Correlation between lipoprotein-associated phospholipase A2 and poststroke mild cognitive impairment.

OBJECTIVES: This study aimed to investigate the correlation between serum lipoprotein-associated phospholipase A2 (Lp-PLA2) and poststroke mild cognitive impairment (PSMCI). METHODS: The patients included in the study were divided into PSMCI (68 cases) and cognitively normal (CN) (218 cases) groups and followed up for six months. Demographic and clinical data were collected. A logistic regression analysis was performed to determine whether Lp-PLA2 is an independent risk factor for PSMCI. Spearman's correlation analysis was used to examine the correlation between Lp-PLA2 levels and Montreal Cognitive Assessment (MoCA) scores. A receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic threshold value of Lp-PLA2 for PSMCI. RESULTS: Serum Lp-PLA2 levels were significantly higher in the PSMCI group than in the CN group. The logistic regression analysis showed that Lp-PLA2 was an independent risk factor for PSMCI (OR = 1.05, 95% CI = 1.03-1.07). Spearman's correlation analysis revealed a significant correlation between the Lp-PLA2 levels and MoCA scores (R = -0.49). The area under the ROC curve for Lp-PLA2 was 0.849, and the threshold value for PSMCI occurrence was 236.8 ng/ml. CONCLUSIONS: Elevated serum Lp-PLA2 is an independent risk factor for PSMCI and may serve as a potential biomarker for PSMCI.

The relationships between biological novel biomarkers Lp-PLA2 and CTRP-3 and CVD in patients with type 2 diabetes mellitus.

BACKGROUND: Cardiovascular disease (CVD) is recognized as a primary and severe comorbidity in patients with type 2 diabetes mellitus (T2DM) and is also identified as a leading cause of mortality within this population. Consequently, the identification of novel biomarkers for the risk stratification and progression of CVD in individuals with T2DM is of critical importance. METHODS: This retrospective cohort study encompassed 979 patients diagnosed with T2DM, of whom 116 experienced CVD events during the follow-up period. Clinical assessments and comprehensive blood laboratory analyses were conducted. Age- and sex-adjusted Cox proportional hazard regression analysis was utilized to evaluate the association between lipoprotein-associated phospholipase A2 (Lp-PLA2), C1q/tumor necrosis factor-related protein 3 (CTRP-3), and the incidence of CVD in T2DM. The diagnostic performance of these biomarkers was assessed through receiver operating characteristic (ROC) curve analysis and the computation of the area under the curve (AUC). RESULTS: Over a median follow-up of 84 months (interquartile range: 42 [32-54] months), both novel inflammatory markers, Lp-PLA2 and CTRP-3, and traditional lipid indices, such as low-density lipoprotein cholesterol and apolipoprotein B, exhibited aberrant expression in the CVD-afflicted subset of the T2DM cohort. Age- and sex-adjusted Cox regression analysis delineated that Lp-PLA2 (hazard ratio [HR] = 1.007 [95% confidence interval {CI}: 1.005-1.009], p < 0.001) and CTRP-3 (HR = 0.943 [95% CI: 0.935-0.954], p < 0.001) were independently associated with the manifestation of CVD in T2DM. ROC curve analysis indicated a substantial predictive capacity for Lp-PLA2 (AUC = 0.81 [95% CI: 0.77-0.85], p < 0.001) and CTRP-3 (AUC = 0.91 [95% CI: 0.89-0.93], p < 0.001) in forecasting CVD occurrence in T2DM. The combined biomarker approach yielded an AUC of 0.94 (95% CI: 0.93-0.96), p < 0.001, indicating enhanced diagnostic accuracy. CONCLUSIONS: The findings suggest that the biomarkers Lp-PLA2 and CTRP-3 are dysregulated in patients with T2DM who develop CVD and that each biomarker is independently associated with the occurrence of CVD. The combined assessment of Lp-PLA2 and CTRP-3 may significantly augment the diagnostic precision for CVD in the T2DM demographic.

Serum levels of lipoprotein-associated phospholipase A2 are associated with coronary atherosclerotic plaque progression in diabetic and non-diabetic patients.

