PAF-acether Research Articles

RBCs regulate platelet function and hemostasis under shear conditions through biophysical and biochemical means

AbstractRed blood cells (RBCs) have been hypothesized to support hemostasis by facilitating platelet margination and releasing platelet-activating factors such as adenosine 5′-diphosphate (ADP). Significant knowledge gaps remain regarding how RBCs influence platelet function, especially in (patho)physiologically relevant hemodynamic conditions. Here, we present results showing how RBCs affect platelet function and hemostasis in conditions of anemia, thrombocytopenia, and pancytopenia and how the biochemical and biophysical properties of RBCs regulate platelet function at the blood and vessel wall interface and in the fluid phase under flow conditions. We found that RBCs promoted platelet deposition to collagen under flow conditions in moderate (50 × 103/μL) but not severe (10 × 103/μL) thrombocytopenia in vitro. Reduction in hematocrit by 45% increased bleeding in mice with hemolytic anemia. In contrast, bleeding diathesis was observed in mice with a 90% but not with a 60% reduction in platelet counts. RBC transfusion improved hemostasis by enhancing fibrin clot formation at the site of vascular injury in mice with severe pancytopenia induced by total body irradiation. Altering membrane deformability changed the ability of RBCs to promote shear-induced platelet aggregation. RBC-derived ADP contributed to platelet activation and aggregation in vitro under pathologically high shear stresses, as observed in patients supported by left ventricular assist devices. These findings demonstrate that RBCs support platelet function and hemostasis through multiple mechanisms, both at the blood and vessel wall interface and in the fluidic phase of circulation.

The role of platelets in the blood-brain barrier during brain pathology.

Platelets play critical roles in maintaining hemostasis. The blood brain barrier (BBB), a significant physical and metabolic barrier, helps maintain physiological stability by limiting transportations between the blood and neural tissues. When the brain undergoes inflammation, tumor, trauma, or bleeding, the platelet responses to help with maintaining BBB homeostasis. In the traditional point of view, activated platelets aggregate to form thrombi which cover the gaps of the blood vessels to protect BBB. However, increasing evidences indicate that platelets may harm BBB by enhancing vascular permeability. Hereby, we reviewed recently published articles with a special focus on the platelet-mediated damage of BBB. Factors released by platelets can induce BBB permeability, which involve platelet-activating factors (PAF), P-selectin, ADP, platelet-derived growth factors (PDGF) superfamily proteins, especially PDGF-AA and PDGF-CC, etc. Platelets can also secrete Amyloid-β (Aβ), which triggers neuroinflammation and downregulates the expression of tight junction molecules such as claudin-5 to damage BBB. Additionally, platelets can form aggregates with neutrophils to release reactive oxygen species (ROS), which can destroy the DNA, proteins, and lipids of endothelial cells (ECs). Moreover, platelets participate in neuroinflammation to affect BBB. Conversely, some of the platelet released factors such as PDGF-BB, protects BBB. In summary, platelets play dual roles in BBB integrity and the related mechanisms are reviewed.

Metabolomics evaluation of the photochemical impact of violet-blue light (405nm) on ex vivo platelet concentrates.

Microbicidal violet-blue light in the visible spectrum (405nm) has been under evaluation for pathogen inactivation in ex vivo human plasma and platelets (PLTs) stored in plasma. Results to date have demonstrated that several blood-borne infectious disease-causing pathogens can be successfully reduced to significantly low levels in the light-treated plasma and PLTs. In order to evaluate whether the microbicidal 405nm light is safe for the treatment of PLT concentrates for pathogen inactivation, LC/MS-based metabolomics analyses were performed to evaluate the overall impact of 405nm violet-blue light treatment on ex vivo PLT concentrates suspended in plasma and on plasma itself, and to identify metabolome changes in intra-platelet and extra-cellular medium (i.e., plasma). The metabolomics data identified that platelet activating factors (PAFs), agonists and prostaglandins, which can influence PLT basic functions such as integrity, activation, and aggregation potential were unaltered, suggesting that 405nm light illumination is safe regarding PLT basic functions. Distinct increases in hydroxyl fatty acids and aldehydes, as well as decreases in antioxidant metabolites indicated that reactive oxygen species (ROS) were generated at high levels after only one hour of exposure to 405nm light. Distinctly changed endogenous photosensitizer metabolites after 1h of light exposure provided good evidence that 405nm light was an effective microbicide acting through ROS mechanism and no external additive photosensitizers were required.

