The Role of Lipids in the Development of Diabetic Microvascular Complications

Dyslipidemia is a major factor responsible for coronary heart disease and its reduction decreases coronary risk in patients with diabetes mellitus. However, the association of dyslipidemia with microvascular complications and the effect of intervention with lipid-lowering therapy in diabetes have been less investigated. We present the systematic review of association and intervention studies pertaining to dyslipidemia and microvascular disease in diabetes and also review possible mechanisms. Dyslipidemia may cause or exacerbate diabetic retinopathy and nephropathy by alterations in the coagulation-fibrinolytic system, changes in membrane permeability, damage to endothelial cells and increased atherosclerosis. Hyperlipidemia is associated with faster decline in glomerular filtration rate and progression of albuminuria and nephropathy. Recent evidence also suggests a role of lipoprotein(a) in progression of retinopathy and nephropathy in patients with diabetes mellitus. Lipid-lowering therapy, using single agents or a combination of drugs may significantly benefit diabetic retinopathy and diabetic nephropathy. In particular, hydroxymethyl glutaryl coenzyme A reductase inhibitors may be effective in preventing or retarding the progression of microvascular complications because of their powerful lipid-lowering effects and other additional mechanisms. However, most of the data are based on short-term studies, and need to be ascertained in long-term studies. Until more specific guidelines are available, aggressive management of diabetic dyslipidemia, according to currently accepted guidelines, should be continued for the prevention of macrovascular disease which would also benefit microvascular complications.     

VEGF和HGF与糖尿病血管合并症的相关性研究

目的:探讨血管内皮细胞生长因子(VEGF)和肝细胞生长因子(HGF)与糖尿病血管合并症的关系。方法:用ELISA法测定126例2型糖尿病和30例正常人(对照组)血清VEGF和HGF浓度,观察其与血糖、血脂、血压、肝肾功能以及糖尿病血管合并症的关系。结果:糖尿病组有血管合并症者血清VEGF高于无血管合并症者及对照组(P<0.05),而后2组差异无统计学意义;甘油三酯、低密度脂蛋白、缺血性心脏病、闭塞性动脉硬化和视网膜病变是影响血清VEGF水平的危险因素。糖尿病组血清HGF低于对照组,糖尿病微血管合并症组血清HGF低于大血管合并症组和无血管合并症组(P<0.05);空腹血糖、糖尿病神经病变、肾病和周围神经病变是影响HGF水平的危险因素。VEGF与HGF未见直线相关性。结论:VEGF与血管合并症密切相关,缺氧会代偿性诱导体内合成分泌大量VEGF,而与血糖无关;高血糖抑制HGF的合成,而与血管合并症间未见明显相关。     

抗VEGF药物加激光光凝对糖尿病黄斑水肿的治疗作用分析

目的 探讨抗VEGF药物加激光光凝对糖尿病黄斑水肿的临床疗效.方法 选择糖尿病黄斑水肿患者42例(57眼),随机分为观察组和对照组,各21例(分别28、29眼).对照组给予激光光凝治疗,观察组给予抗VEGF药物加激光光凝治疗.结果 治疗后,观察组黄斑水肿吸收有效率为92.86%,对照组为72.41%(P<0.05).观察组最佳矫正视力高于对照组,黄斑中心凹厚度低于对照组(P<0.05).观察组视力提高率明显高于对照组(P<0.05).结论 抗VEGF药物加激光光凝对糖尿病黄斑水肿疗效确切,可明显减轻患者水肿,提高其视力,值得推广.     

