Platelet-activating Factor Research Articles

Mechanisms for hypothermia during anaphylactic hypotension in awake rats.

Hypothermia develops during systemic anaphylaxis in rodents. The aim of this study was to elucidate the mechanism for the hypothermia by assessing the roles of locomotor activity, tail heat dissipation, heat production in the brown adipose tissue (BAT) activity, and chemical mediators during ovalbumin-induced anaphylactic hypotension in awake rats. We measured the core body temperature (Tcore) and mean blood pressure (MBP), along with the surface temperature of the interscapular region (TiScap), an indirect measure of BAT activity, and the tail (Ttail). During anaphylaxis, MBP decreased to the nadir of 53 ± 2 mmHg at 8 min with recovery toward baseline. Tcore began to decrease at 7.5 min with the nadir of 36.1 ± 0.2°C at 30 min from the baseline of 38.0 ± 0.1°C. TiScap also significantly decreased, but its onset was preceded by that of Tcore. Ttail decreased after antigen, suggesting the absence of increased heat dissipation from the tail. The physical activity, as evaluated by moved distances, did not decrease until 20 min after antigen, followed by a progressive decrease. Reduced movement using a restraint maneuver not only reduced Tcore in nonsensitized rats but also augmented the anaphylactic hypothermia in the early phase (1.5-18 min) in sensitized rats. Combined antagonism against platelet-activating factor (PAF) and histamine H1 receptors abolished antigen-induced hypotension but only attenuated hypothermia. In conclusion, decreased locomotor activity, but not tail heat dissipation or decreased BAT activity, may at least in part contribute to this hypothermia. PAF and histamine are involved mainly in hypotension but only partly in hypothermia during rat anaphylaxis.NEW & NOTEWORTHY Anaphylactic shock is a life-threatening systemic hypotension. Hypothermia is observed during systemic anaphylaxis of rats. We determined the mechanism as follows: decreased locomotor activity, but not tail heat dissipation or decreased BAT activity, may at least in part contribute to this hypothermia. PAF and histamine are involved mainly in hypotension, but only partly in hypothermia during rat anaphylaxis.

PAD4-Induced NETosis Via Cathepsin G-Mediated Platelet-Neutrophil Interaction in ChAdOx1 Vaccine-Induced Thrombosis.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare syndrome characterized by platelet anti-PF4 (platelet-activating antiplatelet factor 4)-related thrombosis. Platelet-neutrophil interaction has been suggested to play a role, but the underlying mechanism has not been fully elucidated. The study included 10 patients with VITT after ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccine administration, 10 patients with ischemic stroke (IS), 10 patients with acute deep vein thrombosis, and 10 control subjects in whom blood levels of neutrophil extracellular traps (NETs), soluble TF (tissue factor), and thrombin generation were examined. Furthermore, we performed in vitro studies comparing the effect of serum from patients and controls on NETs formation. Finally, immunohistochemistry was performed in cerebral thrombi retrieved from a patients with VITT and 3 patients with IS. Compared with patients with IS, patients with deep vein thrombosis, controls, and patients with VITT had significantly higher blood values of CitH3 (citrullinated histone H3), soluble TF, D-dimer, and prothrombin fragment 1+2 (P<0.0001). Blood CitH3 significantly correlated with blood soluble TF (Spearman rank correlation coefficient=0.7295; P=0.0206) and prothrombin fragment 1+2 (Spearman rank correlation coefficient=0.6809; P<0.0350) in patients with VITT. Platelet-neutrophil mixture added with VITT plasma resulted in higher NETs formation, soluble TF and thrombin generation, and platelet-dependent thrombus growth under laminar flow compared with IS and deep vein thrombosis plasma; these effects were blunted by PAD4 (protein arginine deiminase 4) and cathepsin G inhibitors, anti-FcγRIIa, and high doses of heparin. Immunohistochemistry analysis showed a more marked expression of PAD4 along with more diffuse neutrophil infiltration and NETs formation as well as TF and cathepsin expression in VITT thrombus compared with thrombi from patients with IS. Patients with VITT display enhanced thrombogenesis by PAD4-mediated NETs formation via cathepsin G-mediated platelet/neutrophil interaction.

