β-arrestin2 recruitment by β-adrenergic receptor agonists and antagonists / 生理学报

A large number of β-adrenergic receptor (β-AR) agonists and antagonists are widely used in the treatment of cardiovascular diseases and other diseases. Nonetheless, it remains unclear whether these commonly used β-AR drugs can activate downstream β- arrestin-biased signaling pathways. The objective of this study was to investigate β-arrestin2 recruitment effects of β-AR agonists and antagonists that were commonly used in clinical practice. We used TANGO (transcriptional activation following arrestin translocation) assay to detect the β-arrestin2 recruitment by β-AR ligands in HEK293 cell line (HTLA cells) stably transfected with tetracycline transactivator protein (tTA) dependent luciferase reporter and β-arrestin2-TEV fusion gene. Upon activation of β-AR by a β-AR ligand, β-arrestin2 was recruited to the C terminus of the receptor, followed by cleavage of the G protein-coupled receptors (GPCRs) fusion protein at the TEV protease-cleavage site. The cleavage resulted in the release of tTA, which, after being transported to the nucleus, activated transcription of the luciferase reporter gene. The results showed that β-AR non-selective agonists epinephrine, noradrenaline and isoprenaline all promoted β-arrestin2 recruitment at β1-AR and β2-AR. β1-AR selective agonists dobutamine and denopamine both promoted β-arrestin2 recruitment at β1-AR. β2-AR selective agonists procaterol and salbutamol promoted β-arrestin2 recruitment at β2-AR. β-AR non-selective antagonists alprenolol and pindolol promoted β-arrestin2 recruitment at β1-AR. β1-AR selective antagonists celiprolol and bevantolol showed β-arrestin2 recruitment at β1-AR. β2-AR selective antagonists butoxamine showed β-arrestin2 recruitment at β1-AR. These results provide some clues for the potential action of β-AR drugs, and lay a foundation for the screening of β-arrestin-biased β-AR ligands.

Association between beta-2 adrenergic receptor variants and clinical outcomes in children and adolescents with acute asthma

ABSTRACT Objective To investigate whether different genotypes of p.Arg16Gly, p.Gln27Glu, p.Arg19Cys and p.Thr164Ile variants interfere in response to treatment in children and adolescents with moderate to severe acute asthma. Methods This sample comprised patients aged 2 to 17 years with a history of at least two wheezing episodes and current moderate to severe asthma exacerbation. All patients received multiple doses of albuterol and ipratropium bromide delivered via pressurized metered-dose inhaler with holding chamber and systemic corticosteroids. Hospital admission was defined as the primary outcome. Secondary outcomes were changes in forced expiratory volume in the first second after 1 hour of treatment, and for outpatients, length of stay in the emergency room. Variants were genotyped by sequencing. Results A total of 60 patients were evaluated. Hospital admission rates were significantly higher in carriers of the genotype AA relative to those with genotype AG or GG, within the p.Arg16Gly variant (p=0.03, test χ2, alpha=0.05). Secondary outcomes did not differ between genotypes. Conclusion Hospital admission rates were significantly higher among carriers of the genotype AA within the p.Arg16Gly variant. Trial registration: ClinicalTrials.gov: NCT01323010

Association between / 中国当代儿科杂志

OBJECTIVES@#To study the association of β2-drenergic receptor (@*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 @*RESULTS@#Polymorphisms were observed in the @*CONCLUSIONS@#SNP/haplotype of the

Tyrosine hydroxylase and ß2-adrenergic receptor expression in leukocytes of spontaneously hypertensive rats: putative peripheral markers of central sympathetic activity

The sympathetic nervous system (SNS) plays a fundamental role in the pathophysiology of cardiovascular diseases, including primary arterial hypertension. In this study, we aimed to investigate whether the expression of the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and the β2-adrenergic receptor (β2-AR) in immune cells from peripheral blood, reflect central SNS activity in spontaneously hypertensive rats (SHR). TH expression in the lower brainstem and adrenal glands and β2-AR expression in the lower brainstem were analyzed by western blot analyses. In the leukocytes, TH and β2-AR expression was evaluated by flow cytometry before and after chronic treatment with the centrally-acting sympathoinhibitory drug clonidine. Western blot analyses showed increased TH and β2-AR expression in the lower brainstem and increased TH in adrenal glands from SHR compared to normotensive Wistar Kyoto rats (WKY). Lower brainstem from SHR treated with clonidine presented reduced TH and β2-AR levels, and adrenal glands had decreased TH expression compared to SHR treated with vehicle. Flow cytometry showed that the percentage of leukocytes that express β2-AR is higher in SHR than in WKY. However, the percentage of leukocytes that expressed TH was higher in WKY than in SHR. Moreover, chronic treatment with clonidine normalized the levels of TH and β2-AR in leukocytes from SHR to similar levels of those of WKY. Our study demonstrated that the percentage of leukocytes expressing TH and β2-AR was altered in arterial hypertension and can be modulated by central sympathetic inhibition with clonidine treatment.

