The positive impact of smoking on poor sleep quality is moderated by IGF1 levels in cerebrospinal fluid: a case-control study among Chinese adults.

Objective: Previous research indicates associations between cigarette smoking, insulin-like growth factor-1 (IGF1), and sleep disturbances. This study aimed to examine the association between smoking and sleep quality and investigate the moderating role of IGF1. Methods: This case-control study involved 146 Chinese adult males (53 active smokers and 93 non-smokers) from September 2014 to January 2016. Sleep quality and disturbances were evaluated using the Pittsburgh Sleep Quality Index (PSQI), which includes seven scales. Pearson correlation analysis and logistic regression analysis were utilized to examine the link between IGF1 levels in cerebrospinal fluid (CSF) and PSQI scores. The effect of IGF1 was assessed using the moderation effect and simple slope analysis, with adjustments made for potential confounders. Results: Active smokers exhibited significantly higher global PSQI scores and lower IGF1 levels in CSF compared to non-smokers. A significant negative correlation was observed between IGF1 and PSQI scores (â = -0.28, P < 0.001), with a stronger association in non-smokers (Pearson r = -0.30) compared to smokers (Pearson r = -0.01). Smoking was associated with higher global PSQI scores (â = 0.282, P < 0.001), and this association was moderated by IGF1 levels in CSF (â = 0.145, P < 0.05), with a stronger effect at high IGF1 levels (Bsimple = 0.402, p < 0.001) compared to low IGF1 levels (Bsimple = 0.112, p = 0.268). Four subgroup analysis revealed similar results for sleep disturbances (Bsimple = 0.628, P < 0.001), with a marginal moderation effect observed on subjective sleep quality (Bsimple = 0.150, P = 0.070). However, independent associations rather than moderating effects were observed between IGF1 and sleep efficiency and daytime disturbance. Conclusion: We provided evidence to demonstrate the moderation effect of IGF1 on the relationship between smoking and sleep in CSF among Chinese adult males.

Association of cigarette smoking with cerebrospinal fluid biomarkers of insulin sensitivity and neurodegeneration.

INTRODUCTION: Cigarette smoking increases both the risk for insulin resistance and amyloid-ß (Aß) aggregation, and impaired brain insulin/insulin-like growth factor 1 (IGF1) signaling might increase risk factors for Alzheimer's disease (AD). We aimed to investigate the association among cerebrospinal fluid (CSF) insulin sensitivity/IGF1, glucose/lactate, and Aß42 and further explore whether insulin sensitivity contributed to the risk for AD in active smokers. METHODS: In this cross-sectional study, levels of insulin, IGF1, and lactate/glucose of 75 active smokers and 78 nonsmokers in CSF were measured. Three polymorphisms regulating IGF1 were genotyped. Analysis of variance was used to compare differences of variables between groups. Partial correlation was performed to test the relationship between CSF biomarkers and smoking status. General linear models were applied to test the interaction of the effect of single nucleotide polymorphisms and cigarette smoking on CSF IGF1 levels. RESULTS: In the CSF from active smokers, IGF1 and lactate levels were significantly lower (p = .016 and p = .010, respectively), whereas Aß42 (derived from our earlier research) and insulin levels were significantly higher (p < .001 and p = .022, respectively) as compared to the CSF from nonsmokers. The AG + GG genotype of rs6218 in active smokers had a significant effect on lower CSF IGF1 levels (p = .004) and lower CSF insulin levels in nonsmokers (p = .016). CONCLUSIONS: Cigarette smoking as the "at-risk" factor for AD might be due to lower cerebral insulin sensitivity in CSF, and the subjects with rs6218G allele seem to be more susceptible to the neurodegenerative risks for cigarette smoking.

An Update on Nondopaminergic Treatments for Motor and Non-motor Symptoms of Parkinson's Disease.

Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.

Associations of the serum kynurenine pathway metabolites with P50 auditory gating in non-smoking patients with first-episode schizophrenia.