KORELASI KADAR C-REACTIVE PROTEIN DENGAN JUMLAH TROMBOSIT PADA PENDERITA DIABETES MELITUS TIPE 2

Type 2 diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia and insulin resistance, associated with decreased nitric oxide (NO) levels, increased free radical production, inflammation, endothelial dysfunction, and progressive vascular damage. C-reactive protein (CRP), an acute phase protein regulated by pro-inflammatory cytokines like interleukin-6 (IL-6), serves as a systemic inflammation marker. Pentameric CRP (pCRP) and monomeric CRP (mCRP) are implicated in mediating inflammation and endothelial dysfunction, with roles in endothelial cell adhesion, phagocytosis, inflammatory signaling, and interactions with endothelial cells, neutrophils, macrophages, and platelets. Additionally, leukocytes secrete platelet-activating factors, enhancing platelet activation and cytokine and chemokine release. This descriptive analytical study with a cross-sectional design aimed to investigate the correlation between CRP levels and platelet counts in patients with type 2 DM. Utilizing purposive sampling, 47 patients diagnosed with DM at Sultan Syarif Mohamad Alkadrie Hospital, Pontianak, during June 2023 were selected. CRP levels were measured using the fluorescence immunoassay (FIA) method, while platelet counts were determined through the impedance method. Statistical analysis employing Kendall's Tau-b test revealed a significant correlation (p < 0.05, r = -0.508), indicating that elevated CRP levels are significantly associated with reduced platelet counts in type 2 DM patients.

The Involvement of Lipid Mediators in the Mechanisms of Exercise-Induced Muscle Damage

Lipid mediators are a class of signaling molecules that play important roles in various physiological processes, including inflammation, blood pressure regulation, and energy metabolism. Exercise has been shown to affect the production and metabolism of several types of lipid mediators, including prostaglandins, leukotrienes, sphingolipids, platelet-activating factors and endocannabinoids. Eicosanoids, which include prostaglandins and leukotrienes, are involved in the regulation of inflammation and immune function. Endocannabinoids, such as anandamide and 2-arachidonoylglycerol, are involved in the regulation of pain, mood, and appetite. Pro-resolving lipid mediators are involved in the resolution of inflammation. Sphingolipids have a role in the function of skeletal muscle during and after exercise. There are many studies that have examined the effects of exercise on the production and release of these and other lipid mediators. Some of these studies have focused on the effects of exercise on inflammation and immune function, while others have examined the effects on muscle function and metabolism. However, much less is known about their involvement in the phenomenon of exercise-induced muscle damage that follows after intense or unaccustomed exercise.

The Role of Platelet-Activating Factor and Magnesium in Obstetrics and Gynecology: Is There Crosstalk between Pre-Eclampsia, Clinical Hypertension, and HELLP Syndrome?

Clinical hypertension is a complex disease of the cardiovascular system that can affect the body's ability to physiologically maintain homeostasis. Blood pressure is measured as systolic pressure of the heart and diastolic pressure. When the systolic pressure exceeds values of 130-139 and diastolic exceeds 80-89, the body is in stage 1 hypertension. A pregnant woman with hypertension is predisposed to developing pre-eclampsia during gestation between the 1st and 2nd trimester. If the symptoms and changes in the mother's body are not controlled, this can progress to hemolysis, elevated liver enzymes, and low platelet count also known as HELLP syndrome. The onset of HELLP syndrome generally begins before the 37th week of pregnancy. Magnesium is one of the most used cations in clinical medicine with various implications in the body. With a critical role in vascular smooth muscle, endothelium, and myocardial excitability it is used in treatment of clinical hypertension, pre-eclampsia in gestational periods, and HELLP syndrome. Platelet-activating factor (PAF) is an endogenous phospholipid proinflammatory mediator that is released in response to various biological and environmental stressors. When released it causes platelets to aggregate, further exacerbating hypertension. The purpose of this literature review is to investigate the role that magnesium and platelet-activating factors have on clinical hypertension, pre-eclampsia, and HELLP syndrome while focusing on the interplay between these molecules.

