通心络抗动脉粥样硬化机制的研究进展

动脉粥样硬化是心脑血管疾病的重要病理基础,内皮细胞功能异常、多种炎性细胞因子介导炎症反应是动脉粥样硬化的发病机制.通心络是由多种成分构成的中药复方制剂,在临床上广泛用于治疗心脑血管疾病,具有抗炎、保护内皮、抗氧化及稳定斑块等作用,现就近几年来有关通心络抗动脉粥样硬化机制的研究进展综述如下.     

环氧合酶基因多态性与阿司匹林抵抗的关系

目的:研究缺血性脑卒中患者阿司匹林抵抗与血小板环氧合酶(COX)单核苷酸基因多态性(SNP)的相关性.方法:169位缺血性脑卒中患者服用阿司匹林100mg/d至少7d,根据血栓弹力图(TEG)检测结果分为阿司匹林敏感(AS)组和非阿司匹林敏感(NAS)组,并采用PCR产物直接测序分析法对患者的COX-1(-1676A＞G)、COX-2(-765G＞C)基因的单核苷酸多态性进行分析.结果:根据TEG检测结果,非阿司匹林敏感(NAS)组66例,阿司匹林敏感(AS)组103例.两组患者间COX-1基因-1676A＞G SNP位点的基因型和等位基因频率分布差异具有统计学意义(P=0.016和P=0.008),特别是其等位基因频率分布具有显著差异.两组患者间COX-2基因-765G＞C SNP位点的基因型和等位基因频率分布差异无统计学意义(P=0.084和P=0.090).结论:COX-1基因-1676A＞G位点多态性可能与缺血性脑卒中患者患者阿司匹林抵抗的发生相关,COX-2基因-765G＞C位点多态性可能与阿司匹林抵抗的发生无关.     

环氧合酶的研究进展

环氧合酶 (COX)是由花生四烯酸合成前列腺素的关键酶。COX 1和COX 2结构相似 ,但在反应底物、抑制剂 ,以及细胞内定位都有明显不同。COX 1和COX 2催化产生的各种前列腺素可调节机体的生理和病理活动。本文主要就COX 1和COX 2两种同工酶在生化结构、基因表达的调节 ,以及生理和病理功能等方面的进展作一简要介绍     

动脉粥样硬化斑块钙化机制的研究进展

心血管疾病中动脉粥样硬化斑块的钙化是动脉粥样硬化的临床标志之一,主要发生在动脉血管的内膜.动脉粥样硬化斑块核心的钙化不会增加斑块的易损性,而粥样斑块纤维帽上的微钙化会加强纤维帽的周向应力,致使斑块的易损性增加.动脉粥样硬化斑块的钙化机制包括被动钙化和主动钙化,被动钙化受激素和局部信号的调节,主动钙化机制涉及复杂的细胞生命过程,基质囊泡、细胞凋亡、外泌体、氧化应激反应和细胞自噬等均参与了钙化过程.本文对动脉粥样硬化斑块的钙化机制的进展进行综述.     

