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Dysfunction of the LIS1 gene causes lissencephaly, a drastic neurological disorder characterized by a deep disruption of the cortical structure. We aim to uncover alterations of the cortical neuronal networks related with the propagation of epileptiform activity in the Lis1/sLis1 mouse, a model lacking the LisH domain in heterozygosis. We did extracellular field-potential and intracellular recordings in brain slices of the anterior cingulate cortex (ACC) or the retrosplenial cortex (RSC) to study epileptiform activity evoked in the presence of bicuculline (10 µM), a blocker of GABAA receptors. The sensitivity to bicuculline of the generation of epileptiform discharges was similar in wild type (WT) and Lis1/sLis1 cortex (EC50 1.99 and 2.24 µM, respectively). In the Lis1/sLis1 cortex, we observed a decreased frequency of the oscillatory post-discharges of the epileptiform events; also, the propagation of epileptiform events along layer 2/3 was slower in the Lis1/sLis1 cortex (WT 47.69 ± 2.16 mm/s, n = 25; Lis1/sLis1 37.34 ± 2.43 mm/s, n = 15; p = 0.004). The intrinsic electrophysiological properties of layer 2/3 pyramidal neurons were similar in WT and Lis1/sLis1 cortex, but the frequency of the spontaneous EPSCs was lower and their peak amplitude higher in Lis1/sLis1 pyramidal neurons. Finally, the propagation of epileptiform activity was differently affected by AMPA receptor blockers: CNQX had a larger effect in both ACC and RSC while GYKI53655 had a larger effect only in the ACC in the WT and Lis1/sLis1 cortex. All these changes indicate that the dysfunction of the LIS1 gene causes abnormalities in the properties of epileptiform discharges and in their propagation along the layer 2/3 in the anterior cingulate cortex and in the restrosplenial cortex., Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature., This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO/AEI/FEDER, UE; grant numbers SAF2017-83702-R, PID2020-118171RB-I00), Spanish State Research Agency, through the “Programa Severo Ochoa” for Centers of Excellence in R&D (grant number SEV-2017-0723), and Generalitat Valenciana (program Prometeo II, grant number 2018/041).

The physiological effect of Lp(a) on platelet activity is unclear. Previous studies explored the relationship between Lp(a) and platelet aggregation in patients taking statins and antiplatelet agents, but few was conducted in individuals without the bias of those drugs that either influence Lp(a) or platelet activity. The aim of this study was to assess the relationship between Lp(a) levels and platelet aggregation in subjects not taking statins or antiplatelet drugs. A hospital-based cross-sectional study was conducted to investigate the independent contribution of Lp(a) to platelet activity by controlling the effects of potential confounding factors including lipoprotein-associated phospholipase A2 [Lp-PLA2]. Blood samples were collected from 92 subjects without statins or antiplatelet agents from the Second Xiangya Hospital. The univariate correlation analysis showed a significant correlation between AA-induced average aggregation rate [AAR] and ApoB (r = 0.324, P = 0.002), ApoA1 (r = 0.252, P = 0.015), Lp(a) (r = 0.370, P

Objective To investigate the role of NudCD1 in spindle assembly checkpoint regulation and in the prognosis of colorectal cancer. Methods Immunohistochemical staining was used to detect in situ expression of NudCD1 in 100 colorectal cancer tissue samples. A chi-square test was used to analyse the correlation between the NudCD1 protein expression level of the cancer tissues and clinicopathological features. The Kaplan–Meier survival analysis was used to assess the correlation between the NudCD1 mRNA expression and the three-year survival of patients with colorectal cancer. The impact of NudCD1 on the development of colorectal cancer and the underlying molecular mechanisms were assessed by flow cytometry cell cycle and apoptosis assays after lentiviral overexpression of NudCD1 in two colorectal cancer cell lines. Quantitative real-time PCR was used to assess mRNA expression of the cellular spindle assembly checkpoint genes BUB1, BUBR1, MAD1, CDC20 and MPS1, as well as the downstream genes LIS1, DYNC1H1, and DYNLL1 in the NudC/LIS1/dynein pathway. Results Compared with normal intestinal tissue (8.00% with high expression), the expression of NudCD1 protein in colorectal cancer tissue was significantly higher (58.00% with high expression, P P P P P Conclusion NudCD1 can serve as a valuable prognostic marker for colorectal cancer. It may be involved in the regulation of spindle-assembly checkpoint-gene expression and the LIS1 pathway of colorectal cancer cells.

Macrophage-mediated inflammation plays an important role in hypertensive cardiac remodeling, whereas effective pharmacological treatments targeting cardiac inflammation remain unclear. Lipoprotein-associated phospholipase A2 (Lp-PLA2) contributes to vascular inflammation-related diseases by mediating macrophage migration and activation. Darapladib, the most advanced Lp-PLA2 inhibitor, has been evaluated in phase III trials in atherosclerosis patients. However, the role of darapladib in inhibiting hypertensive cardiac fibrosis remains unknown. Using a murine angiotensin II (Ang II) infusion-induced hypertension model, we found that Pla2g7 (the gene of Lp-PLA2) was the only upregulated PLA2 gene detected in hypertensive cardiac tissue, and it was primarily localized in heart-infiltrating macrophages. As expected, darapladib significantly prevented Ang II-induced cardiac fibrosis, ventricular hypertrophy, and cardiac dysfunction, with potent abatement of macrophage infiltration and inflammatory response. RNA sequencing revealed that darapladib strongly downregulated the expression of genes and signaling pathways related to inflammation, extracellular matrix, and proliferation. Moreover, darapladib substantially reduced the Ang II infusion-induced expression of nucleotide-binding oligomerization domain-like receptor with pyrin domain 3 (NLRP3) and interleukin (IL)-1β and markedly attenuated caspase-1 activation in cardiac tissues. Furthermore, darapladib ameliorated Ang II-stimulated macrophage migration and IL-1β secretion in macrophages by blocking NLRP3 inflammasome activation. Darapladib also effectively blocked macrophage-mediated transformation of fibroblasts into myofibroblasts by inhibiting the activation of the NLRP3 inflammasome in macrophages. Overall, our study identifies a novel anti-inflammatory and anti-cardiac fibrosis role of darapladib in Lp-PLA2 inhibition, elucidating the protective effects of suppressing NLRP3 inflammasome activation. Lp-PLA2 inhibition by darapladib represents a novel therapeutic strategy for hypertensive cardiac damage treatment.

Introduction Air pollution is associated with increased risk of cardiovascular disease, possibly through chronic systemic inflammation that promotes the progression of atherosclerosis and the risk of cardiovascular events. This study aimed to investigate the associations between air pollution and established biomarkers of inflammation and cardiovascular disease. Methods The Cardiovascular Subcohort of the Malmö Diet and Cancer cohort includes 6103 participants from the general population of Malmö, Sweden. The participants were recruited 1991–1994. Annual mean residential exposure to particulate matter 2.5 and PM10), and nitrogen oxides (NOx) at year of recruitment were assigned from dispersion models. Blood samples collected at recruitment, including blood cell counts, and biomarkers (lymphocyte- and neutrophil counts, C-reactive protein (CRP), soluble urokinase-type plasminogen activator receptor (suPAR), lipoprotein-associated phospholipase A2 (Lp-PLA2), ceruloplasmin, orosomucoid, haptoglobin, complement-C3, and alpha-1-antitrypsin) were analyzed. Multiple linear regression models were used to investigate the cross-sectional associations between air pollutants and biomarkers. Results The mean annual exposure levels in the cohort were only slightly or moderately above the new WHO guidelines of 5 μg/m3 PM2.5 (10.5 μg/m3 PM2.5). Residential PM2.5 exposure was associated with increased levels of ceruloplasmin, orosomucoid, C3, alpha-1-antitrypsin, haptoglobin, Lp-PLA2 and the neutrophil-lymphocyte ratio. Ceruloplasmin, orosomucoid, C3 and alpha-1-antitrypsin were also positively associated with PM10. There were no associations between air pollutants and suPAR, leukocyte counts or CRP. The associations between particles and biomarkers were still significant after removing outliers and adjustment for CRP levels. The associations were more prominent in smokers. Conclusion Long-term residential exposure to moderate levels of particulate air pollution was associated with several biomarkers of inflammation and cardiovascular disease. This supports inflammation as a mechanism behind the association between air pollution and cardiovascular disease.

