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Asthma is a chronic inflammatory respiratory condition, characterized by variable airflow limitation, leading to clinical symptoms such as dyspnea and chest tightness. These symptoms result from an underlying inflammatory process. The β2 agonists are bronchodilators prescribed for the relief of the disease. Nevertheless, their efficacy exhibits substantial interindividual variability. Currently, there is widespread recognition of the association between specific genetic variants, predominantly located within the ADRB2 and ADCY9 genes and their efficacy. This association, usually represented by the presence of non-synonymous single nucleotide polymorphisms (SNPs) have a strong impact in the protein functionality. The prevalence of these mutations varies based on the ethnic composition of the population and thus understanding the profiles of variability in different populations would contribute significantly to standardizing the use of these medications. In this study, we conducted a sequence-based genotyping of the relevant SNPs within the ADRB2 and ADCY9 genes in patients undergoing treatment with bronchodilators and/or corticosteroids at two healthcare facilities in the state of Rio de Janeiro, Brazil. We investigated the presence of c.46A>G, c.79C>G, c.252G>A, and c.491C>T SNPs within the ADRB2, and c.1320018 A>G within the ADCY9. Our results were in line with existing literature data with both for individuals in Brazil and Latin American.

BackgroundAlcoholic hepatitis is a severe inflammatory liver disease. In recent years, the incidence of AH has been on the rise, leading to an increasingly severe disease burden. Currently, there is a lack of specific biomarkers for the diagnosis and prognosis of AH in clinical practice. Therefore, the main objective of this study is to identify biomarkers closely associated with the progression of AH, to address the shortcomings in pathological diagnosis, and to identify potential therapeutic targets.MethodsBioinformatics and machine learning methods were used to comparatively study the differentially expressed genes (DEGs) between AH patients and healthy individuals by analyzing four mRNA microarray data sets obtained from the GEO database. Subsequently, the role of potential biomarkers in AH and their mechanism of action were further confirmed by AH patients and in vitro and in vivo experiments.ResultsUsing differential analysis and WGCNA of the data set, a total of 167 key genes that may be related to AH were obtained. Among 167 genes, the LASSO logistic regression algorithm identified four potential biomarkers (KCNJ10, RPL21P23, ADRB2, and AC025279.1). Notably, ADRB2 showed biomarker potential in GSE28619, GSE94397, and E-MTAB-2664 datasets, and clinical liver samples. Furthermore, AH patients and in vivo experiments demonstrated ADRB2 inhibition and suppression of SIRT1/PPARα/PGC-1α signaling pathways, accompanied by elevated inflammatory factors and lipid deposition. In vitro experiments showed that ADRB2 overexpression mitigated the inhibition of the SIRT1/PPARα/PGC-1α signaling pathway, reversing the decrease in mitochondrial membrane potential, cell apoptosis, oxidative stress, and lipid deposition induced by alcohol exposure. Besides, the results also showed that ADRB2 expression in AH was negatively correlated with the levels of inflammatory factors (e.g., CCL2, CXCL8, and CXCL10).ConclusionThis study points to ADRB2 as a promising biomarker with potential diagnostic and prognostic value in clinical cohort data. In addition, in AH patients, in vivo and in vitro experiments confirmed the key role of ADRB2 in the progression of AH. These findings suggest that ADRB2 may alleviate AH by activating the SIRT1/PPARα/PGC-1α pathway. This finding provides a new perspective for the diagnosis and treatment of AH.

Feihong Huang,1,2,* Zhiping Su,3,* Chaojie Yu1 1Department of Bone and Soft Tissue Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chaojie Yu, Guangxi Medical University Cancer Hospital, Department of Bone and Soft Tissue Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China, Email h2021020@sr.gxmu.edu.cnObjective: The mechanism of ankylosing spondylitis (AS) remains unclear, and clinical diagnosis still pose challenges. This study aims to explore potential regulatory mechanisms underlying AS and develop a novel diagnostic model.Methods: Interspinous ligament (ISL) tissues were collected from control samples and ankylosing spondylitis with kyphotic deformity (AS-KD) samples during surgery, followed by high-throughput sequencing. By integrating gene expression profiles from publicly available AS peripheral blood (PB) samples, differentially expressed immune genes (DEIRGs) were identified. Through gene set enrichment analysis(GSEA), gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, the regulatory mechanisms of the immune gene family in AS were explored. A diagnostic model for AS were constructed and validated it externally. Additionally, a competing endogenous RNA(ceRNA)-protein regulatory network was built for key immune genes.Results: Adrenergic receptor beta 2 (ADRB2) was downregulated in both ISL and PB samples. It was enriched in common pathways, including natural killer cell-mediated cytotoxicity, B cell receptor signaling pathway, Th1 and Th2 cell differentiation. Using the LASSO algorithm, 12 DEIRGs were identified, including the downregulated ADRB2. Based on the DEIRGs family, a novel diagnostic model was constructed with an AUC of 0.87 for the validation set and 0.7 for the test set. The AUC for ADRB2 alone was 0.75. Subgrouping AS based on these immune genes revealed a close association with neutrophils. GSEA and KEGG analysis of ISL, PB, and subgrouping of AS showed that ADRB2 may be involved in regulating the T cell receptor signaling pathway. Immune infiltration analysis indicated a decrease in CD8+ T cell infiltration, which was positively correlated with ADRB2. ADRB2 in AS-KD was regulated by multiple ceRNA-protein (lncRNA-[hsa-miR-513a-5p]-mRNA-protein).Conclusion: The immune gene family, especially ADRB2, participates in the mechanism and contributes to the diagnosis of AS.Keywords: ankylosing spondylitis, immune genes, adrenergic receptor beta-2, ADRB2, diagnostic model, competing endogenous RNA network, ceRNA network

Purpose: Globally breast cancer accounts for 24.5% in incidence and 15.5% in cancer deaths in women. The triple-negative subtype lacks any specific therapy and is treated with chemotherapy, resulting in significant side-effects. We aimed to investigate if the dose of chemotherapeutic drugs could be diminished by co-administering it with the β2-agonist salbutamol. Methods: Cell proliferation was measured by thymidine incorporation; gene expression, by real-time PCR and protein phosphorylation by WB. Apoptosis was assessed by acridine orange / ethidium bromide and TUNEL tests. Public patient databases were consulted. Cells were inoculated to nude mice and their growth assessed. Results: The β2-agonist salbutamol synergizes in MDA-MB-231 cells in vitro with paclitaxel and doxorubicin on cell proliferation through ADRB2 receptors, while the β-blocker propranolol does not. The expression of this receptor was assessed in patient databases and other cell lines. Triple negative samples had the lowest expression. Salbutamol and paclitaxel decreased MDA-MB-231 cell proliferation while their combination further inhibited it. The pathways involved were analyzed. When these cells were inoculated to nude mice, paclitaxel and salbutamol inhibited tumor growth. The combined effect was significantly greater. Paclitaxel increased the expression of MDR1 while salbutamol partially reversed this increase. Conclusion: While the effect of salbutamol was mainly on cell proliferation, suboptimal concentrations of paclitaxel provoked a very important enhancement of apoptosis. The latter enhanced transporter proteins as MDR1, whose expression were diminished by salbutamol. The expression of ADRB2 should be assessed in the biopsy or tumor to eventually select patients that could benefit from salbutamol repurposing. [ABSTRACT FROM AUTHOR]

Agonists of the β2 adrenergic receptor (ADRB2) are an important class of medications used for the treatment of respiratory diseases. They can be classified as short acting (SABA) or long acting (LABA), with each class playing a different role in patient management. In this work we explored both ligand‐based and structure‐based high‐throughput approaches to classify β2‐agonists based on their duration of action. A completely in‐silico prediction pipeline using an AlphaFold generated structure was used for structure‐based modelling. Our analysis identified the ligands' 3D structure and lipophilicity as the most relevant features for the prediction of the duration of action. Interaction‐based methods were also able to select ligands with the desired duration of action, incorporating the bias directly in the structure‐based drug discovery pipeline without the need for further processing. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinoma (iCCA) is a highly fatal malignancy with rapidly increasing incidence and mortality worldwide. Currently, gemcitabine-based systemic chemotherapy is the main clinical therapeutic regimen; however, its efficacy is poor, and its mechanism has not been elucidated. In this study, we use a Seahorse Extracellular Flux analyser to measure glycolysis capacity (extracellular acidification rate, ECAR) and oxygen consumption rate (OCR). The glucose uptake or lactic acid content is detected, and the effects of saikosaponin D, an active compound derived from Bupleuri Radix (a traditional Chinese medicine for soothing the liver and relieving depression), on gemcitabine cytotoxicity in norepinephrine-stimulated iCCA cells are analysed. We find that adrenergic signaling plays a fundamental role in chronic stress-induced therapeutic resistance in iCCA. Norepinephrine (NE) and epinephrine (E) enhance the proliferation of iCCA cells and interfere with the response to gemcitabine through activation of the β2-adrenergic receptor (ADRB2). Furthermore, we find that NE upregulates the expressions of several drug efflux-related genes (such as ABCG2 and MDR1) and promotes glycolysis in iCCA cells. In addition, saikosaponin D reverses the poor response of iCCA cells to gemcitabine by downregulating ADRB2 level. Furthermore, saikosaponin D inhibits drug efflux and glycolysis in iCCA cells by regulating the expressions of MDR1, ABCG2, HK2, and GLUT1. Collectively, saikosaponin D enhances the antitumor effect of gemcitabine by controlling glucose metabolism and drug efflux by inhibiting the ADRB2 signaling. Therefore, the combination of saikosaponin D and gemcitabine may be a potential therapeutic strategy for the treatment of iCCA.

