catechol-O-methyltransferase Research Articles

Temporomandibular Disorders is associated with Genetic Factors: A Review

Background and objectives: Pain is the most leading cause of visits to physicians and dentists. It is also a common symptom of diseases that can significantly undermine the quality of life and physical activities. This study aimed to review the existing literature for the causes of Temporomandibular Disorders(TMD) from the genetic point of view.
 Methods: Four international scientific databases including Google Scholar, Biomed Central, PubMed, and ProQuest plus two Iranian databases including Magiran and SID. Then all articles published between1980 and 2019were searched using the following keywords: facial pain, genetic factors and temporomandibular disorders (TMDs). A total of 900 articles were found that 36 were review articles.
 Results: Our review shows that genetic factors have an impact on the incidence and pathology of TMDs These factors include TSPAN9 polymorphism and the COMT gene.
 Conclusion: There is growing evidence indicating that genetic factors play a key role in the pathology of temporomandibular disorders, however, the underlying mechanism of pain is still largely unknown.

Point-of-Care Testing of Enzyme Polymorphisms for Predicting Hypnotizability and Postoperative Pain

Hypnotizability is a stable trait that moderates the benefit of hypnosis for treating pain, but limited availability of hypnotizability testing deters widespread use of hypnosis. Inexpensive genotyping of four single-nucleotide polymorphisms in the catechol-o-methyltransferase (COMT) gene was performed using giant magnetoresistive biosensors to determine if hypnotizable individuals can be identified for targeted hypnosis referrals. For individuals with the proposed optimal COMT diplotypes, 89.5% score highly on the Hypnotic Induction Profile (odds ratio,6.12; 95% CI,1.26-28.75), which identified 40.5% of the treatable population. Mean hypnotizability scores of the optimal group were significantly higher than the total population (P=0.015; effect size=0.60), an effect that was present in women (P=0.0015; effect size=0.83), but not in men (P=0.28). In an exploratory cohort, optimal individuals also reported significantly higher postoperative pain scores (P=0.00030; effect size=1.93), indicating a greater need for treatment.

Early life adversity and cardiovascular responses to repeated stress among adolescents: Moderating role of COMT gene rs4680 polymorphism

BackgroundEarly life adversity (ELA) increases the risk of cardiovascular diseases through dysregulation of cardiovascular stress responses manifested by either exaggerated or blunted reactivity. The catechol-O-methyltransferase (COMT) gene rs4680 polymorphism has been identified in gene–environment interaction (G×E) studies to explain individual differences in the effects of ELA on physiological stress responses. However, little is known about whether ELA interacts with COMT gene rs4680 polymorphism to affect cardiovascular responses to repeated stress exposures. ObjectiveThe current study examined the associations between ELA and cardiovascular responses to repeated stress exposures, and the moderating role of COMT rs4680 polymorphism in these associations. MethodsThe childhood trauma questionnaire (CTQ) was administered to 359 junior school students who underwent a two-successive stress exposures protocol with continuous cardiovascular monitoring [heart rate (HR) and systolic and diastolic blood pressure (SBP, DBP)] across four laboratory phases, and their saliva samples for deoxyribonucleic acid (DNA) genotyping were collected. ResultsELA was associated with blunted HR reactivity to the first and second stress exposures, blunted SBP reactivity to the first stress exposure, and attenuated SBP habituation to repeated stress exposures. Moreover, COMT rs4680 moderated these associations, such that the associations between ELA and blunted HR, SBP, and DBP reactivity to the first stress and disrupted DBP habituation to repeated stress exposures only existed in GA/AA genotype carriers but not in GG genotype carriers. ConclusionsThese findings suggest that the A allele of COMT rs4680 is vulnerable to the negative effects of ELA on the developmental dysregulation of stress physiological systems.

Difference in Methylation and Expression of Brain-Derived Neurotrophic Factor in Alzheimer's Disease and Mild Cognitive Impairment.