Treatment with PCSK9 inhibitors in patients with familial hypercholesterolemia lowers plasma levels of platelet activating factor and its precursors: A combined metabolomic and lipidomic approach

Treatment with PCSK9 inhibitors in patients with familial hypercholesterolemia lowers plasma levels of platelet activating factor and its precursors: A combined metabolomic and lipidomic approach

Effects of Lidocaine-Derived Organic Compounds on Eosinophil Activation and Survival.

Lidocaine, a local anesthetic, is known to possess anti-inflammatory properties. However, its clinical use is limited by inconveniences, such as its local synesthetic effects. This study evaluated lidocaine analogs designed and synthesized to overcome the disadvantages of lidocaine, having anti-inflammatory properties. Interleukin 5 (IL-5)-induced eosinophil activation and survival were evaluated using 36 lidocaine analogs with modified lidocaine structure on the aromatic or the acyl moiety or both. Eosinophil survival was evaluated using a CellTiter 96® aqueous cell proliferation assay kit. Superoxide production was determined using the superoxide dismutase-inhibitable reduction of cytochrome C method. Eosinophil cationic protein (ECP), IL-8, and transcription factor expression were determined using enzyme-linked immunosorbent assay. The platelet-activating factor (PAF)-induced migration assay was performed using a Transwell insert system. Compounds EI137 and EI341 inhibited IL-5-induced eosinophil survival and superoxide and ECP production in a concentration-dependent manner. These compounds also significantly reduced IL-8 production. Although compounds EI137 and EI341 significantly reduced phosphorylated ERK 1/2 expression, they did not influence other total and phosphorylated transcription factors. Moreover, 1000 µM of compound EI341 only inhibited PAF-induced migration of eosinophils. Lidocaine analogs EI137 and EI341 inhibited IL-5-mediated activation and survival of eosinophils. These compounds could be new therapeutic agents to treat eosinophilic inflammatory diseases.

Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives.

Resveratrol, a naturally occurring stilbene, exhibits numerous beneficial health effects. Various studies have demonstrated its diverse biological actions, including anti-oxidant, anti-inflammatory, and anti-platelet properties, thereby supporting its potential for cardio protection, neuroprotection, and anti-cancer activity. However, a significant limitation of resveratrol is its weak bioavailability. To overcome this challenge, multiple research groups have investigated the synthesis of new resveratrol derivatives to enhance bioavailability and pharmacological activities. Nevertheless, there are limited data on the effects of resveratrol derivatives on platelet function. Therefore, the objective of this study was to synthesize resveratrol methoxy derivatives and evaluate their anti-platelet and anti-proliferative activity. Platelet-rich plasma (PRP) obtained from healthy volunteers was utilized to assess the derivatives' ability to inhibit platelet aggregation induced by platelet activating factor (PAF), adenosine diphosphate (ADP), and thrombin receptor activating peptide (TRAP). Additionally, the derivatives' anti-tumor activity was evaluated against the proliferation of PC-3 and HCT116 cells. The results revealed that some methoxy derivatives of resveratrol exhibited comparable or even superior anti-platelet activity compared to the original compound. The most potent derivative was the 4'-methoxy derivative, which demonstrated approximately 2.5 orders of magnitude higher anti-platelet activity against TRAP-induced platelet aggregation, indicating its potential as an anti-platelet agent. Concerning in silico studies, the 4'-methyl group of 4'-methoxy derivative is oriented similarly to the fluorophenyl-pyridyl group of Vorapaxar, buried in a hydrophobic cavity. In terms of their anti-tumor activity, 3-MRESV exhibited the highest potency in PC-3 cells, while 3,4'-DMRESV and TMRESV showed the greatest efficacy in HCT116 cells. In conclusion, methoxy derivatives of resveratrol possess similar or improved anti-platelet and anti-cancer effects, thereby holding potential as bioactive compounds in various pathological conditions.