BACKGROUND: Lp-PLA2 is linked to cardiovascular diseases and poor outcomes, especially in diabetes, as it functions as a pro-inflammatory and oxidative mediator. OBJECTIVES: This research aimed to explore if there is a connection between the serum levels of Lp-PLA2 and the progression of coronary plaques (PP) in individuals with type 2 diabetes mellitus (T2DM) and those without the condition. MATERIALS AND METHODS: Serum Lp-PLA2 levels were measured in 137 T2DM patients with PP and 137 T2DM patients with no PP, and in 205 non-diabetic patients with PP and 205 non-diabetic patients with no PP. These individuals met the criteria for eligibility and underwent quantitative coronary angiography at the outset and again after about one year of follow-up. The attributes and parameters of the participants at the outset were recorded. RESULTS: Increased serum levels of Lp-PLA2 were closely associated with coronary artery PP, and also significantly correlated with change of MLD, change of diameter stenosis and change of cumulative coronary obstruction in both diabetic and non-diabetic groups, with higher correlation coefficients in diabetic patients as compared with non-diabetic patients. Moreover, multivariate logistic regression analysis showed that serum Lp-PLA2 level was an independent determinant of PP in both groups, with OR values more significant in diabetic patients than in non-diabetic patients. CONCLUSIONS: Levels of serum Lp-PLA2 show a significant association with the progression of coronary atherosclerotic plaque in patients with T2DM and those without, especially among individuals with diabetes.

Correlation of LP-PLA2 and MMP-9 with the occurrence of early neurological deterioration in patients with acute ischemic stroke.

Early neurological deterioration is a common complication of acute ischemic stroke (AIS), which aggravates symptoms, worsens the condition, and counteracts the benefits of clinical treatment. The aim of this paper was to analyze the correlation between lipoprotein-associated phospholipase A2 (Lp-PLA2), matrix metalloproteinase-9 (MMP-9), and the occurrence of early neurological deterioration (END) in patients with AIS and to explore the clinical prediction of END by the combination of the 2 assays for the clinical prediction of END. A total of 500 AIS patients admitted to our hospital from October 2022 to October 2023 were included as study subjects, and the clinical data of all AIS patients were collected and organized to detect the levels of Lp-PLA2 and MMP-9. Categorized into END and non-END groups according to whether END occurred within 7 days of the onset of AIS, and comparing the clinical baseline data and laboratory index levels of the 2 groups. Logistic regression analysis was performed to determine the independent predictors of END, and the predictive effects of Lp-PLA2 and MMP-9 levels on END were assessed by subject work characteristics (ROC) curves. END occurred in 111 (22.2%) of 500 AIS patients. Multivariate logistic regression analysis showed that diabetes (OR 2.717, 95% CI:1.53-4.81, P < .001), baseline NIHSS score (OR 1.65, 95% CI:1.41-1.94, P < .001), Lp-PLA2 (OR 1.07, 95% CI:1.05-1.09, P < .001) and MMP-9 (OR 1.12, 95% CI:1.09-1.16, P < .001) levels were independent influences on the occurrence of END in patients with AIS after correcting for confounders. ROC curve analysis showed that Lp-PLA2, MMP-9, and a combination of both predicted END with an area under the curve was 0.730, 0.763, and 0.831, respectively, and the area under the curve for the combination of both predicting END was significantly higher than that for any of the inflammatory markers alone (P < .05). Both inflammatory markers, Lp-PLA2 and MMP-9, were independent predictors of the development of END in patients with AIS, and the combination of the two had a higher predictive value.

Melatonin suppresses atherosclerosis by ferroptosis inhibition via activating NRF2 pathway.

Melatonin (MLT), a conserved small indole compound, exhibits anti-inflammatory and antioxidant properties, contributing to its cardioprotective effects. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with atherosclerosis disease risk, and is known as an atherosclerosis risk biomarker. This study aimed to investigate the impact of MLT on Lp-PLA2 expression in the atherosclerotic process and explore the underlying mechanisms involved. In vivo, ApoE-/- mice were fed a high-fat diet, with or without MLT administration, after which the plaque area and collagen content were assessed. Macrophages were pretreated with MLT combined with ox-LDL, and the levels of ferroptosis-related proteins, NRF2 activation, mitochondrial function, and oxidative stress were measured. MLT administration significantly attenuated atherosclerotic plaque progression, as evidenced by decreased plaque area and increased collagen. Compared with those in the high-fat diet (HD) group, the levels of glutathione peroxidase 4 (GPX4) and SLC7A11 (xCT, a cystine/glutamate transporter) in atherosclerotic root macrophages were significantly increased in the MLT group. In vitro, MLT activated the nuclear factor-E2-related Factor 2 (NRF2)/SLC7A11/GPX4 signaling pathway, enhancing antioxidant capacity while reducing lipid peroxidation and suppressing Lp-PLA2 expression in macrophages. Moreover, MLT reversed ox-LDL-induced ferroptosis, through the use of ferrostatin-1 (a ferroptosis inhibitor) and/or erastin (a ferroptosis activator). Furthermore, the protective effects of MLT on Lp-PLA2 expression, antioxidant capacity, lipid peroxidation, and ferroptosis were decreased in ML385 (a specific NRF2 inhibitor)-treated macrophages and in AAV-sh-NRF2 treated ApoE-/- mice. MLT suppresses Lp-PLA2 expression and atherosclerosis processes by inhibiting macrophage ferroptosis and partially activating the NRF2 pathway.