Objective: Our study aimed to investigate the associations between the serum level of kynurenine pathway (KP) metabolites and P50 auditory gating in non-smoking patients with first-episode schizophrenia (FES). Materials and methods: In this study, 82 non-smoking patients with FES and 73 healthy controls (HC). P50 auditory gating was measured using a fully functional digital 64-channel EEG system, and the components included S1 amplitude, S2 amplitude, gating ratio (S2/S1), and amplitude difference (S1-S2). Serum levels of kynurenine and kynurenine acid were assessed using a combination of liquid chromatography with tandem mass spectrometry. Psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS). Results: The serum kynurenine (251.46 ± 65.93 ng/ml vs. 320.65 ± 65.89 ng/ml, t = -6.38, p < 0.001), and kynurenine acid levels (5.19 ± 2.22 ng/ml vs. 13.26 ± 4.23 ng/ml, t = -14.73, p < 0.001), S1 amplitude [2.88 (1.79, 3.78) µV vs. 3.08 (2.46, 4.56) µV, Z = -2.17, p = 0.030] and S1-S2 [1.60 (0.63, 2.49) µV vs. 1.92 (1.12, 2.93) µV, Z = -2.23, p = 0.026] in patients with FES were significantly lower than those in HC. The serum kynurenine and kynurenine acid levels were negatively associated with S1-S2 (r = -0.32, p = 0.004 and r = -0.42, p < 0.001; respectively) and positively correlated with S2/S1 ratio (r = 0.34, p = 0.002 and r = 0.35, p = 0.002; respectively) in patients. Conclusion: Our findings suggested that neuroactive metabolites of the KP might play an important role in sensory gating deficit in first episode patients with schizophrenia. Furthermore, metabolites of the KP may be a new target for the treatment of cognitive impairments in schizophrenia.

Cholinergic receptor nicotinic beta 3 subunit polymorphisms and smoking in male Chinese patients with schizophrenia.

OBJECTIVE: The aim of this study was to examine if cholinergic receptor nicotinic beta 3 subunit (CHRNB3) was a common genetic basis for both nicotine dependence and schizophrenia. METHODS: Two CHRNB3 promoter single nucleotide polymorphisms (SNPs) were genotyped in 773 patients with schizophrenia and 302 healthy volunteers. Associations between smoking, schizophrenia, smoking+schizophrenia and CHRNB3 were analyzed. The mRNA expression of CHRNB3 in human brains was examined, and the expression correlations between CHRNB3 and dopaminergic and GABAergic receptor genes were evaluated. RESULTS: The association between CHRNB3 and smoking was significant in the total sample, less significant in the smoking with schizophrenia, and suggestive in the smoking without schizophrenia. CHRNB3 had significant mRNA expression that was correlated with dopaminergic or GABAergic receptor expression in human brains. The two CHRNB3 SNPs had significant cis-acting regulatory effects on CHRNB3 mRNA expression. CONCLUSIONS: Risk for smoking behavior was associated with CHRNB3. CHRNB3 mRNA is abundant in human brain and could play important role in the pathogenesis of smoking behavior.

Effects of microRNA-181b-5p on cognitive deficits in first-episode patients with schizophrenia: Mediated by BCL-2.

MicroRNA (miR)-181b-5p is considered to be involved in the pathogenesis of schizophrenia, and one of its regulatory target genes BCL-2 (B-cell lymphoma 2) is suggested to associate with cognition of schizophrenia. Cognitive deficit is a core trait of schizophrenia. However, it remains unclear whether miR-181b-5p affects cognition and its possible pathway in schizophrenia. We hypothesized that miR-181b-5p affects cognition by targeting BCL-2 mRNA and downregulating BCL-2 protein expression in schizophrenia patients. In this study, first-episode patients with schizophrenia (FEPS, n = 123) and age- and gender-matched healthy controls (HCs, n = 50) were enrolled in Chinese populations. Expression levels of miR-181b-5p and BCL-2 mRNA in peripheral whole blood were measured with quantitative real-time PCR (Q-PCR) and BCL-2 protein in plasma were measured with Enzyme Linked Immunosorbent Assay (ELISA). Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS), cognitive function was evaluated using the MATRICS Consensus Cognitive Battery (MCCB). Peripheral blood miR-181b-5p expression level was significantly upregulated (p = 0.001) whereas BCL-2 mRNA and BCL-2 protein levels were significantly downregulated (p = 0.002, p = 0.023 respectively) in the FEPS compared with those in the HCs. The miR-181b-5p level was negatively (p = 0.005), whereas the BCL-2 mRNA level was positively (p < 0.001), correlated with working memory in FEPS. Mediating effect analysis showed that the effect of miR-181b-5p on working memory in the FEPS was exerted via targeting BCL-2 mRNA. MiR-181b-5p in combination with BCL-2 mRNA might be suggested as potential biomarker for schizophrenia in our discovery sample. In conclusion, overexpressed miR-181b-5p may affect cognitive function in patients with schizophrenia.