Introduction. Pain is a signal to any aggression that leads to cellular damage and requires a defensive response. Uncontrolled acute perioperative visceral pain can lead to the development of pain chronicity. By studying the characteristics of chronic pain, some scientists have identified relationships with single-nucleotide polymorphisms of the beta2-adrenergic receptor (ADRB2) gene. Purpose - to study the dependence of pain expression in the postoperative period in children on the polymorphism of the molecular structure of the ADRB2 receptor. Materials and methods. The study involved 42 children (20 boys and 22 girls) aged 7 to 18 years who were treated in the surgical department in 2020-2022 for acute appendicitis and peritonitis. Results. Based on the results of examining all the subjects under study, 13 children had the Arg16Gly polymorphism, 15 children had the Arg16Gly polymorphic variant, and 14 children were diagnosed with the homomorphic Gly16Gly polymorphism in the ADRB2. The data obtained confirmed the trend of the preliminary analysis and proved better body response to pain relief and reduced pain intensity in individuals with the Arg16Arg variant of the ADRB2. Analysis of the dependence between the polymorphism of the ADRB2 molecular structure and Visual Analogue Scale (VAS) scores in children in the postoperative period proved that the presence of Arg in the receptor phenotype had a strong negative correlation with the VAS score on discharge day (r=-0.822, p

Abstract G protein-coupled receptors are involved in many biological processes, relaying the extracellular signal inside the cell. Signaling is regulated by the interactions between receptors and their ligands, it can be stimulated by agonists, or inhibited by antagonists or inverse agonists. The development of a new drug targeting a member of this family requires to take into account the pharmacological profile of the designed ligands in order to elicit the desired response. The structure-based virtual screening of chemical libraries may prioritize a specific class of ligands by combining docking results and ligand binding information provided by crystallographic structures. The performance of the method depends on the relevance of the structural data, in particular the conformation of the targeted site, the binding mode of the reference ligand, and the approach used to compare the interactions formed by the docked ligand with those formed by the reference ligand in the crystallographic structure. Here, we propose a new method based on the conformational dynamics of a single protein–ligand reference complex to improve the biased selection of ligands with specific pharmacological properties in a structure-based virtual screening exercise. Interactions patterns between a reference agonist and the receptor, here exemplified on the β2 adrenergic receptor, were extracted from molecular dynamics simulations of the agonist/receptor complex and encoded in graphs used to train a one-class machine learning classifier. Different conditions were tested: low to high affinity agonists, varying simulation duration, considering or ignoring hydrophobic contacts, and tuning of the classifier parametrization. The best models applied to post-process raw data from retrospective virtual screening obtained by docking of test libraries effectively filtered out irrelevant poses, discarding inactive and non-agonist ligands while identifying agonists. Taken together, our results suggest that consistency of the binding mode during the simulation is a key to the success of the method.

Objective To investigate the distribution characteristics of four gene polymorphisms, evaluate the clinical efficacy of drug-gene test results in guiding individualized treatment for pediatric asthma, and provide novel clinical evidence. Methods A total of 396 children with non-acute mild to moderate asthma diagnosed were recruited. Among them, 198 cases were assigned into the intervention group. The exfoliated cells of oral mucosa were collected to detect the polymorphisms of IL-13 gene R110Q （IL-13 R110Q）, IL-4 gene-590C>T （IL-4-590C>T）, β2 adrenergic receptor gene R16G （ADRB2 R16G） and IgE receptor β chain gene E237G （FcER1B E237G） and asthma drug-genes. The distribution characteristics of asthma gene polymorphisms in children were statistically analyzed. The remaining 198 children with asthma without detection of four gene polymorphisms and asthma drug-genes were allocated into the control group. All children in two groups received inhaled corticosteroids （ICS）. Patients in the intervention group were given with appropriate types of ICS according to the results of asthma drug-gene detection. The patients were followed up for 3 months. Appropriate asthma control scoring tools for children were selected to score and record the questionnaire at the time of enrollment, 1 month and 3 months after treatment, and then the efficacy of individualized medication was statistically analyzed and evaluated. Results The genotype frequencies of AA, AG and GG at IL-13 R110Q locus were 7.1%, 40.4% and 52.5%, respectively. The genotype frequencies of TT, CT and CC at IL-4-590C>T locus were 74.3%, 22.2% and 3.5%, respectively. Genotype frequencies of AA, AG and GG at ADRB2 R16G locus were 44.4%, 38.4% and 17.2%, respectively. The AA, AG and GG genotype frequencies at FcER1B E237G site were 69.2%, 26.8% and 4.0%, respectively. The Test for Respiratory and Asthma Control in Kids （TRACK）, Childhood Asthma Control Test （C-ACT） and Asthma Control Test （ACT） scores in the intervention group were significantly better than those in the control group at 3 months after treatment （all P < 0.05）. Conclusions The polymorphisms of IL-13, IL-4, ADRB2 and FcER1B genes have their own distribution characteristics. Asthma can be improved after individualized treatment. Individualized treatment can be carried out according to the drug-gene testing results.

BACKGROUND: Abdominal obesity, usually measured by waist circumference and waist-to-hip ratio, is more closely related to metabolic dysfunctions that are associated with cardiovascular diseases than general obesity, which is usually assessed by body mass index. The purpose of our study was to study the distribution of alleles and genotypes AGTR1, AGТ, LPL and ADRB2 among adolescents of the Kazakh population and to identify the relationship of these genes with predictors of obesity. METHODS: The study involved 184 adolescents aged 15–18 years of the Kazakh population. RESULTS: As a result of the study, it was revealed that the G allele of the rs328 polymorphism of the LPL gene reduces the risk of developing abdominal obesity compared to the C allele.The C/G genotype reduces the risk of developing abdominal obesity. We have identifi ed among the studied adolescents of the Kazakh population an increase in the ratio of waist volume (WV) to hip volume (HV) among boys, which may in the future lead to obesity and cardiovascular diseases in general. CONCLUSION: It was also found that the G allele of the rs328 polymorphism of the LPL gene reduces the risk of abdominal obesity. Therefore, in addition to determining BMI, we recommend determining the ratio WV to HP. It was found that an increase in the ratio of WV/HV by 1 cm increases the chance of developing hypoapolipoproteinemia A1. [ABSTRACT FROM AUTHOR]