Corosolic Acid Inhibits Secretory Phospholipase A2IIa as an Anti-Inflammatory Function and Exhibits Anti-Tumor Activity in Ehrlich Ascites Carcinoma Bearing Mice.

Inflammation is generally connected to tumour progression and development. The secretory phospholipase A2IIa (sPLA2IIa) is an important inflammatory enzyme that catalyse the hydrolysis of membrane phospholipids into arachidonic and lysophosphatidic acid, which are the precursors for production of a lot of pro-inflammatory mediators like prostaglandins, prostacyclins, thromboxanes, leukotrienes and platelet activating factors, which involved in the proliferation, migration, invasion, and metastasis. Therefore, investigating safe and effective sPLA2IIa inhibitors as a therapeutic agent to treat cancer is indeed in need. Anti-inflammatory function of corosolic acid was evaluated by docking it with sPLA2IIa enzyme, sPLA2IIa inhibition, calcium and substrate concentration-dependent assays; intrinsic fluorescence and UV-CD analysis; neutralisation of sPLA2IIa induced indirect hemolytic and edema. Evaluated the anticancer activity of corosolic acid by MTT assays and caspase-3 expression; the anti-tumour activity by EAC-induced cell line and interleukin 6 expression. The corosolic acid inhibits sPLA2IIa activity to 82.21±2.82%. The inhibition was evaluated by increasing calcium from 2.5 to 15 µM and substrate from 20 to 120 nM, it did not affect the level of inhibition. Corosolic acid altered the intrinsic fluorescence and UV-CD spectra of sPLA2IIa enzyme, indicating the direct interaction. It neutralised sPLA2IIa induced hemolytic activity from 97±1.23% to 15.75±1.44% and edema from 171.51±2.39% to 119.3±2.6%. Further, as antiproliferative activity, corosolic acid reduced the PC3 cell viability from 99.66±0.57% to 23±2.64% and suppressed LPS-induced IL-6 level from 94.35±2.2% to 34.36±2.4%. It increased mean survivability time from 30 to 38 days and displayed the drug-like qualities. All the experimental results have proven the corosolic acid as an anti-inflammatory and anticancer molecule that may further be used to develop it as a drug.

Generation and multiomic profiling of a TP53/CDKN2A double-knockout gastroesophageal junction organoid model.

Inactivation of the tumor suppressor genes tumor protein p53 (TP53) and cyclin-dependent kinase inhibitor 2A (CDKN2A) occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, because of a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have not been characterized. Here, we report the development of a wild-type primary human GEJ organoid model and a CRISPR-edited transformed GEJ organoid model. CRISPR-Cas9-mediated TP53 and CDKN2A knockout (TP53/CDKN2AKO) in GEJ organoids induced morphologic dysplasia and proneoplastic features in vitro and tumor formation in vivo. Lipidomic profiling identified several platelet-activating factors (PTAFs) among the most up-regulated lipids in CRISPR-edited organoids. PTAF/PTAF receptor (PTAFR) abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) reduced proliferation and other proneoplastic features of TP53/CDKN2AKO GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts of Eso26, an established human esophageal adenocarcinoma cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly forkhead box M1 (FOXM1). FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. Together, these studies established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and revealed a potential cancer therapeutic strategy. This work provides insights into proneoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia, which may facilitate early diagnosis and prevention of GEJ neoplasms.

Genome-wide transcriptome analysis reveals the regulatory network governing terpene trilactones biosynthesis in Ginkgo biloba.