EXT1 methylation promotes proliferation and migration and predicts the clinical outcome of non-small cell lung carcinoma via WNT signalling pathway.

DNA methylation is important for lung cancer prognosis. In this work, it is aimed to seek novel biomarkers with DNA methylation-expression-pathway pattern and explore its underlying mechanism. Prognostic DNA methylation sites and mRNAs were screened in NSCLC data set from TCGA, and further validated using the samples retrospectively collected, and EXT1 was identified as a potential target. Gene body methylation of three CpG sites (cg03276982, cg11592677, cg16286281) on EXT1 was significantly associated with clinical outcome, and the EXT1 gene expression also predicted prognosis. The expression level of EXT1 was also correlated with its DNA methylation level. This observation was further validated in a new data set consist of 170 samples. Knocking down of EXT1 resulted in decreased proliferation and migration. EXT1 targets were analysed using GSEA. It is found that the WNT signalling is the potential downstream target of EXT1. Further analyses revealed that the EXT1 targets the beta-catenin and effect migration rate of NSCLC cell lines. The WNT signalling inhibitor, XAV-939, effectively disrupted the migration promotion effect induced by EXT1. In summary, EXT1 methylation regulates the gene expression, effects the proliferation and migration via WNT pathway and predicted a poor prognosis for NSCLC.

Significant, replicable, and functional associations between KTN1 variants and alcohol and drug codependence.

The gray matter volume (GMV) of the putamen has been reported to be regulated by kinectin 1 gene (KTN1). As a hub of the dopaminergic circuit, the putamen is widely implicated in the etiological processes of substance use disorders (SUD). Here, we aimed to identify robust and reliable associations between KTN1 SNPs and SUD across multiple samples. We examined the associations between SUD and KTN1 SNPs in four independent population-based or family-based samples (n = 10,209). The potential regulatory effects of the risk alleles on the putamen GMVs, the effects of alcohol, nicotine, marijuana and cocaine on KTN1 mRNA expression, and the relationship between KTN1 mRNA expression and SUD were explored. We found that a total of 23 SNPs were associated with SUD across at least two independent samples (1.4 × 10-4 ≤ p ≤ 0.049), including one SNP (rs12895072) across three samples (8.8 × 10-3 ≤ p ≤ 0.049). Four other SNPs were significantly or suggestively associated with SUD only in European-Australians (4.8 × 10-4 ≤ p ≤ 0.058). All of the SUD-risk alleles of these 27 SNPs increased (ß > 0) the putamen GMVs and represented major alleles (f > 0.5) in Europeans. Twenty-two SNPs were potentially biologically functional. Alcohol, nicotine and cocaine significantly affected the KTN1 mRNA expression, and the KTN1 mRNA was differentially expressed between nicotine or cocaine dependent and control subjects. We concluded that there was a replicable and robust relationship among the KTN1 variants, KTN1 mRNA expression, putamen GMVs, molecular effects of substances, and SUD, suggesting that some risk KTN1 alleles might increase kinectin 1 expression in the putamen, altering putamen structures and functions, and leading to SUD.

Replicated risk CACNA1C variants for major psychiatric disorders may serve as potential therapeutic targets for the shared depressive endophenotype.

Genome-wide association studies (GWASs) have reported numerous associations between risk variants and major psychiatric disorders (MPDs) including schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD) and others. We reviewed all of the published GWASs, and extracted the genome-wide significant (p<10-6) and replicated associations between risk SNPs and MPDs. We found the associations of 6 variants located in 6 genes, including L type voltage-gated calcium channel (LTCCs) subunit alpha1 C gene (CACNA1C), that were genome-wide significant (2.0×10 -8 ≤p≤1.0×10 -6 ) and replicated at single-point level across at least two GWASs. Among them, the associations between MPDs and rs1006737 within CACNA1C are most robust. Thus, as a next step, the expression of the replicated risk genes in human hippocampus was analyzed. We found CACNA1C had significant mRNA expression in human hippocampus in two independent cohorts. Finally, we tried to elucidate the roles of venlafaxine and ω-3 PUFAs in the mRNA expression regulation of the replicated risk genes in hippocampus. We used cDNA chip-based microarray profiling to explore the transcriptome-wide mRNA expression regulation by ω-3 PUFAs (0.72/kg/d) and venlafaxine (0.25/kg/d) treatment in chronic mild stress (CMS) rats. ω-3 PUFAs and venlafaxine treatment elicited significant CACNA1C up-regulation. We concluded that CACNA1C might confer the genetic vulnerability to the shared depressive symptoms across MPDs and CACNA1C might be the therapeutic target for depressive endophenotype as well.

