DRD2 Research Articles

Integrative bioinformatics analysis of biomarkers and pathways for exploring the mechanisms and molecular targets associated with pyroptosis in type 2 diabetes mellitus.

Research has shown that pyroptosis contributes greatly to the progression of diabetes and its complications. However, the exact relationship between this particular cell death process and the pathology of type 2 diabetes mellitus (T2DM) remains unclear. In this study, we used bioinformatic tools to identify the pyroptosis-related genes (PRGs) associated with T2DM and to analyze their roles in the disease pathology. Two microarray datasets, GSE7014 and GSE25724, were obtained from the GEO database and assessed for differentially expressed genes (DEGs). The T2DM-associated DEGs that overlapped with differentially expressed PRGs were noted as T2DM-PRGs. Subsequently, 25 T2DM-PRGs were validated and subjected to functional enrichment analysis through Gene Ontology annotation analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and gene set enrichment analysis (GSEA). The diagnostic and predictive value of the T2DM-PRGs was evaluated using receiver operating characteristic curves (ROC). Additionally, a single-sample GSEA algorithm was applied to study immune infiltration in T2DM and assess immune infiltration levels. We identified 25 T2DM-PRGs that were significantly enriched in the nuclear factor-kappa B signaling and prostate cancer pathways. The top five differentially expressed prognostic T2DM-PRGs targeted by miRNAs were PTEN, BRD4, HSP90AB1, VIM, and PKN2. The top five differentially expressed T2DM-PRGs associated with transcription factors were HSP90AB1, VIM, PLCG1, SCAF11, and PTEN. The genes PLCG1, PTEN, TP63, CHI3L1, SDHB, DPP8, BCL2, SERPINB1, ACE2, DRD2, DDX58, and BTK showed excellent diagnostic performance. The immune infiltration analysis revealed notable differences in immune cells between T2DM and normal tissues in both datasets. These findings suggest that T2DM-PRGs play a crucial role in the development and progression of T2DM and could be used as potential diagnostic biomarkers and therapeutic targets. Investigating the mechanisms and biomarkers associated with pyroptosis may offer valuable insights into the pathophysiology of T2DM and lead to novel therapeutic approaches to treat the disease.

Time-course of cardiac gene profiles post-acute lung injury

Abstract Patients suffering from acute lung injury (ALI) are at high risk of developing cardiac arrhythmias. In a recent study we demonstrated that bleomycin (Bleo)-induced ALI in rats exhibited significantly more spontaneous premature ventricular contractions (PVCs) from 1 to 3 weeks post induction. Although spontaneous PVCs disappeared at 4 weeks post ALI, PVCs were evoked again by electrical stimulation of the decentralized stellate ganglia in Bleo-exposed rats but not in normal rats. The molecular mechanisms underlying cardiac arrhythmia both post ALI and during the recovery of ALI remains unclear. In the current study, we aimed to utilize non-biased RNA-Seq analysis to discover the time-course changes in cardiac gene profiles both post ALI and during the recovery from ALI. We created an ALI rat model using a single tracheal instillation of bleomycin (2.5 mg/kg) with saline as a vehicle (Veh) control. Blood Troponin level was measured and compared between Veh- and Bleo-treated rats varied between W1 to Week 4 post Veh/Bleo. Cardiac tissues were harvested at W1 or W4 post Veh/Bleo for RNA-seq analysis and validation by real time RT-PCR. One week post ALI, cardiac Troponin was significantly increased in Bleo-treated rats whereas it was undetectable in Veh-treated rats. Cardiac Troponin was largely restored at W2 and was undetectable at W4 post ALI. RNA-seq analysis of the left ventricle (LV) indicated 85 downregulated and 147 upregulated genes at 1 W post ALI vs. Veh. Gene Ontology (GO) enrichment analysis demonstrated that genes related to chronic inflammatory signaling, cell adhesion signaling, and extracellular matrix (ECM) signaling pathways were upregulated at W1 post ALI, suggesting cardiac inflammation. Furthermore, genes related to oxygen carrier activity, oxygen binding and oxygen transport signaling were also significantly altered, which may be due to acute hypoxia caused by ALI. In contrast to W1, RNA-seq analysis at W4 post ALI detected a smaller number of altered genes, including 11 downregulated and 13 upregulated genes between ALI and Veh groups. Comparing these two RNA-Seq databases, 4 genes (i.e., Phactr3, Tgm1, Drd4, Selplg) were identified as changed in both the post ALI state and during the recovery from ALI. Following real time RT-PCR validation confirmed significant changes in these four gene mRNA expressions in both post ALI and during the recovery from ALI. Phactr3 was downregulated while Tgm1, Drd4 and Selplg genes were upregulated in cardiac tissues at w1 and w4 post ALI. Phactr3 gene encodes a member of the phosphatase and actin regulator protein family. Tgm1 plays an important role in stabilizing intercellular junctions in myocardial microvascular endothelial cells, by modulating β-actin filaments. Drd4 gene encodes the D4 subtype of the dopamine receptor. Selplg gene encodes a glycoprotein that regulates T lymphocytes. Future studies are needed to examine the functional roles of these genes in cardiac injury post ALI.

