鞘磷脂酶在肝细胞癌中的作用

鞘磷脂酶(SMase)是调节鞘磷脂类信号通路及其相关产物代谢的主要酶类,参与了鞘磷脂复杂代谢过程中的关键步骤。近年来,许多研究表明SMase参与了细胞周期停滞、细胞迁移和炎症等生物学过程,并通过调节肿瘤干细胞的凋亡和增殖来促进肝细胞癌的发生发展。SMase在肝细胞癌的发生发展及诊疗中具有重要潜在生物学价值。就SMase在肝细胞癌发生发展中的作用进行归纳和探讨,以期为其临床治疗和新型药物的开发提供新的思路和策略。     

JAK/STAT信号通路及其负调控因子SOCS与动脉粥样硬化

动脉粥样硬化是多因素疾病,也是心脑血管疾病的重要病理基础.JAK/STAT信号通路与动脉粥样硬化的发生、发展以及防治密切相关,本文就该通路及其负调控因子SOCS与动脉粥样硬化的关系作一概述.     

基于网络药理学的三黄泻心汤抗As作用机制研究

目的 探讨三黄泻心汤抗动脉粥样硬化(As)的作用机制。方法 利用中药系统药理学分析平台(TCMSP),通过设置口服利用度(OB) ≥30%、类药性(DL) ≥0.18为筛选条件并结合文献得到候选化合物,并通过该数据库检索与活性成分相关的作用靶点;通过比较毒物基因组学数据库(CTD)检索出动脉粥样硬化相关基因;利用Cytoscape 3.6.1生物信息学软件构建成分-靶点网络和成分-靶点-信号通路网络图;通过DAVID进行通路注释和分析,预测该三黄泻心汤抗动脉粥样硬化的作用机制。结果 三黄泻心汤抗动脉粥样硬化的成分-靶点-信号通路网络中包含41种成分,22个靶点及39条信号通路。其度值较高的候选化合物分子为槲皮素、黄芩素、汉黄芩素、大黄素,度值较高的靶点为前列腺素G/H合成酶2(PTGS2)、细胞黏附分子1(ICAM-1)、基质金属蛋白酶9(MMP-9)、肿瘤坏死因子(TNF)、白细胞介素6(IL-6),涉及缺氧诱导因子1信号通路、细胞因子受体相互作用、核因子κB信号通路、血管内皮生长因子信号通路、花生四烯酸代谢及过氧化体增殖物激活受体信号通路等39条信号通路。结论 三黄泻心汤中活性成分可作用于PTGS2、ICAM-1、MMP-9、IL-6等靶点,通过调节花生四烯酸代谢、NF-κB信号通路、血管内皮生长因子信号通路等多条信号通路,协同干预动脉粥样硬化。     

脂蛋白在动脉粥样硬化发病中的分子机制及其干预

"滞留-应答"学说提出动脉粥样硬化的起始步骤是含载脂蛋白B的脂蛋白与内皮下基质相互作用导致脂蛋白在内膜下滞留.鉴于动脉粥样硬化发病的分子机制,直接干预血浆脂蛋白已取得显著的临床效益.阻止含载脂蛋白B的脂蛋白与特异性内皮下基质分子的相互作用及阻断辅助分子,如脂蛋白脂酶、分泌性鞘磷脂酶,为治疗动脉粥样硬化性疾病提供新的干预靶点.     

核因子-κB信号通路与动脉粥样硬化

目前研究认为动脉粥样硬化是慢性炎症性疾病，NF-κB／IκB信号通路在调控炎症反应起着重要作用，研究发现NF—κB／IκB信号通路的异常激活与动脉粥样硬化疾病的发生、发展有密切关系。抑制NF—κB／IκB信号通路的活化，可望为动脉粥样硬化的防治开辟一条新的途径。本文就近年来NF—κB／IκB信号通路与动脉粥样硬化研究进展做一复习。     

Wnt信号通路在动脉粥样硬化及血管钙化中的研究进展

Wnt信号调控胚胎发育过程的多种生物学行为,包括细胞增殖、凋亡、细胞极性和器官发生,在胚胎发育过程起着重要作用。而在成人中,该信号处于沉默状态。最近证据表明,Wnt信号通路在许多生物学过程和疾病中被重新激活,参与代谢、炎症、肿瘤等疾病的发生,调节骨稳态,促进成骨细胞分化,诱导骨生成,并与动脉粥样硬化和血管钙化的发展进程密切相关。本文重点就Wnt信号通路的激活在内皮功能障碍、炎症反应、平滑肌细胞增殖及促进动脉粥样硬化和血管钙化等方面的作用进行综述。     

