β-arrestin与β-肾上腺素受体

2012年度诺贝尔化学奖授予了美国科学家罗伯特.莱夫科维茨（Robert J.Lefkowitz）和布莱恩.克比尔卡（Brian K.Kobilka）,以表彰他们在G蛋白偶联受体研究中的贡献。从Robert J.Lefkowitz最初研究β-肾上腺素受体（β-adrenergic receptor,β-AR）减敏机制时发现β-arrestin1至今已有20多年,随着对β-arrestin在细胞信号转导中作用研究的逐渐深入,发现β-arrestin参与β-AR的减敏、内化和降解;近年来又发现,依赖β-arrestin的β-AR信号转导通路具有＂偏向激活＂现象,并提示这种依赖β-arrestin的＂偏向激活＂信号转导通路具有心脏保护作用。β-肾上腺素受体阻滞剂的发现和临床应用被视为20世纪药物治疗学上里程碑式的进展,是药物防治心脏疾病的最伟大突破,很多心血管药物都以β-AR为靶点。但是,由于目前受体药物均是针对受体本身的调控,这样在阻断了受体介导的病理性信号通路和功能的同时,也阻断了受体介导的正常生理性信号通路和功能,造成了严重的毒副作用。所以,研发能选择性阻滞β-AR过度激活介导的病理性信号通路和功能的同时,保留受体介导的正常生理性信号通路和功能（如β-arrestin信号通路）的药物,对治疗心血管疾病有重要意义,受体功能选择性的配体药物将成为未来药物的研究方向。该文将回顾β-arrestin的发现过程,综述其与β-AR的相互作用,期望能为心脏疾病的药物治疗提供参考。     

转化生长因子β

TGFβ广泛存在于动物体多种组织和细胞内,由二条相同的、含112个氨基酸的肽链组成,是细胞的多功能双重调节因子。它对不同组织类型的细胞,可促进生长、分化,也可抑制生长、分化,并直接参与组织修复、胚胎发育等过程,调节细胞外基质形成。     

白细胞介素-1β信号与β细胞功能

由胰岛β细胞功能失调,导致胰岛素分泌的相对或绝对的缺失,进而出现高血糖症状,是糖尿病的重要发病机制.目前认为糖尿病的发病与机体的炎症过程密切相关.作为炎症过程的重要调节因子白细胞介素-1β(IL-1β),通过激活MAPK、NFkB、PKC等信号通路,最终导致b细胞功能失调是糖尿病发生发展的重要原因.IL-1β在介导糖尿病的b细胞功能失调中发挥核心作用.     

Cytotoxic Bis-3,4-dihydro-β-carbolines and Bis-β-carbolines

Ten bis- β -carboline 1, 2 and bis-3,4-dihydro- β -carboline 3, 4 derivatives, linked between carbons 1 and 1′ by a polymethylene spacer, were synthesized from bis-tryptamine amides 9, 10. Some of them display a micromolar IC 50 towards L-1210 cells.     

Untersuchung der N-Acetyl-β-glucosaminidase mit 1-Naphthyl-N-Acetyl-β-glucosaminid