Beta-adrenergic pathway activation in head and neck cancer: a comprehensive analysis of the clinical and genomic features using integrated bioinformatics / Ativação da via beta-adrenérgica no câncer de cabeça e pescoço: uma análise abrangente das características clínicas e gênomicas utilizando a bioinformática

O estresse crônico leva à ativação da via de sinalização beta-adrenérgica. Sua ativação tem sido implicada na progressão de diferentes tipos de câncer, mas seu papel nos carcinomas espinocelulares de cabeça e pescoço (CECPs) permanece indefinido. O objetivo deste estudo foi investigar o papel da ativação da via betaadrenérgica na progressão dos CECPs, avaliar seu impacto na sobrevida dos pacientes e buscar possíveis terapias para pacientes que encontravam-se com a via beta-adrenérgica ativa. Quinhentos e vinte pacientes do The Cancer Genome Atlas com CECPs primários foram divididos em dois grupos: ADRB2baixa / SLC6A2baixa e ADRB2alta / SLC6A2alta. A associação de características clinicopatológicas e genômicas entre os grupos foram analisadas utilizando bioinformática. Os genes diferencialmente expressos (DEGs) foram identificados através da análise da expressão diferencial. A análise de sobrevida também foi realizada com base nas expressões ADRB2 e SLC6A2. Foram identificados medicamentos em potencial para tratamento de CECPs com base nos DEGs. Houve associação entre as expressões ADRB2 e SLC6A2 com idade, raça, localização do tumor, grau histológico, invasão perineural e status do HPV p16. Foram identificados 898 DEGs entre os grupos. Foi demonstrado que a expressão ADRB2alta / SLC6A2alta influenciou a proliferação, adesão e invasão de células CECPs além da angiogênese. Pacientes com carcinomas espinocelular de laringe e faringe apresentando expressão ADRB2alta / SLC6A2alta tiveram menor sobrevida. Por fim, 56 drogas antineoplásicas e imunoterápicas aprovadas pelo Food Drugs Administration foram identificadas como potenciais alvos para o tratamento personalizado. Significância: Estes achados sugerem fortemente um papel proeminente da sinalização beta-adrenérgica no CECPs ao estimular um fenótipo tumoral mais agressivo. Estas alterações tiveram um impacto negativo no prognóstico dos pacientes com CECP em região de faringe e laringe(AU)

Chronic stress leads to the activation of the beta-adrenergic pathway. Its activation has been implicated in the progression of different types of cancer but its role on head and neck squamous cell carcinomas (HNSCCs) remains undefined. The aim of this study was to investigate the influence of the beta-adrenergic pathway activation in the progression of HNSCCs, assess its impact in the survival of the patients, and explore the potential targets. Five hundred and twenty The Cancer Genome Altas patients with primary HNSCCs were divided in two groups: ADRB2low / SLC6A2low and ADRB2high / SLC6A2high. The association of clinicopathological and genomic features between the groups was analyzed using a bioinformatic approach. Differentially expressed genes (DEGs) were identified through differential expression analysis. Survival analysis was also performed based on ADRB2 and SLC6A2 expressions. Potential drugs for treatment of HNSCC were identified based on the DEGs. There was association between ADRB2 and SLC6A2 expressions with age, race, tumor site, histologic grade, perineural invasion, and HPV p16 status. It was identified 898 DEGs between the groups. It was demonstrated that ADRB2high / SLC6A2high expression influenced HNSCC cells proliferation, adhesion, invasion, and angiogenesis. Patients with larynx and pharynx squamous cell carcinomas presenting ADRB2high / SLC6A2high expression showed had lower survival rates. Finally, 56 Food Drugs Administration-approved antineoplastic and immunotherapeutic drugs were identified as potential targets for the personalized treatment. Significance: These findings strongly suggest a prominent role of beta-adrenergic pathway in HNSCC by stimulating a more aggressive tumoral phenotype. These alterations were shown to negatively impact the prognosis of patients with larynx and pharynx squamous cell carcinomas(AU)

Protective effect of dexmedetomidine against organ dysfunction in a two-hit model of hemorrhage/resuscitation and endotoxemia in rats