Due to the increasing number of progressive dementias in the population, numerous studies are being conducted that seek to determine risk factors, biomarkers and pathological mechanisms that could help to differentiate between normal symptoms of aging, mild cognitive impairment (MCI) and dementia. The aim of this study was to investigate the possible association of levels of BDNF and COMT gene expression and methylation in peripheral blood cells with the development of Alzheimer's disease (AD). Our results revealed higher expression levels of BDNF (p < 0.001) in MCI subjects compared to individuals diagnosed with AD. However, no difference in COMT gene expression (p = 0.366) was detected. DNA methylation of the CpG islands and other sequences with potential effects on gene expression regulation revealed just one region (BDNF_9) in the BDNF gene (p = 0.078) with marginally lower levels of methylation in the AD compared to MCI subjects. Here, we show that the level of BDNF expression in the periphery is decreased in subjects with AD compared to individuals with MCI. The combined results from the gene expression analysis and DNA methylation analysis point to the potential of BDNF as a marker that could help distinguish between MCI and AD patients.

Off-time Treatment Options for Parkinson's Disease.

Motor fluctuations (MF) are deemed by patients with Parkinson's disease (PD) as the most troublesome disease feature resulting from the increasing impairment in responsiveness to dopaminergic drug treatments. MF are characterized by the loss of a stable response to levodopa over the nychthemeron with the reappearance of motor (and non-motor) parkinsonian clinical signs at various moments during the day and night. They normally appear after a few years of levodopa treatment and with a variable, though overall increasing severity, over the disease course. The armamentarium of first-line treatment options has widened in the last decade with new once-a-daily compounds, including a catechol O-methyltransferase inhibitor - Opicapone-, two MAO-B inhibitors plus channel blocker - Zonisamide and Safinamide and one amantadine extended-release formulation - ADS5012. In addition to apomorphine injection or oral levodopa dispersible tablets, which have been available for a long time, new on-demand therapies such as apomorphine sublingual or levodopa inhaled formulations have recently shown efficacy as rescue therapies for Off-time treatment. When the management of MF becomes difficult in spite of oral/on-demand options, more complex therapies should be considered, including surgical, i.e. deep brain stimulation, or device-aided therapies with pump systems delivering continuous subcutaneous or intestinal levodopa or subcutaneous apomorphine formulation. Older and less commonly used ablative techniques (radiofrequency pallidotomy) may also be effective while there is still scarce data regarding Off-time reduction using a new lesional approach, i.e. magnetic resonance-guided focused ultrasound. The choice between the different advanced therapies options is a shared decision that should consider physician opinion on contraindication/main target symptom, patients' preference, caregiver's availability together with public health systems and socio-economic environment. The choice of the right/first add-on treatment is still a matter of debate as well as the proper time for an advanced therapy to be considered. In this narrative review, we discuss all the above cited aspects of MF in patients with PD, including their phenomenology, management, by means of pharmacological and advanced therapies, on-going clinical trials and future research and treatment perspectives.

Catechol-O-Methyltransferase Loss Drives Cell-Specific Nociceptive Signaling via the Enteric Catechol-O-Methyltransferase/microRNA-155/Tumor Necrosis Factor α Axis

The etiology of abdominal pain in postinfectious, diarrhea-predominant irritable bowel syndrome (PI-IBS-D) is unknown, and few treatment options exist. Catechol-O-methyltransferase (COMT), an enzyme that inactivates and degrades biologically active catecholamines, plays an important role in numerous physiologic processes, including modulation of pain perception. Our objective was to determine the mechanism(s) of how decreased colonic COMT in PI-IBS-D patients contributes to the chronic abdominal pain phenotype after enteric infections. Colon neurons, epithelial cells, and macrophages were procured with laser capture microdissection from PI-IBS-D patients to evaluate cell-specific colonic COMT, microRNA-155 (miR-155), and tumor necrosis factor (TNF) α expression levels compared to recovered patients (infection cleared: did not develop PI-IBS-D) and control individuals. COMT-/-, colon-specific COMT-/-, and miR-155-/- mice and human colonoids were used to model phenotypic expression of COMT in PI-IBS-D patients and to investigate signaling pathways linking abdominal pain. Citrobacter rodentium and trinitrobenzene sulfonic acid animal models were used to model postinflammatory changes seen in PI-IBS-D patients. Colonic COMT levels were significantly decreased and correlated with increased visual analog scale abdominal pain ratings in PI-IBS-D patients compared to recovered patients and control individuals. Colonic miR-155 and TNF-α were increased in PI-IBS-D patients with diminished colonic COMT. COMT-/- mice had significantly increased expression of miR-155 and TNF-α in both colon tissues and dorsal root ganglia. Introduction of cV1q antibody (anti-TNF-α) into mice reversed visceral hypersensitivity after C rodentium and trinitrobenzene sulfonic acid. Decreased colonic COMT in PI-IBS-D patients drives abdominal pain phenotypes via the COMT/miR-155/TNF-α axis. These important findings will allow new treatment paradigms and more targeted and personalized medicine approaches for gastrointestinal disorders after enteric infections.