Association of DRD2, DRD4 and COMT genes variants and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia

Antipsychotic drugs are the first line of treatment in schizophrenia; although antipsychotic responses indicate a wide interindividual variety in patients with schizophrenia. This study aimed to investigate the association between four polymorphisms in DRD2, DRD4 and COMT genes and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia. A total of 101 patients with schizophrenia were recruited and stratified in treatment responder and treatment resistant groups based on the published criteria of resistant to treatment using PANSS. Clinical and demographic factors were analyzed. Genomic DNA was extracted from whole blood and genotyping for the four polymorphisms were done by ARMS-PCR, PCR-RFLP and gap-PCR. Gene-gene interactions were analyzed by logistic regression. In case of DRD2 A-241G, G allele was significantly associated with resistant to treatment. Regarding DRD4 120-bp duplication, 240/240 genotype was significantly associated with resistant to treatment comparing to other genotypes in a dominant model. The genotype combination of DRD4 240/240 and COMT Val/Val was significantly associated with treatment resistant. Among DRD2 AA genotype, COMT met allele carriers which also had a 120 bp allele of DRD4 had a significantly better response to antipsychotics. Moreover, analysis of clinical and demographic factors demonstrated a significantly longer duration of hospitalization and higher chlorpromazine-equivalent daily dose in resistant to treatment patients. Discovering the polymorphisms which effect treatment response to antipsychotics will provide the possibility of genetic screening before starting an antipsychotic treatment which enhances the chance of responding to antipsychotics and decreases drugs side effects and costs.

"TO BE OR NOT TO BE" GWAS Ends the Controversy about the DRD2 Gene as a Determinant of Reward Deficiency Syndrome (RDS).

Since 1990, there have been thousands of published studies on addiction psychiatry. Several from Blum et al showed the clinical relevance of the Genetic Addiction Risk Severity (GARS) test in identifying risk for reward deficiency behaviors in cohorts from polysubstance abuse and pain clinics, post-surgical bariatrics, and DWI offenders facing prison time. Since Blum et al first published in JAMA (1990) concerning the association of the DRD2 gene polymorphism and severe alcoholism, reactions have been mixed. More recently, however, a meta-analysis of 62 studies showed a significant association between DRD2 rs1800497 and Alcohol Use Disorder (AUD). Other studies from Yale University showed that a haplotype block of the DRD2 gene A1 allele was associated with AUD and heroin dependence. GWAS studies of depression and suicide in 1.2 million veterans confirmed the first psychiatric candidate gene study finding from Blum et al 1990; a significant association between the minor DRD2 allele, Taq A1 and severe alcoholism. Additionally, the DRD2 rs1800497 is robustly associated with suicidal behaviors. Furthermore, DNA polymorphic alleles underlying substance use disorder (SUD) with multiple substances were mapped via chromatin refolding, revealing that the DRD2 gene and associated polymorphism(s) as the top gene signal. Based on these investigations, we conclude that GWAS should end the controversy about the DRD2 gene being one determinant of Reward Deficiency Syndrome (RDS) first reported in 1996.

