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Catechol‐O‐methyltransferase (COMT, EC 2.1.1.6) can transfer the methyl group from S‐adenosyl‐l‐methionine (SAM) to one of the hydroxyl groups of a catechol substrate in the presence of Mg2+. However, there is no consensus view of the kinetic mechanism of COMT involving multiple substrates. Further progress requires the development of methods for determining enzyme kinetic behavior and the binding mode of ligands to the protein. Here, we establish a multisubstrate kinetic system covering the fluorescence and mass spectrometry techniques to quantify the products in a COMT‐catalyzed reaction. The catechol substrate, 3‐BTD, can be methylated by COMT to form a single product, 3‐BTMD, with a sensitive fluorescence response and the conversion of SAM to S‐adenosyl‐l‐homocysteine (SAH) was monitored by LC–MS/MS. The kinetic assays suggested that the reaction occurred via an ordered sequential mechanism, in which SAM first bound to COMT, followed by the addition of Mg2+ and 3‐BTD. The chemical step involved a quaternary complex of COMT‐SAM‐Mg2+‐3‐BTD, followed by the ordered dissociation of 3‐BTMD, Mg2+, and SAH. In cooperation with molecular dynamics simulation, the binding of COMT to Mg2+ induced a shape change in the catechol‐binding site, which accommodated 3‐BTD binding and facilitated catalysis. These findings provide new insights into the kinetic mechanism of COMT, contributing to the development of previously undescribed functional COMT ligands. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of mortality, disability, and long‐term care burden in the United States, with women comprising the majority of AD diagnoses. While AD‐related dementia is associated with tau and amyloid beta accumulation, concurrent derangements in cerebral blood flow have been observed alongside these proteinopathies in humans and rodent models. The homeostatic production of nitric oxide synthases (NOS) becomes uncoupled in AD which leads to decreased NO‐mediated vasodilation and oxidative stress via the production of peroxynitrite (ONOO−∙) superoxide species. Here, we investigate the role of the novel protein arginine methyltransferase 4 (PRMT4) enzyme function and its downstream product asymmetric dimethyl arginine (ADMA) as it relates to NOS dysregulation and cerebral blood flow in AD. ADMA (type‐1 PRMT product) has been shown to bind NOS as a noncanonic ligand causing enzymatic dysfunction. Our results from RT‐qPCR and protein analyses suggest that aged (9−12 months) female mice bearing tau‐ and amyloid beta‐producing transgenic mutations (3xTg‐AD) express higher levels of PRMT4 in the hippocampus when compared to age‐ and sex‐matched C57BL6/J mice. In addition, we performed studies to quantify the expression and activity of different NOS isoforms. Furthermore, laser speckle contrast imaging analysis was indicative that 3xTg‐AD mice have dysfunctional NOS activity, resulting in reduced production of NO metabolites, enhanced production of free‐radical ONOO−, and decreased cerebral blood flow. Notably, the aforementioned phenomena can be reversed via pharmacologic PRMT4 inhibition. Together, these findings implicate the potential importance of PRMT4 signaling in the pathogenesis of Alzheimer's‐related cerebrovascular derangement. [ABSTRACT FROM AUTHOR]

Aim: Pain is reconstructed by brain activities and its subjectivity comes from an interplay of multiple factors. The current study aims to understand the contribution of genetic factors to the neural processing of pain. Focusing on the single‐nucleotide polymorphism (SNP) of opioid receptor mu 1 (OPRM1) A118G (rs1799971) and catechol‐O‐methyltransferase (COMT) val158met (rs4680), we investigated how the two pain genes affect pain processing. Method: We integrated a genetic approach with functional neuroimaging. We extracted genomic DNA information from saliva samples to genotype the SNP of OPRM1 and COMT. We used a percept‐related model, in which two different levels of perceived pain intensities ("low pain: mildly painful" vs "high pain: severely painful") were employed as experimental stimuli. Results: Low pain involves a broader network relative to high pain. The distinct effects of pain genes were observed depending on the perceived pain intensity. The effects of low pain were found in supramarginal gyrus, angular gyrus, and anterior cingulate cortex (ACC) for OPRM1 and in middle temporal gyrus for COMT. For high pain, OPRM1 affected the insula and cerebellum, while COMT affected the middle occipital gyrus and ACC. Conclusion: OPRM1 primarily affects sensory and cognitive components of pain processing, while COMT mainly influences emotional aspects of pain processing. The interaction of the two pain genes was associated with neural patterns coding for high pain and neural activation in the ACC in response to pain. The proteins encoded by the OPRM1 and COMT may contribute to the firing of pain‐related neurons in the human ACC, a critical center for subjective pain experience. [ABSTRACT FROM AUTHOR]

As(III) S‐adenosylmethionine methyltransferases, pivotal enzymes in arsenic metabolism, facilitate the methylation of arsenic up to three times. This process predominantly yields trivalent mono‐ and dimethylarsenite, with trimethylarsine forming in smaller amounts. While this enzyme acts as a detoxifier in microbial systems by altering As(III), in humans, it paradoxically generates more toxic and potentially carcinogenic methylated arsenic species. The strong affinity of As(III) for cysteine residues, forming As(III)‐thiolate bonds, is exploited in medical treatments, notably in arsenic trioxide (Trisenox®), an FDA‐approved drug for leukemia. The effectiveness of this drug is partly due to its interaction with cysteine residues, leading to the breakdown of key oncogenic fusion proteins. In this study, we extend the understanding of As(III)′s binding mechanisms, showing that, in addition to As(III)−S covalent bonds, noncovalent O⋅⋅⋅As pnictogen bonding plays a vital role. This interaction significantly contributes to the structural stability of the As(III) complexes. Our crystallographic analysis using the PDB database of As(III) S‐adenosylmethionine methyltransferases, augmented by comprehensive theoretical studies including molecular electrostatic potential (MEP), quantum theory of atoms in molecules (QTAIM), and natural bond orbital (NBO) analysis, emphasizes the critical role of pnictogen bonding in these systems. We also undertake a detailed evaluation of the energy characteristics of these pnictogen bonds using various theoretical models. To our knowledge, this is the first time pnictogen bonds in As(III) derivatives have been reported in biological systems, marking a significant advancement in our understanding of arsenic's molecular interactions. [ABSTRACT FROM AUTHOR]

Methamphetamine use disorder (MAUD) can substantially jeopardize public security due to its high‐risk social psychology and behaviour. Given that the dopamine reward system is intimately correlated with MAUD, we investigated the association of single nucleotide polymorphisms (SNPs), as well as methylation status of dopamine receptor type 4 (DRD4), catechol‐O‐methyltransferase (COMT) genes, and paranoid and motor‐impulsive symptoms in MAUD patients. A total of 189 MAUD patients participated in our study. Peripheral blood samples were used to detect 3 SNPs and 35 CpG units of methylation in the DRD4 gene promoter region and 5 SNPs and 39 CpG units in the COMT gene. MAUD patients with the DRD4 rs1800955 C allele have a lower percentage of paranoid symptoms than those with the rs1800955 TT allele. Individuals with paranoid symptoms exhibited a reduced methylation degree at a particular DRD4 CpG2.3 unit. The interaction of the DRD4 rs1800955 C allele and the reduced DRD4CpG2.3 methylation degree were associated with a lower occurrence of paranoid symptoms. Meanwhile, those with the COMT rs4818 CC allele had lower motor‐impulsivity scores in MAUD patients but greater COMT methylation levels in the promoter region and methylation degree at the COMT CpG 51.52 unit. Therefore, based only on the COMT rs4818 CC polymorphism, there was a negative correlation between COMT methylation and motor‐impulsive scores. Our preliminary results provide a clue that the combination of SNP genotype and methylation status of the DRD4 and COMT genes serve as biological indicators for the prevalence of relatively high‐risk psychotic symptoms in MAUD patients. [ABSTRACT FROM AUTHOR]

S‐adenosylmethionine (SAM), generated from methionine and ATP by S‐adenosyl methionine synthetase (SAMS), is the universal methyl group donor required for numerous cellular methylation reactions. In Caenorhabditis elegans, silencing sams‐1, the major isoform of SAMS, genetically or via dietary restriction induces a robust mitochondrial unfolded protein response (UPRmt) and lifespan extension. In this study, we found that depleting SAMS‐1 markedly decreases mitochondrial SAM levels. Moreover, RNAi knockdown of SLC‐25A26, a carrier protein responsible for transporting SAM from the cytoplasm into the mitochondria, significantly lowers the mitochondrial SAM levels and activates UPRmt, suggesting that the UPRmt induced by sams‐1 mutations might result from disrupted mitochondrial SAM homeostasis. Through a genetic screen, we then identified a putative mitochondrial tRNA methyltransferase TRMT‐10C.2 as a major downstream effector of SAMS‐1 to regulate UPRmt and longevity. As disruption of mitochondrial tRNA methylation likely leads to impaired mitochondrial tRNA maturation and consequently reduced mitochondrial translation, our findings suggest that depleting mitochondrial SAM level might trigger UPRmt via attenuating protein translation in the mitochondria. Together, this study has revealed a potential mechanism by which SAMS‐1 regulates UPRmt and longevity. [ABSTRACT FROM AUTHOR]

