Biochemistry and molecular cell biology of diabetic complications

Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.     

Vascular respiratory uncoupling increases blood pressure and atherosclerosis

The observations that atherosclerosis often occurs in non-smokers without elevated levels of low-density lipoprotein cholesterol, and that most atherosclerosis loci so far identified in mice do not affect systemic risk factors associated with atherosclerosis, suggest that as-yet-unidentified mechanisms must contribute to vascular disease. Arterial walls undergo regional disturbances of metabolism that include the uncoupling of respiration and oxidative phosphorylation, a process that occurs to some extent in all cells and may be characteristic of blood vessels being predisposed to the development of atherosclerosis. To test the hypothesis that inefficient metabolism in blood vessels promotes vascular disease, we generated mice with doxycycline-inducible expression of uncoupling protein-1 (UCP1) in the artery wall. Here we show that UCP1 expression in aortic smooth muscle cells causes hypertension and increases dietary atherosclerosis without affecting cholesterol levels. UCP1 expression also increases superoxide production and decreases the availability of nitric oxide, evidence of oxidative stress. These results provide proof of principle that inefficient metabolism in blood vessels can cause vascular disease.     

Subendothelial retention of atherogenic lipoproteins in early atherosclerosis

Complications of atherosclerosis are the most common cause of death in Western societies. Among the many risk factors identified by epidemiological studies, only elevated levels of lipoproteins containing apolipoprotein (apo) B can drive the development of atherosclerosis in humans and experimental animals even in the absence of other risk factors. However, the mechanisms that lead to atherosclerosis are still poorly understood. We tested the hypothesis that the subendothelial retention of atherogenic apoB-containing lipoproteins is the initiating event in atherogenesis. The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins. The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively charged sulphate groups on the proteoglycans. Here we present direct experimental evidence that the atherogenicity of apoB-containing low-density lipoproteins (LDL) is linked to their affinity for artery wall proteoglycans. Mice expressing proteoglycan-binding-defective LDL developed significantly less atherosclerosis than mice expressing wild-type control LDL. We conclude that subendothelial retention of apoB100-containing lipoprotein is an early step in atherogenesis.     

冠心病的相关危险因素分析与干预

冠状动脉粥样硬化性心脏病（简称冠心病）是一种最为常见的心脏病,它的病理基础是冠状动脉粥样硬化,国内外学者都对其危险因素进行了大量的研究。现概述其相关危险因素,同时探讨可变的危险因素的干预方法,预防冠心病的发生。     

缺血性脑血管病患者颈动脉硬化与高同型半胱氨酸血症关系的研究

目的：探讨急性缺血性脑血管病患者颈动脉粥样硬化（CAA）的发病情况及血浆同型半胱氨酸（plasma homocysteine,pHcy）与CAA的相关性。方法：对179例急性缺血性脑血管病患者进行颈部血管彩色多普勒检查并按动脉硬化程度分组,比较不同程度CAA组患者pHcy水平的变化,记录所有患者年龄、性别、吸烟、饮酒、高血压及糖尿病等传统危险因素以及pHcy、血脂等生化指标。结果：①入选患者颈动脉粥样斑块的发生率为59.2%,颈动脉狭窄发生率为9.5%;②高同型半胱氨酸血症与颈动脉粥样硬化呈显著性相关;③高同型半胱氨酸血症组（Hhcy）不稳定斑块率（50%）大于正常同型半胱氨酸血症组不稳定斑块率（28.97%）,两者比较有统计学意义（P〈0.05）;④脑梗死患者Hhcy率（46.28%）大于短暂性脑缺血发作（TIA）患者Hhcy率（27.59%）,两者比较有统计学意义（P〈0.05）。结论：急性缺血性脑血管病患者颈动脉狭窄的发生率较低,但普遍存在颈动脉粥样斑块,Hhcy是CAA的独立危险因素,可能是不稳定斑块的危险因素。     

Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine--choline, trimethylamine N-oxide (TMAO) and betaine--were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.     