血栓心脉宁片抗动脉粥样硬化的网络药理学分析

目的通过网络药理学方法探讨血栓心脉宁片抗动脉粥样硬化的可能作用机制。方法采用BATMAN-TCM平台对血栓心脉宁片进行网络药理学分析。结果血栓心脉宁片2201个潜在靶标分子(score≥20分)的功能分布显示,在94个功能条目显著富集,如信号传导活性、脂质代谢、细胞增殖等。运用京都基因与基因组百科全书(KEGG)通路富集分析潜在靶标分子,发现靶标分子KEGG生物学通路显著富集在AMPK信号通路、MAPK信号通路、cGMP-PKG信号通路等78个通路,涉及血管功能的调节、脂质运输与降解、糖脂代谢等过程。通过靶标基因的疾病条目富集分析发现,血栓心脉宁片对心律失常、心力衰竭、冠状动脉粥样硬化性心脏病等疾病有一定治疗作用。结论通过网络药理学预测血栓心脉宁片可能通过调节糖脂代谢、信号转导通路等环节发挥抗动脉粥样硬化作用。     

Wnt/β-catenin信号通路在心血管疾病发生发展及治疗中的作用进展

Wnt/β-catenin信号通路能影响细胞的增殖、迁移、侵袭等行为，参与众多生命活动进程。生理状态下，心血管内Wnt信号缺失，β-catenin被泛素化降解；多种心血管疾病中观察到Wnt/β-catenin通路被重新激活，参与疾病的发生发展。Wnt/β-catenin信号通路在高血压、动脉粥样硬化、心肌梗死、心室重构及其他心血管疾病发生发展中发挥重要作用。干预Wnt/β-catenin信号通路可作为治疗高血压、动脉粥样硬化、心肌梗死、心室重构及其他心血管疾病的潜在靶点。     

mTOR信号通路与动脉粥样硬化

mTOR是一种丝氨酸/苏氨酸激酶,主要参与到两种信号通路的调节中。mTOR信号通路具有调控细胞生长、自噬、增殖和凋亡等生物学功能。mTOR可以调控动脉粥样硬化发生发展过程中内皮细胞的增殖与迁移、巨噬细胞的自噬和平滑肌细胞的增殖与迁移。通过不同时期抑制或激活mTOR可以稳定动脉粥样硬化易损斑块,防止动脉粥样硬化的发生发展。mTOR信号通路在动脉粥样硬化进展中发挥了多方面效应,本文主要针对mTOR信号通路与动脉粥样硬化做一综述,为临床治疗提供新的研究方向。     

CD40-肿瘤坏死因子受体相关因子抑制剂在动脉粥样硬化治疗中的研究进展

CD40-CD40配体(CD40L)信号通路与动脉粥样硬化相关,在动脉粥样硬化起始、发展和并发症中起重要作用。CD40/CD40L是一对互补的跨膜糖蛋白,广泛表达于免疫细胞、内皮细胞、血小板、平滑肌细胞等,参与免疫、炎性反应、血栓形成等多种病理生理过程。动脉粥样硬化启动CD40的表达,激活下游信号通路,上调炎性反应和血栓形成相关基因的表达,阻断该信号通路是抗动脉粥样硬化的策略之一。     

2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy

Despite recent advances in the development of new cancer therapies, the treatment options for glioma remain limited, and the survival rate of patients has changed little over the past three decades. Here, we show that 2-hydroxyoleic acid (2OHOA) induces differentiation and autophagy of human glioma cells. Compared to the current reference drug for this condition, temozolomide (TMZ), 2OHOA combated glioma more efficiently and, unlike TMZ, tumor relapse was not observed following 2OHOA treatment. The novel mechanism of action of 2OHOA is associated with important changes in membrane-lipid composition, primarily a recovery of sphingomyelin (SM) levels, which is markedly low in glioma cells before treatment. Parallel to membrane-lipid regulation, treatment with 2OHOA induced a dramatic translocation of Ras from the membrane to the cytoplasm, which inhibited the MAP kinase pathway, reduced activity of the PI3K/Akt pathway, and downregulated Cyclin D-CDK4/6 proteins followed by hypophosphorylation of the retinoblastoma protein (RB). These regulatory effects were associated with induction of glioma cell differentiation into mature glial cells followed by autophagic cell death. Given its high efficacy, low toxicity, ease of oral administration, and good distribution to the brain, 2OHOA constitutes a new and potentially valuable therapeutic tool for glioma patients.     

