Expression Of COMT Research Articles

Dopaminergic and anti-estrogenic responses in juvenile steelhead (Oncorhynchus mykiss) exposed to bifenthrin

The frequency of detection and concentrations of bifenthrin, a pyrethroid insecticide, in the waterways inhabited by the endangered species, steelhead trout (Oncorhynchus mykiss), has become a significant concern for regulatory agencies. Endocrine disruption has been observed with estrogenic and anti-estrogenic responses in fish species at different life stages. Since several studies have indicated alterations in dopaminergic signaling associated with endocrine responses, juvenile steelhead were exposed to environmentally relevant concentrations of 60 or 120 ng/L bifenthrin for two weeks. Fish brains were assessed for dopamine levels and the expression of genes involved in dopaminergic and estrogenic processes, such as catechol-o-methyltransferase (comt) and monoamine oxidase (mao). Vitellogenin (vtg) and estrogenic receptors (ERα1, ERβ1, and ERβ2) were also evaluated in livers of the animals. Dopamine concentrations were significantly higher in fish brains following bifenthrin exposure. Consistent with a reduction in dopamine clearance, there was a significant decrease in the mRNA expression of comt with increased bifenthrin concentration. Hepatic expression of ERα1 and ERβ2 mRNA was significantly decreased with increased bifenthrin concentration. These data support the possible mechanism of bifenthrin altering the dopaminergic pathway at low ng/L concentrations, in juvenile steelhead, which could interfere with endocrine feedback loops. These findings support the need for and importance of identifying species and life stage differences in pesticide modes of action to reduce uncertainties in risk assessments.

Antidepressant effects of selective adenosine receptor antagonists targeting the A1 and A2A receptors administered jointly with NMDA receptor ligands: behavioral, biochemical and molecular investigations in mice

BackgroundThe objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists.MethodsThe forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L–701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D–cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK–801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined.ResultsThe obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D–cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D–cycloserine-treated group. Adora1 expression increased with L–701,324, DPCPX + D–cycloserine, and DPCPX + CGP 37849, while D–cycloserine, CGP 37849, and MK–801 led to a decrease. Comt mRNA levels dropped with DPCPX + L–701,324, istradefylline + L–701,324/CGP 37849 but increased with D–cycloserine, MK–801, CGP 37849 and DPCPX + MK–801/ CGP 37849. Slc6a15 levels were reduced by D–cycloserine, DPCPX + L–701,324 but rose with DPCPX + CGP 37849/MK–801 and istradefylline + D–cycloserine/MK–801/CGP 37849.ConclusionOur study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.

Abstract LB280: Enhancing glioblastoma radiotherapy by COMT inhibition

Abstract There is an urgent unmet medical need to discover novel therapeutics to enhance the efficacy of glioma radiotherapy. Here we assessed the roles of catechol - o - methyltransferase COMT, a key enzyme in dopamine metabolism and a drug target for Parkinson's disease, in glioma treatment. Analysis of TCGA data showed significantly higher COMT expression levels in glioma versus normal brain tissues. Inhibition of COMT by genetic knockout or FDA - approved COMT inhibitors significantly sensitized glioma cells to radiotherapy in vitro and murine glioma in vivo. Mechanistically, COMT inhibition in glioblastoma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral dsRNA sensing pathway and type I IFN response. Elevated type I IFNs stimulated microglial cells′ phagocytic capacity, enhancing radiotherapy efficacy. Because of the long - established safety record of the COMT inhibitors, our findings provide a solid rationale to evaluate them in combination with radiotherapy in glioma patients. Citation Format: Meng Jiao, Christopher J. Pirozzi, Chen Yu, Xuhui Bao, Mengjie Hu, Dong Pan, Sejiro Littleton, Nathan Reynolds, Daniel R. Saban, Fang Li, Chuan-yuan Li. Enhancing glioblastoma radiotherapy by COMT inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB280.

Identification of genes regulated by trait sensitivity to negative feedback and prolonged alcohol consumption in rats.