Zusammenfassung Mit 1-Naphthyl-N-acetyl--glucosaminid als Substrat wird die N-Acetyl--glucosaminidase (N-A-Gase) histochemisch (Simultankupplung von 1-Naphthol an Hexazonium-p-rosanilin) und mikrochemisch (fluorometrische Messung von 1-Naphthol) in Ratten-, Mäuseund Meerschweinchenorganen untersucht.Das histochemische Inkubationsmedium enthält 5–12 mg 1-Naphthyl-N-acetyl--glucosaminid (gelöst in NN-Dimethylformamid) und 0,8–1 ml 2% Hexazonium-p-rosanilin in 9 ml 0,1 M Citrat-Puffer, pH 5; das mikrochemische 2 mg/ml dieses Substrats (6 mM) im gleichen Puffer, pH 4,5.Zum Nachweis in situ empfiehlt sich wegen der geringeren Hemmrate (32%) Formol-Fixation, in hochaktiven Geweben auch Glutaraldehyd (54% Inhibition im proximalen Konvolut der Rattenniere). Die histochemische Gesamtaktivität der N-A-Gase ist besser an frischen Schnitten mit semipermeablen Membranen zu erfassen.Nach Fixation in Glutaraldehyd kann das Enzym vor allem bei Ratten in den Lysosomen zahlreicher Organe nachgewiesen werden (u.a. Niere, Nebenhoden, Bronchien, Darm, Uterus und Samenblase), wobei artspezifische Unterschiede bestehen: Über die höchste N-A-Gase-Aktivität verfügen Nebenniere, Nebenhoden und Milz von Meerschweinchen. Weniger Enzym enthalten diese Organe bei Ratten und Mäusen; speziell die Nebenniere ist weitgehend N-A-Gase-frei. Am kräftigsten reagiert die Niere bei Ratten. Geschlechtsspezifische Differenzen sind hier nur mikrochemisch faßbar, in der Niere der Maus aber schon histochemisch. — Reich an N-A-Gase sind Speicheldrüsen, Harnblase und Colon sowie andere Organe mit mucopolysaccharid-haltigen Strukturen.Die mit der Naphthol-AS und 1-Naphthyl-Methode für die N-A-Gase erhaltenen Aktivitätsund Verteilungsmuster entsprechen sich. Die Qualität der intrazellulären Enzymlokalisation mit 1-Naphthyl-N-acetyl--glucosaminid als Substrat kommt den Möglichkeiten des Naphthol-AS-Verfahrens in vielen Organen nahe oder ist ihm gleichwertig.

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Investigation of N-acetyl--glucosaminidase by means of 1-naphthyl-N-acetyl--glucosaminide

Summary Using 1-naphthyl-N-acetyl--gIucosaminide as substrate N-acetyl--glucosaminidase (N-A-Gase) has been investigated histochemically (simultaneous coupling of 1-naphthol and hexazonium p-rosaniline) and microchemically (fluorometric measurement of 1-naphthol) in various organs of rats, mice, and guinea-pigs.The histochemical incubation medium consists of 5–12 mg 1-naphthyl-N-acetyl--glucosaminide (dissolved in NN-dimethyl formamide) and 0.8–1 ml hexazotized p-rosaniline in 9 ml 0.1 M citrate buffer, pH 5; for microchemical purposes 2 mg/ml of this substrate (6 mM) in the same buffer, pH 4.5 were used.For the in situ demonstration of N-A-Gase formol fixation is recommended because of its lower inhibition rate (32%); in highly active tissues glutaraldehyde is also suitable (54% inhibition in the proximal convoluted tubules of the rat kidney). The total activity of N-A-Gase can better be detected in fresh frozen sections in connection with semipermeable membranes.Following fixation in glutaraldehyde the enzyme occurs in the lysosomes of many organs, e.g. kidney, epididymis, bronchi, adrenal gland, intestine, uterus, and vesicular gland, especially in rats. Furthermore spezies-dependent differences exist: the suprarenal gland, epididymis, and spleen of guinea-pigs display the highest amount of N-A-Gase. In rats and mice the enzyme activity of these organs is lower; the adrenal cortex is nearly free of N-A-Gase. — The kidney reacts intensely in rats, the sex differences of which can only be detected by means of microchemistry. In the mouse kidney they are more pronounced. Therefore the histochemical N-A-Gase assay reveals them, too. — Organs containing considerable quantities of mucopolysaccharides, e.g. the submandibular gland, urinary bladder, and colon are also rich in N-A-Gase.The activity and distribution pattern of N-A-Gase obtained with the naphthol AS and 1-naphthyl technique are completely in correspondance with one another. In some cases the quality of the intracellular enzyme localization using naphthol AS-BI N-acetyl--glucosaminide as substrate surpasses the possibilities of the 1-naphthyl derivate, in others the latter one enables identical results.