Association of 25-hydroxyvitamin D, lipoprotein-associated phospholipase A2 and asymptomatic coronary artery disease in patients with type 2 diabetes mellitus.

AIM: To evaluate the relationship of 25-hydroxyvitamin D (25(OH)D), lipoprotein-associated phospholipase A2 (Lp-PLA2), and coronary artery disease (CAD) in type 2 diabetes mellitus (T2DM) patients with no history or symptoms of cardiovascular disease. METHODS: The study identified 66 pairs of T2DM patients with and without CAD using propensity score matching. All subjects performed coronary computed tomography angiography (CCTA). Data on 25(OH)D, Lp-PLA2, and metabolic indexes were collected and analyzed. RESULTS: Compared to the patients without CAD, the patients with CAD had lower 25(OH)D levels and the rate of vitamin D sufficiency, but higher Lp-PLA2 levels. Meanwhile, subjects in the vitamin D sufficiency group had a lower prevalence of CAD and Lp-PLA2 levels. Furthermore, 25(OH)D was inversely correlated with Lp-PLA2, Gensini score, Leiden score, segment involvement score, and segment stenosis score (P < 0.05). After adjusting for age, gender, blood lipids and blood pressure, 25(OH)D was associated with a decreased risk of CAD (aOR 0.933, 95 %CI 0.887-0.983, P = 0.009), while Lp-PLA2 was associated with an increased risk of CAD (aOR 1.014, 95 %CI 1.005-1.022, P = 0.002). CONCLUSIONS: Decreased 25(OH)D and increased Lp-PLA2 could identify patients with a high risk of CAD and are associated with the severity of coronary artery stenosis in T2DM.

PAFAH1B3 is a KLF9 target gene that promotes proliferation and metastasis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Uncontrolled cell proliferation, invasion and migration of pancreatic cancer cells are the fundamental causes of death in PDAC patients. Our previous studies showed that KLF9 inhibits the proliferation, invasion and migration of pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In this study, we found that platelet-activating factor acetylhydrolase IB3 (PAFAH1B3) is highly expressed in pancreatic cancer tissues and cells. In vitro and in vivo studies showed that overexpression of PAFAH1B3 promoted the proliferation and invasion of pancreatic cancer cells, while downregulation of PAFAH1B3 inhibited these processes. We found that KLF9 expression is negatively correlated with PAFAH1B3 expression in pancreatic cancer tissues and cells. Western blotting revealed that KLF9 negatively regulates the expression of PAFAH1B3 in pancreatic cancer tissues and cells. Rescue experiments showed that overexpression of PAFAH1B3 could partially attenuate the suppression of pancreatic cancer cell proliferation, invasion and migration induced by KLF9 overexpression. Finally, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried out, and the results showed that KLF9 directly binds to the promoter of PAFAH1B3 and inhibits its transcriptional activity. In conclusion, our study indicated that KLF9 can inhibit the proliferation, invasion, migration and metastasis of pancreatic cancer cells by inhibiting PAFAH1B3.

Correlation between plasma lipoprotein-associated phospholipase A2 levels and risk of ischaemic stroke recurrence by gender in the Chinese population.

OBJECTIVE: To investigate the correlation between gender differences in plasma lipoprotein phospholipase A2 (Lp-PLA2) levels and the risk of recurrent stroke in patients with acute ischaemic stroke in China. METHODS: We conducted a prospective follow-up study that included baselineLp-PLA2 levels and NIH Stroke Scale (NIHSS) scores in patients with ischaemic stroke upon admission. The diagnostic efficacy of the baseline Lp-PLA2 level for stroke recurrence was evaluated. And Kaplan‒Meier method was used to analyse the difference in the risk of recurrent stroke between these two groups among males and females. A paired t test was used to analyse the difference in Lp-PLA2 levels in male and female patients after follow-up. RESULTS: Baseline plasma Lp-PLA2 was higher in men and women with recurrent stroke than in those without recurrent stroke. The correlation between baseline Lp-PLA2 and neurological impairment was higher in female than male stroke patients (R = 0.338 and 0.253, respectively). Although weakly correlated with neurological impairment, baseline Lp-PLA2 was more effective in predicting recurrent stroke (AUC = 0.705 in men, 0.788 in women). A Cox model was used to compare the risk of stroke between the high- and low-Lp-PLA2 groups (OR = 3.98 in men, 2.61 in women). According to the follow-up time of 6 months as the node, Lp-PLA2 will give different risk indicators. CONCLUSION: Elevated plasma Lp-PLA2 is an independent risk factor for recurrent ischaemic stroke but is not strongly associated with the degree of cerebral damage. The predictive value of baseline Lp-PLA2 for stroke recurrence risk was higher in females than in males.