DNA methylation serves a variety of functions across all life domains. In this study, we investigated archaeal methylomics within a tripartite xylanolytic halophilic consortium. This consortium includes Haloferax lucertense SVX82, Halorhabdus sp. SVX81, and an ectosymbiotic Candidatus Nanohalococcus occultus SVXNc, a nano‐sized archaeon from the DPANN superphylum. We utilized PacBio SMRT and Illumina cDNA sequencing to analyse samples from consortia of different compositions for methylomics and transcriptomics. Endogenous cTAG methylation, typical of Haloferax, was accompanied in this strain by methylation at four other motifs, including GDGcHC methylation, which is specific to the ectosymbiont. Our analysis of the distribution of methylated and unmethylated motifs suggests that autochthonous cTAG methylation may influence gene regulation. The frequency of GRAGAaG methylation increased in highly expressed genes, while CcTTG and GTCGaGG methylation could be linked to restriction‐modification (RM) activity. Generally, the RM activity might have been reduced during the evolution of this archaeon to balance the protection of cells from intruders, the reduction of DNA damage due to self‐restriction in stressful environments, and the benefits of DNA exchange under extreme conditions. Our methylomics, transcriptomics and complementary electron cryotomography (cryo‐ET) data suggest that the nanohaloarchaeon exports its methyltransferase to methylate the Haloferax genome, unveiling a new aspect of the interaction between the symbiont and its host. [ABSTRACT FROM AUTHOR]

Background: Poor inhibitory control and enhanced subjective response to alcohol are interrelated risk factors for alcohol use disorder (AUD) that share underlying neural substrates, including dopamine signaling in the right prefrontal cortex, a potential target for pharmacological intervention. Cortical dopamine inactivation is primarily regulated by catechol‐O‐methyltransferase (COMT), an enzyme with large variation in activity as a function of the COMT rs4680 (val158met) single nucleotide polymorphism. In a previous randomized, placebo‐controlled trial of the COMT inhibitor tolcapone (200 mg TID) in non‐treatment‐seeking participants with AUD, we found that tolcapone, relative to placebo, reduced alcohol self‐administration only among rs4680 val‐allele homozygotes, whose COMT activity is higher than in met‐allele carriers. Methods: We conducted secondary analyses of the effects of tolcapone and baseline COMT activity, as indexed by both rs4680 genotype and an enzymatic activity assay, on the subjective response to alcohol in a bar‐laboratory paradigm among 60 participants in the previous trial. Results: Tolcapone did not affect alcohol‐induced stimulation or sedation more than placebo. However, baseline COMT activity moderated the effects of the drug on both outcomes, such that tolcapone‐treated participants with higher baseline COMT activity had less stimulation (p = 0.008) and sedation (p = 0.053) than participants with lower baseline COMT activity and those treated with placebo. Additionally, alcohol‐induced stimulation significantly mediated the interacting effects of baseline COMT activity and tolcapone on bar‐laboratory self‐administration. Conclusions: Tolcapone may reduce subjective response to alcohol more effectively among individuals with preexisting high COMT activity an effect that could account for the drug's reduction of alcohol consumption among these individuals. [ABSTRACT FROM AUTHOR]

The mechanism behind the hydrodeoxygenation (HDO) of guaiacol on Co(0001), Ni(111), Cu(111), Pd(111), and Pt(111) was investigated by constructing a first‐principles microkinetic model from density functional theory (DFT) models for 68 possible intermediates over each surface. We report that the most energetically favorable pathway for this process is the demethylation of guaiacol to catechol over Ni(111), which exhibits highly desirable deoxygenation and hydrogenation kinetics at industrial temperatures. Guaiacol readily undergoes hydrogenation over Pt(111) and Pd(111), but the products exhibit slow desorption from the surfaces at standard operation temperatures. Furthermore, the deoxygenation pathway is hindered by the high energy barrier associated with the scission of the Calkyl−O bond. [ABSTRACT FROM AUTHOR]

Directed evolution of the O‐methyltransferase ZgOMT from Zooshikella ganghwensis focusing on active site residues resulted in highly regioselective biocatalysts (regioisomeric ratios up to 99 : 1) for the preparation of the taste active hesperetin dihydrochalcone and related compounds. These newly constructed enzyme variants provide an attractive synthesis route for para‐methylation of catechol scaffolds, which is challenging to perform with high regioselectivity utilizing wild‐type O‐methyltransferases. [ABSTRACT FROM AUTHOR]

Adjunct therapy with the catechol‐O‐methyltransferase inhibitor entacapone is a first‐line approach to treat wearing‐off type motor fluctuations in levodopa‐treated Parkinson's disease (PD) patients. Five randomized placebo‐controlled trials including a total of >1000 patients have established its efficacy, showing increases in ON time between 0.7 and 1.6 h, with corresponding OFF‐time reductions. These and other trials also found improvements in ON motor function and quality of life. Additional trials have tested the efficacy of adjunct entacapone in patients either without or with early and mild motor fluctuations and also found enhanced motor control and improved activities of daily living function and quality of life, whereas the STRIDE‐PD trial failed to show efficacy of early entacapone use in delaying the onset of dyskinesias. Adjunct entacapone enhances dopaminergic activity and may increase levodopa‐induced adverse events like dyskinesias, which can usually be controlled by modest levodopa dose reductions. There is no formal requirement to monitor liver function during entacapone treatment. Entacapone can be a rare cause of lymphocytic colitis with severe diarrhoea and need for treatment discontinuation. In 2003, a triple‐combination pill of levodopa, carbidopa, and entacapone (LCE) was first introduced onto the market, and since then proprietary LCE (Stalevo®) is indicated on the basis of those trials for patients with idiopathic PD to (i) substitute for immediate‐release carbidopa/levodopa and entacapone previously administered as individual products or (ii) replace immediate‐release carbidopa/levodopa therapy (without entacapone) when patients taking a total daily dose of levodopa of ≤600 mg and not experiencing dyskinesias experience signs and symptoms of end‐of‐dose wearing off. [ABSTRACT FROM AUTHOR]

Background and purpose: Motor fluctuations are a significant driver of healthcare resource utilization (HCRU) in people with Parkinson's disease (pwPD). A common management strategy is to include catechol‐O‐methyltransferase (COMT) inhibition with either opicapone or entacapone in the levodopa regimen. However, to date, there has been a lack of head‐to‐head data comparing the two COMT inhibitors in real‐world settings. The aim of this study was to evaluate changes in HCRU and effect on sleep medications when opicapone was initiated as first COMT inhibitor versus entacapone. Methods: In this retrospective cohort study, we assessed HCRU outcomes in pwPD naïve to COMT inhibition via UK electronic healthcare records (Clinical Practice Research Datalink and Hospital Episodes Statistics databases, June 2016 to December 2019). HCRU outcomes were assessed before (baseline) and after COMT inhibitor prescription at 0–6 months, 7–12 months and 13–18 months. Opicapone‐treated pwPD were algorithm‐matched (1:4) to entacapone‐treated pwPD. Results: By 6 months, treatment with opicapone resulted in 18.5% fewer neurology outpatient visits compared to entacapone treatment; this effect was maintained until the last follow‐up (18 months). In the opicapone group, the mean levodopa equivalent daily dose decreased over the first year and then stabilized, whereas the entacapone‐treated group showed an initial decrease in the first 6 months followed by a dose increase between 7 and 18 months. Neither COMT inhibitor had a significant impact on sleep medication use. Conclusions: This head‐to‐head study is the first to demonstrate, using 'real‐world' data, that initiating COMT inhibition with opicapone is likely to decrease the need for post‐treatment HCRU versus initiation of COMT inhibition with entacapone. [ABSTRACT FROM AUTHOR]

