Attenuated and delayed niacin skin flushing in schizophrenia and affective disorders: A potential clinical auxiliary diagnostic marker.

AIM: Schizophrenia and affective disorders all show high heterogeneity in clinical manifestations. A lack of objective biomarkers has long been a challenge in the clinical diagnosis of these diseases. In this study, we aimed to investigate the performance of niacin skin flushing in schizophrenia and affective disorders and determine its clinical potential as an auxiliary diagnostic marker. METHODS: In this case-control study, niacin skin-flushing tests were conducted in 613 patients (including 307 schizophrenia patients, 179 bipolar disorder patients, and 127 unipolar depression patients) and 148 healthy controls (HCs) with a modified method. Differences in niacin skin-flushing responses were compared with adjustment for gender, BMI, age, nicotine dependence, alcohol consumption and educational status. A diagnostic model was established based on a bivariate cut-off. RESULTS: Schizophrenia and affective disorders showed similar performance of niacin bluntness, characterized by attenuated flushing extent and reduced flushing rate. An innovative bivariate cut-off was established according to these two features, by which we could identify -patients with either schizophrenia or affective disorders from HCs with a sensitivity of 55.28%, a specificity of 83.56% and a positive predictive value of 93.66%. CONCLUSIONS: The niacin-induced skin flushing was prevalently blunted in patients with schizophrenia or affective disorders, indicating a promising potential as an auxiliary diagnostic marker in risk prediction and clinical management of these disorders. Additionally, the niacin-blunted subgroup implies a common biological basis in the investigated disorders, which provokes new thoughts in elucidating the pathological mechanisms.

Antithrombin, an Important Inhibitor in Blood Clots.

Blood coagulation is healthy and lifesaving because it can stop bleeding. It can, however, be a troublemaker as well, causing serious medical problems including heart attack and stroke. Body has complex blood coagulation cascade to modulate the blood clots. In the environment of plasma, the blood coagulation cascade is regulated by antithrombin, which is deemed one of the most important serine protease inhibitors. It inhibits thrombin; it can inhibit factors IXa and Xa as well. Interestingly, its inhibitory ability will be significantly increased with the existence of heparin. In this minireview paper, we are to summarize the structural features of antithrombin, as well as its heparin binding modes and anti-coagulation mechanisms, in hopes that the discussion and analysis presented in this paper can stimulate new strategies to find more effective approaches or compounds to modulate the antithrombin.

The effects of SP110's associated genes on fresh cavitary pulmonary tuberculosis in Han Chinese population.

SP110 is a promising anti-Mycobacterium tuberculosis (MTB) gene. To investigate the effects of SP110 and its associated genes, i.e., MYBBP1A and RELA, on pathological progression of MTB infection, an association study with 424 patients of fresh pulmonary tuberculosis (PTB) and 424 healthy controls was performed. Moreover, classification and regression tree and multifactor dimensionality reduction were employed to explore the effects of gene-gene interactions on cavitary PTB. The results indicated that both the heterozygous genotype GC and homozygous genotype CC in rs3809849 had significant effects on the risk of PTB (OR 1.42, 95 % CI 1.06-1.92, p 0.019; OR 1.55, 95 % CI 1.04-2.33, p = 0.033, respectively), and heterozygous genotype CT in rs9061 also had similar effects (OR 1.43, 95 % CI 1.07-1.90, p = 0.014). The rs3809849 and rs9905742 in MYBBP1A were also significantly associated with cavitary PTB (p = 0.00046 and 0.039, respectively), while rs9061 in SP110 had no such association (p = 0.06931) except its significant association with non-cavitary PTB (p = 0.0093). The interaction of MYBBP1A and RELA had significant effect on cavitary PTB (OR 4.24, 95 % CI 1.44-12.49, p = 0.005). These suggest that MYBBP1A instead of SP110 may be a genetic risk factor for cavitary PTB and play important effects on its whole progress.

Meta-Analysis-Based Preliminary Exploration of the Connection between ATDILI and Schizophrenia by GSTM1/T1 Gene Polymorphisms.

