Activation of β_2-Adrenergic Receptor Induced by Three Catecholamine Agonists:a Docking and Molecular Dynamics Study

We studied the activation of β2-adrenergic receptor（β2AR） by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics（MD） simulation. The simulation was done on the assumption that β2AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature. So the result should be close to that under the physiological conditions. We calculated the structure of binding sites in β2AR for the three ac- tivators. We also simulated the change of the conformation ofβ2AR in the transmembrane regions（TMs）, in the mo- lecular switches, and in the conserved DRY（Aspartic acid, Arginine and Tyrosine） motif. This study provides detailed information concerning the structure ofβ2AR during activation process.

Effects ofβ_2-Adrenergic Antagonist on Cytosolic Ca^(2+) in Ventricular Myocytes from Infarcted Rat Heart

Objectives To investigate the effects of β2-adrenergic antagonist on cytosolic Ca^2 ＋ （[Ca^2＋ ]i） in ventricular myocytes from infarcted rat heart. Methods A ligature was placed around left anterior descending coronary artery of rat hearts. Rats in the control group were sham-operated. Cardiomyocytes were dissociated at two, four, eight weeks after myocardial infarction （MI） and [Ca^2＋]i was measured via fura-2 fluorescence. The response of cardiomyocytes to isoproterenol in presence or absence of betal-adrenergic antagonist atenolol, beta2-adrenergic antagonist ICI118, 551 or non-selective β1, 2- adrenergic antagonists propranolol was examined. Results The followings were found that ICI 118, 551 had no significant effects on the rise of [Ca^2＋]i induced by isoproterenol in normal ventricular myocytes （P 〉 0.05）, ICI118, 551 only significantly attenuated the rise of [Ca^2＋]i induced by isoproterenol at four weeks and eight weeks after MI （24.5%±5.7% vs 57.8% ± 13.2%, P〈 0.01; 12.2%±7.9% vs 44.6%±11.3%, P〈 0.01）. Atenolol had suppressive effects only in the control group and the post-MI group of two weeks （P 〈 0.05）, and propranolol had suppressive effects in the control and all the three post-MI groups （P 〈 0.01）. Conclusions Beta2-adrenergic antagonist ICI118, 551 may exert negative effects on Ca^2＋ overload initiated by sympathetic stimulation after MI.

Beta-adrenergic receptor polymorphisms: A basis for pharmacogenetics

Aims: Polymorphisms of the β-adrenergic receptor, the frequency of which may differ in ethnic groups, alters β-receptor function. The aim of this study was to elucidate the frequency of β1 and β2-adrenergic receptor polymorphisms in healthy Greeks and to compare with those of Caucasian European (Euro) and African American (AA) origin. Methods: Ninety-nine individuals with a median age of 63 without clinical evidence of any disease were studied. Blood samples were obtained and common β1 and β2-adrenergic receptor polymorphisms that change the en-coded amino acid were determined by pyrosequencing. Results: The most common β1-adrenergic receptor polymorphism in Greeks is nucleotide substitution cytosine for guanine at position 1165 (1165 C/G) resulting in amino acid substitution arginine for glycine at position 389 (389 Arg/Gly) with a minor allele frequency of 28% (Euro 27%, AA 42%);this polymorphism increases the sensitivity of the β1-receptor. The most common β2-adrenergic receptor polymorphism in Greeks is the nucleotide substitution guanine for adenine at position 46 (46 G/A) resulting in amino acid substitution glycine for arginine at position 16 (16 Gly/Arg) with a minor allele frequency of 38% (Euro 41%, AA 50%);this polymerphism facilitates receptor down-regulation during chronic adrenergic stimulation. Conclusion: The most common β1 and β2-adrenergic receptor polymorphisms in the Greek population are similar to those of other European ancestry, and less common than in those of African origin indicating variability in ethnic groups. This information provides insight into common polymorphisms that may assist in optimizing β-antagonist and agonist therapy.