Molecular mechanism of dynein-dynactin complex assembly by LIS1.

Cytoplasmic dynein is a microtubule motor vital for cellular organization and division. It functions as a ~4-megadalton complex containing its cofactor dynactin and a cargo-specific coiled-coil adaptor. However, how dynein and dynactin recognize diverse adaptors, how they interact with each other during complex formation, and the role of critical regulators such as lissencephaly-1 (LIS1) protein (LIS1) remain unclear. In this study, we determined the cryo-electron microscopy structure of dynein-dynactin on microtubules with LIS1 and the lysosomal adaptor JIP3. This structure reveals the molecular basis of interactions occurring during dynein activation. We show how JIP3 activates dynein despite its atypical architecture. Unexpectedly, LIS1 binds dynactin's p150 subunit, tethering it along the length of dynein. Our data suggest that LIS1 and p150 constrain dynein-dynactin to ensure efficient complex formation.

The value of Lp(a) and TG/HDLC in peripheral blood to assess the stability of carotid plaque in patients with ischemic stroke.

OBJECTIVE: The objective of this study was to investigate the relationship between lipoprotein (a) (Lp(a)), triglyceride/high-density lipoprotein cholesterol (TG/HDL-C), and the stability of carotid atherosclerotic plaque in patients with acute ischemic stroke. METHODS: A total of 142 patients with acute ischemic stroke were selected and divided into group A (59 cases of stable plaque formation) and group B (83 cases of unstable plaque formation) according to the characteristics of carotid artery plaque formation detected by carotid color Doppler ultrasound. The serum Lp(a), lipid metabolism indexes, peripheral blood routine indexes, and related serum inflammatory factors indexes were compared between the two groups. Receiver operating characteristic curve and multivariate logistic regression model were used to analyze the relationship between each index and the formation of carotid unstable plaque. RESULTS: There were no significant differences in serum total cholesterol (TC), HDL-C, and low-density lipoprotein cholesterol (LDL-C) between groups A and B (p > .05). The values of Lp(a), TG, and TG/HDL-C in group B were higher than those in group A, and the differences were statistically significant (p < .05). There were no significant differences in serum TC, HDL-C, and LDL-C between groups A and B (p > .05). The values of Lp(a), TG, and TG/HDL-C in group B were higher than those in group A, and the differences were statistically significant (p < .05). The values of HBA1C, Lp-PLA2, CRP, CysC, Hcy, TNF-α, neutrophils, and NLR in group B were higher than those in group A, and the differences were statistically significant (p < .05). There was no significant difference in FPG, systolic blood pressure, diastolic blood pressure, Hb, white blood cells, platelets, and lymphocytes between groups A and B (p > .05). The results of logistic regression model showed that the increase of Lp(a), TG/HDL-C, HBA1C, Lp-PLA2, CRP, CysC, Hcy, and NLR could increase the risk of carotid artery unstable plaque in patients with ischemic stroke (p < .05). CONCLUSION: Lp(a) and TG/HDL-C have certain value in evaluating the stability of carotid atherosclerotic plaque in patients with acute ischemic stroke, and the increased levels of LP (a) and TG/HDL-C will significantly increase the risk of carotid unstable plaque in patients.

Clinical analysis of PAFAH1B1 gene variants in pediatric patients with epilepsy.