Dexmedetomidine (DEX), a selective agonist of α2-adrenergic receptors, has anti-inflammation properties and potential beneficial effects against trauma, shock, or infection. Therefore, this study aimed to investigate whether DEX might protect against multiple-organ dysfunction in a two-hit model of hemorrhage/resuscitation (HS) and subsequent endotoxemia. Eighty Wistar rats were randomized into four groups: NS (normal saline), HS/L (HS plus lipopolysaccharide), HS/L+D (HS/L plus dexmedetomidine), and HS/L+D+Y (HS/L+D plus yohimbine). Six hours after resuscitation, blood gas (PaO2) and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urine nitrogen (BUN), creatinine (Cr), TNF-α, IL-β, IL-6, IL-8, IL-10, and nitric oxide (NO) were measured. The histopathology was assayed by staining. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels and heme oxygenase-1 (HO-1) were assayed. The PaO2 levels in HS/L rats were lower whereas the ALT, AST, BUN, Cr, TNF-α, IL-β, IL-6, IL-8, IL-10, and NO levels were higher compared to the control group. The HS/L+D increased PaO2 and further increased IL-10 and decreased ALT, AST, BUN, Cr, TNF-α, IL-β, IL-6, IL-8, and NO levels of the HS/L groups. In addition, the MDA in the HS/L groups increased whereas SOD activity decreased compared to the control group. Moreover, the HO-1 expression levels were increased by DEX administration in lung, liver, and kidney tissues. Lungs, livers, and kidneys of the HS/L group displayed significant damage, but such damage was attenuated in the HS/L+D group. All of the above-mentioned effects of DEX were partly reversed by yohimbine. DEX reduced multiple organ injury caused by HS/L in rats, which may be mediated, at least in part, by α2-adrenergic receptors.

ADRB2 Gene Knockout in Human Primary T Cells by Multiple sgRNAs Construced using CRISPR/Cas9 Technology / 中国实验血液学杂志

OBJECTIVE@#To knockout ADRB2 gene rapidly and efficiently in human primary T cells by using CRISPR/Cas9 technology and multiple sgRNAs strategy.@*METHODS@#Six paired-sgRNAs, which were designed to target the 5' constitutive coding exons of ADRB2 gene, were cloned into pGL3-U6-sgRNA-PGK-Puro vector separately. The expre-ssion vectors containing the single sgRNAs were constructed and transiently co-transfected into HEK-293T cell line with Cas9 expression vector. The sgRNA-mediated cleavage efficiency was tested by T7EN I digestion assay. Concatenating four highly efficient paired sgRNAs were cloned into pGL3-U6-sgRNA-ccdB-EF1α-Puro expression vector. The reco-mbinant plasmid allows the cells to express 4 sgRNAs, which target different sites on the ADRB2 genomic locus. The cleavage efficiency and mutation model were tested by T7EN I digest assay and T-A cloning technique. Multiple sgRNAs plasmid and Cas9 plasmid was transiently transferred into human primary T cells by electroporation. Flow cytometry (FCM) was used to detect the knockout efficiency of β2 adrenergic receptor (β2-AR).@*RESULTS@#The results of T7EN I digestion and TA cloning sequencing showed that the multiple sgRNAs strategy could obtain more abundant mutation types and higher gene editing efficiency than single sgRNA. In addition to the deletion and insertion of bases, large fragment DNA deletions and inversions could be observed. All of the random 10 TA clones for detection were genetically modified, thus the mutation efficiency was as high as 100%. FCM assay showed that 43.09% of the cells in the control T cells were β2-AR positive, but the proportion of β2-AR positive cells in the multiple sgRNAs electrotransformed T cells decreased to 25.61%.@*CONCLUSION@#A method, which is simple and operable, for knocking out β2-AR in human primary T cells has been established preliminarily. The results are helpful for the further study of the role of β2-AR in human T cells.

Role of long non-coding RNA BC088414 in hypoxic-ischemic injury of neural cells / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the role of long non-coding RNA (lncRNA) BC088414 in hypoxic-ischemic injury of neural cells.</p><p><b>METHODS</b>Rat adrenal pheochromocytoma (PC12) cells were divided into four groups: normoxic, oxygen glucose deprivation (OGD), siRNA-normoxic (siRNA group) and siRNA-OGD (n=3 each). Cells were incubated in glucose-free and serum-free DMEM medium under the conditions of 37℃ and 1% O2+99% N2/CO2 for 6 hours to establish an in vitro hypoxic-ischemic model. Quantitative real-time PCR was used to measure mRNA expression of lncRNA BC088414, β2-adrenoceptor (Adrb2), and caspase-6 (CASP6). siRNAs were used to inhibit BC088414 expression in PC12 cells. The TUNEL method was used to measure cell apoptosis.</p><p><b>RESULTS</b>The OGD group had a significantly higher cell apoptotic index than the normoxic group (P<0.01). After inhibition of BC088414 expression, the OGD group had a significantly reduced apoptotic index (P<0.05). The OGD group had significantly higher mRNA expression levels of lncRNA BC088414, Adrb2, and CASP6 compared with the normoxic group (P<0.05). The siRNA -normoxic group had significantly lower mRNA expression levels of Adrb2 and CASP6 than the normoxic group (P<0.05), and the siRNA-OGD group also had significantly lower mRNA expression levels of Adrb2 and CASP6 than the OGD group (P<0.05).</p><p><b>CONCLUSIONS</b>LncRNA BC088414 may promote apoptosis through Adrb2 and CASP6 and aggravate neural cell injury induced by hypoxia-ischemia.</p>