Mdm2、bcl-2、AR的表达与脑膜瘤病理类型的关系

目的研究凋亡相关蛋白Mdm2、bel-2和雄激素受体（AR）与脑膜瘤病理类型之间的关系，为脑膜瘤的治疗和预后提供一些新信息。方法从华西医院病理科获得2001～2003年间病理诊断明确的脑膜瘤病例共394例，计算机随机抽样60例，将60例蜡块每份切片3张，做免疫组化染色，检测Mdm2、bel-2、AR的表达。结果在不同病理级别的脑膜瘤中Mdm2、bel-2、AR的表达率均有差别，但仅AR的表达差异有统计学意义。结论AR的表达与脑膜瘤的病理级别有关．提示AR在脑膜瘤的增殖作用中的重要性，它可以作为脑膜瘤的预后参考因子。

Mdm2、Bc1-2、AR在良性脑膜瘤中表达的关系

目的研究凋亡相关蛋白mdm2、bcl-2和AR（雄激素受体）之间的关系，为脑膜瘤的性激素对抗治疗提供一些新信息。方法从华西医院病理科获得04年1月-07年12月病理诊断明确的脑膜瘤共394例，计算机随机抽样60例，其中良性脑膜瘤（WH0I）41例，用LsAB法做免疫组化染色，检测mdm2、bcl-2、AR的表达。结果在良性脑膜瘤中mdm2、bcl-2、AR的表达率分别为67％、62％、33％，三者之间没有相关关系。结论（1）是否能够作为抗性激素治疗疗效的筛选和／或预测指标，bcl-2比mdm2更有潜在价值。（2）AR在脑膜瘤中的促进生长作用的相对独立性，提示AR可以作为脑膜瘤对抗激素治疗的新靶点进一步研究。

β-2 Adrenergic receptor gene polymorphism and response to propranolol in cirrhosis

AIM: To evaluate the association of β-2 adrenergic receptor(β2-AR) gene polymorphism with response of variceal pressure to propranolol in cirrhosis.METHODS: Sixty-four non-related cirrhotic patients participated in this study and accepted variceal pressure measurement before and after propranolol administration. Polymorphism of the β 2-AR gene was determined by directly sequencing of the polymerase chain reaction products from the DNA samples that were prepared from the patients.RESULTS: The prevalence of Gly16-Glu/Gln27 and Arg16-Gln27 homozygotes, and compound heterozygotes was 29.7%, 10.9%, and 59.4%, respectively.Patients with cirrhosis with Gly16-Glu/Gln27 homozygotes had a greater decrease of variceal pressure after propranolol administration than those with Arg16-Gln27 homozygotes or with compound heterozygotes(22.4% ± 2.1%, 13.1% ± 2.7% and 12.5% ± 3.1%,respectively, P < 0.01).CONCLUSION: The variceal pressure response to propranolol was associated with polymorphism of β 2-AR gene. Patients with the Gly16-Glu/Gln27 homozygotes probably benefit from propranolol therapy.

Dexmedetomidine Promotes Angiogenesis and Vasculogenic Mimicry in Human Hepatocellular Carcinoma through α^(2)-AR/HIF-1α/VEGFA Pathway

Objective Dexmedetomidine(DEX),the most specificα^(2)-adrenergic receptor agonist widely used for its sedative and analgesic properties,has been reported to upregulate HIF-1αexpression to protect hypoxic and ischemic tissues.However,it is largely unclear whether DEX can also upregulate Hypoxiainducible factor-1 alpha(HIF-1α)expression and its downstream vascular endothelial growth factor-A(VEGFA)in cancer tissues with oxygen-deficient tumor microenvironment.Methods We used SMMC-7721 cells,MHCC97-H cells,and a mouse model of orthotopic hepatic carcinoma to explore the effect of DEX on angiogenesis and vasculogenic mimicry(VM)and its mechanism.Under normoxic(20%O^(2))and hypoxic(1%O^(2))conditions,DEX was used to intervene cells,and yohimbine was used to rescue them.Results The results showed that DEX promoted angiogenesis and VM in human liver cancer cells within a certain dose range,and the addition of yohimbine inhibited this effect.DEX could activate HIF-1α/VEGFA pathway,which was further verified by silencing HIF-1α.Consistently,in vivo results also showed that DEX can up-regulate HIF-1α/VEGFA expression,and enhance the number of VM channels and microvessel density(MVD).Conclusion We believe that HIF-1α/VEGFA might be an important signaling pathway by which DEX promotes angiogenesis and VM formation in human hepatocellular carcinoma,whereasα^(2)-adrenergic receptor mediation might be the critical mechanisms.

Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A_(2)receptors

The adenosine subfamily G protein-coupled receptors A_(2A)R and A_(2B)R have been identified as promising cancer immunotherapy candidates.One of the A_(2A)R/A_(2B)R dual antagonists,AB928,has progressed to a phaseⅡclinical trial to treat rectal cancer.However,the precise mechanism underlying its dual-antagonistic properties remains elusive.Herein,we report crystal structures of the A_(2A)R complexed with AB928 and a selective A_(2A)R antagonist 2-118.The structures revealed a common binding mode on A_(2A)R,wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets.In contrast,the cAMP assay and A_(2A)R and A_(2B)R molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A_(2B)R.Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A_(2B)R pocket,while 2-118 did not due to intrinsic differences.This disparity potentially accounted for the difference in inhibitory efficacy between A_(2B)R and A_(2A)R.This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A_(2A)R/A_(2B)R for cancer therapy.

Effect of polymorphisms in the β2-adrenergic receptor on the susceptibility and pulmonary function of patients with chronic obstructive pulmonary disease： a meta analysis

Background 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 （β2AR） result in single amino acid substitution. Two loci had been extensively studied and found that they could change the function of β2AR. 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 62-adrenergic receptor （ADRB2） gene on the risk of COPD and lung function. Methods 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 （FEV1%） in both the case and control. Results 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 Gin/Gin 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. Conclusions 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.

2型5a还原酶抑制剂和a1A受体阻滞剂对良性前列腺增生患者尿道角影响价值的研究

目的评估2型5a还原酶抑制剂(2-5ARIS)、a1A受体阻滞剂(a1-AR)对良性前列腺增生患者(BPH)尿道角(PUA)的影响。方法观察成都中医药大学附属医院双流分院·双流区中医医院28例BPH患者经药物(非那雄胺+坦洛辛)干预前及干预后3、6、9、12个月前列腺尿道角(PUA)、前列腺体积(PV)、最大尿流率(Qmax)、国际前列腺症状(IPSS)评分的变化,对比PUA、PV的差异性;分析PUA、PV的变化对Qmax、IPSS评分的影响。结果持续2-5ARIS、a1-AR干预可缩小BPH患者的PV、PUA,增加Qmax,降低IPSS评分(P<0.05)。结论2-5ARIS、a1-AR可通过缩小BPH移行带的PV来改变PUA的形态,从而降低尿道阻力并改善Qmax、IPSS评分,减轻下尿路症状(LUTS);药物干预<9个月,药物对PUA>38°、PV>40 mL的BPH疗效更佳。