PURPOSE: PAFAH1B1, also known as LIS1, is associated with type I lissencephaly in humans, which is a severe developmental brain disorder believed to result from abnormal neuronal migration. Our objective was to characterize the genotypes and phenotypes of PAFAH1B1-related epilepsy. METHODS: We conducted a comprehensive analysis of the medical histories, magnetic resonance imaging findings, and video-electroencephalogram recordings of 11 patients with PAFAH1B1 variants at the Neurology Department of Beijing Children's Hospital from June 2017 to November 2022. RESULTS: The age of onset of epilepsy ranged from 2 months to 4 years, with a median onset age of 5 months. Among these 11 patients (comprising 6 boys and 5 girls), all were diagnosed with lissencephaly type 1. Predominantly, generalized tonic-clonic and spasm seizures characterized PAFAH1B1-related epilepsy. Additionally, 10 out of the 11 patients exhibited severe developmental disorders. All patients exhibited de novo variants, with three individuals displaying 17p13.3 deletions linked to haploinsufficiency of PAFAH1B1. Four variants were previously unreported. Notably, three patients with 17p13.3 deletions displayed developmental delay and drug resistant epilepsy, whereas the single patient with mild developmental delay, Intelligence Quotient (IQ) 57 and well-controlled seizures had a splicing-site variant. CONCLUSION: The severity of the phenotype in patients with PAFAH1B1 variants ranged from drug-responsive seizures to severe epileptic encephalopathy. These observations underscore the clinical heterogeneity of PAFAH1B1-related disorders, with most patients exhibiting developmental disorders. Moreover, the severity of epilepsy appears to be linked to genetic variations.

Role of uranium toxicity and uranium-induced oxidative stress in advancing kidney injury and endothelial inflammation in rats.

OBJECTIVE: Uranium exposure may cause serious pathological injury to the body, which is attributed to oxidative stress and inflammation. However, the pathogenesis of uranium toxicity has not been clarified. Here, we evaluated the level of oxidative stress to determine the relationship between uranium exposure, nephrotoxic oxidative stress, and endothelial inflammation. METHODS: Forty male Sprague-Dawley rats were divided into three experimental groups (U-24h, U-48h, and U-72h) and one control group. The three experimental groups were intraperitoneally injected with 2.0 mg/kg uranyl acetate, and tissue and serum samples were collected after 24, 48, and 72 h, respectively, whereas the control group was intraperitoneally injected with 1.0 ml/kg normal saline and samples were collected after 24 h. Then, we observed changes in the uranium levels and oxidative stress parameters, including the total oxidative state (TOS), total antioxidant state (TAS), and oxidative stress index (OSI) in kidney tissue and serum. We also detected the markers of kidney injury, namely urea (Ure), creatine (Cre), cystatin C (CysC), and neutrophil gelatinase-associated lipocalin (NGAL). The endothelial inflammatory markers, namely C-reactive protein (CRP), lipoprotein phospholipase A2 (Lp-PLA2), and homocysteine (Hcy), were also quantified. Finally, we analyzed the relationship among these parameters. RESULTS: TOS (z = 3.949; P < 0.001), OSI (z = 5.576; P < 0.001), Ure (z = 3.559; P < 0.001), Cre (z = 3.476; P < 0.001), CysC (z = 4.052; P < 0.001), NGAL (z = 3.661; P < 0.001), and CRP (z = 5.286; P < 0.001) gradually increased after uranium exposure, whereas TAS (z = -3.823; P < 0.001), tissue U (z = -2.736; P = 0.001), Hcy (z = -2.794; P = 0.005), and Lp-PLA2 (z = -4.515; P < 0.001) gradually decreased. The serum U level showed a V-shape change (z = -1.655; P = 0.094). The uranium levels in the kidney tissue and serum were positively correlated with TOS (r = 0.440 and 0.424; P = 0.005 and 0.007) and OSI (r = 0.389 and 0.449; P = 0.013 and 0.004); however, serum U levels were negatively correlated with TAS (r = -0.349; P = 0.027). Partial correlation analysis revealed that NGAL was closely correlated to tissue U (rpartial = 0.455; P = 0.003), CysC was closely correlated to serum U (rpartial = 0.501; P = 0.001), and Lp-PLA2 was closely correlated to TOS (rpartial = 0.391; P = 0.014), TAS (rpartial = 0.569; P < 0.001), and OSI (rpartial = -0.494; P = 0.001). Pearson correlation analysis indicated that the Hcy levels were negatively correlated with tissue U (r = -0.344; P = 0.030) and positively correlated with TAS (r = 0.396; P = 0.011). CONCLUSION: The uranium-induced oxidative injury may be mainly reflected in enhanced endothelial inflammation, and the direct chemical toxicity of uranium plays an important role in the process of kidney injury, especially in renal tubular injury. In addition, CysC may be a sensitive marker reflecting the nephrotoxicity of uranium; however, Hcy is not suitable for evaluating short-term endothelial inflammation involving oxidative stress.

Lipoprotein-associated phospholipase A2 predicts cardiovascular death in patients on maintenance hemodialysis: a 7-year prospective cohort study.