Psychological and genetic parameters associated with the codependency: analytical review

Relevance. The number of people suffering from various kinds of addictions (alcohol, drugs, gambling and others) is growing every year. This is also associated with an increase in domestic violence and a deterioration in the quality of life. An important place in partnership, family relations has a family member (partner) living with an addict. Co-dependency as a personal characteristic of other family members in these conditions becomes important for rehabilitation and support, as well as therapy for antisocial behavior of addicts.Intention. The study was aimed to analyze the results of empirical and theoretical studies in psychology and related sciences on the phenomenon of codependency and identify genes that are most likely to be associated with codependency, attachment, behavior in relationships and the formation of adaptive and maladaptive codependent behavior strategies.Methodology. A theoretical analysis of the scientific literature on the problem has been carried out using the PubMed database, the Google Academy search platforms, and using the resources of the Scientific Electronic Library (eLIBRARY.ru).Results and Discussion. It is shown that with a complex structure, the codependency has a large number of connections with personality traits, which in turn have biological predictors and are associated with various genes. The results of psychogenetic studies on the role of genes in the formation of emotional and personal characteristics, dependent behavior, emotional attachment and features of human social behavior are described. These are mostly genes associated with the work of neurotransmitter systems and neuropeptide genes.Conclusion. In order to identify the biological determination of codependency, the study of polymorphisms of the DRD2, DAT, and OXTP genes will be the most promising. Also of interest are the DRD4, COMT, 5-HTTLPR, BDNF, MAOA, 5HT2A, 5HT1A, and PKNOX2 genes.

An integrated targeted metabolomics and network pharmacology approach to exploring the mechanism of ellagic acid against sleep deprivation-induced memory impairment and anxiety.

As a neuroprotective agent, ellagic acid (EA) is extremely beneficial. Our previous study found that EA can alleviate sleep deprivation (SD)-induced abnormal behaviors, although the mechanisms underlying this protective effect have not yet been fully elucidated. An integrated network pharmacology and targeted metabolomics approach was utilized in this study to investigate the mechanism of EA against SD-induced memory impairment and anxiety. Behavioral tests were conducted on mice after 72 h of SD. Hematoxylin and eosin staining and nissl staining were then carried out. Integration of network pharmacology and targeted metabolomics was performed. Eventually, the putative targets were further verified using molecular docking analyses and immunoblotting assays. The present study findings confirmed that EA ameliorated the behavioral abnormalities induced by SD and prevented histopathological and morphological damage to hippocampal neurons. Through multivariate analysis, clear clustering was obtained among different groups, and potential biomarkers were identified. Four key targets, catechol-O-methyltransferase (COMT), cytochrome P450 1B1 (CYP1B1), glutathione S-transferase A2 (GSTA2), and glutathione S-transferase P1 (GSTP1), as well as the related potential metabolites and metabolic pathways, were determined by further integrated analysis. Meanwhile, in-silico studies revealed that EA is well located inside the binding site of CYP1B1 and COMT. The experimental results further demonstrated that EA significantly reduced the increased expression of CYP1B1 and COMT caused by SD. The findings of this study extended our understanding of the underlying mechanisms by which EA treats SD-induced memory impairment and anxiety, and suggested a novel approach to address the increased health risks associated with sleep loss.