前列腺癌细胞系中结肠癌相关转录因子2与雄激素受体基因的转录调控关系

雄激素受体(androgen receptor,AR)是经典的前列腺癌主效基因。结肠癌相关转录因子2(colon cancer associated transcript 2,CCAT2)是基于GWAS大数据结果发现的前列腺癌相关长链非编码基因,二者关系尚未见报道。依据AR表达模式的不同,前列腺癌(prostate cancer,PCa)可以划分为普通前列腺癌以及恶性程度更高的去势抵抗性前列腺癌(castration-resistance prostate cancer,CRPC)两种截然不同的发展阶段,其机制尚不明确。AR与CCAT2是否存在调控关系以及是否在其中发挥作用是本研究的切入点。本文采用雄激素依赖型与非依赖型的前列腺癌细胞研究模型LNCaP与DU145细胞系,研究发现了CCAT2与AR存在转录调控关系。首先,采用过表达与敲低的分子生物学研究策略,发现二者的RNA水平存在相互调控。在DU145细胞中,G型CCAT2激活AR mRNA水平到2.6倍,T型CCAT2抑制AR mRNA水平至0.2(P<0.05);在LNCap细胞中,G型CCAT2激活AR mRNA水平1.5倍,T型CCAT2对AR mRNA水平变化无显著意义(P<0.05)。在DU145细胞中过表达AR,CCAT 2的表达量上升2.9倍(P<0.05);在LNCaP细胞中沉默AR的表达,CCAT 2的表达水平下降至0.48(P<0.05)。报告基因分析结果显示,CCAT2对AR启动子相对活性影响与RNA水平改变相一致。由于CCAT2研究的缺乏,本文进一步研究了其与细胞活性以及对AR蛋白质水平的影响,数据显示与转录水平的结果基本一致。最后,本文初步分析了AR与CCAT2可能相关的靶基因,包括CTNNB1,MYC和TCF7L 2,初步探讨可能的机制并验证了转录水平的发现。结果表明,在LNCaP细胞中G型CCAT2分子激活AR的转录,U型CCAT2无作用。在DU145细胞中,G型CCAT2激活AR转录,U型CCAT2抑制AR的转录。在2个细胞系中,AR都激活CCAT 2整体的转录活性,提示二者存在反馈调节机制。研究发现,CCAT2与AR的转录调控关系,为真核基因表达与调控的机制研究以及前列腺癌的发病机制与治疗提供了理论与实验数据。

Effect of transmembrane Ca^(2+) gradient on ligand binding of reconstituted β-adrenergic receptors

It is well known that, under physiological conditions, the cytosolic free Ca2+ in most cells is around 10-7—10-6 mol/L, whereas the extracellular Ca2+ concentration is about 10-3 mol/L. This results in a 1 000—10 000-fold transmembrane Ca2+ gradient. The maintenance of such a concentration gradient has been proved to be of vital importance in cell function. Although a transmembrance Ca2+ gradient exists across the plasma membrance, little attention has

113例前列腺癌AR与凋亡相关因子表达的研究

目的探讨113例人前列腺癌AR与凋亡相关因子表达的相关性。方法应用免疫组化标记AR及细胞凋亡相关因子bcl-2、Bax及Tunel标记等,结合光镜、电镜观察及图像分析等方法,研究不同AR表达与PCa凋亡的相互关系。结果AR(-)组较AR(+)组bcl-2阳性表达明显增强,Bax表达增强,bcl-2/Bax比值增高,前列腺癌AR(-)组细胞凋亡作用较AR(+)组明显增强。结论AR表达缺失促进了bcl-2和Bax的表达,Bax表达上调促进细胞凋亡的发生,而bcl-2有癌基因的作用,其表达上调则促进了的细胞增殖,导致前列腺癌凋亡及增殖作用均增强。

Hot Spring Hydro Therapy Regulates Peripheral Leukocyte Together with Emotional Hormone and Receptor Positive Lymphocytes According to Each Constitution/Condition

Two primary defense systems develop in vertebrates, innate and adaptive. Despite those defense systems, the overwhelming problems of possessing this dual system, the innate or adoptive do not seem to guard or even prevent the development of one internal threat to survival, moreover sometimes direct to autoimmunity accompanying hypersensitivity. Further, every individual exposes to the risk of immunodeficiency in daily life with both internal and external stimuli. In this report, we tried to report the suitable menu for regulating the immune system modulate and discuss how we can compare and select each menu by evidence-based manner more than VAS. In a series of investigation, we have assessed the various health promoting menus such as hot spring hydrotherapy, acupuncture & moxibustion, light walking, independent to the western medicine. In this report, we try to summarize the regulatory effect of hot spring hydrotherapy as our representative menu under the influence of hypothalamus system. Their effects of elements were evaluated by the total number of peripheral leukocyte, its subsets, granulocyte and lymphocyte ratio, emotional hormones, receptor positive lymphoid cells. The regulative effects were confirmed also by other menu than hydrotherapy, acupuncture, walking etc. However, just by the simple comparison between the group before and after the hydrotherapy, we cannot exhibit the real regulatory effect by each menu. So we tried to show the effect by trying to indicate the constitution/condition dependent manner. Because the effect was not uniformly to each individual but it was dependent on each condition/constitution before the start of the menu. This is the one of the main proposes of this report for summaries that it is important to regulate the number and levels of each factor as ideal value. In other words, the regulation of each factor affected under the hypothalamus system is regulated with each constitution, under the influence of daily circumstances. The mode of regulation was the same in each menu, indicating that the higher leveler was down regulated and lower leveler was up regulated. Moreover, each vector of change was reversely correlated to the value of the day before. The other purpose of this study was designed to establish the regulatory effect of this hydrotherapy being not limited in the number of leukocyte in peripheral but in the emotional hormones. They were adrenaline and dopamine but not found another hormone for healthy individuals. Hot spring hydrotherapy for a short duration was expected to influence the immune system combining with hormone levels in the blood quantitatively. These hormones were evidenced by adrenalin and dopamine as well as adrenergic receptor positive lymphocytes. The final subject was to confirm and compare the effect of hot spring hydrotherapy and other menu. The reproducible effects were expressed by the linear slant and could compare each other with the value of slope. We tried to discuss the advantage and demerit, how we can compare each medicine with the peripheral leukocyte in number and function.

