Interaction between catechol-O-methyltransferase Val/Met polymorphism and cognitive reserve for negative symptoms in schizophrenia

BACKGROUND Cognitive reserve(CR)and the catechol-O-methyltransferase(COMT)Val/Met polymorphism are reportedly linked to negative symptoms in schizophrenia.However,the regulatory effect of the COMT genotype on the relationship between CR and negative symptoms is still unexamined.AIM To investigate whether the relationship between CR and negative symptoms could be regulated by the COMT Val/Met polymorphism.METHODS In a cross-sectional study,54 clinically stable patients with schizophrenia underwent assessments for the COMT genotype,CR,and negative symptoms.CR was estimated using scores in the information and similarities subtests of a short form of the Chinese version of the Wechsler Adult Intelligence Scale.RESULTS COMT Met-carriers exhibited fewer negative symptoms than Val homozygotes.In the total sample,significant negative correlations were found between negative symptoms and information,similarities.Associations between information,similarities and negative symptoms were observed in Val homozygotes only,with information and similarities showing interaction effects with the COMT genotype in relation to negative symptoms(information,β=-0.282,95%CI:-0.552 to-0.011,P=0.042;similarities,β=-0.250,95%CI:-0.495 to-0.004,P=0.046).CONCLUSION This study provides initial evidence that the association between negative symptoms and CR is under the regulation of the COMT genotype in schizophrenia.

Analytical methodologies for sensing catechol-O-methyltransferase activity and their applications

Mammalian catechol-O-methyltransferases(COMT)are an important class of conjugative enzymes,which play a key role in the metabolism and inactivation of catechol neurotransmitters,catechol estrogens and a wide range of endobiotics and xenobiotics that bear the catechol group.Currently,COMT inhibitors are used in combination with levodopa for the treatment of Parkinson’s disease in clinical practice.The crucial role of COMT in human health has raised great interest in the development of more practical assays for highly selective and sensitive detection of COMT activity in real samples,as well as for rapid screening and characterization of COMT inhibitors as drug candidates.This review summarizes recent advances in analytical methodologies for sensing COMT activity and their applications.Several lists of biochemical assays for measuring COMT activity,including the probe substrates,along with their analytical conditions and kinetic parameters,are presented.Finally,the challenges and future perspectives in the field,such as visualization of COMT activity in vivo and in situ,are highlighted.Collectively,this review article overviews the practical assays for measuring COMT activities in complex biological samples,which will strongly facilitate the investigations on the relevance of COMT to human diseases and promote the discovery of COMT inhibitors via high-throughput screening.

Overexpression of catechol-O-methyltransferase occurs early in the progression of pancreatic cancer

Aims:Catechol-O-methyltransferase(COMT)plays a role in many kinds of cancer,and its high expression in pancreatic cancer has been found to be related to better prognosis.However,the expression and biological significance of COMT in multistep pancreatic cancerogenesis is not clear.Main methods:Six LSL-Kras^(G12D)-positive and Pdx1-Cre-positive mice(Kras^(G12D)mice),6 wild-type mice and 1 human tissue microarray were used in this study.COMT protein expression was measured by immunohistochemistry,and DNA chips were made for use in COMT mRNA assays.Keyfindings:The expression of COMT in pancreatic intraepithelial neoplasias(PanINs)from Kras^(G12D)mice was significantly higher than that in normal pancreatic tissue from wild-type mice,both in terms of protein level and mRNA expression.The median COMT immunohistochemistry expression scores in human PanIN-1 and PanIN-2 were 70 and 160,respectively,which were significantly lower than the score of 170 observed in pancreatic ductal adenocarcinoma(PDAC)(P=.024 and.037,respectively)and significantly higher than the score of 25 observed in pancreatitis(P=.01 and.008,respectively).Significance:In the development of pancreatic cancer from chronic pancreatitis and in the transition of PanIN to PDAC,we observed significantly increased expression of COMT.These data predict that the overexpression of COMT is an early event in the multistep process of pancreatic cancerogenesis.

