The imidazoline-like drug S23515 affects lipid metabolism in hepatocyte by inhibiting the oxidosqualene: lanosterol cyclase activity

Imidazoline-like drugs are centrally-acting antihypertensive agents that inhibit the activity of the sympathetic nervous system by interacting with the alpha2-adrenoreceptor and also with a non-adrenergic imidazoline binding site called the imidazoline 1 receptor. Recently, these molecules were proposed to play an additional role in cardiovascular diseases by acting on glucose and lipid metabolism. We used S23515, a potent imidazoline-like molecule acting selectively on blood pressure through the imidazoline 1 receptor, to decipher the effects of these drugs on lipid metabolism. We found that S23515 inhibited specifically and dose-dependently cholesterol synthesis in cultured rodent and primate hepatocytes. This hypocholesterolemic effect was likely due to the inhibition of the oxido:lanosterol cyclase (OSC), a rate-limiting enzyme in the cholesterol biosynthetic pathway. Partial OSC inhibition induced by S23515 led to the generation of 24(S),25-epoxycholesterol, a potent ligand for the liver X receptor (LXR). Furthermore, S23515 increased in human macrophages the expression of both ABCA1 and G1, the 2 ATP binding cassette transporters, which play a pivotal role in the reverse cholesterol transport. Thus, these results suggest that S23515, and potentially other imidazoline-like drugs, could exert hypolipidemic effects in addition to their hypotensive activities.     

Genetic variant R952Q in LRP8 is associated with increased plasma triglyceride levels in patients with early-onset CAD and MI

We previously identified a novel locus for plasma triglyceride (TG) levels on chromosome 1p31-32 by genome-wide linkage analysis in the GeneQuest population with familial and premature coronary artery disease (CAD). Here we tested a hypothesis that variants in LRP8, a gene that is under the 1p31-32 linkage peak and associated with risk of familial and premature CAD and increased platelet activation, are associated with TG levels. Seven tagSNPs that cover the entire LRP8 gene were characterized in 358 GeneQuest Caucasian probands. Only SNP R952Q (rs5174) was associated with TG levels (P-adj = 0.0016), and this finding was replicated in one other independent population of 134 patients with early-onset myocardial infarction (males <45; females <55; P-adj = 0.0098). TG levels were higher in the group with higher body mass index (BMI ≥ 25) than in the group with lower BMI (BMI < 25). The association was significant in the overweight group (P-adj = 0.0029) or in the smoking group (P-adj = 0.0004), but not in the group with normal BMI or without smoking history. These results suggest that genetic variant R952Q of LRP8 is associated with increased plasma TG levels in patients who are overweight and have premature CAD/MI and history of smoking.     

盐霉素抑制人肺腺癌耐顺铂细胞株A549/DDP增殖及诱导凋亡的机制

目的: 探讨盐霉素对人肺腺癌耐药细胞株A549/DDP增殖的抑制作用及其可能机制。方法: 采用MTT法检测盐霉素对A549/DDP细胞生长的抑制作用;流式细胞术检测盐霉素对A549/DDP细胞凋亡及线粒体膜电位(ΔΨ_m)的影响;比色法检测caspase-3、8和9活性;Western blotting分析细胞色素C、Bcl-2、Bax、β-catenin和磷酸化低密度脂蛋白受体相关蛋白6(p-LRP6)蛋白水平。结果: 盐霉素对A549/DDP细胞生长具有剂量依赖性抑制作用。0.2 μmol/L盐霉素作用于A549/DDP细胞,ΔΨ_m显著下降,而细胞内活性氧和Ca²⁺浓度在短期显著升高,胞浆细胞色素C蛋白水平、caspase-3、8和9酶活性均显著增加,与对照组比较差异均有统计学意义(P<0.01);Bcl- 2 的表达下调,Bax 的表达明显增加,Bcl-2/Bax 比值显著降低。48 h时增殖抑制率为(34.61±1.97)%,细胞凋亡率为(18.74±2.08)%。盐霉素也减少A549/DDP细胞内β-catenin和p-LRP6蛋白水平。结论: 盐霉素通过抑制Wnt信号通路抑制A549/DDP细胞增殖,通过Bcl-2/Bax途径和线粒体凋亡途径诱导人肺腺癌耐药细胞株A549/DDP凋亡。     