BACKGROUND: Depending on the polymorphism of genes that that are involved in metabolism, the response of patients to different types of therapy may differ. Despite the potential effect of rs7903146 TCF7L2 and rs1042712 ADRB2 on changes in body composition in different types of therapy of early carbohydrate metabolism disorders, these associations haven’t been studied yet. AIM: To study the influence of rs7903146 TCF7L2, rs1042714 ADRB2 on changes in body fat composition in different types of therapy of early carbohydrate metabolism disorders.MATERIALS AND METHODS: The study involved patients with overweight or obesity and risk factors for Type 2 Diabetes development. All patients underwent genotyping with the real-time polymerase chain reaction, oral glucose tolerance test and bioimpedancemetry. Further, the patients were divided into two groups. First group kept a diet with the exclusion of simple and limitation of complex carbohydrates and fats. Second group took metformin in addition to the diet. Three months after bioimpedancemetry was performed again.RESULTS: The research involved 73 patients (the mean age 48±12 y.o., the mean BMI 34,27±6,18 kg/m2 ). The diet therapy group consisted of 47 people. Other 26 patients took metformin in addition to the diet. In group of diet, T allele carriers of rs7903146 TCF7L2 were characterized with more decrease in fat mass compared with CC homozygotes (- 7.90 ± 9.46% vs. -1.54 ± 8.98%, p = 0.027). CC genotype carriers of rs7903146 TCF7L2 in group of metformin and the diet had a tendency for more decrease in hip circumference compared with T allele carriers (-4.95 ± 3.34% vs. — 2.5 ± 2.96%, p = 0.064). Carriers of C allele in homozygous state of rs1042714 ADRB2, who took metformin with the diet, demonstrated more decrease in hip circumference (- 5.81 ± 3.00% vs. -2.50 ± 2.7%, p = 0.009), the tendency for decrease in fat mass (-8.28 ± 8.86% vs. — 3.20 ± 5.09%, p = 0.068) and waist circumference (-5.91 ± 4.29% vs. -3.03 ± 4.01 %, p = 0.091) compared with G allele carriers. The association of rs7903146 TCF7L2 and rs1042714 ADRB2 with changes in total body weight was not observed (p> 0.05).CONCLUSION: Single nucleotide polymorphisms rs7903146 TCF7L2 and rs1042714 ADRB2 influence on body fat composition in patients with early carbohydrate metabolism disorders in various types of treatment.

Mast cells are key effector cells that elicit immunoglobulin E (IgE)-mediated allergic inflammations. Allergen cross-linking of IgE bound to the high-affinity IgE receptor, FcεRI, on mast cells triggers signaling cascades that activate signal proteins and evoke extracellular Ca2+ influx, which are crucial for cytokine production. The β2-adrenergic receptor (Adrb2) on mast cells negatively regulates FcεRI signaling, as demonstrated by the inhibition of IgE/antigen (Ag)-induced activation by Adrb2 agonists. Although β2-adrenergic-related reagents are known to influence mast cell functions, the specific intrinsic role of Adrb2 in these cells is not fully understood, potentially because of off-target effects. In this study, the additional roles of Adrb2 in mast cells were investigated, specifically the involvement of Adrb2 in FcεRI signaling, using Adrb2 −/− mice. Adrb2 −/− mice were used to investigate the roles of Adrb2 in mast cells by examining bone marrow-derived mast cells (BMMCs) for surface expression of mast cell markers, granule numbers, and gene expression of mast cell proteases. Cytokine production, Ca2+ influx, and nuclear factor of activated T cells (NFAT) nuclear translocation were measured in Adrb2 −/− and Adrb2 +/+ BMMCs upon IgE/Ag stimulation. Adrb2 −/− did not affect the generation of BMMCs, their surface expression of mast cell markers, granule numbers, or gene expression of mast cell proteases, indicating that the absence of Adrb2 had no adverse effect on mast cell development. However, Adrb2 −/− BMMCs exhibited reduced tumor necrosis factor α (TNFα) production and diminished Ca2⁺ influx upon IgE/Ag stimulation, which correlated with decreased NFAT translocation. Restoration of Adrb2 in Adrb2 −/− BMMCs rescued cytokine production. Notably, FcεRI-mediated phosphorylation of the phospholipase PLCγ1 and mitogen-activated protein kinases (MAPKs) remained unchanged in the absence of Adrb2. These results suggest that Adrb2 has a novel ligand-independent function, increasing Ca2+ entry in mast cells when stimulated with IgE/Ag. • Adrb2 deficiency does not alter mast cell development or surface marker expression. • Adrb2-deficient mast cells show reduced TNFα production upon IgE/Ag stimulation. • IgE/Ag-induced Ca2+ influx is decreased in Adrb2-deficient mast cells. • Adrb2 boosts Ca2+ entry in mast cells without ligand, promoting NFAT translocation. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors are involved in many biological processes, relaying the extracellular signal inside the cell. Signaling is regulated by the interactions between receptors and their ligands, it can be stimulated by agonists, or inhibited by antagonists or inverse agonists. The development of a new drug targeting a member of this family requires to take into account the pharmacological profile of the designed ligands in order to elicit the desired response. The structure-based virtual screening of chemical libraries may prioritize a specific class of ligands by combining docking results and ligand binding information provided by crystallographic structures. The performance of the method depends on the relevance of the structural data, in particular the conformation of the targeted site, the binding mode of the reference ligand, and the approach used to compare the interactions formed by the docked ligand with those formed by the reference ligand in the crystallographic structure. Here, we propose a new method based on the conformational dynamics of a single protein–ligand reference complex to improve the biased selection of ligands with specific pharmacological properties in a structure-based virtual screening exercise. Interactions patterns between a reference agonist and the receptor, here exemplified on the β2 adrenergic receptor, were extracted from molecular dynamics simulations of the agonist/receptor complex and encoded in graphs used to train a one-class machine learning classifier. Different conditions were tested: low to high affinity agonists, varying simulation duration, considering or ignoring hydrophobic contacts, and tuning of the classifier parametrization. The best models applied to post-process raw data from retrospective virtual screening obtained by docking of test libraries effectively filtered out irrelevant poses, discarding inactive and non-agonist ligands while identifying agonists. Taken together, our results suggest that consistency of the binding mode during the simulation is a key to the success of the method. [ABSTRACT FROM AUTHOR]

Background: Psychological stress can exacerbate the development of allergies; however, the underlying mechanisms remain poorly understood. IgE-mediated cutaneous allergic inflammation (IgE-CAI) is a basophil-dependent skin allergy with eosinophil infiltration at inflammatory sites. Its resolution involves anti-inflammatory programmed death ligand 2 (PD-L2) + macrophages., Objective: This study sought to elucidate the cellular and molecular mechanisms by which psychological stress exacerbates IgE-CAI., Methods: Neural tissue involved in stress-induced IgE-CAI exacerbation was identified by performing denervation and brain destruction experiments in mice. Immune cell transplantation, RNA sequencing, flow cytometry, and ELISA were used to identify and characterize immune cells with stress-altered functioning, followed by identification of key factors involved in IgE-CAI exacerbation., Results: Stress-induced exacerbation of IgE-CAI was found to be sympathetic and β2-adrenergic receptor (Adrb2)-dependent. Adoptive transfer experiments revealed that stress diminished the anti-inflammatory functions of PD-L2 + macrophages through Adrb2, exacerbating the inflammation. RNA sequencing analysis indicated that PD-L2 + macrophages in stressed mice exhibit reduced expression of efferocytosis-related genes, including Gas6 and MerTK. Consequently, the efferocytic capacity of these macrophages decreased, resulting in increased numbers of dead cells in the lesions. The exacerbation and upregulation of Ccl24 expression in IgE-CAI skin lesions were countered by a caspase-1 inhibitor., Conclusions: Psychological stress diminishes the efferocytotic capacity of PD-L2 + macrophages, causing an accumulation of dead cells. This, in turn, heightens eosinophil infiltration through caspase-1-dependent production of Ccl24, exacerbating IgE-CAI., (Copyright © 2024. Published by Elsevier Inc.)

