Ischemic stroke is a condition characterized by the obstruction of blood flow to the brain, typically caused by a blood clot, leading to brain tissue damage and impaired neurological function. This study aims to use proteomic analysis to reveal the protein expression differences between different recovery results (meaningful recanalization [MFR] and futile recanalization [FTR]) in the recovery process of patients with ischemic stroke after thrombosis. We collected plasma samples from the healthy control (CON), MFR, and FTR groups, and used high-throughput data-independent collection (DIA) mass spectrometry for proteomic analysis. A total of 5,040 proteins were identified in the study, of which 775 were differentially expressed proteins (DEPs). The functional enrichment analysis revealed that these proteins are involved in lipid metabolism, amino acid synthesis, cell signaling regulation, and other pathways, especially between the FTR and MFR groups; the expression differences of specific proteins reflect biological differences in the recovery process. We identified 11 key DEPs, including Phospholipid Transfer Protein, Fructose-Bisphosphate Aldolase A, Alpha-Enolase 1, and Fatty Acid-Binding Protein, which may be potential biomarkers for predicting stroke recovery. This study provides new insights into the molecular mechanisms underlying recovery after ischemic stroke, particularly the molecular differences associated with distinct recovery outcomes, and identifies potential markers for personalized treatment and prognostic evaluation.

Ginseng is widely praised for its benefits on cancer patients, often attributed to its metabolite compound K (CK). Here, we synthesized a derivative (CKD-4) that, compared with CK, exhibited enhanced cellular uptake, threefold greater cytotoxicity, and improved pharmacokinetics. CKD-4 induced significant growth inhibition on lung cancer patient-derived organoids, and on cell line-derived xenografts with minimal systemic toxicity. CKD-4 also suppressed orthotopic lung tumor growth in immunocompetent mice with enhanced antitumor immune infiltration. Using proteome integral solubility alteration and ProTargetMiner analyses, the mitochondrial phospholipid transfer protein PRELID3B was unbiasedly identified as a shared anticancer target of CK and CKD-4. PRELID3B is a potential pancancer therapeutic target and prognostic biomarker supported by cancer genetics and transcriptomics evidence. Both CK and CKD-4 stabilize PRELID3B in cellular thermal shift assay and bind PRELID3B with Kd of 23 µM and 5 µM, respectively, measured by biolayer interferometry. Multiomics analyses revealed that CK and CKD-4 share similar anticancer mechanisms, involving mitochondrial phospholipid depletion, integrated stress response activation, and immunomodulatory pathways induction associated with PRELID3B inhibition. This study provides the basis for the immunomodulatory and anticancer effects of ginseng metabolites through targeting PRELID3B, and illustrates the application of orthogonal proteomics in target identification of natural compounds.

Uniqueness of CETP in transferring neutral lipids: A comparative study on lipid-carrying/binding proteins.

Growing evidence implicates neuroinflammation, gut-derived endotoxemia, and dysregulated lipid metabolism in the pathogenesis of Parkinson’s disease (PD). However, the relationships among circulating lipopolysaccharide (LPS), LPS-handling proteins, systemic inflammatory activation, and lipid fractions remain insufficiently characterized. The aim of this study was to compare LPS levels, LPS-related inflammatory mediators, and plasma lipid parameters between PD patients and matched controls, and to explore correlations among these biomarkers. Twenty PD patients and twenty matched controls underwent fasting venous sampling. Circulating LPS, lipopolysaccharide binding protein (LBP), soluble cluster of differentiation 14 (sCD14), high-sensitivity C-reactive protein (hsCRP), and phospholipid transfer protein (PLTP) were quantified via LAL assay and ELISAs. Serum cholesterol, HDL cholesterol (HDL-C), phospholipids (PLs), HDL-PLs and triacylglycerols (TAGs) were assessed using validated biochemical techniques. LPS concentrations did not differ between groups. However, PD patients showed elevated sCD14 and hsCRP levels, reduced LBP, and increased PLTP. Lipid profiling revealed lower total cholesterol and reduced HDL-associated cholesterol and phospholipids in PD, while TAG levels remained unchanged. Correlation analyses indicated coordinated associations between inflammatory markers and lipid fractions, with distinct interaction patterns in PD compared with controls. These findings support a mechanistic interplay among endotoxemia, innate immune activation, and lipid dysregulation in the pathophysiology of PD.