Objective: Individuals born with cleft lip and palate may face difficulties in speech function, nutrition, facial aesthetics, and long‐term care. These difficulties may increase the risk of psychological and psychiatric diseases. This work aimed to test if the variant allele of COMT was carried more frequently among individuals that have psychological and psychiatric outcomes within a cohort of patients born with cleft lip and palate. Method: DNA extraction from saliva of two hundred and fifteen individuals born with cleft lip with and/or palate and genotyping was performed, and the frequency of COMT rs4818 alleles was determined. The domain 'Psychological Function' of Cleft‐Q™ was used to generate scores for analysis. The scores were computed, and differences in genotype or allele frequencies between individuals with psychological function scores 60 or above and 59 or below were compared. The history of psychiatric illness (family history of psychiatric disease or self‐reported psychiatric illness) was registered. Results: Genotype and allele frequencies were compared between individuals with and without a family history of psychiatric illness. Individuals with lower Psychological Function (Cleft‐Q™) scores were more likely to be GG (P =.04) or carriers of allele G (P <.001). The reported psychiatric illness and positive family history of psychiatric illness were compared to COMT rs4818 allele and genotype frequencies of individuals without these indicators, and individuals with psychiatric illness and positive family history of psychiatric illness were more likely to carry allele G (P =.03 and P =.008, respectively). Conclusion: The study confirms previously suggested role of COMT rs4818 in psychiatric and psychological outcomes in a distinct cohort of patients born with cleft lip and palate. [ABSTRACT FROM AUTHOR]

The catechol‐O‐methyltransferase (COMT) gene is thought to have an important role in the etiopathogenesis of schizophrenia, but there are conflicting results regarding its role in clinical presentation. We aimed to elucidate the relationship between the single nucleotide polymorphisms (SNPs) in the COMT gene and the severity of positive and negative symptoms. In order to investigate the relationship, the PubMed, PubMed Central, Scopus, and Cochrane CENTRAL databases were screened for eligible articles. Thirty‐eight studies, including 4443 adult patients with schizophrenia, were included in the quantitative analyses, and four studies were qualitatively assessed. Quantitative analyses were performed for acutely ill and clinically stable patient subgroups regarding the different genotypes of rs4680 SNP. Our results showed that the severity of negative symptoms was higher in patients who were rs4680 Met homozygous compared to Val/Met heterozygotes only in acutely ill samples. There was no other significant difference between genotypes. Meta‐regression did not reveal any significant moderator effect on the difference in negative symptoms. General psychopathology, positive, negative, and total psychotic symptom levels also were similar between Val homozygotes and Met carriers. Nonetheless, there are some limitations in the study. First, SNPs except for rs4680 were under‐researched because of the limited number of studies. Second, high heterogeneity across studies was the main concern. Our results suggested that the COMT rs4680 Met allele was associated with higher levels of negative symptoms within acutely ill patients. Future studies should focus on specific patient subgroups to reveal the moderating effects of SNPs. [ABSTRACT FROM AUTHOR]

Therapy of molybdenum cofactor (Moco) deficiency has received US Food and Drug Administration (FDA) approval in 2021. Whereas urothione, the urinary excreted catabolite of Moco, is used as diagnostic biomarker for Moco‐deficiency, its catabolic pathway remains unknown. Here, we identified the urothione‐synthesizing methyltransferase using mouse liver tissue by anion exchange/size exclusion chromatography and peptide mass fingerprinting. We show that the catabolic Moco S‐methylating enzyme corresponds to thiopurine S‐methyltransferase (TPMT), a highly polymorphic drug‐metabolizing enzyme associated with drug‐related hematotoxicity but unknown physiological role. Urothione synthesis was investigated in vitro using recombinantly expressed human TPMT protein, liver lysates from Tpmt wild‐type and knock‐out (Tpmt−/−) mice as well as human liver cytosol. Urothione levels were quantified by liquid‐chromatography tandem mass spectrometry in the kidneys and urine of mice. TPMT‐genotype/phenotype and excretion levels of urothione were investigated in human samples and validated in an independent population‐based study. As Moco provides a physiological substrate (thiopterin) of TPMT, thiopterin‐methylating activity was associated with TPMT activity determined with its drug substrate (6‐thioguanin) in mice and humans. Urothione concentration was extremely low in the kidneys and urine of Tpmt−/− mice. Urinary urothione concentration in TPMT‐deficient patients depends on common TPMT polymorphisms, with extremely low levels in homozygous variant carriers (TPMT*3A/*3A) but normal levels in compound heterozygous carriers (TPMT*3A/*3C) as validated in the population‐based study. Our work newly identified an endogenous substrate for TPMT and shows an unprecedented link between Moco catabolism and drug metabolism. Moreover, the TPMT example indicates that phenotypic consequences of genetic polymorphisms may differ between drug‐ and endogenous substrates. [ABSTRACT FROM AUTHOR]

This work was aimed at analyzing the correlation between the methylation level of the M6A gene in esophageal cancer (EC) and the prognosis of patients based on bioinformatics technology and evaluating the prognostic predictive values of different data mining models. 80 EC patients and 80 healthy people were selected, and the serum of the patients was collected to detect the level of DNA methyltransferase. During the radical resection of EC, tumor tissues and adjacent normal tissues were collected from patients to detect the methylation level of the M6A gene. COX regression analysis was employed to analyze the independent risk factors (IRFs) of M6A gene methylation and other treatments affecting the prognosis of EC patients. The particle swarm optimization (PSO) algorithm was introduced to improve the fuzzy C -means clustering (FCM) algorithm. The differences in the prognostic prediction efficiency of logistic regression analysis (LRA), decision tree (DT) C5.0, artificial neural network (ANN), support vector machine (SVM), and improved FCM (IFCM) models were compared. The levels of DNA methyltransferase and human histone deacetylase 1 (HSD-1) in EC patients were increased greatly (P < 0.05). The methylation rates and methylation levels of M6A methylation regulators (ALKBH5, HNRNPC, METTL3, WTAP, RBM15, YTHDC1, YTHDF1, and FTO) in EC tissues were obviously higher (P < 0.05). The survival time of high-risk EC patients was much shorter than that of low-risk patients (P < 0.05). Univariate and multivariate COX regression analysis showed that gender, tumor grade, TNM grade, degree of infiltration, and methylation of ALKBH5, HNRNPC, and METTL3 genes were IRFs for the prognosis of EC patients (P < 0.05). The areas under the ROC curve (AUCs) of LRA, DT C5.0, ANN, SVM, and IFCM algorithms for predicting the prognosis of patients were 0.813, 0.857, 0.895, 0.926, and 0.958, respectively, and the IFCM model had the best diagnostic effect. In conclusion, the detection of bioinformatics technology showed no obvious DNA methylation in EC patients, and the elevated levels of M6A methylation regulators in patients were an IRF affecting the prognosis of patients. In addition, the fuzzy data mining model can be undertaken as the preferred method for prognosis prediction of EC patients. [ABSTRACT FROM AUTHOR]

Objectives. Kabuki syndrome (KS) is a rare genetic disorder characterized by developmental delay, retarded growth, and cardiac, gastrointestinal, neurocognitive, renal, craniofacial, dental, and skeletal defects. KS is caused by mutations in the genes encoding histone H3 lysine 4 methyltransferase (KMT2D) and histone H3 lysine 27 demethylase (KDM6A), which are core components of the complex of proteins associated with histone H3 lysine 4 methyltransferase SET1 (SET1/COMPASS). Using single-cell RNA data, we examined the expression profiles of Kmt2d and Kdm6a in the mouse dental pulp. In the incisor pulp, Kmt2d and Kdm6a colocalize with other genes of the SET1/COMPASS complex comprised of the WD-repeat protein 5 gene (Wdr5), the retinoblastoma-binding protein 5 gene (Rbbp5), absent, small, and homeotic 2-like protein-encoding gene (Ash2l), nuclear receptor cofactor 6 gene (Ncoa6), and Pax-interacting protein 1 gene (Ptip1). In addition, we found that Kmt2d and Kdm6a coexpress with the downstream target genes of the Wingless and Integrated (WNT) and sonic hedgehog signaling pathways in mesenchymal stem/stromal cells (MSCs) at different stages of osteogenic differentiation. Taken together, our results suggest an essential role of KMT2D and KDK6A in directing lineage-specific gene expression during differentiation of MSCs. [ABSTRACT FROM AUTHOR]

Kojic acid (KA) is a hydroxypyranone natural metabolite mainly known as tyrosinase inhibitor. Currently, this compound is used as a whitening agent in cosmetics and as an anti‐browning agent in food industry. Given the easy‐manipulation in different positions of the KA molecule, many investigations have been carried out to find new tyrosinase inhibitors derived from KA. Beside anti‐tyrosinase activity, many KA‐based compounds have been designed for targeting other enzymes including human neutrophil elastase, catechol‐O‐methyltransferase, matrix metalloproteinases, monoamine oxidase, human lactate dehydrogenase, endonucleases, D‐amino acid oxidase, and receptors such as histamine H3 and apelin (APJ) receptors. This review could help biochemists and medicinal chemists in designing diverse KA‐derived enzyme inhibitors. [ABSTRACT FROM AUTHOR]

