The Use of Lipoprotein-Associated Phospholipase A2 in a Chinese Population to Predict Cardiovascular Events

Objective To explore associations between lipoprotein-associated phospholipase A2(Lp-PLA2)and the risk of cardiovascular events in a Chinese population,with a long-term follow-up.Methods A random sample of 2,031 participants(73.6%males,mean age=60.4 years)was derived from the Asymptomatic Polyvascular Abnormalities Community study(APAC)from 2010 to 2011.Serum Lp-PLA2 levels were determined by enzyme-linked immunosorbent assay(ELISA).The composite endpoint was a combination of first-ever stroke,myocardial infarction(MI)or all-cause death.Lp-PLA2 associations with outcomes were assessed using Cox models.Results The median Lp-PLA2 level was 141.0 ng/m L.Over a median follow-up of 9.1 years,we identified 389 events(19.2%),including 137 stroke incidents,43 MIs,and 244 all-cause deaths.Using multivariate Cox regression,when compared with the lowest Lp-PLA2 quartile,the hazard ratios with95%confidence intervals for developing composite endpoints,stroke,major adverse cardiovascular events,and all-cause death were 1.77(1.24–2.54),1.92(1.03–3.60),1.69(1.003–2.84),and 1.94(1.18–3.18)in the highest quartile,respectively.Composite endpoints in 145(28.6%)patients occurred in the highest quartile where Lp-PLA2(159.0 ng/m L)was much lower than the American Association of Clinical Endocrinologists recommended cut-off point,200 ng/m L.Conclusion Higher Lp-PLA2 levels were associated with an increased risk of cardiovascular event/death in a middle-aged Chinese population.The Lp-PLA2 cut-off point may be lower in the Chinese population when predicting cardiovascular events.

Lipoprotein-associated phospholipase A2 prognostic role in atherosclerotic complications

Atherosclerosis manifests itself clinically at advanced stages when plaques undergo hemorrhage and/or rupture with superimposed thrombosis, thus abruptly stopping blood supply. Identification of markers of plaque destabilization at a pre-clinical stage is, therefore, a major goal of cardiovascular research. Promising results along this line were provided by studies investigating the lipoprotein-associated phospholipase A2(Lp-PLA2), a member of phospholipase A2 proteins family that plays a key role in the metabolism of pro-inflammatory phospholipids, as oxidized low-density lipoproteins, and in the generation of pro-atherogenic metabolites, including lysophosphatidylcholine and oxidized free fatty acids. We herein review the experimental and clinical studies supporting use of Lp-PLA2 activity for predicting cardiovascular events. To his end we considered not only Lp-PLA2 activity and mass, but also Lp-PLA2 gene variations and their association with incident coronary artery disease, stroke, and cardiovascular mortality. Based on these evidences the major scientific societies have included in their guidelines the measurement of Lp-PLA2 activity among the biomarkers that are useful in risk stratification of adult asymptomatic patients at intermediate cardiovascular risk. The results of two recently published major clinical trials with the LpPLA2 inhibitor darapladib, which seem to challenge the pathogenic role of Lp-PLA2, will also be discussed.

Research Advance of Chinese Medicine in Treating Atherosclerosis:Focus on Lipoprotein-Associated Phospholipase A2

As a serious cardiovascular disease,atherosclerosis(AS)causes chronic inflammation and oxidative stress in the body and poses a threat to human health.Lipoprotein-associated phospholipase A2(Lp-PLA2)is a member of the phospholipase A2(PLA2)family,and its elevated levels have been shown to contribute to AS.Lp-PLA2 is closely related to a variety of lipoproteins,and its role in promoting inflammatory responses and oxidative stress in AS is mainly achieved by hydrolyzing oxidized phosphatidylcholine(ox PC)to produce lysophosphatidylcholine(lyso PC).Moreover,macrophage apoptosis within plaque is promoted by localized Lp-PLA2 which also promotes plaque instability.This paper reviews those researches of Chinese medicine in treating AS via reducing Lp-PLA2 levels to guide future experimental studies and clinical applications related to AS.