Phospholipid transfer protein (PLTP) is a lipid transfer protein classically studied in the context of plasma lipoprotein metabolism, high-density lipoprotein (HDL) remodeling, and cardiovascular disease risk. PLTP facilitates phospholipid transfer between lipoproteins and regulates HDL particle size and composition through interactions with apolipoprotein A-I and apolipoprotein A-II. While its systemic roles in cholesterol handling, reverse cholesterol transport, and inflammatory signaling are well established, the cell-autonomous functions of PLTP within cardiomyocytes remain poorly defined, particularly in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Extensive experimental and clinical studies demonstrate that PLTP enhances ABCA1-dependent cholesterol efflux primarily by stabilizing ABCA1 at the plasma membrane and by promoting the generation of lipid-poor apolipoprotein A-I and pre-β HDL particles, which serve as efficient cholesterol acceptors; the magnitude of these effects depends on cellular context, PLTP expression levels, and the availability of lipid acceptors. PLTP expression is metabolically regulated and widely distributed across tissues, including macrophages and other non-hepatic cells, supporting roles beyond circulating lipoprotein remodeling. Altered PLTP activity has been linked to atherosclerosis, cardiovascular disease, and inflammatory pathways, underscoring its relevance to cardiac pathophysiology. Emerging evidence further suggests that intracellular cholesterol distribution, rather than total cholesterol content alone, critically influences mitochondrial membrane composition, bioenergetics, and stress signaling in cardiomyocytes. These observations raise the possibility that PLTP-regulated lipid flux may indirectly shape mitochondrial function by modulating cellular cholesterol homeostasis. This review synthesizes current knowledge of PLTP biology, cholesterol metabolism, and lipoprotein remodeling, and integrates these concepts with emerging frameworks in cardiomyocyte lipid metabolism and mitochondrial physiology. We highlight human iPSC-derived cardiomyocytes as a strategic and translationally relevant platform to investigate PLTP's non-canonical, cell-intrinsic roles, identify critical knowledge gaps, and propose future directions for elucidating how PLTP may influence mitochondrial function in human cardiac cells.

Background: Phospholipid transfer protein (PLTP) regulates high density lipoprotein (HDL) remodelling by transferring cholesterol and phospholipids and affecting particle size and function. Pregnancy alters lipid metabolism, but the adaptation of PLTP to pregnancy remains poorly understood. This study investigated longitudinal changes in PLTP gene expression and concentration through healthy pregnancy and pregnancy with cardiometabolic complications, as well as their associations with maternal lipid metabolism and inflammatory status. Methods: We followed 84 healthy and 20 pregnant women who developed gestational diabetes mellitus and hypertensive disorders during pregnancy. PLTP gene expression, PLTP concentration, advanced lipid profile parameters and inflammatory status were analyzed throughout trimesters. Results: A comparable trajectory of changes in PLTP gene expression and PLTP concentrations was observed in both groups, but PLTP gene expression in the first trimester was significantly lower in the group with complications (p < 0.05). Analysis of serum non-cholesterol sterols in HDL subfractions (NCSHDL) and plasma ceramides [ceramide C16:0 (Cer C16:0), ceramide C24:0 (Cer C24:0)], has revealed significantly lower desmosterolHDL (p < 0.05), while significantly higher C24:0 (p < 0.001) concentrations in the group with complications in the first trimester. Higher levels of resistin (p < 0.05) were found in the first trimester in the group with complications. PLTP gene expression in the first trimester was independently associated with pregnancy complications. Conclusions: Our results showed altered PLTP gene expression, advanced lipid profile, and inflammatory status in the first trimester of pregnancy with cardiometabolic complications. Our findings emphasize the importance of a thorough investigation of lipid metabolism and inflammatory pathways in early pregnancy to improve the outcomes.