阿司匹林通过调节Hippo途径抑制大鼠颅内动脉瘤的形成和机制

摘要 目的：探讨阿司匹林通过调节Hippo途径抑制大鼠颅内动脉瘤形成的机制。方法：选择40只健康SD大鼠分为对照组（不做任何处理）、假手术组（暴露双侧肾动脉后支和左颈总动脉,但不结扎）、动脉瘤组（结扎双侧肾动脉后支和左颈总动脉后生理盐水灌胃）和阿司匹林组（动脉结扎后阿司匹林灌胃）,各10只。灌胃12周后检测血清炎性因子[肿瘤坏死因子-α（TNF-α）、单核细胞趋化蛋白-1（MCP-1）、白细胞介素-6（IL-6）、IL-10]、血管内皮损伤标志物[一氧化氮（NO）、内皮素-1（ET-1）、血管内皮生长因子（VEGF）]。处死大鼠后,检测动脉瘤大小、壁厚比、内腔面积和中膜变薄长度,检测动脉瘤血管组织中Yes相关蛋白（YAP）表达情况。结果：（1）动脉瘤组和阿司匹林组大鼠Willis环上有明显凸起,且阿司匹林组大鼠凸起明显小于动脉瘤组。阿司匹林组大鼠动脉瘤大小、内腔面积和中膜变薄长度均显著小于动脉瘤组,壁厚比显著大于动脉瘤组（P＜0.05）。（2）动脉瘤组和阿司匹林组大鼠血清TNF-α、MCP-1、IL-6水平显著高于对照组和假手术组,IL-10水平显著低于对照组和假手术组（P<0.05）;阿司匹林组大鼠血清TNF-α、MCP-1、IL-6水平显著低于动脉瘤组,IL-10水平显著高于动脉瘤组（P<0.05）。（3）动脉瘤组和阿司匹林组大鼠血清NO水平显著低于对照组和假手术组,ET-1和VEGF水平显著高于对照组和假手术组（P<0.05）;阿司匹林组大鼠血清NO水平显著高于动脉瘤组,ET-1和VEGF水平显著低于动脉瘤组（P<0.05）。（4）动脉瘤组和阿司匹林组大鼠YAP蛋白表达相对吸光值显著高于对照组和假手术组（P<0.05）;阿司匹林组大鼠YAP蛋白表达相对吸光值显著低于动脉瘤组（P<0.05）。结论：阿司匹林能够显著减轻颅内动脉瘤大鼠炎性反应,改善血管内皮功能,抑制颅内动脉瘤形成,这可能与阿司匹林调控Hippo信号通路有关。     

不同剂量阿伐他汀联合阿司匹林治疗原发性高血压并动脉粥样硬化的临床研究

目的:探讨不同剂量阿托伐他汀联合阿司匹林治疗原发性高血压并动脉粥样硬化的临床疗效。方法:选取2015年1月-2016年12月在我院治疗的原发性高血压并动脉粥样硬化患者80例,随机分为对照组和实验组,每组40例。实验组给予口服高剂量阿托伐他汀(40 mg/d)联合阿司匹林肠溶片(100 mg/d)治疗,对照组给予口服高剂量阿托伐他汀(20 mg/d)联合阿司匹林肠溶片(100 mg/d)治疗,疗程均为3个月。观察和比较两组患者治疗前后的总胆固醇(total cholesterol,TC)、高密度脂蛋白胆固醇(high-density lipoproteincholesterol,HDL-C)、甘油三酯(triglyceride,TG)、低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)、收缩压(systolic blood pressure,SBP)、舒张血压(diastolic blood pressure,DBP)以及颈动脉斑块分级。结果:两组治疗后的SBP、DBP、血清TC、TG和LDL-C水平均较治疗前显著降低,血清HDL-C水平较治疗前明显升高,且实验组SBP、DBP、血清TC、TG和LDL-C水平均显著低于对照组(P0.05),血清HDL-C水平明显高于对照组(P0.05)。实验组颈动脉斑块0-Ⅰ级的比例显著高于对照组(P0.05)。结论:口服高剂量阿托伐他汀(40 mg/d)联合阿司匹林肠溶片(100 mg/d)治疗原发性高血压并动脉粥样硬化较低剂量阿托伐他汀(20 mg/d)联合阿司匹林肠溶片(100 mg/d)疗效更好,可以有效降低血压,调节血脂并改善患者预后。     

释放一氧化氮型阿司匹林的抗癌作用机制

释放一氧化氮(NO)型阿司匹林(NO-ASA)有望成为防治肿瘤的药物.本文阐述NO-ASA防治肿瘤的作用及其分子机制等方面所取得的进展.     