Plasma Lysophosphatidylcholine and Phospholipase A2 Activity in Chagas Disease Patients: A Comparative Analysis

Chagas disease (CD) affects 21 countries in the Americas and is caused by the parasite Trypanosoma cruzi. A key molecule involved in CD is lysophosphatidylcholine (LPC), which has been studied in various contexts: in the saliva of insect vectors, during the establishment of infection in the vertebrate host, and for the parasite itself. This lipid can be produced by the action of phospholipases A2 (PLA2), enzymes that catalyze the hydrolysis of phospholipids releasing fatty acids and lysophospholipids, such as LPC. This study investigates LPC levels and PLA2 activities in the plasma of CD patients and compares these levels with those in healthy individuals and patients with idiopathic dilated cardiomyopathy (IDCM). Plasma from 64 CD patients, 54 healthy individuals, and 16 IDCM patients were analyzed. LPC levels and the activity of two types of phospholipase A2: secreted (sPLA2) and lipoprotein-associated (Lp-PLA2) were measured. LPC levels and sPLA2 activity were similar between CD patients and the control groups. However, there were notable differences in LPC levels and sPLA2 activity between subgroups of CD patients and IDCM patients. This study is the first to identify LPC in patients with CD across various stages of the disease. It also offers new insights into the biochemical changes observed in the plasma of patients with IDCM.

Oxidized phospholipids and lipoprotein-associated phospholipase A_2 as important determinants of Lp(a) functionality and pathophysiological role

Lipoprotein（a） [Lp（a）] is composed of a low density lipoprotein（LDL）-like particle to which apolipoprotein（a）[apo（a）] is linked by a single disulfide bridge. Lp（a） is considered a causal risk factor for ischemic cardiovascular disease（CVD） and calcific aortic valve stenosis（CAVS）. The evidence for a causal role of Lp（a） in CVD and CAVS is based on data from large epidemiological databases, mendelian randomization studies, and genome-wide association studies. Despite the well-established role of Lp（a） as a causal risk factor for CVD and CAVS, the underlying mechanisms are not well understood. A key role in the Lp（a） functionality may be played by its oxidized phospholipids（OxPL） content. Importantly, most of circulating OxPL are associated with Lp（a）; however, the underlying mechanisms leading to this preferential sequestration of OxPL on Lp（a） over the other lipoproteins,are mostly unknown. Several studies support the hypothesis that the risk of Lp（a） is primarily driven by its OxPL content.An important role in Lp（a） functionality may be played by the lipoprotein-associated phospholipase A_2（Lp-PLA_2）,an enzyme that catalyzes the degradation of OxPL and is bound to plasma lipoproteins including Lp（a）. The present review article discusses new data on the pathophysiological role of Lp（a） and particularly focuses on the functional role of OxPL and Lp-PLA_2 associated with Lp（a）.

Elevated plasma lipoprotein-associated phospholipase A2 activity is associated with plaque rupture in patients with coronary artery disease

