PLK1 promotes cholesterol efflux and alleviates atherosclerosis by up-regulating ABCA1 and ABCG1 expression via the AMPK/PPARγ/LXRα pathway

Polo-like kinase 1 (PLK1) is a serine/threonine kinase involving lipid metabolism and cardiovascular disease. However, its role in atherogenesis has yet to be determined. The aim of this study was to observe the impact of PLK1 on macrophage lipid accumulation and atherosclerosis development and to explore the underlying mechanisms. We found a significant reduction of PLK1 expression in lipid-loaded macrophages and atherosclerosis model mice. Lentivirus-mediated overexpression of PLK1 promoted cholesterol efflux and inhibited lipid accumulation in THP-1 macrophage-derived foam cells. Mechanistic analysis revealed that PLK1 stimulated the phosphorylation of AMP-activated protein kinase (AMPK), leading to activation of the peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα) pathway and up-regulation of ATP binding cassette transporter A1 (ABCA1) and ABCG1 expression. Injection of lentiviral vector expressing PLK1 increased reverse cholesterol transport, improved plasma lipid profiles and decreased atherosclerotic lesion area in apoE-deficient mice fed a Western diet. PLK1 overexpression also facilitated AMPK and HSL phosphorylation and enhanced the expression of PPARγ, LXRα, ABCA1, ABCG1 and LPL in the aorta. In summary, these data suggest that PLK1 inhibits macrophage lipid accumulation and mitigates atherosclerosis by promoting ABCA1- and ABCG1-dependent cholesterol efflux via the AMPK/PPARγ/LXRα pathway.     

Static pressure drives proliferation of vascular smooth muscle cells via caveolin-1/ERK1/2 pathway

Intimal hyperplasia plays an important role in various types of vascular remodeling. Mechanical forces derived from blood flow are associated with the proliferation of vascular smooth muscle cells (VSMC). This contributes to many vascular disorders such as hypertension, atherosclerosis and restenosis after percutaneous transluminal angioplasty (PTA). In this study, we show that static pressure induces the proliferation of VSMC and activates its related signal pathway. VSMC from a rat aorta were treated with different pressures (0, 60, 90, 120, 150 and 180 mm Hg) in a custom-made pressure incubator for 24 h. The most active proliferation of VSMC was detected at a pressure of 120 mm Hg. VSMC was also incubated under a static pressure of 120 mm Hg for different time intervals (0, 2, 4, 8, 12 and 24 h). We found that static pressure significantly stimulates VSMC proliferation. Extracellular signal-regulated kinases 1/2 (ERK1/2) activation showed a peak at the pressure of 120 mm Hg at 4-h time point. Moreover, caveolin-1 expression was significantly inhibited by rising static pressure. Downregulation of VSMC proliferation could be found after PD98059 (ERK1/2 phosphorylation inhibitor) treatment. Our data also showed that a siRNA-mediated caveolin-1 knock down increased ERK1/2 phosphorylation and VSMC proliferation. These results demonstrate that static pressure promotes VSMC proliferation via the Caveolin-1/ERK1/2 pathway.     

The mitochondrial calcium uniporter is involved in mitochondrial calcium cycle dysfunction: Underlying mechanism of hypertension associated with mitochondrial tRNAIle A4263G mutation

Recent studies have shown that the mitochondrial DNA mutations are involved in the pathogenesis of hypertension. Our previous study identified mitochondrial tRNA^Ile A4263G mutation in a large Chinese Han family with maternally-inherited hypertension. This mutation may contribute to mitochondrial Ca²⁺ cycling dysfuntion, but the mechanism is unclear. Lymphoblastoid cell lines were derived from hypertensive and normotensive individuals, either with or without tRNA^Ile A4263G mutation. The mitochondrial calcium ([Ca²⁺]_m) in cells from hypertensive subjects with the tRNA^Ile A4263G mutation, was lower than in cells from normotension or hypertension without mutation, or normotension with mutation (P < 0.05). Meanwhile, cytosolic calcium ([Ca²⁺]_c) in hypertensive with mutation cells was higher than another three groups. After exposure to caffeine, which could increase the [Ca²⁺]_c by activating ryanodine receptor on endoplasmic reticulum, [Ca²⁺]_c/[Ca²⁺]_m increased higher than in hypertensive with mutation cells from another three groups. Moreover, MCU expression was decreased in hypertensive with mutation cells compared with in another three groups (P < 0.05). [Ca²⁺]_c increased and [Ca²⁺]_m decreased after treatment with Ru360 (an inhibitor of MCU) or an siRNA against MCU. In this study we found decreased MCU expression in hypertensive with mutation cells contributed to dysregulated Ca²⁺ uptake into the mitochondria, and cytoplasmic Ca²⁺ overload. This abnormality might be involved in the underlying mechanisms of maternally inherited hypertension in subjects carrying the mitochondrial tRNA^Ile A4263G mutation.     

Anti-inflammatory iridoid glycosides from fruits of Cornus officinalis

Three undescribed iridoid glycosides, cyc(7β-O-6′)-morroniside (1), 6′-methyl succinate-7β-O-methylmorroniside (2), and 7β-O-methyl phenyllactate morroniside (3) were isolated from 50% ethanol extract of Cornus officinalis fruits. The structures of the isolated compounds were determined by HRESIMS, ¹D NMR, ²D NMR, UV and IR spectroscopic methods. Compounds 1-3 exhibited moderate anti-inflammatory activities in vivo in a CuSO₄-induced zebrafish inflammation model (when evaluated at 50 μM).     