Platelet-activating factor antagonist-based intensive antiplatelet strategy in acute ischemic stroke: A propensity score matched with network pharmacology analysis.

Diterpene ginkgolides meglumine injection (DGMI) is a platelet-activating factor receptor (PAFR) antagonist that can be used to treat acute ischemic stroke (AIS). This study evaluated the efficacy and safety of an intensive antiplatelet strategy based on PAFR antagonists and explored the underlying mechanisms of PAFR antagonists in AIS treatment. This is a retrospective study applying propensity score methods to match AIS patients treated with DGMI to nontreated patients. The primary outcome was functional independence (modified Rankin Scale [mRS] 0-2) at 90 days. The safety outcome was bleeding risk. We used McNemar test to compare the efficacy outcome. Subsequently, the network pharmacology analysis was performed. 161 AIS patients treated with DGMI in the study were matched with 161 untreated patients. Compared with untreated patients, DGMI-treated patients had a significantly higher rate of mRS ranking 0-2 at 90 days (82.0% vs. 75.8%, p < 0.001), without increased risk of bleeding. The gene enrichment analysis showed that the overlap genes of DGMI targeted and AIS-related enriched in thrombosis and inflammatory-related signaling pathways. An intensive antiplatelet strategy of DGMI plus traditional antiplatelet agents is effective in treating AIS and may work by mediating post-stroke inflammation and thrombosis.

Anti-heat shock protein 10 IgG in chronic spontaneous urticaria: Relation with miRNA-101-5p and platelet-activating factor.

Anti-heat shock protein (HSP) autoantibodies are detected in autoimmune diseases. We sought to ascertain whether anti-HSP10 IgG is present in patients with CSU and to elucidate the role of HSP10 in CSU pathogenesis. Using a human proteome microarray, six potential autoantibodies had higher expression in 10 CSU samples compared with 10 normal controls (NCs). Among them, HSP10 IgG autoantibody was quantified by immune dot-blot assay in sera from 86 CSU patients and 44 NCs. The serum levels of HSP10 and microRNA-101-5p were measured in CSU patients and NCs. The effects of HSP10 and miR-101-5p on mast cell degranulation in response to IgE, compound 48/80, and platelet-activating factor (PAF) were investigated. CSU patients had higher IgG positivity to HSP10 (40.7% vs. 11.4%, p = .001), lower serum HSP10 levels (5.8 ± 3.6 vs. 12.2 ± 6.6 pg/mL, p < .001) than in NCs, and their urticaria severity was associated with anti-HSP10 IgG positivity, while HSP10 levels were related to urticaria control status. MiR-101-5p was increased in CSU patients. PAF enhanced IL4 production in PBMCs from CSU patients. IL-4 upregulated miR-101-5p and reduced HSP10 expression in keratinocytes. Transfection of miR-101-5p reduced HSP10 expression in keratinocytes. MiR-101-5p promoted PAF-induced mast cell degranulation, while HSP10 specifically prevented it. A new autoantibody, anti-HSP10 IgG was detected in CSU patients, which showed a significant correlation with UAS7 scores. A decreased serum HSP10 level was associated with upregulation of miR-101-5p due to increased IL-4 and PAF in CSU patients. Modulation of miR-101-5p and HSP10 may be a novel therapeutic approach for CSU.