Effects of Acute Caffeine Intake on Insulin-Like Growth Factor-1 Responses to Total Sleep Deprivation: Interactions with COMT Polymorphism – A Randomized, Crossover Study

Introduction: Genes encoding catechol-O-methyl-transferase (COMT) and adenosine A2A receptor (ADORA2A) have been shown to influence cognitive performances and responses to caffeine intake during prolonged wakefulness. The rs4680 single-nucleotide polymorphism (SNP) of COMT differentiates on memory score and circulating levels of the neurotrophic factor IGF-1. This study aimed to determine the kinetics of IGF-1, testosterone, and cortisol concentrations during prolonged wakefulness under caffeine or placebo intake in 37 healthy participants, and to analyze whether the responses are dependent on COMT rs4680 or ADORA2A rs5751876 SNPs. Methods: In caffeine (2.5 mg/kg, twice over 24 h) or placebo-controlled condition, blood sampling was performed at 1 h (08:00, baseline), 11 h, 13 h, 25 h (08:00 next day), 35 h, and 37 h of prolonged wakefulness, and at 08:00 after one night of recovery sleep, to assess hormonal concentrations. Genotyping was performed on blood cells. Results: Results indicated a significant increase in IGF-1 levels after 25, 35, and 37 h of prolonged wakefulness in the placebo condition, in subjects carrying the homozygous COMT A/A genotype only (expressed in absolute values [±SEM]: 118 ± 8, 121 ± 10, and 121 ± 10 vs. 105 ± 7 ng/mL for A/A, 127 ± 11, 128 ± 12, and 129 ± 13 vs. 120 ± 11 ng/mL for G/G, and 106 ± 9, 110 ± 10, and 106 ± 10 vs. 101 ± 8 ng/mL for G/A, after 25, 35, and 37 h of wakefulness versus 1 h; p < 0.05, condition X time X SNP). Acute caffeine intake exerted a COMT genotype-dependent reducing effect on IGF-1 kinetic response (104 ± 26, 107 ± 27, and 106 ± 26 vs. 100 ± 25 ng/mL for A/A genotype, at 25, 35, and 37 h of wakefulness vs. 1 h; p < 0.05 condition X time X SNP), plus on resting levels after overnight recovery (102 ± 5 vs. 113 ± 6 ng/mL) (p < 0.05, condition X SNP). Testosterone and cortisol concentrations decreased during wakefulness, and caffeine alleviated the testosterone reduction, unrelated to the COMT polymorphism. No significant main effect of the ADORA2A SNP was shown regardless of hormonal responses. Conclusion: Our results indicated that the COMT polymorphism interaction is important in determining the IGF-1 neurotrophic response to sleep deprivation with caffeine intake (NCT03859882).

PS-BPB08-3: OFF-TARGET EFFECTS OF SLEEVE GASTRECTOMY ON BLOOD PRESSURE INDEPENDENT OF BODY WEIGHT REDUCTION IN DIET-INDUCED OBESITY RATS: ROLE OF CHOLECYSTOKININ

Objective: Sleeve gastrectomy (SG) is currently the most selected surgical bariatric procedure for weight loss by shrinking the stomach. SG has been reported to improve glucose metabolism by altering gastrointestinal hormones, but the details of why blood pressure improves are not known. The purpose of this study is to elucidate the mechanism of why SG lowers blood pressure in diet induced obese rats. Design and method: Male Sprague Dawley (SD) rats were subjected to surgical [sham operation (SO) or SG] and dietary interventions [fed a normal diet or high fat diet (HFD) ad libitum or pair fed (PF)]. Diet induced obese rats fed 60% HFD for 12 weeks. Systolic blood pressure (SBP), urinary sodium excretion, and gastrointestinal hormones and renin angiotensin system in renal tissue were examined 4 weeks after surgery. In addition, cholecystokinin (CCK) was administered intraperitoneally to SD rats and evaluated for changes in blood pressure and renal tissue renin angiotensin system. Results: Both SG and PF treatments reduced body weight compared with SO. SG exhibited a reduction in SBP compared with PF, which was associated with a reduction in renal renin (536 ± 48.5 U/g kidney and 1385 ± 55.1 U/g kidney, p &lt; 0.01), angiotensin II (Ang II) (48.2 ± 5.8 ng/g kidney and 258.7 ± 16.9 ng/g kidney, p &lt; 0.01), and catechol O methyltransferase (COMT) levels (0.68 ± 0.05 /αtub and 1.34 ± 0.13/αtub, p &lt; 0.01). SG increased plasma CCK levels compared with PF (p &lt; 0.01 for each), whereas GLP1 and PYY were not changed in fasting. SD rats after CCK administration showed decreased SBP (107.7 ± 2.3 mmHg and 118.0 ± 1.8 mmHg, p &lt; 0.01), COMT (0.49 ± 0.04 /GAPDH and 1.11 ± 0.19/GAPDH, p = 0.02), renin (967 ± 71.3 U/g kidney and 1394 ± 90.8 U/g kidney, p &lt; 0.01), and Ang II (598 ± 76.7 ng/g kidney and 874 ± 86.6 ng/g kidney, p = 0.02) in the kidney compared to controls. Conclusions: The SG reduced SBP, at least in part, through suppression of the sympathetic nerve action by elevation of CCK which is followed by suppression of the intrarenal renin angiotensin system. Conclusions: CCK may have a blood pressure lowering effect, and further research is needed to determine whether CCK can be used as a new antihypertensive agent in the future.

