Notch信号通路在脑缺血的研究进展

Notch信号通路对中枢神经系统、血管细胞及免疫细胞生长分化发挥重要的调节作用。脑血管疾病引起的脑缺血激活Notch信号通路,活化的Notch信号通路调控神经前体细胞增殖和分化、介导炎症介质释放和促进血管细胞生成等在神经损伤修复、炎症反应、血管缺血区血管生成等起重要的调节作用。此外,Notch还与遗传性疾病CADASIL发病有关。本文就Notch信号通路在脑血管病中的作用及机制进行了分析。     

糖原合酶激酶-3β:神经炎症的潜在重要调节靶点

中枢神经系统的炎症反应在神经退行疾病、精神疾病等中起重要作用,其涉及到胶质细胞的激活、炎症因子的释放等,其炎症反应涉及许多信号调节通路,但具体仍需深入研究。目前越来越多的研究证据表明糖原合酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)参与了神经炎症反应的多条调控途径,包括内质网应激、线粒体损伤等,其激活状态可增强与炎症反应调控相关信号促进神经炎症反应导致中枢神经系统损伤。     

小胶质细胞极化信号通路在神经炎症中的研究进展

小胶质细胞是大脑神经炎症的主要参与者,具有经典激活的促炎M1型和替代激活的抗炎M2型。研究表明不同的信号通路改变小胶质细胞极化状态从而发挥对神经炎症的调控作用。因此,本文主要就该领域中的可行性通路进行综述,以期为后续神经炎症的机制研究和治疗靶点提供参考。     

脑缺血小胶质细胞的表型转化与靶向治疗研究

炎症反应在脑缺血的发病机制中起重要作用。小胶质细胞(MG)是中枢神经系统的固有免疫细胞,脑缺血发生后MG可被迅速活化为M1、M2不同表型,参与炎症反应的发生及后期的组织修复等过程。MG的过度活化可导致一系列细胞毒性因子的累积,对参与MG激活过程中的受体、信号通路及分泌物等的调节都可能是一个新的治疗策略。临床前研究表明几类药物具有上述作用,本文主要从脑缺血损伤后MG的活化表型、作用及临床前研究中对靶向抑制MG激活的药物进行综述。     

成分血中的细胞外囊泡在输血相关免疫调节中作用的研究进展

不同成分血在保存过程中产生的大量细胞外囊泡均富含多种生物活性分子,它们促进细胞与细胞之间的相互作用,介导细胞间的信号传递,广泛参与机体的炎症、代谢及免疫调控等。近年来的研究发现这些细胞外囊泡不仅能激活中性粒细胞引起输血相关急性肺损伤,还能作用于单核细胞刺激炎症反应,对患者免疫系统可起多种不同的调节作用。本文即是对不同成分血中的细胞外囊泡在输血相关免疫调节中的作用及其作用机制所作的综述。     

血清炎症趋化因子CXCL16与心力衰竭关系的研究进展

血清CXC趋化因子配体16 (CXC chemokine ligand 16, CXCL16)是近年来新发现一种趋化因子,同时是一种以膜蛋白结合形式及可溶性蛋白形式两种方式存在的跨膜蛋白,具有清道夫受体作用,同时还能促进大量炎性细胞浸润。心力衰竭的的病理生理过程与神经内分泌功能失调及炎症细胞因子的调控息息相关,且炎症系统的异常激活在心力衰竭中扮演着重要作用,早期已有研究证实CXCL16炎症趋化因子与心血管疾病的发展密切相关,尤其与心力衰竭的关系受到越来越多的关注。因此本文就 CXCL16 的结构、表达与调控及其与心力衰竭关系及研究进展作一综述。     

动脉粥样硬化相关的炎性信号通路的研究进展

动脉粥样硬化(AS)是冠心病、脑卒中等心脑血管疾病的重要病理基础,除脂质代谢紊乱、血管平滑肌细胞(VSMC)激活、氧化应激反应等危险因素外,炎性信号通路介导的炎症反应作为新的危险因素贯穿AS的形成、发展,已得到广大研究者的认可。本文就主要炎性信号通路在AS中的作用机制及信号通路间的联系研究进展作综述,旨在为通过抑制炎症治疗AS提供新思路。     

