Molecular targets of diabetic cardiovascular complications

Both the macro- and microvascular complications adversely affect the life quality of patients with diabetes and have been the leading cause of mortality and morbidity in this population. With the advancement of technologies in biomedical research, we have gained a great deal of understanding of the mechanisms underlying these complications. While euglycemic control still remains the best strategy, it is often difficult to maintain at a level that can completely prevent the vascular complications. Therefore, it is necessary to use the processes leading to vascular dysfunction as a framework for designing novel molecular therapeutic targets. Several of the mechanisms by which diabetes induces vascular complications include increased flux through the polyol pathway, increased oxidative stress, activation of protein kinase C (PKC), vascular inflammation, and abnormal expression and actions of cytokines in the vasculature. Many of the therapies that target these pathways have proven successful in experimental models of diabetic complications. However, clinical studies using these treatments have mainly yielded inconclusive results. The pathogenesis of diabetic vascular complications and results from animal studies and key clinical studies are reviewed here.     

Microvesicles and diabetic complications - novel mediators,potential biomarkers and therapeutic targets

Microvesicles （MVs）, also known as microparticles, are small membrane vesicles released from different cell types under different conditions. MVs have been detected in the circulation and in organs/tissues in various diseases, including diabetes. Patients with different types of diabetes and complications have different cellular MV patterns. Studies have shown that MVs may mediate vascular thrombosis, vascular inflammation, angiogenesis, and other pathological processes of the disease through their procoagulant, pro-inflammatory, pro-angiogenic, proteolytic, and other properties. Therefore, MVs contribute to the development of diabetic macrovascular and microvascular complications. In addition, clinical studies have indicated that changes in MV number and composition may reflect the pathophysiological conditions of disease, and therefore, may serve as potential biomarkers for diagnostic and prognostic use. Understanding MVs＇ involvement in the pathophysiological conditions may provide insight into disease mechanisms and would also be helpful for the development of novel therapeutic strategies in the future. Here, we review the latest publications from our group and other groups and focus on the involvement of MVs in diabetic complications.     

Atorvastatin and diabetic vascular complications

Statins inhibit 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme for cholesterol synthesis, and share the common mechanism of lowering circulating levels of low-density lipoprotein cholesterol. Among various statins, atorvastatin is the most widely used statin for the treatment of hypercholesterolemia. Recent clinical trials show that atorvastatin reduces the risk of cardiovascular events and slows the progression of atherosclerosis in patients with coronary artery diseases. Further, intensive therapy with atorvastatin is also associated with an early clinical benefit in patients with acute coronary syndrome. These observations support the concept that beyond lipid-lowering effects of atorvastatin, that is, pleiotropic effects, could contribute at least in part to cardiovascular event reduction. Diabetic vascular complication is a leading cause of end-stage renal failure, acquired blindness, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. However, whether atorvastatin therapy decreases the risk for the development and progression of diabetic vascular complications and the way that it might achieve these effects are not fully elucidated. In this paper, we focus on diabetic vascular complications and review the efficacy and safety of atorvastatin in the treatment of these devastating disorders. We further discuss here the possible vasculoprotective properties of atorvastatin in patients with diabetes.     

以抗炎为潜在靶点的治疗糖尿病肾病的新药研究进展

糖尿病肾病（DN）是1型糖尿病（T1DM）和2型糖尿病（T2DM）常见的微血管并发症,也是慢性肾病(CKD)和终末期肾病（ESRD）的主要原因,但目前治疗手段有限。越来越多的证据表明,炎症反应参与了DN的发病和进展。针对特定炎症介质（转录因子、促炎性细胞因子、趋化因子、黏附分子）和细胞内信号通路的几种抗炎策略在DN模型中显示出其是一个有利因素,重点综述炎症在DN发生和进展中的相关机制,并简单讨论基于炎症来预防或治疗DN的新策略。     

New drugs and new targets

At the 8th World Congress on Clinical Pharmacology and Therapeutics, held August 1-6, 2004, in Queensland, Australia, there were late-breaking news symposia on presynaptic receptors as targets in the treatment of schizophrenia; cyclooxygenase inhibition, present and future; adiposity, drug treatment and causes; G-protein-coupled receptors, important new targets; osteoporosis, causes, prevention and cures; ischemic stroke; drugs and arrhythmias, causes and cures; and the pharmacology of cardiac protection. One of the plenary lectures was of targeted cancer therapies. The new drugs and new targets for therapeutic intervention from these presentations are discussed in this report.     