B cell activation factor (BAFF) induces inflammation in the human fallopian tube leading to tubal pregnancy.

BACKGROUND: Tubal pregnancy is recognized as one of the most common ectopic pregnancy types. Salpingitis may result in tubal pregnancy by causing fallopian tube occlusion and hydrosalpinx. B cell activation factor (BAFF) is a proinflammatory cytokine that helps regulate both innate and adaptive immune responses. Our previous study firstly showed that BAFF immunostaining appeared on the cellular membrane and in the cytoplasm of tubal epithelial cells, and both BAFF protein and mRNA in human inflamed fallopian tubes had higher expression levels than those in normal fallopian tubes. This study aimed to elucidate the association between the expression of BAFF gene and the inflammation in the human fallopian tube leading to tubal pregnancy. METHODS: We examined 70 patients undergoing salpingectomy for salpingitis (n = 35) and tubal pregnancy (n = 35). Twenty patients with benign uterine diseases undergoing complete hysterectomy and salpingectomy were recruited into control group. BAFF mRNA and protein in tissue samples were detected by qPCR and Western blotting methods. Furthermore, serum levels of BAFF, tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were measured using ELISA kits. RESULTS: We found statistically significantly elevated expressions of BAFF mRNA or protein in whole tissue samples, and serum levels of BAFF, TNF-α and IL-6 in whole blood samples from patients with salpingitis and tubal pregnancy, in comparison to the control group. CONCLUSION: Based on the results, high expression of BAFF gene might induce inflammation in the human fallopian tube, suggesting its possible role in the tubal pregnancy process.

Transcriptome-wide piRNA profiling in human brains for aging genetic factors.

OBJECTIVE: Piwi-interacting RNAs (piRNAs) represent a molecular feature shared by all nonaging biological systems, including the germline and somatic cancer stem cells, which display an indefinite renewal capacity and lifespan-stable genomic integrity and are potentially immortal. Here, we tested the hypothesis that piRNA is a critical genetic determinant of aging in humans. METHODS: Expression of transcriptome-wide piRNAs (n=24k) was profiled in the human prefrontal cortex of 12 subjects (84.9±9.5, range 68-100, years of age) using microarray technology. We examined the correlation between these piRNAs' expression levels and age, adjusting for covariates including disease status. RESULTS: A total of 9,453 piRNAs were detected in brain. Including seven intergenic and three intronic piRNAs, ten piRNAs were significantly associated with age after correction for multiple testing (|r|=0.9; 1.9×10-5≤p≤9.9×10-5). CONCLUSION: We conclude that piRNAs might play a potential role in determining the years of survival of humans. The underlying mechanisms might involve the suppression of transposable elements (TEs) and expression regulation of aging-associated genes.

Principal component analysis of early alcohol, drug and tobacco use with major depressive disorder in US adults.

Early alcohol, tobacco and drug use prior to 18 years old are comorbid and correlated. This study included 6239 adults with major depressive disorder (MDD) in the past year and 72,010 controls from the combined data of 2013 and 2014 National Survey on Drug Use and Health (NSDUH). To deal with multicollinearity existing among 17 variables related to early alcohol, tobacco and drug use prior to 18 years old, we used principal component analysis (PCA) to infer PC scores and then use weighted multiple logistic regression analyses to estimate the associations of potential factors and PC scores with MDD. The odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. The overall prevalence of MDD was 6.7%. The first four PCs could explain 57% of the total variance. Weighted multiple logistic regression showed that PC1 (a measure of psychotherapeutic drugs and illicit drugs other than marijuana use), PC2 (a measure of cocaine and hallucinogens), PC3 (a measure of early alcohol, cigarettes, and marijuana use), and PC4 (a measure of cigar, smokeless tobacco use and illicit drugs use) revealed significant associations with MDD (OR = 1.12, 95% CI = 1.08-1.16, OR = 1.08, 95% CI = 1.04-1.12, OR = 1.13, 95% CI = 1.07-1.18, and OR = 1.15, 95% CI = 1.09-1.21, respectively). In conclusion, PCA can be used to reduce the indicators in complex survey data. Early alcohol, tobacco and drug use prior to 18 years old were found to be associated with increased odds of adult MDD.