PHD2/HIF-1α介导β-AR调控大鼠心梗后心力套竭

目的观察PHD2、HIF-1α在心肌梗死后心衰时表达量的变化,探讨β肾上腺受体(β-AR)调控PHD2/HIF-1α通路对心肌梗死后心衰发生影响。方法采用冠状动脉左前降支结扎法制备大鼠急性心梗模型,实验分为3组:假手术组、模型组、普蔡洛尔组。记录冠脉结扎前后心电图变化,12周后利用心脏超声检测心功能变化,PCR和Western Blot检测PHD2、HIF-1α的mRNA及蛋白表达的变化。结果结扎冠脉后心电图示ST段显著抬高。结扎12周后心脏射血分数(Ejection fraction,EF)从假手术组的(79.45±2.86)%下降到模型组的(61.10±2.78)%(P<0.05),普蔡洛尔组则高于模型组为(67.33±2.66)%(P<0.05)。PHD2的mRNA及蛋白表达在模型组显著下降(P<O.05),而普蔡洛尔组较模型组明显上升(P<O.05)。HIF-1α的mRNA及蛋白表达在模型组显著上升(P<0.05),而普蔡洛尔组较模型组明显下降(P<0.05)。结论PHD2/HIF-1α通路在大鼠心梗后心衰的发生过程中可能具有重要作用;而心肌梗死后B-肾上腺系统激活,可能通过对PHD2/HIF-1α通路的调节进而促进心衰的发生。

A novel β_(2)-AR agonist,Higenamine,induces β-arrestin-biased signaling

The biased ligands in G protein-coupled receptors(GPCRs)have opened new avenues for developing safer and more effective drugs.However,the identification of such biased ligands as drug candidates is highly desirable.Here,we report that Higenamine,a compound isolated from a Chinese herb,functions as a novel β-arrestin-biased ligand of the β_(2)-adrenergic receptor(β_(2)-AR).The radioligand binding assays demonstrated that Higenamine was the ligand of β_(2)-AR.Higenamine induced phosphorylation of extracellular signal-regulated kinase 1/2(ERK1/2),which can be blocked by propranolol,an inhibitor of β_(2)-AR.The Gi protein inhibitor,pertussis toxin,had no effect on the phosphorylation of ERK1/2 induced by Higenamine.Furthermore,Higenamine induced ERK1/2 phosphorylation through transactivation of Epithelial growth factor receptor(EGFR).We also found that Higenamine-induced-ERK1/2 phosphorylation is dependent on β-arrestin1/2,and HG inhibits Doxorubicin-induced cardiomyocyte apoptosis.Our results identify Higenamine as a novel biased ligand via the β-arrestin-dependent pathway.These findings give us a better understanding of Higenamine’s potential role in designing diagnostic and therapeutic strategies.