There are no effective therapies to prevent the occurrence and progression of vertebrobasilar dolichoectasia (VBD). In this study, we investigated the relationship between serum levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the occurrence and progression of VBD. Sixty (60) cases without VBD and ischemia stroke were considered as Group A, 100 cases with VBD were further divided into Group B (VBD without ischemic stroke, n = 54) and Group C (VBD with first ever acute posterior circulation ischemic stroke, n = 46). Demographic data (such as gender and age) and past medical history (such as hypertension, diabetes, and smoking history) were collected. The levels of serum low-density lipoprotein cholesterol (LDL-C), hypersensitivity C reactive protein (hs-CRP), glycosylated hemoglobin (HbAlc), homocysteine (HCY), uric acid (UA), fibrinogen (Fib), and Lp-PLA2, etc. were measured. Logistic regression analysis was used to assess the related factors of VBD and ischemic stroke secondary to VBD. Logistic multivariate regression analysis showed that only age and the level of serum Lp-PLA2 were significantly higher in group B than those in group A (P

The purpose of this study was to evaluate the contribution of DNA methylation at the phospholipase A2 group VII (PLA2G7) gene, to the risk of developing brain arteriovenous malformations (BAVMs) and intracranial aneurysms (IAs) in a Han Chinese population. Seventy patients with BAVMs or IAs and 26 control subjects were recruited to evaluate PLA2G7 methylation by bisulfite pyrosequencing. CpG3 methylation at the PLA2G7 was significantly higher in BAVM patients than in the control group (Chr6,46735560, p = 0.042). Gender subgroup analysis showed that PLA2G7 CpG4 (Chr6,46735574, p = 0.033) and mean methylation (p = 0.037) levels were significantly associated with BAVM in males. However, in females, PLA2G7 methylations were much lower in IAs than in controls [CpG2 (Chr6,46735558), p = 0.030] and BAVMs [CpG2, p = 0.001; CpG4, p = 0.007; CpG6 (Chr6, 46735579), p = 0.024; mean, p = 0.013]. In addition, mean methylation of the PLA2G7 significantly correlated with apoB levels in all individuals (r = 0.288, p = 0.006), and with apoE in BAVM patients (r = 0.259, p = 0.016). The receiver operating characteristic (ROC) curve showed that PLA2G7 CpG3 methylation might be a predictor of BAVM risk in Han Chinese (area under curve (AUC) = 0.76, p = 0.008). PLA2G7 DNA methylation was significantly associated with the risk of developing BAVMs in males or IAs in females. Future studies on the PLA2G7 mechanisms should be performed on the pathogenesis of these cerebrovascular disorders.

Background The association of lipoprotein(a) [Lp(a)] and stroke functional outcomes was conflicting. The aim of the study was to clarify whether high Lp(a) is associated with unfavorable functional outcomes in patients with ischemic stroke. Methods A total of 9709 individuals from the third China National Stroke Registry cohort were recruited. Plasma level of Lp(a) at admission was measured with enzyme-linked immunosorbent assay. The cut-off was set at the median for Lp(a). Functional outcome was assessed using the modified Rankin scale (mRS) at 3 months and 1 year after ischemic stroke. The association between Lp(a) and functional outcomes was evaluated using a logistic regression model. Results The median age was 63.0 years, and 31.1% participants were women. Patients in higher Lp(a) group had higher incidences of unfavorable functional outcomes at 3 months. In logistic regression model, elevated Lp(a) levels were associated with unfavorable functional outcomes at 3 months (Q4 vs. Q1: odds ratio 1.33, 95% confidence interval 1.11–1.61). Subgroup analysis showed that in the lower Lp-PLA2 group, Lp(a) level was not associated with functional outcomes, but in the higher Lp-PLA2 group, Lp(a) level was significantly associated with functional outcomes. After grouped by different levels of Lp(a) and Lp-PLA2, the Lp(a) high/ Lp-PLA2 high group showed the highest incidence of unfavorable functional outcomes at 3 months and 1 year. Conclusions Elevated Lp(a) level is associated with unfavorable functional outcomes in patients with ischemic stroke. The increment in both Lp(a) and Lp-PLA2 are associated with unfavorable functional outcomes at 3 months and 1 year after ischemic stroke.

Background Atherosclerotic plaque vulnerability is a key feature of atheroprogression and precipitating acute cardiovascular events. Although the pivotal role of epigenetic regulation in atherosclerotic plaque destabilization is being recognized, the DNA methylation profile and its potential role in driving the progression and destabilization of atherosclerotic cardiovascular disease remains largely unknown. We conducted a genome-wide analysis to identify differentially methylated genes in vulnerable and non-vulnerable atherosclerotic lesions to understand more about pathogenesis. Results We compared genome-wide DNA methylation profiling between carotid artery plaques of patients with clinically symptomatic (recent stroke or transient ischemic attack) and asymptomatic disease (no recent stroke) using Infinium Methylation BeadChip arrays, which revealed 90,368 differentially methylated sites (FDR 0.03) corresponding to 14,657 annotated genes. Among these genomic sites, 30% were located at the promoter regions and 14% in the CpG islands, according to genomic loci and genomic proximity to the CpG islands, respectively. Moreover, 67% displayed hypomethylation in symptomatic plaques, and the differentially hypomethylated genes were found to be involved in various aspects of inflammation. Subsequently, we focus on CpG islands and revealed 14,596 differentially methylated sites (|delta beta|> 0.1) located at the promoter regions of 7048 genes. Integrated analysis of methylation and gene expression profiles identified that 107 genes were hypomethylated in symptomatic plaques and showed elevated expression levels in both advanced plaques and ruptured plaques. The imprinted gene PLA2G7, which encodes lipoprotein-associated phospholipase A2 (Lp-PLA2), was one of the top hypomethylated genes with an increased expression upon inflammation. Further, the hypomethylated CpG site at the promoter region of PLA2G7 was identified as cg11874627, demethylation of which led to increased binding of Sp3 and expression of Lp-PLA2 through bisulfate sequencing, chromatin immunoprecipitation assay and enzyme-linked immunosorbent assay. These effects were further enhanced by deacetylase. Conclusion Extensive DNA methylation modifications serve as a new and critical layer of biological regulation that contributes to atheroprogression and destabilization via inflammatory processes. Revelation of this hitherto unknown epigenetic regulatory mechanism could rejuvenate the prospects of Lp-PLA2 as a therapeutic target to stabilize the atherosclerotic plaque and reduce clinical sequelae.