脊髓损伤后神经再生相关信号通路研究进展

随着神经再生相关机制研究不断深入,脊髓损伤后神经再生相关的信号通路也被广泛关注。有针对性地抑制细胞凋亡信号通路,可以降低脊髓损伤后细胞凋亡、炎症反应和神经变性。丝裂原活化蛋白激酶(MAPK)信号通路在调控基因表达、细胞增殖、细胞凋亡方面均发挥着重要作用,其下4条通路之间尚存在着交互作用。Janus激酶/信号转导子和转录激活子(JAK/STAT)信号通路除参与机体细胞的存活、增殖、分化、凋亡等过程外,还参与体内的炎性反应、氧化应激等过程。中枢神经系统损伤后,阻断Wnt信号通路可抑制神经轴突再生,而外源性Wnt3a可以增加脊髓损伤后的神经元数量,促进轴突传导及神经功能的改善。脊髓损伤后抑制哺乳动物雷帕霉素靶蛋白(m TOR)信号通路,可以显著减少神经元丢失、细胞死亡等,而且可促进功能恢复。Notch信号通路激活时,神经干细胞增殖活跃,分化被抑制;信号通路被抑制时,干细胞进入分化阶段。Ras同源基因/Rho相关卷曲螺旋蛋白激酶(Rho/ROCK)信号通路激活导致生长锥塌陷、轴突再生受制,而选择性抑制Rho可促进脊髓损伤后轴突再生和运动功能恢复。     

Notch信号通路在小胶质细胞活化中的作用

Notch信号通路是一种相邻细胞之间相互作用调控细胞命运的短程信号转导通路。Notch信号通路可以直接接收邻近细胞的信号,转导至细胞核,激活并调控相关转录因子,进而调控细胞的活化。作为中枢神经系统免疫防御的第一道防线,小胶质细胞是维持中枢神经系统稳态的固有免疫细胞,其活化与多种神经系统疾病有关。Notch信号通路在小胶质细胞的活化过程中发挥着重要作用,并可调控小胶质细胞释放炎症介质。     

急性心肌梗死心肌损伤的免疫学机制研究进展

早在20世纪初Mallory等就报道在急性心肌梗死(AMI)猝死的患者尸检中发现心肌组织的炎症浸润.急性心肌梗死后心肌局部和全身性炎症反应在心室重塑和心力衰竭的发生发展过程中起重要作用[1].AMI后除了心肌缺血性损伤外,免疫介导的炎症反应则起到加重心肌损伤和扩大心肌梗死范围的作用.AMI后坏死的心肌组织引起补体的激活、细胞因子的释放、炎症和免疫细胞的趋化和浸润,同时亦通过病理性自身免疫应答参与了心肌损伤.笔者就AMI后免疫介导的炎症反应引起心肌损伤的机制作一综述.     

Signal transduction in heart failure

Heart failure is the final culmination of protracted disease status precipitated by underlying ischemic disease, valvular insufficiency and viral myocarditis. The factors that lead to the development of heart failure are still not fully understood. In mammalian cells, four parallel kinase cascades have been described that finally lead to the activation of members of the mitogen-activated protein kinase(MAPK) family, such as ERKs (p42 and p44), JNK and p38 protein kinase. Apoptosis signal-regulating kinase 1 (ASK1), an upstream activator of JNK and p38, was shown to promote heart dysfunction and dilation as well as cardiac fibrosis. Meanwhile, not only myocyte apoptosis but also myocardial interstitial changes such as extracellular matrix deposition, activation of fibroblasts, and narrowing of vessel lumens play important roles for the progression of heart failure.     