Analysis of PTPRK polymorphisms in association with risk and age at onset of Alzheimer's disease, cancer risk, and cholesterol.

The human receptor-type protein-tyrosine phosphatase kappa (PTPRK) gene is highly expressed in human brain and was previously associated with an increased risk of neuropsychiatric disorders and cancer. This study investigated the association of 52 single nucleotide polymorphisms (SNPs) in PTPRK with the risk and age at onset (AAO) of Alzheimer's disease (AD) in 791 AD patients and 782 controls. Our data analysis showed that five SNPs (top SNP rs4895829 with p = 0.0125) were associated with the risk of AD based on a multiple logistic regression (p < 0.05); while six SNPs (top SNP rs1891150 with p = 8.02 × 10-6) were associated with AAO by using a multiple linear regression analysis. Interestingly, rs2326681 was associated with both the risk and AAO of AD (p = 4.65 × 10-2 and 5.18 × 10-3, respectively). In a replication study, the results from family-based association test - generalized estimating equation (GEE) statistics and Wilcoxon test showed that seven SNPs were associated with the risk of AD (top SNP rs11756545 with p = 1.02 × 10-2) and 12 SNPs were associated with the AAO (top SNP rs11966128 with p = 1.39 × 10-4), respectively. One additional sample showed that four SNPs were associated with risk of cancer (top SNP rs1339197 with p = 4.1 × 10-3), 12 SNPs associated with LDL-cholesterol (top SNP rs4544930 with p = 3.47 × 10-3), and eight SNPs associated with total cholesterol (top SNP rs1012049 with p = 6.09 × 10-3). In addition, the AD associated rs4895829 was associated with the gene expression level in the cerebellum (p = 7.3 × 10-5). The present study is the first study providing evidence of several genetic variants within the PTPRK gene associated with the risk and AAO of AD, risk of cancer, LDL and total cholesterol levels.

Resting-State Functional Connectivity of the Basal Nucleus of Meynert in Cigarette Smokers: Dependence Level and Gender Differences.

INTRODUCTION: Numerous studies have characterized impaired cerebral functioning in nicotine-addicted individuals. Whereas nicotine interacts with multiple neurotransmitters in cortical and subcortical circuits, it directly targets the cholinergic system, sourced primarily from the basal nucleus of Meynert (BNM). However, no studies have examined how this cholinergic system is influenced by cigarette smoking. Here, we addressed this gap of research. METHODS: Using a dataset from the Functional Connectome Projects, we investigated this issue by contrasting seed-based BNM connectivity of 40 current smokers and 170 age- and gender-matched nonsmokers. We followed our data analytic routines in recent work and examined differences between smokers and nonsmokers in men and women combined as well as separately. RESULTS: Compared to nonsmokers, female but not male smokers demonstrated greater positive BNM connectivity to the supplementary motor area, bilateral anterior insula, and right superior temporal/supramarginal gyri as well as greater negative connectivity to the posterior cingulate cortex and precuneus. Further, BNM connectivity to the supplementary motor area is negatively correlated to the Fagerström Test for Nicotine Dependence score in male but not female smokers. CONCLUSIONS: Along with a previous report of upregulated nicotinic acetylcholine receptor in male but not female smokers, these new findings highlight functional changes of the cholinergic systems in cigarette smokers. The results suggest sex-specific differences in cholinergic dysregulation and a need for multiple imaging modalities to capture the neural markers of nicotine addiction. IMPLICATIONS: Nicotine influences cognition via cholinergic projections of the basal forebrain to the cerebral cortex. This study examined changes in resting-state whole-brain functional connectivity of the BNM in cigarette smokers. The new findings elucidate for the first time sex differences in BNM-cerebral connectivity in cigarette smoking.