Broiler Heart Muscle Monoaminergic Receptors Alteration in Response to Chronic Heat Stress: Based on Transcription Analysis.

Chronic heat stress affects numerous physiological and behavioral mechanisms. Epigenetic changes following prolonged cyclic heat stress, creating new opportunities for molecular biology research. One of these changes involves monoamines, such as serotonin, epinephrine, norepinephrine, dopamine, and their transmission. Broiler chickens are highly susceptible to heat stress, and their hearts become insufficient during the growth phase, leading to hypertrophy of the left heart. RNA-seq data were obtained from NCBI with accession number SRP082125. The expression level of genes was determined with DESeq2 packages. Gene Ontology qualification, including biological processes, cellular components, and molecular role (MF), was performed from the Gene Ontology Resource. Cyclic heat stress in broilers significantly altered monoamine receptor expression. Twenty-nine genes of the monoamine pathway changed their expression in the left heart. Significant downregulation of expression was statistically associated with the ADRB1, HTR2A, and PNMT genes and upregulation of the MAOA gene (P<0.01). STRING database was used to construct the protein-protein interaction network; based on network analysis, the HTR2C, HTR2A, and HTR5A genes were identified as the major nodal genes in the network followed by MAOA, DRD2, DRD5, HTR1B, DRD1, DRD3, and HTR2B genes occupying the second important place in the network module. In conclusion, heat stress treatment prevented cardiac hypertrophy and altered the expression of monoamine genes. This would imply that monoamine transmission plays an important role in the development of cardiac hypertrophy, and that cyclic-chronic heat treatment modulates the cardiac monoaminergic system. These molecular biomarkers could be useful for screening, diagnosis, and treatment of cardiac hypertrophy.

Associations of polymorphisms in prolactin and dopamine receptor D2 genes with reproductive traits on Silkie chicken

The Silkie chicken (Gallus gallus domesticus Brisson) is one of domestic chicken breeds with commercial rearing and breeding potentials for egg production. Prolactin (PRL) and dopamine D2 receptor (DRD2) are potential genes associated with reproductive traits in chickens. This study was conducted to analyze the association of PRL and DRD2 insertion/deletion (Indel) polymorphisms with chicken reproductive traits in Silkie chickens. A total of 380 hens from 16-40 weeks of age were used, with each one being placed in a separate cage. DNA isolation was performed using feather samples, and genotypes were detected using the Indel technique. Two polymorphisms consisting of 24 base pair (bp) Indel in the promoter region of the PRL gene and 22 bp Indel in the promoter region of the DRD2 gene were identified. At both sites, the Indel polymorphisms did not follow the Hardy-Weinberg equilibrium. In addition, with the exception of total eggs over 23 weeks of laying in the PRL gene, the analysis revealed no association between these polymorphic loci and any traits collected. In conclusion, birds with the DD genotype produced the maximum egg yield (73.6 eggs/hen), whereas those with the II genotype produced approximately 9 fewer eggs (64.1 eggs/hen), resulting in laying rates of 45.7% and 40.1%, respectively. For enhancing the egg-laying capacity of Silkie chickens via selective breeding, opting for DD birds with DD genotype of PRL Indel is highly recommended.

Subcutaneous adipose tissue dopamine D2 receptor is increased in prediabetes and T2D