Background Diffuse large B-cell lymphoma is the most common form of non-Hodgkin lymphoma globally, and patients with relapsed or refractory DLBCL typically experience poor long-term outcomes. Methods Differentially expressed genes associated with DLBCL were identified using two GEO datasets in an effort to detect novel diagnostic or prognostic biomarkers of this cancer type, after which receiver operating characteristic curve analyses were conducted. Genes associated with DLBCL patient prognosis were additionally identified via WCGNA analyses of the TCGA database. The expression of PLA2G7 in DLBCL patient clinical samples was further assessed, and the functional role of this gene in DLBCL was assessed through in vitro and bioinformatics analyses. Results DLBCL-related DEGs were found to be most closely associated with immune responses, cell proliferation, and angiogenesis. WCGNA analyses revealed that PLA2G7 exhibited prognostic value in DLBCL patients, and the upregulation of this gene in DLBCL patient samples was subsequently validated. PLA2G7 was also found to be closely linked to tumor microenvironmental composition such that DLBCL patients expressing higher levels of this gene exhibited high local monocyte and gamma delta T cell levels. In vitro experiments also revealed that knocking down PLA2G7 expression was sufficient to impair the migration and proliferation of DLBCL cells while promoting their apoptotic death. Furthmore, the specific inhibitor of PLA2G7, darapladib, could noticeably restrained the DLBCL cell viability and induced apoptosis. Conclusions PLA2G7 may represent an important diagnostic, prognostic, or therapeutic biomarker in patients with DLBCL.

Cell migration plays pivotal roles in many biological processes; however, its underlying mechanism remains unclear. Here, we find that NudC-like protein 2 (NudCL2), a cochaperone of heat shock protein 90 (Hsp90), modulates cell migration by stabilizing both myosin-9 and lissencephaly protein 1 (LIS1). Either knockdown or knockout of NudCL2 significantly increases single-cell migration, but has no significant effect on collective cell migration. Immunoprecipitation–mass spectrometry and western blotting analyses reveal that NudCL2 binds to myosin-9 in mammalian cells. Depletion of NudCL2 not only decreases myosin-9 protein levels, but also results in actin disorganization. Ectopic expression of myosin-9 efficiently reverses defects in actin disorganization and single-cell migration in cells depleted of NudCL2. Interestingly, knockdown of myosin-9 increases both single and collective cell migration. Depletion of LIS1, a NudCL2 client protein, suppresses both single and collective cell migration, which exhibits the opposite effect compared with myosin-9 depletion. Co-depletion of myosin-9 and LIS1 promotes single-cell migration, resembling the phenotype caused by NudCL2 depletion. Furthermore, inhibition of Hsp90 ATPase activity also reduces the Hsp90-interacting protein myosin-9 stability and increases single-cell migration. Forced expression of Hsp90 efficiently reverses myosin-9 protein instability and the defects induced by NudCL2 depletion, but not vice versa. Taken together, these data suggest that NudCL2 plays an important role in the precise regulation of cell migration by stabilizing both myosin-9 and LIS1 via Hsp90 pathway.

Background The level of lipoprotein-associated phospholipase A2 (LP-PLA2) in serum is independently correlated to coronary artery diseases (CAD). The aim of the study was to determine whether LP-PLA2 activity is positively associated with the seriousness of CAD. Methods Amount to 1056 patients suspected of having CAD underwent coronary angiography (CAG) to determine the seriousness of CAD. According to the amount of diseased coronary branches, the 1056 patients were split into three groups: single-vessel stenosis group, multiple-vessels stenosis group (> or = 2 diseased coronary branches),and control group (no diseased coronary branches). According to CAG results, electrocardiography, cardiac biomarker, and clinical presentation, all patients were split into four groups: acute myocardial infarction (AMI), unstable angina (UA), stable angina (SA), and control groups (excluding CAD). The activity of LP-PLA2 was compared statistically among the subgroups. Receiver operating characteristic analysis was applied to investigate the role of LP-PLA2 in evaluating the presence and seriousness of CAD. Results The level of LP-PLA2 increased in line with the number of diseased coronary branches. The levels of LP-PLA2 in the AMI and UA groups were observably higher when compared with the control and SA groups. LP-PLA2 had 75.6% sensitivity and 67.3% specificity for recognizing CAD, and 53.0% sensitivity and 80.3% specificity for recognizing severe coronary artery lesions. Conclusion The activity of LP-PLA2 is positively correlated to the seriousness of CAD.

Objective Coronary slow flow (CSF) is characterized by delayed opacification of distal epicardial coronary arteries without significant coronary stenosis. In addition, The changes of lipoprotein-associated phospholipase A2 (Lp-PLA2) as a significant predictive factor for CSF remain controversial. The study aims to investigate the association between plasma Lp-PLA2 and CSF. Methods In this retrospective study, 170 consecutive patients who underwent coronary angiography were enrolled in Beijing Anzhen Hospital from January 2017 to September 2019, and were divided into CSF group and normal control groups. According to coronary blood flow rate measured by the thrombolysis in myocardial infarction frame count (TFC) method, CSF was defined as TFC > 27. Serum Lp-PLA2 levels were measured in an enzyme-linked immunosorbent assay. Results Lp-PLA2 levels were higher in the CSF group than in the control group (288.6 ± 50.3 versus 141.9 ± 49.7, P 2 was independently associated with CSF after adjustment for conventional risk factors (OR = 1.040, CI = 1.022–1.059, PP = 0.016) and hypertension (OR = 1.965, CI = 1.034–3.736, P = 0.039) were also CSF risk factors. Receiver-operating characteristic curve (ROC) analysis showed that Lp-PLA2 levels can predict CSF severity; the predictive power was higher than the other risk factors. Conclusion Our study demonstrated that patients with CSF had higher circulating levels of Lp-PLA2 than normal controls. After adjustment for potential confounders, increased Lp-PLA2 was independently associated with presence of CSF.

We studied serum content of some polyunsaturated fatty acids and their correlations with parameters of oxidative stress (FORT), antioxidant protection (FORD), lipoprotein-associated phospholipase A2 (LP-PLA2), and serum level of LPO products in male patients with coronary atherosclerosis. The mass fraction of polyunsaturated fatty acids and FORD were lower, while LP-PLA2, FORT, and concentration of LPO products were higher than in the control group (conventionally healthy men). Negative correlations of medium strength of polyunsaturated fatty acids with inflammation markers and oxidative stress were revealed, which can indicate that the decrease in polyunsaturated fatty acids content is associated with enhanced generation of free radicals, and consequently with increased risk of early atherosclerosis development.

Lipoprotein-associated phospholipase AWe enrolled 102 dialyzed patients, 63% male, age 71 years (59-78), 35% with diabetes, 54% hypertension, 40% coronary artery disease and 31% peripheral vascular disease. They were investigated for Lp-PLA2 (cut-off 194 nmol/min/ml), lipoprotein profile and the occurrence of acute CV events and death in the subsequent 3 years of follow-up.The median (interquartile ranges) levels of Lp-PLA2, total-, HDL-, LDL-cholesterol and ApoB/ApoA lipoprotein ratio were 184.5 (156.5-214.5) nmol/min/ml, 158 (127-191) mg/dl, 41 (33-51) mg/dl, 79 (63-102) mg/dl and 0.72 (0.58-0.89), respectively. In 42% of patients, Lp-PLA2 was 194 nmol/min/ml and total- and LDL-cholesterol were higher, as well as CV morbidity and mortality. During follow-up, 51% of patients developed at least one CV event; the median survival time was 36 months, with a total and CV mortality of 42 and 29%, respectively. At multivariate Cox regression, Lp-PLA2 194 nmol/min/ml (HR = 2.98, p = 0.005), age (HR = 1.03, p = 0.029), diabetes (HR = 2.86, p = 0.002) and hypertension (HR = 2.93, p = 0.002) were independently associated with time to CV events.Lp-PLA2 activity is elevated among dialyzed patients and is an independent risk factor for acute CV events in a mean follow-up of 3 years.

