警报素家族研究进展

警报素最早在2004年提出,是一类可应答于危险因子,对固有免疫细胞具有趋化和激活作用,可激发和促进适应性免疫应答的内源性生物介质。目前公认的警报素家族成员主要来自防御素家族,抗菌肽家族,嗜酸粒细胞衍生神经毒素和高迁移率族蛋白等。在炎症或损伤因素的刺激下,警报素能够迅速地从储存部位释放。警报素可以通过促进抗原的摄取、处理和呈递来增强对抗原特异性免疫反应的诱导,是一类可增强免疫活性的佐剂。对警报素家族深入研究将有助于阐明其在免疫系统中的地位,并可能为免疫治疗提供新的手段或靶点。     

警报素家族研究进展

警报素最早在2004年提出,是一类可应答于危险因子,对固有免疫细胞具有趋化和激活作用,可激发和促进适应性免疫应答的内源性生物介质.目前公认的警报素家族成员主要来自防御素家族,抗菌肽家族,嗜酸粒细胞衍生神经毒素和高迁移率族蛋白等.在炎症或损伤因素的刺激下,警报素能够迅速地从储存部位释放.警报素可以通过促进抗原的摄取、处理和呈递来增强对抗原特异性免疫反应的诱导,是一类可增强免疫活性的佐剂.对警报素家族深入研究将有助于阐明其在免疫系统中的地位,并可能为免疫治疗提供新的手段或靶点.     

选择素家族与子痫前期的研究进展

子痫前期是一种严重的妊娠期并发症,严重威胁孕产妇和胎儿的生命,也一直是产科研究的热点。子痫前期的发病机制尚不明确,目前比较一致的观点是胎盘浅着床、子宫螺旋动脉重塑障碍、胎盘的低灌注状态使胎盘缺氧,发生氧化应激,引起全身炎症反应和内皮功能紊乱与其相关。炎症反应是该疾病过程的主要环节,而选择素家族,包括P-选择素、E-选择素、L-选择素在炎症反应过程中发挥着重要作用。     

钙调神经磷酸酶在大鼠肺组织合成和释放鸟苷素中的作用

研究钙调神经磷酸酶 (CaN)依赖的信号通路在肺组织合成和释放鸟苷素中的作用。以乙酰胆碱 (Ach)刺激孵育的大鼠离体肺组织 ,用放射免疫法测定肺组织和孵育液中鸟苷素的含量 ,以及肺组织CaN活性 ;同时观察CaN抑制剂环孢霉素A(CsA)对鸟苷素生成的影响。结果发现 :( 1)Ach呈浓度依赖性增加孵育液中鸟苷素的含量 ,孵育4h后 ,分别较对照组增加了 63 2 % ,13 5 1%和 15 6 6% (P <0 0 1)。肺组织鸟苷素的含量 ,分别较对照组增加了2 9% ,3 4 3 % (P <0 0 1)和 42 0 % (P <0 0 1)。 ( 2 )Ach 10 -5mol L呈时间依赖性增加孵育液中鸟苷素的含量 ,在 2 ,4,6h分别较对照组增加了 90 7% ,13 5 1%和 173 8% (P <0 0 1) ;肺组织鸟苷素含量分别增加了 7 0 % ,3 4 3 % (P <0 0 1)和 3 3 8% (P <0 0 1)。 ( 3 )CaN抑制剂CsA呈浓度 ( 10 -8、10 -7和 10 -6mol L)依赖性抑制Ach 10 -5mol L刺激的孵育液中鸟苷素的含量 ,分别下降了 9% (P <0 0 5 ) ,2 0 4% (P <0 0 5 )和 3 6 1% (P <0 0 1)。肺组织鸟苷素的含量分别降低 2 3 % ,10 1% (P <0 0 5 )和 2 0 3 % (P <0 0 1)。 ( 4 )Ach 10 -5mol L作用 4h可刺激肺组织CaN活性增加2 1 5 % (P <0 0 5 ) ,CsA 10 -6mol L则抑制Ach刺激的肺组织CaN活性 (P <0     

内源性一氧化碳对循环系统的调节作用

内源性一氧化碳是循环系统中的一种新型的第二信使，它能够活化细胞内的可溶性鸟苷酸环化酶，松驰血管平滑肌，抑制血小板活化和中性粒细胞的粘附，参与循环系统的神经体液调节和机体的免疫调节。     