PurposeTo evaluate the dopaminergic signaling in human adipose tissue in the context of obesity and type 2 diabetes (T2D) and potential direct implications in adipose tissue metabolism.MethodsmRNA and protein expression of dopamine receptors D1 and D2 (DRD1 and DRD2) were determined in subcutaneous adipose tissue from subjects without or with T2D and with different body weight, and correlated with markers of obesity, hyperglycemia, and insulin resistance. Glucose uptake and lipolysis were measured in adipocytes ex vivo following short-term exposure to dopamine, DRD1 receptor agonist (SKF81297), or DRD2 receptor agonist (bromocriptine).ResultsDRD1 and DRD2 gene expression in subcutaneous adipose tissue correlated positively with clinical markers of insulin resistance (e.g. HOMA-IR, insulin, and triglycerides) and central obesity in subjects without T2D. Protein expression of DRD2 in subcutaneous adipose tissue, but not DRD1, is higher in subjects with impaired fasting glucose and T2D and correlated positively with hyperglycemia, HbA1c, and glucose AUC, independent of obesity status. DRD1 and DRD2 proteins were mainly expressed in adipocytes, compared to stromal vascular cells. Dopamine and dopaminergic agonists did not affect adipocyte glucose uptake ex vivo, but DRD1 and DRD2 agonist treatment inhibited isoproterenol-stimulated lipolysis.ConclusionThe results suggest that protein expression of DRD2 in subcutaneous adipose tissue is up-regulated with hyperglycemia and T2D. Whether DRD2 protein levels contribute to T2D development or occur as a secondary compensatory mechanism needs further investigation. Additionally, dopamine receptor agonists inhibit adipocyte beta-adrenergic stimulation of lipolysis, which might contribute to the beneficial effects in lipid metabolism as observed in patients taking bromocriptine.

Evaluation of the methylation status of the MB-COMT, APC2, NR3C1, and DRD2 genes in Turkish patients with microtia

Aims: Microtia is defined as a congenital malformation of the middle and external ears. DNA methylation is the major epigenetic modification of genomic DNA that is regulated in the early embryonic stage. In this study, we analyzed the methylation status of the MB-COMT, APC2, NR3C1, and DRD2 genes in patients with microtia. Methods: The blood samples were taken from microtia patients and healthy controls. Genomic DNA was isolated using a commercial kit. The methylation status of the MB-COMT, APC2, NR3C1, and DRD2 genes was analyzed using the methylation-specific polymerase chain reaction (MS-PCR) method. The results were evaluated statistically. Results: The DRD2 methylation status was found to be associated with microtia (p?0.001). We found that the DRD2 gene was partially methylated in all patients with microtia. There was no significant difference between the methylation status of the MB-COMT, APC2, and NR3C1 genes and microtia. Conclusion: To our knowledge, this is the first study in our country to evaluate the relationship between the methylation of these genes and the risk of microtia. Our results demonstrate the presence of epigenetic changes in the DRD2 gene during microtia development. Methylation may have contributed to the pathogenesis of microtia as it affects gene expression. Studies with larger sample sizes and in different ethnic groups are needed to further investigate the role of these genes in microtia.

Analysis of Dopamine Receptor D2 Gene Polymorphism and Correlation with Dyslipidemia in the Chinese Population

Objective: The study aimed to explore the genotype and allele distributions of dopamine D2-like receptor (DRD2) gene -141C and C957T polymorphisms in the Chinese Han population with dyslipidemia, as well as their association with serum lipid levels. Methods: One hundred fifty patients with dyslipidemia and 150 healthy people were recruited as the case and the control groups, respectively. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol levels were detected. The target sequence of DRD2 polymorphisms was amplified by polymerase chain reaction and genotyped via Sanger sequencing. Results: In DRD2 gene C957T (rs6277), three genotypes of CC, CT, and TT were detected with the frequencies of 92.67%, 6.67%, 0.67% in dyslipidemia cases, and 83.33%, 14.67%, 2.00% in the controls, respectively. The CT genotype and T allele frequencies were significantly low in the case group relative to the control group. After adjusting to other clinical indicators, the CT genotype of C957T polymorphism (hazard ratio = 0.401, 95% confidence interval = 0.181–0.890, p < 0.05) was still related to a significantly reduced risk of dyslipidemia. The C957T CT genotype carriers had the lowest values of serum TC, TG, LDL, and the highest values of serum HDL-C. Conclusion: DRD2 gene C957T polymorphism was an independent influencing factor associated with the susceptibility to dyslipidemia, and the CT genotype was associated with decreased odds of susceptibility to dyslipidemia.

Genetic risk scores associated with temperament clusters in Finnish depression patients.