Ginkgo biloba L. is currently the only remaining gymnosperm of the Ginkgoaceae Ginkgo genus, and its history can be traced back to the Carboniferous 200 million years ago. Terpene trilactones (TTLs) are one of the main active ingredients in G. biloba, including ginkgolides and bilobalide. They have a good curative effect on cardiovascular and cerebrovascular diseases because of their special antagonistic effect on platelet-activating factors. Therefore, it is necessary to deeply mine genes related to TTLs and to analyze their transcriptional regulation mechanism, which will hold vitally important scientific and practical significance for quality improvement and regulation of G. biloba. In this study, we performed RNA-Seq on the root, stem, immature leaf, mature leaf, microstrobilus, ovulate strobilus, immature fruit and mature fruit of G. biloba. The TTL regulatory network of G. biloba in different organs was revealed by different transcriptomic analysis strategies. Weighted gene co-expression network analysis (WGCNA) revealed that the five modules were closely correlated with organs. The 12 transcription factors, 5 structural genes and 24 Cytochrome P450 (CYP450) were identified as candidate regulators for TTL accumulation by WGCNA and cytoscape visualization. Finally, 6 APETALA2/ethylene response factors, 2 CYP450s and bHLH were inferred to regulate the metabolism of TTLs by correlation analysis. This study is the comprehensive in authenticating transcription factors, structural genes and CYP450 involved in TTL biosynthesis, thereby providing molecular evidence for revealing the comprehensive regulatory network involved in TTL metabolism in G. biloba.

Factors Impacting Teachers’ Continued IT Adoption in Pre-College Education

Aim/Purpose: This study was designed to examine the extent to which high school teachers intend to continue using the tablet PC in their teaching within the context of the Tablet Project initiative in Kuwait. It explores what drives their adoption intention. Background: Blended learning offers teachers the potential to adopt IT to augment their instructions and refocus their content, target group, context, and ethical facets; explore new modes of education and consider effective methods to educate students; and experience more flexibility in both course design and delivery method. To reap the potential benefits of integrating IT in education, the Ministry of Education in Kuwait introduced the “Tablet Project” in public high schools during the 2015–2016 academic year; three years later, it was unclear whether the teachers would continue using the tablet PCs in their teaching. Methodology: The research model adapts constructs from the Unified Theory of Acceptance and Use of Technology (UTAUT) and the Technological, Pedagogical, and Content Knowledge (TPACK) models. It includes facilitating conditions (FC), social influence (SI), and teaching efficacy (TE) as predictors of teachers’ behavioral intentions (BI) to continue using the tablet PC in future teaching. The model also proposes a moderating effect of gender, age, and tablet PC experience on BI. To test the research hypotheses, a data set was collected from 206 teachers and analyzed using the partial least squares structural equation modeling (PLS-SEM) method. Contribution: This study provides empirical evidence on important predictors of continuous IT adoption in teaching activities and identifies lessons that could guide initiatives aimed to embed IT in the pre-college education system in Kuwait as well as other similar systems. It contributes results to advance theories and models aimed to explain and predict sustainable IT adoption in education systems across cultures. Findings: While TE arises as a non-significant predictor of BI, SI emerges as the strongest predictor of BI. FC is the second significant predictor of BI, although its direct effect on BI is non-significant. Gender, age, and tablet PC experience have non-significant moderating effects on BI. These results provide significant statistical support for the predictive power of the model, as it explains approximately 50% of the variance in BI. Recommendations for Practitioners: Since this research is directly connected to the reality of IT adoption in teaching in the Kuwaiti high school system, the findings should be of value for the Kuwaiti educational system and future teachers’ professional development initiatives. They should inform future actions and strategies aimed at successfully integrating IT in pre-college education in Kuwait and other similar countries. Recommendation for Researchers: The findings add to the ongoing research effort aimed to develop a better understanding of the intention to continue using IT in instruction and its influential factors across cultures (e.g., Arabian culture), especially since most earlier TPACK studies were carried out in Asian countries and the US. Our findings also confirm the value of UTAUT constructs (i.e., SI and FC) in explaining and predicting the intention to continue using IT by high school teachers, as the research model explains approximately 50% of the variance in the teachers’ BI. Impact on Society: This research offers empirical evidence that adds much-needed nuance to the discourse on teachers’ IT adoption intention and behavior and informs policies and strategies in support of initiatives aimed to integrate IT into education. The provision of a technical and organizational ecosystem that is conducive to sustainable IT integration in the Kuwaiti education system must be part of a more comprehensive initiative to digitize the entire education system. Education policy makers should embrace a digital mindset to adopt IT and transform the teaching, learning, and managerial processes in the system. Future Research: Future research could replicate this study and compare the results, employ other research methods (e.g., focus-group discussions and observations) to investigate teachers’ IT adoption in various educational contexts, adapt research models that include other predictors, and investigate and produce results on students’ perspectives regarding their initial and continuous adoption of the tablet PC within the Tablet Project context.

