甘草酸免疫调节机制研究进展

甘草酸作为甘草的重要活性成分具有抗病毒、抗炎、抗氧化、抗变态反应、抗肿瘤及免疫调节等作用.其中免疫调节作用备受关注.甘草酸通过多种信号转导通路来调节固有免疫及适应性免疫.因而对甘草酸的免疫调节作用的研究具有重要意义.     

Toll/IL-1R家族信号转导机制研究进展

Toll是广泛参与机体天然和获得性免疫应答的分子, 其胞外段可与相应配体结合, 通过胞内段激活细胞内信号转导系统。在研究其胞内信号转导的分子机制时发现, Toll的胞内段与Il 1R家族分子的胞内段(TIR区)有高度同源性, 并都可通过MyD88依赖途径激活细胞内信号转导。另外, Toll家族的个别成员还可在MyD88缺失时通过替代途径 MyD88非依赖途径激活信号转导, 现将其研究进展综述如下。1　Toll/IL 1R家族及其成员的结构特点已知Toll是果蝇胚胎发育过程中控制果蝇腹背模式形成的一类蛋白, 并可介导对多种细菌和真菌感染的天然免疫,目前…     

瘦素的免疫调节作用及信号转导研究进展

瘦素(leptin)是一种主要调节能量代谢的蛋白类激素。瘦素可以促进多种免疫细胞的增殖、活化及细胞因子合成,促使免疫反应向Th1方向漂移,促进NK细胞的细胞毒作用,促进炎症反应,因此,瘦素在免疫系统中发挥着重要的调节作用。瘦素受体(leptin receptor,LEP-R)与其配体结合后主要通过JAK-STAT3通路来向胞内转导活化信号,调节转录。文章就瘦素对免疫组织器官、免疫细胞的生物学作用及其信号转导通路的研究进展作如下综述。     

树突状细胞参与免疫调节的相关受体及其介导的信号转导通路研究进展

树突状细胞(DC)是体内最重要的抗原递呈细胞(APC),具有摄取、处理和提呈抗原至T细胞的功能.DC通过其模式识别受体(PRR)能够识别区分不同类别的病原体,PRR与病原相关分子模式(PAMP)相结合,诱导适应性免疫反应.DC表达的PRR主要包括:Toll样受体(TLR)、C型凝集素受体(CLRs)、NOD样受体(NLR)等.这些受体可以通过启动信号转导通路参与免疫调节.现就DC参与免疫调节的主要相关受体及其介导的信号转导通路研究进展进行综述.     

疼痛治疗的信号转导机制研究进展

目的：疼痛是当代医学研究活跃的领域之一,目前对其研究已进入到分子生物学水平。笔者检索有关疼痛产生机制以及镇痛作用机理的相关资料,发现该类文献中诸多是从信号转导的不同环节进行研究,经归纳整理,从第一信使、第二信使等层面展开分析,概述了疼痛的产生以及镇痛作用机理。     

埃兹蛋白参与调控的信号转导通路研究进展

埃兹蛋白（Ezrin）是细胞骨架连接蛋白（Ezrin-Radixin-Moesin,ERM）家族成员之一,主要分布于细胞皮层。Ezrin作为膜蛋白和肌动蛋白连接蛋白,在调控细胞的形态、生长、生存、黏附、增殖和迁徙等生物学功能中发挥重要作用。其作用机制复杂,涉及Rho、PKA、PKC、MAPK及细胞凋亡等多条信号传导通路。因此,研究Ezrin相关的信号转导,对认识疾病的发展及治疗具有重要意义。     

细胞内早期信号转导的NT-PTK机制研究进展

继细胞外的信号与细胞膜上的受体结合之后 ,细胞内的信号转导机构发生各种反应 ,最终引起细胞的分化、增殖、效应、死亡等各种应答。其中 ,酪氨酸磷酸化和去磷酸化占据重要地位。本文主要对由MIRR启动的早期NT PTK(non transmembraneproteintyrosinekinase)信号转导机制、细胞因子受体启动的与核内转录直接相联系的Jak STAT途径以及对它们的调控机制作一综述     