Development in the research of molecular mechanism of Alzheimer’s disease

Alzheimer's disease (AD) is a kind of central nervous system disease. The cause of AD is unclear. It is found that the remarkable histopathological characters of AD are senile plaques and neurofibrillary tangles. β-amyloid plays an important role in the formation of senile plaques and the abnormal phosphorylation of Tau protein is the main reason of neurofibrillary tangles. Apolipoprotein E is correlated to AD' s access, and the third pathological character-AMY plaque perhaps represents a new cause of AD. Presenlin and proteinaceous infectious particles are also related with AD. A summary of molecular mechanism for AD and the development of research is presented.     

Translating molecular discoveries into new therapies for atherosclerosis

Atherosclerosis is characterized by the thickening of the arterial wall and is the primary cause of coronary artery disease and cerebrovascular disease, two of the most common causes of illness and death worldwide. Clinical trials have confirmed that certain lipoproteins and the renin-angiotensin-aldosterone system are important in the pathogenesis of atherosclerotic cardiovascular disease, and that interventions targeted towards these are beneficial. Furthermore, efforts to understand how risk factors such as high blood pressure, dysregulated blood lipids and diabetes contribute to atherosclerotic disease, as well as to understand the molecular pathogenesis of atherosclerotic plaques, are leading to new targets for therapy.     

炎症因子在兔动脉粥样硬化易损斑块模型中表达

目的探讨在兔动脉粥样硬化易损斑块模型中的炎症因子C反应蛋白（CRP）及白介素-6（IL-6）的表达特点。方法雄性纯种新西兰大白兔分为对照模型组（n=8）、兔动脉粥样硬化模型组（n=8）和兔易损斑块模型组,采用ELISI法检测血清CRP、IL-6浓度。结果兔动脉粥样硬化斑块模型及易损斑块模型血清浓度CRP（8．68±1．30、13．97±2．85）mg／L均明显高于兔对照组模型（0．80±0．15）mg／L;兔动脉粥样硬化斑块模型及易损斑块模型血清浓度IL-6（180．67±14．93、237．99±41．10）pg/ml均明显高于兔对照组模型（85．65±13．55）pg／ml;兔易损斑块模型组的血清CRP、IL-6浓度（13．97±2．85mg／L、237．99±41．10pg／ml）明显高于兔动脉粥样硬化斑块模型组（8．68±1．30mg／L、180．67±14．93pg／ml）。结论兔动脉粥样硬化模型组及易损斑块模型组血清CRP、IL-6浓度明显高于兔对照组模型组血清CRP、IL-6浓度;兔易损斑块模型组血清CRP、IL-6浓度明显高于兔动脉粥样硬化组。     

Progress and challenges in translating the biology of atherosclerosis

Atherosclerosis is a chronic disease of the arterial wall, and a leading cause of death and loss of productive life years worldwide. Research into the disease has led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke. Yet, despite these advances, we still lack definitive evidence to show that processes such as lipoprotein oxidation, inflammation and immunity have a crucial involvement in human atherosclerosis. Experimental atherosclerosis in animals furnishes an important research tool, but extrapolation to humans requires care. Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications.     

Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families

The gene coding for the amyloid protein, a component of neuritic plaques found in brain tissue from patients with Alzheimer's disease, has been localized to chromosome 21, and neighbouring polymorphic DNA markers segregate with Alzheimer's disease in several large families. These data, and the association of Alzheimer's disease with Down's syndrome, suggest that overproduction of the amyloid protein, or production of an abnormal variant of the protein, may be the underlying pathological change causing Alzheimer's disease. We have identified a restriction fragment length polymorphism of the A4-amyloid gene, and find recombinants in two Alzheimer's disease families between Alzheimer's disease and the A4-amyloid locus. This demonstrates that the gene for plaque core A4-amyloid cannot be the locus of a defect causing Alzheimer's disease in these families. These data indicate that alterations in the plaque core amyloid gene cannot explain the molecular pathology for all cases of Alzheimer's disease.     