Chimeric antigen receptor (CAR)-T cell therapy has shown limited success in patients with solid tumors. Recent in vitro and in vivo data have shown that adrenoceptor beta-2 (ADRB2) is a novel checkpoint receptor that inhibits T cell-mediated anti-tumor responses. To inhibit ADRB2-mediated inhibitory signaling, we downregulated ADRB2 in CAR-T (shβ 2 -CAR-T) cells via RNA interference, assessed different parameters, and compared them with conventional second-generation CAR-T cells. ADRB2 knockdown CAR-T cells exhibited enhanced cytotoxicity against prostate cancer cell lines in vitro, by increasing CD69, CD107a, GzmB, IFN-γ, T-bet, and GLUT-1. In addition, ADRB2 deficiency led to improved proliferation, increased CD8/CD4 T cell ratio, and decreased apoptosis in CAR-T cells. shβ 2 -CAR-T cells expressed more Bcl-2 and led to the generation of more significant proportions of T central memory cells. Finally, the ZAP-70/NF-κB signaling axis was shown to be responsible for the improved functions of novel CAR-T cells. In tumor-bearing mice, shβ 2 -CAR-T cells performed better than conventional CAR-T cells in eradicating prostate tumors. The study provides the basis for future clinical and translational CAR-T cell research to focus on adrenergic stress-mediated challenges in the tumor microenvironment of stressed tumors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Single nucleotide polymorphisms (SNPs) are pivotal in clinical genetics, serving to link genotypes with disease susceptibility and response to environmental factors, including pharmacogenetics. They also play a crucial role in population genetics for mapping the human genome and localizing genes. Despite their utility, challenges arise when molecular genetic studies yield insufficient or uninformative data, particularly for socially significant diseases. This study aims to address these gaps by proposing a method to predict allelic variants of SNPs., Method: Using quantitative PCR and analyzing body composition data from 150 patients with their voluntary informed consent, we employed IBM SPSS Statistics 29.0 for data analysis. Our prototype formula, exemplified by allelic variant ADRB2 (rs1042713) = 0.257 + 0.639 * allelic variant ADRB2 (rs1042714) - 0.314 * allelic variant ADRB3 (rs4994) + 0.191 * allelic variant PPARA (rs4253778) - 0.218 * allelic variant PPARD (rs2016520) + 0.027 * body weight + 0.00001 * body weight², demonstrates the feasibility of predicting SNP allelic variants., Results: This method holds promise for diverse diseases, including those of significant social impact, due to its potential to streamline and economize molecular genetic research. Its ability to stratify disease risk in the absence of complete SNP data makes it particularly compelling for clinical and laboratory geneticists., Conclusion: However, its translation into clinical practice necessitates the establishment of a comprehensive SNP database, especially for frequently analyzed SNPs within the implementing institution., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

ObjectiveNeuroblastoma (NB), originating from sympathetic spinal tissue, is a serious threat to the life of children. Especially in the high-risk group, an overall five-year survival rate less than 50% indicates an extremely poor clinical outcome. Here, the expression the of β-2 adrenergic (ADRB2) receptor gene in tumor tissues of children with NB was detected and the correlation between its expression and clinical characteristics and prognosis was analyzed.MethodsForty-five tumor tissue samples and forty-eight paraffin sections of NB were obtained from Children’s Hospital of Chongqing Medical University from 2015 to 2021. Real-time fluorescence quantitative polymerase chain reaction (RT–qPCR) was utilized to detect the expression of ADRB2 at the mRNA level and immunohistochemistry (IHC) at the protein level.ResultsFor the RT–qPCR, the analysis showed that the expression of ADRB2 in the high-risk group was significantly lower (P = 0.0003); in addition, there were also statistically significant differences in Shimada classification (P = 0.0025) and N-MYC amplification (P = 0.0011). Survival prognosis analysis showed that the prognosis was better with high ADRB2 expression (P = 0.0125), and the ROC curve showed that ADRB2 has a certain accuracy in predicting prognosis (AUC = 0.707, CI: 0.530–0.884). Moreover, the expression of ADRB2, N-MYC amplification and bone marrow metastasis were the factors that independently affected prognosis, and at the protein level, the results showed that the differential expression of ADRB2 was conspicuous in risk (P = 0.0041), Shimada classification (P = 0.0220) and N-MYC amplification (P = 0.0166). In addition, Kaplan–Meier curves showed that the prognosis in the group with high expression of ADRB2 was better (P = 0.0287), and the ROC curve showed that the score of ADRB2 had poor accuracy in predicting prognosis (AUC = 0.662, CI: 0.505–0.820).ConclusionADRB2 is a protective potential biomarker and is expected to become a new prognostic biomolecular marker of NB.

Meibomian gland dysfunction is one of the main causes of dry eye disease and has limited therapeutic options. In this study, we investigated the biological function of the beta 2-adrenergic receptor (ADRB2)/protein kinase A (PKA) pathway in lipid synthesis and its underlying mechanisms in human meibomian gland epithelial cells (HMGECs). HMGECs were cultured in differentiation media with or without forskolin (an activator of adenylate cyclase), salbutamol (an ADRB2 agonist), or timolol (an ADRB2 antagonist) for up to 4 days. The phosphorylation of the cAMP-response element-binding protein (CREB) and the expression of peroxisome proliferator activator receptor (PPAR)γ and sterol regulatory element-binding protein (SREBP)-1 were measured by immunoblotting and quantitative PCR. Lipid synthesis was examined by LipidTOX immunostaining, AdipoRed assay, and Oil Red O staining. PKA pathway activation enhanced PPARγ expression and lipid synthesis in differentiated HMGECs. When treated with agonists of ADBR2 (upstream of the PKA signaling system), PPARγ expression and lipid synthesis were enhanced in HMGECs. The ADRB2 antagonist timolol showed the opposite effect. The activation of the ADRB2/PKA signaling pathway enhances lipid synthesis in HMGECs. These results provide a potential mechanism and therapeutic target for meibomian gland dysfunction, particularly in cases induced by beta-blocker glaucoma drugs. [ABSTRACT FROM AUTHOR]

目的 观察运动后低血压在校男生心率变异性 (HRV) 改变及ADRB1、ADRB2、神经前体细胞表达发育调 控样蛋白 4(NEDD4L) 基因多态性, 并分析其关系. 方法 选择运动后低血压在校男生 91 例为观察组, 与其体质 量、BMI匹配的运动后血压正常在校男生91例为对照组. 两组行24 h动态心电图检查测定HRV相关参数 [平均正 常NN间期标准差 (SDNN)、相邻NN间期相差>50 ms的百分数 (PNN50)、低频功率 (LF)、高频功率 (HF)、LF/HF], 采 用 Sanger 测序法检测两组静脉血血压调节相关基因 ADRB1、ADRB2 和 NEDD4L 分别在 rs1801253、rs1042713 和 rs4149601 位点的单核苷酸多态性, 多元线性回归法观察 ADRB1、ADRB2、NEDD4L 基因多态性对 HRV 的影响. 结果 Hardy-Weinberg遗传平衡检验显示, 两组基因多态性分布具有人群代表性. 与对照组比较, 观察组SDNN降 低、LF升高 (P均<0. 05); 两组PNN50、HF、LF/HF比较差异均无统计学意义 (P均>0. 05). 两组ADRB1等位基因频 率比较 P>0. 05; 观察组 ADRB2、NEDD4L A 等位基因频率均高于对照组, G 等位基因频率均低于对照组 (P 均 <0. 05). NEDD4L携带A等位基因是LF升高的独立危险因素 (P<0. 05), ADRB2、NEDD4L基因多态性与SDNN无关 (P均>0. 05). 结论 运动后低血压男性存在SDNN降低、LF升高及ADRB2、NEDD4L基因A等位基因频率升高, 其 中NEDD4L rs4149601G>A突变是LF升高的危险因素, ADRB1、ADRB2基因多态性对HRV的影响不大. [ABSTRACT FROM AUTHOR]

This study investigated the release and proteomic profile of tissue factor microparticles (TFMPs) prospectively (up to 6 months) following a myocardial infarction (MI) in a chronic porcine model to establish their utility in tracking cellular level activities that predict physiologic outcomes. Our animal groups (n = 6 to 8 each) consisted of control, noninfarcted (negative control); infarcted only (positive control); and infarcted animals treated with cardiac resynchronization therapy (CRT) and a β-blocker (BB) (metoprolol succinate). The authors found different protein profiles in TFMPs between the control, infarcted only group, and the CRT + BB treated group with predictive impact on the outward phenotype of pathological remodeling after an MI within and between groups. This novel approach of monitoring cellular level activities by profiling the content of TFMPs has the potential of addressing a shortfall of the current crop of cardiac biomarkers, which is the inability to capture composite molecular changes associated with chronic maladaptive signaling in a spatial and temporal manner.