The purpose of this study was to test the hypothesis that an experimental high fat (HF) animal with metabolic syndrome results in structural degeneration of the aortic valve. Domestic pigs were divided (n = 12) and administered either a normal or HF diet. After 16-weeks, the HF diet group had increased weight (p ≤ 0.05), total cholesterol (p ≤ 0.05), and systolic and diastolic pressure (p ≤ 0.05). The aortic valve extracellular matrix showed loss of elastin fibers and increased collagen deposition in the HF diet group. Collagen was quantified with ELISA, which showed an increased concentration of collagen types 1 and 3 (p ≤ 0.05). In the HF diet group, the initial stages of microcalcification were observed. Uniaxial mechanical testing of aortic cusps revealed that the HF diet group expressed a decrease in ultimate tensile strength and elastic modulus compared to the control diet group (p ≤ 0.05). Western blot and immunohistochemistry indicated the presence of proteins: lipoprotein-associated phospholipase A2, osteopontin, and osteocalcin with an increased expression in the HF diet group. The current study demonstrates that experimental metabolic syndrome induced by a 16-week HF diet was associated with a statistically significant alteration to the physical architecture of the aortic valve.

Aim: Aspirin resistance has an incidence of 5%–65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A 2 receptor (TXA 2 receptor, encoded by TBXA2R ), lipoprotein-associated phospholipase A 2 (Lp-PLA 2 , encoded by PLA2G7 ) and platelet endothelial aggregation receptor-1 ( PEAR1 , encoded by PEAR1 ) are crucial in regulating platelet activation, and P-glycoprotein (P-gp, encoded by MDR1 ) influences the absorption of aspirin in the intestine. In this study we examined the correlation between MDR1 , TBXA2R , PLA2G7 , PEAR1 genetic polymorphisms and platelet activity in Chinese ischemic stroke patients receiving aspirin therapy. Methods: A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB 2 ELISA kit. Results: Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233–0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080–6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590–42.638). Conclusion: A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931–rs7756935) polymorphisms.

Background Obesity is associated with a change in high-density lipoprotein (HDL) function and subclass. Exercise training reduces cardiovascular risk in obese patients. We aimed to explore the effect of an exercise training stimulus on HDL functionality and subclass in obese women. Methods Thirty-two obese black South African women were randomly assigned to exercise (combined aerobic and resistance exercise) or control (no exercise) conditions for 12-weeks. Pre- and post-testing included venous blood sampling for analysis of lipid profile and HDL functionality, by measuring cellular cholesterol efflux capacity, reduction in endothelial vascular cell adhesion molecule (VCAM) expression (anti-inflammatory function), paraoxonase (PON) (antioxidative function) and platelet activating factor acetylhydrolase (PAF-AH) activities (anti-thrombotic function). PON-1 and PAF-AH expression were determined in serum and in isolated HDL using Western blotting. Levels of large, intermediate and small HDL subclasses were measured using the Lipoprint® system. Results Exercise training resulted in a decrease in body mass index (− 1.0 ± 0.5% vs + 1.2 ± 0.6%, p = 0.010), PON activity (− 8.7 ± 2.4% vs + 1.1 ± 3.0%, p = 0.021), PAF-AH serum expression (− 22.1 ± 8.0% vs + 16.9 ± 9.8, p = 0.002), and the distribution of small HDL subclasses (− 10.1 ± 5.4% vs + 15.7 ± 6.6%, p = 0.004) compared to controls. Exercise did not alter HDL cellular cholesterol efflux capacity and anti-inflammatory function. Conclusions These results demonstrate the potential for exercise training to modify HDL subclass distribution and HDL function in obese women. Trial registration Clinical trials number: PACTR201711002789113 .

Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays an important role in coronary heart disease (CHD). This study was aimed to investigate the associations of polymorphisms (R92H, V279F, I198T, and A379V) in PLA2G7 with CHD. A total of 322 patients with CHD and 414 CHD-free controls were included in the study. Polymorphisms in PLA2G7 were sequenced by DNA Sequencer and statistical analyses were performed to study the associations between polymorphisms and CHD. RH + HH genotype, RH genotype, and H allele of R92H were significantly associated with an increased risk of CHD (P = 0.005, P = 0.009, and P = 0.003, respectively), while no associations were observed between V279F and I198T and CHD (A379V was not analyzed because of deviation from Hardy-Weinberg equilibrium). Correlations between R92H and CHD still existed after adjustment for confounding risk factors of CHD (P = 0.001). Furthermore, stratified analyses showed subgroups of the senior, hypertension, non-smoking, non-diabetics, and male subjects brought a higher risk for CHD (P = 0.015, P = 0.001, P = 0.001, P = 0.002, and P = 0.004, respectively). We also observed a lower level of protective factor HDL-C in CHD patients carrying genotype RH + HH than patients with RR (P = 0.047). Furthermore, we conducted haplotype analysis and detected more harmful effects of haplotypes HVI and RVT as compared with other haplotypes (P = 2.538 × 10(-3) and P = 0.031). These findings indicated that R92H variant in PLA2G7 gene might contribute to CHD susceptibility in a southern Chinese population.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a risk factor for acute coronary syndrome (ACS), but this remains controversial. This study investigated the role of Lp-PLA2 in young Chinese patients with ACS. 228 young patients (aged ≤55 years) with ACS and 237 age-matched controls were included. Lp-PLA2 and oxidized low-density lipoprotein (ox-LDL) levels were measured by sandwich enzyme-linked immunosorbent assay. Lp-PLA2 levels were significantly correlated with smoking, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and ox-LDL levels (all P

Coronary heart disease (CHD) accounts for one in every six deaths in US individuals. Great advances have been made in identifying important risk factors for CHD, such as hypertension, diabetes mellitus, smoking and hypercholesterolaemia, which have led to major developments in therapy. In particular, statins represent one of the greatest successes in the prevention of CHD. While these standard risk factors are important, an obvious opportunity exists to take advantage of ongoing scientific research to better risk-stratify individuals and to identify new treatment targets. In this Review, we summarize ongoing scientific research in a number of metabolic molecules or features, including lipoproteins, homocysteine, calcium metabolism and glycaemic markers. We evaluate the current state of the research and the strength of evidence supporting each emerging biomarker. We also discuss whether the associations with CHD are strong and consistent enough to improve current risk stratification metrics, and whether these markers enhance our understanding of the underlying biology of CHD and thus point towards new treatment options.