BACKGROUND: Cardiovascular diseases (CVD) is the leading cause of death among maintenance hemodialysis patients, with dyslipidemia being a prevalent complication. The paradoxical relationship between cardiovascular outcomes and established lipid risk markers, such as low-density lipoprotein cholesterol (LDL-C), complicates lipid management in this population. This study investigated Lipoprotein-associated phospholipase A2 (Lp-PLA2), an emerging biomarker known for its proinflammatory and proatherogenic properties, as a potential cardiovascular prognostic marker in this cohort. In this context, the association between Lp-PLA2 levels and cardiovascular outcomes was evaluated, with the aim to facilitate more accurate stratification and identification of high-risk individuals. METHODS: From August 2013 to January 2014, 361 hemodialysis patients were prospectively enrolled. Lp-PLA2 activity and laboratory measures at baseline were quantified. Comorbidities and medications were recorded. All patients were followed until the end of April, 2022. The individual and combined effects of Lp-PLA2 activity and LDL-C on patient outcomes were examined. The association between Lp-PLA2 activity and all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACEs) was analyzed. RESULTS: The median Lp-PLA2 activity was 481.2 U/L. In subjects with Lp-PLA2 activity over 481.2 U/L, significantly higher total cholesterol (4.89 vs. 3.98 mmol/L; P < 0.001), LDL-C (3.06 vs. 2.22 mmol/L; P < 0.001), and apolipoprotein B (0.95 vs. 0.75 mmol/L; P < 0.001) were observed. Over a median follow-up of 78.1 months, 182 patients died, with 77 cases identified as cardiovascular death, 88 MACEs happened. Cardiovascular mortality and MACEs, but not all-cause mortality, were significantly increased in the high Lp-PLA2 group. Cox regression analyses showed that high Lp-PLA2 activity was associated with cardiovascular mortality and MACE occurrence. After comprehensive adjustment, high Lp-PLA2 activity was independently associated with cardiovascular mortality(as a dichotomous variable: HR:2.57, 95%CI:1.58,4.18, P < 0.001; as a continuous variable: HR:1.25, 95%CI:1.10,1.41, P = 0.001) and MACEs(as a dichotomous variable: HR:2.17, 95%CI:1.39,3.40, P = 0.001; as a continuous variable: HR:1.20, 95%CI:1.07,1.36, P = 0.002). When participants were grouped by median Lp-PLA2 activity and LDL-C values, those with high Lp-PLA2 and low LDL-C had the highest CV mortality. The addition of Lp-PLA2 significantly improved reclassification (as a dichotomous variable NRI = 42.51%, 95%CI: 5.0%,61.33%; as a continuous variable, NRI = 33.32%, 95% CI: 7.47%,56.21%). CONCLUSIONS: High Lp-PLA2 activity is an independent risk factor for cardiovascular mortality and MACEs occurrence in patients on hemodialysis. The combined measures of Lp-PLA2 and LDL-C help to identify individuals with a higher risk of cardiovascular death.

Inhibiting PLA2G7 reverses the immunosuppressive function of intratumoral macrophages and augments immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an exceptionally immunosuppressive malignancy characterized by limited treatment options and a dismal prognosis. Macrophages constitute the primary and heterogeneous immune cell population within the HCC microenvironment. Our objective is to identify distinct subsets of macrophages implicated in the progression of HCC and their resistance to immunotherapy. METHODS: Intratumoral macrophage-specific marker genes were identified via single-cell RNA sequencing analyses. The clinical relevance of phospholipase A2 Group VII (PLA2G7), a pivotal enzyme in phospholipid metabolism, was assessed in patients with HCC through immunohistochemistry and immunofluorescence. Flow cytometry and an in vitro co-culture system were used to elucidate the specific role of PLA2G7 in macrophages. Orthotopic and subcutaneous HCC mouse models were employed to evaluate the potential of the PLA2G7 inhibitor in complementing immune checkpoint blockade (ICB) therapy. RESULTS: Single-cell RNA sequencing analyses disclosed predominant PLA2G7 expression in intratumoral macrophages within the HCC microenvironment. The macrophage-specific PLA2G7 was significantly correlated with poorer prognosis and immunotherapy resistance in patients with HCC. PLA2G7high macrophages represent a highly immunosuppressive subset and impede CD8 T-cell activation. Pharmacological inhibition of PLA2G7 by darapladib improved the therapeutic efficacy of anti-programmed cell death protein 1 antibodies in the HCC mouse models. CONCLUSIONS: Macrophage-specific PLA2G7 serves as a novel biomarker capable of prognosticating immunotherapy responsiveness and inhibiting PLA2G7 has the potential to enhance the efficacy of ICB therapy for HCC.