Background Lipoprotein-associated phospholipase A2 （Lp-PLA2） has recently been shown to be positively related to coronary events in patients with coronary artery disease （CAD）. However, direct evidence about the relationship between circulation Lp-PLA2 activity and vulnerable plaque in patients with CAD remains lacking. Methods Plasma Lp-PLA2 activity was determined in 146 consecutive patients with CAD who underwent clinically-indicated coronary angiography and preinterventional intravascular ultrasound （IVUS）. Results Eighty-three patients were included in the final analysis after the initial screening. Sixty （72.3%） were acute coronary syndrome （ACS） patients and 23 （27.7%） were stable angina pectoris （SAP） patients. Plaque rupture occurred in 39 （47.0%） patients, and 34 （87.2%） were from ACS patients and 5 （12.8%） from SAP patients. There were no significant differences in clinical and angiographic characteristics between patients with plaque rupture and those without plaque rupture, except for smoking, high-sensitive C-reactive protein （hs-CRP） level and Lp-PLA2 activity （all P 〈0.05）. IVUS measurement uncovered that patients with plaque rupture had more frequent positive remodeling （74.4% vs. 43.2%, P=0.004）, soft plaques （64.1% vs. 36.4%, P=-0.012） and higher remodeling index （1.13~0.16 vs. 0.99＋_0.11, P=0.041） as compared with those without plaque rupture. Multivariate Logistic regression analysis showed that plasma Lp-PLA2 activity was independently associated with plaque rupture after adjusting for smoking, positive remodeling and soft plaque （Model 1： odds ratio （OR） 1.13, 95% confidence interval （CO ： 1.06-1.20） or adjusting for smoking, hs-CRP level, positive remodeling and soft plaque （Model 2： OR 1.11,95%C1： 1.04-1.19）. Conclusions Plasma Lp-PLA2 activity is associated with plaque rupture in patients with CAD, independently of traditional CAD risk factors, hs-CRP level and IVUS parameters. Lp-PLA2 may be a risk marker for vulnerable plaques.

Study on the correlation between the concentration of plasma lipoprotein-associated phospholipase A2 and coronary heart disease

Objective: This study explores the correlation between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) and coronary heart disease (CHD) by comparing the level of plasma Lp-PLA2 in the plasma of patients with different types of CHD. Methods: Blood samples were collected from 56 patients diagnosed with CHD by the Department of Cardiology of the First People's Hospital of Foshan and 34 healthy subjects from February 2013 to January 2014. We measured the concentration of plasma Lp-PLA2 and determined the levels of total cholesterol (Tch), triglyceride (TG), apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B), high density lipoprotein-cholesterol (HDL-c), low density lipoprotein-cholesterol (LDL-c), lipoprotein a (Lp(a)), glucose (Glu), and high-sensitivity C-reactive protein (hs-CRP). The concentration of plasma Lp-PLA2 in the healthy control group and each subgroup of CHD patients were compared and analyzed for correlations of plasma Lp-PLA2 between the patients in different CHD subgroups and several laboratory indicators. Results: The concentration of plasma Lp-PLA2 in each subgroup of CHD was significantly higher than in the control group (P<0.05). The concentration of Lp-PLA2 in the unstable angina pectoris (UAP) group and acute myocardial infarction (AMI) group were significantly higher than in the stable angina pectoris (SAP) group (P<0.05), and the concentration of plasma Lp-PLA2 in the AMI group was significantly higher than in the UAP group (P<0.05). The concentration of plasma Lp-PLA2 in the CHD group merely showed a positive correlation (r ? 0.493, P<0.05) with the hs-CRP group, but the levels of Tch, TG, Apo-A1, Apo-B, HDL-c, LDL-c, Lp(a) and Glu did not. Conclusions: The concentration of plasma Lp-PLA2 in patients with CHD was higher than that in the control group. The concentration of plasma Lp-PLA2 in the subgroups of CHD patients varied greatly from each other. The inflammatory response of atherosclerosis might be resulted from the synergy of plasma Lp-PLA2 and hs-CRP. Copyright ? 2015, Chinese Medical Association Production. Production and hosting by Elsevier B.V. on behalf of KeAi Com-munications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