Association between Beta Adrenergic Receptor Polymorphism and Ischemic Stroke: A Meta-Analysis / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: The purpose of this meta-analysis was to determine the precise association between beta-2 adrenergic receptor (beta2AR) polymorphism and Ischemic stroke. METHODS: Published case control studies on association between beta2AR and ischemic stroke were searched from electronic databases. Pooled Odds ratio and 95% Confidence interval were calculated by using software RevMan version 5.2. RESULTS: A total of three studies involving 1,642 cases and 1,673 controls, which were published from 2007 to 2014, were subjected to meta-analysis for allelic association and 518 cases and 510 controls for genotypic association. Pooled analysis of two studies for genotypic association suggested that subjects carrying Gln27Glu polymorphism of beta2AR had an increased risk for Ischemic stroke under recessive model (OR 2.09; 95% CI; 1.20 to 3.64) and under dominant model (OR 1.47; 95% CI 1.14 to 1.90). Pooled analysis of three studies for allelic association showed a significantly higher Glu27 allele of beta2AR in the patients with ischemic stroke (OR 1.58; 95% CI; 1.38 to 1.81). CONCLUSIONS: The present meta-analysis suggests that Gln27Glu polymorphism of beta2AR gene is associated with increased risk for ischemic stroke.

Genetic polymorphisms and asthma: findings from a case - control study in the Madeira island population

BACKGROUND: Asthma is a complex disease influenced by multiple genetic and environmental factors. While Madeira has the highest prevalence of asthma in Portugal (14.6%), the effect of both genetic and environmental factors in this population has never been assessed. We categorized 98 asthma patients according to the Global Initiative for Asthma (GINA) guidelines, established their sensitization profile, and measured their forced expiratory volume in 1second (FEV1) and forced vital capacity (FVC) indexes. Selected single nucleotide polymorphisms (SNPs) were analysed as potential markers for asthma susceptibility and severity in the interleukin 4 (IL4), interleukin 13 (IL13), beta-2-adrenergic receptor (ADRB2), a disintegrin and metalloprotease 33 (ADAM33), gasdermin-like (GSDML) and the signal transducer and activator of transcription 6 (STAT6) genes comparatively to a population reference set. RESULTS: Although mites are the major source of allergic sensitization, no significant difference was found amongst asthma severity categories. IL4-590*CT/TT and IL4-RP2*253183/183183 were found to predict the risk (2-fold) and severity (3 to 4-fold) of asthma and were associated with a lower FEV1 index. ADRB2-c.16*AG is a risk factor (3.5-fold), while genotype GSDML-236*TT was protective (4-fold) for moderate-severe asthma. ADAM33-V4*C was associated to asthma and mild asthma by the transmission disequilibrium test (TDT). Finally, ADAM33-V4*CC and STAT6-21*TT were associated with higher sensitization (mean wheal size ≥10mm) to house dust (1.4-fold) and storage mite (7.8-fold). CONCLUSION: In Madeira, IL4-590C/T, IL4-RP2 253/183, GSDML-236C/T and ADAM33-V4C/G SNPs are important risk factors for asthma susceptibility and severity, with implications for asthma healthcare management.

The expression and significance of beta2-AR and VEGFR-2 in infantile hemangioma / 中华整形外科杂志