This study investigated whether norepinephrine (NE) and epinephrine (E) interfere in the response of head and neck squamous cell carcinoma (SCC) cel l lines to cisplatin and explored the mechanisms of chemoresistance. Head and neck SCC-derived cell lines SCC-9, Cal27, SCC-25, and FaDu were stimulated with NE or E and treate d with the inhibitory concentration of cisplatin for 24 h. As for adrenergic receptors (ADRB) inhibition, cells were treated with propranolol. The results showed that, when combined with NE, cisplatin effectiveness against SCC-9 and Cal27 but not SCC-25 and FaDu ce lls were notably reduced. E did not affect the response of the cells to cisplatin. Further experiments were performed with the responsive SCC-9 and SCC-25 cell lines and the hormone NE. The time course assay showed that stimulation of oral SCC cells with NE decreased the cleavage of caspase-3 and expression of multidrug resistance protein 1 (MDR-1) but only transiently affected ATP-binding cassette (ABC) subfamily G, isoform 2 protein (ABCG2) expression. The expression of cleaved caspase-3 and Bcl-2 were, respectively, decreased and increased by the combination of NE and cisplatin in SCC-9 and C al27 cells. NE-induced resistance was reverted by previous treatment with propranolol. Expressions of ABCG2, and p-Akt but not of MDR-1, were enhanced by NE plus cisplatin when compared to cisplatin only in both cell lines. Migratory activity of oral SCC cells challenged with cisplatin was not affected by NE. These findings reveal for the first time that stress hormone NE induces resistance of oral cancer cells to cisplatin in vitro through the ADRB/Akt/ABCG2 pathway, pumping the drug out of the cell and inhibiting apopto sis. [ABSTRACT FROM AUTHOR]

Background: Takotsubo Cardiomyopathy (TC) is a rare disorder that is mostly caused by stress and is often misdiagnosed. We aimed to analyze Takotsubo Syndrome at the molecular level by using the Oxford Nanopore Minion Device and its protocol. Methods and results: Ten patients who were previously diagnosed with Takotsubo Syndrome (increased after decrease in ejection fraction and without critical stenosis in coronary arteries) and 10 healthy individuals in the control group were included in our project. The mean age was 53 ± 12.2 for the patient group and 52.4 ± 9.9 for the control group, and the left ventricular ejection fraction was 50.3 ± 11.5 for the patient group and 64.2 ± 2.8 for the control group (p < 0.05). Peripheral blood of patients and healthy individuals was taken and their DNA was obtained. By making long reads throughout the genome, the most studied regions responsible for β-adrenergic signaling pathways; The gene expression level of cardiac β-1 ADRB1 (rs1801253-ENST00000369295.4), G > C, (Gly389Arg) and cardiac β-2 ADRB2 (rs1800888-ENSG00000169252), C > T, (Thr165Ile) adrenoceptors was investigated. As a result; no structural variation was detected leading to Takotsubo Cardiomyopathy. The results obtained from the bioinformatics analysis were also checked from the VarSome Tools and similar results were found. Conclusions: Many publications in TC susceptibility have that may lead to adrenergic pathway dysregulation, most studied adrenergic receptor genes in the similar literatures too. We searched for genetic variants in b1AR and b2AR genes in our study and however we could not find any variants in this study, we think larger numbers of cohort studies are needed. [ABSTRACT FROM AUTHOR]

Abstract Background Previous studies suggest that persistent exposure to social stress in mammals may be associated with multiple physiological effects. Here, we examine the effects of social stress in rats, i.e. repeated social defeat, on behavior, hypothalamic–pituitary–adrenal (HPA)-axis and immune system. Methods A resident-intruder paradigm, where an intruder rat was exposed to social stress by a dominant resident rat for 1 hour each day for 7 consecutive days was used. The day after the last stress exposure in the paradigm the data were analyzed. Variation in social interaction was observed manually, whereas locomotion was analyzed off-line by a purpose-made software. Gene expression in the pituitary gland, adrenal gland and myeloid cells isolated from the spleen was measured by qPCR. Results The exposure to social stress induced decreased weight gain and increased locomotion. An increased nuclear receptor subfamily group C number 1 (NR3C1) expression in the pituitary gland was also shown. In myeloid cells harvested from the spleen, we observed decreased expression of the β2-adrenergic receptor (ADRB2) and β-arrestin-2 (ARRB2), but increased expression of interleukin-6 (IL-6). Subsequent analyses in the same cells showed that ARRB2 was negatively correlated with IL-6 following the stress exposure. Conclusion Our results show that that the experience of social stress in the form of repeated social defeat in rats is a potent stressor that in myeloid cells in the spleen promotes persistent inflammatory changes. Future research is needed to examine whether similar inflammatory changes also can explain the impact of social stress, such as bullying and harassment, among humans.

Asthma is a chronic inflammatory respiratory condition, characterized by variable airflow limitation, leading to clinical symptoms such as dyspnea and chest tightness. These symptoms result from an underlying inflammatory process. The β2 agonists are bronchodilators prescribed for the relief of the disease. Nevertheless, their efficacy exhibits substantial interindividual variability. Currently, there is widespread recognition of the association between specific genetic variants, predominantly located within the ADRB2 and ADCY9 genes and their efficacy. This association, usually represented by the presence of non-synonymous single nucleotide polymorphisms (SNPs) have a strong impact in the protein functionality. The prevalence of these mutations varies based on the ethnic composition of the population and thus understanding the profiles of variability in different populations would contribute significantly to standardizing the use of these medications. In this study, we conducted a sequence-based genotyping of the relevant SNPs within the ADRB2 and ADCY9 genes in patients undergoing treatment with bronchodilators and/or corticosteroids at two healthcare facilities in the state of Rio de Janeiro, Brazil. We investigated the presence of c.46A>G, c.79C>G, c.252G>A, and c.491C>T SNPs within the ADRB2 , and c.1320018 A>G within the ADCY9 . Our results were in line with existing literature data with both for individuals in Brazil and Latin American.

Background: The polymorphism Arg16 in β2‐adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long‐acting β2‐agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. Objective: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. Methods: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi‐ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma‐related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta‐analysed using the inverse variance weighting method assuming random‐effects. Results: In subjects treated with ICS and LABA (n = 832, age: 3–21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05–1.87, I2 = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05–1.94, I2 = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71–1.39, I2 = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as‐required short‐acting β2‐agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686). Conclusion and clinical relevance: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype‐guided treatment which might improve clinical outcomes in asthmatic patients. [ABSTRACT FROM AUTHOR]

Objective: Neuroimmune interactions between the sympathetic nervous system (SNS) and macrophages are required for the homeostasis of multiple tissues, including the adipose tissue. It has been proposed that the SNS maintains adipose tissue macrophages (ATMs) in an anti-inflammatory state via direct norepinephrine (NE) signaling to macrophages. This study aimed to investigate the physiological importance of this paradigm by utilizing a mouse model in which the adrenergic signaling from the SNS to macrophages, but not to other adipose tissue cells, was disrupted. Methods: We generated a macrophage-specific B2AR knockout mouse (Adrb2ΔLyz2) by crossing Adrb2fl/fl and Lyz2Cre/+ mice. We have previously shown that macrophages isolated from Adrb2ΔLyz2 animals do not respond to NE stimulation in vitro. Herein we performed a metabolic phenotyping of Adrb2ΔLyz2 mice on either chow or high-fat diet (HFD). We also assessed the adipose tissue function of Adrb2ΔLyz2 animals during fasting and cold exposure. Finally, we transplanted Adrb2ΔLyz2 bone marrow to low-density lipoprotein receptor (LDLR) knockout mice and investigated the development of atherosclerosis during Western diet feeding. Results: We demonstrated that SNS-associated ATMs have a transcriptional profile indicative of activated beta-2 adrenergic receptor (B2AR), the main adrenergic receptor isoform in myeloid cells. However, Adrb2ΔLyz2 mice have unaltered energy balance on a chow or HFD. Furthermore, Adrb2ΔLyz2 mice show similar levels of adipose tissue inflammation and function during feeding, fasting, or cold exposure, and develop insulin resistance during HFD at the same rate as controls. Finally, macrophage-specific B2AR deletion does not affect the development of atherosclerosis on an LDL receptor-null genetic background. Conclusions: Overall, our data suggest that the SNS does not directly modulate the phenotype of adipose tissue macrophages in either lean mice or mouse models of cardiometabolic disease. Instead, sympathetic nerve activity exerts an indirect effect on adipose tissue macrophages through the modulation of adipocyte function.