The circulating level of platelet-activating factor acetylhydrolase (PAF-AH) is a novel biomarker to predict the presence of coronary heart disease. PAF-AH gene polymorphisms may be responsible for the variance of circulating PAF-AH levels in individuals. However, the association of PAF-AH gene polymorphisms with circulating PAF-AH levels and the susceptibility to coronary heart disease (CHD) remains unsolved. Blood stasis syndrome (BSS) of CHD is the most common type of TCM syndromes, and a previous study discovered its relationship with the elevated circulating PAF-AH levels. However, the association of gene polymorphisms and CHD with BSS is unclear at present. In this study, four polymorphisms (R92H, I198T, A379V, V279F) of the PAF-AH gene were genotyped in 570 CHD patients, of which 299 had BSS. In addition, 317 unaffected individuals from the same hospitals served as controls. Plasma PAF-AH levels were measured in 155 controls and 271 CHD patients selected randomly, including 139 CHD patients with BSS. In the Chinese Han population, plasma PAF-AH levels in CHD patients with BSS or without BSS were significantly higher (12.9 ± 6.5 and 11.1 ± 5.0 μM, respectively) than in controls (9.3 ± 5.2 μM); this difference still remained significant after adjustment for traditional risk factors or the inflammatory factors. The R92H polymorphism was highly related to the plasma PAF-AH levels and the risk of CHD, especially among patients with BSS, even with the adjustment for the effects of traditional factors. The I198T polymorphism was highly associated with risk of CHD with BSS, but was associated with neither the risk of CHD with no BSS nor with elevated plasma PAF-AH levels.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a unique circulating phospholipase with inflammatory and oxidative activities and the limited data regarding the relationship between Lp-PLA2 and cognitive impairment are conflicted. We conducted a cross-sectional study including 1,374 Chinese adults recruited from 2010 to 2011, aiming to evaluate the relationship between Lp-PLA2 levels and the prevalence of cognitive impairment in a Chinese community-based population. Participants underwent standardized evaluation. Serum Lp-PLA2 mass was measured by ELISA. Cognition status was evaluated via the Mini-Mental Status Exam (MMSE) and cognitive impairment was identified as MMSE 2 mass with cognitive impairment. Lp-PLA2 mass was significantly associated with the prevalence of cognitive impairment after adjusting for other potential confounding factors (compared with the first quartile, adjusted ORs of the second, third, and fourth quartile were 2.058 (95% CI, 0.876–4.835), 2.834 (95% CI, 1.255–6.398), and 4.882 (95% CI, 2.212–10.777), p 2 mass was independently associated with the prevalence of cognitive impairment in Chinese adults.

Atopaxar is a reversible protease activated receptor (PAR)-1 thrombin receptor antagonist that interferes with platelet signaling. The effects of PAR-1 antagonists on biomarkers remain unknown. The primary objective was to assess the effects of atopaxar on biomarkers of inflammation and platelet activation. The LANCELOT-CAD trial randomized 720 subjects to atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks. Biomarkers were assessed at serial time points. A linear mixed model to account for repeated measures was used to evaluate the change in biomarker concentration from randomization across time to week 24. Least square means were determined from the linear mixed models. The concentration of sCD40L decreased on average over time by -553 (95 % CI -677, -429) ng/L in the combined atopaxar group versus -30.3 (-249 to 189) ng/L fall in the placebo arm (P < 0.001) and a dose-dependent trend was seen across treatment groups (P < 0.001 for trend). In contrast, Lp-PLA(2) mass rose on average over time by 12.6 (95 % CI 10.0, 15.3) ng/ml in the combined atopaxar group as compared with 2.6 (95 % CI -2.1, 7.3) ng/ml in the placebo arm (P < 0.001). Similarly, the concentration of IL-18 rose by 17.5 (95 % CI 12.4, 22.6) pg/ml in the atopaxar group versus a -1.2 (95 % CI -10.2, 7.8) pg/ml fall in the placebo group (P < 0.001). The effects of atopaxar on Lp-PLA(2) and IL-18 appeared to be dose-dependent (P < 0.001 for trend) and were observed in J-LANCELOT. Atopaxar did not have a significant effect on other inflammatory markers. In conclusion, atopaxar appeared to decrease sCD40L, but did not demonstrate an anti-inflammatory effect in patients with stable CAD. Although atopaxar increased the concentration of Lp-PLA(2) and IL-18, the clinical relevance of these findings remains unknown and warrants further investigation and validation.

Treacher-Collins-Franceschetti syndrome (TCS) is an autosomal dominant craniofacial disorder characterised by midface hypoplasia, micrognathia, downslanting palpebral fissures, eyelid colobomata, and ear deformities that often lead to conductive deafness. A total of 182 patients with signs consistent with a diagnosis of TCS were screened by DNA sequence and dosage analysis of the TCOF1 gene. In all, 92 cases were found to have a pathogenic mutation by sequencing and 5 to have a partial gene deletion. A further case had a novel in-frame deletion in the alternatively spliced exon 6A of uncertain pathogenicity. The majority of the pathogenic sequence changes were found to predict premature protein termination, however, four novel missense changes in the LIS1 homology motif at the 5' end of the gene were identified. The partial gene deletions of different sizes represent ~5.2% of all the pathogenic TCOF1 mutations identified, indicating that gene rearrangements account for a significant proportion of TCS cases. This is the first report of gene rearrangements resulting in TCS. These findings expand the TCOF1 mutation spectrum indicating that dosage analysis should be performed together with sequence analysis, a strategy that is predicted to have a sensitivity of 71% for patients in whom TCS is strongly suspected.

A member of the A2 phospholipase superfamily, the enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2), is involved in atherogenic processes. Lp-PLA2 mass and activity were measured by the enzyme-linked immunosorbent assay and by a colorimetric method, respectively, and compared among 63 multiple sclerosis (MS) patients and 47 age-matched healthy controls (HCs). Lp-PLA2 plasma levels were significantly higher in MS patients (236.7 ± 10 ng/ml) compared to HCs (197.0 ± 7 ng/ml) (p = 0.003), but LP-PLA2 activity did not differ between the two groups. Both Lp-PLA2 plasma mass and activity were higher in secondary progressive (mass 247.0 ± 15.5 ng/ml, p = 0.05; activity 156.1 ±6 nmol/min/ml, p = 0.003) compared to relapsing-remitting MS patients (mass 227.0 ± 16 ng/ml; activity 128.8 ± 5 nmol/min/ml) and compared to HCs. Lp-PLA2 plasma activity was associated with measures of MS clinical disability. However, this association was attenuated after adjustment for the components of lipid profiles.

Background Since chronic apical periodontitis (CAP) appears to be a risk factor for coronary heart disease, the aim of the study was to determine the relationship between the size of CAP lesion and inflammatory markers (hsCRP, IL-6, TNF-α), as well as lipids and lipoproteins (LpPLA2, apoAI, apoB level) in blood serum of patients with CAP. Methods The patients studied (n = 43) were divided into groups: patients under 50 and over 50 years of age, and a separate subgroup of the oldest age with the largest size of CAP lesions. Apolipoprotein AI (apoAI) above 150 mg/dL and below 150 mg/dL was used as an important criterion for the division of patients into groups. The CAP lesion size was measured using the Kodak digital imaging system software. The control group consisted of clinically healthy volunteers (n = 20) without CAP. Lipids were measured on a Siemens analyzer (Germany), apoAI, apoB, hsCRP levels were determined by immunonephelometric method, using the Health Care Diagnostic Product (Siemens GmbH, Germany), and IL-6, TNF-α and LpPLAG7 assay kits (ELISA, R&D Systems) were used. Results The findings suggested that in patients with CAP and their age increase, the CAP lesion size, the concentration of inflammatory markers and LpPLA2 mass increased. Correlations between the CAP lesion size and LpPLA2 mass and between the CAP lesion size and TG level in patients with apoAI 150 ≤ mg/dL showed increase TG in atherogenic apoB-containing triglyceride-rich lipoprotein and TC in cholesterol-rich lipoprotein. The patients with a low apoAI and high LpPLA2 level can have a higher risk of odontogenic disease and progression of atherosclerosis and coronary heart disease. Conclusion We have found a positive correlation between apoAI level and the CAP lesion size and a negative correlation between LpPLA2 level and the CAP lesion size. The results suggest that apoAI and LpPLA2 in HDL particles have antiinflammatory action and together can limit the CAP lesion size in patient with a higher apoAI level. The literature data on the distribution of lipoprotein particles in subjects are still insufficient, so this problem requires further studies.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an enzyme which binds to oxidized LDL and has a pro-inflammatory role in the pathogenesis of atherosclerosis. The Lp-PLA(2) Studies Collaboration showed the relationship between Lp-PLA(2) levels and activity with coronary heart disease and ischemic stroke. Levels and activity of Lp-PLA(2) are reduced by statins. There have been limited studies focused on dietary factors and effects on LpPLA(2). A recent article from the Nurses' Health Study (HNS) and the Health Professionals Follow-up Study (HPFS) has provided interesting insights. In this cross sectional study, a lower LpPLA(2) activity was found to be related to several dietary factors including higher percentage of energy consumed as protein instead of carbohydrate, mild to moderate intake of alcohol, higher mono-unsaturated fat intake instead of carbohydrate, and not being overweight. It is unknown whether changes in Lp-PLA(2) by diet alter cardiovascular risk.