<p><b>OBJECTIVE</b>To investigate the significance of beta-adrenergic receptor 2 (beta2-AR) and vascular endothelial growth factor-2 (VEGFR-2) in the occurrence and development of infantile hemangioma through detecting the expression of beta2-AR and VEGFR-2 in the different stages of infantile hemangiomas.</p><p><b>METHODS</b>According to the Mulliken's classification standard, we classified the specimens as proliferating group (32 cases), involuting group (17 cases) and involuted group (11 cases). Normal skin tissue surrounding the hemangioma from 7 cases were chosen as control group. The expression of beta2-AR and VEGFR-2 was detected by immunohistochemical technique in proliferating hemangioma, involuting hemangioma, involuted hemangioma. The mean optical density was measured by image analysis system (Image Pro Plus 6.0) and SPSS 16.0 software was applied for statistical analysis.</p><p><b>RESULTS</b>The expression of beta2-AR and VEGFR-2 was strongly positive in proliferating hemangioma, while positive in involuting hemangioma and weakly positive in the involuted stage. The mean optical density of each phase was 0.064 751 2 +/- 0.012 747, 0.031 6017 +/- 0.006 848,0.011 869 8 +/- 0.039 349 for beta2-AR, and 0.068 940 9 +/- 0.029 274, 0.028 445 5 +/- 0.006 396, 0.011 184 1 +/- 0.004 198 for VEGFR-2. The differences between different stages had a statistically significance (P < 0.05). Correlation analysis on the mean optical density between beta2-AR and VEGFR-2 had a statistically significance (P < 0. 05).</p><p><b>CONCLUSIONS</b>Beta2-AR and VEGFR-2 may be involved in the occurrence and development of infantile hemangioma.</p>

Association of β-adrenergic receptor genes polymorphisms with incidence of subsequent cardiovascular events in Han Chinese patients with coronary artery disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Sequence variants in the β-adrenergic receptor (ADRB) genes have a close relationship with the development of coronary artery disease (CAD) and the patient's prognosis. However, there is a lack of data on the role of the variants in ADRBs genes in Han Chinese patients with CAD. We aimed to investigate the association of genetic variants in the ADRB1 and ADRB2 genes with the incidence of major adverse cardiac event (MACE) in Han Chinese patients with CAD.</p><p><b>METHODS</b>A total of 545 Han Chinese patients with CAD undergoing percutaneous coronary intervention (PCI) were recruited to the study and followed for one year. Three variant sites in ADRB1 (rs1801253) and ADRB2 (rs1042713 and rs1042714) were genotyped. The effect of the ADRB1 and ADRB2 genotypes on MACE within one year was assessed.</p><p><b>RESULTS</b>There were 47 cases of MACE during follow-up. There was no significant difference in the incidence of MACE among patients carrying different genotypes of the three variants in ADRB1 and ADRB2 (Log-rank, all P > 0.05). Cox regression analysis showed no association between three variants in ADRB1 and ADRB2 genes and the incidence of MACE during one-year follow-up, the adjusted hazard ratios (95% confidence interval) for rs1801253, rs1042713 and rs1042714 were 1.05 (0.54-2.02), 1.24 (0.58-2.64) and 1.66 (0.81-3.42), respectively.</p><p><b>CONCLUSION</b>Our data did not support a relationship between the three polymorphisms of ADRB1 (rs1801253) and ADRB2 (rs1042713 and rs1042714) genes and risk of subsequent cardiovascular events after PCI in Han Chinese patients with CAD.</p>

effects of isoproterenol and propranolol on cytokine profile secretion by cultured tumor-infiltrating lymphocytes derived from colorectal cancer patients

Anti-tumor immunity and cytokine profiles have important roles in the development of cancer. Norepinephrine [NE] release due to sympathetic activation leads to a Th2 deviation via the beta-2 adrenergic receptor [beta -2AR] and could increase cancer progression. This study intends to determine the effects of isoproterenol [ISO; betaagonist] and propranolol [PRO; beta-antagonist] on the production of IFN-gamma, IL-4, and IL-17. Cytokine levels have been examined in tumor-infiltrating lymphocytes [TILs] and peripheral blood mononuclear cells [PBMCs] of patients with colorectal cancer [CRC]. The beta-2AR expression on lymphocyte subsets was also assessed. In this experimental study, TILs were isolated from fresh CRC tissue and patient PBMCs were obtained just prior to surgery. The cells were cultured in medium for 72 hours. Concomitantly, cells were stimulated with 10 micro g/ ml phytohemagglutinin [PHA] alone or in the presence of either 1 micro mol/L of PRO or 1 micro mol/L ISO. The concentration of cytokines in the supernatants was measured by ELISA. Three-color flow cytometry was used to determine the expression of beta-2AR on the lymphocyte subsets. Statistical analyses were performed via paired or independent t-test. Levels of IFN-gamma, IL-4 and IL-17 were elevated after PHA-stimulation of PBMCs and TILs. However, the elevation of IFN-gamma and IL-17 production by TILs in response to PHA was significantly lower than PBMCs. In the presence of ISO, the IFN-gamma/IL-4 ratio reduced in all groups, but this reduction was very low in TILs. Interestingly, the effects of PRO on cytokine production were, at least partially, comparable to those of ISO. Depressed levels of beta-2AR expression were demonstrated on CD4+IFN-gamma+ and CD4+IL-17+ lymphocytes in patients' PBMCs and TILs. This study has demonstrated the effects of ISO and PRO on cytokine production by TILs and determined beta-2AR expression on these cells. ISO failed to induce a shift toward the expected Th2 cytokine profile in CRC patients' TILs, which might be due to the downregulation of beta-2AR expression on TILs. Additionally, in this study, PRO induced a shift to a Th2 profile in PBMCs

