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

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)

In vitro effects of propranolol and isoproterenol on the expression of beta-2 adrenergic receptor on infantile hemangioma endothelial cells / 中华皮肤科杂志

Objective To explore the role of beta-2 adrenergic receptor in the pathogenesis of infantile hemangioma.Methods In vitro cultured infantile hemangioma endothelial cells were divided into propranolol and isoproterenol groups.The propranolol groups were further classified into 5 groups to be treated with propranolol solutions at concentrations of 10,15,20 μg/ml,EGM-2 medium (blank control group 1),and EGM-2 medium containing 0.16％ DMSO (DMSO group) respectively,while the isoproterenol groups were classified into 4 groups to be treated with isoproterenol solutions at concentrations of 5,10,20 μg/ml and EGM-2 medium (blank control group 2) respectively.After 24-and 48-hour treatment,enzyme-linked immunosorbent assay (ELISA) was performed to measure the expression of beta-2 adrenergic receptor in cell culture supernatants in the above groups.Results After 24-hour treatment,15-μg/ml and 20-μg/ml propranolol groups showed significantly decreased expression of beta-2 adrenergic receptor compared with blank control group 1 and DMSO group (all P ＜ 0.05).After 48-hour treatment,all the propranolol groups showed significantly decreased expression of beta-2 adrenergic receptor compared with the blank control group 1 (all P ＜ 0.05).However,the expression of beta-2 adrenergic receptor was significantly higher in the 10-and 20-μg/ml isoproterenol groups than in the blank control group 2 after 24-hour treatment (all P ＜ 0.05),and higher in the 20-μg/ml isoproterenol group than in the blank control group 2 after 48-hour treatment (P ＜ 0.05).Conclusion Propranolol can down-regulate the expression of beta-2 adrenergic receptor on the surface of vascular endothelial cells,while isoproterenol can up-regulate its expression.

Relationship Between β2-Adrenergic Receptor Gln27Glu Gene Polymorphism and Essential Hypertension Occurrence in Tibetan Population Living at High Altitude Area / 中国循环杂志

Objective: To investigate β2 adrenergic receptor (β2-AR) gene polymorphism, Arg16Gly, Gln27Glu and essential hypertension (EH) occurrence in Tibetan population living at high altitude area. Methods: Our research included in 2 groups: EH group, n=385 patients and Control group,n=297 normal healthy subjects. β2-AR polymorphisms of Arg16Gly and Gln27Glu were detected by Snapshot mini-sequencing technique and their frequencies were compared between 2 groups and male, female genders. Results: The genotype and allele frequency distributions of Arg16Gly and Gln27G1u were similar between 2 groups, P>0.05; there were no signiifcant differences between male and female genders,P>0.05. Conclusion: No obvious relationship was found between β2-AR gene polymorphism (Arg16Gly, Gln27Glu) and EH occurrence in Tibetan population living at high altitude area.

Role of β2-adrenergic receptor polymorphisms in prognosis of myasthenia gravis with other autoimmune diseases / 中华神经科杂志

