Cell Types Promoting Goosebumps Form a Niche to Regulate Hair Follicle Stem Cells.

Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual-component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by down-regulating the cell cycle and metabolism while up-regulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages and demonstrate sympathetic nerves can modulate stem cells through synapse-like connections and neurotransmitters to couple tissue production with demands.

Intrinsic ADRB2 inhibition improves CAR-T cell therapy efficacy against prostate cancer.

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 (shß2-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. shß2-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, shß2-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.

ADRB2 and ADCY9 Sequence Variations in Brazilian Asthmatic Patients.

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 ß2 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.

Ligand-independent function of ß2-adrenergic receptor affects IgE-mediated Ca2+ influx in mast cells.

BACKGROUND: 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 ß2-adrenergic receptor (Adrb2) on mast cells negatively regulates FcεRI signaling, as demonstrated by the inhibition of IgE/antigen (Ag)-induced activation by Adrb2 agonists. OBJECTIVE: Although ß2-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. METHODS: 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. RESULTS: 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. CONCLUSION: These results suggest that Adrb2 has a novel ligand-independent function, increasing Ca2+ entry in mast cells when stimulated with IgE/Ag.

Association between tissue stress reaction and ACE2/TMPRSS2 expression in endometria of reproductive aged women before and during Covid-19 pandemic.

BACKGROUND: A potential concern has been raised regarding fertility and reproductive outcome during the Covid-19 pandemic with growing stress and anxiety. However, information on the association between tissue stress reaction and expression profiles of SARS-CoV-2 viral entry proteins, ACE2 and TMPRSS2, in endometria collected from women before (pre-pandemic) and during the Covid-19 pandemic (in-pandemic) is unknown. We aim to investigate the relationship between the expression of stress-reactive proteins and of ACE2 and TMPRSS2 in endometria collected from women during these two different time frames. METHODS: We retrospectively retrieved tissue blocks of endometrial samples from 25 women in 2019 (pre-pandemic) and 25 women in 2020 (in-pandemic) who underwent hysterectomy for different gynecological indications. Immunohistochemical analysis was performed with endometrial tissue samples that were collected before and during the pandemic, using respective antibodies targeting ACE2/TMPRSS2, ADRB2 and NK1R (stress and anxiety receptor markers, respectively). The quantification of immunoreactive cells for each marker was calculated by the immunoreactive score (IRS) analysis. This retrospective cohort study was limited to small sample size. RESULTS: No significant differences in the IRS of ACE2 and TMPRSS2 were found between the endometria that were collected before and during the pandemic with a lack of correlation between ACE2 and TMPRSS2 expression in respective endometria (r = 0.11, pre-pandemic; r = 0.04, in-pandemic). The immunostaining levels of stress marker, ADRB2 were significantly higher in the endometria of in-pandemic group (p = 0.015) comparing to that of pre-pandemic group. Pearson's correlation coefficient analysis showed a significant correlation in the expression between ADRB2 and TMPRSS2 (r = 0.41, p = 0.042) in the endometria of in-pandemic group but not in the pre-pandemic group. CONCLUSION: The rise in stress and anxiety among women during current pandemic may elicit substantial amount of tissue stress reaction with consequent increase in the expression of SARS-CoV-2 viral entry proteins in their endometria. A lack of correlation between ACE2 and TMPRSS2 expression in endometria may reassure women in their reproductive age that they are not more susceptible to infection by SARS-CoV-2 and suggest that stressful women during this pandemic can safely decide to conceive naturally or by artificial reproductive technology.

Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling.

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 ß2-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.

Norepinephrine promotes triglyceride storage in macrophages via beta2-adrenergic receptor activation.

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.

Activation of ADRB2/PKA Signaling Pathway Facilitates Lipid Synthesis in Meibocytes, and Beta-Blocker Glaucoma Drug Impedes PKA-Induced Lipid Synthesis by Inhibiting ADRB2.

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.

Adrenergic signaling promotes the expansion of cancer stem-like cells of malignant peripheral nerve sheath tumors.

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.

ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta-analysis.

BACKGROUND: The polymorphism Arg16 in ß2 -adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting ß2 -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 ß2 -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.

A meta-analysis of the influence of ADRB2 genetic polymorphisms on albuterol (salbutamol) therapy in patients with asthma.

AIMS: The associations of 2 nonsynonymous single nucleotide polymorphisms (Arg16Gly and Gln27Glu) in the adrenoceptor ß2 (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.

Investigating changes in ß-adrenergic gene expression (ADRB1 and ADRB2) in Takotsubo (stress) cardiomyopathy syndrome; a pilot study.

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 ß-adrenergic signaling pathways; The gene expression level of cardiac ß-1 ADRB1 (rs1801253-ENST00000369295.4), G > C, (Gly389Arg) and cardiac ß-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.