糖化血红蛋白检测在糖尿病微血管病变中的应用

目的探讨糖化血红蛋白检测在糖尿病微血管病变中的应用价值。方法分为微血管病变组102例,无微血管病变组196例;并选取同期进行健康体检正常组150例。对3组患者均进行空腹血糖（FBG）、糖化血红蛋白（HbA1c）检测并比较。结果微血管病变组与无微血管病变组进行FBG、HbA1c比较P〈0.05有统计学意义。微血管病变组、无微血管病变组与健康体检组进行FBG、HbA1c比较P〈0.05有统计学意义。结论 HbAle升高,其发生糖尿病性微血管病变的风险明显增加,糖化血红蛋白检测在糖尿病微血管病变中有着良好的指导作用[5],能够及早的发现发生微血管病变的指导性指标。     

Therapeutic Potential of p38 MAP Kinase Inhibition in the Management of Cardiovascular Disease

p38 mitogen-activated protein kinases (p38 MAPKs) are key signalling molecules that regulate cellular behavior in response to environmental stresses. They regulate pro-inflammatory cytokines and therefore p38 MAPKs are implicated in the pathogenesis of many inflammatory-driven conditions, including atherosclerosis. Therapeutic inhibition of p38 MAPKs to attenuate inflammation has been the focus of comprehensive research in the last 2 decades, following the discovery of p38α as the molecular target of pyrindinyl imidazole compounds, which suppress the cytokines tumor necrosis factor-α and interleukin-1. The potential of p38 MAPK inhibitors was initially explored within archetypal inflammatory conditions such as rheumatoid arthritis and Crohn’s disease, but early studies demonstrated poor clinical efficacy and unacceptable side effects. Subsequent clinical trials evaluating different p38 MAPK inhibitor compounds in disease models such as chronic obstructive pulmonary disease (COPD) and atherosclerosis have shown potential clinical efficacy. This review aims to provide succinct background information regarding the p38 MAPK signaling pathway, a focus of p38 MAPKs in disease, and a brief summary of relevant pre-clinical studies. An update of human clinical trial experience encompassing a clinically orientated approach, dedicated to cardiovascular disease follows. It provides a current perspective of the therapeutic potential of p38 MAPK inhibitors in the cardiovascular domain, including safety, tolerability, and pharmacokinetics.     

Pharmacologic Prevention of Microvascular and Macrovascular Complications in Diabetes Mellitus

Observational epidemiologic data indicate that lower blood glucose levels, blood pressure (BP), and lipid parameters are associated with a lower incidence of micro- and macrovascular complications in people with diabetes. While no threshold for this effect is discernible in these observational studies, intervention studies do not mirror this finding. The earliest glycemia target study in type 2 diabetes mellitus, UKPDS, demonstrated unequivocal benefits of tight glucose control on microvascular complications, but needed a prolonged follow-up to demonstrate a benefit on macrovascular outcomes and mortality. Recently, three major studies, ACCORD, ADVANCE, and VADT, evaluated the impact of attaining euglycemia (ACCORD) or near-euglycemia (ADVANCE, VADT) in older patients with diabetes and high cardiovascular (CV) risk. None of these studies, either individually or on pooled analysis, demonstrated any reduction in all-cause or CV mortality, although the meta-analyses revealed 15-17% reductions in the incidence of non-fatal myocardial infarction in those exposed to tight glucose control. A higher mortality was observed in the intensive glucose control arm of ACCORD, resulting in the premature termination of the glucose-lowering component of this study. Also, the occurrence of hypoglycemic episodes (total and major) was significantly higher in the intensive glucose control arm. ADVANCE and ACCORD also had BP-lowering components. While data from ADVANCE demonstrated a benefit of routine use of a combination of perindopril and indapamide, with a decline in all-cause mortality, CV mortality, and new-onset microalbuminuria, reducing systolic BP to <120?mmHg in ACCORD did not result in any incremental benefits over a systolic BP<140?mmHg. A residual CV risk observed in people with diabetes even after low-density lipoprotein (LDL) cholesterol lowering has led to trials evaluating additional therapy with fibric acid derivatives to reduce triglyceride levels. The lipid-lowering arm of ACCORD failed to demonstrate any benefit of add-on therapy with fibric acid derivatives to LDL-lowering treatment with HMG-CoA reductase inhibitors (statins) on vascular outcomes in patients with diabetes. However, data from earlier studies, and also from the subgroup analysis of ACCORD, indicate a probable benefit of adding treatment with fibric acid derivatives to individuals with persistently elevated triglyceride levels despite statin therapy. The most compelling evidence comes from studies assessing the impact of multiple risk factors - glucose, BP, and cholesterol. Studies like the Steno study unequivocally demonstrate the benefit of aggressive control of all three parameters on vascular outcomes in patients with diabetes. In conclusion, attempts to achieve euglycemia in older patients with type 2 diabetes with co-morbidities are not associated with any survival benefit, but may reduce the occurrence of non-fatal CV events. There is a significant risk of major hypoglycemia with this approach, thereby probably limiting its utility to younger patients with new-onset disease. Similarly, lowering systolic BP below 120?mmHg in high CV risk people with diabetes is associated with significant excess adverse events, limiting the utility of such an intervention. However, a clear benefit, which is also cost effective, is observed with strategies for multiple risk-factor control, which should be universally adopted in clinical practice.     