Objective To explore the correlation of β2-adrenergic receptor (β2-AR)polymorphisms (Arg16Gly) with the prognosis of myasthenia gravis (MG) complicated with other autoimmune diseases.Methods Among the 75 MG patients in analysis,17 cases were complicated with other autoimmune diseases (AIDMG),58 cases without other autoimmune diseases (NAIDMG).MG patients,AIDMG patients,NAIDMG patients were separately divided into recurrence groups and nonrecurrence groups according to the progression at 2 years after onset.The genotypes of β2-AR in 75 MG patients were determined by gene sequecing.Results The frequencies of three genotypes (Arg/Arg,Arg/Gly and Gly/Gly) in position 16 were 30.8％,50.0％,19.2％ in recurrence MG group and 42.9％,38.8％,18.3％ in non-recurrence MG group respectively.The difference in distribution of the genotypes between recurrence MG group and non-recurrence MG group was not statistically significant (x2 =1.150,P=0.563).The frequencies of Arg and Gly allele were 55.8％ and 44.2％ in recurrence MG group,and 62.2％ and 37.8％ in non-recurrence MG group.The difference in distribution of the alleles between the two groups was not statistically significant.The frequencies of 3 genotypes in position 16 were 27.3％,63.6％ and 9.1％ in recurrence AIDMG group and 100.0％,0,0 in non-recurrence AIDMG group,respectively.The frequencies of Arg and Gly allele were 59.1％,40.9％ in recurrence AIDMG group,and 100.0％,0 in non-recurrence AIDMG group.The difference in distribution of the genotypes between recurrence AIDMG group and non-recurrence AIDMG group was statistically significant (P =0.009).There also was significant difference in distribution of alleles between recurrence and non-recurrence AIDMG groups (x2 =6.676,P =0.010).The frequencies of 3 genotypes in position 16 were 33.3％,40.0％ and 26.7％in recurrence NAIDMG group and 34.9％,44.2％,20.9％ in non-recurrence NAIDMG group,respectively.The frequencies of Arg and Gly allele were 53.3％,46.7％ in recurrence NAIDMG group,and 57.0％,43.0％ in non-recurrence NAIDMG group.There was no significant difference in distribution of genotypes or alleles between recurrence and non-recurrence NAIDMG groups.Conclusion β2-AR gene polymorphism in position 16 may predict the prognosis of AIDMG,and there is no correlation between the polymorphism in position 16 of β2-AR and the prognosis of MG and NAIDMG.

The study of single nucleotide polymorphisms of β2-adrenergic receptor in pancreatic carcinoma / 中华肝胆外科杂志

Objective To investigate the single nucleotide polymorphisms (SNPs) at codons 16 and 27 of β2-AR gene in pancreatic carcinoma and non-neoplastic pancreatic tissues,and the correlations between these SNPs and the expression of β2-AR protein in pancreatic carcinoma.Methods A total of 64 cases of pancreatic carcinoma (PC) and 20 non-neoplastic pancreatic tissues (NPC) were genotyped at codons 16 and 27 by PCR-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing.The correlations between the distribution of genotypes and clinicopathological characteristics of pancreatic carcinoma were analyzed.The expression of β2-AR protein was detected by immunohistochemistry in pancreatic carcinoma.Results The distributions of genotype frequency at codons 16 and 27 in PC and NPC were in accordance with the Hardy-Weinbery equeilibrium.The frequencies of their genotypes (AA,AG and GG) and frequencies of alleles A and G at codon 16 between PC and NPC showed no difference.The genotype frequencies were associated with TNM grade,lymph node metastasis,one-year survival rate (P=0.03,0.05,0.04),but they were not associated with patients' gender,age,histological differentiation and size of tumor.The allele G at codon 16 was frequently appeared in tumors with high TNM grade,lymph node metastasis,low one-year survival rate (P＝ 0.01,0.03,0.02),and high expressions of β2-AR protein (P =0.02).The frequencies of two genotypes (CC and CG) and frequencies of alleles C and G at codon 27 showed no difference between PC and NPC.The genotype frequencies and allele frequencies of codon 27 were not associated with patients' clinicopathological features,and expressions of β2-AR protein.Conclusions SNPs of β2-AR gene were associated with biological behaviors of pancreatic carcinoma.Allele G at codon 16 was associated with high risks of lymph node metastasis,high TNM grade,low one-year survival rate,and high expressions of β2-AR protein.Allele G at codon 16 might facilitate the progression and metastasis of pancreatic carcinoma through elevating the expression of β2-AR.SNPs at codon 16 of β2-AR are new useful biomarkers for predicting biological behaviors and survival of pancreatic carcinoma and might be used as a new gene therapeutic target.