Metabolomic profiling revealed altered lipid metabolite levels in childhood food allergy

The pathophysiology of childhood food allergy (FA) and its natural history are poorly understood. Clarification of the underlying mechanism may help identify novel biomarkers and strategies for clinical intervention in children with FA. This study aimed to identify metabolites associated with the development and resolution of FA. The metabolomic profiles of 20 children with FA and 20 healthy controls were assessed by liquid chromatography-tandem mass spectrometry. Comparative analysis was performed to identify metabolites associated with FA and FA resolution. For subjects with FA, serum samples were collected at the time of diagnosis and after resolution to identify the changes in metabolite levels. The selected metabolites were then quantified in a quantification cohort to validate the results. Finally, genome-wide association analysis of the metabolite levels was performed. The study demonstrated a significantly higher level of sphingolipid metabolites and a lower level of acylcarnitine metabolites in children with FA than those in healthy controls. At diagnosis, subjects with resolving FA had a significantly high level of omega-3 metabolites and a low level of platelet-activating factors compared to persistent FA. However, the level of omega-3 metabolites decreased in children with resolving FA but increased in children with persistent FA during the same time. The quantification data of omega-3-derived resolvins, platelet-activating factor, and platelet-activating factor acetylhydrolase activity further supported these results. The lipid metabolite profile is closely related to childhood FA and FA resolution. This study suggests potential predictive biomarkers and provides insight into the mechanisms underlying childhood FA.

High glucose removes natural anti-α-galactoside and anti-β-glucoside antibody immune complexes adhering to surface O-glycoproteins of normal platelets and enhances platelet aggregation.

Human natural anti-α-galactoside (anti-Gal) and anti-β-glucoside (ABG) antibodies were previously reported to recognize the serine- and threonine-rich peptide sequences (STPS) of albumin-associated O-glycoproteins (AOP1 and AOP2) as surrogate antigens, forming anti-Gal/ABG-AOP1/AOP2-albumin triplet immune complexes in plasma. Since antibodies in these triplets still possessed unoccupied binding sites, the presence of triplets on human platelets that abound in surface O-glycoproteins was examined. Upon treatment with α-galactosides and β-glucosides, normal platelets freshly isolated from young healthy individuals released triplets identical with plasma triplets according to ELISA results. The resulting denuded platelets, unless pre-treated with fibrinogen or the O-glycan-binding lectin jacalin, recaptured these sugar-extracted triplets in the absence of antibody-specific sugars, suggesting that the triplet antibodies recognized the STPS of O-glycosylated receptors on platelets. Molecular weight of the dominant jacalin-binding subunit on triplet-free platelet membrane was 116 kDa, close to the ~120 kDa reported for the IIb subunit of the most abundant fibrinogen-binding platelet O-glycoprotein, GPIIb/IIIa. Denuded, but not native, platelets underwent slow spontaneous aggregation and rapid ADP-mediated GPIIb/IIIa-dependent aggregation according to spectrophotometric assay. Pre-treatment of denuded platelets with jacalin significantly reduced their ADP-mediated aggregation. Amyloid β (Aβ-42 monomer) was reported to bind triplet O-glycoproteins through their STPS but not to albumin or the antibodies. This peptide bound to the triplets on normal platelets and to surface membrane O-glycoproteins on denuded platelets, suggesting that the surface O-glycoproteins on the normal platelets were engaged and masked by the triplets. The ABG-specific sugar glucose denuded the platelets at concentrations typically reached in diabetic sera, since anti-Gal specific or ABG-specific sugar released the triplets of both the antibodies from the platelets. In conclusion, the present study offered rationale for the presence of anti-Gal/ABG-O-glycoprotein-albumin triplets on normal platelets, for the role of triplets in platelet physiology amidst circulating platelet-activating factors such as ADP, and for platelet vulnerability during diabetes.

In Vitro Antiplatelet Activity of Mulberroside C through the Up-Regulation of Cyclic Nucleotide Signaling Pathways and Down-Regulation of Phosphoproteins.