Anti-tuberculosis drugs have some adverse effects such as anti-tuberculosis drug-induced liver injury (ATDILI) and mental disorders. The involvement of glutathione S-transferase (GST) genes in pathogenesis of ATDILI or schizophrenia (SCZ) has been reported. Therefore, GST genes may exemplify molecular connectors between ATDILI and SCZ. However, association studies of GSTM1/T1 polymorphisms with these two diseases have yielded conflicting results. After searching case-control association studies in PubMed, ISI Web of Science, EMBASE, Chinese National Knowledge Infrastructure (CNKI), and Chinese BioMedical Literature Database, we performed meta-analyses across a total of 20 published association studies on 3146 subjects for the association of GSTM1 and ATDILI, 2587 for the GSTT1-ATDILI association, 2283 for GSTM1-SCZ and 1116 for GSTT1-SCZ to test the associations of GSTM1/T1 polymorphisms with ATDILI and SCZ. The GSTM1 present genotype was significantly associated with decreased risks of ATDILI (risk ratio(RR): 0.81, 95% confidence interval (CI): 0.75-0.88, P < 0.0001) and SCZ (RR: 0.88, 95%CI: 0.80-0.96, P = 0.004) according to the fixed-effect model, while the GSTT1 present genotype was significantly associated only with a high risk of SCZ (RR: 1.17, 95%CI: 1.04-1.32, P = 0.01) according to both the random- and fixed-effect models, but not with ATDILI (P = 0.82) according to the fixed-effect model. Moreover, these significant results were supported with moderate evidence according to the Venice criteria. These results indicate that GSTM1 represents a genetic connection between ATDILI and SCZ, and suggest that ATDILI and SCZ may be co-occurring for the subjects with GSTM1 null genotype.

Role of Nogo­A in the regulation of hepatocellular carcinoma SMMC­7721 cell apoptosis.

Nogo-A has been identified as an inhibitor of neurite outgrowth specific to the central nervous system. However, little is known about the role of Nogo-A in hepatocellular carcinoma (HCC), the most common primary malignant tumor with a high mortality rate. This study aimed to investigate the role of endogenous Nogo-A in human liver cancer cells. Reverse transcription polymerase chain reaction was used to detect the expression of Nogo-A in four liver cancer cell lines. A lentivirus vector was then constructed to mediate RNA interference (RNAi) targeting of Nogo­A (LV­Nogo-A­siRNA) and was confirmed to successfully suppress the expression of the Nogo-A gene in SMMC-7721 cells. Furthermore, Nogo-A was observed to be highly expressed in liver cancer cell lines. RNAi of Nogo-A using the LV­Nogo-A­siRNA construct significantly decreased Nogo-A protein expression and specifically inhibited the growth of SMMC-7721 cells. This growth inhibitory effect may be attributed to an increase in G2/M phase arrest and apoptosis in SMMC-7721 cells containing Nogo-A­siRNA. The results of this study demonstrate that Nogo-A may represent a novel therapeutic target for the treatment of liver cancer, in addition to its potent roles in neural systems.

Identification of genetic associations of SP110/MYBBP1A/RELA with pulmonary tuberculosis in the Chinese Han population.

Genetic factors play important roles in the development of tuberculosis (TB). SP110 is a promising candidate target for controlling TB infections. However, several studies associating SP110 single nucleotide polymorphisms (SNPs) with TB have yielded conflicting results. This may be partly resolved by studying other genes associated with SP110, such as MYBBP1A and RELA. Here, we genotyped 6 SP110 SNPs, 8 MYBBP1A SNPs and 5 RELA SNPs in 702 Chinese pulmonary TB patients and 425 healthy subjects using MassARRAY and SNaPshot methods. Using SNP-based analysis with Bonferroni correction, rs3809849 in MYBBP1A [Pcorrected (cor) = 0.0038] and rs9061 in SP110 (Pcor = 0.019) were found to be significantly associated with TB. Furthermore, meta-analysis of rs9061 in East Asian populations showed that the rs9061 T allele conferred significant risk for TB [P = 0.002, pooled odds ratio (OR), 1.24, 95% confidence interval (CI) = 1.08-1.43]. The MYBBP1A GTCTTGGG haplotype and haplotypes CGACCG/TGATTG within SP110 were found to be markedly and significantly associated with TB (P = 2.00E-06, 5.00E-6 and 2.59E-4, respectively). Gene-based analysis also demonstrated that SP110 and MYBBP1A were each associated with TB (Pcor = 0.011 and 0.035, respectively). The logistic regression analysis results supported interactions between SP110 and MYBBP1A, indicating that subjects carrying a GC/CC genotype in MYBBP1A and CC genotype in SP110 possessed the high risk of developing TB (P = 1.74E-12). Our study suggests that a combination of SP110 and MYBBP1A gene polymorphisms may serve as a novel marker for identifying the risk of developing TB in the Chinese Han population.