磷脂酶A_2氨基末端衍生肽的合成及其抗细菌活性的研究

目的 探讨磷脂酶A_(2)(PLA_(2))氨基末端衍生肽的合成及抗菌活性。方法 根据PLA_(2)氨基末端氨基酸残基的顺序合成为多肽PLA_(2)N_(11)、PLA_(2)N_(15)、PLA_(2)N_(20),将其分别与2种细菌(大肠埃希菌、枯草杆菌)在特定条件下培养,并以生理盐水作为对照,分析抗菌活性。结果 与对照比较,多肽不同作用浓度时PLA_(2)N_(11)、PLA_(2)N_(15)、PLA_(2)N_(20)对革兰氏阳性枯草杆菌杀菌活性更强,各多肽间比较,差异有统计学意义(P<0.05);当多肽作用浓度为500μg/ml时,PLA_(2)N_(15)对革兰氏阳性枯草杆菌杀菌活性可达99.8%,高于PLA_(2)N_(11)、PLA_(2)N_(20),及对照(P<0.05)。与对照比较,各多肽不同作用浓度时对大肠埃希菌杀菌活性比较,差异有统计学意义(P<0.05);多肽作用浓度为7.81、125.00、500.00μg/ml时,PLA_(2)N_(15)的杀菌活性均高于PLA_(2)N_(11)和PLA_(2)N_(20),及对照(P<0.05);多肽作用浓度为31.25μg/ml时,PLA_(2)N_(15)的杀菌活性低于PLA_(2)N_(11)的杀菌活性,且高于PLA_(2)N_(20)的杀菌活性(P<0.05)。结论 多肽PLA_(2)N_(11)、PLA_(2)N_(15)、PLA_(2)N_(20)对枯草杆菌、大肠埃希菌有很强的杀菌作用。

Functions and mechanisms of cytosolic phospholipase A_(2)in central nervous system trauma

Central nervous system(CNS)trauma,including traumatic brain injury and spinal cord injury,has a high rate of disability and mortality,and effective treatment is currently lacking.Previous studies have revealed that neural inflammation plays a vital role in CNS trauma.As the initial enzyme in neuroinflammation,cytosolic phospholipase A_(2)(cPLA2)can hydrolyze membranous phosphatides at the sn-2 position in a preferential way to release lysophospholipids andω3-polyunsaturated fatty acid dominated by arachidonic acid,thereby inducing secondary injuries.Although there is substantial fresh knowledge pertaining to cPLA2,in-depth comprehension of how cPLA2 participates in CNS trauma and the potential methods to amelio rate the clinical res ults after CNS trauma are still insufficient.The present review summarizes the latest understanding of how cPLA2 participates in CNS trauma,highlighting novel findings pertaining to how cPLA2 activation initiates the potential mechanisms specifically,neuroinflammation,lysosome membrane functions,and autophagy activity,that damage the CNS after trauma.Moreover,we focused on testing a variety of drugs capable of inhibiting cPLA2 or the upstream pathway,and we explored how those agents might be utilized as treatments to improve the results following CNS trauma.This review aimed to effectively understand the mechanism of cPLA2 activation and its role in the pathophysiological processes of CNS trauma and provide clarification and a new referential framework for future research.

Changes of gastric and intestinal blood flow, serum phospholipase A_2 and interleukin-1β in rats with acute necrotizing pancreatitis

AIM:To explore the relationship between gastric and intestinal microcirculatory impairment and inflammatory mediators released in rats with acute necrotizing pancreatitis (ANP). METHODS: A total of 64 rats were randomized into control group and ANP group. ANP model was induced by injection of 5% sodium taurocholate under the pancreatic membrane. Radioactive biomicrosphere technique was used to measure the gastric and intestinal tissue blood flow at 2 and 12 h after the induction of ANP, meanwhile serum phospholipase A2 (PLA2) activities and interleukin-1β levels were determined. Pathologic changes in pancreas, gastric and intestinal mucosae were studied. RESULTS: The gastric blood flow in ANP group (0.62±0.06 and 0.35±0.05) mL/(min·g) was significantly lower than that in control group (0.86±0.11 and 0.85±0.06) mL/(min·g) (P<0.01) at 2 and 12 h after induction of ANP. The intestinal blood flow in ANP group (0.80±0.07 and 0.50±0.06) mlV(min·g) was significantly lower than that in control group (1.56±0.18 and 1.61±0.11) mL/(min·g) (P<0.01). Serum PLA2 activities (94.29±9.96 and 103.71± 14.40) U/L and IL-1β levels (0.78±0.13 and 0.83±0.20)μg/L in ANP group were higher than those in control group (65.27±10.52 and 66.63±9.81) U/L, (0.32±0.06 and 0.33±0.07)μg/L (P<0.01). At 2 and 12 h after introduction of the model, typical pathologic changes were found in ANP. Compared with control group, the gastric and intestinal mucosal pathologic changes were aggravated significantly (P<0.01) at 12 h after induction of ANP. Gastric and intestinal mucosal necrosis, multiple ulcer and hemorrhage occurred. CONCLUSION: Decrease of gastric and intestinal blood flow and increase of inflammatory mediators occur simultaneously early in ANP, both of them are important pathogenic factors for gastric and intestinal mucosal injury in ANP.