RhoA/ROCK信号通路与动脉粥样硬化关系的研究进展

动脉粥样硬化是一种常见的全身性血管疾病,同时也是多种急性心血管疾病的病理基础。而急性心血管疾病的死亡率高,严重危害人们的生命健康。近年来,越来越多的研究表明RhoA/ROCK信号通路与动脉粥样硬化的形成有密切联系。抑制RhoA/ROCK信号通路可以通过稳定血管内皮功能、抑制血管平滑肌细胞增殖和迁移、抑制血管钙化、调控炎症细胞聚集以及抑制血小板增殖变形来延缓或抑制动脉粥样硬化的形成。     

基于网络药理学与分子对接技术探究三棱-莪术药对治疗动脉粥样硬化的作用机制

目的]运用网络药理学与分子对接技术探究三棱-莪术药对治疗动脉粥样硬化(As)的作用机制。 [方法]通过TCMSP、Swiss Target Prediction、STRING数据库和Cytoscape软件发现并探究相关治疗靶点的作用关系,通过Omicshare平台进行GO富集分析与KEGG通路富集分析,运用DockThor平台进行分子对接。 [结果]研究结果发现158个相关治疗靶点,其中丝氨酸/苏氨酸激酶1、SRC原癌基因、肿瘤坏死因子、丝裂原激活蛋白激酶3、白细胞介素6等49个靶点为核心靶点。GO富集分析发现三棱-莪术药对可以在多方面影响As的发生发展。KEGG通路富集分析发现,三棱-莪术药对可能通过C型凝集素受体信号通路、癌症通路等多条代谢通路来发挥治疗As的作用。分子对接显示靶点TNF与常春藤皂苷元的结合活性最高。 [结论]三棱-莪术药对治疗As的作用机制复杂,主要通过C型凝集素受体信号通路、癌症通路等多条代谢通路发挥作用。     

Sphingomyelin biosynthesis and efflux correlates with cholesterol metabolism and is higher in vascular endothelial cells than in smooth muscle cells

We compared the metabolism of cellular phospholipids in bovineaortic endothelial and smooth muscle cells in culture [³H]Cholinewas incorporated in both cell types into phosphatidylcholine(86–90%) and sphingomyelin (10–14%) Endothelialcells demonstrated preferential efflux of sphingomyelin whichrepresented 22.5% of the radiolabelled phospholipids in theincubation medium while in smooth muscle cells it represented10%, so that after 7 days, the sphingomyelin b the medium represented40% and 16% of total synthesized sphingomyelin in endothelialand smooth muscle cells, respectively. Incorporation of [³H]choline by endothelial and smooth muscle cells was reduced inthe presence of serum, but not in the presence of lipoproteindeficient serum, indicating that cells can acquire phosphatidylcholineand sphingomyelin fron lipoproteins. Lipoproteins were shownalso to support the efflux of cellular radiolabelled phospholipidsfrom both cell types but at a higher degree from endothelialcells than from smooth muscle cells. Exposure of these culturesto cholesterol rich serum increased the synthesis of phosphatidylcholine,and to a higher extent of sphingomyelin, with concomitant decreasein the efflux of these two phospholipids. These results demonstratethe role of cholesterol in the regulation of phosphatidyl cholineand sphingomyelin biosynthesis and efflux in vascular cells.Furthermore, the higher efflux of sphingomyelin in endothelialcells than in smooth muscle cells may support the extensiveefflux of cholesterol observed in endothelial cells am indicatebiochemical differences in lipid metabolism between vascularendothelial and smooth muscle cells.     