Background Dizziness/vertigo is a multifactorial neurological disorder with complex ge-netic and cellular bases, yet its molecular mechanisms remain unclear. Understanding how gene regulation contributes to dizziness/vertigo may reveal novel neurobiological and therapeutic insights. Methods We established a multi-omics integrative framework combining genome-wide association study (GWAS) data with expression quantitative trait loci (eQTL) from brain single-cell types, CD4+ T cells, oneK1K immune cells, and plasma. Two-sample Mendelian randomization (MR) and colocalization analyses were applied to identify causal genes. Single-cell RNA sequencing (scRNA-seq) of the auditory nerve was used to as-sess cell type–specific expression, intercellular communication, and pseudotime dynam-ics. Gene–gene interaction and drug–target networks were further constructed to identify potential therapeutic candidates. Results Six key genes—Activin A Receptor Type 2 A (ACVR2A), Phospholipid Transfer Protein (PLTP), Androgen Dependent TFPI Regulating Protein (ADTRP), Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 1 Like (MTHFD1L), Collagen Type VII Alpha 1 Chain (COL7A1), and Pantothenate Kinase 4 (PANK4)—showed strong causal and colocalization evidence for dizziness/vertigo. Single-cell analysis revealed distinct cell type–specific expression, with fibroblasts and adipocytes playing central roles in signaling and gene regulation. Pseudo-time trajectories indicated coordinated upregulation of ACVR2A, MTHFD1L, PANK4, and PLTP during later developmental stages. Interaction network analysis positioned these genes as major hubs, and DrugBank screening identified Sotatercept as a promising candidate targeting ACVR2A. Conclusion This integrative analysis links gene expres-sion regulation to dizziness/vertigo across neuroimmune and metabolic systems. The findings uncover coordinated molecular pathways underlying disease susceptibility and highlight novel therapeutic targets, providing a foundation for precision treatment strate-gies.

We examined gene expression profiles in abdominal aortic aneurysm (AAA) lesions vs. normal aortas by cDNA microarray and real-time quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Phosphorus (32P)-labeled cDNA from AAA specimens (mean AAA size 6.65 cm) and normal aortas were hybridized with a 588-gene microarray primarily of the cardiovascular system. The results were validated by qRT-PCR. A total of 35 out of the 588 genes were differentially expressed, with either log2 ratio of AAAs/controls ≥1 (upregulated; 20 genes) or ≤-1 (downregulated; 15 genes) in AAA lesions vs. normal aorta, and 25 of these were significantly different (71%). Expression of matrix metalloproteinase 9, TIMP metallopeptidase inhibitor 3, collagen type I α 1 chain (COL1A1), COL6A3, COL15A1, intercellular adhesion molecule 1 (ICAM1), ICAM2, decorin, endoglin, apolipoprotein D (APOD), APOE, phospholipid transfer protein, calcium and integrin binding 1 (CIB1), phospholipase A2 group IIA, von Willebrand factor, serpin family B member 6 (SERPINB6), urokinase-type plasminogen activator, H19, C-C motif chemokine ligand 2, and platelet-derived growth factor receptor beta was upregulated in AAA vs. normal aorta. Expression of collagen type IV α 4 chain (COL4A4), COL11A2, gap junction protein α 1 (GJA1), biglycan, integrin subunit α 8, galectin-1, low-density lipoprotein receptor-related protein 1, acetyl-CoA acyltransferase, serpin family E member 1, melanoma cellular adhesion molecule, sodium channel epithelial 1 subunit beta (SCNN1B), natriuretic peptide receptor 1 (NPR1), superoxide dismutase 3, actinin α 1 (ACTN1) and cardiac phospholamban (PLN) was downregulated. Eleven genes differentially expressed (p≤0.05) in AAA lesions vs. normal aortas were not reported previously: upregulated: COL6A3, COL15A1, ICAM2, APOD, CIB and SERPINB6; downregulated: GJA1, SCNN1B, NPR1, ACTN1 and PLN. Remaining results confirmed previous reports regarding 21 genes differentially expressed in AAA. qRT-PCR results were in general in agreement with microarray results.