Chronotype, Longitudinal Volumetric Brain Variations Throughout Adolescence, and Depressive Symptom Development.

Adolescence is a critical period for circadian rhythm, with a strong shift toward eveningness around age 14. Also, eveningness in adolescence has been found to predict later onset of depressive symptoms. However, no previous study has investigated structural variations associated with chronotype in early adolescence and how this adds to the development of depressive symptoms. Assessment of 128 community-based adolescents (51% girls) at age 14 and 19 years was performed. Using whole-brain voxel-based morphometry, baseline (at age 14) regional gray matter volumes (GMVs), follow-up (at age 19) regional GMVs, and longitudinal changes (between 14 and 19) associated with Morningness/Eveningness Scale in Children score and sleep habits at baseline were measured. The association of GMV with depressive symptoms at 19 years was studied, and the role of potential clinical and genetic factors as mediators and moderators was assessed. Higher eveningness was associated with larger GMV in the right medial prefrontal cortex at ages 14 and 19 in the whole sample. GMV in this region related to depressive symptoms at age 19 in catechol-O-methyltransferase (COMT) Val/Val, but not in Met COMT, carriers. Larger GMV also was observed in the right fusiform gyrus at age 14, which was explained by later wake-up time during weekends. In adolescence, eveningness and its related sleep habits correlated with distinct developmental patterns. Eveningness was specifically associated with GMV changes in the medial prefrontal cortex; this could serve as a brain vulnerability factor for later self-reported depressive symptoms in COMT Val/Val carriers.

Genetic predictors of interpersonal dependence

For several decades, numerous scientific discussions about the definition and essence of the codependency phenomenon have been ongoing. At the same time, some researchers note a close relationship between this phenomenon and the concept of interpersonal dependence, considering its destructive and positive impact on personality. The relevance and value of the conducted research lies in the fact that despite numerous studies, including interdisciplinary ones, the question about the nature of interpersonal dependence remains open. The aim is to study the differences in levels of interpersonal dependence in different polymorphic variants of catechol-O-methyltransferase (COMT) and dopamine D2 receptor (DRD2) genes. An interdisciplinary molecular genetic and psychological study of 132 women with drug addiction in remission for more than two years was conducted. As a psychological tool was used, “The Interpersonal Dependency Inventory” developed by R. Hirschfield and adapted by O.P. Makushina was used. For determining the polymorphic variants of candidate genes, a method of isolating genomic DNA from buccal epithelial cells was used. The candidate genes considered were genotypes and alleles of the neurotransmitter pathways COMT and DRD2. For statistical processing of the obtained data, the nonparametric Mann-Whitney U-test was used. Substantial differences were found between the levels of interpersonal dependence in the genotypes VV and VM of the catechol-O-methyltransferase (COMT) enzyme; a trend of statistically significant differences was detected between the levels of interpersonal dependence in the genotypes CT and TT of the DRD2 gene. The features identified during the study should be taken into account in the process of carrying out psychological and preventive measures for people with addictive behaviour.