Emerging therapeutic targets in diabetic vascular disease

Diabetes affects nearly 14 m persons in the United States alone; worldwide, the incidence of diabetes is on the rise. It is a heterogeneous disorder of impaired insulin production/sensitivity and is associated with enhanced development of accelerated micro- and macrovasculature disease. Multiple epidemiologic studies have demonstrated that even after correction of typical risk factors, such as obesity, hyperlipidaemia, hypertension and cigarette smoking, patients with diabetes continue to experience enhanced risk of cardiovascular complications [1-2]. Thus, delineation of the factors specific and unique to diabetes that impart increased risk for the development of aggressive heart attacks and strokes is critical for the development of targeted therapy to prevent/delay accelerated macrovascular disease in diabetic patients.     

Towards newer molecular targets for chronic diabetic complications

Prior to the discovery of insulin, the major cause of death in the diabetic population was ketoacidosis. Although insulin and improved glycemic control have improved the longevity of diabetic patients, they still suffer from significant morbidity and mortality due to chronic secondary complications. Long standing diabetes leads to structural and functional alterations in both the micro- and macrovasculature. These complications, involving the retina, kidney, and peripheral nerves, as well as cardiovascular system, severely compromise the quality and expectancy of life. Large scale clinical trials have identified hyperglycemia as the key determinant for the development of such complications. Therapeutic modalities have been developed to target glucose-induced alterations, such as protein kinase C activation, augmented polyol pathway activity, non-enzymatic glycation and oxidative stress to ameliorate chronic complications. However, clinical trials targeting these biochemical alterations have failed to show significant beneficial effects. The plethora of biochemical anomalies that govern the development of chronic diabetic complications may therefore be subject to cross-interaction and complex interplays. Studies in both animal and human diabetes have, however, showed alteration of several vasoactive effector molecules such as endothelins. These molecules may be instrumental in mediating diabetes-induced structural and functional deficits at both the early and late stages of the disease. This review will discuss the current mechanistic understanding of chronic diabetic complications and will explore the potential novel therapeutic interventions.     

治疗糖尿病并发症的药物研究进展

糖尿病并发症是一种由糖尿病病变转化而来的常见慢性疾病,主要包括糖尿病心血管病变、糖尿病肾病、糖尿病眼病等,这些并发症是糖尿病致死致残的主要原因。目前糖尿病并发症已成为我国面临的巨大公共卫生问题,如何通过药物有效地防治糖尿病并发症已成为糖尿病治疗研究的热点和难点。本文就近几年来有关治疗糖尿病并发症的药物研究进展进行综述。     

糖尿病血管并发症的循证防治

<正> 糖尿病是一组由遗传与环境因素相互作用引起的临床综合征。其特征为胰岛素分泌或作用缺陷或两者的共同缺陷所导致的以高血糖为特征的临床综合征。在糖尿病的最主要类型中,1型糖尿病的主要病理生理特征为胰岛素绝对缺乏和高血糖,在严重胰岛素缺乏时还可出现脂质代谢紊乱。随着年龄     

Microbial genomics - new targets,new drugs

Genomics has changed our view of the biological world in the past decade, providing both new information and new tools to characterise biological systems. Over 100 microbial genomes - including many of substantial clinical importance - have been fully or partially sequenced, pushing the search for novel antimicrobial compounds into the post-genomic era. Genomic information and associated new technologies have the potential to revolutionise the drug discovery process. Genomic methods have created a wealth of potential new antimicrobial targets; strategies are evolving to provide validation for these targets before chemical inhibitors are identified. The ability to obtain large amounts of purified target proteins and advances in X-ray crystallography have caused significant increases in available protein structures, which may foreshadow an increased effort in structure-based drug design. The post-genomics strategies used in antimicrobial drug discovery may have application for small molecule drug discovery in numerous therapeutic areas.     

Small molecule vascular disrupting agents: potential new drugs for cancer treatment

Vascular disrupting agents (VDAs) are a new class of potential anticancer drugs that selectively destroy tumor vasculature and shutdown blood supply to solid tumors, causing extensive tumor cell necrosis. VDAs target established tumor blood vessels, which are distinct from antiangiogenic agents that prevent the formation of new blood vessels. There are two types of VDAs, small molecules and ligand-directed agents. Most of the small molecule VDAs are tubulin inhibitors, including CA4P, ZD6126, AVE8062, OXi-4503, NPI-2358, MN-029 and EPC2407. The others are synthetic flavonoids including FAA and DMXAA that induce the production of local cytokines such as TNF-alpha. VDAs have shown good antitumor efficacy in animal models, especially in combination with established anticancer agents. Several VDAs, including CA4P and DMXAA, have demonstrated good safety profile as well as some promising efficacy in phase I clinical trials. Currently CA4P and DMXAA are in phase II clinical trials and AVE8062, OXi-4503, NPI-2358 and MN-029 are in phase I clinical trials. This review will focus on recent progress in the discovery and development of small molecule VDAs, including recently published patent applications and issued patents related with small molecule VDAs.     