动脉硬化血管疲劳裂纹扩展与破裂理论与数值分析

 动脉粥样硬化的斑块破裂是中风和心肌梗死的主要原因.斑块破裂与血液和剪切应力存在一定的关系.基于血管是天然的周期性低应力环境,本文将血管斑块破裂处理成一个疲劳问题,将血管简化成圆筒,探讨斑块中的裂纹扩展与疲劳破坏,并考查血管内外径比、血栓、血压等因素对疲劳寿命的影响.应力强度因子的计算采用经典圆筒内壁单边裂纹的理论公式,疲劳裂纹扩展利用著名的Paris法则,并利用数值方法求解裂纹扩展过程.研究发现,在血管内外径比不变时,内径的大小对疲劳裂纹扩展的影响几乎可以忽略不计;血栓形成会增加血管壁厚,降低应力集中,该单一因素在疲劳意义上反而会有利;血压对血管疲劳寿命的影响非常大,成指数次减小或增加.     

通心络对脑梗死患者颈动脉粥样硬化软斑块影响的临床研究

目的探讨通心络治疗脑梗死伴颈动脉粥样硬化软斑块其能否有效干预颈动脉粥样硬化斑块中软斑块的发生发展及其能否降低脑梗死复发。方法符合人选标准的100例患者随机分成通心络治疗组和对照组,每组50例。对照组为常规治疗组,通心络治疗组在常规治疗组的基础上加用通心络胶囊3粒（0．7Sg）3次／d,疗程均为6月。两组每3月后复查色多普勒颈动脉和椎动脉超声,记录斑块性质、大小和数目,并检查血糖和血脂,同时记录不良事件。结果通心络治疗组和对照组在性别、年龄方面及斑块数目体积等各危险因素等方面比较,差异无显著性（P〉0．05）。治疗组和对照组经治疗后在软斑块消退、软斑转为硬斑、软斑体积数目减少、无变化和恶化等方面比较,差异有显著性（P〈0．01）。两组治疗6个月后至1年脑血管病事件发生和再住院情况比较,治疗组较对照组低,差异有显著性（P〈0．01）。结论通心络能有效地干预颈动脉粥样硬化斑块中软斑块的发生发展和降低脑血管疾病事件复发。     

Myocardial infarction accelerates atherosclerosis

During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.     

低密度脂蛋白胆固醇、载脂蛋白B与颈动脉粥样硬化斑块的关系

目的 :观察颈动脉粥样硬化患者颈动脉的结构变化及粥样硬化斑块情况 ,研究低密度脂蛋白胆固醇 (L DL - C)、载脂蛋白 B(Apo B)与颈动脉粥样硬化斑块的关系。方法 :测定 10 0例患者空腹血中 L DL - C、Apo B浓度 ,并行颈动脉超声检查 ,测量斑块面积 ,并计算斑块积分和斑块指数。分别计算 L DL - C、Apo B与颈动脉粥样硬化斑块总积分的相关性。按 L DL - C/ Apo B比值分组 ,计算各组的平均斑块指数。结果 :L DL - C、Apo B与颈动脉粥样硬化斑块总积分之间均呈正相关 ,且二者的相关性相当 (r=0 .6 6 5 7,P<0 .0 1;r=0 .6 86 4 ,P<0 .0 1)。L DL - C/ Apo B<1.2 5组颈动脉粥样硬化斑块指数比 L DL - C/ Apo B>1.6 2组高 ,两者相比有显著性差异 (1.76± 0 .80 ,3.30± 1.4 6 ;P<0 .0 5 )。结论 :L DL - C、Apo B与颈动脉粥样硬化斑块的形成均有密切关系 ,其中 Apo B与颈动脉粥样硬化斑块的关系更密切     

他汀类药物在心血管疾病治疗中的新进展

他汀类药物已广泛应用于临床高脂血症的治疗，大量临床试验证明，他汀类药物不仅可降低血脂水平，而且还有抑制炎症反应、稳定动脉粥样硬化斑块、抑制血栓形成、调节血管内皮细胞舒张功能及血管平滑肌功能等非降脂作用。文章就他汀类药物对心血管疾病的非降脂作用进行综述。     