Генетические предикторы развития вегетативной дисфункции

Aim: To study the association of the HTR2C gene rs6318, rs6313 of the HTR2A gene, rs4680 of the COMT gene, rs3785143 of the SLC6A2 gene, rs1799913 of the TPH1 gene, rs7997012 of the HTR2A gene with the development of neurotic disorders in young people living in the Krasnoyarsk Territory. Design: A comparative study. Materials and methods. The study included 133 clinically healthy volunteers. The age of the participants ranged from 16 to 24 years. Molecular genetic studies were carried out on the basis of the Laboratory of Medical Genetics of the V.F. Voino-Yasenetsky Moscow State Medical University of the Ministry of Health of Russia. Psychological testing was performed using the questionnaire of depressive symptoms of Beck, the scale of socio-situational anxiety of O. Kondash in the modification of A.M. Parishioner, Hospital scale of anxiety and depression, as well as carrier study of the association of single nucleotide variants (ONV) rs7997012 of the HTR2A gene, rs6318 of the HTR2C gene, rs6313 of the HTR2A gene, rs4680 of the COMT gene, rs3785143 of the SLC6A2 gene, rs1799913 of the TPH1 gene with neurotic disorders (anxiety and subclinical depression). Results. According to multivariate analysis, the association of the COMT G gene allele carrier (odds ratio (OR) = 2.784; 95% confidence interval (CI): 1.291–6.001; χ2 = 6.986; p = 0.009) and the AH genotype (OR = 2,208; 95% CI: 1,032–4,724; χ2 = 16.716; p &lt; 0.001) with subclinical depression according to the total index of the Beck scale. Carrying the SS genotype of the rs1799913 TRN1 gene increases the risk of learning anxiety by 3 times (OR = 3.011; 95% CI: 1.138–7.967; χ2 = 7.622; p = 0.023). Conclusion. The carriage of the G allele and the rs4680 genotype and AG of the COMT gene is associated with subclinical depression, and the carriage of the SS genotype of the rs1799913 TRN1 gene increases the risk of learning anxiety by 3 times. Thus, the ONV of these genes can be considered as predictors of neurotic disorders, significant already at the subclinical level. Keywords: COMT gene, TRN1 gene, anxiety, depression, neurotic disorders.

Investigation of Methylation Levels in COMT Gene Promoter among Smokers and Opium Addicted Individuals Undergoing Methadone Treatment

1.1. Background: Previous studies have demonstrated that the COMT gene is associated with alcohol, nicotine, and illicit substances. The aim of the present study was to examine the methylation status of a remarkable region in the COMT gene promoter in methadone-treated smokers and addicts. Methods: All male samples, including 30 smokers, 30 opium addicts receiving methadone treatment, and 30 healthy individuals, had their DNAs extracted from their whole blood and processed with a sodium bisulfite kit. 61 CpG dinucleotides were included in the study region and were sequenced.

Exploration of plasma adiponectin, leptin, and COMT genotype on blood pressure among women who are post-menopause.

Research suggests that adiponectin, leptin, and genetic polymorphisms such as catechol-O-methyltransferase (COMT) genotype may play an integral role in blood pressure status and thereby cardiovascular health. This is an area especially important for women who are post-menopause; however, the current literature investigating these associations is limited. This study was a cross-sectional secondary analysis of baseline data (N 237) from the Minnesota Green Tea Trial (MGTT). The current study explored the relationships between plasma adiponectin, leptin, and COMT genotype on blood pressure measures. Plasma adiponectin and leptin were obtained after an overnight fast of at least 10 h and were measured by the radioimmunoassay method. The relationships were analysed using multiple linear regression after adjusting for potential confounders. Effect modifications by age, body mass index (BMI) category, blood pressure category, antihypertensive medication use, and COMT genotype were also investigated. The majority of participants were non-Hispanic (97⋅9%) and Caucasian (94⋅9%). Mean (sd) age and BMI were 60⋅7 (5⋅0) years and 28⋅2 (2⋅9) kg/m2, respectively. After adjustment for confounding variables, neither plasma adiponectin, plasma leptin nor COMT genotype was associated with systolic or diastolic blood pressure measures. The results of stratified analyses also did not reveal any significant interactions or associations. Based on the findings of this study, which utilised more rigorous statistical methods than previous research, neither adiponectin, leptin nor COMT genotype play a role in blood pressure measures in women who are post-menopause.