哺乳动物可溶性鸟苷酸环化酶的表达及其调控

鸟苷酸环化酶(guanylate cyclase,GCs)是把GTP转化为cGMP的蛋白酶.第二信使cGMP作用于信号级联反应下游元件:蛋白激酶G(protein kinase G,PKG)、cGMP依赖性磷酸二酯酶(cGMP phosphodiesterase,cGMP-PDEs)及cGMP门控离子通道(cyclic nucleotide-gated ion channels,CNGs),参与血管舒缩、神经信号传递、抑制血小板凝集及细胞增殖与调亡等调节.GCs有两种存在形式:可溶性鸟苷酸环化酶(soluble guanylate cyclase,sGC)和非可溶性鸟苷酸环化酶(particle guanylate cyclase,pGC).pGC同功酶是尿钠肽的受体,sGC是NO的受体.除了配体与亚细胞分布不同以外,两种GCs存在形式也不同.进一步理解sGC亚单元的结构及其在转录及翻译后水平上的调控,有助于深入认识GCs在cGMP信号通路及生理功能中的作用.     

选择素家族的分布及生物学功能研究进展

选择素广泛表达于白细胞、活化的内皮细胞以及血小板表面,可在血流状态下介导白细胞与血管内皮细胞和血小板的初始粘附,主要参与细胞与细胞之间选择性的相互作用.本文介绍选择素家族(L、P和E)蛋白分子的结构特征、生理病理分布及生理功能,并简要叙述近年来有关选择素功能、选择素与疾病相关性等研究进展情况.     

可溶性鸟苷酸环化酶及其调节

可溶性鸟苷酸环化酶 (sGC)是迄今所知的一氧化氮 (NO)的唯一受体 ,它启动NO信号转导通路 ,是NO cGMP通路中的关键酶 ,参与细胞信号调节     

鸟苷环－磷酸和人嗜中性白细胞

鸟苷环－磷酸（ｃＧＭＰ）对人嗜中性白细胞的许多功能起精密调节作用。一定浓度的ｃＧＭＰ可增加入嗜中性白细胞的游走性，增强一些炎症介质对人嗜中性白细胞的趋化作用，调节不同种类及不同浓度的炎症介质引起的人嗜中性白细胞脱颗粒及呼吸爆发效应。胞浆内鸟苷环－磷酸依赖性蛋白激酶ＰＫＧ（ｃｙｃｌｉｃＧＭｐ－ｄｅｐｅｎｄｅｎｔｐｒｏｔｅｉｎｋｉｎａｓｅ）是人嗜中性白细胞内主要的ｃＧＭＰ受体，ｃＧＭＰ通过激活ＰＫＧ影响人嗜中性白细胞的功能。     

From Escherichia coli heat-stable enterotoxin to mammalian endogenous guanylin hormones

The isolation of heat-stable enterotoxin (STa) from Escherichia coli and cholera toxin from Vibrio cholerae has increased our knowledge of specific mechanisms of action that could be used as pharmacological tools to understand the guanylyl cyclase-C and the adenylyl cyclase enzymatic systems. These discoveries have also been instrumental in increasing our understanding of the basic mechanisms that control the electrolyte and water balance in the gut, kidney, and urinary tracts under normal conditions and in disease. Herein, we review the evolution of genes of the guanylin family and STa genes from bacteria to fish and mammals. We also describe new developments and perspectives regarding these novel bacterial compounds and peptide hormones that act in electrolyte and water balance. The available data point toward new therapeutic perspectives for pathological features such as functional gastrointestinal disorders associated with constipation, colorectal cancer, cystic fibrosis, asthma, hypertension, gastrointestinal barrier function damage associated with enteropathy, enteric infection, malnutrition, satiety, food preferences, obesity, metabolic syndrome, and effects on behavior and brain disorders such as attention deficit, hyperactivity disorder, and schizophrenia.     

Guanylin ligand protects the intestinal immune barrier by activating the guanylate cyclase-C signaling pathway

Inflammatory bowel disease (IBD) impacts patient quality of life significantly. The dysfunction of intestinal immune barrier is closely associated with IBD. The guanylate cyclase-C (GC-C) signaling pathway activated by the guanylin (Gn) ligand is involved in the occurrence and development of IBD. However, how it regulates the intestinal immune barrier is still unclear. To investigate the effect of the GC-C pathway on intestinal mucosal immunity and provide experimental basis for seeking new therapeutic strategies for IBD, we focused on Caco-2 cells and intestinal intra-epithelial lymphocytes (IELs), which displayed inflammatory responses induced by lipopolysaccharide (LPS). GC-C activity was modulated by transfection with Gn overexpression or GC-C shRNA plasmid. Levels of Gn, GC-C, and CFTR; transepithelial electrical resistance (TER); paracellula r permeability; and levels of IL-2, IFN-γ, and secretory IgA (sIgA) were examined. The study found that after stimulation with LPS, Gn, GC-C, CFTR, TER, and sIgA levels were all significantly reduced, IL-2 and IFN-γ levels as well as paracellular permeability were significantly increased. These indicators changed inversely and significantly after transfection with the Gn overexpression vector. Compared to the vector controls, GC-C-silenced cells displayed significantly decreased levels of GC-C, CFTR, and TER and increased levels of IL-2, IFN-γ, and paracellular permeability stimulated by LPS. The results show that Gn ligand can protect the intestinal immune barrier by activating the GC-C signaling pathway, which may be helpful for the development of new treatments for IBD.Data availability statementThe data used to support the findings of this study are available from the corresponding author upon request.     