The Th17/Treg imbalance exists in patients with heart failure with normal ejection fraction and heart failure with reduced ejection fraction

BackgroundImmune activation and inflammation participate in the progression of chronic heart failure (CHF), and T helper (Th) lymphocytes play critical roles in it. Th17 cells and CD4⁺CD25⁺ regulatory T (Treg) cells both come from naive Th cells, share reciprocal development pathways but exhibit opposite effects, and the balance between them controls inflammation and autoimmune diseases. We hypothesized that the Th17/Treg balance was impaired in patients with CHF.MethodsTo assess our hypothesis, patients with CHF were divided into 2 groups: heart failure with normal ejection fraction (HFNEF) group and heart failure with reduced ejection fraction (HFREF) group. Peripheral Th17 and Treg frequencies were analyzed by flow cytometry.ResultsPatients with HFNEF and HFREF both revealed significant increase in the frequencies of Th17 and obvious decrease in the frequencies of Treg compared with the controls.ConclusionThe results indicate that the Th17/Treg imbalance exists in patients with CHF, suggesting the imbalance potentially plays a role in the pathogenesis, and the Th17/Treg balance may be a promising therapeutic approach in patients with CHF.     

Beta-adrenergic pathways in human heart failure

Beta-adrenergic receptor activation plays an important role in the progression of human heart failure and the treatment of patients with beta-blockers has greatly improved the outcome of the disease. However, heart failure still is one of the leading causes of death in various countries and there is an imperative need for additional targets for the treatment of the disease. Recent studies by various groups have analyzed the downstream signaling pathways activated in response to beta-adrenergic stimulation that have the potential to become important targets for future treatments of heart failure. This review focuses on the significance of these pathways in the pathophysiology of heart failure in response to beta-adrenergic stimulation. More specifically the roles of PDE3, phosphorylation of phospholamban, and CaMKII activation are extensively discussed.     

Roles of cytokines in the pathogenesis of heart failure

Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. Our recent study showed that the various drugs for heart failure modulated the production of cytokines, and some of these drugs inhibited activation of NF-kappa B. Cytokine gene therapy which inhibits inflammatory response by viral IL-10 and IL-1 receptor antagonist has been shown to be effective in the animal models of heart failure. Mast cells have been shown to play important role in the pathogenesis of heart failure due to viral myocarditis, and transition from compensated hypertrophy to heart failure.     

Differential regulation of gap junctions by proinflammatory mediators in vitro.

The development of inflammation is an important component of host defense against infection. The cellular and molecular processes underlying inflammation are well-studied, and it is known that cells of the blood vessel wall, such as endothelial cells and smooth muscle cells, play pivotal roles. Additionally, a wide variety of proinflammatory mediators have been defined, which coordinate the multicellular processes of inflammation. Knowledge of the potential role of blood vessel gap junctional intercellular communication (GJIC) in coordinating the inflammation process, however, is limited. In this study, we report that bacterial lipopolysaccharide (LPS), as well as the proinflammatory cytokines TNF-alpha and IL-1beta, selectively inhibit human myoendothelial GJIC in vitro without affecting GJIC between the respective homologous cell populations. This finding may represent a physiologically relevant component of the inflammatory response to infection. The work also provides some of the first clear evidence suggesting that a single eukaryotic cell can differentially regulate its GJIC between homologous and heterologous cell types in a simultaneous manner.     

Treatment of life-threatening arrhythmias in patients with chronic heart failure

Several proven medical therapies such as beta-blockers and angiotensin converting enzyme inhibitors play important roles in preventing sudden death of patients with heart failure. Therapy with amiodarone and therapy with implantable cardioverter defibrillator (ICD) have developed specifically to prevent sudden death by life-threatening arrhythmias. But recently many large-scale clinical trials have proved that ICD therapy improves prognosis of patients with heart failure better than amiodarone therapy. Because ICD is not a treatment to prevent the occurrence of ventricular arrhythmias, it may not necessarily improve quality of life of patients. In that respect catheter ablation may play a role in preventing life-threatening arrhythmias.     