Physiological agonists trigger signaling cascades, called “inside-out signaling”, and activated platelets facilitate adhesion, shape change, granule release, and structural change of glycoprotein IIb/IIIa (αIIb/β3). Activated αIIb/β3 interacts with fibrinogen and begins second signaling cascades called “outside-in signaling”. These two signaling pathways can lead to hemostasis or thrombosis. Thrombosis can occur in arterial and venous blood vessels and is a major medical problem. Platelet-mediated thrombosis is a major cause of cardiovascular disease (CVD). Therefore, controlling platelet activity is important for platelet-mediated thrombosis and cardiovascular diseases. In this study, focus on Morus Alba Linn, a popular medicinal plant, to inhibit the function of platelets and found the containing component mulberroside C. We examine the effect of mulberroside C on the regulation of phosphoproteins, platelet-activating factors, and binding molecules. Agonist-induced human platelet aggregation is dose-dependently inhibited by mulberroside C without cytotoxicity, and it decreased Ca2+ mobilization and p-selectin expression through the upregulation of inositol 1, 4, 5-triphosphate receptor I (Ser1756), and downregulation of extracellular signal-regulated kinase (ERK). In addition, mulberroside C inhibited thromboxane A2 production, fibrinogen binding, and clot retraction. Our results show antiplatelet effects and antithrombus formation of mulberroside C in human platelets. Thus, we confirm that mulberroside C could be a potential phytochemical for the prevention of thrombosis-mediated CVDs.

Immune activation during Paenibacillus brain infection in African infants with frequent cytomegalovirus co-infection

SummaryInflammation during neonatal brain infections leads to significant secondary sequelae such as hydrocephalus, which often follows neonatal sepsis in the developing world. In 100 African hydrocephalic infants we identified the biological pathways that account for this response. The dominant bacterial pathogen was a Paenibacillus species, with frequent cytomegalovirus co-infection. A proteogenomic strategy was employed to confirm host immune response to Paenibacillus and to define the interplay within the host immune response network. Immune activation emphasized neuroinflammation, oxidative stress reaction, and extracellular matrix organization. The innate immune system response included neutrophil activity, signaling via IL-4, IL-12, IL-13, interferon, and Jak/STAT pathways. Platelet-activating factors and factors involved with microbe recognition such as Class I MHC antigen-presenting complex were also increased. Evidence suggests that dysregulated neuroinflammation propagates inflammatory hydrocephalus, and these pathways are potential targets for adjunctive treatments to reduce the hazards of neuroinflammation and risk of hydrocephalus following neonatal sepsis.

Dysregulated Lipid Metabolism and Its Role in α-Synucleinopathy in Parkinson's Disease.

Parkinson’s disease (PD) is the second most common neurodegenerative disease, the main pathological hallmark of which is the accumulation of α-synuclein (α-syn) and the formation of filamentous aggregates called Lewy bodies in the brainstem, limbic system, and cortical areas. Lipidomics is a newly emerging field which can provide fresh insights and new answers that will enhance our capacity for early diagnosis, tracking disease progression, predicting critical endpoints, and identifying risk in pre-symptomatic persons. In recent years, lipids have been implicated in many aspects of PD pathology. Biophysical and lipidomic studies have demonstrated that α-syn binds preferentially not only to specific lipid families but also to specific molecular species and that these lipid-protein complexes enhance its interaction with synaptic membranes, influence its oligomerization and aggregation, and interfere with the catalytic activity of cytoplasmic lipid enzymes and lysosomal lipases, thereby affecting lipid metabolism. The genetic link between aberrant lipid metabolism and PD is even more direct, with mutations in GBA and SMPD1 enhancing PD risk in humans and loss of GALC function increasing α-syn aggregation and accumulation in experimental murine models. Moreover, a number of lipidomic studies have reported PD-specific lipid alterations in both patient brains and plasma, including alterations in the lipid composition of lipid rafts in the frontal cortex. A further aspect of lipid dysregulation promoting PD pathogenesis is oxidative stress and inflammation, with proinflammatory lipid mediators such as platelet activating factors (PAFs) playing key roles in arbitrating the progressive neurodegeneration seen in PD linked to α-syn intracellular trafficking. Lastly, there are a number of genetic risk factors of PD which are involved in normal lipid metabolism and function. Genes such as PLA2G6 and SCARB2, which are involved in glycerophospholipid and sphingolipid metabolism either directly or indirectly are associated with risk of PD. This review seeks to describe these facets of metabolic lipid dysregulation as they relate to PD pathology and potential pathomechanisms involved in disease progression, while highlighting incongruous findings and gaps in knowledge that necessitate further research.