Combination therapy with single inhaler of long-acting β2-adrenoceptor agonists/inlaled corticosteroids compared with higher dose of inhaled corticosteroids in asthmatic patients / 中国基层医药

Objective To provide a quantitative summary estimate on the efficacy and safety measures of the combination therapy.Methods We searched databases(Medline and Embase)from January 1997 to December 2009 using‘ Fluticasone and salmerterol' or‘ Seretide' or‘ Advair' or‘ budesonide/formoterol' or‘ Symbicort Turbuhaler' in combination with ‘ Randomised controlled trial'.The databases of GlaxoSmithKline Clinical Trial Register and Cochrane Controlled Trials Register,or relevant original studies and review articles were approached for additional studies or details of all relevant studies.Results Morning peak expiratory flow(PEF),evening PEF and clinic FEV1 were 17.59L/min,14.95L/min and 0.08L/min higher with combination therpy than with increasing ICSs by two fold or more at endpoint,respectively.The risk of asthmatic exacerbation was reduced in the combination therpy group compared with the increased doses of ICS groups,with OR being 0.61(95 ％ CI 0.53 ～ 0.70,P ＜ 0.01).Significantly increases in the percent of symptom-free days 6.30(95％ CI 3.52 ～9.10),asthma-control days 9.49(95％ CI 4.74 ～14.25)and relieve-free days 6.59(95％ CI 6.10 ～ 7.08)were observed in patients treated with ICS/LABA compared with increased doses of ICSs at endpoint.Reduction in reliever medication use(inhalations/day)0.22(95 ％ CI 0.11 ～0.33)with significant difference was also observed at endpoint.Conclusion Combination products of ICS/LABA were more effective than a high dose of ICSs in improving lung function,reducing asthmatic exacerbation and use of reliever medication and improving control of asthma.

The protective effect of the 27-β2 adrenergic receptor genetic polymorphisms in airway hyperreactivity / 中国基层医药

Objective To analyze the association between β2-AK 27 locus genetic polymorphisms and asthma, and the protective effect in airway hyperreactivity. Methods The allel polymerase chain reaction were used to determine β2-AR 27 locus genetic polymorphisms in 149 patients with cough variant asthma who have the airway hyperreactivity. To observe these people for two years in order to know the proportion of changed to typical asthma. And compare with 90 people in healthy group. Results (1) The distribution frequency of β2-AR 27 locus genetic polymorphisms is major in heterozygote (57 % ) , and the Glu/Glu homozygote has the least ( 20% ) , (2) There was a significant decrease in the frequency of Glu/Glu genotype in asthmatics compared with healthy group(9% VS 20% ) ,OR = 0.4(P<0.05) ,95% CI (0.2 ～0. 9) ,but there was no significant difference in the allele frequency of asthmatics compared with healthy group,(3)The frequency of Glu/Glu genotype in severe asthma was lower than stable asthma group(P<0. 05). Conclusion These results suggesteded that β2-AR 27 locus genetic polymorphisms is correlated with asthma,and the Glu27 could have the protective effect to the airway.

Study on relationship between serum total IgE and β《,2》-adrenoreceptor polymorphism in asthmatic patients / 中国医师杂志

Objective To study the association between serum total IgE level and β2-adrenoreceptor polymorphism (β2-AR) in asthmatic patients. Methods ELISA was used to determine serum total IgE and AS-PCR was used to determine β2-adrenoreceptor polymor- phism in 44 asthmatic patients. Results In β2-AR 16 locus genotype, the distribution frequencies of Arg/Arg, Gly/Gly showed increasing tendency, whereas Arg/Gly showed decreasing tendency, in normal serum total IgE group and increased serum total IgE group. But there was no significant difference between this two groups. In β2- AR 27 locus genotype, the distribution frequency of Gln/Gln genotype accounts for 76.2% and Gln/Glu genotype for 19.0% in increased serum total IgE group, while Gln/Gln genotype accounts for 9.0% and Gln/Glu geno- type for 73.9% in normal serum total IgE group. There was significant difference between two groups ( P<0.01 ). Conclusions Serum total IgE was correlated with β2-AR 27 locus genetic polymorphism, which may contribute to understand the mechanism of asthma in the peo- ple of the Han nationality in GuiZhou.