The role of ADRB2 gene polymorphisms in malignancies.

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.

GPCR Pharmacological Profiling of Aaptamine from the Philippine Sponge Stylissa sp. Extends Its Therapeutic Potential for Noncommunicable Diseases.

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 ß-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 ß-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).

Association between ADRB2 regulatory region polymorphisms and susceptibility to childhood asthma. / ADRB2åŸºå› è°ƒæŽ§åŒºå¤šæ€æ€§ä¸Žå„¿ç«¥å“®å–˜æ˜“æ„Ÿæ€§çš„ç›¸å ³æ€§ç ”ç©¶.

OBJECTIVES: To study the association of ß2-drenergic receptor (ADRB2) regulatory region single nucleotides polymorphism (SNP)/haplotypes at rs11168070, rs17108803, rs2053044, rs12654778, rs11959427, and rs2895795 loci with childhood asthma. METHODS: A total of 143 children with asthma who attended the hospital from October 2016 to October 2020 were enrolled as the asthma group, among whom 61 children had mild symptoms (mild group) and 82 children had moderate-to-severe symptoms (moderate-to-severe group). A total of 137 healthy children were enrolled as the control group. Peripheral venous blood samples were collected from the two groups. The SNaPshot SNP technique was used to analyze the SNP and haplotypes of the ADRB2 regulatory region at rs11168070, rs17108803, rs2053044, rs12654778, rs11959427, and rs2895795 loci in all children. The asthma group and the control group were compared in terms of the association of ADRB2 regulatory region SNP and haplotypes at the above six loci with susceptibility to asthma and severity of asthma. RESULTS: Polymorphisms were observed in the ADRB2 regulation region at the above six loci in both the asthma group and the control group, with significant differences between the two groups in the distribution of genotype and allele frequencies at rs2895795 (-1429T /A), rs2053044(-1023G/A), and rs12654778 (-654G/A) loci (P<0.05). Linkage disequilibrium of SNP was observed at the six loci of the ADRB2 regulatory region.The haplotypes of TATGCT, TATGGC, and AGTGCT were associated with susceptibility to childhood asthma, among which TATGCT and TATGGC were risk factors for childhood asthma (OR=1.792 and 1.946 respectively, P<0.05), while AGTGCT was a protective factor (OR=0.523, P<0.05). CONCLUSIONS: SNP/haplotype of the ADRB2 regulatory region is associated with the susceptibility to childhood asthma. The haplotypes of TATGCT and TATGGC formed by such SNP/haplotype are risk factors for childhood asthma, while AGTGCT is a protective factor.

Repeated social defeat promotes persistent inflammatory changes in splenic myeloid cells; decreased expression of ß-arrestin-2 (ARRB2) and increased expression of interleukin-6 (IL-6).

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 ß2-adrenergic receptor (ADRB2) and ß-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.

[Study on mechanism of Tibetan medicine Zuomua Decoction in treatment of hypertension based on network pharmacology and molecular docking technology].

Hypertension is a kind of chronic cardiovascular system disease caused by a series of factors and carriers dysfunction, which belongs to the category of Tibetan medicine "Chalong disease", and has a high rate of disability and mortality. Zuomua Decoction is a classical Tibetan medicine for Chalong disease, but its mechanism is not clear. Therefore, in this paper we explored the multi-components, multi-targets and multi-channels mechanism of Zuomua Decoction in the treatment of hypertension based on network pharmacology and molecular docking technology. First of all, the chemical components of Zuomua Decoction were obtained in the retrieval of traditional Chinese medicine systems pharmacology database(TCMSP), China National Knowledge Infrastructure(CNKI) and Wanfang database. The potential targets of Zuomua Decoction were predicted by BATMAN-TCM database, and the targets of hypertension were obtained by using DisGeNET database. The intersection of these two targets set was taken to obtain the potential targets of Zuomua Decoction in the treatment of hypertension, and then the chemical compositions-targets network was constructed. Secondly, the intersection targets were imported into STRING database to obtain the interaction relationship of intersection targets, and the protein interaction network of Zuomua Decoction in the treatment of hypertension was constructed in Cytoscape. Topological, GO, and KEGG enrichment analysis were used to construct the key targets-signal pathways-biological processes network diagram and explore the mechanism of Zuomua Decoction in the treatment of hypertension. Finally, the key targets were selected to construct the pharmacodynamic identification models to verify the effect mode of Zomua Decoction in treating hypertension. The results showed that there were 61 chemical components and 90 potential targets in the compounds-targets network. We obtained 21 key targets, 154 signal pathways, and 382 biological processes in topological, GO, and KEGG enrichment analysis of the protein interaction network, and in the comprehensive analysis, it was found that Zuomua Decoction could reduce blood pressure by regulating renin angiotension aldosterone system, balancing the concentration of intracellular calcium and sodium ions and regulating vasoconstriction and relaxation. ACE, AGTR1, and ADRB2 were used as the carriers for molecular docking study on the components of Zuoma Decoction, and the results showed that the chemical components of Zuomua Decoction had a good binding activity with key targets. The purpose of this study is to provide ideas for the in-depth study of Zuoma Decoction in the treatment of hypertension, and provide scientific basis for its clinical rational application.