Bioinformatics Analysis Identifies PLA2G7 as a Key Antigen-Presenting Prognostic Related Gene Promoting Hepatocellular Carcinoma through the STAT1/PD-L1 Axis.

BACKGROUND: Antigen presentation may be an important factor contributing to immune evasion in cancer. This study investigated antigen-presenting prognostic related genes (APPGs) and their potential mechanisms in hepatocellular carcinoma (HCC). METHODS: We constructed a score built upon the core APPGs (APP.Score) through nonnegative matrix factorization (NMF) clustering, weighted gene co-expression network analysis (WGCNA), random forest (RF), and least absolute shrinkage and selection operator (LASSO) methods. We also compared the clinical and molecular characteristics of different APP.Score. Furthermore, in vitro experiments were conducted to validate the expression of core APPGs and investigate the effects of phospholipase A2, group 7 (PLA2G7) knockdown on HCC cell development and programmed death-ligand 1 (PD-L1) expression. RESULTS: APP.Score was positively correlated with immune cell infiltration and levels of immune checkpoint inhibitor-related genes, and negatively correlated with overall survival (OS). The area under the curve values were 0.734, 0.747, and 0.679 for survival periods of 1, 2, and 3 years, respectively, indicating that APP.Score could be an independent prognostic factor for patients with HCC. OS of the high expression group of these genes, including PLA2G7, musculin, heat shock protein family A, secreted phosphoprotein 1, and neutrophil cytosolic factor 2 (NCF2) was lower than that of their low expression group. Moreover, the upregulation of key components of APPGs, except NCF2, was observed in HCC. The inhibition of PLA2G7 suppressed HCC progression and reduced PD-L1 and phosphorylated signal transducer and activator of transcription 1 (p-STAT1)/STAT1 levels in HepG2 and Huh-7 cells. Remarkably, the decrease in PD-L1 expression caused by PLA2G7 silencing was reversed upon treatment with a STAT1 activator. CONCLUSION: The results of this study show that APP.Score could be an independent prognostic factor for patients with HCC, and that PLA2G7 silencing inhibits cancer cell development and PD-L1 expression. We provide a new perspective and potential target for immune research on antigen presentation in HCC.

Associations between healthy food groups and platelet-activating factor, lipoprotein-associated phospholipase A2 and C-reactive protein: a cross-sectional study.

PURPOSE: To investigate the association between pro-inflammatory markers platelet-activating factor (PAF), lipoprotein-associated phospholipase A2 (Lp-PLA2), hsCRP, and intake of core food groups including fruit, cruciferous and other vegetables, grains, meat and poultry, fish and seafood, nuts and legumes, and dairy. METHODS: A cross-sectional study was conducted. 100 adults (49 ± 13 years, 31% male) with variable cardiovascular disease risk were recruited. Data were collected in 2021 and 2022. Fasting PAF, Lp-PLA2 activity, hsCRP and usual dietary intake (via a validated food frequency questionnaire) were measured. Intake of foods were converted into serves and classified into food groups. Correlations and multiple regressions were performed with adjustment for confounders. RESULTS: A one-serve increase in cruciferous vegetables per day was associated with 20-24% lower PAF levels. An increase of one serve per day of nuts and legumes was associated with 40% lower hsCRP levels. There were small correlations with PAF and Lp-PLA2 and cheese, however, these were not significant at the Bonferroni-adjusted P < 0.005 level. CONCLUSION: The lack of associations between PAF and Lp-PLA2 and other healthy foods may be due to confounding by COVID-19 infection and vaccination programs which prevents any firm conclusion on the relationship between PAF, Lp-PLA2 and food groups. Future research should aim to examine the relationship with these novel markers and healthy food groups in a non-pandemic setting.

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 (oxPC) to produce lysophosphatidylcholine (lysoPC). 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.

The value of serum lipoprotein-associated phospholipase A2, ischemia-modified albumin, and cystatin C in predicting coronary heart disease risk: a single center retrospective cohort study.