Mechanisms of actions of guanylin peptides in the kidney

After a salty meal, stimulation of salt excretion via the kidney is a possible mechanism to prevent hypernatremia and hypervolemia. Besides the well known hormonal regulators of salt and water excretion in the distal nephron, arginine vasopressin and aldosterone, guanylin (GN) peptides produced in the intestine were proposed to be intestinal natriuretic peptides. These peptides inhibit Na⁺ absorption in the intestine and induce natriuresis, kaliuresis and diuresis in the kidney. The signaling pathway of GN peptides in the intestine is well known. They activate enterocytes via guanylate cyclase C (GC-C) and increase the cellular concentration of cGMP which leads to secretion of Cl^–, HCO₃^– and water into the intestinal lumen and to inhibition of Na⁺ absorption. Guanylin peptides are filtered in the glomerulus, and additionally synthesized and excreted by tubular cells. They activate receptors located in the luminal membrane of the tubular cells along the nephron. In GC-C deficient mice renal effects of GN peptides are retained. In human, rat, and opossum proximal tubule cells, a cGMP-dependent signaling was demonstrated, but in addition GN peptides apparently also activate a PT-sensitive G-protein coupled receptor. A similar dual signaling pathway is also known for other natriuretic peptides like atrial natriuretic peptide. A cGMP-independent signaling pathway of GN peptides is also shown for principal cells of the human cortical collecting duct where the final hormonal regulation of electrolyte homeostasis takes place. This review will focus on the current knowledge on renal actions of GN peptides and specifically address novel GC-C- and cGMP-independent signaling mechanisms.     

Intravenous injection of guanylin induces mucus secretion from goblet cells in rat duodenal crypts

 Guanylin, structurally related to the heat-stable enterotoxin of E. coli, is a 15-amino-acid peptide isolated from rat small intestine. We investigated the morphological effects of an intravenous injection of rat and human guanylin upon the rat intestine. Various doses of rat guanylin were injected intravenously in anesthetized rats. After 5, 10 and 30 min, rats were killed by intracardiac perfusion with aldehyde fixative, and specimens of the intestine were then prepared for light and electron microscopy. Intravenously injected rat guanylin rapidly induced mucus secretion from crypt goblet cells in the duodenum. About half of the crypt goblet cells secreted mucous granules by compound exocytosis within 5 min. The villus goblet cells, in contrast, were not sensitive to guanylin. Goblet cells in the jejunum were less responsive than those in the duodenum. This secretory response was rare in the ileum and colon. Human guanylin produced similar results. The mucus secretion induced by guanylin was inhibited by a prior-injection of atropine, but not hexamethonium. Moreover, guanylin induced intense edema in the mucosa and submucosa of the small intestine 5 min after the injection, which disappeared after 30 min. A prior-injection of atropine did not block the appearance of edema. In conclusion, the intravenous injection of guanylin induces two phenomena related to water movement: (1) compound exocytosis of mucous granules from crypt goblet cells in the rat duodenum and jejunum; (2) perineural, inter-epithelial and intra-epithelial edema in the rat small intestine. Accepted: 27 October 1997     

哺乳动物腺苷酸环化酶亚型的研究进展

腺苷酸环化酶(adenylyl cyclase,AC)作为G蛋白偶联受体(G protein-coupled receptors,GPCRs)下游的关键信号分子,参与了多种生理和病理进程.由于存在多种AC亚型(AC1～9及sAC),且各个膜型AC亚型在组织及不同细胞膜微区(脂筏)的分布、定位、活性及表达水平不尽一致,目...     