Cloninger's temperament dimensions have been studied widely in relation to genetics. In this study, we examined Cloninger's temperament dimensions grouped with cluster analyses and their association with single nucleotide polymorphisms (SNPs). This study included 212 genotyped Finnish patients from the Ostrobothnia Depression Study. The temperament clusters were analysed at baseline and at six weeks from the beginning of the depression intervention study. We selected depression-related catecholamine and serotonin genes based on a literature search, and 59 SNPs from ten different genes were analysed. The associations of single SNPs with temperament clusters were studied. Using the selected genes, genetic risk score (GRS) analyses were conducted considering appropriate confounding factors. No single SNP had a significant association with the temperament clusters. Associations between GRSs and temperament clusters were observed in multivariate models that were significant after permutation analyses. Two SNPs from the DRD3 gene, two SNPs from the SLC6A2 gene, one SNP from the SLC6A4 gene, and one SNP from the HTR2A gene associated with the HHA/LRD/LP (high harm avoidance, low reward dependence, low persistence) cluster at baseline. Two SNPs from the HTR2A gene were associated with the HHA/LRD/LP cluster at six weeks. Two SNPs from the HTR2A gene and two SNPs from the COMT gene were associated with the HP (high persistence) cluster at six weeks. GRSs seem to associate with an individual's temperament profile, which can be observed in the clusters used. Further research needs to be conducted on these types of clusters and their clinical applicability.

Gene Interaction of Dopaminergic Synaptic Pathway Genes in Attention-Deficit Hyperactivity Disorder: a Case-Control Study in Chinese Children

Attention-deficit hyperactivity disorder is a highly inherited neurodevelopmental disorder. Previous genetic research has linked ADHD to certain genes in the dopaminergic synaptic pathway. Nonetheless, research on this relationship has produced varying results across various populations. China is a multi-ethnic country with its own unique genetic characteristics. Therefore, such a population can provide useful information about the relationship between gene polymorphisms in dopaminergic synaptic pathways and ADHD. This study looked at the genetic profiles of 284 children in China’s Xinjiang. In total, 142 ADHD children and 142 control subjects were enrolled. Following the extraction of DNA from oral mucosal cells, 13 SNPs for three candidate genes (SLC6A3, DRD2, and GRIN2B) in the dopaminergic synaptic pathway of ADHD were screened. Based on the results of single nucleotide polymorphism (SNP) analyses, we found that the DRD2 gene variants rs6277 and rs6275, and the SLC6A3 gene variant rs2652511, were significantly associated with ADHD in boys and girls, respectively, after adjusting for false discovery rate (FDR) in terms of allele frequencies. Furthermore, our generalized multifactorial downscaling approach identified a significant association between rs6275 and rs1012586. These findings suggest that DRD2 and SLC6A3 genes have a crucial role in ADHD susceptibility. Additionally, we observed that the interaction between GRIN2B and DRD2 genes may contribute to the susceptibility of Chinese children with ADHD.

Linkage and association of variants in the dopamine receptor 2 gene (DRD2) with polycystic ovary syndrome

Polycystic ovarian syndrome (PCOS) is a disorder with a foundation of neuroendocrine dysfunction, characterized by increased gonadotropin-releasing hormone (GnRH) pulsatility, which is antagonized by dopamine. The dopamine receptor 2 (DRD2), encoded by the DRD2 gene, has been shown to mediate dopamine’s inhibition of GnRH neuron excitability through pre- and post-synaptic interactions in murine models. Further, DRD2 is known to mediate prolactin (PRL) inhibition by dopamine, and high blood level of PRL have been found in more than one third of women with PCOS. We recently identified PRL as a gene contributing to PCOS risk and reported DRD2 conferring risk for type 2 diabetes and depression, which can both coexist with PCOS. Given DRD2 mediating dopamine’s action on neuroendocrine profiles and association with metabolic-mental states related to PCOS, polymorphisms in DRD2 may predispose to development of PCOS. Therefore, we aimed to investigate whether DRD2 variants are in linkage to and/or linkage disequilibrium (i.e., linkage and association) with PCOS in Italian families. In 212 Italian families, we tested 22 variants within the DRD2 gene for linkage and linkage disequilibrium with PCOS. We identified five novel variants significantly linked to the risk of PCOS. This is the first study to identify DRD2 as a risk gene in PCOS, however, functional studies are needed to confirm these results.