Association between a COMT polymorphism and clinical response to risperidone treatment: a pharmacogenetic study.

A total of 130 Chinese schizophrenic patients (45 male, 85 female) were enrolled in the study. Clinical efficacy was determined using Brief Psychiatric Rating Scale (BPRS) scores. We genotyped 10 single-nucleotide polymorphisms (SNPs) of the catechol-O-methyl transferase gene (COMT) in our patients and re-examined them for association with changes in BPRS scores after 8 weeks of risperidone monotherapy. COMT is one of the genes that confer susceptibility to schizophrenia, both because of its role in neurotransmitter metabolism and because of its location in the high-risk schizophrenia-related region 22q11. Recent studies also found that COMT functional polymorphisms influenced individual response to antipsychotic medication. Our aim in this study was to explore the influence of COMT polymorphisms on pharmacological response to risperidone in the Chinese population. Statistical analysis revealed a significant association between an upstream COMT SNP, rs9606186, and scores reduction of BPRS in all patients and in the male subgroup but not in the female subgroup (allele analysis: P=0.055 for all, P=0.012 for male patients; genotype analysis: P=0.046 for all, P=0.020 for male patients, uncorrected, odds ratio=3.95). The COMT gene polymorphism, SNP rs9606186, is associated with risperidone therapy efficiency in the Chinese population. This association exhibited a sexually dimorphic difference, which may shed light on the genetics of COMT and its enzymatic sex-dependent mechanism.

HTR2C promoter polymorphisms are associated with risperidone efficacy in Chinese female patients.

AIMS: A number of studies demonstrate that the polymorphisms in the 5 region of HTR2C play a pivotal role in antipsychotic drug efficacy. Since risperidone is an antagonist of HTR2C, polymorphic variations in HTR2C may explain variability in response to risperidone treatment. We analyzed HTR2C polymorphisms for association with efficacy of risperidone monotherapy. MATERIALS & METHODS: We genotyped five SNPs distributed throughout the HTR2C gene and examined them for association using the Brief Psychiatric Rating Scale score in 130 Chinese schizophrenic patients following an 8-week period of risperidone monotherapy. All the patients were receiving the atypical antipsychotic drug treatment for the first time and had a 4-week medication-free period before research began. RESULTS: We found rs518147, rs1023574 and rs9698290 were significantly associated with risperidone treatment in female patients (F = 4.75, degrees of freedom = 2 and p = 0.011; F = 4.329, degrees of freedom = 2 and p = 0.016; F = 4.188, degrees of freedom = 2 and p = 0.019, respectively) and they were also found to be in one linkage disequilibrium block. CONCLUSION: Our results indicate that variants in the HTR2C promoter region are likely to affect the risperidone therapeutic effect in female mainland patients. It may be helpful to investigate a combination of other clinical factors to predict atypical antipsychotic efficacy.

No association between EGR gene family polymorphisms and schizophrenia in the Chinese population.

Early growth response (EGR) genes are thought to have a role in the pathogenesis of schizophrenia because of their conserved DNA binding domain and biologically activity in neuronal plasticity. This zinc-finger motif could influence gene post-translational modification and expression. The multigenetic association model, using markers in genes of similar or antagonistic biological effects within a signal pathway or gene family, might be more appropriate to this aspect of the schizophrenia hypothesis than the single gene strategy. In this study we investigated the role of EGR1, EGR2, EGR3 and EGR4 within the EGR family. Taqman technology was used to examine 12 single nucleotide polymorphisms (SNPs) covering these four genes in 2044 Chinese Han subjects. Case-control analyses were performed to detect association of these 4 genes with schizophrenia and multifactor dimensionality reduction (MDR) analysis was employed to examine their potential gene-gene interaction in schizophrenia. Neither allelic nor genotypic single-locus tests revealed any significant association between EGR1-4 and the risk of schizophrenia nor was any such association found with regard to interaction within EGR1-4 (p(min)=0.623, CV Consistency=10/10). We concluded that although multiple candidate genes are involved in schizophrenogenic development, the EGR family may not play a major role in schizophrenia susceptibility in the Chinese Han population.