SNHG8 is identified as a key regulator of epstein-barr virus(EBV)-associated gastric cancer by an integrative analysis of lncRNA and mRNA expression.

The Epstein-Barr virus (EBV) is associated with a variety of cancers, including gastric cancer, which has one of the highest mortality rates of all human cancers. Long non-coding RNAs (lncRNAs) have been suggested to have important causal roles in gastric cancer. However, the interaction between lncRNAs and EBV has not yet been studied. To this end, we sequenced 11,311 lncRNAs and 144,826 protein-coding transcripts from four types of tissue: one non-EBV-infected gastric carcinoma (EBVnGC) and its adjacent normal tissue, and one EBV-associated gastric carcinoma (EBVaGC) and its adjacent normal tissue. Five lncRNAs showed EBVaGC-specific expression; of those, one (SNHG8) was validated using real-time PCR in an independent cohort with 88 paired gastric cancer and adjacent tissue samples. To explore the functions of SNHG8, we identified its mRNA targets on the lncRNA-mRNA co-expression network of the Illumina Body Map, which contains the RNA sequencing data of mRNAs and lncRNAs from 16 normal human tissues. SNHG8 lncRNA was found to affect several gastric cancer-specific pathways and target genes of EBV. Our results reveal the intertwined tumorigenesis mechanisms of lncRNA and EBV and identify SNHG8 as a highly possible candidate biomarker and drug target of gastric cancer.

Associations of rare nicotinic cholinergic receptor gene variants to nicotine and alcohol dependence.

Nicotine's rewarding effects are mediated through distinct subunits of nAChRs, encoded by different nicotinic cholinergic receptor (CHRN) genes and expressed in discrete regions in the brain. In the present study, we aimed to test the associations between rare variants at CHRN genes and nicotine dependence (ND), and alcohol dependence (AD). A total of 26,498 subjects with nine different neuropsychiatric disorders in 15 independent cohorts, which were genotyped on Illumina, Affymetrix, or PERLEGEN microarray platforms, were analyzed. Associations between rare variants (minor allele frequency (MAF) <0.05) at CHRN genes and nicotine dependence, and alcohol dependence were tested. The mRNA expression of all Chrn genes in whole mouse brain and 10 specific brain areas was investigated. All CHRN genes except the muscle-type CHRNB1, including eight genomic regions containing 11 neuronal CHRN genes and three genomic regions containing four muscle-type CHRN genes, were significantly associated with ND, and/or AD. All of these genes were expressed in the mouse brain. We conclude that CHRNs are associated with ND (mainly) and AD, supporting the hypothesis that the full catalog of ND/AD risk genes may contain most neuronal nAChRs-encoding genes. © 2016 Wiley Periodicals, Inc.

Associations of THBS2 and THBS4 polymorphisms to gastric cancer in a Southeast Chinese population.

Thrombospondin-2 (THBS2) and Thrombospondin-4 (THBS4) play an important role in cancer development and progression. However, genetic evidence for their roles in gastric cancer (GC) is lacking. The aim of this study was to explore the association of THBS2/THBS4 polymorphisms with risk and clinicopathological features of GC in a Southeast Chinese population. Eight tagging SNPs in THBS2 and THBS4 were genotyped in 761 GC cases and 739 controls from Chinese case-control sets using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. THBS2/THBS4 mRNA expression was studied in 82 human GC tumors and in mouse stomach tissues by real-time PCR. We found that both THBS2 and THBS4 were abundantly expressed in mouse stomach. THBS4 mRNA expression in human stomach was associated with tumor size (P = 0.002) and tumor-node-metastasis (TNM) (P = 0.010), and THBS2 mRNA expression was associated with the TNM (P = 0.010). Patients with the rs77878919^AG genotype were more prone to developing diffuse-type GC. THBS4 SNPs (rs77878919 and rs7736549) had a modest cumulative effect on the risk of poor prognosis (TNM), with that risk in the highest trend for patients carrying both these unfavorable genotypes. In addition, individuals carrying the THBS4 rs10474606 variant homozygous AA had a modest reduced GC risk. We conclude that THBS2/THBS4 may be functional in playing important role in GC, which was supported by the evidence of the mRNA overexpression in GC and the modest associations of THBS2/THBS4 polymorphisms to GC. These findings might be useful for risk assessment and prognosis prediction of GC.