巨噬细胞移动抑制因子及其在动脉粥样硬化中的作用

巨噬细胞移动抑制因子（macrophage migration inhibitory factor,MIF）,其主要作用为抑制巨噬细胞的游走移动、促进巨噬细胞在炎症局部浸润、聚集、激活及分泌一些细胞因子,如IL-1、TNF—α、NO等,从而间接增强巨噬细胞的功能。巨噬细胞不仅是产生MIF的主要细胞,也是MIF作用的靶细胞,因此MIF在巨噬细胞参与调节的各种疾病尤其是动脉粥样硬化中发挥着重要作用。研究表明,血管发生动脉粥样硬化部位的MIF表达水平明显上调,且随着斑块的发展逐渐上升;相反,阻断MIF的表达则可以显著廷缓动脉粥样硬化的发撮并稳定斑块。因此,MIF在单核巨噬细胞的血管粘附、跨膜移动、内皮下聚集、泡沫细胞的形成及斑块稳定中的作用可能与动脉粥样硬化的发生和发展有密切关系。本文将主要就MIF的生理及病理生理学功能特别是其在动脉粥样硬化发病及治疗中的作用作一综述。     

动脉粥样硬化动物模型研究进展

动脉粥样硬化是严重危害人类健康的常见病、多发病之一.动脉粥样硬化动物模型的研制对研究其发病机制、病理变化及其防治起着重要作用.近年来,对动脉粥样硬化模型的研究颇多.本文从模型动物的选择、造模方法及模型的评价指标方面对动脉粥样硬化动物模型的研究进行综述,为今后动脉粥样硬化的研究提供一定的线索.     

二苯乙烯苷抗动脉粥样硬化的作用和机制

二苯乙烯苷是中药何首乌中主要的水溶性生物活性成分。大量研究表明,二苯乙烯苷能够通过调脂、抗氧化、抗炎、舒张血管及增强免疫力等作用而抑制动脉粥样硬化的发生和发展,作为抗动脉粥样硬化的一种有效成分极具研究价值。但目前对其抗动脉粥样硬化的潜在作用机制还不完全清楚,本文就二苯乙烯苷在调节脂质、抗氧化、降低炎性反应等方面作用和机制作一综述。     

Exercise might favor reverse cholesterol transport and lipoprotein clearance: potential mechanism for its anti-atherosclerotic effects

Livers of C57 BL/6 mice exercised for 2 weeks showed a dramatic increase in scavenger receptor B1 (SR-B1), CD36 and low density lipoprotein (LDL) receptor and a decrease in acetyl LDL receptor gene expression. These effects on lipoprotein receptors are reminiscent of the effects mediated by peroxisome proliferator-activated receptor (PPARgamma) ligands.     

The effects of pro- and anti-atherosclerotic factors on intracellular nucleotide concentration in murine endothelial cells

Abstract

Endothelial cell activation and dysfunction could lead to endothelial injury that is an important factor in the development of vascular diseases. Vascular injury is strongly associated with disturbed endothelial cell energetics and pyridine nucleotide pool. This study aimed to evaluate the effects of inflammatory stimuli (IL-6, LPS), uric acid, hyperglycemia, fatty acids, flavonoids, statins and nonsteroidal anti-inflammatory drugs on cellular concentration of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and nicotinamide adenine dinucleotide (NAD⁺) in cultured endothelial cells. Murine-immortalized heart endothelial cells (H5V cells) were treated with different concentrations of pro- and anti-atherosclerotic factors and intracellular concentration of nucleotides were measured using high performance liquid chromatography. Intracellular ATP concentration in H5V cells was not changed by inflammatory stimuli (IL-6 and LPS), uric acid, glucose, atorvastatin, acetylsalicylic acid, monounsaturated and polyunsaturated fatty acids. Only high concentration of palmitic acid (1?mM) and kaempferol (>0.1?mM) decreased intracellular ATP concentration. The concentration of intracellular ADP has not been altered by any of tested compounds. In turn, intracellular NAD⁺ pool was modified only by polyunsaturated fatty acids and atorvastatin. Linoleic acid, docosahexaenoic acid and atorvastatin increased cellular NAD⁺ concentration. Tested compounds have a small influence on murine endothelial cell energetics, but polyunsaturated fatty acids and atorvastatin increased intracellular NAD⁺ concentration that could be an important protective mechanism against endothelial cell injury.     