Pigment epithelium-derived factor (PEDF): its potential therapeutic implication in diabetic vascular complications

Diabetic micro- and macroangiopathies are leading causes of acquired blindness, end-stage renal failure and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Recent large landmark clinical studies have shown that intensive control of blood glucose or blood pressure (BP) reduces the risk for vascular complications in diabetes. However, the strict control of blood glucose or BP is often difficult to maintain, and current therapeutic options are far from satisfactory. Therefore, to develop novel therapeutic strategies that specifically target vascular complications in diabetes may be actually desired for most patients with diabetes. Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors with complex neurotrophic, neuroprotective, anti-angiogenic, anti-oxidative, and anti-inflammatory properties, any of which could potentially be exploited as a therapeutic option for the treatment of vascular complications in diabetes. This article summarizes the pathophysiological role of PEDF for vascular complication in diabetes and its potential therapeutic implication in this devastating disorder.     

Molecular mechanisms of host-pathogen interactions and their potential for the discovery of new drug targets

Vaccines and chemotherapy have undeniably been the discoveries in the field of biomedical research that have exerted the biggest impact on the improvement of public health. Nevertheless, the development of bacterial resistance to antibiotics has co-evolved over time with the discovery of new drugs. This entails the necessity for continuous research on new anti-infectious agents. The current review highlights recent discoveries in the molecular mechanisms of specific host pathogen interactions and their potential for drug discovery. The focus is on facultative and obligate intracellular pathogens (Mycobacterium, Chlamydia and Legionella) and their manipulation of host cells in regard to inhibition of phagosome maturation and cell death. Furthermore, the composition and role of the SecA2 and the ESX-1 secretion pathways in bacterial virulence and manipulation of infected host cells is discussed. The central hypothesis proposed in this review is that the characterization of bacterial proteins and lipids involved in host cell manipulation (modulins) will provide an abundance of new drug targets. One advantage of targeting such bacterial modulins for drug development is that these anti-modulin drugs will not disrupt the beneficial host microflora and therefore have fewer side effects.     

清热药治疗糖尿病并发症的研究进展

糖尿病患者机体在持续的高血糖状态影响下,常常发生多种糖尿病并发症,包括糖尿病肾病、糖尿病脑病、糖尿病心脏病、糖尿病眼病等,这些并发症已经成为糖尿病患者致死、致残的主要原因,中医药在治疗糖尿病并发症中发挥着重要的作用。中医药理论认为,热毒是糖尿病并发症发生的重要因素之一,主要是因糖尿病后期,脏腑功能低下,致气机及脏腑疏泄功能失调,引起浊瘀痰湿内蕴,日久而化热毒。针对此病机,中医在治疗糖尿病并发症时,多采取清热解毒的治疗方式,广泛应用清热类中药,因此,围绕近年来清热中药在治疗糖尿病并发症中的临床应用及基础研究作一综述。     

常见糖尿病慢性并发症的药物研发进展

糖尿病慢性并发症是由糖尿病病变转化而来的一系列慢性疾病,常见的主要包括糖尿病肾病、糖尿病视网膜病变和糖尿病神经病变等,严重影响着人们的生活。目前直接治疗糖尿病慢性并发症的药物很少,为了研发出治疗这些病的药物,各国的科研人员正在做不懈的努力。将对糖尿病肾病、糖尿病视网膜病变和糖尿病神经病变三大慢性并发症的药物研发进展进行综述。     

Antiherpesvirus drugs: a promising spectrum of new drugs and drug targets

In the absence of effective vaccines to control herpesvirus infections, nucleosidic antiviral drugs have been the mainstay of clinical treatment since their development in the late 1970s. However, given the drawbacks of these drugs, including the increasing emergence of drug-resistant clinical isolates, new strategies for treating herpesvirus infections are warranted. A range of promising new drugs with novel molecular targets has been developed, but will they cure latent infections?     

Hypothalamic neuropeptide systems as targets for potential anti-obesity drugs

Food intake and energy homeostasis are controlled by peripheral humoral signals, afferent neuronal pathways to the brain and central signals, represented, in particular, by neuropeptides. This review reports the status of development of novel compounds targeting some hypothalamic neuropeptide systems which are currently viewed as potential targets to treat obesity.