Glutamate carboxypeptidase II gene knockout attenuates oxidative stress and cortical apoptosis after traumatic brain injury.

BACKGROUND: Glutamate carboxypeptidase II (GCPII) inactivates the peptide co-transmitter N-acetylaspartylglutamate following synaptic release. Inhibition of GCPII elevates extracellular levels of the peptide, inhibits glutamate release and is neuroprotective in an animal model of traumatic brain injury. GCPII gene knockout mice were used to examine the cellular mechanisms underlying the neuroprotective efficacy of this transmitter system. RESULTS: Following controlled cortical impact injury, GCPII knockout (KO) mice exhibited reduced TUNEL-positive nuclei in the contusion margin of the cerebral cortex relative to wild type mice. Impact injury reduced glutathione levels and superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde. Each of these effects was moderated in KO mice relative to wild type. Similarly, the injury-induced increases in cleaved caspase-3, cytosolic cytochrome c levels and Bcl-2/Bax ratio observed in wild type mice were attenuated in the knockout mice. CONCLUSIONS: These data support the hypothesis that the neuroprotective efficacy of GCPII KO in traumatic brain injury is mediated via a reduction in oxidative stress.

A functional polymorphism in the interleukin-1beta and severity of nicotine dependence in male schizophrenia: a case-control study.

Previous studies have shown that the functional 511C/T polymorphism in the IL-1beta-gene may be implicated in the susceptibility for schizophrenia. Moreover, recent studies suggested that IL-1 participates in the progression of lung disease in smokers, which are overrepresented in schizophrenia. We aimed to investigate the possible relationship between the IL-1beta-511C/T polymorphism and smoking behavior in schizophrenia versus healthy controls in a Chinese population. The IL-1beta-511C/T polymorphism was genotyped in 638 male patients with chronic schizophrenia (smoker/never-smoker = 486/152) and 469 male controls (smoker/never-smoker = 243/226). The cigarettes smoked per day, the Heaviness of Smoking Index (HSI) and the Fagerstrom Test for nicotine dependence (FTND) were assessed. Patients were also rated on the Positive and Negative Syndrome Scale (PANSS). The results showed no significant differences in genotype and allele distribution between patients and controls, and between smokers and never-smokers in either the patient or control group. However, in patients, smokers with the C/C genotype had significantly higher HSI (p < 0.005) and FTND (p < 0.05) scores than smokers with the T/T genotype, without significant differences in controls. Furthermore, there was a linear positive correlation between the number of C alleles and the HSI (p < 0.005) in patients. Our findings suggest that the IL-1beta-511C/T polymorphism may not be related to schizophrenia or smoking status in Chinese individuals, but may affect the severity of nicotine dependence among male smokers with schizophrenia.

Smoking and BDNF Val66Met polymorphism in male schizophrenia: a case-control study.

Some recent studies show an association between a functional polymorphism of BDNF gene (Val66Met) and the susceptibility to nicotine dependence and we hypothesized that this polymorphism was associated with smoking in both schizophrenia patients and healthy controls. The BDNF Val66Met gene polymorphism was genotyped in 690 chronic male schizophrenia patients (smoker/nonsmoker = 522/169) and 628 male controls (smoker/nonsmoker = 322/306) using a case-control design. Nicotine dependence (ND) was assessed by the cigarettes smoked per day (CPD), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). Patients also were rated on the Positive and Negative Syndrome Scale (PANSS). The results showed no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls or between smokers and nonsmokers in either patients or healthy controls alone. In patient groups, however, the smokers with the Met allele had significantly higher HSI scores (Met/Met: 2.8 ± 1.7 vs. Met/Val: 2.2 ± 1.7 vs. Val/Val: 2.0 ± 1.6, p < 0.01) and a trend toward a significantly higher FTND score (p = 0.09) than those with the Val/Val genotype. In addition, the smokers showed significantly lower PANSS negative symptom and total scores, longer duration of illness and more hospitalizations (all p < 0.05). In the control group, the smokers with the Met allele started smoking significantly earlier than those with the Val/Val genotype (both p < 0.05). These results suggest that the BDNF Val66Met polymorphism may affect a smoker's response to nicotine in both schizophrenia and healthy controls from a Chinese Han population, but with differential effects in different aspects of smoking behaviors.