血浆脂蛋白(a)水平与冠状动脉病变程度的相关性研究

目的 探讨血浆脂蛋白(a)[LP(a)]水平与冠心病及冠状动脉病变程度的相关性.方法 对363例胸部不适患者进行冠状动脉造影并评价冠状动脉病变程度,按照造影结果分为冠心痛组及对照组,测定血浆LP(a)、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C)浓度,进行多因素Logistic回归分析.结果 冠心病组LP (a)、TG、TC、LDL-C浓度分别为(206.00±146.00)mg/L、( 1.88±0.92)mmol/L、(5.09±0.98)mmol/L、(3.20±1.02)mmol/L、明显高于对照组(137.00±107.00)mg/L、( 1.61±0.69)mmol/L、( 4.68±0.87 )mmol/L、(2.87±0.91 )mmol/L(均P＜0.05).HDL-C浓度(0.98±0.21 )mmol/L低于对照组(1.01±0.25 )mmol/L(P ＞0.05).回归分析发现,LP(a)是冠心痛的独立危险因素.高LP(a)组Gensini积分(45.6±21.5)分明显高于低积分组(25.9±19.4)分.结论 血浆LP(a)水平是冠心病的独立危险因素,对冠状动脉病变程度有较好的预测价值.     

老年人血清胆固醇、低密度脂蛋白、高密度脂蛋白与复发性脑梗死关系的研究

目的探讨老年人高密度脂蛋白(HDL-L)、低密度脂蛋白(LDL-C)、血清胆固醇(TC)水平与复发性脑梗死的关系。方法选择我院2009年5月至2011年5月收治的复发性脑梗死老年患者80例,并与同期收治的初发脑梗死78例患者和健康人群80例高危因素相关指标进行对比分析。结果与健康组比较,复发、初发脑梗死组患者血清TC、LDL-C水平均呈较高水平,其中复发组给高于初发组,差异均有统计学意义(P<0.05);初发、复发脑梗死组HDL-C水平差异无统计学意义(P>0.05),但与健康组HDL-C比较,两组均呈较低水平,差异有统计学意义(P<0.05)。结论针对重要危险因素进行控制和治疗,是对疾病进行预防的关键,可降低复发率,提高患者的生存质量。     

Improved neuronal survival of focal ischemia after delipid extracorporeal lipoprotein treatment in hyperlipidemic rabbits

A delipid extracorporeal lipoprotein filter (DELP) system has been used to treat patients with stroke and has shown favorable prognosis. However, the mechanism for the neuronal functional recovery remains unclear. This study aimed to investigate the neuronal histological assessment, and the levels of C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and oxidized low-density lipoprotein (oxLDL) after ischemic stroke following DELP treatment. Hyperlipidemic rabbits underwent middle cerebral artery occlusion. After 30 min, the animals received an extracorporeal apheresis treatment with a DELP filter. Total cholesterol (TC), triglyceride, and low-density lipoprotein (LDL) of the plasma were measured. The levels of CRP, TNF-α, and oxLDL in brain tissue were also measured by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining, cresyl violet staining, neuron-specific enolase (NSE) and glial fibrillary acidic protein immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed. DELP apheresis reduced TC and LDL by >30%. The number of neurons at day 7 (P < 0.01) and the integrated optical density of NSE at day 1 (P < 0.05) and day 7 (P < 0.01) were significantly increased in the DELP group. TUNEL-positive cells were significantly decreased (P < 0.05). Astrocytes were moderately activated, and this activation persisted up to 7 days. Gliosis was not found in the DELP group. After treatment, the level of CRP declined at day 1 (P < 0.05); TNF-α and oxLDL declined at day 7 (P < 0.05). DELP apheresis decreased neuronal apoptosis, reduced inflammatory markers and oxidative stress in cerebral ischemia, and improved neuronal survival.     

