Potential therapeutic targeting of platelet-mediated cellular interactions in atherosclerosis and inflammation

Cellular interactions among platelets, leukocytes and endothelial cells are considered as a major cause of inflammation and atherosclerosis in many diseases. Via exposed surface receptors and released soluble substances, activated platelets play a crucial role in the initiation of inflammatory processes, resulting in endothelial injury and leading to formation of atherosclerotic plaque with possible thrombotic complications. Classic anti-platelet treatments (e.g. cyclooxygenase inhibitor or ADP-receptor antagonist) have favorable effects in patients with vascular diseases, but they also have several limitations such as increased bleeding risk or non-responsiveness. Thus, the need and opportunities for developing novel therapeutic inhibitors for platelet-mediated events are obvious. Animal and (pre)clinical human studies have suggested that some recently produced specific antagonists of P-selectin from α-granules, as well as its main ligand/receptor P-selectin Glycoprotein Ligand-1, the two major platelet chemokines CXCL4 and CCL5, as well as CD40L, may be considered potential new candidates in the treatment of atherogenesis and inflammation. In this review, we summarize the pathophysiological roles of these effectors in platelet activation and acute or chronic inflammation, and discuss the latest findings on promising antagonistic agents in basic and clinical studies in the prevention of platelet-mediated cellular interactions.     

P2X_7受体在炎症和疼痛中的潜在作用及治疗应用

P2X7受体为胞外ATP激活的非选择性阳离子通道,并能触发白介素-1β、白介素-18、肿瘤坏死因子和一氧化氮等前炎性物质的释放。临床研究表明,P2X7受体参与炎症和疼痛机制,调节P2X7受体功能的化合物,具有潜在的新抗炎药物的作用。因此,P2X7受体在炎症和疼痛中发挥重要的生理作用及潜在的临床应用,成为疼痛治疗的药物作用新靶点。     

Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock

Soluble phospholipase A2 has been implicated in the pathogenesis of local and systemic inflammatory reactions. Elevated levels of circulating phospholipase A2 (PLA2) correlate with the severity of circulatory collapse and pulmonary dysfunction in gram-negative septic shock. Characterization of septic shock serum PLA2 revealed a calcium-dependent enzyme with absolute 2-acyl specificity with a pH optimum of 7.5. We tested a number of therapeutic agents for their ability to inhibit PLA2 from human septic shock serum. Chloroquine, chlorpromazine, dexamethasone base, dexamethasone sodium phosphate, indomethacin, lidocaine, oleic acid, palmitic acid, promethazine, trans-retinoic acid, rutin and dl-alpha-tocopherol were all studied over the range of 10(-2) to 10(-7) M. All agents, with the sole exception of dexamethasone base, inhibited PLA2 activity at concentrations greater than 10(-3) M. PLA2 inhibition by dexamethasone sodium phosphate was factitious, due to the formation of calcium-phosphate complexes. Of the 11 agents studied, chlorpromazine was the most effective, with an IC50 of 7.5 X 10(-5) M, a membrane concentration achievable within its therapeutic range. Inhibition was non-competitive with an apparent Ki of 5 nM. Since serum PLA2 levels correlate with mortality in both experimental endotoxemia and clinical gram-negative septic shock, and chlorpromazine was previously shown to improve survival in these conditions, we postulate that its therapeutic efficacy resides at least in part in its PLA2-inhibitory activity.     

宁泌泰胶囊对大鼠大肠杆菌感染性盆腔炎的改善作用研究

目的 探究宁泌泰胶囊对盆腔炎病症的改善作用。方法 选用大鼠大肠杆菌感染性盆腔炎模型,苯酚胶浆引起大鼠化学性盆腔炎模型,用妇科千金片(1.0 g/kg)及宁泌泰胶囊高、中、低剂量(2.0、1.0、0.5 g/kg)连续ig 7 d,每天2 次。以动物体质量变化、白细胞计数、病理学检查评价宁泌泰胶囊对盆腔炎的治疗作用。结果 宁泌泰胶囊3 个剂量组对大肠杆菌引起的感染性盆腔炎大鼠子宫肉眼可见的炎性症状有一定的改善作用,可不同程度地抑制炎症引起的血中白细胞的数量升高,并且能改善炎症引起的体质量下降。宁泌泰胶囊高、中(2.0、1.0 g/kg)剂量组可显著减轻子宫的质量,提示抑制炎症引起的肿胀。子宫组织病理学检查结果表明,宁泌泰胶囊可改善大肠杆菌感染引起的大鼠子宫组织学病变,且有一定的剂量相关性。对于苯酚胶浆引起的大鼠盆腔炎,宁泌泰胶囊3 个剂量组均能改善炎症引起的体质量下降。宁泌泰胶囊高剂量组(2.0g/kg)可显著抑制炎症引起的血中白细胞的数量升高,并且可显著减轻子宫的质量,提示抑制炎症引起的肿胀。子宫组织病理学检查结果表明,宁泌泰胶囊可改善苯酚胶浆引起的大鼠子宫组织学病变,且有一定的剂量相关性。结论 宁泌泰胶囊对于化学性和细菌性等多种因素引起的盆腔炎动物模型的相关症状具有明显的改善作用。     