Malignant peripheral nerve sheath tumor (MPNST), a highly malignant tumor that arises in peripheral nerve tissues, is known to be highly resistant to radiation and chemotherapy. Although there are several reports on genetic mutations and epigenetic changes that define the pathogenesis of MPNST, there is insufficient information regarding the microenvironment that contributes to the malignancy of MPNST. In the present study, we demonstrate that adrenaline increases the cancer stem cell population in MPNST. This effect is mediated by adrenaline stimulation of beta-2 adrenergic receptor (ADRB2), which activates the Hippo transducer, YAP/TAZ. Inhibition and RNAi experiments revealed that inhibition of ADRB2 attenuated the adrenaline-triggered activity of YAP/TAZ and subsequently attenuated MPNST cells stemness. Furthermore, ADRB2-YAP/TAZ axis was confirmed in the MPNST patients' specimens. The prognosis of patients with high levels of ADRB2 was found to be significantly worse. These data show that adrenaline exacerbates MPNST prognosis and may aid the development of new treatment strategies for MPNST. • Adrenaline induces the expansion of cancer stem-like cell population of MPNST. • Adrenaline promotes YAP/TAZ activity of cancer stem-like cells of MPNST. • Inhibition of adrenoreceptor signaling attenuates malignancy of MPNST cells. • ADRB2-YAP/TAZ axis is correlated with poor prognosis of MPNST patients. [ABSTRACT FROM AUTHOR]

The review is devoted to a new and rapidly developing area related to the application of ideas and methods of nonlinear mathematics and theoretical physics to study the internal dynamics of DNA and, in particular, the behavior of the open states of DNA. There are two main competing approaches to this research. The first approach is based on the molecular dynamics method, which takes into account the motions of all structural elements of the DNA molecule and all interactions between them. The second approach is based on prior selection of the main (dominant) motions and their mathematical description using a small number of model equations. This review describes the results of the study of the open states of DNA performed within the framework of the second approach using the McLaughlin-Scott equation. We present the results obtained both in the case of homogeneous sequences: poly (A), poly (T), poly (G) and poly (C), and in the inhomogeneous case when the McLaughlin-Scott equation has been used for studying the dynamics of open states activated in the promoters A1, A2 and A3 of the bacteriophage T7 genome, in the genes IFNA17, ADRB2, NOS1 and IL-5, in the pBR322 and pTTQ18 plasmids. Particular attention is paid to the results concerning the effect of various external fields on the behavior of open states. In the concluding part of the review, new possibilities and prospects for the development of the considered approach and especially of the McLaughlin-Scott equation are discussed. [ABSTRACT FROM AUTHOR]

Abstract Background The published data on the association between β2-adrenergic receptor gene polymorphisms and asthma susceptibility are inconclusive. To derive a more precise estimation of this association, a meta-analysis was performed. Methods A literature search was conducted in PubMed, Web of Science, EMBASE, Wanfang, and the China National Knowledge Infrastructure (CNKI) databases to identify eligible studies. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to calculate the strength of the association. A sensitivity analysis was performed to evaluate the influence of individual studies on the overall effect estimates, and funnel plots and Egger’s tests were used for indications of publication bias. Results Seventy three studies with three single nucleotide polymorphisms (SNP) (rs1042713, c.G46A, p.Gly16Arg; rs1042714, c.G79C, p.Gln27Glu; rs1042711, c.T-47C, p.Cys19Arg) were finally identified. For the rs1042713 polymorphism, no significant association with asthma risk was found in the overall population. However, a significant protective association was found in the Indian population in the dominant model comparison (OR = 0.72, 95% CI = 0.59–0.87, I2 = 25%, studies = 5, cases = 1190, controls = 1241). A significant risk association was found in the Arab population in the dominant model comparison (OR = 1.75, 95% CI = 1.14–2.70, I2 = 0%, studies = 2, cases = 307, controls = 361) and the homozygote model comparison (OR = 1.88, 95% CI = 1.17–3.02, I2 = 0%, studies = 2, cases = 307, controls = 361), and in the Hispanic-Latino population in the dominant model comparison (OR = 1.68, 95% CI = 1.10–2.55, I2 = 77%, studies = 5, cases = 1026, controls = 1412). For the rs1042714 polymorphism, we found a significant association in the recessive model comparison (OR = 0.83, 95% CI = 0.70–0.98, I2 = 44%, studies = 52, cases = 8242, controls = 16,832), the homozygote genotype comparison (OR = 0.84, 95% CI = 0.72–0.98, I2 = 25%, studies = 52, cases = 8242, controls = 16,832) and the allelic genetic model (OR = 0.91, 95% CI = 0.83–0.99, I2 = 59%, studies = 52, cases = 8242, controls = 16,832) in the overall population. When stratified by age, a significant association was also found in children in the recessive model comparison (OR = 0.59, 95% CI = 0.39–0.88, I2 = 58%, studies = 18, cases = 2498, controls = 2510) and the homozygote genotype comparison (OR = 0.63, 95% CI = 0.43–0.92, I2 = 46%, studies = 18, cases = 2498, controls = 2510), but not in adult. For the rs1042711 polymorphism, no significant associations were found in the any genetic model. Conclusion The meta-analysis suggests that the ADRB2 rs1042714 polymorphism has a protective association with asthma in the overall population and the pediatric subgroup.

The beta-2 adrenergic receptor (ADRB2) regulates the proliferation, apoptosis, angiogenesis, migration, and metastasis of cancer cells. However, its function in the progression of clear cell renal cell carcinoma (ccRCC) is unknown. Here, we report that ADRB2 can be a novel prognostic factor for patients with ccRCC. The differential expression of ADRB2 in low-stage (stages I and II), high-stage (stages III and IV), low-grade (grades I and II), and high-grade (grades III and IV) ccRCC was identified in cohorts of patients from The Cancer Genome Atlas and the International Cancer Genome Consortium. We evaluated ADRB2 expression as a prognostic factor using the Kaplan-Meier survival curve, multivariate analysis, time-dependent area under the curve (AUC) of Uno’s C-index, and AUC of the receiver operating characteristics (ROC) at five years. Kaplan-Meier analysis revealed that reduced ADRB2 expression is associated with poor prognosis in ccRCC patients. Analysis of C-indices and AUC-ROC further confirmed this result. Moreover, multivariate analysis confirmed the prognostic significance of ADRB2 expression. Collectively, these findings suggest that ADRB2 is a potential prognostic factor for ccRCC.

Aims: The associations of 2 nonsynonymous single nucleotide polymorphisms (Arg16Gly and Gln27Glu) in the adrenoceptor β2 (ADRB2) gene with response after albuterol use are conflicting. We conducted a meta‐analysis to examine the cumulative evidence of the effects of these 2 variants on percent forced expiratory volume in 1 second (FEV1.0%) after albuterol use in asthma patients. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials to identify studies examining the association between ADRB2 Arg16Gly and Gln27Glu and FEV1.0% shortly after albuterol administration. The individual study results were combined with weights based on the inverse variance method. This systematic review was registered in the PROSPERO (registration number: CRD42019074554). Results: Among 273 initial studies identified, 7 studies met the inclusion criteria for quantitative evaluation. Results of the overall meta‐analysis indicated no statistically significant mean difference of FEV1.0% between genotypes of Arg16Gly and Gln27Glu. In subgroup analyses, significant associations were found for Arg16Gly GG (vs AA) among studies where no methacholine bronchoconstriction was conducted (mean difference, −3.92; 95% confidence interval, −7.29 to −0.54; I2 = 0%), and for Arg16Gly GG (vs GA) among studies that included patients with no comorbidities (mean difference, −1.93; 95% confidence interval, −3.77 to −0.10; I2 = 0%). Conclusion: Synthesis of the studies to date shows weak evidence for an association between ADRB2 Arg16Gly and Gln27Glu and FEV1.0% after albuterol use, results of which underscore significant heterogeneity across studies and the need for careful design and sample size considerations. [ABSTRACT FROM AUTHOR]

Beta-2-adrenergic receptor is a member of the G protein-coupled receptor superfamily, which is highly expressed in most malignancies. There is increasing evidence showing that beta-2-adrenergic receptors are associated with carcinogenesis, proliferation, immune regulation, invasion, angiogenesis, clinical prognosis and treatment resistance in malignancies. Polymorphisms of the ADRB2 gene have been confirmed to be associated with transcriptional activity, mRNA translation, and beta-2-adrenergic receptor expression and sensitivity. This review discusses clinically relevant examples of single nucleotide polymorphisms of ADRB2 in malignancies and the effects of these polymorphisms on cancer susceptibility, prognosis and treatment response of cancer patients. [ABSTRACT FROM AUTHOR]