Cobalt (CoII) ions have been an attractive candidate for the biomedical modification of orthopedic implants for decades. However, limited research has been performed into how immobilized CoII ions affect the physical properties of implant devices and how these changes regulate cellular behavior. In this study we modified biocompatible poly(vinyl alcohol) with terpyridine and catechol groups (PVA‐TP‐CA) to create a stable surface coating in which bioactive metal ions could be anchored, endowing the coating with improved broad‐spectrum antibacterial activity against Escherichia coli and Staphylococcus aureus, as well as enhanced surface stiffness and cellular mechanoresponse manipulation. Strengthened by the addition of these metal ions, the coating elicited enhanced mechanosensing from adjacent cells, facilitating cell adhesion, spreading, proliferation, and osteogenic differentiation on the surface coating. This dual‐functional PVA‐TP‐CA/Co surface coating offers a promising approach for improving clinical implantation outcomes. [ABSTRACT FROM AUTHOR]

SUMMARY: Plants supply both food and medicinal compounds, which are ascribed to diverse metabolites produced by plants. However, studies on domestication‐driven changes in the metabolome and genetic basis of bioactive molecules in perennial fruit trees are generally lacking. Here, we conducted multidimensional analyses revealing a singular domestication event involving the genomic and metabolomic selection of jujube trees (Ziziphus jujuba Mill.). The genomic selection for domesticated genes was highly enriched in metabolic pathways, including carbohydrates and specialized metabolism. Domesticated metabolome profiling indicated that 187 metabolites exhibited significant divergence as a result of directional selection. Malic acid was directly selected during domestication, and the simultaneous selection of specialized metabolites, including triterpenes, consequently lead to edible properties. Cyclopeptide alkaloids (CPAs) were specifically targeted for the divergence between dry and fresh cultivars. We identified 1080 significantly associated loci for 986 metabolites. Among them, 15 triterpenes were directly selected at six major loci, allowing the identification of a homologous cluster containing seven 2,3‐oxidosqualene cyclases (OSCs). An OSC gene was found to contribute to the reduction in the content of triterpenes during domestication. The complete pathway for synthesizing ursolic acid was dissected by integration of the metabolome and transcriptome. Additionally, an N‐methyltransferase involved in the biosynthesis of CPA and responsible for inter‐cultivar content variation was identified. The present study promotes our understanding of the selection process of the global metabolome subsequent to fruit tree domestication and facilitates the genetic manipulation of specialized metabolites to enhance their edible traits. Significance Statement: The present study promotes our understanding of the selection process of the global metabolome subsequent to fruit tree domestication and facilitates the genetic manipulation of specialized metabolites to enhance their edible traits. [ABSTRACT FROM AUTHOR]

Background: Irritable bowel syndrome (IBS) is characterized by abdominal pain, bowel habit alterations, and psychiatric comorbidities. Although pathophysiology remains incompletely understood, prior work demonstrates associations with brain‐derived neurotrophic factor (BDNF) and catechol‐O‐methyltransferase (COMT). The purpose of this study was to quantify BDNF and COMT in plasma and in neuronal‐enriched extracellular vesicles (nEVs), assess relationships with psychological symptoms, and gain insight on the brain‐gut connection in IBS. Methods: Clinical data and biorepository samples from a parent investigation were used, including scores on the Perceived Stress Scale (PSS) and Center for Epidemiological Studies Depression Scale (CES‐D). Distinct subpopulations of nEVs were isolated using neural cell adhesion molecule L1CAM; levels of COMT, mature BDNF, and pro‐BDNF were quantified in plasma and in nEVs using ELISA. Key Results: Data from 47 females (28.11 ± 6.85 years) included 18 IBS and 29 healthy control (HC) participants. IBS participants displayed reduced plasma levels of mature BDNF compared with HC (p = 0.024). Levels of COMT plasma and IBS grouping significantly predicted CES‐D scores (p = 0.034). Exploratory analyses by IBS subtype and race revealed African American HC display lower levels of COMT EV than Caucasian HC (p = 0.022). Conclusions & Inferences: Lower levels of mature BDNF in IBS participants, preliminary patterns detected in cargo content of nEVs, and relevance of COMT and IBS status to CES‐D scores, offer insight on depressive symptomatology and brain‐gut dysregulation in IBS. Lower COMT levels in nEVs of African Americans highlight the relevance of race when conducting such analyses across diverse populations. [ABSTRACT FROM AUTHOR]

Dopamine functioning is an essential mechanism underlying addictive behaviors. This paper evaluates the association of Internet gaming disorder (IGD) with the catechol‐O‐methyltransferase (COMT) val158met polymorphism and examines the roles of impulsivity and reinforcement sensitivity in this association. Using diagnostic interviews, this study recruited 69 participants with IGD and 138 participants without. All participants underwent diagnostic interviews for IGD and an evaluation for the COMT val158met polymorphism, impulsivity, and reinforcement sensitivity. Among participants with the Val/Val genotype, the odds ratio (95% confidence interval) for IGD was 2.09 (1.15–3.80). The IGD–Val/Val genotype association was mediated by impulsivity and fun‐seeking. The Val/Val genotype is indicative of low frontal functioning and is a predictive factor of IGD, with this effect being confounded by impulsivity and fun‐seeking. Interventions targeting impulsivity and fun‐seeking might attenuate the risk of IGD, particularly among individuals with the Val/Val genotype. Additional studies are necessary to elucidate the possible role of dopamine functioning. [ABSTRACT FROM AUTHOR]

Importance Adapting one's gait speed to external circumstances is critical for safe ambulation. Dopamine (DA), critical for adapting to increased task demands, predicts usual gait speed and may exert a greater role in complex tasks like rapid gait speed. Objective: We hypothesized that a genotypic proxy indicator of greater prefrontal DA signaling would predict significantly faster rapid gait. Design Longitudinal cohort study over 8 years. Setting: Community‐dwelling adults with no baseline mobility disability. Participants: N = 2353 participants from the Health ABC Study. Measurements Repeated measures of walking speed (meters/sec) were obtained in response to: "walk as fast as possible... (rapid gait) or "walk at your usual pace (usual gait)." Catechol‐O‐methyltransferase (COMT) val158met polymorphism indicated DA signaling (val/val = higher metabolism, lower DA signaling; met/met = lower metabolism, higher DA signaling). Results: Participants declined in rapid gait from 1.55 (SD = 0.33) to 1.35 m/s (SD = 0.34). Across the full follow‐up period, the met/met genotype was associated with significantly greater rapid gait slowing. In mixed effect models, between‐group differences were independent of covariates, and remained similar after adjustment for sensorimotor function, cognition, depressive symptoms, and energy. Follow‐up analyses indicated the met/met genotype had a significantly faster rapid gait speed compared to the val/val genotype for the first 3 years (p < 0.01) but not years 4–8 (p > 0.05). Conclusion: Greater prefrontal DA measured with COMT polymorphism may facilitate short‐term adaptation to rapid walking demands that are lost over time. Studies should examine whether these effects are long‐term and the underlying mechanistic pathways. [ABSTRACT FROM AUTHOR]

Opicapone (OPC) is a third‐generation catechol‐O‐methyltransferase inhibitor developed to treat Parkinson disease and motor fluctuations. This open‐label, single‐center, phase 1 study aimed to evaluate the pharmacokinetics (PK) of OPC and its metabolites when administered as single and multiple doses in healthy White and Chinese subjects. The study enrolled a total of 30 White and Chinese healthy subjects, equally balanced among groups. The first dose of OPC was administered orally as a single dose of 50 mg on day 1, followed by a 10‐day once‐daily treatment from day 5 to day 14. Plasma concentrations of OPC and its metabolites were measured at 0 to 72 and 0 to 144 hours after dosing for single dose and multiple dose, respectively. Moreover, urine concentrations of OPC and its metabolite were measured 0 to 24 hours after dosing. PK parameters were derived from noncompartmental analysis. Geometric mean ratios and 90% confidence intervals for the main PK parameters were conducted to evaluate the ethnic difference between White and Chinese subjects. The plasma and urine exposure of OPC and its metabolites in Chinese subjects were similar to those in White subjects. These results indicated that ethnicity had no significant impact on PK of OPC between White and Chinese subjects. [ABSTRACT FROM AUTHOR]

Protein L-isoaspartyl methyltransferase (PIMT/PCMT1), an enzyme repairing isoaspartate residues in peptides and proteins that result from the spontaneous decomposition of normal L-aspartyl and L-asparaginyl residues during aging, has been revealed to be involved in neurodegenerative diseases (NDDs) and diabetes. However, the molecular mechanisms for a putative association of PIMT dysfunction with these diseases have not been clarified. Our study aimed to identify differentially expressed microRNAs (miRNAs) in the brain and kidneys of PIMT-deficient mice and uncover the epigenetic mechanism of PIMT-involved NDDs and diabetic nephropathy (DN). Differentially expressed miRNAs by sequencing underwent target prediction and enrichment analysis in the brain and kidney of PIMT knockout (KO) mice and age-matched wild-type (WT) littermates. Sequence analysis revealed 40 differentially expressed miRNAs in the PIMT KO mouse brain including 25 upregulated miRNAs and 15 downregulated miRNAs. In the PIMT KO mouse kidney, there were 80 differentially expressed miRNAs including 40 upregulated miRNAs and 40 downregulated miRNAs. Enrichment analysis and a systematic literature review of differentially expressed miRNAs indicated the involvement of PIMT deficiency in the pathogenesis in NDDs and DN. Some overlapped differentially expressed miRNAs between the brain and kidney were quantitatively assessed in the brain, kidney, and serum-derived exosomes, respectively. Despite being preliminary, these results may aid in investigating the pathological hallmarks and identify the potential therapeutic targets and biomarkers for PIMT dysfunction-related NDDs and DN. [ABSTRACT FROM AUTHOR]