This study was designed to investigate and characterize the ability of platelet-activating factor (PAF) to induce the expression of platelet-activating factor acetylhydrolase (PAF-AH).Ribonuclease protection assays and quantitative real-time PCR were used to investigate the ability of lipopolysaccharide (LPS) and PAF to regulate PAF-AH mRNA expression in human monocyte-macrophage 6 (MM6) cells. Pharmacological inhibitors of mitogen activated protein kinases (MAPK) and PAF receptor antagonists were used to investigate the mechanism of regulation of PAF-AH.PAF-AH mRNA levels were increased upon exposure to LPS or PAF in a dose-dependent manner. LPS elicited a more potent and rapid increase in PAF-AH expression than the PAF-stimulated response. However, when administered concomitantly, PAF augmented the LPS-stimulated response. LPS-stimulated PAF-AH expression was susceptible to partial inhibition by a p38 MAPK inhibitor and PAF receptor antagonists. PAF-induced up-regulation of PAF-AH levels was solely mediated via the PAF receptor and was p38 MAPK-independent.The proinflammatory mediators, LPS and PAF, increased levels of PAF-AH mRNA via distinct signaling pathways.

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is an enzyme that generates inflammatory mediators within atherosclerotic plaques. In epidemiologic studies there is an association between higher plasma Lp-PLA₂ activity and myocardial infarction, stroke and cardiovascular mortality. In animal models, darapladib, a specific inhibitor of Lp-PLA₂, decreases the size of the atheroma necrotic core and plaques with thin fibrous caps. Early clinical trials suggest darapladib effectively and safely inhibits Lp-PLA₂ activity both in plasma and in carotid atheroma. Two large phase III clinical trials that are currently in progress will determine whether darapladib will reduce the risk of myocardial infarction, stroke, and cardiovascular death by stabilizing atherosclerotic plaques.

Type 2 diabetes is an established risk factor for cardiovascular disease (CVD). This increased risk may be due in part to the increased levels of inflammatory factors associated with diabetes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a risk marker for CVD and has pro-inflammatory effects in atherosclerotic plaques. We therefore sought to determine whether Lp-PLA(2) levels partially explain the greater prevalence of subclinical CVD and greater incidence of CVD outcomes associated with type 2 diabetes in the Cardiovascular Health Study.We conducted a cross-sectional and prospective study of 4,062 men and women without previous CVD from the Cardiovascular Health Study (1989 to 2007). Lp-PLA(2) mass and activity were measured in baseline plasma. Subclinical disease was determined at baseline and incident CVD was ascertained annually. We used logistic regression for cross-sectional analyses and Cox proportional hazards models for incident analyses.At baseline, Lp-PLA(2) mass did not differ significantly by type 2 diabetes status; however, Lp-PLA(2) activity was significantly higher among type 2 diabetic individuals. Baseline subclinical disease was significantly associated with baseline diabetes and this association was similar in models unadjusted or adjusted for Lp-PLA(2) (OR 1.68 [95% CI 1.31-2.15] vs OR 1.67 [95% CI 1.30-2.13]). Baseline type 2 diabetes was also significantly associated with incident CVD events, including fatal CHD, fatal myocardial infarction (MI) and non-fatal MI in multivariable analyses. There were no differences in these estimates after further adjustment for Lp-PLA(2) activity.In this older cohort, differences in Lp-PLA(2) activity did not explain any of the excess risk for subclinical disease or CVD outcomes related to diabetes.

The deletion of the locus 17p13 was associated with Miller–Dieker lissencephaly syndrome (MDLS). Deletion (Delatycki and Leventer 2009) or mutations (Lo Nigro et al. 1997) in the PAFAH1B1 (601545) gene cause lissencephaly (Gu and Lupski 2008), but facial dysmorphology and other abnormalities in patients with MDLS seem to be the result of the deletion of additional genes distal to PAFAH1B1 (Cardoso et al. 2003; Saillour et al. 2009). The gene responsible for the greater severity of MDLS compared to isolated lissencephaly is the YWHAE (Haverfield et al. 2009) (605066) gene, encoding 14-3-3-epsilon. It was very recently demonstrated that the duplication in 17p13 is a new clinical entity (OMIM 613215), characterized by mental retardation and other variable clinical and radiological findings (Roos et al. 2009; Spalice et al. 2009). There are three different areas within the MDS region containing dosage-sensitive genes. One containing the PAFAH1B1 gene and the other, more distal, which includes the TUSC5, YWHAE, CRK, and MYO1C genes. Until now, few cases have been described with duplication in the MDS region (Mei et al. 2008; Bi et al. 2009) and only two of them show a duplication including only the PAFAH1B1 area. All patients with duplication in the MDS region have common clinical and phenotypic features. Nevertheless, there are several important differences between those with only duplication in the PAFAH1B1 area as compared with those who have also (or only) a duplication in the distal area. Clinical report

Lipoprotein associated phospholipase A(2) (Lp-PLA(2)) is a novel inflammatory factor that has been independently associated with stroke and cardiovascular disease (CVD). Omega-3 fats have been implicated in reducing inflammation associated with CVD. The aim of this study was to determine if an 8-week isocaloric diet supplemented with eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) in the form of fish oil or α-linolenic acid (ALA) in the form of flaxseed oil would alter Lp-PLA(2) among healthy adults ages 50 years and older.Fifty-nine healthy adults (~75% female, average age 61 years) were randomized to one of three groups with equal amounts of total fat intake. All capsules contained ~1 g of fat. The control group (n = 19) consumed olive oil capsules (~11 g/day); the ALA group (n = 20) consumed flaxseed oil capsules (~11 g/day) and the EPA/DHA group (n = 20) consumed fish oil capsules (~2 g/day + 9 g/day of olive oil). Fasting blood samples were obtained before and after the 8-week intervention for determination of Lp-PLA(2) mass and activity as well as lipid values.We did not find any significant changes in Lp-PLA(2) mass or activity after the intervention in any of the groups; however, change in oxidized LDL was associated with change in Lp-PLA(2) mass (r = 0.37, p0.01).Supplementing the diet with omega-3 fatty acids for 8-weeks did not influence Lp-PLA(2) activity or mass among older adults; altering oxidized LDL may be necessary to see changes in Lp-PLA(2) levels.