Biochemical and Signaling Functions of Plasmalogens in the Norm and in Various Diseases

Plasmalogens (PL) are alkenyl ether glycerophospholipids that perform many physiologically important functions in the body and have a variety of properties. The role of PLs as endogenous antioxidants is well studied, as well as PLs that determine the physicochemical properties of biomembranes, deposit polyunsaturated fatty acids, participate in cholesterol biosynthesis, the process of ferroptosis and adaptation of cells to hypoxia, are sources for the synthesis of platelet activating factor and act as its antagonists. At the same time, LPs are involved in the pathogenesis of neurodegenerative, inflammatory, oncological diseases and a number of other pathologies. These conditions are united by the development of chronic inflammation and oxidative stress, accompanied by a change in the activity of synthesis and the content of PL in cells. Despite the fact that PL replacement therapy inhibits inflammation, the molecular mechanisms of the association of PL with inflammation have not been fully elucidated. The purpose of this review is to summarize the latest literature data on the structure, biosynthesis, and functions of PL, their relationship with signaling cascades involved in the pathogenesis of chronic inflammatory and neuroinflammatory diseases, as well as to show current achievements and future prospects for the use of PL in the treatment of certain diseases.

Pharmacological Studies on the Ca2+ Influx Pathways in Platelet-Activating Factor (PAF)-Induced Mouse Urinary Bladder Smooth Muscle Contraction.

Platelet-activating factor (PAF) not only acts as a mediator of platelet aggregation, inflammation, and allergy responses but also as a constrictor of various smooth muscle (SM) tissues, including gastrointestinal, tracheal/bronchial, and pregnancy uterine SMs. Previously, we reported that PAF induces basal tension increase (BTI) and oscillatory contraction (OC) in mouse urinary bladder SM (UBSM). In this study, we examined the Ca2+ influx pathways involved in PAF-induced BTI and OC in the mouse UBSM. PAF (10-6 M) induced BTI and OC in mouse UBSM. However, the PAF-induced BTI and OC were completely suppressed by extracellular Ca2+ removal. PAF-induced BTI and OC frequencies were markedly suppressed by voltage-dependent Ca2+ channel (VDCC) inhibitors (verapamil (10-5 M), diltiazem (10-5 M), and nifedipine (10-7 M)). However, these VDCC inhibitors had a minor effect on the PAF-induced OC amplitude. The PAF-induced OC amplitude in the presence of verapamil (10-5 M) was strongly suppressed by SKF-96365 (3 × 10-5 M), an inhibitor of receptor-operated Ca2+ channel (ROCC) and store-operated Ca2+ channel (SOCC), but not by LOE-908 (3 × 10-5 M) (an inhibitor of ROCC). Overall, PAF-induced BTI and OC in mouse UBSM depend on Ca2+ influx and the main Ca2+ influx pathways in PAF-induced BTI and OC may be VDCC and SOCC. Of note, VDCC may be involved in PAF-induced BTI and OC frequency, and SOCC might be involved in PAF-induced OC amplitude.

Venous Thromboembolism Risk Assessment among Beta-thalassemia Patients

BACKGROUND: Thromboembolic (TE) disorders are among the most common complications of beta-thalassemia. We designed this cross-sectional study to investigate the state of hypercoagulability and platelet activation in patients with beta-thalassemia. PATIENTS AND METHODS: Seventy-five patients diagnosed with beta-thalassemia by hemoglobin electrophoresis were divided into three groups of 25 patients each: Group I (thalassemia trait), Group II (thalassemia intermedia [TI]), and Group III (thalassemia major). In addition, 50 healthy individuals were included as controls. Both patients and control groups were subjected to clinical and laboratory assessment, which included measurement of protein C, anti-thrombin III, D-dimer, CD41, CD42, CD61, and CD62P, and detection of beta-chain mutations. RESULTS: Levels of the platelet activation marker CD62P were significantly higher in beta-thalassemia patients (26.28 ± 18.01%) than in controls (4.78 ± 2.27%) (P &lt; 0.001). The D-dimer level was significantly higher in beta-thalassemia patients (348.41 ± 571.01 ng/mL) than in controls (71.6 ± 39.61 ng/mL) (P &lt; 0.001). Protein-C and AT-III levels were significantly lower in beta-thalassemia patients (71.45 ± 13.26%, 78.38 ± 15.32%) in comparison with controls (94.9 ± 13.03%, 96.52 ± 11.01%) (P &lt; 0.001 and P &lt; 0.001, respectively). TE disorders were found in 7/25 (9%) beta-thalassemia patients, especially in older and postsplenectomy patients. TE was most commonly found in beta-TI. Beta-chain mutations were found in all patients with TE disorders, especially compound heterozygous intervening sequence (IVS) (IVS1.6 [T &gt; C]/IVS1.110 [G &gt; A]). CONCLUSION: Postsplenectomy teenagers and adults with beta-thalassemia with lower levels of natural anticoagulant in the blood, an increased level of D-dimer, and platelet activator factor had a significantly higher risk for TE than those with childhood beta-thalassemia and the control group. In comparison with other beta-thalassemia patients, TI with beta-chain mutations is more likely to develop TE.