The results of our previous studies demonstrated that low sensitivity to negative feedback (NF) is associated with increased vulnerability to the development of compulsive alcohol-seeking in rats. In the present study, we investigated the molecular underpinnings of this relationship. Using TaqMan Gene Expression Array Cards, we analyzed the expression of the genes related to NF sensitivity and alcohol metabolism in three cortical regions (medial prefrontal cortex [mPFC], anterior cingulate cortex [ACC], orbitofrontal cortex [OFC]) and two subcortical regions (nucleus accumbens [Nacc], amygdala [Amy]). Gene expression differences were confirmed at the protein level with Western blot. Sensitivity to NF was characterized by differences in Gad2, Drd2, and Slc6a4 expression in the ACC, Maoa in the mPFC, and Gria1, Htr3a, and Maoa in the OFC. Chronic alcohol consumption was associated with differences in the expression of Comt and Maoa in the ACC, Comt, Adh1, and Htr2b in the mPFC, Adh1, and Slc6a4 in the Nacc, Gad2, and Htr1a in the OFC, and Drd2 in the Amy. Interactions between the sensitivity to NF and alcohol consumption were observed in the expression of Gabra1, Gabbr2, Grin2a, Grin2b, and Grm3 in the ACC, and Grin2a in the OFC. The observed differences were confirmed at the protein level for MAO-A in the mPFC, and ADH1 in the mPFC and Nacc. Our findings contribute to a better understanding of the molecular mechanisms underlying the relationship between trait sensitivity to NF and compulsive alcohol consumption.

269P Prostate cancer harboring low COMT expression correlates with a poor prognosis and response to enzalutamide

269P Prostate cancer harboring low COMT expression correlates with a poor prognosis and response to enzalutamide

Dysregulated COMT Expression in Fragile X Syndrome.

Transcriptional and proteomics analyses in human fragile X syndrome (FXS) neurons identified markedly reduced expression of COMT, a key enzyme involved in the metabolism of catecholamines, including dopamine, epinephrine and norepinephrine. FXS is the most common genetic cause of intellectual disability and autism spectrum disorders. COMT encodes for catechol-o-methyltransferase and its association with neuropsychiatric disorders and cognitive function has been extensively studied. We observed a significantly reduced level of COMT in in FXS human neural progenitors and neurons, as well as hippocampal neurons from Fmr1 null mice. We show that deficits in COMT were associated with an altered response in an assay of dopaminergic activity in Fmr1 null mice. These findings demonstrate that loss of FMRP downregulates COMT expression and affects dopamine signaling in FXS, and supports the notion that targeting catecholamine metabolism may be useful in regulating certain neuropsychiatric aspects of FXS.

Prognostic and immunomodulatory roles of schizophrenia-associated genes HTR2A, COMT, and PRODH in pan-cancer analysis and glioma survival prediction model.

The shortened life expectancy in schizophrenia (SCZ) patients may be correlated with most cancers, yet there is heterogeneity in the studies examining these correlations. This study explored the expression of SCZ-related genes (HTR2A, COMT, and PRODH) in pan-cancer analysis. It helped to enhance the mechanistic understanding of the SCZ-cancer relationship and their immune mechanisms at the genetic level. Additionally, this study established a survival prediction model for glioblastoma and low-grade glioma (GBMLGG). SCZ-associated genes (HTR2A, COMT, and PRODH) were subjected to pan-cancer analysis. COX regression analysis and survival analysis were carried out for differentially expressed genes in multiple cancers, and finally, GBMLGG was derived as the focus for further detailed analysis. The immune scores and immune cell infiltration analyses were performed. All three genes were considerably linked with immune infiltration in GBMLGG, consistent with survival analysis. Based on the immunocyte analysis, it was observed that CD8+ T cells might be critically involved in the survival of GBMLGG. Genomic heterogeneity studies identified correlations of three genes with GBMLGG in tumor mutational burden (TMB) and mutant-allele tumor heterogeneity (MATH). HTR2A and COMT were significantly negatively correlated in TMB. Furthermore, it was found that HTR2A had a significant positive correlation with MATH, whereas PRODH had a significant negative correlation with MATH. Accordingly, a survival prediction model was constructed for GBMLGG using these three genes and clinical data, with better results obtained when evaluated in two separate datasets. Finally, gene expression validation and further immunocyte analysis were carried out in the single-cell RNA sequencing (scRNA-seq) data of glioma. SCZ-associated genes (HTR2A, COMT, and PRODH) were significantly differentially expressed in the carcinogenesis and survival of multiple cancers. The up or downregulation of gene expression varied across cancer types. In the GBMLGG analysis, upregulation of HTR2A and COMT was significantly positively correlated with carcinogenesis, while the opposite was noted for PRODH. Furthermore, a negative correlation was found between the upregulation of HTR2A and COMT and the survival of GBMLGG, and the opposite was also noted for PRODH. As reflected in the immunocyte analysis, abnormal expression of the three genes might be linked with CD8+ T cell infiltration, which might be critically involved in the survival of GBMLGG patients. The expression of HTR2A and COMT may inversely affect the efficacy of immunotherapy through the TMB pathway and further affect the prognosis of patient survival. The expression of HTR2A might positively indicate the degree of tumor heterogeneity through MATH and further affect the survival and prognosis of patients. The negative correlation of PRODH led to the opposite effect. Finally, the constructed survival prediction model demonstrated good predictive value, which was well validated in scRNA-seq analysis.