OBJECTIVE: This study aims to explore the value of serum lipoprotein-associated phospholipase A2 (Lp-PLA2), ischemia-modified albumin (IMA), and cystatin C (Cys-C) in predicting the risk of coronary heart disease (CHD). PATIENTS AND METHODS: Clinical data from 104 CHD patients admitted to our hospital from January 2020 to December 2022 were analyzed. Of them, 31 patients had stable angina (Group-S), 36 patients were diagnosed with unstable angina (Group-U), and 37 patients had acute myocardial infarction (Group-A). Additionally, clinical data from 35 healthy individuals undergoing physical examination during the same time period were selected as the control group. Levels of blood lipid indicators and serum Lp-PLA2, IMA, and Cys-C levels were compared between the groups. RESULTS: The rates of diabetes, hypertension, and smoking in Group-S, Group-U, and Group-A were significantly higher than those in the control group (p<0.05). Levels of Lp-PLA2, IMA, and Cys-C in Group-S, Group-U, and Group-A were significantly higher than those in the control group (p<0.05). Levels of Lp-PLA2, IMA, and Cys-C in Group-U and Group-A were significantly higher than those in Group-S, and Group-A had the highest value of these indexes (p<0.05). Multivariate logistic regression analysis showed that Lp-PLA2, Cys-C, and IMA were important risk factors for the onset of CHD (p<0.05). Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of Lp-PLA2, IMA, and Cys-C predicting the occurrence of CHD was 0.775, 0.835, and 0.735, respectively. The combined prediction of the three factors has an AUC of 0.920, which is higher than the individual prediction. CONCLUSIONS: Lp-PLA2, IMA, and Cys-C are closely related to the onset and progression of CHD. These indicators, therefore, can be used in clinical practice to predict and evaluate CHD.

Nde1 promotes Lis1-mediated activation of dynein.

Cytoplasmic dynein drives the motility and force generation functions towards the microtubule minus end. The assembly of dynein with dynactin and a cargo adaptor in an active transport complex is facilitated by Lis1 and Nde1/Ndel1. Recent studies proposed that Lis1 relieves dynein from its autoinhibited conformation, but the physiological function of Nde1/Ndel1 remains elusive. Here, we investigate how human Nde1 and Lis1 regulate the assembly and subsequent motility of mammalian dynein using in vitro reconstitution and single molecule imaging. We find that Nde1 recruits Lis1 to autoinhibited dynein and promotes Lis1-mediated assembly of dynein-dynactin adaptor complexes. Nde1 can compete with the α2 subunit of platelet activator factor acetylhydrolase 1B (PAF-AH1B) for the binding of Lis1, which suggests that Nde1 may disrupt PAF-AH1B recruitment of Lis1 as a noncatalytic subunit, thus promoting Lis1 binding to dynein. Before the initiation of motility, the association of dynactin with dynein triggers the dissociation of Nde1 from dynein by competing against Nde1 binding to the dynein intermediate chain. Our results provide a mechanistic explanation for how Nde1 and Lis1 synergistically activate the dynein transport machinery.

Risk factors for acute ischemic stroke in patients with type 2 diabetes mellitus.

To investigate the risk factors for acute ischemic stroke (AIS) in patients with type 2 diabetes mellitus (T2DM) patients. a total of 120 T2DM patients who met the inclusion and exclusion criteria, from between January 2021 to June 2022, were randomly selected and divided into T2DM and T2DM + AIS groups based on the presence or absence of a history of AIS. Blood samples were collected by fasting, 24 hours after admission, and levels of serum uric acid (UA), serum homocysteine (Hcy), serum creatinine (SCR), blood urea nitrogen (BUN), fasting blood glucose (FBG), glycated hemoglobin A1c (HbA1c), serum total cholesterol (TC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein (hs-CRP), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured. Multivariate logistic regression analysis was performed for the significantly associated indicators to analyze the risk factors for AIS, and finally ROC curve analysis was carried out to explore the predictive value of the above risk factors for AIS in T2DM patients. the levels of FBG, Hcy, Hs-CRP and Lp-PLA2 were significantly higher in the T2DM + AIS group than those in T2DM group (P < .05). Multivariate logistic regression analysis revealed that hs-CRP and Lp-PLA2 were independent risk factors for the development of AIS in patients with T2DM with an OR of 2.85 (95% CI: 1.26-6.43, P = .012) and 3.64 (95% CI: 1.63-8.12, P = .002), respectively. ROC curve analysis showed that plasma hs-CRP and Lp-PLA2 showed good performance to predict AIS occurrence in T2DM patients (AUC = 0.749, 95% CI: 0.663, 0.835; and 0.791, 95% CI: 0.712, 0.870), with a sensitivity of 58.1% and 83.9%, and a specificity of 84.5% and 60.3%, respectively. The optimal concentration cutoff points of hs-CRP and Lp-PLA2 were 3.38 mg/L and 204.2 ng/mL. our findings suggested that plasma hs-CRP and Lp-PLA2 were independent risk factors for developing AIS in T2DM patients. Hs-CRP and Lp-PLA2 are potential biomarker for risk for AIS in patients with T2DM.