Eating healthy under work stress: A gene stress interaction model.

Some employees tend to eat less healthy food when under work stress, while others tend to maintain a healthy diet. The factors underlying these different dietary choices are not yet clear. Individual differences in people's reactions to environmental stress may help explain this phenomenon. This study proposed a Gene × Stress interaction model of dietary choice, suggesting that different dietary choices under stress may be related to DRD2 genes, which moderate the reward circuitry and have been associated with habitual use of alcohol, obesity, and eating behaviors. 12,269 employees completed genotyping of their saliva samples and questionnaires on work stress, healthy dietary intentions, and healthy dietary behaviors. Nonlinear multiple regressions were used to test the hypothesized interaction of DRD2 genes and work stress on healthy dietary intentions and healthy dietary behaviors. Individuals with higher work stress reported lower healthy dietary intentions, whereas healthy dietary behaviors exhibited an inverted U shape. DRD2 genes significantly moderated this relationship, and the above relationship was only detected among C allele carriers, whereas for the AA genotype, work stress was not associated with healthy dietary intentions or behaviors. Healthy dietary intentions and healthy dietary behaviors showed different patterns of association with work stress. The DRD2 genes helped explain the individual differences in dietary choice under work stress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Repeated Experience of Aggression Changes Gene Expression in Hypothalamus in Male Mice of Two Strains

Repeated positive fighting experience can lead to changes in the neurophysiology and behavior of animals and to the formation of pathological aggression. Mechanisms of adaptation to repeated aggression are thought to be controlled through hypothalamus and HPA axis. In this work, we studied the effect of repeated (30 days) experience of aggression on gene expression in the hypothalamus in male mice of two strains – C57BL/6J and CD1. We measured expression levels of the HPA axis genes (Crh, Crhr1, Crhbp, Fkbp5, Nr3c1), as well as early response gene (Fos) and dopamine receptor D1 gene (Drd1). Repeated experience of aggression led to prolongation of Fos activation in C57BL/6J, although the expression of other studied genes remained unchanged. CD1 aggressors are characterized by decreased expression level of Crhr1 and Crhbp genes, whose products inhibit the secretion of corticotropin-releasing hormone. Most of the studied genes showed strain variation in gene expression that is probably associated with different levels of locomotor activity and anxiety in mice of these strains. The basal expression level of Crh gene was higher in C57BL/6J mice, while Crhr1, Crhbp, Fkbp5, Fos, and Drd1 genes were higher in CD1 mice. Thus, the repeated experience of aggression leads to gene expression changes in the hypothalamus of male mice, that depend on the genetic background and related psychophysiological features of individuals.

Antipsychotic-Induced Parkinsonism and Dyskinesia in a 43- years Old Male with Schizophrenia: Clinical Case

The development of neurological adverse drug reactions (ADRs) from the extrapyramidal system while taking antipsychotics (APs) is well known. The common forms of neurological ADRs from the side of the extrapyramidal system are AP-induced parkinsonism (AIP) with a frequency of about 36% and AP-induced tardive dyskinesia (AITD) with an incidence of about 25%. Patients with AIP and AITD make up a significant proportion of patients in psychiatric hospitals and neuropsychiatric dispensaries with AP-induced extrapyramidal disorders requiring neurological care. These ADRs make a significant contribution to the structure of the overall morbidity and mortality of the population around the world. We presented a clinical example of 43 years old male, who developed acute AIP and AITD while taking APs. This condition was resolved with amantadine 200 mg/day after several unsuccessful attempts. It is also known that the patient had a father with Parkinson's disease in his anamnesis. The patient underwent pharmacogenetic testing of SNV rs1800497 of the DRD2 gene. According to the results the patient was a homozygous carrier of the major allele. These results did not show a positive association. At the same time, such a patient needs to undergo pharmacogenetic testing using a complete genetic risk panel for developing AIP, AITD, and Parkinson's disease.