Association of ß2-adrenergic receptor gene polymorphisms (rs1042713, rs1042714, rs1042711) with asthma risk: a systematic review and updated meta-analysis.

BACKGROUND: The published data on the association between ß2-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.

Differential lipid metabolism outcomes associated with ADRB2 gene polymorphisms in response to two dietary interventions in overweight/obese subjects.

BACKGROUND AND AIMS: A precise nutrigenetic management of hypercholesterolemia involves the understanding of the interactions between the individual's genotype and dietary intake. The aim of this study was to analyze the response to two dietary energy-restricted interventions on cholesterol changes in carriers of two ADRB2 polymorphisms. METHODS AND RESULTS: A 4-month nutritional intervention was conducted involving two different hypo-energetic diets based on low-fat (LF) and moderately high-protein (MHP) dietary patterns. A total of 107 unrelated overweight/obese individuals were genotyped for two ADRB2 non-synonymous polymorphisms: Arg16Gly (rs1042713) and Gln27Glu (rs1042714). Genotyping was performed by next-generation sequencing and haplotypes were phenotypically screened. Anthropometric measurements and the biochemical profile were assessed by conventional methods. Both diets induced cholesterol decreases at the end of both nutritional interventions. Interestingly, phenotypical differences were observed according to the Arg16Gly polymorphism. Within the MHP group, Gly16Gly homozygotes had lower reductions in total cholesterol (-6.5 mg/dL vs. -24.2 mg/dL, p = 0.009), LDL-c levels (-1.4 mg/dL vs. -16.5 mg/dL, p = 0.005), and non-HDL-c (-4.5 mg/dL vs. -21.5 mg/dL, p = 0.008) than Arg16 allele carriers. Conversely, within the LF group, Gly16Gly homozygotes underwent similar falls in total cholesterol (-18.5 mg/dL vs. -18.7 mg/dL, ns), LDL-c levels (-9.7 mg/dL vs. -13.1 mg/dL, ns), and non-HDL-c (-15.3 mg/dL vs. -15.7 mg/dL, ns) than Arg16 allele carriers. The Gln27Glu polymorphism and the Gly16/Glu27 haplotype showed similar, but not greater effects. CONCLUSIONS: An energy-restricted LF diet could be more beneficial than a MHP diet to reduce serum cholesterol, LDL-c, and non-HDL-c among Gly16Gly genotype carriers. CLINICALTRIALS.GOV: Identifier: NCT02737267.

The correlation between SNPs within the gene of adrenergic receptor and neuropeptide Y and risk of cervical vertigo.

BACKGROUND: The current investigation was aimed to explore the potential associations of SNPs within ADRB2, ADRB1, NPY, and ADRA1A with risk and prognosis of cervical vertigo. METHODS: Altogether 216 patients with cervical vertigo and 204 healthy controls were gathered, and their DNAs were extracted utilizing the whole-blood DNA extraction kit. Besides, the PCR reactions were conducted using the TaqManR single nucleotide polymorphism (SNP) genotyping assays, and the SNPs were detected on the 7900HT real-time fluorogenic quantitative polymerase chain reaction (PCR) instrument. Finally, the severity of cervical vertigo was classified according to the JOA scoring, and the recovery rate (RR) of cervical vertigo was calculated in light of the formula as: [Formula: see text] RESULTS: The SNPs within ADRA1A [rs1048101 (T>C) and rs3802241 (C>T)], NPY [rs16476 (A>C), rs16148 (T>C), and rs5574 (C>T)], ADRB1 [rs28365031 (A>G)] and ADRB2 [rs2053044 (A>G)] were all significantly associated with regulated risk of cervical vertigo (all P < .05). Haplotypes of ADRA1A [CT and TC] and NPY [CCT and ATT] were also suggested as the susceptible factors of cervical vertigo in comparison with other haplotypes. Furthermore, the SNPs within ADRA1A [rs1048101 (T>C)], NPY [rs16476 (A>C), rs16148 (T>C)], as well as ADRB1 [rs28365031 (A>G)] all appeared to predict the prognosis of cervical vertigo in a relatively accurate way (all P < .05). Ultimately, the haplotypes of ADRA1A (CC) and NPY (CCT) tended to decrease the RR. CONCLUSIONS: The SNPs within ADRB2, ADRB1, NPY, and ADRA1A might act as the diagnostic biomarkers and treatment targets for cervical vertigo.