Semaglutide reduces alcohol intake and relapse-like drinking in male and female rats.

Glucagon-like peptide1 receptor (GLP-1R) agonists have been found to reduce alcohol drinking in rodents and overweight patients with alcohol use disorder (AUD). However, the probability of low semaglutide doses, an agonist with higher potency and affinity for GLP-1R, to attenuate alcohol-related responses in rodents and the underlying neuronal mechanisms is unknown. In the intermittent access model, we examined the ability of semaglutide to decrease alcohol intake and block relapse-like drinking, as well as imaging the binding of fluorescently marked semaglutide to nucleus accumbens (NAc) in both male and female rats. The suppressive effect of semaglutide on alcohol-induced locomotor stimulation and invivo dopamine release in NAc was tested in male mice. We evaluated effect of semaglutide on the invivo release of dopamine metabolites (DOPAC and HVA) and gene expression of enzymes metabolising dopamine (MAOA and COMT) in male mice. In male and female rats, acute and repeated semaglutide administration reduced alcohol intake and prevented relapse-like drinking. Moreover, fluorescently labelled semaglutide was detected in NAc of alcohol-drinking male and female rats. Further, semaglutide attenuated the ability of alcohol to cause hyperlocomotion and to elevate dopamine in NAc in male mice. As further shown in male mice, semaglutide enhanced DOPAC and HVA in NAc when alcohol was onboard and increased the gene expression of COMT and MAOA. Altogether, this indicates that semaglutide reduces alcohol drinking behaviours, possibly via a reduction in alcohol-induced reward and NAc dependent mechanisms. As semaglutide also decreased body weight of alcohol-drinking rats of both sexes, upcoming clinical studies should test the plausibility that semaglutide reduces alcohol intake and body weight in overweight AUD patients. Swedish Research Council (2019-01676), LUA/ALF (723941) from the Sahlgrenska University Hospital and the Swedish brain foundation.

Expression of chronic pain genes in apical periodontitis tissues.

To evaluate the expression of genes involved in chronic pain conditions in apical periodontitis (AP) tissues. An electronic search was performed in Scopus and MEDLINE (via PubMed) databases to identify articles (n = 173) related to genes involved in chronic pain conditions. Full-text reviews of the selected articles allowed the prioritization of 16 genes to be investigated with regards to their expression in AP tissues. Periapical lesions (n = 42) were collected during surgical endodontic procedures and processed for mRNA extraction and investigation of target genes via RT-qPCR. Healthy periodontal ligament tissues obtained from third molar extractions were used as controls. Relative levels of target gene expression in AP and control tissues were normalized to GAPDH expression and compared using the 2-ΔΔCt method. Data analysis was performed using the Mann-Whitney U test with a statistical significance threshold set at p < .05. mRNA expression levels of MMP9, TIMP1, TNFA, CAMK4 and COMT were significantly increased in AP tissue samples compared with controls (p < .05). Positive correlations were observed between the expression of TIMP1 with COMT and CAMK4, TNFA with TIMP1 and CAMK4, COMT with CAMK4. This study confirms the upregulation of MMP9, TIMP1, TNFA in AP tissues and reports for the first time, the expression of CAMK4 and COMT as suggestive of their involvement in AP pathogenesis.

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.