TLR家族分子信号转导新进展

TLR（Toll—like reeepter）家族成员以胞内区高度进化保守的TIR结构域（Toll／IL-1R domain）为特征，可通过胞外区的亮氨酸重复序列（leucine-rich repeat，LRR）功能区识别各种病原体相关分子模式（pathogen associated molecular pattern，PAMP）引发机体免疫应答。TLR识别配体后由MyD88、Mal、TRIF、TRAM等含TIR的接头蛋白介导，通过MyD88依赖途径或MyD88非依赖途径进行信号转导，不同的接头蛋白决定了不同TLR的信号转导途径，本文针对各含TIR的接头蛋白对TLR信号转导通路研究进展作一综述。     

036 细胞内早期信号转导的NT-PTK机制研究进展

继细胞外的信号与细胞膜上的受体结合之后,细胞内的信号转导机构发生各种反应,最终引起细胞的分化、增殖、效应、死亡等各种应答.其中,酪氨酸磷酸化和去磷酸化占据重要地位.本文主要对由MIRR启动的早期NT-PTK(non-transmembrane protein tyrosine kinase)信号转导机制、细胞因子受体启动的与核内转录直接相联系的Jak-STAT途径以及对它们的调控机制作一综述.     

TLR家族分子信号转导新进展

TLR(Toll-like recepter)家族成员以胞内区高度进化保守的TIR结构域(Toll/IL-1R domain)为特征,可通过胞外区的亮氨酸重复序列(leucine-rich repeat,LRR)功能区识别各种病原体相关分子模式(pathogen associated molecular pattern,PAMP)引发机体免疫应答。TLR识别配体后由MyD88、Mal、TRIF、TRAM等含TIR的接头蛋白介导,通过MyD88依赖途径或MyD88非依赖途径进行信号转导,不同的接头蛋白决定了不同TLR的信号转导途径,本文针对各含TIR的接头蛋白对TLR信号转导通路研究进展作一综述。     

巨噬细胞的激活及其信号传导机制的研究进展

巨噬细胞广泛存在于全身各组织,一般处于静息状态,活化以后成为具有活跃生物学功能的效应细胞。巨噬细胞激活的刺激因子主要有细菌、细胞因子、植物血凝素、寄生虫等。巨噬细胞激活的信号传导途径主要有LPS信号传导途径、Ca2 信号传导途径、PKC信号传导途径、JAK-STAT信号传导途径、MAPK信号传导途径、PI3K信号传导途径等。通过不同刺激因子和各种信号传导途径激活的巨噬细胞,构成了可以执行不同免疫功能的复杂群体。     

Corticotropin-releasing hormone (CRH)-immunoreactive (IR) axon varicosities target a subset of growth hormone-releasing hormone (GHRH)-IR neurons in the human hypothalamus

It is a general consensus that stress is one of the major factors that suppresses growth. Previous studies revealed that the catecholaminergic and neuropeptide Y (NPY) systems, involved in the activation of stress-related neuronal circuits, influence growth hormone (GH)-release via modulating growth hormone-releasing hormone (GHRH) secretion. Indeed, catecholaminergic and NPY-immunoreactive (IR) axon varicosities abut on the surface of the GHRH neurons forming contacts. These juxtapositions appear to be real synapses and may represent the morphological substrate of the impact of stress on growth. In addition to catecholamines and NPY, there is a vast amount of evidence that corticotropin-releasing hormone (CRH), a major stress hormone, also influences GH secretion. Whether this modulatory effect is direct, or indirect, via the hypothalamic GHRH system, has not been elucidated yet.In the present study, we examined the possibility that CRH influences GH secretion via modulating the GHRH release by direct synaptic mechanisms. Since the verification of these synapses by electron microscopy is problematic in human due to the long post mortem time, in order to reveal the putative CRH-GHRH juxtapositions, light microscopic double label immunohistochemistry was utilized. In the infundibular nucleus, a subset (6%) of the GHRH perikarya received abutting CRH fiber varicosities forming multiple contacts while passing by. No gaps appeared between the contacting elements. The morphology of these CRH-GHRH juxtapositions suggests that, among other neurotransmitters/neuromodulators, CRH influences growth by modulating the hypothalamic GHRH secretion via direct synaptic mechanisms.     