Background: Genetic variation in the catechol‐O‐methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is conditioned pain modulation (CPM). We hypothesized that variation in CPM may have a genetic basis. Methods: We evaluated CPM in 77 healthy pain‐free Caucasian subjects by applying repeated mechanical stimuli to the dominant forearm using 26‐g von Frey filament as the test stimulus with immersion of the non‐dominant hand in hot water as the conditioning stimulus. We assayed COMT SNP genotypes by the TaqMan method using DNA extracted from saliva. Results: SNP rs4680 (val158met) was not associated with individual differences in CPM. However, CPM was associated with COMT low pain sensitivity haplotypes under an additive model (p = 0.004) and the effect was independent of gender. Conclusions: We show that, although four SNPs are used to infer COMT haplotypes, the low pain sensitivity haplotype is determined by SNP rs6269 (located in the 5′ regulatory region of COMT), suggesting that inherited variation in gene expression may underlie individual differences in pain modulation. Analysis of 13 global populations revealed that the COMT low pain sensitivity haplotype varies in frequency from 13% to 44% and showed that two SNPs are sufficient to distinguish all COMT haplotypes in most populations. [ABSTRACT FROM AUTHOR]

Ethanol (ET) causes cerebrovascular dysfunction by altering homocysteine (Hcy) metabolism and by causing oxidative stress. However, there are no strategies to prevent ET‐induced epigenetic deregulation of tight junction protein (hyper‐methylation) and endothelial cell permeability to date. Hydrogen sulfide (H2S) has an antioxidative, antiapoptotic, and anti‐inflammatory effect. Here, we investigated the protective role of H2S in ET‐induced endothelial permeability through epigenetic changes in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to 50 mM ET treatment in the presence or absence of 50 μM NaHS (H2S donor). The result demonstrates that ET‐induced cellular toxicity increased intracellular Hcy levels, which further intensified mitochondrial dysfunction and energy defects. Using miScript microRNA (miRNA) polymerase chain reaction array‐based screening, we identified a particular miRNA, miR‐218, as a novel target of ET‐induced DNA methyltransferase‐3a (DNMT3a) activation. miR‐218 influences CpG island methylation of the zonula occludens 1 (ZO‐1) promoter in the endothelial cells. We discovered that ET suppressed miR‐218 levels and induced endothelial permeability via DNMT3a‐mediated ZO‐1 hyper‐methylation. Treatment with mito‐TEMPO (mitochondria‐targeted antioxidant), 5′‐azacitidine (DNMT inhibitor), or miR‐218 overexpression was shown to protect endothelial cells against ET‐induced permeability. Also, bEnd3 cells pretreated with NaHS attenuated ET‐induced vascular permeability and prevented CpG island methylation at the promoter. In conclusion, our data provide evidence that H2S treatment protects vascular integrity from ET‐induced stress by mitigating CpG (ZO‐1 promoter) DNA hyper‐methylation. This finding uncovers a new mechanistic understanding of NaHS/H2S, that may have therapeutic potential in preventing or diminishing ET‐induced brain vascular permeability and dysfunction induced by alcoholism. [ABSTRACT FROM AUTHOR]

Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol‐O‐methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use. [ABSTRACT FROM AUTHOR]

The early social environment an animal experiences may have pervasive effects on its behaviour. The social decision‐making network (SDMN), consisting of interconnected brain nuclei from the forebrain and midbrain, is involved in the regulation of behaviours during social interactions. In species with advanced sociality such as cooperative breeders, offspring are exposed to a large number and a great diversity of social interactions every day of their early life. This diverse social environment may have life‐long consequences on the development of several neurophysiological systems within the SDMN, although these effects are largely unknown. We studied these life‐long effects in a cooperatively breeding fish, Neolamprologus pulcher, focusing on the expression of genes involved in the monoaminergic and stress response systems in the SDMN. N. pulcher fry were raised until an age of 2 months either with their parents, subordinate helpers and same‐clutch siblings (+F), or with same‐clutch siblings only (−F). Analysis of the expression of glucocorticoid receptor, mineralocorticoid receptor, corticotropin releasing factor, dopamine receptors 1 and 2, serotonin transporter and DNA methyltransferase 1 genes showed that early social experiences altered the neurogenomic profile of the preoptic area. Moreover, the dopamine receptor 1 gene was up‐regulated in the preoptic area of −F fish compared to +F fish. −F fish also showed up‐regulation of GR1 expression in the dorsal medial telencephalon (functional equivalent to the basolateral amygdala), and in the dorsolateral telencephalon (functional equivalent to the hippocampus). Our results suggest that early social environment has life‐long effects on the development of several neurophysiological systems within the SDMN. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of single nucleotide polymorphisms in the COMT, OPRM1, 5HT1A, 5HT2A and 5HTR3B genes on the intensity of postoperative pain following root canal treatment. Methodology: Ninety‐five patients with mandibular and maxillary molar teeth diagnosed with symptomatic apical periodontitis and a level of preoperative pain greater than 50 on a 100 mm visual analogue scale (VAS) were included. Salivary DNA was collected from the participants and stored in Eppendorf tubes at −80 °C. Preoperative percussion pain values were recorded before the root canal treatment procedures. After completion of root canal treatment, the participants were given instructions to record their postoperative pain intensity levels at 24, 48 and 72 h, 5 days and 1 week after treatment, using the VAS. A second visit for the patients after seven days was planned to record their intensity levels of percussion pain on VAS. The percussion test was performed by tapping on the occlusal surface of the tooth with a blunt instrument. A QIAamp DNA Mini Kit was used to isolate DNA from saliva, and SNP Genotyping Analysis software version 1 was used to analyse the genotypes by calculating FAM and HEX signals. The Kruskal–Wallis and Mann–Whitney U‐tests were used to evaluate pain intensity values amongst the genotypes, alleles, haplotypes and allele combinations. Nominal data (gender, intake and tooth number) were analysed using a Chi‐square test. Bonferroni correction was performed. Thus, the significance level was set at 1.6% (P = 0.016), 2.5% (P = 0.025) and 1.25% (P = 0.0125) for genotype, allele and haplotype comparisons, respectively. Results: There was no significant difference amongst the genotypes and alleles in terms of pre‐ and postoperative pain intensity. There was no significant difference amongst the haplotypes formed for the COMT gene in terms of pain intensity. Additionally, there was no significant association between the allelic combination formed for 5HT1A + 5HT2A genes and the intensity of postoperative pain. Conclusion: The findings indicate that none of the evaluated SNPs for COMT, OPRM1, 5HT1A, 5HT2A and 5HTR3B genes were associated with the intensity of postoperative pain. [ABSTRACT FROM AUTHOR]

Statins belong to the most often prescribed medications, which efficiently normalise hyperlipidaemia and prevent cardiovascular complications in obese and diabetic patients. However, beside expected therapeutic results based on the inhibition of 3‐hydroxyl‐3‐methylglutaryl‐CoA reductase, these drugs exert multiple side effects of poorly understood characteristic. In this study, side effects of pravastatin and atorvastatin on EA.hy926 endothelial cell line were investigated. It was found that both statins activate proinflammatory response, elevate nitric oxide and reactive oxygen species (ROS) generation and stimulate antioxidative response in these cells. Moreover, only slight stimulation of the mitochondrial biogenesis and significant changes in the mitochondrial network organisation have been noted. Although biochemical bases behind these effects are not clear, they may partially be explained as an elevation of AMP‐activated protein kinase (AMPK) activity and an increased activating phosphorylation of sirtuin 1 (Sirt1), which were observed in statins‐treated cells. In addition, both statins increased nicotinamide N‐methyltransferase (NNMT) protein level that may explain a reduced fraction of methylated histone H3. Interestingly, a substantial reduction of the total level of histone H3 in cells treated with pravastatin but not atorvastatin was also observed. These results indicate a potential additional biochemical target for statins related to reduced histone H3 methylation due to increased NNMT protein level. Thus, NNMT may directly modify gene activity. Beside expected therapeutic results, statins exert multiple side effects of poorly understood characteristic. In our study, side effects of pravastatin and atorvastatin on EA.hy926 endothelial cell line were investigated. It was found that both statins activate proinflammatory response, elevate nitric oxide and ROS generation, stimulate antioxidative response and cause significant changes in the mitochondrial network organisation. Moreover, both statins increased nicotinamide N‐methyltransferase (NNMT) protein level, which may influence histone H3 methylation, thus directly modifying gene activity. [ABSTRACT FROM AUTHOR]