脑缺血损伤的炎症反应及治疗策略展望

研究表明炎症反应在脑缺血损伤中发挥重要作用。脑缺血损伤诱导的炎症反应是一个复杂的动态过程,包括一系列炎症细胞和炎症因子的参与。脑缺血诱导促炎症介质表达,促进白细胞浸润,激活脑内的小胶质细胞和星形胶质细胞,产生炎症反应,加重脑损伤。脑缺血损伤的炎症机制研究为临床寻找有效的治疗方法提供了重要的思路。本文从基础研究和临床试验方面简单阐述了参与脑缺血损伤炎症反应的几类研究较多的炎症细胞和促炎症介质,并探讨了针对脑缺血损伤中炎症反应的治疗方案及其应用前景。     

Cardiac inflammation and fibrosis following chemo/radiation therapy: mechanisms and therapeutic agents

Inflammopharmacology - The incidence of cardiovascular disorders is one of the most concerns among people who underwent cancer therapy. The heart side effects of cancer therapy may occur during...     

Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury

A vast amount of circumstantial evidence implicates oxygen-derived free radicals (especially superoxide and hydroxyl radical) and high-energy oxidants (such as peroxynitrite) as mediators of inflammation, shock, and ischemia/reperfusion injury. The aim of this review is to describe recent developments in the field of oxidative stress research. The first part of the review focuses on the roles of reactive oxygen species (ROS) in shock, inflammation, and ischemia/reperfusion injury. The second part of the review deals with the novel findings using recently identified pharmacological tools (e.g., peroxynitrite decomposition catalysts and selective superoxide dismutase mimetics (SODm) in shock, ischemia/reperfusion, and inflammation. 1) The role of ROS consists of immunohistochemical and biochemical evidence that demonstrates the production of ROS in shock, inflammation, and ischemia/reperfusion injury. ROS can initiate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane sodium/potassium ATPase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of shock, inflammation, and ischemia/reperfusion. 2) Treatment with either peroxynitrite decomposition catalysts, which selectively inhibit peroxynitrite, or with SODm, which selectively mimic the catalytic activity of the human superoxide dismutase enzymes, have been shown to prevent in vivo the delayed vascular decompensation and the cellular energetic failure associated with shock, inflammation, and ischemia/reperfusion injury. ROS (e.g., superoxide, peroxynitrite, hydroxyl radical, and hydrogen peroxide) are all potential reactants capable of initiating DNA single-strand breakage, with subsequent activation of the nuclear enzyme poly(ADP-ribose) synthetase, leading to eventual severe energy depletion of the cells and necrotic-type cell death. Antioxidant treatment inhibits the activation of poly(ADP-ribose) synthetase and prevents the organ injury associated with shock, inflammation, and ischemia/reperfusion.     

序贯疗法与标准三联疗法治疗幽门螺杆菌的临床疗效比较

目的：研究序贯疗法与标准三联疗法治疗幽门螺杆菌的临床疗效。方法选取幽门螺杆菌阳性患者120例,按照数字表法将患者分为A组和B组,每组60例。 A组给予序贯疗法（奥美拉唑＋阿莫西林治疗5 d以后继续以奥美拉唑＋克拉霉素＋替硝唑治疗5 d）治疗,B组给予标准三联疗法（奥美拉唑＋阿莫西林＋克拉霉素）治疗,比较两组幽门螺杆菌根除率、溃疡愈合总有效率以及不良反应。结果 A组幽门螺杆菌的根除率91．7％（55／60）,显著高于对照组的71．7％（43／60）（χ^2＝11．915,P＝0．023）;A组溃疡愈合总有效率96．7％（58／60）,显著高于B组的88．3％（53／60）（χ^2＝9．915,P＝0．038）;两组不良反应发生率差异无统计学意义（χ^2＝4．735,P＝0．072）。结论序贯疗法相比标准三联疗法治疗幽门螺杆菌具有较好的效果,能显著提高幽门螺杆菌的根除率,且无严重不良反应。     

Endocannabinoid degradation, endotoxic shock and inflammation

Endocannabinoids are an emerging class of lipid mediators, which include amides and esters of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the main endogenous agonists of cannabinoid receptors. Endotoxic shock is a potentially lethal failure of multiple organs that can be initiated by the inflammatory agent lipopolysaccharide (LPS), present in the outer membrane of gram-negative bacteria. LPS has been recently shown to stimulate the production of AEA in rat macrophages, and of 2-AG in rat platelets. The mechanism responsible for this effect has not been elucidated. On the other hand, mast cells are multifunctional bone marrow-derived cells found in mucosal and connective tissues and in the nervous system, where they play an essential role in inflammation. As yet, little is known about endogenous modulators and mechanisms of mast cell activation. Here, we review recent literature on the role of endocannabinoids in endotoxic shock and inflammation, and report our recent research on the effects of LPS on the production of AEA and 2-AG in human lymphocytes, and on AEA degradation by a specific AEA membrane transporter (AMT) and an AEA-degrading enzyme (fatty acid amide hydrolase, FAAH). We also report the ability of the HMC-1 human mast cells to degrade AEA through a nitric oxide-sensitive AMT and a FAAH. The role of endocannabinoids in HMC-1 degranulation is discussed as well. Taken together, it can be suggested that human lymphocytes and mast cells take part in regulating the peripheral endocannabinoid system, which can affect some activities of these cells.     