Sex Differences in Rats with the Valproate Model of Autism: Disturbances in Social Behavior and Changes in Drd1 Gene Expression in Various Brain Structures

Sex Differences in Rats with the Valproate Model of Autism: Disturbances in Social Behavior and Changes in Drd1 Gene Expression in Various Brain Structures

Variation in the Dopamine-4-Receptor Gene in Patients with Type 1 Diabetes

Introduction: Because dopaminergic signaling pathways are one of the regulators of autoimmunity, we hypothesize that the −521C>T DRD4 gene polymorphism may associate with the risk of diabetes mellitus type 1 (DM1) and its comorbidities. Methods: In this case-control study, we have examined 300 patients with DM1 in comparison to 300 healthy age-matched controls. Utilizing the amplification refractory mutation system-polymerase chain reaction method, we have analyzed the −521C>T polymorphism of dopamine D4 receptor-encoding gene. Obtained results have been evaluated according to diabetes comorbidities, inflammatory markers, CD14⁺⁺CD16⁻, and CD14⁺CD16⁺ monocyte subsets as well as lipid profile. Results: The key results of our study are as follows: (1) CC genotype and C allele are associated with a reduced risk of DM1 development (OR = 0.593, p = 0.005 and OR = 0.725, p = 0.003, respectively), whereas TT genotype and T allele are associated with a higher risk of DM1 (OR = 1.408, p = 0.04 and OR = 1.380, p = 0.003, respectively); (2) CC genotype is associated with an increased risk of dyslipidemia and retinopathy in diabetic patients (OR = 2.376, p = 0.001 and OR = 2.111, p = 0.01, respectively); (3) CC genotype and C allele carriers had the highest frequency of pro-inflammatory CD16⁺ monocytes (p = 2*10⁻⁴ and 0.04, respectively); (4) the DRD4 −521C>T polymorphism modifies the inflammatory status as well as lipid profile in DM1 patients. Conclusion: Our data imply that the dopaminergic signaling pathways may play an important role in the etiology of DM1 as well as its comorbidities and will provide a new insight into the DM1 risk management. The −521C>T DRD4 gene polymorphism could be considered a genetic marker to predict susceptibility to DM1 as well as retinopathy and dyslipidemia progress in patients with already established disease.

Broiler Heart Muscle Monoaminergic Receptors Alteration in Response to Chronic Heat Stress: Based on Transcription Analysis

Chronic heat stress affects numerous physiological and behavioral mechanisms. Epigenetic changes following prolonged cyclic heat stress, creating new opportunities for molecular biology research. One of these changes involves monoamines, such as serotonin, epinephrine, norepinephrine, dopamine, and their transmission. Broiler chickens are highly susceptible to heat stress, and their hearts become insufficient during the growth phase, leading to hypertrophy of the left heart. RNA-seq data were obtained from NCBI with accession number SRP082125. The expression level of genes was determined with DESeq2 packages. Gene Ontology qualification, including biological processes, cellular components, and molecular role (MF), was performed from the Gene Ontology Resource. Cyclic heat stress in broilers significantly altered monoamine receptor expression. Twenty-nine genes of the monoamine pathway changed their expression in the left heart. Significant downregulation of expression was statistically associated with the ADRB1, HTR2A, and PNMT genes and upregulation of the MAOA gene (P&lt;0.01). STRING database was used to construct the protein-protein interaction network; based on network analysis, the HTR2C, HTR2A, and HTR5A genes were identified as the major nodal genes in the network followed by MAOA, DRD2, DRD5, HTR1B, DRD1, DRD3, and HTR2B genes occupying the second important place in the network module. In conclusion, heat stress treatment prevented cardiac hypertrophy and altered the expression of monoamine genes. This would imply that monoamine transmission plays an important role in the development of cardiac hypertrophy, and that cyclic-chronic heat treatment modulates the cardiac monoaminergic system. These molecular biomarkers could be useful for screening, diagnosis, and treatment of cardiac hypertrophy.

Evaluation of the Relationship Between Dopamine Receptor D2 Gene TaqIA1 Polymorphism and Alcohol Dependence Risk.