膀胱癌中雄激素受体与Pax2的表达研究

[目的]探讨雄激素受体(AR)和Pax2在膀胱癌中的表达及与膀胱癌的侵袭、转移及预后的关系。[方法]用免疫组织化学SP法检测103例膀胱癌组织中AR和Pax2的表达。[结果]AR在103例膀胱癌肿瘤组织中有48例表达,阳性率为46.6%。AR的表达在膀胱癌不同的病理分级、T分期、远处转移及复发情况时差异有统计学意义(P<0.05)。Pax2在103例肿瘤组织中有49例阳性表达,阳性率为47.6%。Pax2在不同T分期、有无远处转移时差异有统计学意义(P<0.05)。Spearman等级相关分析表明Pax2和AR表达明显相关。[结论]AR及Pax2可能参与了膀胱癌的侵袭与转移,可作为预后判断因子,结合病理分级和T分期分析能提高对膀胱癌患者预后判断的准确性。

沉默LMTK2对去势抵抗性前列腺癌PC3细胞增殖的影响

[目的]研究Lemur酪氨酸激酶2(Lemur tyrosine kinase 2,LMTK2)在去势抵抗性前列腺癌(castration resistant prostate cancer,CRPC)中对雄激素受体(androgen receptor,AR)的调节作用并提出可能的作用机制。[方法]设计合成针对LMTK2基因的siRNA(siLMTK2),阴性对照siRNA(NC);采用瞬时转染法将以上siRNA转入前列腺癌PC3细胞,不转染的细胞设置为空白对照(Mock);采用Western blot检测转入LMTK2 siRNA对前列腺癌细胞及空白对照(Mock)中LMTK2蛋白表达的影响;通过克隆形成实验和细胞增殖实验考察沉默LMTK2基因对PC3细胞的肿瘤形成和增殖的影响。[结果]研究发现沉默LMTK2基因后,前列腺癌PC3细胞中LMTK2 mRNA和蛋白质表达水平显著降低;相反地,雄激素相关基因的转录显著升高。另外,LMTK2基因沉默会导致PC3细胞成瘤能力和增殖能力增强,即致癌性增强。[结论]本研究发现LMTK2是一种AR活性的负调节因子,沉默LMTK2基因能上调AR活性从而增强前列腺癌PC3细胞的增殖。这也为CRPC患者的治疗提供了一种新靶标,从而能够采取更有效的治疗方法。

雄激素受体对乳腺癌细胞增殖及相关分子表达作用的研究进展

乳腺癌是激素依赖性肿瘤。除雌激素外,雄激素在乳腺癌的发生发展中也发挥重要作用。雄激素受体(AR)经雄激素作用激活,通过不同方式调控雌激素受体(ER)及芳香化酶的表达,影响人表皮生长因子受体-2(HER-2)、孕激素受体(PR)、E-钙黏蛋白的转录,对乳腺癌细胞的增殖既有抑制也有促进作用。AR还与雌激素受体调节剂(SERMs)他莫昔芬及芳香化酶抑制剂(AIs)的耐药机制有关。深入研究AR调控乳腺癌分子表达的机制有助于将AR作为治疗靶点,提高乳腺癌内分泌治疗的疗效。

Dexmedetomidine:chaperone of anesthesia

Aim:In this review,it will mainly focus on clarifying the pharmacology of dexmedetomidine and discussing the past,present and future clinical applications of dexmedetomidine as an adjunct in anesthesia.Method:We have searched and reviewed the articles about the use of dexmedetomidine in clinical anesthesia,intensive care unit(ICU),painless gastroenteroscopy and painless labor over the past two decades.Recent findings:Dexmedetomidine,a highly selective agonist of alpha2-adrenergic receptors(alpha2-AR),was primarily approved by the U.S.Food and Drug Administration(FDA)for sedation in ICU due to its pharmacological characteristics with sedative,analgesic and sympatholytic effects.These properties make up the limitations of anesthetics,and it produces a“dexmedetomidine assisted”anesthesia mode as an adjuvant combining with other anesthesia methods,which are all termed as“DEX+”.These new methods can reduce the anesthetics requirement but prolong the action period and alleviate the adverse reactions of anesthetics,thus improving the anesthesia more effectively and safely.Summary:Dexmedetomidine possesses the unique properties exerting synergistic effects and alleviating the side effects as an adjuvant in anesthesia through different administration routes.It is beneficial for the patients’long-term outcome and will be bound to be the leading innovator of anesthesia in future.