Effect of temperature and dietary pesticide exposure on neuroendocrine and olfactory responses in juvenile Chinook salmon (Oncorhynchus tshawytscha)

Projected water temperature increases based on predicted climate change scenarios and concomitant pesticide exposure raises concern about the responses of aquatic organisms. To better understand the effect of pesticide mixtures and influence of water temperature to fish, juvenile Chinook salmon (Oncorhynchus tshawytscha) were dietarily exposed to a mixture of legacy and current use pesticides (p,p’-DDE, bifenthrin, chlorpyrifos, esfenvalerate, and fipronil) at concentrations detected from field-collected prey items in the Sacramento-San Joaquin Delta, California (Delta) and exposed under current and predicted future water temperature scenarios, 11, 14, or 17 °C, for 14 days. The expression of a subset of genes (deiodinase 2-dio2, gonadotropin releasing hormone 2-gnrh2, and catechol-o-methyltransferase-comt) involved in neuroendocrine, dopaminergic, and olfactory function previously shown to be altered by individual pesticide exposures germane to this study were determined and olfactory function assessed using a Y-maze behavioral assay. When total body burdens of pesticides were measured, a significant decrease in dio2 expression was observed in Chinook salmon exposed at 14 °C compared to fish kept at 11 °C. Increases in gnrh2 expression were also observed in fish exposed to 14 °C. Similarly, increases in comt expression was noted at 14 and 17 °C. Additionally, altered expression of all transcripts was observed, showing interactions between temperature and individual pesticide concentrations. Chinook salmon spent significantly more time actively avoiding the odorant arm at baseline conditions of 11 °C in the Y-maze. At higher temperatures, Chinook spent significantly more time not making a choice between the odorant or clean arm following exposure to the low pesticide mixture, relative to 11 °C. These results suggest that dietary exposure to pesticide mixtures can potentially induce neuroendocrine effects and behavior. Impaired olfactory responses exhibited by Chinook salmon could have implications for predator avoidance in the wild under increased temperature scenarios and impact populations in the future.

Transcriptome profiling of Saposhnikovia divaricata growing for different years and mining of key genes in active ingredient biosynthesis

Saposhnikovia divaricata is a commonly used bulk medicinal plant. To explore the key enzyme genes and their expression in the biosynthesis of chromone and coumarin, the key active components, we carried out transcriptome sequencing(Illumina HiSeq) and bioinformatics analysis for the 1-year-old(S1) and 2-year-old(S2) plants of S. divaricata. A total of 40.8 Gb data was obtained. After the sequence assembly via Trinity, 110 732 transcripts and 86 233 unigenes were obtained, which were aligned and annotated with NR, Swiss-Prot, GO, KEGG, and PFAM. Daucus carota and S. divaricata had the highest sequence homology. KEGG pathway enrichment showed that the differentially expressed genes were mainly enriched in plant hormone signal transduction, phenylpropanoid biosynthesis, and flavonoid biosynthesis pathways. A total of 27 differentially expressed unigenes, including 13 enzyme genes, were identified in the pathways related to the synthesis of active ingredients in S. divaricata. Compared with S1 plant, S2 plant showed up-regulated expression of PAL, BGL, C4H, 4CL, CYP98A, CSE, REF, and CCoAOMT and down-regulated expression of CHS, CAD, and COMT. HCT and POD had both up-regulated and down-regulated unigenes. Among them, PAL, C4H, 4CL, BGL, and CHS can be used as candidate genes for the synthesis of the active ingredients in S. divaricata. The four key enzyme genes were verified by RT-qPCR, which showed the results consistent with transcriptome sequencing. This study enriches the genetic information of S. divaricata and provides support for the identification of candidate genes in the biosynthesis of secondary metabolites.

Maternal exposure to genistein during pregnancy and oxidative DNA damage in testes of male mouse offspring.