The gasotransmitter hydrogen sulfide (H2S) is implicated in a myriad of biological processes, including disease causing alterations. Besides acting as an antioxidant molecule, H2S reacts with thiol groups from cysteine residues found in proteins. This post-translational modification (PTM), called S-persulfidation, plays an essential role during endoplasmic reticulum (ER) stress. Here we demonstrated that yeast cystathionine beta-synthase (Cys4), is the main responsible for ER H2S-mediated homeostasis. We also found that during ER stress, Cys4 interacts with specific proteins that we identified with at least one cysteine residue modified by hydrogen sulfide. Finally, we focused on one interactor with reported tunicamycin sensitivity, the phospholipid transfer protein Sec14. In addition to Cys4 immunoprecipitation, we confirmed this interaction by pulling down Sec14 interactors. Deleting CYS4 generated the accumulation of lipid droplets inside the cytosol, similar to Sec14. For the first time, we described a set of protein-protein interactions of Cys4 during ER stress with cysteines susceptible to S-persulfidation, leaving an open question about the role and regulation of the rest of the interactors. SIGNIFICANCE: In this study, we identified several interactor partners of yeast cystathionine beta synthase and analyzed cysteine residues with cysteine S-persulfidations. Although yeast have multiple H2S producing enzymes, Cys4 seems to play a predominant role during ER stress. Temporal and spatial generation of H2S is becoming significant in the field, and our findings contribute to that understanding. Besides, Cys4/Sec14 complex found here, seven different Cys4 complexes that may be regulated by H2S were also reported. Because the biogenesis of this PMT is still controversial, findings like these support the hypothesis of interaction mediated biogenesis. H2S producing enzymes specificity would help control their signaling across the cell. Finally, all Cys4 interactors with modified cysteines, including Sec14, are excellent targets to study how this PTM regulates enzyme functioning. Structural and functional assays with cysteine mutants in these proteins will shed light on new regulatory mechanisms.

Proteomic and metabolomic alterations in response to systemic stress in vivo

Residual cardiovascular risk is tracked by apolipoprotein B in coronary patients with elevated serum triglyceride levels: the ESC EORP EUROASPIRE IV survey.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation expansions (55-200 CGG repeats) in the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Despite its clinical significance, FXTAS currently lacks reliable molecular markers for disease monitoring and evaluation of therapeutic efficacy. To address this critical gap, we performed an integrated multi-omics study combining plasma metabolomics (lipidomics, amine, and primary metabolites) with proteomics analyses in plasma and peripheral blood mononuclear cells (PBMCs) from FXTAS participants (n = 5, FXTAS stages 3-5) and age-matched non-carrier healthy controls (HC, n = 15). Integrated analyses revealed molecular differences distinguishing FXTAS from HC, including alterations in metabolites related to energy metabolism (e.g., UDP-glucuronic acid, succinic acid, mannose), lipids (e.g., cholesterol, triglycerides, glycerophospholipids, ceramide), and selected amines (e.g., cystine, glycerophosphocholine, histidine). Proteomic analyses identified proteins associated with FXTAS clinical stage and CGG repeat size, implicating pathways related to mitochondrial function, immune-inflammatory signaling, and lipid metabolism. Comparative analysis of plasma and PBMC proteomes identified Basigin (CD147) and phospholipid transfer protein C2CD2 as overlapping candidate markers across biological matrices. Although limited by sample size and the cross-sectional design, this exploratory study demonstrates the value of integrated, cross-matrix multi-omics profiling for identifying molecular patterns associated with advanced FXTAS. These findings reinforce prior mechanistic models and provide a foundation for future validation in larger, longitudinal cohorts.