Plants Used in the Management of Diabetic Complications

Diabetes is a disease, which has assumed vital public health importance because of the complications associated with it. Various mechanisms including polyol pathway along with a complex integrating paradigm have been implicated in glucose-mediated complications. Though polyol pathway was established as a major mechanism, precise pathogenesis of these complications is not yet completely elucidated. Thus research focus was shifted towards key enzyme, aldose reductase in the pathway. Even though various compounds with aldose reductase inhibitory activity were synthesised, a very few compounds are under clinical use. However, studies on these compounds were always under conflicting results and an attempt has been made to review various natural substances with aldose reductase inhibitory activity and their role in management of diabetic complications.     

慢性收缩性心力衰竭的神经内分泌抑制治疗

慢性收缩性心力衰竭是心室重构的结果。神经内分泌－细胞因子系统的过度激活是关键因素，是心室进行性重构、心衰恶化的核心，涉及的主要介质是去甲肾上腺素、血管紧张素Ⅱ、醛固酮、内皮素、炎症性细胞因子和氧化应激等。阻断上述介导因素对心脏的多种有害作用的治疗，即心衰的神经内分泌抑制治疗（又称生物学治疗），已成为心衰的标准治疗。     

Inhibition of Acetylcholinesterase (AChE): A Potential Therapeutic Target to Treat Alzheimer's Disease

A new series of icariin derivatives were synthesized and evaluated for their in vitro acetylcholinesterase (AChE) inhibitory activity. Most of the tested compounds exhibited high AChE inhibition and low toxicity, and among which compounds 1 , 2 , and 10 were the most potent (IC₅₀ = 71.52 ± 22.43, 8.28 ± 1.45, 5.830 ± 1.78 nm , respectively).     

钒对糖尿病小鼠实验治疗作用的研究

微量元素钒(Vanadium,V)有多种氧化价态.不同的钒化合物.其生物活性不同.我们比较了Na-VO_3与VOSO_4的降血糖作用.前者稍强.但VOSO_4的毒性较低.VOSO_4虽不影响正常动物的血糖.但可显著降低高血糖动物的血糖,其降血糖机制与胰岛素类似.     

Therapeutic targeting of VEGF in the treatment of glioblastoma

Introduction: Glioblastoma (GBM) is the most common and aggressive type of primary malignant brain tumor in adults. Despite therapy with maximal safe surgical resection, radiation and temozolomide, prognosis remains poor at 14.6 months. Hence, there is an urgent need for developing novel therapeutic agents. In GBMs, the balance of angiogenic growth factors is skewed toward pro-angiogenesis and VEGF is identified as the key growth factor responsible for neovasculature. Targeting angiogenesis is hypothesized to arrest tumor growth and hence VEGF is an attractive therapeutic target. Areas covered: The purpose of this review is to discuss VEGF pathway inhibitors, their efficacy as monotherapy or in combination with other drugs, the effects on the radiographic response/assessment for GBMs, mechanisms of resistance and associated biomarkers. A short summary of angiogenesis and of the biological characteristics of angiogenesis will also be provided to enhance the understanding of VEGF pathway inhibitors. Expert opinion: Therapeutic targeting of VEGF has lead to improvements in progression-free survival in GBM patients without any change in the overall survival. VEGF-targeted therapy remains a promising therapeutic opportunity if improvements in biomarkers, imaging techniques and rational combination therapy are used to help advance the clinical efficacy of this approach.     