Identification of the proteins related to cytochrome P450 induced by fenvalerate in a Trichoplusia ni cell line.

In order to reveal the metabolic reaction to the presence of fenvalerate mediated by P450 in insects, we used the trypan blue exclusion technique and 3-(4,5-dimethylthiazol)-2,5-diphenyltrazolium bromide (MTT) reduction assay to assess the vitality of Trichoplusia ni (Tn) cells treated with fenvalerate, and observed dose- and time-dependent changes in total cellular P450s. In addition, two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) were used to identify the proteins involved in the fenvalerate reaction process. Finally, the cDNA of P450 fragments was cloned and real-time RT-PCR was performed. Our data showed that at the 0-15 mumol/L challenge concentration of fenvalerate, at which the vitality of Tn cells was not affected (p > 0.05), there was a tendency toward a dose- and time-response of total cellular P450s, which peaked at the 9 h (p < 0.05) and 12 h (p < 0.01) time points following 12.5 mumol/L stimulation with fenvalerate. The 2-DE assay detected more than 1300 protein spots in each two-dimensional gel, of which 33 spots displayed significant differences. Among the changed spots, three isoforms of P450 were identified. One of the three P450 cDNA fragments (CYP4L4) was cloned and sequenced, and its expression in treated Tn cells increased significantly (p < 0.01). It was found that fenvalerate induced the expression of P450s in insect cells. This suggests that fenvalerate could be metabolized by CYP4L4 through a hydroxylation reaction in insect cells.

Association between the brain-derived neurotrophic factor (BDNF) gene and schizophrenia in the Chinese population.

Brain-derived neurotrophic factor (BDNF) belongs to a family of the neurotrophin which plays important roles in the development of the brain. BDNF has been suggested as a factor that increases the risk of schizophrenia. In this study, we genotyped three single nucleotide polymorphisms (SNPs) in the BDNF gene using a set sample of Han Chinese subjects consisting of 560 schizophrenes and 576 controls. No significant differences were found for either the genotype or allele distribution of analyzed polymorphisms, nor was any gender-specific association found. Thus, our data suggest that the BDNF gene may not be an important factor in susceptibility to schizophrenia.

Neither the tumor necrosis factor alpha-308 A/G polymorphism nor the alpha2-macroglobulin polymorphism was associated with late-onset Alzheimer's disease in the Chinese population.

Late-onset Alzheimer's disease (LOAD) is the most common cause of dementia in the elderly. It is a complex and genetically heterogeneous disorder. Epidemiological studies demonstrated that nonsteroidal anti-inflammatory drugs could prevent or delay the onset of LOAD suggesting inflammation may be involved in AD. Tumor necrosis factor (TNF) is a potent immunomodulator and it might increase the production of amyloid beta(Abeta), which makes it an appropriate AD candidate gene. Alpha2 macroglobulin (A2M) is a serum protease inhibitor and a major low-density lipoprotein receptor-related protein (LRP) ligand. It can bind Abeta and mediate its clearance and degradation, suggesting it might be another AD candidate gene. In the present study, we analyzed the a 5 bp Ins/Del polymorphism of A2M gene (A2M-2), TNF alpha-308 A/G polymorphism and apolipoprotein E (APOE) polymorphisms of 67 sporadic late-onset AD patients and 142 normal elderly controls in the Chinese population. Our data showed that the APOE epsilon4 allele frequency in AD was significantly higher than that in the normal controls (chi2 = 11.66, P < 0.01) neither the frequencies of genotypes nor alleles of the TNF alpha-308 A/G and A2M polymorphisms were significantly different between AD and controls,suggesting the two polymorphisms were not risk factors to LOAD in Chinese.

[Role of uncoupling proteins in the pathogenesis of obesity and type II diabetes].

Uncoupling proteins (UCPs) are mitochondria carrier proteins,which are able to dissipate the proton gradient of the inner mitochondria membrane. The uncoupling procedure reduces the amount of ATP generated through an oxidation of fuels. Therefore, UCPs are suggested as candidate genes for human obesity or type II diabetes mellitus. Experimental evidences,that genetically engineered mice over expressing different UCP homologues were resistant to diet-induced obesity and 45 bp insertion polymorphism in the UCP2 3' untranslated region and C-55T in UCP3 promoter region were associated with obesity related phenotype, supported the hypothesis. The roles of UCP genes in polygenic obesity and type II diabetes are evaluated and discussed in this paper.