High levels of M2 macrophages in the hepatocellular carcinoma (HCC) tumor microenvironment (TME) are associated with poor response to immune checkpoint inhibitors (ICIs). This study comprehensively investigated the role of phospholipid transfer protein (PLTP) in driving M2 macrophage polarization through bioinformatics, clinicopathological analysis, molecular docking, proteomics, biochemical and cellular assays. Additionally, strategies to enhance ICIs sensitivity are validated in multiple animal models. Results demonstrated that high M2 macrophage infiltration independently predicted inferior ICIs outcomes, and PLTP overexpression in HCC promoted M2 macrophage polarization. Mechanistically, PLTP bound to aurora kinase A (AURKA) and P65, forming a complex that induced P65 phosphorylation, thereby activating NF-κB and upregulating IL-6, IL-8, and CSF-1. Molecular docking revealed that GMB-475 specifically bound to PLTP's functional domain (25-245 AA), which competitively inhibited PLTP-P65-AURKA interactions and suppressing P65 phosphorylation. In vivo, GMB-475 reduced M2 macrophage infiltration and suppressed tumor growth. Fibrates downregulated PLTP expression, decreased P65 phosphorylation, and synergized with ICIs in orthotopic and Myc-driven HCC models. These findings highlight PLTP as a key mediator of M2 macrophage polarization via AURKA-dependent NF-κB activation. Targeting PLTP with inhibitor GMB-475 or fibrates may improve ICIs efficacy, offering a promising therapeutic strategy for HCC.

Abstract Background Elevated lipoprotein(a) [Lp(a)] increases the risk of aortic stenosis (AS); however, the role of Lp(a) in valvular tissue remodeling and fibro-calcification in AS remains unclear. Aims To assess associations between elevated Lp(a) and valvular fibrosis and calcification as well as changes in the valvular proteome in severe AS. Methods We recruited 30 symptomatic AS patients (69±6 years), 11 of whom had Lp(a) levels ≥50mg/dL (high Lp(a) group) and 19 had Lp(a) levels <50mg/dL (normal Lp(a) group). Routine tests measured Lp(a), glucose, creatinine, lipid profile and CRP. Proteomic analysis of calcified and non-calcified valve regions (5 from each Lp(a) group) was performed using mass spectrometry. The structural characteristics of valvular calcification were examined ex vivo using micro-CT, including bone volume (BV), surface volume (SV), and trabecular thickness (TbThmax). Results No intergroup differences were observed in demographics, risk factors, medication use, or laboratory parameters, except for higher total and LDL cholesterol levels in high Lp(a) patients (both p<0.05). High Lp(a) patients had 11.6% increased peak transvalvular velocity (Vmax) and about 20% higher both transvalvular gradients (PGmean, PGmax) compared to normal Lp(a) subjects (all p<0.05). Among the detected valvular proteins high Lp(a) patients had 11.7-fold higher apolipoprotein(a), 9.8-fold higher calmodulin 1 (CALM1, involved in calcium signaling), 7.8-fold higher calcium-binding protein (S100-B) and 4.7-fold higher Wnt11 (implicated in valve calcification) compared to normal Lp(a) subjects. Calcified valve regions compared to non-calcified regions showed 54.6-fold higher macrophage metalloelastase (MMP-12), 31.6-fold higher CRP, 25.1-fold higher phospholipid transfer protein (PLTP), 20.5-fold higher cholesteryl ester transfer protein (CETP), 19.8-fold higher plasminogen activator inhibitor 1 (PAI-1) and 11.2-fold higher transforming growth factor-β (TGF-β). Micro-CT showed less calcium deposits within leaflets of patients with normal Lp(a) compared to high Lp(a) subjects (Figure 1A-B). Valves from normal Lp(a) patients showed reduced BV (-77.9%), SV (-69.3%) and TbThmax (-17.6%) compared to high Lp(a) (all p<0.05). Lp(a) correlated with PGmean (r=0.36, p=0.047) and with micro-CT indices, including BV, SV and TbThmax (Figure 1C-E). Additionally, BV and SV correlated with PGmean (r=0.44, p=0.016 and r=0.38, p=0.038). Conclusions In severe AS patients elevated Lp(a) is associated with more pronounced valve calcification and higher level of proteins involved in different molecular pathways such as tissue remodelling, inflammation, lipid metabolism, fibrinolysis and calcification, expressed mainly within calcified regions.Figure 1