Expression of beta 2 adrenergic receptor in marrow cells of mice and its significance / 吉林大学学报(医学版)

Objective To explore the expression of beta 2 adrenergic receptors(?2-AR) in bone marrow cells and its significance and provide a scientific basis for the theory of hematopoietic regulation by nerve factors.Methods After bone marrow mononuclear cells were isolated from normal mouse bone marrow by the Ficoll density gradient centrifugation,the expressions of ?2-AR were studied by immunohistochemistry in bone marrow mononuclear cells,cultured bone marrow stromal cells,GM-CFUs,paraffin sections and smears of bone marrow.Mouse models of immune-mediated aplastic anemia(AA) were made by lymphocyte infusion.Mice were divided into 3 groups including animal model group,?2-AR antagonist (ICI 118551) group,and control group,and the expression of ?2-AR in bone marrow mononuclear cells at the 8 th day was detected by Western blotting.Results The positive expression of ?2-AR in cytoplasm or membrane of normal mouse bone marrow cells showed different brown by immunohistochemical staining.There were intensive positive expressions of ?2-AR in mononuclear cells(48%) and bone marrow stromal cells (68%),while progenitor cells only showed middle-positive(55%)or weak positive(45%),and other hematopoietic accessory cells were positive in varying degrees.The relative values of ?2-AR of bone marrow mononuclear cells in 3 groups were 1.03?0.31,1.72?0.29 and 1.41?0.35,respectively;the expression of ?2-AR in animal model group was more lower than that in control group(P

?_2-AR gene cloning from human detrusor cell and the construction of its antisense eukaryotic expression vector / 中华泌尿外科杂志

Objective To clone human beta-2 adrenoceptor gene from human bladder smooth muscle and to construct its antisense eukaryotic expression vector. Methods The ?_2-AR full length cDNA was cloned from human detrusor cells through RT-PCR and subcloned into clone vector (pUC18).The objective gene was then cut from ClaⅠ/HindⅢ sites of pUC18 with restriction endonulcease and subcloned into pLNCX vector in trans-direction.Finally the constructed ?_2-AR gene antisense expresstion vector was identified through restriction endonuclease analysis and sequencing. Results The sequence of cloned ?_2-AR full length cDNA was certified by comparison with the database of the Genebank.The constructed antisense eukaryotic expression vector was proved to be same with designed by restriction endonuclease analysis and sequencing. Conclusions ?_2-AR full length cDNA was cloned and its antisense eukaryotic expression vector was successfully constructed.This technique establishs the foundation for the further research on drug treatment of bladder dysfunction.

Study on single nucleotide polymorphism of ?_2 adrenoceptor gene in patients with pregnancy induced hypertension of northern China / 中华妇产科杂志

0.05). (2) There was a significant difference in the distribution frequency of ?_2-AR at locus +46 between mild, moderate and severe degrees of PIH (P

Correlation between intracellular magnesium and expression of beta 2-adrenergic receptor mRNA in the lung of C57BL/6 asthmatic mice / 中国病理生理杂志

0.05,respectively).Plasma Mg2+,intracellular Mg2+,the beta 2-AR mRNA and protein in lung tissue in group C at 21st d and 34th d were significantly higher than those in group A at 21st d and 34th d 21st d:(0.84?0.09)mmol/L vs 0.57?0.10)mmol/L,(2.39?0.14)mmol/L vs(2.11?0.08)mmol/L,(0.75?0.09)pmol/g vs(0.59?0.06)pmol/g,(88.50?8.50)pmol/g vs(60.10?7.70)pmol/g,P