免疫损伤结合高脂饲料致兔动脉粥样硬化斑块形成的相关因素分析

摘要: 目的利用免疫损伤结合高脂饲料方法建立兔实验性动脉粥样硬化( AS) 斑块形成模型,探讨影响其斑块形 成的相关因素。方法日本大耳白兔30 只。免疫损伤和高脂饲料组兔经耳缘静脉注射牛血清白蛋白( BSA) 生理 盐水溶液( 250mg / kg) 并喂食高脂饲料,7d 后再次经耳缘静脉注射同等剂量的BSA。另设单纯喂养高脂饲料的AS 模型组和普通饲料喂食的正常兔组,72 d 后取血测定动物的血脂指标、炎症因子、血管活性物质、血小板聚集黏附 及血管内皮功能等指标,分析上述测定指标和兔主动脉斑块形成及病理变化的相关性。结果72 d 后,免疫损伤 结合高脂饲料组和单纯高脂饲料的两组经病理观察主动脉均有斑块形成,其前者的血脂水平、血清炎症因子白介 素－ 6( IL － 6) 、白介素－ 8( IL － 8) 、高敏C － 反应蛋白( hs-CRP) 含量均比单纯高脂饲料组显著增高( P ＜ 0. 05,P ＜0. 01) 。经Pearson 相关系数统计处理,上述指标和免疫损伤加高脂饲料致斑块的形成具有正相关性,和HDL-C( r = － 0. 58) 、NO( r = － 0. 26) 等指标具有负相关性。结论免疫损伤结合高脂饲料导致兔AS 斑块形成和血脂水 平、炎症因子、血小板聚集及血管活性物质等经典指标的异常有显著相关性,具有评价价值。     

Role of cholesterol and lipid organization in disease

Membrane lipids are essential for biological functions ranging from membrane trafficking to signal transduction. The composition of lipid membranes influences their organization and properties, so it is not surprising that disorders in lipid metabolism and transport have a role in human disease. Significant recent progress has enhanced our understanding of the molecular and cellular basis of lipid-associated disorders such as Tangier disease, Niemann-Pick disease type C and atherosclerosis. These insights have also led to improved understanding of normal physiology.     

Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice

Atherosclerosis is a chronic inflammatory disease, and is the primary cause of heart disease and stroke in Western countries. Derivatives of cannabinoids such as delta-9-tetrahydrocannabinol (THC) modulate immune functions and therefore have potential for the treatment of inflammatory diseases. We investigated the effects of THC in a murine model of established atherosclerosis. Oral administration of THC (1 mg kg(-1) per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, we detected the CB2 receptor (the main cannabinoid receptor expressed on immune cells) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-gamma secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist. Our data demonstrate that oral treatment with a low dose of THC inhibits atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis.     

Bayesian optimization algorithm-based methods searching for risk/protective factors

The risks of developing complex diseases are likely to be determined by single nucleotide polymorphisms (SNPs), which are the most common form of DNA variations. Rapidly developing genotyping technologies have made it possible to assess the influence of SNPs on a particular disease. The aim of this paper is to identify the risk/protective factors of a disease, which are modeled as a subset of SNPs (with specified alleles) with the maximum odds ratio. On the basis of risk/protective factor and the relationship between nucleotides and amino acids, two novel risk/protective factors (called k-relaxed risk/protective factors and weighted-relaxed risk/protective factors) are proposed to consider more complex disease-associated SNPs. However, the enormous amount of possible SNPs interactions presents a mathematical and computational challenge. In this paper, we use the Bayesian Optimization Algorithm (BOA) to search for the risk/protective factors of a particular disease. Determining the Bayesian network (BN) structure is NP-hard; therefore, the binary particle swarm optimization was used to determine the BN structure. The proposed algorithm was tested on four datasets. Experimental results showed that the algorithm proposed in this paper is a promising method for discovering SNPs interactions that cause/prevent diseases.