Bromophenacyl bromide,a phospholipase A_2 inhibitor attenuates chemically induced gastroduodenal ulcers in rats

AIM: To study the effect of bromophenacyl bromide (BPB), a phospholipase A2 inhibitor on gastric secretion and to protect chemically induced gastric and duodenal ulcers in rats. METHODS: Acid secretion studies were undertaken in pylorus-ligated rats with BPB treatment (0, 5, 15 and 45 mg/kg). Gastric and duodenal lesions in the rats were induced by ethanol and cysteamine respectively. The levels of gastric wall mucus, nonprotein sulfhydryls (NP- SH) and myeloperoxidase (MPO) were also measured in the glandular stomach of rats following ethanol induced gastric lesions. RESULTS: BPB produced a dose-dependent inhibition of gastric acid secretion and acidity in rats. Pretreatment with BPB significantly attenuated the formation of etha- nol induced gastric lesion. BPB also protected intestinal mucosa against cysteamine-induced duodenal ulcers. The antiulcer activity of BPB was associated with signifi- cant inhibition of ethanol-induced depletion of gastric wall mucus, NP-SH and MPO. These findings pointed towards the mediation of sulfhydryls in BPB induced gas- trointestinal cytoprotection. CONCLUSION: BPB possesses significant antiulcer and cytoprotective activity against experimentally induced gastroduodenal lesions.

Phospholipase A_2 and Its Relationship with Acute Lung Injury in Acute Pancreatitis in Dogs

Acute fulminant pancreatitis was produced in dogs by injection of autobile into the main pancreatic duct.After injection the phospholipase A_2(PLA_2)activities in serum,lung lymph and bronchoalveolar lavage fluid(BAL)were elevated significantly,lung lymph flow and pulmonary transvascular potein clearance increased progressively,protein content and cell numbers in BAL in the experimental animals were significantly higher than those in the control animals.Furthermore the lung index,wet to dry lung weight ratio,extravascular lung water to bloodless dry lung weight ra- tio,extravascuar lung water to bloodless dry lung weight ratio increased significantly as compared to control animals.Pretreatment with PLA_2 inhibitor,chloroquine,blocked the changes mentioned above.This experiment suggests:1.PLA_2 activity in lung lymph fluid as well as in serum and BAL is elevated in acute hemorrhagic pancreatitis.2.Elevated PLA_2 activity may increase the pulmonary vascular permeability.3.PLA_2 is the major factor leading to pulmonary edema in acute hemorrhagic pancreatitis.4.Phagocytes contribute to the lung injury induced by PLA_2 to some ex- tent.

Regulatory effects of phospholipase A_2 inhibitors on platelet activating factor in endotoxic shock in rabbits