姜黄素通过HO/GC途径对抗高糖诱导的血管收缩功能下降

目的:研究姜黄素是否可对抗高糖诱导的血管收缩功能下降,并探讨其作用机制。方法:采用血管环离体灌流装置,观察SD大鼠胸主动脉环的收缩反应;测定主动脉胆红素生成量反映血红素加氧酶-1(HO-1)的活性。结果:(1)与空白对照组(含11mmol/L葡萄糖)相比,经44mmol/L葡萄糖(高糖)孵育血管4h后,主动脉环对苯肾上腺素(PE)引起的血管收缩反应下降;(2)姜黄素(3×10-11-3×10-10mol/L)与高糖联合孵育,均能不同程度地抑制高糖诱导的血管PE收缩反应的下降;(3)姜黄素孵育后可引起血管HO活性增高;HO-1抑制剂锌原卟啉Ⅸ(ZnPP)可完全取消姜黄素的抗高糖损伤作用;(4)鸟苷酸环化酶(GC)抑制剂亚甲蓝可部分阻断姜黄素的保护作用。结论:姜黄素可能通过诱导HO-1活性增加和激活GC途径对抗高糖引起的血管收缩功能降低。     

Duodenal bicarbonate secretion in rats: stimulation by intra-arterial and luminal guanylin and uroguanylin

Aim: Uroguanylin and guanylin are endogenous ligands for guanylate cyclase C, an upstream regulator of the cystic fibrosis transmembrane resistance (CFTR) anion channel, and both peptides increase intestinal anion export in vitro. We have compared the effects of close intra‐arterial and luminal administration of uroguanylin and guanylin on duodenal bicarbonate secretion in vivo and studied the interactions with melatonin and cholinergic stimulation. Methods: Lewis × Dark Agouti rats were anaesthetized and a segment of the proximal duodenum with intact blood supply was cannulated in situ. Mucosal bicarbonate secretion (pH stat) was continuously recorded and peptides were infused intra‐arterially or added to the luminal perfusate. Results: Intra‐arterial (50–1000 pmol kg^?1 h^?1) as well as luminal administration (50–500 nmol L^?1) of guanylin or uroguanylin caused dose‐dependent increases in the duodenal secretion. Luminal administration induced more rapidly appearing rises in secretion and the two peptides induced secretory responses of similar shape and magnitude. The melatonin MT₂‐selective antagonist luzindole (600 nmol kg^?1) significantly depressed the response to intra‐arterial guanylins but did not affect secretion induced by luminal guanylins. Similarly, the muscarinic antagonist atropine (0.75 μmol kg^?1 followed by 0.15 μmol kg^?1 h^?1) abolished the response to intra‐arterial uroguanylin but caused only slight suppression of the response to luminal uroguanylin. Conclusions: Intra‐arterial as well as luminal uroguanylin and guanylin are potent stimuli of duodenal mucosal bicarbonate secretion in vivo. The response to luminal guanylins reflects an action at apical receptors. Stimulation by parenteral guanylins, in contrast, is under cholinergic influence and interacts with melatonin produced by mucosal enteroendocrine cells.     

Effect of molsidomine on ex vivo platelet aggregation and plasma guanosine 3′∶5′-cyclic monophosphate levels in healthy volunteers

Summary To find out whether 3-morpholino-sydnonimine (SIN 1), the active metabolite of molsidomine, exerts its antiaggregatory effects not only in vitro but also in vivo, we tested ex vivo aggregation before and after intravenous application of molsidomine in healthy volunteers. We also measured plasma levels of guanosine 35-cyclic monophosphate (cyclic GMP) as SIN 1, the bioactive metabolite of molsidomine, becomes effective via activation of soluble guanylate cyclase. In eight out of ten subjects molsidomine had an inhibitory effect on platelet aggregation and a higher threshold concentration of platelet-activating factor was required after molsidomine application to induce irreversible aggregation. Despite the effect on platelets, plasma cyclic GMP levels did not increase. These results suggest that the nitric oxide-containing SIN 1 inhibits platelet aggregation not only in vitro but also in vivo and that this property can be a beneficial effect in antianginal therapy.Abbreviations Cyclic GMP guanosine 35-cyclic monophosphate - NO nitric oxide - PAF platelet-activating factor - PRP platelet-rich plasma - SIN 1 3-morpholino-sydnonimine     

TRIM家族在宫颈癌中的研究进展

宫颈癌是女性中常见恶性肿瘤之一,病死率较高,全球死亡女性超过88％发生在发展中国家,其中以宫颈鳞癌最为常见.三方基序蛋白(tripartite motif-containing protein,TRIM)家族大多数具有E3泛素连接酶活性,且与多种生理过程有关,包括细胞增殖、DNA修复、信号转导和转录.近年大量研究发现TRIM家族通过多种通路参与宫颈癌的发生和发展.     

整合素相互作用蛋白Kindlin家族的生物学功能研究进展

整合素相互作用蛋白Kindlin是一种新型的黏着斑蛋白,是进化上高度保守的含有FERM结构域的蛋白家族,目前已知有3个家族成员Kindlin-1、Kindlin-2和Kindlin-3。近年来研究表明,Kindlin家族不仅与整合素活化和多种遗传性疾病有关,而且作为重要的信号分子参与了肿瘤的发生发展过程。我们将从Kindlin的结构特征、组织分布及生物学功能的研究进展作一综述。