ABSTRACTIntroductionCrescentic glomerulonephritis (CrGN) with rapidly progressive renal function loss necessitates prompt pathology diagnosis and treatment. Non-invasive biomarkers are crucial in cases where renal biopsy is unavailable or unsuitable. Urinary proteomics, particularly data-independent acquisition (DIA) proteomics, might provide potential indicators.MethodsWe recruited crescentic nephritis proved by renal biopsy at Peking Union Medical College Hospital (PUMCH) from May 2022 to April 2023 and age-matched nephritis, acute kidney injury (AKI), and health controls. The CrGN group is the patients with extensive glomerular crescents over 50%. We performed liquid chromatography with tandem mass spectrometry analysis to identify differentially expressed proteins (DEPs), ingenuity pathway analysis (IPA), and the proteome map for significant pathways and crucial proteins among patients and controls, then validated using enzyme-linked immunosorbent assay analysis.ResultsWe enrolled a total of 137 participants, 55 in the proteomics cohort [15 CrGN (Type I: n = 1, II: n = 3, III: n = 11), 10 AKI, 15 non-crescentic nephritis, 15 healthy controls] and 82 in the validation cohort (33 CrGN, 6 AKI, 43 nephritis). Males occupied 42.3%, and the average age was 48 years of age. IPA analysis showed that neutrophil degranulation and complement cascade were the top two pathways in CrGN but not in the healthy and nephritis groups. Pathway analysis revealed activation of the neddylation pathway in CrGN compared to AKI patients. After integrating the DEPs among three groups via the Venn plot, we observed eight DEPs significantly associated with the CrGN, among which Coagulation factor V (F5), Phospholipid transfer protein (PLTP), and alcohol dehydrogenase 1C were significant proteins. The area under the curve values of F5 and PLTP in the validation cohort for predicting CrGN were 0.831 and 0.780 (P < .001).ConclusionBy non-invasive urine proteomics, the new biomarkers F5/UCr and PLTP/UCr hold promise in identifying the CrGN patient.

Fibrinolysis phenotypes are integral in the pathogenesis of trauma-induced coagulopathy and its sequelae. Of the various phenotypes of dysregulated fibrinolysis, hyperfibrinolysis (HF) is most associated with the highest mortality and has been implicated directly in death due to bleeding. While the dominant regulators of fibrinolysis are well established, additional yet crucial candidate biomediators of HF are less known. Thus, our hypothesis is that the early proteomic signature of HF would expand our comprehension of this dysregulated pathway after severe trauma. Mass spectrometry-based proteomics methods were leveraged to characterize plasma samples from trauma patients enrolled in the Control of Major Bleeding After Trauma randomized control trial. In this post hoc analysis, the plasma fraction of samples collected at the emergency department from highly injured, hypotensive patients in HF was subjected to proteomics workflows. Projection to latent structures and principal component analyses were performed using rapid thromboelastogram-based percent decrease in clot strength 30 minutes after it reaches its maximum amplitude to identify statistically significant proteins. Fibrinogen γ' (odds ratio [OR], 21.85; p = 0.001) and Golgi casein kinase (FAM20C) (OR, 4.25; p = 0.025) were among the top proteins most associated with HF. Other significant proteins included phospholipid transfer protein (OR, 2.39; p = 0.025) and 3-hydroxy-3-methylglutaryl coenzyme A synthase (OR, 217.36; p = 0.003). Proteins least associated with decreased HF included complement proteins, coagulation factors, and other procoagulant proteins such as thrombin-activatable fibrinolysis inhibitor (OR, 0.394; p = 0.011) and actin β (OR, 0.732; p = 0.027). Cutting-edge proteomic analyses have uncovered potential biomediators of HF, a novel yet crucial next step in understanding these maladaptive syndromes. This provides a platform to characterize numerous additional proteins associated with HF from where we can start investigating potential therapeutic targets as the next step in treating HF and thus trauma-induced coagulopathy. Prognostic and Epidemiological; Level IV.

SummaryReliable predictive biomarkers to reduce unnecessary coronary angiograms (CAGs) in non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA) patients displaying high-risk features are still lacking. Here, we show that profiling patient-derived circulating extracellular vesicles (EVs) can not only improve their risk stratification but also reduce unnecessary CAGs. Analysis of EVs and their miR cargo revealed that CD62p+EVs enriched in miR-130a-3p correlated with the absence of non-critical coronary artery disease (CAD). Proteomic analysis identified nine proteins differentially enriched in patients with or without critical-CAD (NO CAD), irrespective of their diagnosis. Multivariate analysis identified miR-130a-3p (odds ratio [OR]:0.35 [0.19–0.67]), phospholipid transfer protein (OR 0.96 [0.94–0.98]), and subunit beta of mitochondrial trifunctional enzyme (OR:0.96 [0.94–0.98]) as predictors of NO CAD. Furthermore, EV-miR-130a-3p enrichment predicted the absence of multivessel disease (OR:0.46 [0.23–0.90]). These findings establish EV profiling as a valuable tool for stratifying and optimizing the clinical management of patients with acute coronary syndrome.