The regulatory effects of phospholipase A2(PLA2) inhibitors, chloroquine and dexamethasone, on the activity of blood PLA2 and its related lipid mediators during endotoxic shock were observed in rabbits. The rabbits were randomized into 4 groups as follows : The normal control (NC) group consisted of 12 rabbits with sham injection . the endotoxic shork (ES) group of 31 rabbits, the chloquine pretreated (CQ) group of 16 rabbits receiving 3 mg/kg of chlorqouine and the dexamethasone-pretreated (DM) group of 10 rabbits receiving 5 mg/kg of dexamethasone. Blood was sampled before and 5 and 30 min, 1 ,3, 5 and 8 h after the administration of endotoxin for the determination of PLA2, platelet activating factor (PAF) , TXB2 and 6-keto-PGF1α. In addrtion, changes of mean arterial pressure (MAP) and respiratory rate (RR) were also carefully recorded. It was found that the activities of PLA2 and PAF and the levels of TXB2 and 6-keto-PGF1α. were significantly increased after the infusion of endotoxin. CQ and DM markedly suppressed the activities of PLA2 and PAF. The inhibition of CQ on TXB2 and 6-keto-PGF1α was greater than that of DM. Besides, CQ and DM could increase the survival rate of the animals from 48% to 75% (CQ group) and 70% (DM group). These findings suggest that PLA2 inhibitors such as CQ and DM can significantly attenuate the formation of shock mediators such as PLA2, PAF, TXB2 and 6-keto-PGF1α, and so improve the prognosis of the victims of endotoxic shock.

CONTROL OF ANGIOGENESIS BY INHIBITOR OF PHOSPHOLIPASE A_2

Objective To investigate the potential effects of angiogenic process by secretory phospholipase A2 (sPLA2)inhibitor-HyPE(linking N-derivatized phosphatidyl-ethanolamine to hyaluronic acid)on human bone marrow endothelial cell line(HBME-1). Methods In order to examine the suppressing effects of HyPE on HBME-1 proliferation, migration, and capillary-like tube formation, HBME-1 were activated by angiogenic factor, specifically by basic fibroblast growth factor(b-FGF), vascular endothelial growth factor(VEGF),and oncostatin M(OSM)(at a final concentration of 25, 20, and 2.5 ng/mL, respectively), then HBME-1 proliferation, migration, and tube forma-tion were studied in the absence or presence of HyPE. HBME-1 tube formation was specially analyzed in fibrin gel. Results HyPE effectively inhibited HBME-1 proliferation and migration as a dose-dependent manner, whatever HBME-1 were grown in the control culture medium or stimulated with b-FGF, VEGF, or OSM. In fibrin, the formations of HBME-1 derived tube-like structures were enhanced by all angiogenic factors, but these were strongly suppressed by HyPE. Conclusions The results support the involvement of sPLA2 in angiogenesis. It is proposed that sPLA2 inhibitor introduces a novel approach in the control of cancer development.

Cytosolic phospholipase A2α modulates cell-matrix adhesion via the FAK/paxillin pathway in hepatocellular carcinoma

Objective: To explore the effect of cytosolic phospholipase A2α(cPLA2α) on hepatocellular carcinoma(HCC) cell adhesion and the underlying mechanisms.Methods: Cell adhesion, detachment, and hanging-drop assays were utilized to examine the effect of cPLA2α on the cell-matrix and cell-cell adhesion. Downstream substrates and effectors of cPLA2α were screened via a phospho-antibody microarray.Associated signaling pathways were identified by the functional annotation tool DAVID. Candidate proteins were verified using Western blot and colocalization was investigated via immunofluorescence. Western blot and immunohistochemistry were used to detect protein expression in HCC tissues. Prognosis evaluation was conducted using Kaplan-Meier and Cox-proportional hazards regression analyses.Results: Our findings showed that cPLA2α knockdown decreases cell-matrix adhesion but increases cell-cell adhesion in HepG2 cells. Microarray analysis revealed that phosphorylation of multiple proteins at specific sites were regulated by cPLA2α. These phosphorylated proteins were involved in various biological processes. In addition, our results indicated that the focal adhesion pathway was highly enriched in the cPLA2α-relevant signaling pathway. Furthermore, cPLA2α was found to elevate phosphorylation levels of FAK and paxillin, two crucial components of focal adhesion. Moreover, localization of p-FAK to focal adhesions in the plasma membrane was significantly reduced with the downregulation of cPLA2α. Clinically, cPLA2α expression was positively correlated with p-FAK levels. Additionally, high expression of both cPLA2α and p-FAK predicted the worst prognoses for HCC patients.Conclusions: Our study indicated that cPLA2α may promote cell-matrix adhesion via the FAK/paxillin pathway, which partly explains the malignant cPLA2α phenotype seen in HCC.