Due to the spread of the western style diet, which is characterized by high intake of processed food, micronutrients (vitamins and minerals) deficiency is increasing in the Japanese population of all ages and genders. During pregnancy, the elevated demand for micronutrients put pregnant women at even higher risk of micronutrients deficiency. Some micronutrients are relatively famous such that women with reproductive age are recommended to take folic acid supplementation for the prevention of neural tube defect. However, it is not generally known that folate is also important for fetal growth throughout the pregnancy course and for prevention of pregnancy complications, and that pregnant women should continue to take supplementation during pregnancy and lactation. The types of micronutrients and the duration of supplementation are both important factors to maintain normal pregnancies. This review focused on four micronutrients that are commonly deficient in Japanese pregnant women, folate, vitamin B12, vitamin D, calcium, and magnesium. The detrimental effects of homocysteine accumulation associated with the above micronutrient defects and its link to catechol‐o‐methyltransferase insufficiency are described. We also discussed possible molecular mechanisms of pregnancy complications and the development origin of health and disease (DOHaD) regarding micronutrient deficiencies from the point of view of one carbon metabolism. [ABSTRACT FROM AUTHOR]

Summary: The tea plant (Camellia sinensis) is a thermophilic cash crop and contains a highly duplicated and repeat‐rich genome. It is still unclear how DNA methylation regulates the evolution of duplicated genes and chilling stress in tea plants. We therefore generated a single‐base‐resolution DNA methylation map of tea plants under chilling stress. We found that, compared with other plants, the tea plant genome is highly methylated in all three sequence contexts, including CG, CHG and CHH (where H = A, T, or C), which is further proven to be correlated with its repeat content and genome size. We show that DNA methylation in the gene body negatively regulates the gene expression of tea plants, whereas non‐CG methylation in the flanking region enables a positive regulation of gene expression. We demonstrate that transposable element‐mediated methylation dynamics significantly drives the expression divergence of duplicated genes in tea plants. The DNA methylation and expression divergence of duplicated genes in the tea plant increases with evolutionary age and selective pressure. Moreover, we detect thousands of differentially methylated genes, some of which are functionally associated with chilling stress. We also experimentally reveal that DNA methyltransferase genes of tea plants are significantly downregulated, whereas demethylase genes are upregulated at the initial stage of chilling stress, which is in line with the significant loss of DNA methylation of three well‐known cold‐responsive genes at their promoter and gene body regions. Overall, our findings underscore the importance of DNA methylation regulation and offer new insights into duplicated gene evolution and chilling tolerance in tea plants. Significance Statement: Our results show solid evidence that DNA methylation not only drives transposable element (TE)‐mediated functional diversification of duplicated genes in the tea plant, but also facilitates the enhancement of chilling tolerance in the tea plant through suppressing the activities of DNA methyltransferase under chilling stress. The overall findings underscore the importance of DNA methylation regulation on gene expression through TE insertions and broaden our understanding of duplicated gene evolution and chilling tolerance in plants. [ABSTRACT FROM AUTHOR]

Genetic factors are assumed to contribute to memory performance, especially genes affecting the dopaminergic neurotransmission. We aimed to evaluate leading functional genetic variants of the dopamine system, Catechol‐O‐methyltransferase (COMT) SNP rs4680 and Brain‐derived neurotropic factor (BDNF) SNP rs6265, previously found to be associated with memory performance. In two independent general population cohorts (total N = 5937) we investigated direct and interaction effects between COMT and BDNF SNPs on declarative memory performance. We found significant two‐way interactions for COMT and BDNF in both cohorts but no direct genetic effects. Sensitivity analyses revealed that an interaction between COMT and BDNF was mainly carried by females. While direct associations of COMT and BDNF on memory have been reported previously, we could demonstrate that the interaction of COMT and BDNF is sex‐dependent and more complex and needs further investigation. Our results could be demonstrated in two independent cohorts of valuable size. [ABSTRACT FROM AUTHOR]

Acetylserotonin O‐methyltransferase (ASMT) is a key enzyme in the synthesis of melatonin. Although melatonin has been shown to exhibit anticancer activity and prevents endocrine resistance in breast cancer, the role of ASMT in breast cancer progression remains unclear. In this retrospective study, we analyzed gene expression profiles in 27 data sets on 7244 patients from 11 countries. We found that ASMT expression was significantly reduced in breast cancer tumors relative to healthy tissue. Among breast cancer patients, those with higher levels of ASMT expression had better relapse‐free survival outcomes and longer metastasis‐free survival times. Following treatment with tamoxifen, patients with greater ASMT expression experienced longer periods before relapse or distance recurrence. Motivated by these results, we devised an ASMT gene signature that can correctly identify low‐risk cases with a sensitivity and specificity of 0.997 and 0.916, respectively. This signature was robustly validated using 23 independent breast cancer mRNA array data sets from different platforms (consisting of 5800 patients) and an RNAseq data set from TCGA (comprising 1096 patients). Intriguingly, patients who are classified as high‐risk by the signature benefit from adjuvant chemotherapy, and those with grade II tumors who are classified as low‐risk exhibit improved overall survival and distance relapse‐free outcomes following endocrine therapy. Together, our findings more clearly elucidate the roles of ASMT, provide strategies for improving the efficacy of tamoxifen treatment and help to identify those patients who may maximally benefit from adjuvant or endocrine therapies. What's new? Melatonin is associated with delayed breast cancer progression and improved survival in tamoxifen‐treated, estrogen receptor (ER)‐negative breast cancer patients. Whether acetylserotonin O‐methyltransferase (ASMT), which has a key role in melatonin synthesis, influences these effects of melatonin on breast cancer remains unclear. Here, ASMT expression was found to be significantly reduced in human breast cancer tumors. Moreover, patients with relatively high ASMT expression experienced improved relapse‐free survival outcomes and increased metastasis‐free survival times, particularly following tamoxifen therapy. These findings suggest that in certain subsets of ER‐negative patients, knowledge of ASMT expression could be used to better tailor treatment strategies. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine whether the association between dopamine‐related genotype and gait speed differs according to frailty status or race. DESIGN: Cross‐sectional population‐based study (Cardiovascular Health Study). SETTING: Multicenter study, four U.S. sites. PARTICIPANTS: Volunteer community‐dwelling adults aged 65 years and older, without evidence of Parkinsonʼs disease (N = 3,744; 71 years; 82% White; 39% male). MEASUREMENTS: Gait speed (usual pace; m/s), physical frailty (Fried definition), and genetic polymorphism of catechol‐O‐methyltransferase (COMT; rs4680), an enzyme regulating tonic brain dopamine levels, were assessed. Interaction of COMT by frailty and by race predicting gait speed were tested, and, if significant, analyses were stratified. Multivariable regression models of COMT predicting gait speed were adjusted for demographics and locomotor risk factors. Sensitivity analyses were repeated, stratified by clinical cutoffs of gait speed (0.6 and 1.0 m/s) instead of frailty status. RESULTS: The interaction of COMT by frailty and COMT by race were P =.02 and P =.01, respectively. Compared with Met/Met (higher dopaminergic signaling), the Val/Val group (lower dopaminergic signaling) walked marginally more slowly in the full cohort (0.87 vs 0.89 m/s; P =.2). Gait speed differences were significant for frail (n = 220; 0.55 vs 0.63 m/s; P =.03), but not for prefrail (n = 1,691; 0.81 vs 0.81 m/s; P =.9) or nonfrail (n = 1,833; 0.98 vs 0.97 m/s; P =.7); results were similar in fully adjusted models. Among frail, associations were similar for Whites and Blacks, with statistical significance for Whites only. Associations stratified by clinical cutoffs of gait speed were not significant. CONCLUSION: The association of dopamine‐related genotype with gait speed is stronger among adults with frailty compared with those without frailty. The potential effects of dopaminergic signaling on preserving physical function in biracial cohorts of frail adults should be further examined. [ABSTRACT FROM AUTHOR]