Atorvastatin exerts its anti-atherosclerotic effects by targeting the receptor for advanced glycation end products

Recent studies demonstrated the beneficial role of atorvastatin in reducing the risk of cardiovascular morbidity and mortality in patients with diabetes mellitus and/or metabolic syndrome. To investigate the mechanisms underlying the anti-atheroscleroic action of atorvastatin, we examined the expression of the receptor for advanced glycation end products (RAGE) and its downstream target gene, monocyte chemoattractant protein-1 (MCP-1) using real-time PCR. In in vitro studies, exposure to high glucose or AGE induced oxidative stress and activation of the AGE/RAGE system in human umbilical vein endothelial cells. Treatment of the cells with atorvastatin significantly released the oxidative stress by restoring the levels of glutathione and inhibited the RAGE upregulation. In diabetic Goto Kakisaki (GK) rats fed with a high-fat diet for 12 weeks, RAGE and MCP-1 were upregulated in the aortas, and there was a significant correlation between RAGE and MCP-1 mRNA abundance (r = 0.482, P = 0.031). Treatment with atorvastatin (20 mg/kg qd) significantly downregulated the expression of RAGE and MCP-1. These data thus demonstrate a novel “pleiotropic” activity of atorvastatin in reducing the risk of cardiovascular diseases by targeting RAGE expression.     

Anti-hypercholesterolemic and anti-atherosclerotic effects of polarized-light therapy in rabbits fed a high-cholesterol diet

The effects of polarized-light therapy (PLT) on high-cholesterol diet (HCD)-induced hypercholesterolemia and atherosclerosis were investigated in comparison with that of lovastatin in rabbits. Hypercholesterolemia was induced by feeding male New Zealand white rabbits with 1% cholesterol in diet for 2 weeks and maintained with 0.5% cholesterol for 6 weeks, followed by normal diet for 2 weeks for recovery. Lovastatin (0.002% in diet) or daily 5-min or 20-min PLT on the outside surface of ears was started 2 weeks after induction of hypercholesterolemia. Hypercholesterolemic rabbits exhibited great increases in serum cholesterol and low-density lipoproteins (LDL) levels, and finally severe atheromatous plaques formation covering 57.5% of the arterial walls. Lovastatin markedly reduced both the cholesterol and LDL, but the reducing effect (47.5%) on atheroma formation was relatively low. By comparison, 5-min PLT preferentially decreased LDL, rather than cholesterol, and thereby potentially reduced the atheroma area to 42.2%. Notably, 20-min PLT was superior to lovastatin in reducing both the cholesterol and LDL levels as well as the atheromatous plaque formation (26.4%). In contrast to the increases in blood alanine transaminase and aspartate transaminase following lovastatin treatment, PLT did not cause hepatotoxicity. In addition, PLT decreased platelets and hematocrit level. The results indicate that PLT attenuates atherosclerosis not only by lowering blood cholesterol and LDL levels, but also by improving blood flow without adverse effects. Therefore, it is suggested that PLT could be a safe alternative therapy for the improvement of hypercholesterolemia and atherosclerosis.     

肠道病毒溶瘤机制的研究进展

肠道病毒是引起人类无症状或轻微病变的病毒,以此为基础的溶瘤病毒已受到广泛关注。大量实验结果显示,利用肠道病毒靶向杀伤肿瘤(溶瘤)具有较好的安全性和有效性,但不同肠道病毒作为溶瘤病毒的作用机制尚不完全清楚。本文就溶瘤性肠道病毒的分子机制、肠道病毒的改造与临床试验等方面的研究进展进行综述。     

洞穴鱼类眼部退化机制的研究进展

黑暗环境中的洞穴鱼类眼部结构发生了退化,但不同洞穴鱼物种眼部退化程度存在差异,从眼部结构的部分缺失到完全消失的情况均存在。目前研究表明,不论是达尔文的自然选择学说,还是木村资生的中性进化理论均不能很好地解释洞穴鱼类眼部退化的产生机制。洞穴鱼类眼部退化是一个复杂的过程,若要揭示其机制需汇集多个学科的研究优势。该文介绍了国内外洞穴鱼类眼部退化研究领域的形态解剖学、发育生物学、动物行为学及分子遗传学研究进展,并对洞穴鱼眼部退化的研究现状与发展提出了一些思考和建议。     

