Na⁺ transport system.