Catechol-O-methyltransferase (COMT) Val158Met polymorphism in schizophrenia patients: response to antipsychotic treatment and cognitive function

Catechol-O-methyltransferase (COMT) Val158Met polymorphism in schizophrenia patients: response to antipsychotic treatment and cognitive function

Cytokinin Modulates Responses to Phytomelatonin in Arabidopsis thaliana under High Light Stress

Fine-tuned interactions between melatonin (MT) and hormones affected by environmental inputs are crucial for plant growth. Under high light (HL) conditions, melatonin reduced photodamage in Arabidopsis thaliana and contributed to the restoration of the expression of the cytokinin (CK) synthesis genes IPT3, IPT5 and LOG7 and genes for CK signal transduction AHK2,3 and ARR 1, 4, 5 and 12 which were downregulated by stress. However, CK signaling mutants displayed no significant changes in the expression of CK genes following HL + MT treatment, implying that a fully functional cytokinin signaling pathway is a prerequisite for MT-CK interactions. In turn, cytokinin treatment increased the expression of the key melatonin synthesis gene ASMT under both moderate and HL in wild-type plants. This upregulation was further accentuated in the ipt3,5,7 mutant which is highly sensitive to CK. In this mutant, in addition to ASMT, the melatonin synthesis genes SNAT and COMT, as well as the putative signaling genes CAND2 and GPA1, displayed elevated transcript levels. The results of the study suggest that melatonin acts synergistically with CK to cope with HL stress through melatonin-associated activation or repression of the respective hormonal genes.

Генетические факторы и течение синдрома раздраженного кишечника: ассоциации и взаимосвязи

Aim: to evaluate the effect of the interaction of genetic and epigenetic factors on the formation and persistence of signs concerning irritable bowel syndrome (IBS). Patients and Methods: the study included 263 patients with IBS (189 female, 74 male, mean age — 29 [25; 35] years), including: IBS with diarrhea (n=84), IBS with constipation (n=92), mixed IBS (n=87); mild (n=110), moderate (n=99), severe (n=54) course. The control group consisted of 40 subjects comparable by gender and age. In each group, the polymorphism prevalence of candidate genes associated with IBS (COMT, DRD2, SLC6A4, LCT, FTO, TLR9), nutritional characteristics, the level of anxiety and depression, including specific gastrointestinal anxiety, life quality, cortisol content in saliva, blood serotonin, dopamine blood level, fecal zonulin. Results: Val/Val genotype of the COMT gene, characterized by high enzyme activity, was more common among patients with IBS with diarrhea and mixed IBS (χ2=55.75, p&lt;0.001), in severe course (χ2=32.66, p&lt;0.001) and was associated with diarrhea (χ2=53.39, p&lt;0.001), anxiety (χ2=20.01, p&lt;0.001); Met/Met genotype was associated with constipation (χ2=16.09, p&lt;0.001), abdominal pain (χ2=11.04, p=0.004) and depression (χ2=13.12, p=0.001). T/T genotype of the DRD2 gene, leading to a decrease in the density of dopamine D2 receptors, was more commonly found in patients with IBS with constipation (χ2=13.05, p=0.042) and severe course (χ2=30.37, p&lt;0.001), and was associated with abdominal pain (χ2=42.84, p&lt;0.001), episodes of overeating (χ2=29.05, p&lt;0.001), sugar cravings (χ2=16.82, p=0.002) and depression (χ2=39.63, p&lt;0.001). S/S genotype of the SLC6A4 gene, leading to a decrease in serotonin reuptake, was more common in patients with IBS with diarrhea (χ2=28.77, p&lt;0.001), and was associated with abdominal pain (χ2=9.15, p&lt;0.001), diarrhea (χ2=39.98, p&lt;0.001) and anxiety (χ2=7.87, p=0.02), genotype L/L — with constipation (χ2=12.4, p=0.002). A/A genotype of the FTO gene was associated with overweight (χ2=41.33, p&lt;0.001), episodes of overeating (χ2=31.49, p&lt;0.001), increased consumption of added sugar (χ2=9.25, p=0.010), and cravings for sweet (χ2=26.19, p=0.001), farinaceous and confectionery products (χ2=7.85, p=0.019). CC genotype of the TLR9 gene, leading to excessive activation of TLR9, was more commonly detected in individuals with a history of acute intestinal infection (χ2=8.45, p=0.038). Conclusion: the identified associations suggest the impact of genetic and environmental factors on the severity and nature of the IBS course. KEYWORDS: irritable bowel syndrome, genetic factors, epigenetic factors, catechol-O-methyltransferase, dopamine D2 receptors, serotonin reuptake transporter, fat mass and obesity-associated gene, LCT gene, toll-like receptors. FOR CITATION: Gaus O.V., Livzan M.A. Genetic factors and the course of irritable bowel syndrome: associations and interactions. Russian Medical Inquiry. 2023;7(5):237–248 (in Russ.). DOI: 10.32364/2587-6821-2023-7-5-1.