Systematic Understanding of Bioactive Lipids in Neuro-Immune Interactions: Lessons from an Animal Model of Multiple Sclerosis.

Bioactive lipids, or lipid mediators, are utilized for intercellular communications. They are rapidly produced in response to various stimuli and exported to extracellular spaces followed by binding to cell surface G protein-coupled receptors (GPCRs) or nuclear receptors. Many drugs targeting lipid signaling such as non-steroidal anti-inflammatory drugs (NSAIDs), prostaglandins, and antagonists for lipid GPCRs are in use. For example, the sphingolipid analog, fingolimod (also known as FTY720), was the first oral disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (MS), whose mechanisms of action (MOA) includes sequestration of pathogenic lymphocytes into secondary lymphoid organs, as well as astrocytic modulation, via down-regulation of the sphingosine 1-phosphate (S1P) receptor, S1P1, by in vivo-phosphorylated fingolimod. Though the cause of MS is still under debate, MS is considered to be an autoimmune demyelinating and neurodegenerative disease. This review summarizes the involvement of bioactive lipids (prostaglandins, leukotrienes, platelet-activating factors, lysophosphatidic acid, and S1P) in MS and the animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation, along with pharmacological inhibition, of lipid metabolic enzymes and lipid GPCRs revealed that each bioactive lipid has a unique role in regulating immune and neural functions, including helper T cell (TH1 and TH17) differentiation and proliferation, immune cell migration, astrocyte responses, endothelium function, and microglial phagocytosis. A systematic understanding of bioactive lipids in MS and EAE dredges up information about understudied lipid signaling pathways, which should be clarified in the near future to better understand MS pathology and to develop novel DMTs.

Analysis of platelet-activating factors in severe sepsis by flow cytometry and its correlation with clinical sepsis scoring system: A pilot study

BackgroundSepsis is a major global healthcare concern. Platelets and leucocytes play a key role in sepsis. Whole blood flow cytometry (FCM) is a powerful new technique for the assessment of leucocyte and platelet parameters and their functional state. In the present study, we have used FCM to examine platelet and leucocyte functions and parameters in sepsis patients. MethodsProspective, non-interventional cohorts of all adult patients with sepsis and history of intensive care unit stay for more than 24 h at mixed surgical- medical ICU were evaluated. The Simplified Acute Physiology Score-3 (SAPS 3) admission score was obtained, and whole blood FCM analysis of select platelets and leukocyte parameters were performed using a combination of monoclonal antibodies in a predefined panel. We also evaluated the correlation between these parameters and the severity of the illness, based on SAPS 3 admission score. ResultsTotal leucocyte count (TLC) was statistically and significantly different between all the study samples, but platelet count was not. SAPS 3 acted as the best discriminant between the study groups. With a cut-off score of 55.5, SAPS 3 score predicted hospital mortality with a sensitivity of 82.8% and a specificity of 83.9%, with an area under receiver operating curves (AUROC) of 0.888 (95% CI = 0.807–0.969, p < 0.000). Parameters for CD62P, platelet-leucocyte aggregates (PLAs) and CD11b showed statistically significant differences between the patients and healthy volunteers. CD62P expression was positively correlated to PLA variables in severe sepsis patients. The median fluorescence intensity was found to be more informative than mean fluorescence intensity. New “62P adhesion index (62P AI)” and “PLA adhesion index” are proposed and is likely to be more informative. ConclusionSAPS 3 score was the most robust of the parameters evaluated. Our study suggest the idea that the incorporation of platelet and leucocyte activation parameters, rather than mere static counts, will add the existing prognostic model though we could not conclusively prove the same in this study.