During corticogenesis, neurons adopt different migration pathways to reach their final position. The precursors of pyramidal neurons migrate radially, whereas most of the GABA-containing interneurons are generated in the ventral telencephalon and migrate tangentially into the neocortex. Then, they use a radial migration mode to establish themselves in an inside-out manner in the neocortex, similarly to pyramidal neurons. In humans, the most severe defects in radial migration result in lissencephaly. Lately, a few studies suggested that lissencephaly was also associated with tangential neuronal migration deficits. In the present report, we investigated potential anomalies of this migration mode in three agyric/pachygyric syndromes due to defects in the LIS1, DCX and ARX genes. Immunohistochemistry was performed on paraffin-embedded supra- and infratentorial structures using calretinin, calbindin and parvalbumin antisera. The results were compared with age-matched control brain tissue. In the Miller-Dieker syndrome, GABAergic neurons were found both in upper layers of the cortex and in heterotopic positions in the intermediate zone and in ganglionic eminences. In the DCX mutant brain, few interneurons were dispersed in the cortical plate, with a massive accumulation in the intermediate zone and subventricular zone as well as in the ganglionic eminences. In the ARX-mutated brain, the cortical plate contained almost exclusively pyramidal cells and was devoid of interneurons. The ganglionic eminences and basal ganglia were poorly cellular, suggesting an interneuron production and/or differentiation defect. These data argue for different mechanisms of telencephalic tangential migration impairment in these three agyric/pachygyric syndromes.

Summary Brain structure and size requires precise division of neural stem cells (NSCs), which self-renew and generate intermediate neural progenitors (INPs) and neurons. The factors that regulate NSCs remain poorly understood, as do mechanistic explanations of how aberrant NSC division causes reduced brain size as seen in microcephaly. Here we demonstrate that Magoh, a component of the exon junction complex (EJC) that binds RNA, controls mouse cerebral cortical size by regulating NSC division. Magoh haploinsufficiency causes microcephaly due to INP depletion and neuronal apoptosis. Defective mitosis underlies these phenotypes as depletion of EJC components disrupts mitotic spindle orientation and integrity, chromosome number, and genomic stability. In utero rescue experiments revealed that a key function of Magoh is to control levels of the microcephaly-associated protein, LIS1, during neurogenesis. This study uncovers new requirements for the EJC in brain development, NSC maintenance, and mitosis, thus implicating this complex in the pathogenesis of microcephaly.

Inflammation lies at the base of endothelial dysfunction, eventually leading to plaque formation. The degree of inflammation defines the "vulnerability" of plaque to rupture. Numerous strategies have been adopted to identify and eventually treat high-risk vulnerable plaque. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has emerged as one such candidate marker of inflammation that may play a direct role in the formation of rupture-prone plaque. Epidemiologic studies have clearly demonstrated the prognostic ability of increased Lp-PLA(2) levels and their association with increased risk of future coronary and cerebrovascular events. Moreover, Lp-PLA(2) might have similar predictive power for both incident coronary heart disease in initially healthy individuals as well as for recurrent events in those with clinically manifest atherosclerosis. The latest evidence has also suggested its incremental value for risk determination over the well-established traditional risk factors and biomarkers in patients with congestive heart failure. These data support an integral role of Lp-PLA(2) activity in lipid peroxidation and cardiovascular risk assessment. This review summarizes the current body of evidence supporting the clinical utility of Lp-PLA(2) and its future applications in cardiovascular medicine.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a calcium-independent phospholipase A(2) enzyme secreted by leukocytes and associated with circulating low-density lipoprotein and macrophages in atherosclerotic plaques. Until recently, the biological role of Lp-PLA(2) in atherosclerosis was controversial, but now the preponderance of evidence demonstrates a proatherogenic role of this enzyme. Lp-PLA(2) generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a major role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. These findings have opened the door to a potential novel therapeutic target, selective inhibition of Lp-LPA(2). Recently, both animal models and human studies have shown that selective inhibition of Lp-PLA(2) reduces plasma Lp-PLA(2) activity, plaque area, and necrotic core area. This article reviews the most recent developments with Lp-PLA(2) inhibitors.

Although assessment of traditional coronary heart disease risk factors can often stratify individuals into low- or high-risk categories, additional means are needed to more precisely classify people clinically defined as intermediate-risk, to guide the intensity of risk-reducing therapies. The recognition that inflammatory pathways are important in the progression of atherosclerosis and its complications has prompted investigation to identify circulating risk markers that may be useful in risk stratification. This article summarizes recent studies on the current use of an emerging group of inflammatory markers: soluble CD-40 ligand, interleukin-18, myeloperoxidase, B-type natriuretic peptides, secretory phospholipase A(2), lipoprotein-associated phospholipase A(2), and C-reactive protein. The demonstration that lowering C-reactive protein along with low-density lipoprotein cholesterol with statins reduces events beyond cholesterol lowering alone suggests that titration of therapies using other emerging inflammatory markers may further reduce the toll of atherosclerosis in adult populations.

Classical lissencephaly, or isolated lissencephaly sequence (ILS), and subcortical band heterotopia (SBH) are neuronal migration disorders associated with severe mental retardation and epilepsy. Abnormalities of the LIS1 and DCX genes are implicated in the majority of patients with these disorders and account for approximately 75% of patients with ILS, whereas mutations of DCX account for 85% of patients with SBH. The molecular basis of disease in patients with ILS and SBH, in whom no abnormalities have been identified, has been questioned. We studied a series of 83 patients with ILS, SBH or pachygyria, in whom no abnormalities of the LIS1 or DCX genes had been identified, for intragenic deletions and duplications by multiplex ligation-dependent probe amplification (MLPA). In 52 patients with ILS, we identified 12 deletions and 6 duplications involving the LIS1 gene (35%), with the majority resulting in grade 3 lissencephaly. Three deletions of the DCX gene were identified in the group of nine female patients with SBH (out of 31 patients with DCX-suggestive brain anomalies), ie 33%. We estimate an overall mutation detection rate of approximately 85% by LIS1 and DCX sequencing and MLPA in ILS, and 90% by DCX sequencing and MLPA in SBH. Our results show that intragenic deletions and duplications of the LIS1 and DCX genes account for a significant number of patients with ILS and SBH, where no molecular defect had previously been identified. Incorporation of deletion/duplication analysis of the LIS1 and DCX genes will be important for the molecular diagnosis of patients with ILS and SBH.

The human PLA2G7 gene encodes lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an emerging risk factor for cardiovascular diseases. In the present study, seven single nucleotide polymorphisms (SNPs) in the PLA2G7 gene were genotyped in 827 patients with coronary heart disease (CHD), of which 512 were patients with myocardial infarction (MI), and 947 age- and gender-matched controls in a Chinese Han population. Plasma Lp-PLA(2) activity was measured in 416 randomly selected controls and 689 randomly selected CHD patients, including 423 MI patients. Lp-PLA(2) activity in CHD and MI cases was significantly higher (233.42+/-57.66 and 234.27+/-59.51 nmol ml(-1) min(-1), respectively) than in controls (211.47+/-58.61 nmol ml(-1) min(-1)). After adjusting for traditional risk factors by logistic regression, the odds ratios for CHD and MI per 1 standard deviation increment of Lp-PLA(2) activity were 1.27 (95% CI, 1.07-1.50) and 1.27 (95% CI, 1.05-1.54), respectively. Both single SNP analysis and haplotype analysis showed that the V279F and I198T polymorphisms were significantly associated with the reduced Lp-PLA(2) activity, but neither was associated with increased CHD risk. Both univariate and multivariate analyses, adjusting effects of conventional factors, indicated that the rs13210554 T allele increased the risk of MI in this Chinese Han population. In summary, an independent association of increased plasma Lp-PLA(2) activity with CHD and MI existed in this Chinese Han Population. Although V279F and I198T mutations significantly decreased the activity of Lp-PLA(2), only the promoter rs13210554 polymorphism was associated with MI. Lp-PLA(2) activity appears to influence the CHD and MI risk in Chinese Han population.