Tolerance to endotoxin-induced expression of the interleukin-1 beta gene in blood neutrophils of humans with the sepsis syndrome.

The induction of genes of host cells stimulated by microbial products such as endotoxin and the tolerance of cells to endotoxin excitation play critical roles in the pathogenesis of microbial-induced acute disseminated inflammation with multiorgan failure (the sepsis syndrome). One gene that is induced in phagocytic cells by endotoxin and that appears to play an essential role in the pathogenesis of the sepsis syndrome is IL-1 beta. We report here that blood neutrophils (PMN) of patients with the sepsis syndrome (sepsis PMN) are consistently tolerant to endotoxin-induced expression of the IL-1 beta gene, as determined by decreased synthesis of the IL-1 beta protein and reductions in IL-1 beta mRNA. This down-regulation of the IL-1 beta gene in sepsis PMN occurs concomitant with an upregulation in the constitutive expression of the type 2 IL-1 receptor (IL-1R2). These phenotypic changes do not persist in PMN of patients recovering from the sepsis syndrome. Tolerance has stimulus and response specificity since sepsis PMN tolerant to endotoxin can respond normally to Staphylococcus aureus stimulation of IL-1 beta production and they normally secrete elastase. Uninfected patients with severe trauma or shock from causes are not tolerant to endotoxin and tolerance is not limited to patients infected with Gram-negative bacteria. The mechanism responsible for tolerance involves pretranslational events and is not due to loss of the CD14 surface protein, a receptor required for endotoxin induction of IL-1 beta in PMN. The physiological significance of the tolerance to endotoxin and increased expression of IL-1R2 on sepsis PMN is unknown, but may represent an attempt by the host to protect itself from the deleterious effects of disseminated inflammation.     

老年冠心病患者外周血粘附细胞产生白细胞介素1的研究

目的 探讨老年冠心病人外周血粘附细胞产生白细胞介素1(IL-1)的变化及其与动脉粥样硬化的关系。方法 采用细胞培养生物学活性检测及放免分析的方法测定冠心病人外周血粘附细胞产生IL-1的活性。结果 老年冠心病人外周血粘附细胞产生IL-1的活性明显高于正常老年人。结论 老年冠心病人IL-1活性的增高可通过对血管平滑肌细胞、内皮细胞、补体以及在炎症损伤中的作用对动脉粥样硬化的发生产生重要影响。     

Brain natriuretic peptide in the contemporary management of congestive heart failure

Brain natriuretic peptide is a cardiac neurohormone that is secreted by the left ventricle in response to an increase in wall stress. Brain natriuretic peptide has emerged as a neurohormone with multiple roles in heart failure management. This review will discuss the role of brain natriuretic peptide in heart failure diagnosis, prognostic assessment, screening for asymptomatic left-ventricular dysfunction, and in the treatment of heart failure.     

TAK1 is required for the survival of hematopoietic cells and hepatocytes in mice

Transforming growth factor beta-activated kinase 1 (TAK1), a member of the MAPKKK family, is a key mediator of proinflammatory and stress signals. Activation of TAK1 by proinflammatory cytokines and T and B cell receptors induces the nuclear localization of nuclear factor kappaB (NF-kappaB) and the activation of c-Jun N-terminal kinase (JNK)/AP1 and P38, which play important roles in mediating inflammation, immune responses, T and B cell activation, and epithelial cell survival. Here, we report that TAK1 is critical for the survival of both hematopoietic cells and hepatocytes. Deletion of TAK1 results in bone marrow (BM) and liver failure in mice due to the massive apoptotic death of hematopoietic cells and hepatocytes. Hematopoietic stem cells and progenitors were among those hematopoietic cells affected by TAK1 deletion-induced cell death. This apoptotic cell death is autonomous, as demonstrated by reciprocal BM transplantation. Deletion of TAK1 resulted in the inactivation of both JNK and NF-kappaB signaling, as well as the down-regulation of expression of prosurvival genes.