肥大细胞在动脉粥样硬化形成中的作用

动脉粥样硬化,是冠心病的病理基础,被认为是一种慢性炎症性疾病,涉及如巨噬细胞和T淋巴细胞等许多炎性细胞。肥大细胞是一种重要的免疫细胞,其功能主要是在超敏反应方面的作用。有病理学研究表明:肥大细胞在动脉粥样硬化斑块周围表达增加,这表明肥大细胞可能与疾病的进展有关。最近的研究表明,肥大细胞在动脉粥样硬化中确实起着重要的作用。本文通过总结肥大细胞在动脉粥样硬化形成中的作用,为在疾病进程中,通过调节肥大细胞功能来改善动脉粥样硬化的这种治疗方式的可能性提供依据。     

RNA结合蛋白调节mRNA稳定性的作用机制

免疫稳态的维持涉及多种细胞因子的基因表达调控,其中在转录后水平对mRNA稳定性的调控起重要作用。ARE(AU-rich element)位于mRNA 3'UTR(非编码区),富含AU碱基,某些RNA结合蛋白通过识别结合ARE影响mRNA的稳定性。本文综合最新研究,概述了TTP、HUR等RNA结合蛋白对mRNA稳定性的调节机制及其在信号通路中的作用。     

小鼠腹腔注射硫酸铍的病理形态学观察

目的研究腹腔注射硫酸铍（BeSO4.4H2O）对小鼠主要脏器的损害作用。方法将30只6周龄昆明（KM）雄性小鼠随机分为三组,分别予以不同剂量硫酸铍生理盐水溶液腹腔注射染毒,隔日一次,染毒两周。观察主要脏器的病理组织学变化并测定脏器系数。结果与对照组比较,染毒组心、脾、肾、睾丸脏器系数无显著差异,肝、肺脏器系数差异有统计学意义（P〈0.05）;对照组肺、肝病理学组织检查未见异常,低剂量组小鼠肺组织可见淤血、出血、支气管扩张出血,肺泡腔内有少量炎性渗出物、支气管周围炎、间质性肺炎、小叶性肺炎等;高剂量组小鼠肺组织可见支气管扩张出血,支气管腔内有大量炎性渗出物,支气管周围肺泡扩张,间质性肺炎、小叶性肺炎、融合性小叶性肺炎;低剂量组肝细胞水肿,可见点状坏死和小灶性坏死;高剂量组小鼠肝组织损伤严重,肝细胞排列紊乱,多数肝细胞呈细胞水肿,肝细胞胞质成空泡状,可见明显的点状坏死和小灶性坏死,并伴有炎细胞浸润,坏死区周围肝细胞细胞质呈嗜酸性变,轻度核固缩,并且肝细胞呈不同程度的胞质疏松,肝窦以及肝中央静脉扩张有广泛变性、坏死等病理改变。睾丸、心、脾、肾未见明显异常。结论小鼠腹腔注射本试验剂量的硫酸铍后主要引起肺组织和肝脏损伤,其它脏器未见明显异常。     

Bio-resolution of a chiral epoxide using whole cells of Bacillus megaterium ECU1001 in a biphasic system

Optically active epoxides can be prepared by kinetic resolution of racemic mixtures using stereospecific epoxide hydrolases. To increase the bio-resolution efficiency of a sparingly water-soluble epoxide (glycidyl phenyl ether, GPE), we investigated the use of organic/aqueous two-phase system. Various conditions were systematically examined and optimized in shake flasks. Isooctane was found to be the most suitable solvent as the organic phase. The phase volume ratio (ϕ_o/w) and biocatalyst concentration were shown to be sensitive parameters affecting both the reaction rate and the enzyme enantiospecificity in the biphase system. An isooctane/aqueous system was developed to overcome the low solubility and instability of GPE in the aqueous phase, resulting in a significant improvement of enatiomeric ratio (E-value) from 39.5 to 94.0 and an average productivity of 18.8 mg GPE/(h g) biocatalyst to 48.9 mg GPE/(h g) biocatalyst, respectively. Resolution of a 90.1 g/l solution of racemic glycidyl phenyl ether in isooctane phase was successfully carried out in a mechanically stirred reactor (120 ml), affording (S)-glycidyl phenyl ether in high (100%) enantiomeric excess with a yield of 44.5%.     

鼻咽癌相关新基因NPCEDRG表达对CNE2细胞生长的影响

为研究鼻咽癌相关新基因NPCEDRG的功能,探讨其对鼻咽癌细胞生长特性的影响,利用Tet-on调控系统,建立受强力霉素(deoxycycline,Dox)诱导NPCEDRG基因表达的CNE2细胞系.运用RT-PCR选择背景表达低、诱导活性高的细胞克隆,以不同浓度Dox诱导CNE2/Tet/TRE-NPCEDRG细胞,确定Dox的最佳诱导浓度.借助形态学观察、细胞生长曲线、软琼脂克隆形成试验和流式细胞仪分析等方法,对Dox诱导NPCEDRG高表达后CNE2细胞的生物学行为进行了检测.结果显示,NPCEDRG高表达后CNE2细胞增殖速度显著减慢(P<0.05),克隆形成能力显著降低(P<0.01),瘤细胞群体中处于G0/G1期细胞数增加,S期细胞数减少,细胞阻滞于G0/G1期.Tet调控NPCEDRG基因表达CNE2细胞系成功建立,恢复NPCEDRG表达能部分逆转CNE2的恶性表型,证明NPCEDRG是一个鼻咽癌相关的抑瘤基因.