BackgroundThe high‐density lipoprotein (HDL) and the phospholipid transfer protein (PLTP) have been demonstrated to enhance endotoxin elimination and inactivation in animal models of sepsis. This study aimed to confirm such a role in patients presenting with abdominal sepsis undergoing emergent surgery and explore the relationships between HDL, PLTP and the lipopolysaccharide (LPS) burden (mass and activity).MethodsPatients operated for abdominal sepsis were prospectively included in the study. Blood samples were obtained before surgery, at the end of the operation (H0), 4 h (H4) and 24 h (H24) later. Peritoneal fluid was also sampled. HDL cholesterol, LDL cholesterol, PLTP activity, LPS mass and activity were measured.ResultsTwenty‐seven patients were included. At H0, LPS mass was mostly measured in the lipoprotein fractions (46% [23; 58] in HDL and 36% [29; 54] in LDL). Overall, LPS mass and LPS activity did not decrease in the 24 h following admission to the ICU. Both HDLc concentrations and PLTP activity were associated with increased H4‐LPS elimination (drop in LPS concentration, −3% [−26;10] vs. 29% [13;52], p < 0.01 and −2% [−15;10] vs. 20% [8:52], p = 0.03, respectively). Increased H4‐LPS elimination was associated with reduced inflammation (plasma cytokine concentration) and mortality. High HDL cholesterol was associated with reduced mortality but not with inflammation.ConclusionOur data support the role of HDL and PLTP in the elimination of LPS during human peritonitis with sepsis. Increased H4‐LPS elimination was associated with reduced inflammation and lower mortality.ClinicalTrials.gov: NCT04126577.

BackgroundThis study aims to elucidate the effect and mechanism of phospholipid transfer protein (PLTP) on vascular dysfunction in DR and explore the molecular mechanism of abnormal PLTP expression based on DNA methylation.MethodsHuman retinal microvascular endothelial cells (HRMECs) cultured in high glucose (HG) and streptozotocin-treated mice were used as DR models to detect and screen the key genes with abnormal promoter DNA methylation. Single-cell sequencing, tube formation and migration assays were employed to verify the relationship between PLTP and vascular function. Additionally, siRNA and luciferase reporter assay were used to study the key enzymes regulating the DNA methylation of PLTP. Transcriptome sequencing, coimmunoprecipitation and GSK3β inhibitor were utilized to identify and validate the key downstream pathways of PLTP.ResultsDR models exhibited DNA hypermethylation and decreased expression of PLTP. Abnormal PLTP expression was implicated in vascular dysfunction, and PLTP overexpression reversed HG-induced effects on the migration and tube formation of endothelial cells. The siDNMT3B and luciferase reporter assay indicated that DNMT3B is the primary enzyme affecting abnormal methylation. Interestingly, PLTP promoted the phosphorylation of AKT and GSK3β, indicating that PLTP modulates angiogenesis via the AKT/GSK3β signaling pathway.ConclusionsPLTP regulates the proliferation, migration and tube formation of HRMECs, and is involved in maintaining vascular function via the AKT/GSK3β signaling pathway. In HG environment, increased DNMT3B expression upregulates DNA methylation of the PLTP promoter, downregulating PLTP expression and leading to vascular dysfunction in DR.Graphical abstractPLTP promotes the phosphorylation of AKT and GSK3β, leading to the enhancement of endothelial cell proliferation, migration and tube formation, thereby maintaining vascular function. In HG environment, increased DNMT3B expression results in abnormally increased DNA methylation of the PLTP promoter, leading to decreased PLTP expression and subsequent vascular dysfunction.

Characterization of familial chylomicronemia syndrome in a compound heterozygote for 2 APOA5 nonsense variants.