COMT Val^(158)Met多态型青年在数字工作记忆任务中的视觉事件相关电位的研究

目的:针对不同COMT基因型健康青年被试,进行连续3-back任务1h共12Block,探讨健康成人数字工作记忆能力变化情况。方法:将112名健康青年分组抽取出18名不同基因型作为被试,利用视觉事件相关电位P3来观测被试连续工作记忆任务中COMT基因多态型与脑皮层电生理的关系。结果:Val/Val基因型的被试P3波幅显著高于Val/Met基因型(P<0.01),但和Met/Met基因型被试的波幅无差异。结论:Val/Met基因型被试关联着最差的工作记忆任务的成绩,被试者的P3波幅和3-back任务成绩成正相关。

COMT多态性与连续3-back任务相关ERP的关联研究

不同COMT基因型被试者,进行连续3-back任务测试,以探讨被试者工作记忆能力的变化情况。抽取21名不同COMT基因型被试者,观测被试者在连续工作记忆任务中记忆能力和脑电生理的差异。结果表明,Val/Met基因型被试者P300波幅显著低于Val/Val型,Met/Met型被试者的P300波幅居中。Val/Met型被试者显示了最差记忆任务成绩,被试者的P300波幅和记忆能力相关。COMT基因多态性和3-back任务事件相关电位相关联,工作记忆任务的灵活性和稳定性及其交互作用受到遗传因素的调控。

HPLC法同时测定大鼠肝微粒中原儿茶酸和香草酸的含量

目的：建立测定大鼠离体肝微粒中儿茶酚氧甲基转移酶（ COMT）底物（原儿茶酸）和代谢产物（香草酸）含量的HPLC法。方法离体肝微粒体样品经酸化后，乙酸乙酯提取。以绿原酸作为内标，色谱柱为 Welchrom C18，流动相为甲醇：0.1％磷酸＝25：75，流速为1 ml/min，检测波长为260 nm、326 nm，柱温30℃，进样量20μl。结果原儿茶酸和香草酸分别在0.5-20μg/ml和0.375-15μg/ml范围内线性关系良好，r≥0.9995；原儿茶酸的日内精密度和日间精密度RSD≤13.2％，方法回收率为90.3％-115.4％，提取率≥94.9％；香草酸的日内精密度和日间精密度RSD≤8.5％，方法回收率为93.4％-103.1％，提取回收率≥88.5％。结论该方法灵敏、简便、准确，可用于大鼠肝微体中COMT活性的测定。

长时间工作记忆任务中COMT多态性与ERP的关联研究

针对不同COMT基因型的被试者,首次利用视觉事件相关电位P3来观测被试者在长时间心算任务中COMT基因多态型与脑皮层电生理的关系。选取20名不同基因型人员作为被试者,在执行9组不同难度的心算任务后即刻,进行5 min的3-back任务,探讨健康成人数字工作记忆能力变化情况。Val/Val基因型的被试者P3波幅显著高于Val/Met基因型(P<0.01),但和Met/Met基因型被试者的波幅无差异;Val/Met基因型被试者在不同的工作记忆任务中都显示了最差的成绩。

Sevoflurane plays a reduced role in cognitive impairment compared with isoflurane: limited effect on fear memory retention

Isoflurane and sevoflurane are both inhalation anesthetics,but in clinical application,sevoflurane has been considered to be less suitable for long-term anesthesia because of its catabolic compounds and potential nephrotoxicity.Nevertheless,recent studies have shown that these two inhalation anesthetics are similar in hepatorenal toxicity,cost,and long-term anesthetic effect.Moreover,sevoflurane possibly has less cognitive impact on young mice.In this study,C57BL/6 mice aged 8–10 weeks were exposed to 1.2%isoflurane or 2.4%sevoflurane for 6 hours.Cognitive function and memory were examined in young mice using the novel object recognition,contextual fear conditioning,and cued-fear extinction tests.Western blot assay was performed to detect expression levels of D1 dopamine receptor,catechol-O-methyltransferase,phospho-glycogen synthase kinase-3β,and total glycogen synthase kinase-3βin the hippocampus.Our results show that impaired performance was not detected in mice exposed to sevoflurane during the novel object recognition test.Contextual memory impairment in the fear conditioning test was shorter in the sevoflurane group than the isoflurane group.Long-term sevoflurane exposure did not affect memory consolidation,while isoflurane led to memory consolidation and reduced retention.Downregulation of hippocampal D1 dopamine receptors and phosphorylated glycogen synthase kinase-3β/total glycogen synthase kinase-3βand upregulation of catechol-O-methyltransferase may be associated with differing memory performance after exposure to isoflurane or sevoflurane.These results confirm that sevoflurane has less effect on cognitive impairment than isoflurane,which may be related to expression of D1 dopamine receptors and catechol-O-methyltransferase and phosphorylation of glycogen synthase kinase-3βin the hippocampus.This study was approved by the Institutional Animal Care and Use Committee,Nanjing University,China on November 20,2017(approval No.20171102).