BackgroundGenistein is a dietary supplement with phyto-estrogenic properties. Therefore, high intake of genistein during pregnancy may have adverse effects on the genetic integrity of testes and germ cells of male offspring. In this study, we examined whether maternal exposure to genistein during pregnancy induced oxidative DNA damage in the male germline at adolescence.MethodsAtm-ΔSRI mice have lower glucose-6-phosphate dehydrogenase (G6PDH) activity, which is important for maintaining levels of reduced glutathione and therefore these mice have an increased susceptibility to oxidative stress. Parental heterozygous Atm-ΔSRI mice received a genistein-rich or control diet, after which they were mated to obtain offspring. During pregnancy, mothers remained on the respective diets and after delivery all animals received control diets. Redox status and oxidative DNA damage were assessed in testes and sperm of 12 weeks old male offspring. Gene expression of Cyp1b1, Comt, and Nqo1 was assessed in testes, and DNA methylation as possible mechanism for transmission of effects to later life.ResultsIntake of genistein during pregnancy increased oxidative DNA damage in testes of offspring, especially in heterozygous Atm-ΔSRI mice. These increased DNA damage levels coincided with decreased expression of Comt and Nqo1. Heterozygous Atm-ΔSRI mice had higher levels of DNA strand breaks in sperm compared to wild type littermates, and DNA damage was further enhanced by a genistein-rich maternal diet. G6PDH activity was higher in mice with high maternal intake of genistein compared to control diets, suggesting compensation against oxidative stress. A positive correlation was observed between the levels of DNA methylation and oxidative DNA damage in testes.ConclusionThese data indicate that prenatal exposure to genistein altered gene expression and increased DNA damage in testes and sperm of adolescent male offspring. These effects of genistein on DNA damage in later life coincided with alterations in DNA methylation.

Ocimum sanctum, OscWRKY1, regulates phenylpropanoid pathway genes and promotes resistance to pathogen infection in Arabidopsis.

OscWRKY1 from Ocimum sanctum positively regulates phenylpropanoid pathway genes and rosmarinic acid content. OscWRKY1 overexpression promotes resistance against bacterial pathogen in Arabidopsis. WRKY transcription factor (TF) family regulates various developmental and physiological functions in plants. PAL genes encode enzymes which are involved in plant defense responses, but the direct regulation of PAL genes and phenylpropanoid pathway through WRKY TF's is not well characterized. In the present study, we have characterized an OscWRKY1 gene from Ocimum sanctum which shows induced expression by methyl jasmonate (MeJA), salicylic acid (SA), and wounding. The recombinant OscWRKY1 protein binds to the DIG-labeled (Digoxigenin) W-box cis-element TTGAC[C/T] and activates the LacZ reporter gene in yeast. Overexpression of OscWRKY1 enhances Arabidopsis resistance towards Pseudomonas syringae pv. tomato Pst DC3000. Upstream activator sequences of PAL and C4H have been identified to contain the conserved W-box cis-element (TTGACC) in both O. sanctum and Arabidopsis. OscWRKY1 was found to interact with W-box cis-element present in the PAL and C4H promoters. Silencing of OscWRKY1 using VIGS resulted in reduced expression of PAL, C4H, COMT, F5H and 4CL transcripts. OscWRKY1 silenced plants exhibit reduced PAL activity, whereas, the overexpression lines of OscWRKY1 in Arabidopsis exhibit increased PAL activity. Furthermore, the metabolite analysis of OscWRKY1 silenced plants showed reduced rosmarinic acid content. These results revealed that OscWRKY1 positively regulates the phenylpropanoid pathway genes leading to the alteration of rosmarinic acid content and enhances the resistance against bacterial pathogen in Arabidopsis.

Genome-wide association study for circulating FGF21 in patients with alcohol use disorder: Molecular links between the SNHG16 locus and catecholamine metabolism