Effect of polymorphisms in the β2-adrenergic receptor on the susceptibility and pulmonary function of patients with chronic obstructive pulmonary disease: a meta analysis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Chronic obstructive pulmonary disease (COPD) is a heterogeneous and complex disease of which the pathogenesis remains largely unknown. Many factors could influence COPD development and progression. One of them is the genetic risk factor. A severe hereditary deficiency of alpha-1 antitrypsin is the best genetic proof. Four single nucleotide polymorphisms (SNPs) of beta2-adrenergic receptor (β(2)AR) result in single amino acid substitution. Two loci had been extensively studied and found that they could change the function of β(2)AR. Two SNPs consist of substitutions of glycine for arginine at amino acid position 16, glutamic acid for glutamine at position 27. Many studies proved that polymorphisms at position 16 and 27 altered the lung function of COPD patients or the patient's susceptibility to the development of COPD. However, there was no exclusive conclusion. Therefore, a meta analysis was done to investigate the effect of polymorphisms in the β2-adrenergic receptor (ADRB2) gene on the risk of COPD and lung function.</p><p><b>METHODS</b>Comprehensive searches of MEDLINE, Embase, Ovid, HighWire, Cochrane Library, and Chinese databases (CBMdisc, VIP, CNKI, and Wanfang data) from January 1980 to September 2011 were performed, using the keywords: COPD OR chronic obstructive pulmonary disease AND adrenoreceptor OR adrenergic receptor AND polymorphism OR mutation OR variation. Case-control research or cross sectional studies in which diagnosis of COPD met the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines; all the studies reported the ADRB2 genotype at position 16 or 27. Outcomes measured were genotype frequency and forced expiratory volume in the first second (FEV(1)%) in both the case and control.</p><p><b>RESULTS</b>Twelve case-control studies and eight cross-sectional studies were included. Compared to the control (n = 1225), neither Gly/Gly (n = 527) nor Arg/Arg (n = 422) homozygotes at position 16 demonstrated increased susceptibility to COPD, with odds ratios (ORs) of 0.95 (95%CI (0.68, 1.31), z = 0.33, P = 0.740) and 0.82 (95%CI (0.52, 1.28), z = 0.88, P = 0.381), respectively. Similar results were obtained for position 27, with ORs of 0.97 (95%CI (0.77, 1.23), z = 0.21, P = 0.833) for Glu/Glu homozygotes (n = 357) and 0.82 (95%CI (0.53, 1.29), z = 0.85, P = 0.393) for Gln/Gln homozygotes (n = 704) (control = 1183). In patients with COPD, Arg/Arg homozygotes (n = 41) had a similar FEV1% compared with Gly/Gly homozygotes (n = 102) (standardized mean difference (SMD) = 0.88, 95%CI (-0.85, 2.62), z = 1.00, P = 0.319). The genotype distribution was different between Caucasian and Asian populations (all P < 0.05 except the genotype Arg/Gly) for both position 16 and 27.</p><p><b>CONCLUSIONS</b>Polymorphisms of ADRB2 at positions 16 and 27 did not change the risk of COPD nor affect lung function or disease severity. The genotype distribution for these polymorphisms was different between Caucasian and Asian populations.</p>