Reduced expression of COMT in placenta correlates with term preeclampsia

Objective: To investigate the expression of catechol-O- methyltransferase (COMT) in placentas from term preeclampsia patients in a Chinese cohort and to analyze the relationships between COMT and mean artery pressure (MAP), serum uric acid and 24-hour urine protein. Methods: 15 term pregnant patients with preeclampsia and 15 normal pregnant women were enrolled. Clinical characteristics and placental tissue were collected. Placental COMT expression was determined by quantitative real-time PCR technique and immunohistochemistry. Results: The level of COMT mRNA in placentas from the preeclampsia group was significantly decreased than that in the normal pregnant women (0.00179 ± 0.00051 vs. 0.00289 ± 0.00066, t = 5.145, P 0.001). Adjusted by age and body mass index (BMI), the COMT expression was negatively correlated with serum uric acid (r = ?0.660, P r = ?0.717, P r = ?0.619, P < 0.001). Conclusion: The decreased expression of COMT in placentas from term preeclamptic patients and the significant relation between COMT and severity index of preeclampsia suggest that COMT may play a role in the pathogenesis of term preeclampsia.

DNA methylation in schizophrenia: progress and challenges

Schizophrenia is a heterogeneous psychiatric disorder broadly accepted being caused by genetic and environmental factors. Although conventional genetic studies have identified some candidate genes for schizophrenia, low odds ratios and penetrance, and a lack of reproducibility have limited their explanatory power. Despite the major efforts made toward identifying environmental factors in schizophrenia, methodological limitations and inconsistent findings of epidemiological reports have obstructed attempts to identify exogenous causal factors. Epigenetic mechanisms, mediating between environment and genes, have recently been proposed to play an important role in the pathogenesis of schizophrenia. DNA methylation is the most stable and well-characterized epigenetic modification. In this paper, we briefly introduce DNA methylation mechanisms, genome-wide DNA methylation studies, and identify specific genomic methylation sites in individuals diagnosed with schizophrenia. The outline candidate genes such as Reelin and COMT, are also outlined before paying attention to the conundrum of recent researches.

Spontaneous Regional Brain Activity in Healthy Individuals is Nonlinearly Modulated by the Interaction of ZNF804A rs1344706 and COMT rs4680 Polymorphisms

ZNF804A rs1344706 has been identified as one of the risk genes for schizophrenia.However,the neural mechanisms underlying this association are unknown.Given that ZNF804A upregulates the expression of COMT,we hypothesized that ZNF804 A may influence brain activity by interacting with COMT.Here,we genotyped ZNF804A rs1344706 and COMT rs4680 in 218 healthy Chinese participants.Amplitudes of low-frequency fluctuations(ALFFs)were applied to analyze the main and interaction effects of ZNF804A rs1344706 and COMT rs4680.The ALFFs of the bilateral dorsolateral prefrontal cortex showed a significant ZNF804A rs1344706 x COMT rs4680 interaction,manifesting as a U-shaped modulation,presumably by dopamine signaling.Significant main effects were also found.These findings suggest that ZNF804A affects the resting-state functional activation by interacting with COMT,and may improve our understanding of the neurobiological effects of ZNF804A and its association with schizophrenia.