Among other lipid related biomarkers, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and type II secretory phospholipase A(2) (sPLA(2)) represent emerging candidates for refined assessment of future cardiovascular disease (CVD) risk. Indeed, emerging evidence from more than prospective 15 studies conducted since 2000, clearly demonstrate the prognostic ability of increased Lp-PLA(2) concentrations or elevated activity for risk of future coronary heart disease (CHD) and stroke. Moreover, Lp-PLA(2) might have similar predictive power for both, incident CHD in initially healthy subjects, as well as for recurrent events in those with clinically manifest atherosclerosis.By contrast, to date, there are only few prospective studies that have investigated the relationship of sPLA(2) with future CVD risk. However, most of them show a positive association between increased mass or elevated activity and future atherosclerotic complications. Nonetheless, since inhibitors of Lp-PLA(2) and sPLA(2) have already been developed, these enzymes may be considered as novel therapeutic targets to treat residual risk in certain high risk patient groups.This review summarizes the epidemiologic evidence on the association between increased mass or elevated activity of these two phospholipases and risk of CVD.

Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.

Identification of high-risk patients presenting with chest pain remains challenging. The use of a single biomarker or a panel of biomarkers to detect occult plaque destabilization or rupture without frank infarction would allow for appropriate triage of such patients. Current data suggest that plaque vulnerability is determined by the relationship between forces that increase the size of the lipid core and destabilize the overlying thin fibrous cap. A variety of interrelated pathways are imputed to play important roles in this process of plaque evolution, destabilization, and rupture. These mechanisms include increased systemic and local inflammation, increased oxidative stress, matrix metalloproteinase modulation, and hemodynamic variables related to altered shear stress. Select candidate biomarkers that either reflect or influence these underlying processes and may ultimately have clinical application are highlighted in this review, which focuses on emerging biomarkers to define and predict the risks associated with the complex nature of vulnerable plaque biology.

Lipoprotein-associated phospholipase A(2)(Lp-PLA(2)) is a biomarker that can be used to assess the risk for cardiovascular disease and events. In addition to being a useful marker of a risk factor, several studies suggest that Lp-PLA(2) has a pathophysiologic role in the atherosclerotic disease process. In this article, we review this aspect and its therapeutic implications.

Platelet activating factor (PAF) is a potent phospholipid mediator involved in anaphylaxis and chronic inflammatory disorders, including bronchial asthma. PAF is able to act both, directly as a chemotactic factor and indirectly through the release of other inflammatory agents. Apart from its known potent ability to activate platelets, PAF influences other immune and inflammatory cells function involved in asthma, which may be of importance in the pathogenesis of the disease. In addition, PAF administration can mimic some of abnormalities observed in asthma, including bronchoconstriction, bronchial hyper responsiveness, and gas exchange impairment, which may be mediated by leukotrienes acting as secondary mediators of some PAF effects. Therefore, there has been an extensive interest in the role of PAF in human asthma and major efforts have been continued to discover drugs acting thorough inhibition of PAF effects in the disease. Surprisingly, PAF receptor antagonists have not clearly proven their clinical benefits. It may appear that the combined blockage of PAF effects and other mediators involved in asthma is a way to improve clinical efficacy and also an interesting approach to control inflammation in the disease. This review will focus on two main issues: the role of PAF and PAF antagonists in asthma.

Numerous markers have been identified as useful predictors of major adverse cardiac events (MACE) in patients with suspected acute coronary syndrome (ACS). However, only little is known about the relative benefit of the single markers in risk stratification and the best combination for optimising prognostic power. The aim of the present study was to define the role of the emerging cardiovascular risk marker lipoprotein-associated phospholipase A2 (Lp-PLA2) in a multi-marker approach in combination with troponin I (TnI), NT-proBNP, high sensitivity (hs)CRP, and D-dimer in patients with ACS.A total of 429 consecutive patients (age 60.5+/-14.1 years, 60.6% male) who were admitted to the emergency room with suspected ACS were analysed in the study. Biochemical markers were measured by immunoassay techniques. All patients underwent point-of-care TnI testing and early coronary angiography if appropriate, in accordance with the current guidelines. Classification and regression trees (CART) and logistic regression techniques were employed to determine the relative predictive power of markers for the primary end-point defined as any of the following events within 42 days after admission: death, non-fatal myocardial infarction, unstable AP requiring admission, admission for decompensated heart failure or shock, percutaneous coronary intervention, coronary artery bypass grafting, life threatening arrhythmias or resuscitation. The incidence of the primary end-point was 13.1%, suggesting a mild to moderate risk population. The best overall risk stratification was obtained using NT-proBNP at a cut-off of 5000 pg/mL (incidence of 40% versus 10.3%, relative risk (RR) 3.9 (95% CI 2.4-6.3)). In the remaining lower risk group with an incidence of 10.3%, further separation was performed using TnI (cut-off 0.14 microg/L; RR=3.1 (95% CI 1.7-5.5) 23.2% versus 7.5%) and again NT-proBNP (at a cut-off of 140 ng/L) in patients with negative TnI (RR=3.2 (95% CI 1.3-7.9), 11.7% versus 3.6%). A final significant stratification in patients with moderately elevated NT-proBNP levels was achieved using Lp-PLA2 at a cut-off of 210 microg/L) (17.9% versus 6.9%; RR=2.6 (95% CI 1.1-6.6)). None of the clinical or ECG variables of the TIMI (Thrombolysis In Myocardial Infarction) risk score provided comparable clinically relevant information for risk stratification.In the setting of stateof- the-art coronary care for patients with suspected ACS in the emergency room, NT-proBNP, troponin I, and Lp-PLA2 are effective independent markers for risk stratification that proved to be superior to the TIMI risk score. Lp-PLA2 turned out to be a more effective risk marker than hsCRP in these patients.

Platelet-activating factor (PAF) is a potent endogenous phospholipid modulator of diverse biological activities, including inflammation. The aim of this study was to investigate the effects of PAF inactivator, recombinant PAF acetylhydrolase (rPAF-AH) on post-paracetamol treatment functional outcome of the liver in the rat. Fifty male Wistar rats were divided into two groups: the control group received by gastric tube a toxic dose of paracetamol (3.5 g/kg body weight) and the rPAF-AH-treated group received the same dose of paracetamol followed by a dose of rPAF-AH (10 mg/kg body weight) intraperitoneally. The animals were sacrificed at 8, 16, 24, 32, and 40 hr after paracetamol treatment. APAP was found to cause acute hepatic injury, evident by alterations of biochemical (serum enzymes: ALT, AST, and ALP) and liver histopathological (degree of inflammation and apoptosis) indexes, which was followed by liver regeneration evident by three independent indexes ([(3)H]thymidine incorporation into hepatic DNA, liver thymidine kinase activity, and hepatocyte mitotic index). Hepatic levels of malondialdehyde (MDA) and serum cholesterol/HDL cholesterol fraction were also measured as parameters of oxidant-antioxidant balance. The positive effects of rPAF-AH were expressed by (1) a reduction of oxidative stress, (2) a large decrease in hepatic injury, and (3) a reduction of regenerating activity. These results suggest that PAF plays an important role in paracetamol-induced liver injury and regeneration. Furthermore, PAF inactivator enhances liver's recovery and attenuates the severity of experimental liver injury, providing important means of improving liver function following paracetamol intoxication.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that belongs to the superfamily of phospholipase A2 enzymes. Although initial studies showed that Lp-PLA2 might be protective against atherosclerosis, emerging data seem to suggest that Lp-PLA2 may be proatherogenic, which is an effect thought to be mediated by lysophosphatidylcholine and oxidized nonesterified fatty acids, two mediators generated by Lp-PLA2. This article reviews the potential mechanisms by which Lp-PLA2 may participate in the pathogenesis of atherosclerosis and its clinical manifestations, namely, coronary artery disease and stroke.