Metabolomics analyses identify platelet activating factors and heme breakdown products as Lassa fever biomarkers

Lassa fever afflicts tens of thousands of people in West Africa annually. The rapid progression of patients from febrile illness to fulminant syndrome and death provides incentive for development of clinical prognostic markers that can guide case management. The small molecule profile of serum from febrile patients triaged to the Viral Hemorrhagic Fever Ward at Kenema Government Hospital in Sierra Leone was assessed using untargeted Ultra High Performance Liquid Chromatography Mass Spectrometry. Physiological dysregulation resulting from Lassa virus (LASV) infection occurs at the small molecule level. Effects of LASV infection on pathways mediating blood coagulation, and lipid, amino acid, nucleic acid metabolism are manifest in changes in the levels of numerous metabolites in the circulation. Several compounds, including platelet activating factor (PAF), PAF-like molecules and products of heme breakdown emerged as candidates that may prove useful in diagnostic assays to inform better care of Lassa fever patients.

Pharmacokinetics-pharmacodynamics correlation of protocatechuic aldehyde and hydroxysafflor yellow A alone or their combination use in rats with hyperlipidemia

To study the pharmacokinetics-pharmacodynamics correlation of protocatechuic aldehyde and hydroxysafflor yellow A alone or their combination use in rats with hyperlipidemia. In this study, the hyperlipidemia model was established by intravenous injection of protocatechuic aldehyde (20 mg•kg⁻¹) and hydroxysafflor yellow A (12 mg•kg⁻¹). The HPLC-DAD method was applied to determine the plasma concentration of protocatechuic aldehyde and hydroxysafflor yellow A at different time points and draw the drug effect-time curve. Meanwhile, the platelet activating factors (PAF) and plasma a granule membrane protein (GMP-140) contents were determined at different time points to draw the time-effect curve. Then DAS 3.2.6 software was used to process the data, analyze their correlation, and compare the difference of pharmacokinetics and pharmacodynamics of protocatechuic aldehyde and hydroxysafflor yellow A in hyperlipidemia rats after alone or their combined application, so as to evaluate the effect of protocatechuic aldehyde and hydroxysafflor yellow A on hyperlipidemia rats. According to the result, the pharmacokinetics and pharmacodynamics process of protocatechuic aldehyde and hydroxysafflor yellow A in hyperlipidemia rats after alone or their combination were consistent to the three-compartment model. In model group, the plasma PAF and GMP-140 were significantly increased, and the PAF and GMP-140 in vivo contents were decreased in a certain time after treatment. The effects of protocatechuic aldehyde and hydroxysafflor yellow A against the pharmacodynamic action may be related with their level in vivo, and their plasma concentration was positively related to the PAF and GMP-140 contents. The pharmacodynamic indexes were better after the combined use of protocatechuic aldehyde and hydroxysafflor yellow A, with certain influence on each other in hyperlipidemia rats; at the same time, it also reflected the rationality of protocatechuic aldehyde and hydroxysafflor yellow A combined application.

A Chinese perspective on factors and molecular mechanisms that influence the curative effects of platelet transfusion

Platelet transfusion, as the primary treatment for severely low platelet count (thrombocytopenia) or disorders of platelet function, is used extensively in patients with blood system diseases or active hemorrhaging. In recent decades platelet related researches in China have steadily increased. In the clinical application of platelet transfusion, there are large differences between the treatment’s effects on different patients. Immune or nonimmune factors, such as platelet-specific antibodies, platelet gene analysis and matches, and auxiliary treatment, may affect the curative effect, and even result in ineffective platelet transfusion. Platelets used in clinical therapy include platelets made from whole blood and hemapheresis platelets, and the latter is the main application type used in China. Both preparation and preservation methods can affect the quality of platelets and influence the therapeutic effect. Researches on the molecular basis or the curative effect of platelet transfusion are increasing, such as the relationship between platelet-activating factors, tissue factors, thrombopoietin, membrane glycoprotein and platelet activation, and their influence on the curative effect of platelet transfusion, the inhibition of antiplatelet therapy in platelet activation, and platelet signal transduction pathways and their significance in the curative effect of platelet transfusion. This article aims to review the research progress on the curative effect of platelet transfusion and its molecular mechanisms.