Several studies are published, that investigated dopamine receptor 2 (DRD2) gene TaqIA polymorphism as a risk factor for alcohol dependence (AD) with positive and negative associations. To derive a more precise estimation of the relationship, a meta-analysis of case-control studies that examined the association between DRD2 gene Taq1A polymorphism and alcohol dependence was performed. Eligible articles were identified through a search of databases including PubMed, Science Direct, Springer link, and Google Scholar. The association between the DRD2 TaqIA polymorphism and AD susceptibility was conducted using odds ratios (ORs) and 95% confidence intervals (95% CIs) as association measures. A total of 69 studies with 9125 cases and 9123 healthy controls were included in the current meta-analysis. Results of the present analysis showed significant association between DRD2 TaqIA polymorphism and AD risk using five genetic modes (allele contrast model-OR 1.22, 95% CI 1.13-1.32, p < 0.0001; homozygote model-OR 1.35, 95%CI 1.18-1.55; p ≤ 0.0001; dominant model-OR 1.29; 95% CI 1.20-1.39; p < 0.0001; recessive model-OR 1.21; 95% CI 1.08-1.36; p = 0.0006). There was no significant association found in subgroup analysis, TaqIA polymorphism was not significantly associated with AD risk in the Asian population under all genetic models, but in the Caucasian population, TaqIA polymorphism was significantly associated with AD risk. Overall, results support the hypothesis that DRD2 Taq1A polymorphism plays a role in alcohol dependence.

Animal model for high consumption and preference of ethanol and its interplay with high sugar and butter diet, behavior, and neuroimmune system.

Mechanisms that dictate the preference for ethanol and its addiction are not only restricted to the central nervous system (CNS). An increasing body of evidence has suggested that abusive ethanol consumption directly affects the immune system, which in turn interacts with the CNS, triggering neuronal responses and changes, resulting in dependence on the drug. It is known that neuroinflammation and greater immune system reactivity are observed in behavioral disorders and that these can regulate gene transcription. However, there is little information about these findings of the transcriptional profile of reward system genes in high consumption and alcohol preference. In this regard, there is a belief that, in the striatum, an integrating region of the brain reward system, the interaction of the immune response and the transcriptional profile of the Lrrk2 gene that is associated with loss of control and addiction to ethanol may influence the alcohol consumption and preference. Given this information, this study aimed to assess whether problematic alcohol consumption affects the transcriptional profile of the Lrrk2 gene, neuroinflammation, and behavior and whether these changes are interconnected. An animal model developed by our research group has been used in which male C57BL/6 mice and knockouts for the Il6 and Nfat genes were subjected to a protocol of high fat and sugar diet intake and free choice of ethanol in the following stages: Stage 1 (T1)-Dietary treatment, for 8 weeks, in which the animals receive high-calorie diet, High Sugar and Butter (HSB group), or standard diet, American Institute of Nutrition 93-Growth (AIN93G group); and Stage 2 (T2)-Ethanol consumption, in which the animals are submitted, for 4 weeks, to alcohol within the free choice paradigm, being each of them divided into 10 groups, four groups continued with the same diet and in the other six the HSB diet is substituted by the AIN93G diet. Five groups had access to only water, while the five others had a free choice between water and a 10% ethanol solution. The weight of the animals was evaluated weekly and the consumption of water and ethanol daily. At the end of the 12-week experiment, anxiety-like behavior was evaluated by the light/dark box test; compulsive-like behavior by Marble burying, transcriptional regulation of genes Lrrk2, Tlr4, Nfat, Drd1, Drd2, Il6, Il1β, Il10, and iNOS by RT-qPCR; and inflammatory markers by flow cytometry. Animals that the diet was replaced had an ethanol high preference and consumption. We observed that high consumption and preference for ethanol resulted in (1) elevation of inflammatory cells in the brain, (2) upregulation of genes associated with cytokines (Il6 and Il1β) and pro-inflammatory signals (iNOS and Nfat), downregulation of anti-inflammatory cytokine (Il10), dopamine receptor (Drd2), and the Lrrk2 gene in the striatum, and (3) behavioral changes such as decreased anxiety-like behavior, and increased compulsive-like behavior. Our findings suggest that interactions between the immune system, behavior, and transcriptional profile of the Lrrk2 gene influence the ethanol preferential and abusive consumption.