Opicapone, a peripheral, long‐acting catechol‐O‐methyltransferase inhibitor has been shown to improve wearing‐off phenomenon in randomized, double‐blind studies. This study compared the pharmacokinetic characteristics of opicapone small‐tablet and size 1 capsule formulations after single oral administration to healthy Japanese subjects. In this open‐label, randomized, 2‐way and 2‐period crossover phase 1 study, 48 healthy male subjects (aged 20 to 45 years; body mass index, 18.5 to <30.0 kg/m2) were randomly assigned to 2 cohorts (n = 24 each), which were administered opicapone 25 or 50 mg in a tablet‐capsule or capsule‐tablet sequence under fasted conditions. Blood samples were collected for pharmacokinetic analysis before opicapone capsule/tablet administration and at regular intervals over 24 hours after administration. Compared with capsules, tablets were associated with higher Cmax and AUClast/0‐∞ values. However, t1/2 and tmax values were similar with opicapone 25‐ and 50‐mg capsules/tablets. Geometric mean ratios (tablets/capsules) of Cmax, AUClast, and AUC0‐∞ were 1.24, 1.18, and 1.19, respectively, for the 25‐mg dose and 1.42, 1.28, and 1.27, respectively, for the 50‐mg dose. Opicapone was well tolerated, and no serious adverse events occurred. A small tablet formulation of opicapone proposed for use in Japanese clinical trials was associated with apparent greater exposure compared with the existing hard capsule formulation, which should be considered when developing opicapone for Japanese patients. [ABSTRACT FROM AUTHOR]

Objectives: Histone methyltransferase G9a, also known as Euchromatic Histone Lysine Methyltransferase 2 (EHMT2), mediates H3K9 methylation which is associated with transcriptional repression. It possesses immunomodulatory effects and is overexpressed in multiple types of cancer. In this study, we investigated the role of G9a in the induction of trained immunity, a de facto innate immune memory, and its effects in non‐muscle‐invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette‐Guérin (BCG). Methods: EHMT2 expression was assessed upon induction of trained immunity by RNA sequencing and Western blotting. G9a inhibitor BIX‐01294 was used to investigate the effect on trained immunity responses in vitro. Subsequent cytokine production was measured by ELISA, epigenetic modifications were measured by ChIP‐qPCR, Seahorse technology was used to measure metabolic changes, and a luminescence assay was used to measure ROS release. RNA sequencing was performed on BIX‐01294‐treated monocytes ex vivo. Results: The expression of EHMT2 mRNA and protein decreased in monocytes during induction of trained immunity. G9a inhibition by BIX‐01294 induced trained immunity and amplified trained immunity responses evoked by various microbial ligands in vitro. This was accompanied by decreased H3K9me2 at the promoters of pro‐inflammatory genes. G9a inhibition was also associated with amplified ex vivo trained immunity responses in circulating monocytes of NMIBC patients. Additionally, altered RNA expression of inflammatory genes in monocytes of NMIBC patients was observed upon ex vivo G9a inhibition. Furthermore, intravesical BCG therapy decreased H3K9me2 at the promoter of pro‐inflammatory genes. Conclusion: Inhibition of G9a is important in the induction of trained immunity, and G9a may represent a novel therapeutic target in NMIBC patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: Rho kinase (ROCK) activation is involved in neuroinflammatory processes leading to progression of neurodegenerative diseases such as Parkinson's disease. Furthermore, ROCK plays a major role in angiogenesis. Neuroinflammation and angiogenesis are mechanisms involved in developing l-DOPA-induced dyskinesias (LID). However, it is not known whether ROCK plays a role in LID and whether ROCK inhibitors may be useful against LID.Experimental Approach: In rats, we performed short- and long-term dopaminergic lesions using 6-hydroxydopamine and developed a LID model. Effects of dopaminergic lesions and LID on the RhoA/ROCK levels were studied by western blot, real-time PCR analyses and ROCK activity assays in the substantia nigra and striatum. The effects of the ROCK inhibitor fasudil on LID were particularly investigated.Key Results: Short-term 6-hydroxydopamine lesions increased nigrostriatal RhoA/ROCK expression, apparently related to the active neuroinflammatory process. However, long-term dopaminergic denervation (completed and stabilized lesions) led to a decrease in RhoA/ROCK levels. Rats with LID showed a significant increase of RhoA and ROCK expression. The development of LID was reduced by the ROCK inhibitor fasudil (10 and 40 mg·kg-1 ), without interfering with the therapeutic effect of l-DOPA. Interestingly, treatment of 40 mg·kg-1 of fasudil also induced a significant reduction of dyskinesia in rats with previously established LID.Conclusion and Implications: The present results suggest that ROCK is involved in the pathophysiology of LID and that ROCK inhibitors such as fasudil may be a novel target for preventing or treating LID. Furthermore, previous studies have revealed neuroprotective effects of ROCK inhibitors. [ABSTRACT FROM AUTHOR]

Childhood adversity may act as a stressor to produce a cascade of neurobiological effects that irreversibly alter neural development, setting the stage for developing psychopathology in adulthood. The catechol‐O‐methyltransferase (COMT) Val158Met polymorphism has received much attention as a candidate gene associated with environmental adversity, modifying risk for psychopathology. In this study, we aim to see how gene × brain × environment models give a more integrative understanding of brain modifications that contribute to predicting psychopathology related to childhood adversity. A large nonclinical sample of young adults completed Childhood Trauma Questionnaire (CTQ), behavioral scores, multimodal magnetic resonance imaging (MRI) scans, and genotyping. We utilized graph‐based connectivity analysis in morphometric similarity mapping and resting‐state functional MRI to investigate brain alterations. Relationships among COMT genotypes, CTQ score, imaging phenotypes, and behavioral scores were identified by multiple regression and mediation effect analysis. Significant main effect of CTQ score was found in anatomic connectivity of orbitofrontal cortex that was an outstanding mediator supporting the relationship between CTQ score and anxiety/harm‐avoiding personality. We also noted the main effect of childhood trauma on reorganization of functional connectivity within the language network. Additionally, we found genotype × CTQ score interactions on functional connectivity of the right frontoparietal network as well as anatomic connectivity of motor and limbic regions. Our data demonstrate childhood adversity and COMT genotypes are associated with abnormal brain connectivity, structurally and functionally. Early identification of individuals at risk, assessment of brain abnormality, and cognitive interventions may help to prevent or limit negative outcomes. [ABSTRACT FROM AUTHOR]

The transcription factor nuclear factor‐κB (NF‐κB) signaling is a mediator of viral infection‐mediated inflammation and SET‐domain containing 6 (SETD6) is known as a methyltransferase that suppresses the activity of NF‐κB signaling. However, the downside of the SETD6 is that it cannot be directly utilized as an inflammatory regulator due to the short half‐life and poor intracellular delivery. Here, a ferritin nanocage‐based delivery system is presented that can maintain the activity of SETD6 in vivo. According to the analysis of severe COVID‐19 patients' peripheral blood mononuclear cells (PBMCs), the SETD6 expression is downregulated while that of NF‐κB is upregulated. By engineering the structure of ferritin, a protein scaffold is fabricated in which short ferritin is decorated with cell‐penetrating peptide and nuclear‐localizing TAT‐NBD peptide together with SETD6, termed TFS. The TFS enhances the SETD6 level and reduces the NF‐κB signaling in PBMCs of severe COVID‐19 patients and subsequently suppresses the cytokine storm. When the TFS is intravenously administered in the cytokine storm mouse model, the survival rate is rescued and the lung tissue damage and cytokine expression are also inhibited. These results indicate that the ferritin nanocage‐based peptide delivery system allows stable in vivo delivery and efficient suppression of NF‐κB signaling‐mediated inflammation. [ABSTRACT FROM AUTHOR]

The aim of this systematic review was to qualitatively synthesise the available research that investigated the influence of COMT genotype at SNP rs4680 on both task-based and resting-state connectivity in healthy adults. Thirty-five studies were identified that met inclusion criteria. Of the included studies, 20 studies reported resting-state findings and 16 studies reported task-based findings (emotion-processing, memory, working memory, reward-based learning and executive function). Studies were highly heterogeneous but an overall trend towards an association of the Val allele with greater resting-state connectivity and the Met allele with greater task-based connectivity is reported. A possible interpretation of current findings is discussed, whereby the Val allele is associated with improved cognitive flexibility allowing integration of novel relevant stimuli, and the Met allele allows improved sustained attention and targeted neural processing, particularly between limbic regions and prefrontal cortex. The most promising brain regions implicated in a COMT genotype influence on functional connectivity include prefrontal regions, amygdala and hippocampus. [ABSTRACT FROM AUTHOR]

In eukaryotes, mature mRNA is formed through modifications of precursor mRNA, one of which is 5' cap biosynthesis, involving RNA cap guanine‐N7 methyltransferase (N7‐MTase). N7‐MTases are also encoded by some eukaryotic viruses and facilitate their replication. N7‐MTase inhibitors have therapeutic potential, but their discovery is difficult because long RNA substrates are usually required for activity. Herein, we report a universal N7‐MTase activity assay based on small‐molecule fluorescent probes. We synthesized 12 fluorescent substrate analogues (GpppA and GpppG derivatives) varying in the dye type, dye attachment site, and linker length. GpppA labeled with pyrene at the 3'‐O position of adenosine acted as an artificial substrate with the properties of a turn‐off probe for all three tested N7‐MTases (human, parasite, and viral). Using this compound, a N7‐MTase inhibitor assay adaptable to high‐throughput screening was developed and used to screen synthetic substrate analogues and a commercial library. Several inhibitors with nanomolar activities were identified. [ABSTRACT FROM AUTHOR]