Corticotropin-releasing hormone acts on guinea pig ileal smooth muscle via protein kinase A

In contraction studies corticotropin-releasing hormone (CRH) was found to relax ileal but not gastric and jejunal smooth muscles of the guinea-pig, precontracted with BaCl₂. Under whole-cell patch-clamp conditions, CRH concentration-dependently activated Ca²⁺-sensitive K⁺ currents (I _K) with ED₅₀=20 pM at 100 nM and ED₅₀=0.13 pM at 500 nM intracellular Ca²⁺ respectively. This increase was accompanied by significant hyperpolarization of the cell membranes. CRH 9–41 peptide fragment did not affect I _K amplitude, membrane potential or contraction. The CRH-induced increase of I _K densities was accelerated in the presence of high intracellular Ca²⁺ concentrations (500 nM) and was abolished by pretreatment of cells with either ryanodine or thapsigargin, which cause depletion of intracellular Ca²⁺ stores, as well as in cells treated under conditions prohibiting intracellular Ca²⁺ store refilling. The effect of CRH on I _K was not affected by bath application of various selective inhibitors of membrane-bound phospholipases, protein kinase C, cGMP-dependent protein kinase or Ca²⁺/calmodulin-dependent protein kinase II, but was effectively antagonized by blockers of protein kinase A (PKA) or adenylyl cyclase. Neither forskolin nor the catalytic subunit of PKA could mimic the effect of CRH on I _K. Thus, it was suggested that CRH exerts its relaxing activity on ileal smooth muscle cells via PKA-dependent phosphorylation of some intracellular target coupled to sarcoplasmic reticulum Ca²⁺ storage machinery. Received: 18 January 1999 / Received after revision: 8 March 1999 / Accepted: 9 March 1999     

Reproductive functions of corticotropin-releasing hormone. Research and potential clinical utility of antalarmins (CRH receptor type 1 antagonists)

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis exerts a complex, mostly inhibitory, effect on the female reproductive system. In addition, the principal regulator of this axis, the hypothalamic neuropeptide corticotropin-releasing hormone (CRH) and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, CRH is secreted in peripheral inflammatory sites where it exerts strong inflammatory actions. Antalarmins (CRH receptor type 1 antagonists) have been used to elucidate the roles of CRH in stress, inflammation and reproduction. METHOD OF STUDY: We review existing data on the effects of CRH in the female reproductive system. RESULTS: Ovarian CRH participates in female sex steroid production, follicular maturation, ovulation and luteolysis. Uterine CRH participates in decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of parturition. Circulating placental CRH is secreted mostly during the latter half of pregnancy and is responsible for the concurrently increasing physiologic hypercortisolism of this period. After labor and delivery, this hypercortisolism is ensued by a transient suppression of hypothalamic CRH secretion, which may explain the postpartum blues and depression and the increased autoimmune manifestations depression of period, the postpartum period. CONCLUSIONS: These data show that CRH is present in female reproductive tissues, and is regulating key reproductive functions with an inflammatory component, such as ovulation, luteolysis, implantation, and parturition.     