Destabilization of acrosome and elastase influence mediate the release of secretory phospholipase A2 from human spermatozoa

Aim： To determine the cellular distribution of secretory phospholipase A2 （sPLA2） in dependence on the acrosomal state and under the action of elastase released under inflammatory processes from leukocytes. Methods： Acrosome reaction of spermatozoa was triggered by calcimycin. Human leukocyte elastase was used to simulate inflammatory conditions. To visualize the distribution of sPLA2 and to determine the acrosomal state, immunofluorescence techniques and lectin binding combined with confocal laser scanning fluorescence microscopy and flow cytometry were used. Results： Although sPLA2 was detected at the acrosome and tail regions in intact spermatozoa, it disappeared from the head region after triggering the acrosome reaction. This release of sPLA2 was associated with enhanced binding of annexin V-fluoroscein isothiocyanate （FITC） to spermatozoa surfaces, intercalation of ethidium-homodimer I, and binding of FITC-labelled concanavalin A at the acrosomal region. Spermatozoa from healthy subjects treated with elastase were characterized by release of sPLA2, disturbance of acrosome structure, and loss of vitality. Conclusion： The ability of spermatozoa to release secretory phospholipase A2 is related to the acrosomal state. Premature destabi- lization of the acrosome and loss of sPLA2 can occur during silent inflammations in the male genital tract. The distribution pattern of sPLA2 in intact spermatozoa might be an additional parameter for evaluating sperm quality.

髓过氧化物酶和脂蛋白相关磷脂酶A_(2)与急性冠状动脉综合征关系的研究进展

心血管疾病是全球死亡的主要原因。急性冠状动脉综合征(ACS)作为一种临床心脏急症,及时开通病变血管能够明显改善患者预后。对于胸痛患者,如果能够在初期尽早鉴别ACS并采取精准处理措施,将会极大地降低患者的死亡风险,同时改善患者预后。近年来,髓过氧化物酶(MPO)和脂蛋白相关磷脂酶A_(2)(Lp-PLA_(2))与ACS之间关系的研究取得了一定进展,这有助于深入理解ACS的发病机制,对ACS的发生、发展及预后评估有明显预测价值。未来深入研究MPO和Lp-PLA_(2)与ACS的关系将为ACS患者的治疗和预后提供临床借鉴。

穿山龙总皂苷对膜性肾病大鼠肾组织M型PLA2R和IgG4表达的影响及其机制

目的 分析穿山龙总皂苷对膜性肾病大鼠肾组织M型磷脂酶A2受体(Phospholipase A2 receptor, PLA2R)和免疫球蛋白G亚型4(Immunoglobulin G4,IgG4)表达影响及可能机制。方法 将40只SPF级雄性SD大鼠按随机数字表法分为对照组、模型组、贝那普利组(10 mg/kg)、低和高剂量穿山龙总皂苷组(80 mg/kg、160 mg/kg),每组各8只。除对照组,其余4组采用Border法制备膜性肾病模型,造模成功后,贝那普利组灌胃给予贝那普利10 mg/(kg·d),低和高剂量穿山龙总皂苷组分别灌胃给予穿山龙总皂苷80 mg/(kg·d)、160 mg/(kg·d),对照组、模型组灌胃给予10 ml/(kg·d)生理盐水。连续给药4周后,检测24 h尿蛋白、白蛋白、血肌酐、血尿素氮、尿酸水平,HE染色观察肾脏病理改变,蛋白免疫印迹法检测肾脏中M型PLA2R、IgG4、磷酸化磷脂酰肌醇3-激酶(Phosphorylated phosphoinositide 3-kinase, p-PI3K)、磷酸化蛋白激酶B(Phosphorylated protein kinase B,p-AKT)、核因子E2相关因子2(Nuclear factor E2-related factor 2,Nrf2)、血红素加氧酶(Heme oxygenase-1,HO-1)表达水平。结果 与模型组比较,贝那普利组、高剂量穿山龙总皂苷组白蛋白水平明显升高,血肌酐、血尿素氮、尿酸水平明显降低,差异均有统计学意义(P>0.05)。与模型组比较,贝那普利组、低剂量和高剂量穿山龙总皂苷组肾脏病理改变明显改善,24 h尿蛋白水平及肾脏中M型PLA2R、IgG4、p-PI3K、p-AKT表达水平明显降低,肾脏中Nrf2、HO-1表达水平明显增加,差异均有统计学意义(P<0.05)。结论 穿山龙总皂苷对膜性肾病大鼠的肾脏具有保护作用,其机制可能与降低PLA2R、IgG4表达,抑制PI3K/AKT通路,激活Nrf2/HO-1通路相关。