ObjectiveAlcohol consumption can increase circulating levels of fibroblast growth factor 21 (FGF21). The effects of FGF21 in the central nervous system are associated with the regulation of catecholamines, neurotransmitters that play a crucial role in reward pathways. This study aims to identify genetic variants associated with FGF21 levels and evaluate their functional role in alcohol use disorder (AUD). MethodsWe performed a genome-wide association study (GWAS) using DNA samples from 442 AUD subjects recruited from the Mayo Clinic Center for the Individualized Treatment of Alcoholism Study. Plasma FGF21 levels were measured using Olink proximity extension immunoassays. Alcohol consumption at time of entry into the study was measured using the self-reported timeline followback method. Functional genomic studies were performed using HepG2 cells and induced pluripotent stem cell (iPSC)-derived brain organoids. ResultsPlasma FGF21 levels were positively correlated with recent alcohol consumption and gamma-glutamyl transferase levels, a commonly used marker for heavy alcohol use. One variant, rs9914222, located 5’ of SNHG16 on chromosome 17 was associated with plasma FGF21 levels (p = 4.60E-09). This variant was also associated with AUD risk (β: −3.23; p:0.0004). The rs9914222 SNP is an eQTL for SNHG16 in several brain regions, i.e., the variant genotype was associated with decreased expression of SNHG16. The variant genotype for the rs9914222 SNP was also associated with higher plasma FGF21 levels. Knockdown of SNHG16 in HepG2 cells resulted in increased FGF21 concentrations and decreased expression and enzyme activity for COMT, an enzyme that plays a key role in catecholamine metabolism. Finally, we demonstrated that ethanol significantly induced FGF21, dopamine, norepinephrine, and epinephrine concentrations in iPSC-derived brain organoids. ConclusionsGWAS for FGF21 revealed a SNHG16 genetic variant associated with FGF21 levels which are associated with recent alcohol consumption. Our data suggest that SNHG16 can regulate FGF21 concentrations and decrease COMT expression and enzyme activity which, in turn, have implications for the regulation of catecholamines.(The ClinicalTrials.gov Identifier: NCT00662571)

Transcriptome Analysis of Response to Aluminum Stress in Pinus massoniana

Pinus massoniana is a vital kind of coniferous species rich in rosin. Aluminum stress is a severe problem for P. massoniana growth in acidic soil causing root poisoning. However, the molecular mechanisms of aluminum-responsive are still unclear. We performed a transcriptome analysis of the P. massoniana root in response to aluminum stress. Through WGCNA analysis, we identified 338 early and 743 late response genes to aluminum stress. Gene Ontology analysis found many critical functional pathways, such as carbohydrate binding, cellulase activity, and phenylalanine ammonia-lyase activity. In addition, KEGG analysis revealed a significant enrichment of phenylpropanoid biosynthesis pathways. Further analysis showed that the expression of lignin synthesis genes 4CL, CAD, and COMT were up-regulated, indicating that they may play a crucial role in the process of aluminum tolerance in P. massoniana roots. These results provide method support for studying the regulation mechanism of P. massoniana aluminum stress.

Catecholamines' accumulation and their disturbed metabolism at perilesional site: a possible cause of vitiligo progression.

Catecholamines (epinephrine, norepinephrine and dopamine) are considered toxic to the melanocytes and may play an important role in the development of depigmented patches on the skin. This study was done to evaluatethe levels of catecholamines in skin and plasma samples of active vitiligo patients' and gene expression changes in catecholamines' metabolism regulatory genes (COMT and GTPCH1), immunoregulatory genes (CTLA4 and PTPN22), and Catalase in active vitiligo patients. In this single-centre, prospective, case-control study, 30 patients with active vitiligo were recruited and skin biopsies from the perilesional site and plasma samples were collected. Skin biopsies from the normal site in vitiligo patients and healthy controls (n = 15) and plasma samples from controls were also obtained. Catecholamines' estimation was done via high-performance liquid chromatography. Gene expression variations were investigated via reverse transcription-polymerase chain reaction (PCR) and real-time PCR. Epinephrine, norepinephrine and dopamine levels were significantly higher in perilesional skin biopsies as compared to controls (P = 0.035, 0.024, and 0.006, respectively). However, epinephrine, norepinephrine and dopamine levels observed in patients' plasma samples were comparable to controls. The mRNA expression level of the Catalase gene was found to be upregulated at the perilesional site of patients as compared to the non-affected site of same patients (P < 0.001) and healthy controls (P = 0.037). Transcriptional expression of GTPCH1 and COMT were observed to be increased significantly at the perilesional site of patients in comparison to controls (P = 0.004 and P = 0.046, respectively). Our results support the presence of oxidative stress, inflammation and induced immune response in vitiligo patients at the perilesional sites. The increased inflammatory response may lead to catecholamines upregulation resulting in oxidative stress and melanocyte damage.

The Value of Comprehensive Nursing Intervention on Anxiety in Patients with Acute Heart Failure and Diabetes via Expression of Stress-related Genes.