Corticotropin-releasing hormone receptor 1 coexists with endothelin-1 and modulates its mRNA expression and release in rat paraventricular nucleus during hypoxia

To determine whether corticotropin-releasing hormone receptor 1 (CRHR1) coexists with endothelin-1 (ET-1) in rat paraventricular nucleus (PVN), ET-1 expression and its regulation by CRH and CRHR1 under hypoxia, rats were exposed to simulated continuous hypoxia at 5 km altitude (CH5km, equal to 10.8% O(2)) in a hypobaric chamber for 1, 2, 5, 10, 15 or 25 days. ET-1, CRH, and its mRNA were measured using radioimmunoassay (RIA), immunohistochemistry, and in situ hybridization. The coexistence of ET-1 and CRHR1 was identified by confocal immunofluorescence. The results showed that CH5km caused a significant decrease of ET-1 level in PVN at 5 days, but decreased CRH on days 1 and 2 while it increased on days 5 and 10. CH5km induced ET-1 mRNA upregulation and ET-1 decrease at 5 days, the effects were completely reversed by treatment with five-daily-injections of a CRHR1 antagonist (butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl]-ethylamine: CP-154,526). Also, this treatment significantly reversed the CH5km-induced increase in CRH and CRHmRNA in PVN at 5 days. Moreover we found that the changes in expression of ET-1 and CRHR1 induced by CH5km were co-localized in parvocellular PVN cells. In conclusion, CRHR1 coexists with ET-1 in parvocellular PVN, continuous hypoxia stimulates ET-1 and ET-1mRNA as well as CRH and CRHmRNA, and CRHR1 evidently modulates ET-1 release and ET-1mRNA activation caused by continuous hypoxia.     

骨组织力学信号转导的研究

力学因素对骨组织的生长和重建有着很大的影响 ,成骨细胞和骨细胞在这一过程中起着非常重要的作用。本文概述了骨骼对力学刺激的感受、信号转导、基因表达改变以及效应细胞在此反应中所起作用的新进展     

T-cell antigen receptor peptides inhibit signal transduction within the membrane bilayer

Previous studies have shown that a synthetic peptide (core peptide, CP) corresponding to a 9-amino-acid region in the transmembrane domain of the alpha subunit of the T-cell antigen receptor (TCR) can suppress T-cell function in vitro and in vivo. The aim of these experiments was to determine the cellular site and molecular mechanism of CP inhibition in T cells. The cytochrome c-sensitive TCR-expressing hybridoma (2B4) was stimulated with pigeon cytochrome c antigen, anti-CD3 crosslinking, or PMA and ionomycin, in the presence or absence of CP, and the resulting IL-2 produced was measured in a bioassay using an IL-2-dependent cell line (CTLL-2). In the presence of CP, IL-2 production was inhibited following antigen-induced stimulation. By contrast, when stimulated with cross-linking antibodies to the CD3 complex or with PMA and ionomycin, both of which activate T cells downstream of the TCR antigen recognition site, CP had no effect on IL-2 production. These experiments suggest that CP interferes with TCR function by inhibiting T-cell activation at the transmembrane/receptor level. In addition, we show that CP inhibits early TCR signal transduction events such as TCR zeta chain phosphorylation following stimulation with either antigen or anti-CD3-crosslinking antibodies, although this is unlikely to be the mechanism leading to the reduced IL-2 production.     

The neuroprotective actions of corticotropin releasing hormone

Corticotropin-releasing hormone (CRH) modulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and has a key role in mediating neuroendocrine effects that occur in response to stressful stimuli. Disruption of the CRH system however has been shown to be closely associated with the progression of Alzheimer's disease (AD), and these observations prompted an investigation into the potential neuroprotective effects of the hormone. In addition to its regulatory affects on the molecular processes that underlie AD i.e., amyloid precursor protein (APP) processing and potentially tau phosphorylation, evidence is provided that the neuroprotective effects of CRH are mediated by a number of diverse mechanisms. These stem from activation of its high affinity receptor, the CRH type 1 receptor, and involve the induction of protective intracellular pathways including PKA-CREB that eventually lead to expression of neurotrophic factors. Conversely, inhibition of harmful events, such as caspase activation during apoptosis may also occur. Taken together, an impressive amount of evidence has accumulated recently, highlighting this new and potentially important function of CRH.