Tissue‐resident macrophages are required for homeostasis, but also contribute to tissue dysfunction in pathophysiological states. The sympathetic neurotransmitter norepinephrine (NE) induces an anti‐inflammatory and tissue‐reparative phenotype in macrophages. As NE has a well‐established role in promoting triglyceride lipolysis in adipocytes, and macrophages accumulate triglyceride droplets in various physiological and disease states, we investigated the effect of NE on primary mouse bone marrow‐derived macrophage triglyceride metabolism. Surprisingly, our data show that in contrast to the canonical role of NE in stimulating lipolysis, NE acting via beta2‐adrenergic receptors (B2ARs) in macrophages promotes extracellular fatty acid uptake and their storage as triglycerides and reduces free fatty acid release from triglyceride‐laden macrophages. We demonstrate that these responses are mediated by a B2AR activation‐dependent increase in Hilpda and Dgat1 gene expression and activity. We further show that B2AR activation favors the storage of extracellular polyunsaturated fatty acids. Finally, we present evidence that macrophages isolated from hearts after myocardial injury, for which survival critically depends on leukocyte B2ARs, have a transcriptional signature indicative of a transient triglyceride accumulation. Overall, we describe a novel and unexpected role of NE in promoting triglyceride storage in macrophages that could have potential implications in multiple diseases. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that macroautophagy/autophagy-lysosomal pathway deficits contribute to the accumulation of amyloid-β (Aβ) in Alzheimer disease (AD). Aerobic exercise (AE) has long been investigated as an approach to delay and treat AD, although the exact role and mechanism are not well known. Here, we revealed that AE could reverse autophagy-lysosomal deficits via activation of ADRB2/β2-adrenergic receptor, leading to significant attenuation of amyloid-β pathology in APP-PSEN1/PS1 mice. Molecular mechanism research found that AE could reverse autophagy deficits by upregulating the AMP-activated protein kinase (AMPK)-MTOR (mechanistic target of rapamycin kinase) signaling pathway. Moreover, AE could reverse V-ATPase function by upregulating VMA21 levels. Inhibition of ADRB2 by propranolol (antagonist, 30 μM) blocked AE-attenuated Aβ pathology and cognitive deficits by inhibiting autophagy-lysosomal flux. AE may mitigate AD via many pathways, while ADRB2-VMA21-V-ATPase could improve cognition by enhancing the clearance of Aβ through the autophagy-lysosomal pathway, which also revealed a novel theoretical basis for AE attenuating pathological progression and cognitive deficits in AD.

Previous studies have shown that environmental exposure to heavy metals has been related to epigenetic changes, such as DNA methylation in receptors involved in pathogenesis of asthma. One of these receptors is beta-2 adrenergic receptor (ADRB2). We conducted this study to examine the association between blood aluminum concentration, blood ADRB2 5′ untranslated region (5′-UTR) methylation level, and childhood asthma control level. Our results showed a significant positive association between high blood aluminum concentration (odds ratio, 16, 95% confidence interval (CI) [3.57 to 71.76], p < 0.001) and high blood ADRB2 5′-UTR methylation level (odds ratio, 4.75, 95% CI [1.39 to 16.2], p = 0.013), and risk of uncontrolled asthma. Multivariable logistic regression revealed that higher blood aluminum concentration was independently associated with increased risk of uncontrolled bronchial asthma (odds ratio, 9.10, 95% CI [2.38 to 34.85], p = 0.0013], after controlling for age, sex, and blood ADRB2 5′-UTR methylation level. In addition, blood ADRB2 5′-UTR methylation level significantly correlated with whole blood aluminum concentration in asthmatic children (r = 0.480, p < 0.001). We concluded that increasing blood aluminum concentration is an important independent correlate of risk for uncontrolled bronchial asthma as well as increased blood aluminum concentration caused ADRB2 5′-UTR hyper-methylation with increasing risk of uncontrolled bronchial asthma. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggest that persistent exposure to social stress in mammals may be associated with multiple physiological effects. Here, we examine the effects of social stress in rats, i.e. repeated social defeat, on behavior, hypothalamic-pituitary-adrenal (HPA)-axis and immune system.Methods: A resident-intruder paradigm, where an intruder rat was exposed to social stress by a dominant resident rat for 1 hour each day for 7 consecutive days was used. The day after the last stress exposure in the paradigm the data were analyzed. Variation in social interaction was observed manually, whereas locomotion was analyzed off-line by a purpose-made software. Gene expression in the pituitary gland, adrenal gland and myeloid cells isolated from the spleen was measured by qPCR.Results: The exposure to social stress induced decreased weight gain and increased locomotion. An increased nuclear receptor subfamily group C number 1 (NR3C1) expression in the pituitary gland was also shown. In myeloid cells harvested from the spleen, we observed decreased expression of the β2-adrenergic receptor (ADRB2) and β-arrestin-2 (ARRB2), but increased expression of interleukin-6 (IL-6). Subsequent analyses in the same cells showed that ARRB2 was negatively correlated with IL-6 following the stress exposure.Conclusion: Our results show that that the experience of social stress in the form of repeated social defeat in rats is a potent stressor that in myeloid cells in the spleen promotes persistent inflammatory changes. Future research is needed to examine whether similar inflammatory changes also can explain the impact of social stress, such as bullying and harassment, among humans. [ABSTRACT FROM AUTHOR]

• The ADRB2 rs1042713 is known to be associated with elite athletic performance. • The ADRB2 rs10422713 G/G, G are more frequent in Korean elite athletes. • The rs1042713 is associated with elite athletic performance in Korean. Athletic performance is a multifactorial trait influenced by environmental and genetic factors. Previous studies have identified various genes associated with athletic performance, including the β2-adrenergic receptor (ADRB2) gene, which has been consistently shown to be linked with elite athletic performance in diverse populations. The ADRB2 gene is known to play a key role in various biological systems, including cardiovascular, pulmonary, metabolic, and musculoskeletal functions. It acts by interacting with adrenaline. In particular, the ADRB2 rs1042713 (A > G) polymorphism has been associated with cardiovascular and respiratory functions. In addition, the association between the ADRB2 rs1042713 polymorphism and athletic performance has been reported. Thus, we conducted a case-control study to analyze the genetic association with ADRB2 rs1042713 polymorphism with 150 elite athletes, 116 college athletes, and 145 controls (control I) in the Korean population. The genotypes were determined by PCR-RFLP. As a result, we found significant differences in the distributions of genotype (p = 0.005) and allele (p = 0.002) frequencies between elite athletes and the control Ⅱ (control I + college athletes). We also found that the ADRB2 rs1042713 G/G genotype [odds ratio (OR) 2.42, 95% CI 1.384–4.235, p = 0.002] and the G allele (OR 1.58, 95% CI 1.184–2.098, p = 0.002) were significantly associated with elite athletic performance. Additionally, we observed a gender-specific association in female elite athletic performance (p = 0.0002 and p = 0.0002, respectively). In conclusion, our results suggest that the ADRB2 rs1042713 polymorphism may be associated with elite athletic performance in the Korean population. To validate these findings, additional studies with larger samples, including elite athletes from various sports types and diverse ethnic origins are needed. [ABSTRACT FROM AUTHOR]

Temporomandibular disorder (TMD) has a multifactorial etiology that includes environmental, psychological, and genetic factors. This study aimed to evaluate the possible relationship between polymorphisms in Catechol-O-methyltransferase (COMT) and β2-adrenergic receptor (ADRB2) genes with TMD. This observational case-control study included 80 patients and 70 healthy controls. The diagnosis of TMD was made using the diagnostic criteria for TMD and the following TMD categories were used for the case group: muscular TMD and articular TMD (disc displacement and arthralgia). A genotyping study of gene polymorphisms in COMT (rs 9332377) and ADRB2 (rs20530449) was performed from genomic DNA isolated from blood. The chi-square test was used to analyze the relationships. P < 0.05 was accepted as a significant difference. The polymorphic TT and CT genotype for COMT (rs rs9332377) was significantly higher in the articular TMD group while the non-polymorphic CC genotype was significantly lower in the articular TMD group (P < 0.05). Regarding ADRB2 (rs20530449), the polymorphic GG genotype was similarly considerably more common in the articular TMD group (p < 0.05). In addition, the T allele in the COMT (rs rs9332377) gene was found to be significantly higher in the articular TMD group (p < 0.05). In the Turkish population, gene polymorphisms in COMT (rs9332377) and ADRB2 (rs2053044) were associated with articular TMD. This study supports the hypothesis that changes in COMT and ADRB2 genes may play a role in temporomandibular joint pain and predisposition to TMD. • Polymorphism in the COMT (rs9332377) gene is linked to temporomandibular disorders. • Polymorphism in the ADRB2 (rs2053044) gene is linked to temporomandibular disorders. • Gene polymorphisms in COMT and ADRB2 may play a role in temporomandibular joint pain [ABSTRACT FROM AUTHOR]