Soluble Fas ligand activates the sphingomyelin pathway and induces apoptosis in luteal steroidogenic cells independently of stress-activated p38(MAPK)

Fas ligand (FasL) is implicated as a mediator of luteolysis. However, a gap exists in our understanding of the Fas-mediated signaling mechanisms that are involved in either the loss of progesterone production or the structural regression of the corpus luteum. In the present study we investigated the acute and chronic effects of FasL with respect to activation of cytokine/stress-induced signaling pathways and apoptosis in bovine steroidogenic cells. More specifically, we investigated soluble FasL (sFasL)-activated production of ceramide, a second messenger of the sphingomyelin pathway, and activation of p38(MAPK), a member of the MAPK family. sFasL activated the sphingomyelin pathway, as evidenced by a 2-fold increase (P < 0.05) in the production of ceramide. Pretreatment with imipramine (50 micro M), an inhibitor of acid sphingomyelinase activity, attenuated (75%; P < 0.05) sFasL-induced ceramide production, suggesting that the increase in ceramide was partially the result of acid sphingomyelinase-mediated hydrolysis of sphingomyelin. Treatment of luteal cells with sFasL or a cell-permeable ceramide analog (C8) for 24-48 h resulted in a significant increase (P < 0.05) in apoptosis. Western blot analysis revealed that sFasL had little effect on the activation of p38(MAPK) in primary bovine luteal steroidogenic cells. Furthermore, pretreatment with the p38(MAPK) inhibitor SB203580 failed (P > 0.05) to inhibit sFasL- or C8-induced death. Although sFasL did not alter basal progesterone levels detected in the culture medium, C8 caused a significant increase (P < 0.05) in progesterone concentrations within the medium. Collectively, these data suggest that the role of FasL in luteolysis may be to activate the stress-induced sphingomyelin pathway that, in turn, serves as a mediator of apoptosis.     

昼夜节律变化对动脉粥样硬化形成的影响及其相关通路的研究进展

地球上几乎所有的生命都存在昼夜节律,控制昼夜节律的生物钟具有重要的生理功能,同时也是疾病的重要调节器。昼夜节律与动脉粥样硬化关系密切。研究表明受损的生物钟会影响造血过程和糖脂代谢,并改变局部斑块病变中的细胞功能。在分子水平上,昼夜节律可以通过Toll样受体(TLR)通路调节动脉粥样硬化炎症状态和血管重塑,通过蛋白激酶B(Akt)通路改善内皮功能和胰岛素信号传导,并通过CCL2-CCR2信号轴影响单核细胞的招募与淋巴细胞的活化。本篇综述讨论了动脉粥样硬化中昼夜节律的作用及分子机制,以及动脉粥样硬化与生物钟系统的联系。     

Insulin resistance and atherosclerosis

The epidemic of obesity in the developed world over the last two decades is driving a large increase in type 2 diabetes and consequentially setting the scene for an impending wave of cardiovascular morbidity and mortality. It is only now being recognized that the major antecedent of type 2 diabetes, insulin resistance with its attendant syndrome, is the major underlying cause of the susceptibility to type 2 diabetes and cardiovascular disease. In metabolic tissues, insulin signaling via the phosphatidylinositol-3-kinase pathway leads to glucose uptake so that in insulin resistance a state of hyperglycemia occurs; other factors such as dyslipidemia and hypertension also arise. In cardiovascular tissues there are two pathways of insulin receptor signaling, one that is predominant in metabolic tissues (mediated by phosphatidylinositol-3-kinase) and another being a growth factor-like pathway (mediated by MAPK); the down-regulation of the former and continued activity of the latter pathway leads to atherosclerosis. This review addresses the metabolic consequences of the insulin resistance syndrome, its relationship with atherosclerosis, and the impact of insulin resistance on processes of atherosclerosis including insulin signaling in cells of the vasculature.     

The role of skeletal muscle sphingolipids in the development of insulin resistance

Insulin resistance is an important risk factor for type 2 diabetes, obesity, cardiovascular disease, polycystic ovary syndrome and other diseases. The most important stage in the development of insulin resistance is impairment of insulin-stimulated skeletal muscle glucose uptake. There is evidence that intramyocellular lipids might be responsible for this process through inhibition of insulin signaling. One of the important intracellular lipid pools is associated with the sphingomyelin signaling pathway. The second messenger in this pathway is ceramide. In vitro data indicate that ceramide inhibits insulin signaling, mainly through inactivation of protein kinase B. In vivo data suggest that ceramide accumulation within muscle cells might be associated with the development of insulin resistance. In this review, we discuss both in vitro and in vivo evidence for the role of muscle ceramide in the impairment of insulin action with particular focus on the question whether findings from animal studies are applicable to humans. We describe problems that are unresolved so far and topics of potential interest for future research.