     

Action of rat liver Galβ1-4GlcNAc α(2-6)-sialyltransferase on Manβ1-4GlcNAcβ-OMe,GalNAcβ1-4GlcNAcβ-OMe,Glcβ1-4GlcNAcβ-OMe and GlcNAcβ1-4GlcNAcβ-OMe as synthetic substrates

Incubation of synthetic Man\1-4GlcNAc-OMe, GalNAc1-4GlcNAc-OMe, Glc1-4GlcNAc-OMe, and GlcNAc1-4GlcNac-OMe with CMP-Neu5Ac and rat liver Gal1-4GlcNAc (2-6)-sialyltransferase resulted in the formation of Neu5Ac2-6Man1-4GlcNAc-OMe, Neu5Ac2-6GalNAc1-4GlcNAc-OMe, Neu5Ac2-6Glc1-4GlcNAc-OMe and Neu5Ac2-6GlcNAc1-4GlcNAc-OMe, respectively. Under conditions which led to quantitative conversion of Gal1-4GlcNAc-OEt into Neu5Ac2-6Gal1-4GlcNAc-OEt, the aforementioned products were obtained in yields of 4%, 48%, 16% and 8%, respectively. HPLC on Partisil 10 SAX was used to isolate the various sialyltrisaccharides, and identification was carried out using 1- and 2-dimensional 500-MHz¹H-NMR spectroscopy.Abbreviations 2D 2-dimensional - CMP cytidine 5-monophosphate - CMP-Neu5Ac cytidine 5-monophospho--N-acetylneuraminic acid - COSY correlation spectroscopy - DQF double quantum filtered - HOHAHA homonuclear Hartmann-Hahn - MLEV composite pulse devised by M. Levitt - Neu5Ac N-acetylneuraminic acid - Neu5Ac2en 2-deoxy-2,3-didehydro-N-acetylneuraminic acid     

胸腺肽β4研究进展

β胸腺肽是一个多肽家族,由高度保守的极性氨基酸组成,相对分子质量约5000.研究表明,在绝大多数哺乳动物组织中,胸腺肽β4都是该家族丰度最高的成员。1991年发现胸腺肽β4是人血小板中主要的肌动蛋白隐蔽肽,随后发现它在创伤愈合和血管生成、角膜修复、抑制炎症及肿瘤转移等方面具有重要作用。我们简要综述胸腺肽β4的上述作用及临床应用的研究进展。     

雌激素受体β亚型

1996年发现雌激素受体存在亚型,即ERβ。ERβ与ERα结构相似。广泛分布于多种组织内,其表达受体激素的影响但不依赖于ERα,并与组织分化、发育过程相关。ERβ可能在生殖系统和神经系统中发挥重要作用,还可能参与肿瘤发生与进展过程ERβ与ERα在体内分布、与配体亲和力、促转录活性上存在差异,对ERβ及其特异性配体的进一步研究具有重要意义。     

整合素β4研究进展

整合素又名整联蛋白,是一种介导细胞与其外环境如细胞外基质之间连接的跨膜受体。整合素β4因其特殊的结构,发挥着诸多功能:与整合素α6亚单位组成α6β4,参与构成半桥粒;介导细胞与细胞外基质相互作用、细胞与细胞间相互作用;介导细胞的增殖与存活,迁移和侵袭;通过激活多条信号通路参与各种疾病进程。本文将对整合素β4的结构组成、生理功能及其在呼吸系统、肿瘤、神经系统等相关疾病中的作用进行综述。     

β-D-galactosidase ofLactobacillus species

The activity of β-D-galactosidase was studied in 13 strains of lactobacilli (groupsStreptobacterium, Thermobacterium andBetabacterium). Using 2-nitrophenyl galactopyranoside as substrate, the enzyme activity varied with the strain. The values found in theThermobacterium group were superior to those in theStreptobacterium group. The optimum pH for the species belonging to theThermobacterium group was uniform, in contrast to the ph for those from theStreptobacterium which varied according to the species. The optimum temperature was quite uniform within each group and higher in theStreptobacterium. Lactose acted as a competitive inhibitor. MgCl₂ protected the enzyme from thermal denaturation. The calcium ions inhibited the activity in all cases. The behaviour of the protectors of the SH groups varied according to the strain. 6-Phospho-β-D-galactosidase activity was also determined, levels lower than β-D-galactosidase were found, except inLactobacillus plantarum ATCC 8014 and 14917.     