Macrophage as a target of quercetin glucuronides in human atherosclerotic arteries: implication in the anti-atherosclerotic mechanism of dietary flavonoids

Epidemiological studies suggest that the consumption of flavonoid-rich diets decreases the risk of cardiovascular diseases. However, the target sites of flavonoids underlying the protective mechanism in vivo are not known. Quercetin represents antioxidative/anti-inflammatory flavonoids widely distributed in the human diet. In this study, we raised a novel monoclonal antibody 14A2 targeting the quercetin-3-glucuronide (Q3GA), a major antioxidative quercetin metabolite in human plasma, and found that the activated macrophage might be a potential target of dietary flavonoids in the aorta. Immunohistochemical studies with monoclonal antibody 14A2 demonstrated that the positive staining specifically accumulates in human atherosclerotic lesions, but not in the normal aorta, and that the intense staining was primarily associated with the macrophage-derived foam cells. In vitro experiments with murine macrophage cell lines showed that the Q3GA was significantly taken up and deconjugated into the much more active aglycone, a part of which was further converted to the methylated form, in the activated macrophages. In addition, the mRNA expression of the class A scavenger receptor and CD36, which play an important role for the formation of foam cells, was suppressed by the treatment of Q3GA. These results suggest that injured/inflamed arteries with activated macrophages are the potential targets of the metabolites of dietary quercetin. Our data provide a new insight into the bioavailability of dietary flavonoids and the mechanism for the prevention of cardiovascular diseases.     

应激诱发抑郁症机制的研究进展

慢性应激或长期使用外源性应激激素糖皮质类固醇,可以引起机体神经系统功能失调,诱导抑郁、学习和记忆障碍、衰老过程加速等。其中,应激激素对海马的选择性损伤是导致这些疾患发展的关键原因。其表现为海马出现糖皮质激素（GC）受体下调、神经元萎缩甚至缺失等退行性变化。其机制可能与GC及继发性释放的兴奋性氨基酸（EAAs)协同作用,最终使神经营养因子（如NGF）表达低下有关。本文就慢性应激诱发抑郁症机制的研究进展进行综述。     

Mechanisms of anti-atherosclerotic functions of soy-based diets

Soy-based diets have been reported to protect against the development of atherosclerosis. However, the underlying mechanism(s) for this protection remains unknown. Although atherosclerosis was traditionally considered a disease associated with impaired lipid metabolism, in recent years the inflammatory components of atherosclerosis have been explored. Recent studies have convincingly delineated that uncontrolled chronic inflammation is the principal contributing factor for the initiation and progression of atherosclerosis. Interaction between activated monocytes and vascular endothelial cells is an early event in atherogenesis. The adhesion of leukocytes, including monocytes, to the inflamed-vascular endothelium and their transmigration into intima initiate the inflammatory processes. Following transmigration, monocytes in the intima are transformed to macrophages, which take up oxidized-LDL (oxLDL) to generate lipid-laden macrophages, also known as foam cells. Hence, in this review article the inflammatory processes associated with atherosclerosis and possible anti-inflammatory functions of soy-based diets contributing to the prevention of atherosclerosis are presented.     

Differential requirement for nitric oxide in IGF-1-induced anti-apoptotic, anti-oxidant and anti-atherosclerotic effects

We have shown previously that insulin like-growth factor I (IGF-1) suppressed atherosclerosis in Apoe(-/-) mice and activated endothelial nitric oxide (NO) synthase. To determine whether IGF-1-induced atheroprotection depends on NO, IGF-1- or saline-infused mice were treated with l-NAME, the pan-NO synthase inhibitor or with d-NAME (control). IGF-1 reduced atherosclerosis in both the d-NAME and l-NAME groups suggesting that IGF-1's anti-atherogenic effect was NO-independent. IGF-1 increased plaque smooth muscle cells, suppressed cell apoptosis and downregulated lipoprotein lipase and these effects were also NO-independent. On the contrary, IGF-1 decreased oxidative stress and suppressed TNF-α levels and these effects were blocked by l-NAME. Thus IGF-1's anti-oxidant effect is dependent on its ability to increase NO but is distinct from its anti-atherosclerotic effect which is NO-independent.