Many patients with acute heart failure and diabetes experience varying degrees of anxiety upon entering the cardiac intensive care unit, which has adverse effects on the recovery process of these patients. Anxiety syndrome in these patients increases the risk of death up to three times. This study aimed to determine the effect of comprehensive nursing intervention on anxiety in patients with acute heart failure and diabetes by evaluating the expression of stress-related genes, i.e. COMT and BDNF genes. In this clinical trial study, 74 patients with acute heart failure and diabetes hospitalized in the cardiac intensive care unit were selected by convenience sampling method and randomly assigned to intervention and control groups. The control group received routine ward care, and the intervention group received nursing support program-based interventions in three informational, emotional, and physical dimensions in addition to regular care. Beck Anxiety Inventory was completed before and after the intervention in both groups. The expression of COMT and BDNF genes was evaluated by the qRT-PCR technique. Data were analyzed by Mann-Whitney U and independent T-test in SPSS software version 16. Before the intervention, no significant difference was observed between patients' anxiety scores in the intervention and control groups (p = 0.162). While, after the intervention, the anxiety score of the intervention group was lower than the control group (p = 0.02). The expression of COMT gene results showed that this gene expression was no statistical difference between the control group and intervention group, before intervention (p = 0.83). But, after the intervention, the expression of this gene was statistically decreased in the intervention group in comparison with the control group (p = 0.006). The BDNF gene expression results demonstrated that there was no difference between the two groups, before intervention (p = 0.46). After intervention, statistical increase was observed in control group (p = 0.042) and intervention group (p = 0.007). According to the results of this study, the comprehensive nursing intervention reduced patients' anxiety in the intervention group compared to the control group. This result was also confirmed by evaluating the expression of stress-related genes. Therefore, it is suggested that this intervention method be used to reduce anxiety in these patients.

Computational Analysis Of Potential Key Genes Associated With Dopamine Neurotransmission In Pheochromocytoma And Paraganglioma

Pheochromocytoma and Paraganglioma (PCPG) are rare and potentially lethal neuroendocrine tumors. PCPG that predominantly or exclusively produce and secrete DA is rarely seen and it has been known that exclusively dopamine-secreting PCPG is related with advanced malignant features and metastases. Up to the present, little has known about the role of dopamine neurotransmission and dopaminergic system in the initiation and progression of PCPG. The genes with significant expression differences between normal tissue and pheochromocytoma and paraganglioma, survival and correlation analysis, CpG islands prediction, and miRNA-target enrichment analysis were performed by several bioinformatics tools. In the present study, it was determined that COMT gene was significantly less expressed in PCPG than in normal tissue and COMT gene showed a remarkable relationship between differential expression with shorter overall survival among the individuals with PCPG (HR=1, p=0.011). MAOA and COMT gene pair was significantly correlated with PCPG (p=0.012; R=0.19) and hsa-miR-5000-5p regulates the expression of both COMT and MAOA genes (p=0.00215, FDR=0.127). Our findings suppose that COMT may potentially be implicated in tumor suppressive mechanism. The expression values of COMT and MAOA genes, and hsa-miR-5000-5p may have the potential to be used in the genetic evaluation of the pathogenesis and prognosis of PCPG. Further in vitro and in vivo studies are required to clarify the molecular mechanism of dopaminergic system in the pathogenesis and prognosis of PCPG.

MiRNAs in the Expression Regulation of Dopamine-Related Genes and Proteins in Endometrial Cancer.

Disruption of the dopaminergic system leads to many diseases, including cancer. Dopamine and its receptors are involved in the regulation of proliferation, cell death, invasion, and migration. Better understanding of the mechanisms involved in these processes could reveal new molecular markers and therapeutic targets. The aim of this study was to determine the expression profile of dopamine-related genes and proteins in endometrial cancer and to assess whether miRNAs are involved in its regulation. Sixty women were recruited for the study: 30 with endometrial cancer and 30 without cancer. The expression profiles of dopamine-related genes were determined in endometrial tissue samples using microarrays and qRT-PCR. Then, protein concentration was determined with the ELISA test. In the last step, miRNA detection was performed using microarrays. The matching of miRNAs to the studied genes was carried out using the TargetScan tool. The analysis showed DRD2 and DRD3 overexpression, with a reduction in DRD5 expression, which could be due to miR-15a-5p, miR-141-3p, miR-4640-5p, and miR-221-5p activity. High levels of OPRK1 and CXCL12, related to the activity of miR-124-3p.1 and miR-135b-5p, have also been reported. Low COMT expression was probably not associated with miRNA regulation in endometrial cancer.