β-Amylase fromBacillus megaterium

Bacillus megaterium strain B₆ producing extracellular β-amylase was isolated and grown in a medium supplemented with waste potato starch. It showed highest enzyme synthesis in the early stationary phase. The partially purified β-amylase had a temperature optimum at 60°C and a pH optimum at 6.9 and was not affected by Schardinger dextrins. These properties would allow its application in sugar industry.     

β-Hydroxy-β-methylbutyrate (HMB) prevents dexamethasone-induced myotube atrophy

High levels of glucocorticoids result in muscle wasting and weakness. β-hydroxy-β-methylbutyrate (HMB) attenuates the loss of muscle mass in various catabolic conditions but the influence of HMB on glucocorticoid-induced muscle atrophy is not known. We tested the hypothesis that HMB prevents dexamethasone-induced atrophy in cultured myotubes. Treatment of cultured L6 myotubes with dexamethasone resulted in increased protein degradation and expression of atrogin-1 and MuRF1, decreased protein synthesis and reduced myotube size. All of these effects of dexamethasone were attenuated by HMB. Additional experiments provided evidence that the inhibitory effects of HMB on dexamethasone-induced increase in protein degradation and decrease in protein synthesis were regulated by p38/MAPK- and PI3K/Akt-dependent cell signaling, respectively. The present results suggest that glucocorticoid-induced muscle wasting can be prevented by HMB.     

β-内酰胺酶(β-Lactamase)抑制剂的抑菌试验

自从抗生素被发现以来,许多传染病都得到了控制。然而随着抗生素的广泛应用,尤其是不合理的滥用,微生物对抗生素的耐药性问题也越趋严重,耐青霉素的细菌已达90％。对广泛使用的β-内酰胺类抗生素(青霉素、头孢霉素)的主要耐     

胸腺肽Tβ4

胸腺肽Tβ4是具有多重生物功能的小肽,是肌动蛋白的结合蛋白之一,该多肽的基因差异性表达与肿瘤恶变和转移、胚胎发育等关系密切,本综述了胸腺肽Tβ4的研究进展。     

植物β-淀粉酶

介绍了植物β-淀粉酶的蛋白质结构、热稳定性、突变体和遗传规律、生理功能、基因表达和调控的研究新进展,并对今后此领域的研究作了展望。     

β-arrestin和信号转导

β-arrestin是一类重要的信号调控蛋白和支架蛋白（scaffold）。在G蛋白偶联受体（G-protein-OOU-piedreceptor,GPCR）信号转导中,β-arrestin不但可以作为GPCR信号的负性调控分子,还能作为支架蛋白促进GPCR对其他信号通路的激活,如有丝分裂原激活蛋白激酶（mitogen-activated protein kinase,MAPK）途径。另外β-arrestin还能与转录因子调节蛋白,如IKB和Mdm2相互作用问接调节NF-κB和P53介导的转录。     

雌激素β受体研究进展

雌激素是由芳香化酶催化雄激素转化而来的。脑组织局部产生的雌激素不仅作用于生殖系统,也深刻影响着脑发育、学习记忆和认知等功能。雌激素的信号是由雌激素受体介导的,以前只发现了一种雌激素受体,这面临着许多无法解释的现象,新克隆的雌激素受体即β受体加深了人们对雌激素信号途径的认识,为全面阐明雌激素在不同组织中的作用机制提供了新的线索。     

磷脂酶C-β研究进展

磷脂酶Ｃ β(ＰＬＣ β)是磷脂酶Ｃ的β型同工酶。它与磷脂酶Ｃ γ(ＰＬＣ γ)同是肌醇磷脂信号途径的关键酶。虽然它们同属ＰＬＣ家族 ,但所介导的信号途径及引起的生理效应却有很大差异。ＰＬＣ γ需要酪氨酸激酶激活 ,最终引起细胞的生长和分化等效应 ,而ＰＬＣ β的活化却要靠Ｇ蛋白 ,目前主要发现其介导一些神经内分泌的信息传递。本文对ＰＬＣ β的新进展作一综述。1 .ＰＬＣ β的生物特性迄今为止 ,发现ＰＬＣ β有 4个亚型 :β1、β2 、β3和β4,它们的基因定位于不同的染色体区段。由于ｍＲＮＡ剪接的不同 ,β1和β3各有两种剪接变…