S‐adenosyl‐l‐methionine (SAM)‐dependent methyltransferases (MTs) catalyse the methylation of a vast array of small metabolites and biomacromolecules. Recently, rare carboxymethylation pathways have been discovered, including carboxymethyltransferase enzymes that utilise a carboxy‐SAM (cxSAM) cofactor generated from SAM by a cxSAM synthase (CmoA). We show how MT enzymes can utilise cxSAM to catalyse carboxymethylation of tetrahydroisoquinoline (THIQ) and catechol substrates. Site‐directed mutagenesis was used to create orthogonal MTs possessing improved catalytic activity and selectivity for cxSAM, with subsequent coupling to CmoA resulting in more efficient and selective carboxymethylation. An enzymatic approach was also developed to generate a previously undescribed co‐factor, carboxy‐S‐adenosyl‐l‐ethionine (cxSAE), thereby enabling the stereoselective transfer of a chiral 1‐carboxyethyl group to the substrate. [ABSTRACT FROM AUTHOR]

The cancer stem cell theory states that a subset of tumor cells, termed cancer stem cells (CSCs), has the ability to self‐renew and differentiate within the tumors. According to this theory, CSCs would be mainly responsible for tumor initiation, progression, resistance to therapy, recurrence, and metastasis. In this study, a culture system was setup to enrich CSCs from bladder cancer (T24), lung cancer (A549), colorectal cancer (CaCo‐2), and osteosarcoma (MG63) cell lines, through sphere formation. Magnetic‐activated cell sorting was also used to further increase CSC enrichment. Subsequently, molecular characterization of CSC‐enriched cell populations and parental cells was carried out, by exploring the expression levels of stem markers and the enzyme nicotinamide N‐methyltransferase (NNMT). Results obtained showed a significant upregulation of stem cell markers in CSC‐enriched populations, obtained upon sphere formation, compared with parental counterparts. Moreover, NNMT expression levels were markedly increased in samples enriched with CSCs with respect to control cells. Considering the fundamental role played by CSCs in carcinogenesis, reported data strengthen the hypothesis that sustains a pivotal role of NNMT in cancer growth and metastasis. In addition, these findings could represent an important achievement for the development of new and effective anticancer therapies, based on CSC‐associated targets. [ABSTRACT FROM AUTHOR]

Polydopamine is a mussel‐inspired functional material with a unique ability to form surface coatings. It is a green, environmentally benign product available very easily for a multitude of varied applications. This review attempts to collect useful information with respect to polydopamine‐based catalytic studies with the use of polydopamine and modified polydopamine preparations loaded with varied catalytically active species including metal ions and metal particles. Major sections are about the use of polydopamine as catalyst material, utilization of immobilized enzymes, removal of toxic materials, results in organic synthesis, and fuel cell applications. A few examples of chiral catalysis and results of recycling studies are also treated. Data collected and analyzed indicate the importance and high potential of polydopamine‐based catalysts in sustainable chemistry. [ABSTRACT FROM AUTHOR]

Negative symptoms in schizophrenia have been associated with functional changes in frontostriatal pathways. Dysregulation of the dopamine signal in frontostriatal pathways leads to the symptomology observed in schizophrenia. Although the catechol‐O‐methyltransferase (COMT) gene, one of the susceptibility genes for schizophrenia, has been associated with dopamine activities in prefrontal and striatal regions, it is still unclear whether the disease state and COMT val158met genotype have an interaction effect on the functional connectivity of frontostriatal pathways. In this study, we evaluated the possible interactions between COMT val158met variations and the disease state on the resting‐state functional connectivity (RSFC) of frontostriatal pathways in fifty‐one first episode schizophrenia (FES) patients (val/val: 29, met +: 22) with prominent negative symptoms and forty‐eight healthy controls (val/val: 31, met +: 17). Regions of interest were defined by the result of a meta‐analysis of frontostriatal pathways using the Neurosynth database. We found a significant genotype × disease interaction effect on the RSFC between the bilateral anterior cingulate (ACC) and right caudate, which overlapped with the main effect of the disease state. Behavioural regression analysis suggested that RSFC between the right ACC and right caudate correlated with the severity of SANS avolition–apathy scores in patients who were met carriers but not in patients who were val homozygous. Our findings suggest that the RSFC of frontostriatal pathways may differentially affected by an individual's COMT val158met genotype. [ABSTRACT FROM AUTHOR]

The invasive harlequin ladybird Harmonia axyridis is a textbook example of polymorphism and polyphenism as the temperature during egg development determines the frequency of melanic morphs and the number and size of black spots in nonmelanic morphs. Recent concepts in evolutionary biology suggest that epigenetic mechanisms can translate environmental stimuli into heritable phenotypic changes. To investigate whether epigenetic mechanisms influence the penetrance and expressivity of colour morphs in H. axyridis, we used RNA interference to silence key enzymes required for DNA methylation and histone modification. We found that neither of these epigenetic mechanisms affected the frequency of different morphs, but there was a significant impact on life‐history traits such as longevity and fecundity. Strikingly, we found that silencing the gene encoding for DNA methyltransferase 1 associated protein 1 (DMAP1) severely reduced female fecundity, which correlated with an abundance of degenerated ovaries in DMAP1‐knockdown female beetles. Finally, we observed significant differences in DMAP1 expression when we compared native and invasive H. axyridis populations with a biocontrol strain differing in egg‐laying capacity, suggesting that the DNA methyltransferase 1‐DMAP1 complex may influence the invasive performance of this ladybird. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to evaluate the association of individual and combined single‐nucleotide polymorphisms in brain‐derived neurotrophic factor (BDNF), dopamine transporter (DAT), and catechol‐O‐methyltransferase (COMT) genes with the occurrence of motor levodopa‐induced complications (MLIC) in Parkinson's disease (PD). Materials and Methods: We studied 76 patients with PD (MLIC occurred in 56.6%) and 60 controls. Allelic discrimination of rs6265 BDNF (Val66Met), rs397595 DAT (SLC6A3), and rs4680 COMT (Val158Met) genes were genotyped. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multinominal logistic regression. Orthogonal partial least squares (OPLS) analysis and OPLS discriminant analysis (OPLS‐DA) were used to analyze qualitative genetic data. Results: The risk of PD in subjects with the AG BDNF genotype was increased sixfold (OR = 6.12, 95% CI = 2.88–13.02, p <.0001), and AG BDNF and AG DAT genotypes were correlated with PD in OPLS‐DA (VIP > 1). There were no differences in distributions of BDNF, DAT and COMT genotypes between PD groups with and without MLIC, while OPLS model showed that genotype combination of AG BDNF, AG DAT, and GG COMT was correlated with MLIC and genotypes combination of GG BDNF, AA DAT, and AA COMT with lack of MLIC in PD patients (VIP > 1). Conclusions: Our results confirmed the association of rs6265 BDNF (Val66Met) with the risk of PD and suggest a synergic effect of rs6265 BDNF (Val66Met), rs397595 DAT (SLC6A3), and rs4680 COMT (Val158Met) polymorphisms on the occurrence of MLIC. [ABSTRACT FROM AUTHOR]

In recent studies, we have investigated the monoamine oxidase (MAO) inhibition properties of pyrrolo[3,4‐f]indole‐5,7‐dione and indole‐5,6‐dicarbonitrile derivatives. Since numerous high potency MAO inhibitors are present among these chemical classes, the present study synthesizes 44 additional derivatives in an attempt to further derive structure‐activity relationships (SARs) and to establish optimal substitution patterns for MAO inhibition. The results show that, with the exception of one compound, all indole‐5,6‐dicarbonitrile derivatives (10) exhibit submicromolar IC50 values for the inhibition of MAO, with the most potent MAO‐A inhibitor exhibiting an IC50 value of 0.006 μM while the most potent MAO‐B inhibitor exhibits an IC50 value of 0.058 μM. Interestingly, an N‐oxide derivative (4c) also proved to be a potent and nonspecific MAO inhibitor. With the exception of one compound, all of the pyrrolo[3,4‐f]indole‐5,7‐diones (28) also exhibit submicromolar IC50 values for the inhibition of an MAO isoform. The most potent inhibitor exhibit an IC50 value of 0.011 μM for MAO‐A. This study proposes that high potency MAO inhibitors such as those investigated here, may act as lead compounds for the development of treatments for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression. [ABSTRACT FROM AUTHOR]