Role of β2-adrenoceptor-β-arrestin2-nuclear factor-κB signal transduction pathway and intervention effects of oxymatrine in ulcerative colitis / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate the β2-adrenoceptor (β2AR)-β-arrestin2-nuclear factor-κB (NF-κB) signal transduction pathway and the intervention effects of oxymatrine in a rat model of ulcerative colitis.</p><p><b>METHODS</b>Forty SD rats were randomly divided into four groups, which included the normal control group, the model group, the mesalazine group and the oxymatrine treatment group, with 10 rats per group. Experimental colitis induced with trinitrobenzene sulfonic acid (TNBS) was established in each group except the normal control group. The rats in the oxymatrine treatment group were treated with intramuscular injection of oxymatrine 63 mg/(kg·d) for 15 days and the rats in the mesalazine group were treated with mesalazine solution 0.5 g/(kg·d) by gastric lavage for 15 days. The rats in the normal control group and model group were treated with 3 mL water by gastric lavage for 15 days. Diarrhea and bloody stool were carefully observed. Histological changes in colonic tissue were examined on day 7 in 2 rats per group that were randomly selected. The expression of β2AR, β-arrestin2 and NF-κB p65 in colon tissue and spleen lymphocytes were detected with immunohistochemistry and Western immunoblotting techniques on day 16 after fasting for 24 h. Six rats died of lavage with 2 each in the normal control, the model group and the mesalazine group; and were not included in the analysis.</p><p><b>RESULTS</b>The rats in the model group suffered from looser stool and bloody purulent stool after modeling. But in the oxymatrine and mesalazine groups, looser stool and bloody purulent stool reduced after treatment. And the colonic wall in the model group was thickened and the colon length shortened. The colon mucosa was congested in multiple areas with edema, erosion, superficial or linear ulcer and scar formation, while the intestinal mucosa injury reduced in the mesalazine and oxymatrine groups (P<0.01). In colonic mucosa and in spleen lymphocytes, compared with the normal control group, the expression of NF-κBp65 were significantly increased (P<0.01) in the model group while the expressions of β 2AR and β-arrestin2 were significantly decreased (P<0.01). Compared with the model group, the expression of NF-κ Bp65 was significantly decreased in the mesalazine group (P<0.01) and oxymatrine treatment group (P<0.01) while the expressions of β2AR and β-arrestin2 were significantly increased (P<0.01). There were no statistically significant differences in the expression of β2AR, β-arrestin2 and NF-κBp65 between the mesalazine group and oxymatrine group (P>0.05).</p><p><b>CONCLUSIONS</b>The β2AR-β-arrestin2-NF-κB signal transduction pathway participated in the pathologic course of ulcerative colitis. Oxymatrine attenuated ulcerative colitis through regulating the β2AR-β-arrestin2-NF-κB signal transduction pathway.</p>

Study of genetic susceptibility in 198 children with asthma / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To analyze the frequency distribution of single nucleotide polymorphisms (SNPs) of four asthma-related gene loci (ACE I/D; ADRB2 Arg16Gly; TNF-α G-308A; MS4A2 Glu237Gly) in 198 asthmatic children, and to investigate its association with genetic susceptibility to childhood asthma and some clinical phenotypes of asthma.</p><p><b>METHODS</b>Polymerase chain reaction product electrophoresis identification and real-time quantitative PCR detecting system were used to determine the frequency distributions of the SNPs of the four asthma-related gene loci in 198 asthmatic children and 110 healthy controls. The serum total IgE (TIgE) levels and blood eosinophil proportion (%EOS) of the asthmatic children were measured. Different genotypes at the four asthma-related gene loci were compared in terms of TIgE and %EOS.</p><p><b>RESULTS</b>The genotype DD of angiotensin-converting enzyme (ACE) had a significantly higher frequency in the asthmatic children than in the healthy controls (χ2= 30.667, P<0.01), and the frequency of D allele was also significantly higher in the asthmatic children than in the healthy controls (χ2=7.151, P<0.01). No correlation was found between the polymorphism of each gene locus and serum TIgE level and %EOS (P>0.05).</p><p><b>CONCLUSIONS</b>Genotype DD of ACE is related to genetic susceptibility to childhood asthma and may be the risk factor for childhood asthma.</p>

Association between Major Single Nucleotide Polymorphism and Haplotype of the ADRB2 Gene and Korean Children with Asthma / 소아알레르기및호흡기학회지

PURPOSE: Development of asthma involves the interaction between genetic factors and environmental stimuli. This study aims to investigate whether major single nucleotide polymorphism (SNP)s and their haplotypes of the ADRB2 (beta2-adrenoceptor) gene are associated with children with asthma in Korea. METHODS: Children with asthma aging 5 to 15 years old were recruited as the patient group, and children without respiratory diseases or asthma of the same age were recruited as the control group. Blood samples of 5 mL were collected and DNA was extracted by standard methods. Genotyping was done for 6 SNPs known to have a frequency of more than 4%, including 1309A>G, 1342C>G, 1515G>A, 1786C>A, 2316G>C, 2502G>A. RESULTS: Overall, 438 subjects (214 patients and 224 controls) were included in this study. Minor allele homozygote frequency of 6 SNP were 22%, 1.8%, 11%, 12.3%, 21.2% and 13.0%, respectively. Differences between both groups of individual SNP frequencies were not statistically significant, although the difference of the frequency of the second SNP (1342C>G) has borderline significance (P=0.06). Overall distributions of haplotypes were not significantly different between both groups. However, analysis of specific SNPs among haplotypes revealed that haplotypes including the 2nd SNP were significantly associated with asthma (odds ratio, 1.7; 95% confidence interval, 1.1 to 2.6). Combinations of haplotypes excluding the 2nd SNP did not show significant difference between both groups. CONCLUSION: This study suggests that the ADRB2 gene polymorphism is associated with susceptibility to childhood asthma and that analysis of haplotypes rather than SNPs is more reliable in this association.