Serum Lipoprotein‐Associated Phospholipase A2 and C‐Reactive Protein Levels in Association With Periodontal Disease and Hyperlipidemia

Background: The aim of this study is to evaluate the levels of serum lipoprotein‐associated phospholipase A₂ (Lp‐PLA₂) and high‐sensitivity C‐reactive protein (hsCRP) in association with periodontal disease and hyperlipidemia. Methods: A total of 123 subjects with hyperlipidemia and 68 systemically healthy controls were included in the study. Subjects with hyperlipidemia were divided into two groups: the suggested‐diet (HD) and prescribed‐statin (HS) groups and then into three subgroups: the healthy (HDh and HSh), gingivitis (HDg and HSg), and periodontitis (HDp and HSp) groups. Periodontal parameters were recorded and included the plaque index, gingival index (GI), probing depth (PD), clinical attachment level (CAL), and percentage of sites with bleeding on probing (BOP). Fasting venous blood samples were obtained, and serum lipid, Lp‐PLA₂, and hsCRP levels were evaluated. Results: Median values for the GI, PD, BOP(%), and CAL in the HSg group were statistically significantly higher than those in the HDg and systemically healthy with gingivitis (Cg) groups. The HSp group had higher percentages of BOP compared to those of the chronic periodontitis and HDp groups. The HDg group had higher serum Lp‐PLA₂ and hsCRP levels compared to those of the Cg and HSg groups. The ratio of total cholesterol to high‐density lipoprotein cholesterol (TC/HDL) was significantly associated with the GI, PD, and BOP(%) in both groups with hyperlipidemia. Serum Lp‐PLA₂ and hsCRP levels were significantly correlated with TC/HDL, the GI, PD, and BOP(%) in the HD group. Conclusions: Serum Lp‐PLA₂ and hsCRP levels may play an important role in the association between periodontal disease and hyperlipidemia, and the control of these mediators may affect the inflammatory control of patients with hyperlipidemia and periodontal disease.     

急性缺血性脑卒中患者低密度脂蛋白胆固醇/淋巴细胞比值与颈动脉斑块稳定性及狭窄程度的相关性

目的 探讨急性缺血性脑卒中(AIS)患者低密度脂蛋白胆固醇/淋巴细胞(LDL-C/LYM)与颈动脉斑块稳定性及狭窄程度的相关性。方法 选取2021年4月至2022年4月就诊于青海省人民医院神经内科的336例AIS患者为研究对象,根据超声结果将患者分为无斑块组(42例)、稳定斑块组(63例)和易损斑块组(231例);根据狭窄度将患者分为无狭窄组(42例)、轻度狭窄组(177例)、中度狭窄组(67例)和重度狭窄组(50例),比较各组之间一般资料、低密度脂蛋白胆固醇、淋巴细胞计数、LDL-C/LYM等差异。采用SPSS 23.0统计软件进行数据分析。根据数据类型,分别采用t检验、Kruskal-Wallis H检验或χ²检验进行组间比较。采用Spearman相关分析LDL-C/LYM值与颈动脉狭窄程度的相关性。采用多因素logistic回归分析颈动脉斑块易损性的危险因素。结果 稳定斑块组和易损斑块组年龄、高血压病与糖尿病史、D-二聚体和LDL-C/LYM值均高于无斑块组(均P＜0.05)。易损斑块组糖尿病史、总胆固醇、低密度脂蛋白胆固醇和LDL-C/LYM值的水平高于稳定斑块组,而淋巴细胞水平降低 (均P＜0.001)。多因素logistic回归分析显示,糖尿病史与LDL-C/LYM值是颈动脉斑块易损性的独立危险因素(OR=1.948,95%CI 1.01~3.77,P=0.048;OR=4.543,95%CI 1.10~18.69,P=0.036)。受试者工作特征(ROC)曲线分析显示,LDL-C/LYM值对诊断斑块稳定性的曲线下面积(AUC)为0.676(95%CI 0.605～0.748;P＜0.001),最佳临界值为1.54,灵敏度为61.5%,特异度为69.8%。Spearman相关性分析显示,LDL-C/LYM值与斑块的狭窄程度呈正相关(r=0.654;P＜0.001)。结论 LDL-C/LYM值增高是AIS患者颈动脉斑块易损性的独立危险因素,与颈动脉斑块狭窄程度呈正相关。