Phenethyl Isothiocyanate Protects against High Fat/Cholesterol Diet-Induced Obesity and Atherosclerosis in C57BL/6 Mice

This study concerns obesity-related atherosclerosis, hyperlipidemia, and chronic inflammation. We studied the anti-obesity and anti-atherosclerosis effects of phenethyl isothiocyanate (PEITC) and explored their underlying mechanisms. We established an animal model of high fat/cholesterol-induced obesity in C57BL/6 mice fed for 13 weeks. We divided the mice into five groups: control (CON), high fat/cholesterol (HFCD), HFCD with 3 mg/kg/day gallic acid (HFCD + G), and HFCD with PEITC (30 and 75 mg/kg/day; HFCD + P30 and P75). The body weight, total cholesterol, and triglyceride were significantly lower in the HFCD + P75 group than in the HFCD group. Hepatic lipid accumulation and atherosclerotic plaque formation in the aorta were significantly lower in both HFCD + PEITC groups than in the HFCD group, as revealed by hematoxylin and eosin (H&E) staining. To elucidate the mechanism, we identified the expression of genes related to inflammation, reverse cholesterol transport, and lipid accumulation pathway in the liver. The expression levels of peroxisome proliferator activated receptor gamma (PPARγ), liver-X-receptor α (LXR-α), and ATP binding cassette subfamily A member 1 (ABCA1) were increased, while those of scavenger receptor A (SR-A1), cluster of differentiation 36 (CD36), and nuclear factor-kappa B (NF-κB) were decreased in the HFCD + P75 group compared with those in the HFCD group. Moreover, PEITC modulated H3K9 and H3K27 acetylation, H3K4 dimethylation, and H3K27 di-/trimethylation in the HFCD + P75 group. We, therefore, suggest that supplementation with PEITC may be a potential candidate for the treatment and prevention of atherosclerosis and obesity.     

应用计算机流体力学技术评估症状性颅内动脉狭窄患者卒中复发风险的研究

目的 评估基于计算机流体力学（computational fluid dynamics，CFD）技术的无创血流动力学参数与缺血性卒中复发之间的关系。      

二甲双胍通过激活AMPK/STAT3通路调控巨噬细胞分化抑制小鼠动脉粥样硬化形成

目的 探究二甲双胍(Met)通过腺苷酸活化蛋白激酶(AMPK)/信号转导及转录激活因子3(STAT3)信号通路调控巨噬细胞表型对小鼠动脉粥样硬化(As)形成的影响。方法 体外培养RAW264.7巨噬细胞,使用脂多糖促进巨噬细胞分化,同时使用Met刺激细胞。流式细胞术检测不同表型(CD86、CD206)巨噬细胞比例。Western blot检测相关信号通路蛋白诱导型一氧化氮合酶(iNOS)、精氨酸酶1(Arg-1)、AMPK、磷酸化AMPK(pAMPK)、STAT3、磷酸化STAT3(pSTAT3)蛋白表达水平。高脂饲料喂养ApoE－/－小鼠构建As模型。实验组(Met组)小鼠予Met灌胃干预,对照组(CTL组)小鼠给予同体积生理盐水灌胃干预。3个月后,提取小鼠大动脉全长(头臂干至双侧髂动脉)及主动脉根部,分别行油红O染色和免疫荧光染色,评价主动脉脂质沉积情况和脂质斑块内巨噬细胞不同表型比例。提取大动脉蛋白,Western blot验证相关信号通路的AMPK、pAMPK、STAT3、pSTAT3蛋白表达水平。结果 细胞实验表明,Met刺激后M1巨噬细胞比例明显减少,M2巨噬细胞比例明显增加(P＜0.05),AMPK活性明显增加,而STAT3活性明显下降。动物实验表明,在造模3个月后,油红O染色示Met组小鼠大动脉全长和主动脉瓣膜处脂质沉积均较CTL组明显减少(P＜0.05)；免疫荧光染色示Met组脂质斑块内M1巨噬细胞比例较CTL组明显减少,而M2巨噬细胞比例较CTL组明显增多(P＜0.05)。Western blot实验显示,与CTL组相比,Met组AMPK活性明显增加,而STAT3活性明显降低(P＜0.05)。结论 Met通过激活AMPK抑制STAT3活性,调控斑块内巨噬细胞表型分化,抑制小鼠As形成。     

Animal models to evaluate anti‐atherosclerotic drugs

Atherosclerosis is a multifactorial condition characterized by endothelial injury, fatty streak deposition, and stiffening of the blood vessels. The pathogenesis is complex and mediated by adhesion molecules, inflammatory cells, and smooth muscle cells. Statins have been the major drugs in treating hypercholesterolemia for the past two decades despite little efficacy. There is an urgent need for new drugs that can replace statins or combined with statins. The preclinical studies evaluating atherosclerosis require an ideal animal model which resembles the disease condition, but there is no single animal model which mimics the disease. The animal models used are rabbits, rats, mice, hamsters, mini pigs, etc. Each animal model has its own advantages and disadvantages. The method of induction of atherosclerosis includes diet, chemical induction, mechanically induced injuries, and genetically manipulated animal models. This review mainly focuses on the various animal models, method of induction, the advantages, disadvantages, and the current perspectives with regard to preclinical studies on atherosclerosis.