Therapeutic targeting of VEGF in the treatment of glioblastoma

Introduction: Glioblastoma (GBM) is the most common and aggressive type of primary malignant brain tumor in adults. Despite therapy with maximal safe surgical resection, radiation and temozolomide, prognosis remains poor at 14.6 months. Hence, there is an urgent need for developing novel therapeutic agents. In GBMs, the balance of angiogenic growth factors is skewed toward pro-angiogenesis and VEGF is identified as the key growth factor responsible for neovasculature. Targeting angiogenesis is hypothesized to arrest tumor growth and hence VEGF is an attractive therapeutic target.

Areas covered: The purpose of this review is to discuss VEGF pathway inhibitors, their efficacy as monotherapy or in combination with other drugs, the effects on the radiographic response/assessment for GBMs, mechanisms of resistance and associated biomarkers. A short summary of angiogenesis and of the biological characteristics of angiogenesis will also be provided to enhance the understanding of VEGF pathway inhibitors.

Expert opinion: Therapeutic targeting of VEGF has lead to improvements in progression-free survival in GBM patients without any change in the overall survival. VEGF-targeted therapy remains a promising therapeutic opportunity if improvements in biomarkers, imaging techniques and rational combination therapy are used to help advance the clinical efficacy of this approach.     

血管内皮生长因子、Klotho蛋白与2型糖尿病肾病的研究进展

糖尿病肾病是糖尿病的严重并发症之一。近年来研究表明血管内皮生长因子（VEGF）的异常表达与糖尿病肾病的发生发展密切有关,而klotho蛋白作为一种新发现的基因,也参与其过程,且二者相互作用可以加速糖尿病的发展。深入认识VEGF、klotho蛋白将为预防和治疗糖尿病肾病提供新的思路。     

Therapeutic Potential of Engineered Extracellular Vesicles

Extracellular vesicles (EVs) comprise a heterogeneous group of small membrane vesicles, including exosomes, which play a critical role in intracellular communication and regulation of numerous physiological processes in health and disease. Naturally released from virtually all cells, these vesicles contain an array of nucleic acids, lipids and proteins which they transfer to target cells within their local milieu and systemically. They have been proposed as a means of “cell-free, cell therapy” for cancer, immune disorders, and more recently cardiovascular disease. In addition, their unique properties of stability, biocompatibility, and low immunogenicity have prompted research into their potential as therapeutic delivery agents for drugs and small molecules. In this review, we aim to provide a comprehensive overview of the current understanding of extracellular vesicle biology as well as engineering strategies in play to improve their therapeutic potential.     

Therapeutic Potential of Implantable Replacement Hearts

In patients hospitalized with decompensated life-threatening heart failure, the impact of newer pharmacologic therapies and mechanical circulatory support has not yet been realized, except for those who are bridged to cardiac transplantation. For long-term support of transplant-ineligible patients who have severe biventricular failure that is refractory to optimized pharmacologic therapy, replacement of the natural heart with a totally implantable mechanical replacement heart, capable of producing blood flow of up to 8 to 10 L/min, may become the most well tolerated and effective treatment. This article summarizes the current status of the first generation implantable replacement heart (AbioCor?;¹, ABIOMED. Inc., Danvers, MA). With regard to optimizing the further enhancement of treatment options for end-stage heart failure and other life-threatening illnesses, the pharmacodynamics-like principle of therapeutic efficiency should play a role in the development of both drugs and devices. In keeping with that principle, we recommend that adjusting a product’s design input requirements (i) to maximize the therapeutic effect per exposure and; (ii) to separate the cumulative therapeutic effects of the product from the cumulative adverse effects (of the product, and of the comorbid disease processes in the patients treated) should be part of the good product development process for any therapeutic product.