Potential therapeutic applications of autophagy

Autophagy is a dynamic process of subcellular degradation, which has recently sparked great interest as it is now recognized to be involved in various developmental processes and various diseases including cancer and neurodegeneration. Autophagy can function as a cytoprotective mechanism; however, it also has the capacity to cause cell death. A better understanding of autophagy is needed to allow its manipulation for therapeutic purposes, and new insights into the molecular mechanisms of autophagy are now leading to the discovery of exciting new potential drug targets.     

Cortistatin as a therapeutic target in inflammation

Cortistatin (CST) is a recently discovered neuropeptide from the somatostatin gene family, named after its predominantly cortical expression and ability to depress cortical activity. CST shows many remarkable structural and functional similarities to its related neuropeptide somatostatin, or somatotropin release-inhibiting factor. However, the many physiological differences between CST and somatostatin are just as remarkable as the similarities. CST-29 has recently been shown to prevent inflammation in rodent models for human diseases, raising novel therapeutic properties to this neuropeptide. In this review, the authors address a new possible role for CST in the immune system and evaluate the possible therapeutic use of CST to treat disorders associated with inflammation.     

Potential therapeutic targets in cirrhotic cardiomyopathy

Cirrhotic cardiomyopathy is a recently identified pathological condition defined as "a chronic cardiac dysfunction in patients with cirrhosis characterized by blunted contractile responsiveness to stress and/or altered diastolic relaxation with electrophysiological abnormalities, in the absence of known cardiac disease". Overall there seems to be a link between the progression of liver function impairment, the development of portal hypertension and the degree of hyperdynamic circulation, the hallmark of the deranged cardiovascular function in advanced liver diseases. Although mechanical factors contribute to much of the increased resistance within the liver in portal hypertension, there is clearly a vasculogenic component to the development, perpetuation and progression of this syndrome as well. The vascular component of portal hypertension includes an increase in splanchnic blood flow, as well as an increase in intrahepatic vascular resistance. Dysregulation of the nitric oxide system appears to play a key role in both these processes with a paradoxical reduction of intrahepatic availability despite increased disposal in the splanchnic and other vascular districts with adverse effects on cardiac function and structure. Nevertheless, other putative mediators of cardiac damage in cirrhosis have been proposed and their role in the pathogenesis of cirrhotic cardiomyopathy investigated. This review involves a discussion of data achieved on pathogenesis and clinical features of cirrhotic cardiomyopathy but mainly focuses on considerations on potential therapeutic targets, in the light of the evidence that this mainly subclinical condition merges to clinical relevance when challenged with those therapeutic interventions and procedures currently employed to treat the major complications of cirrhosis that might produce a negative impact on the cardiovascular system.     

Mitochondrial dysfunction and antioxidant therapy in sepsis

Sepsis and septic shock are the major causes of death in intensive care units. Oxidative damage to mitochondria is involved in the development of organ dysfunction associated with sepsis. This syndrome is caused by an excessive defensive and inflammatory response characterised by a massive increases of reactive oxygen species (ROS), nitric oxide (NO) and inflammatory cytokines. Under normal circumstances, complex interacting antioxidant defense systems control oxidative stress within mitochondria The consequences of sepsis is a systemic damage to the vascular endothelium, impaired tissue and a compromised whole body respiration, antioxidant depletion and mitochondrial respiratory dysfunction with diminished levels of ATP and O2 consumption. In general, ROS are essential to the functions of cells and particularly immune cells, but adequate levels of antioxidant defenses are required to protect against the harmful effects of excessive ROS production. This review considers the process of sepsis from a mitochondrial perspective, discussing strategies for the targeted delivery of antioxidants to mitochondria. We will provide a summary of the following areas: the cellular metabolism of ROS and its role in pathophysiological processes such as sepsis; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondria-targeted antioxidants and the future implications for such approaches in patients.     

COPD的抗氧化治疗进展

越来越多的证据表明，在COPD患者中，其氧化剂负荷明显增加。氧化应激在COPD的发病机理中起着十分关键的作用。氧化应激能导致抗蛋白酶的失活、气腔上皮损伤、粘液的过度分泌、移行进入肺部的中性粒细胞数量增加、催炎性介质的基因表达以及各种转录因子的活化。因此，抗氧化剂不仅仅只是保护机体免受各种氧化剂的直接损害，也应该能从根本上改变某些炎性反应的过程，而这些炎性反应在COPD的发病机理中起着主要的作用。