We report the first isolation of the alkaloid aaptamine from the Philippine marine sponge Stylissa sp. Aaptamine possessed weak antiproliferative activity against HCT116 colon cancer cells and inhibited the proteasome in vitro at 50 µM. These activities may be functionally linked. Due to its known, more potent activity on certain G-protein coupled receptors (GPCRs), including α-adrenergic and δ-opioid receptors, the compound was profiled more broadly at sub-growth inhibitory concentrations against a panel of 168 GPCRs to potentially reveal additional targets and therapeutic opportunities. GPCRs represent the largest class of drug targets. The primary screen at 20 µM using the β-arrestin functional assay identified the antagonist, agonist, and potentiators of agonist activity of aaptamine. Dose-response analysis validated the α-adrenoreceptor antagonist activity of aaptamine (ADRA2C, IC50 11.9 µM) and revealed the even more potent antagonism of the β-adrenoreceptor (ADRB2, IC50 0.20 µM) and dopamine receptor D4 (DRD4, IC50 6.9 µM). Additionally, aaptamine showed agonist activity on selected chemokine receptors, by itself (CXCR7, EC50 6.2 µM; CCR1, EC50 11.8 µM) or as a potentiator of agonist activity (CXCR3, EC50 31.8 µM; CCR3, EC50 16.2 µM). These GPCRs play a critical role in the treatment of cardiovascular disease, diabetes, cancer, and neurological disorders. The results of this study may thus provide novel preventive and therapeutic strategies for noncommunicable diseases (NCDs).

Allergic rhinitis (AR) is a common hypersensitive disease that troubles patients a lot. Nasal epithelial cells (NECs), as the outmost protection of inhalation, play an important role in AR allergic response. Adrenoceptor beta 2 (ADRB2) is an important gene in inflammatory response, which has become the hot spot for AR development and treatment in recent years. MiR-15a-5p has been proved to be involved in AR immune response as the upstream regulator of ADRB2. Human primary NECs were isolated and stimulated by IL-13. qRT-PCR assay was used to detect the RNA level of target genes. ELISA and Western blotting were applied to detect target protein levels. Luciferase reporter assay and biotin pull-down assay were performed to test molecules interaction. ADRB2 was highly expressed in nasal mucosa of AR patients and was positively correlated with IL-13 stimulation, and knockdown of ADRB2 inhibited IL-13-induced expression of GM-CSF, eotaxin, and MUC5AC in NECs. ADRB2 was directly targeted by miR-15a-5p, and miR-15a-5p inhibited IL-13-induced expression of GM-CSF, eotaxin, and MUC5AC in NECs. ADRB2 mediated the effect of miR-15a-5p on the regulation of nasal epithelial immune responses. ADRB2 is negatively regulated by miR-15a-5p, which inhibits IL-13-induced nasal epithelial inflammatory responses. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Previous studies have indicated that β2-adrenergic receptor (ADRB2) genetic polymorphism is related to the risk of asthma, but the results still have some controversy and uncertainty. To this end, the meta-analysis was performed, including all studies that can be used to assess the correlation between ADRB2 polymorphism and asthma susceptibility. MATERIALS AND METHODS: The related papers on ADRB2 polymorphisms and asthma were systematically reviewed in databases of PubMed, EMBASE, Cochrane Library, and Wan- Fang, Odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were measured. The sensitivity analysis and publication bias were evaluated to investigate the correlation. RESULTS: This meta-analysis included 57 papers in total involving 11,157 cases and 12,281 controls. Results illustrated that the C79G variant genotypes owned a reduced effect on asthma susceptibility (G vs. C: OR=0.94, p=0.037). In the age stratification analysis, C79G polymorphism owned a reduced effect on asthma risk for children (GG vs. CC: OR=0.69, p=0.002; GG vs. CC+CG: OR=0.65, p<0.001). Furthermore, in the ethnic stratification analysis, the C79G variant genotypes also owned a reduced effect on asthma in Asians (GG vs. CC: OR=0.80, p=0.027; GG vs. CC+CG: OR=0.81, p=0.02). Besides, for A46G polymorphism, the ethnic stratification analysis demonstrated that the A46G variant owned an increased effect on asthma susceptibility among Caucasians (G vs. A: OR=1.15, p=0.043). For C491T polymorphism, a considerable reduced effect was found between C491T and asthma susceptibility for children (CT vs. CC: OR=0.70, p=0.03). In the ethnic stratification analysis, the effect was also considerable in the Caucasian subjects. CONCLUSIONS: The present meta-analysis demonstrated that C79G and C491T polymorphism may be a defensive factor for asthma, while A46G polymorphism may be a risk factor for asthma among the Caucasian population. [ABSTRACT FROM AUTHOR]

BackgroundThyrotoxic periodic paralysis (TPP) is a rare complication of thyrotoxicosis characterized by acute attacks of muscle weakness and hypokalemia. Recently, variation in several genes was suggested to be associated with TPP. This study evaluated the genetic predisposition to TPP in terms of the β2-adrenergic receptor (ADRB2), androgen receptor (AR), and γ-aminobutyric acid receptor α3 subunit (GABRA3) genes.MethodsThis study enrolled 48 men with Graves disease (GD) and TPP, and 48 GD patients without TPP. We compared the frequencies of candidate polymorphisms between the two groups.ResultsThe frequency of the Gly16/Gly16 genotype in ADRB2 was not significantly associated with TPP (P=0.32). More CAG repeats (≥26) in the AR gene were not correlated with TPP (odds ratio [OR], 2.46; 95% confidence interval [CI], 0.81 to 8.09; P=0.08). The allele frequency of the TT genotype in the GABRA3 gene was not associated with TPP (OR, 1.83; 95% CI, 0.54 to 6.74; P=0.41).ConclusionThe polymorphisms in the ADRB2, AR, and GABRA3 genes could not explain the genetic susceptibility to TPP in Korean men with GD.

BACKGROUND: Increasing evidence shows that at least 155 genetic polymorphisms are associated with aerobic performance and elite endurance athlete status. OBJECTIVE: To study the association of α-actin 3 (ACTN3) gene, nuclear respiratory factor 2 (NRF2), β2 adrenergic receptor (ADRB2) gene and peroxisome proliferative activated receptor gamma coactivator 1 alpha(PPARGC1A) polymorphic loci with aerobic performance of rowing athletes and their interaction effect, thereby providing basis for understanding the mechanism of genetic polymorphisms acting on endurance athlete status. METHODS: A case-control experiment was designed to analyze the distribution characteristics of four gene polymorphism loci in 15 excellent rowing athletes and 50 common college freshmen. The association of four polymorphic loci with the aerobic performance-related indexes was analyzed using total genotype scores. RESULTS AND CONCLUSION: The preponderant polymorphism locus distributions of ACTN3, PPARGC1A and NRF2 in the athletes group were higher than those in the control group, and the NRF2 gene loci showed significant difference between two groups. In the athletes group, the mean values of VO2 max was significantly different among three genotypes. That is to say, these three genetic polymorphisms may be the biomarkers to predict the elite endurance athlete status, but the mechanism needs to be studied in depth. [ABSTRACT FROM AUTHOR]

The effectiveness of physical exercise on fat loss and improvement of aerobic capacity varies considerably between individuals. A strong linkage exists between common allelic variants of the adrenergic receptor genes and weight gain, as well as changes in body composition. Therefore we aimed to check if body composition and metabolic variables were modulated by the ADRB2 (Gly16Arg and Glu27Gln), ADRB3 (Trp64Arg) and ADRA2A (rs553668 G/A) gene polymorphisms in 163 Polish sedentary women (age 19-24; body mass index (BMI) 21.7 ± 0.2 kg·m-2) involved in a 12-week aerobic training program. Only 74.8% of participants lost fat mass. On average, participants lost 5.8 (10.4)% of their relative fat mass with training (range: +28.3 to - 63.6%). The improvement of VO2max was significantly greater in women who could lose their fat mass compared to women who were unsuccessful in fat loss (4.5 (5.6)% vs. 1.5 (3.8)%; p = 0.0045). The carriers of a low number (0-3) of obesity-related risk alleles (ADRB2 Gly16, ADRB2 Glu27, ADRA2A rs553668 G) were more successful in fat mass loss compared to the carriers of a high number (5-6) of risk alleles (7.7 (9.8) vs 4.0 (9.4)%, p = 0.0362). The presented results support the assumption that variation within adrenergic receptor genes contributes to interindividual changes of body composition in response to physical exercise. [ABSTRACT FROM AUTHOR]