Mogroside IIE,an in vivo metabolite of sweet agent,alleviates acute lung injury via Pla2g2a-EGFR inhibition

In the face of increasingly serious environmental pollution,the health of human lung tissues is also facing serious threats.Mogroside IIE(M2E)is the main metabolite of sweetening agents mogrosides from the anti-tussive Chinese herbal Siraitia grosvenori.The study elucidated the anti-inflammatory action and molecular mechanism of M2E against acute lung injury(ALI).A lipopolysaccharide(LPS)-induced ALI model was established in mice and MH-S cells were employed to explore the protective mechanism of M2E through the western blotting,co-immunoprecipitation,and quantitative real time-PCR analysis.The results indicated that M2E alleviated LPS-induced lung injury through restraining the activation of secreted phospholipase A2 type IIA(Pla2g2a)-epidermal growth factor receptor(EGFR).The interaction of Pla2g2a and EGFR was identified by co-immunoprecipitation.In addition,M2E protected ALI induced with LPS against inflammatory and damage which were significantly dependent upon the downregulation of AKT and m TOR via the inhibition of Pla2g2a-EGFR.Pla2g2a may represent a potential target for M2E in the improvement of LPS-induced lung injury,which may represent a promising strategy to treat ALI.

In Silico Screening of Potential Inhibitors against dPLA2 from Named Chinese Herbs for Identification of Compounds with Antivenom Effects Due to Deinagkistrodon acutus Snake Bites

Phospholipase A2 (PLA2) is the key enzyme to the venom from Deinagkistrodon acutus which is one of the highly venomous snakes in China. In addition to being a catalyst for the hydrolysis of phospholipases A2 from snake venom, its well known that it possesses a broad spectrum of pharmacological activities, such as myotoxicity, neurotoxicity, cardiotoxicity, and hemolytic, anticoagulant and antiplatelet activities. However, snakebites are not efficiently treated by conventional serum therapy. Acute wounds can still cause poisoning and death. In order to find effective inhibitors of Deinagkistrodon venom acid phospholipase A2 (dPLA2), we obtained 385 compounds in 9 Chinese herbs from the TCMSP. These compounds were further performed to virtual screen using in silico tools like ADMET analysis, molecular docking and molecular dynamics (MD) simulation. After Pharmacokinetics analysis, we found 7 candidate compounds. Besides, analysis of small molecule interactions with dPLA2 confirmed that the amino acid residues HIS47 and GLY29 are key targets. Because they bind not only to the natural substrate phosphatidylcholine and compounds known for having inhibitory functions, but also for combining with potential antidote molecules in Chinese herbal medicine. This study is the first to report experience with virtual screening for possible inhibitor of dPLA2, such as the interaction spatial structure, binding energy and binding interaction analysis, these experiences not only provide reference for further experimental research, but also have a guideline for the study of drug molecular mechanism of action.