SlNPR1 modulates chilling stress resistance in tomato plant by alleviating oxidative damage and affecting the synthesis of ferulic acid

• NPR1 gene and protein content are dramatically induced by chilling stress. • CRISPR/Cas9-mediated SlNPR1 inhibition aggravated the symptoms of chilling injury. • SlNPR1 enhances tolerance to chilling stress by alleviating oxidative damage. • SlNPR1 enhances tolerance to chilling stress by affecting the synthesis of FA. Non-expresser of pathogenesis-related genes 1 (NPR1) has been demonstrated to be a master transcription factor during resistance against pathogens, the mechanisms by which regulates chilling stress, however, remain unclear. Our results revealed that the expression and protein content of SlNPR1 were dramatically induced by low temperature (4 °C). CRISPR/Cas9-mediated SlNPR1 mutagenesis aggravated the symptoms of chilling injury in tomato plant, which was accompanied with the accumulation of malonic dialdehyde (MDA), hydrogen peroxide (H 2 O 2 ) and superoxide anion (O 2 − ), and the decrease of soluble protein content, proline content as well as antioxidant enzymes activity. In addition, slnpr1 mutants showed lower expression of SlICE1 and SlCBF1 in contrast to wild type plants (WT) . PAL, C4H, C3H and COMT genes play important roles in the synthesis of ferulic acid (FA). We found that knockout of SlNPR1 reduced the expression of PAL, C4H, C3H and COMT induced by low temperature (4 °C) and inhibited the accumulation of FA content. Interestingly, FA-treated plants showed greater tolerance to chilling stress and displayed higher expression of SlICE1 and SlCBF1 , exhibited lower levels of MDA and H 2 O 2 , but higher antioxidant enzyme (APX, POD, SOD and CAT) activity than WT. These findings reveal a new regulatory pathway that SlNPR1 enhances tolerance to chilling stress in tomato plant by alleviating oxidative damage and affecting the synthesis of FA.

Efficient automatic construction of atom-economical QM regions with point-charge variation analysis.

The setup of QM/MM calculations is not trivial since many decisions have to be made by the simulation scientist to achieve reasonable and consistent results. The main challenge to be tackled is the construction of the QM region to make sure to take into account all important parts of the adjacent environment and exclude less important ones. In our previous work [F. Brandt and Ch. R. Jacob, Systematic QM Region Construction in QM/MM Calculations Based on Uncertainty Quantification, J. Chem. Theory Comput., 2022, 18, 2584-2596.], we introduced the point charge variation analysis (PCVA) as a simple and reliable tool to systematically construct QM regions based on the sensitivity of the reaction energy with respect to variations of the MM point charges. Here, we assess several simplified variants of this PCVA approach for the example of catechol O-methyltransferase and apply PCVA for another system, the triosephosphate isomerase. Furthermore, we extend its scope by applying it to a DNA system. Our results indicate that PCVA offers an efficient and versatile approach of the automatic construction of atom-economical QM regions, but also identify possible pitfalls and limitations.