The study of beta2-adrenergic receptor gene polymorphism in Sanda athletes / 生物医学工程学杂志

This study observed the disposition of beta2-adrenergic receptor (beta2-AR) Arg16Gly genotype and allele frequency among Sanda athletes in China, and investigated the diversity about the single nucleotide polymorphism of beta2-AR Arg16Gly between Sanda athletes and normal people of Han nationality in China. We used the technique of allele specified primer polymerase chain reaction to detect ADRB2 gene polymorphism of Sanda athletes (61 subjects) and normal Han nation people (50 subjects). The results showed there were significant differences about AA genotype, A allele, and G allele between Sanda athletes group and normal Han nation group (AA: chi2 = 6.646, P = 0.01, P < 0.05; A: chi2 = 4.003, P = 0.045, P < 0.05; G: chi2 = 4.003, P = 0.045, P < 0.05), and the frequency of AA genotype and A allele in the group of normal Han nation was higher than that in the group of Sanda athletes.

Association of beta[2] -adrenergic receptor gene polymorphisms and nocturnal asthma in Saudi patients

Two polymorphisms of beta[2]-adrenergic receptor [beta[2]-AR] gene, namely the substation from arginine [Arg] to [Gly] at codon 16 and from glutamine [Gln] to glutamic [Glu] at codon 27, are linked with functional changes in the beta[2]- AR in the respiratory system even though they are not deemed to be susceptibilitiy genes for asthma per se. the objective of this study was to investigate this association in a subset of asthmatic patients, namely those with nocturnal asthma. The beta[2] -AR gene polymorphisms at codon 16 and 27 were assessed in 40 patients clinically diagnosed with nocturnal asthma and 96 normal controls. Genomic DNA was obtained from whole blood and genotyping was carried out by a PCR based restriction fragment length polymorphism technique. There was a statistically significant difference in genotype frequencies at codon 16 [Arg/Gly] between nocturnal asthmatic patients and normal control subjects [p<0.05]. However, there was no statistically significant difference in allele frequencies between the two groups. In addition, there was a significant association between Arg 16-Gly genotype with nocturnal asthma compared to homozygous Gly 16 [codominant model P= 0.0033, OR = 3.69: 95% CI: 1.49-9.12]. However, there were no statistically significant differences in genotype and allele frequencies at codon 27 [Gln/Glu] between the normal control and nocturnal asthmatic groups [Chi[2] =1.81, P=0.41]. The results also indicate that linkage disequilibrium existed between the beta[2]-AR codon 16 and beta [2] -AR codon 27 polymorphis [ID'I=0.577] The data for all haplotypes did not show a statistically significant association. We present the genotype and allele frequencies of beta[2]-AR gene polymorphisms in normal Saudi subjects and nocturnal asthmatic patients. There was a significant difference in genotype frequencies at codon 16 [Arg/Gly]. However, our study indicates a poor association of individual single nucleotide polymorphisms with nocturnal asthma

Relationship between genetic polymorphisms of β2-adrenergic receptor gene and essential hypertension risk among the Han Chinese population: a Meta analysis / 中华预防医学杂志

<p><b>OBJECTIVE</b>To evaluate the relationship between A46G and C79G polymorphisms in the β2-adrenergic receptor (ADRB2) gene and the incidence of essential hypertension (EH) among the Han Chinese population.</p><p><b>METHODS</b>We conducted a computer retrieval of PUBMED, EMBASE, CNKI, Wanfang and VIP databases prior to May 2010. Articles investigating the relationship of EH and ADRB2 gene polymorphism of Han group were found through literature search, including 15 articles on A46G and 10 articles on C79G. According to the including and excluding criteria, a Meta-analysis was conducted in EH and ADRB2 gene polymorphism of A46G and C79G. The association was examined by RevMan4.2 software through quantitative analysis.</p><p><b>RESULTS</b>Eight articles on A46G polymorphism (including 1078 EH cases and 788 control subjects) and six articles on C79G polymorphism (including 1367 EH cases and 1006 control subjects) were included in the current study. Meta-analysis showed that there was a significant association between A46G polymorphism and EH: genotype GG/(AA + AG) (fixed-effected model, OR = 1.35, 95%CI = 1.04 - 1.74, P = 0.02), genotype GG/AA (fixed-effected model, OR = 1.41, 95%CI = 1.06 - 1.89, P = 0.02). No significant association was found between C79G polymorphism and EH of Han group in China: G/C allele comparison (random-effected model, OR = 0.88, 95%CI = 0.55 - 1.39, P = 0.57).</p><p><b>CONCLUSION</b>Significant association was found between A46G polymorphism of ADRB2 gene and EH, whereas no association could be found between C79G polymorphism and EH among Han Chinese population.</p>