Extrinsic and Intrinsic Modulators of Anaphylaxis.

The severity of anaphylaxis is determined by many factors. The allergenic source as well as the age of the affected individual and the route of allergen exposure encompass the major contributors of the clinical outcome. Moreover, the severity can be modulated further by intrinsic and extrinsic factors. Among these, the genetic predisposition, certain comorbidities such as uncontrolled asthma, and hormonal fluctuations have been proposed as intrinsic and antihypertensive medications or physical activity as extrinsic factors. Recent advances have highlighted immunologic pathways that may exacerbate the response to allergens through receptors on mast cells, basophils, platelets, and other granulocytes. Atopy, platelet-activating factor acetylhydrolase deficiency, hereditary alpha tryptasemia, and clonal mast cell disorders are examples associated with genetic alterations that may predispose to severe anaphylaxis. Identifying risk factors that lower the threshold of reactivity or increase the severity of multisystem reactions is important in the management of this patient population.

Animal Models of IgE Anaphylaxis.

Allergies and atopy have emerged as significant public health concerns, with a progressively increasing incidence over the last two decades. Anaphylaxis is the most severe form of allergic reactions, characterized by a rapid onset and potentially fatal outcome, even in healthy individuals. Due to the unpredictable nature and potential lethality of anaphylaxis and the wide range of allergens involved, clinical studies in human patients have proven to be challenging. Diagnosis is further complicated by the lack of reliable laboratory biomarkers to confirm clinical suspicion. Thus, animal models have been developed to replicate human anaphylaxis and explore its pathophysiology. Whereas results obtained from animal models may not always be directly translatable to humans, they serve as a foundation for understanding the underlying mechanisms. Animal models are an essential tool for investigating new biomarkers that could be incorporated into the allergy workup for patients, as well as for the development of novel treatments. Two primary pathways have been described in animals and humans: classic, predominantly involving IgE and histamine, and alternative, reliant on IgG and the platelet-activating factor. This review will focus essentially on the former and aims to describe the most utilized IgE-mediated anaphylaxis animal models, including their respective advantages and limitations.

The effect of ozone gel as adjunct treatment in patients of periodontitis according to bleeding on probing and platelet-activating factor (A split-mouth randomized controlled clinical trial)

Materials and methods: total sample composed of 58 periodontal pockets was divided into two groups. The control group had 28 periodontal pockets treated with scaling and root planning only, while the test group had 30 periodontal pockets treated with scaling and root planning and ozone gel. Two applications of the gel were applied at baseline and one month after the treatment .platelet activating factor (biomarker) and clinical parameters of bleeding on probing are measured at baseline, after one month, and after three months. In the second visit of periodontal therapy (after one day), GCF samples were obtained from patients by gently inserting periocol paper into the selected depth of the pocket when resistance was encountered. The periocol paper was then left in position for 30 seconds before being removed and weighed on a chemical balance. Each paper strip was placed in a tube keeping o.3ml of buffer phosphate saline, then transferred and stored at -40C. Calculated the difference between the weight of periocol paper before and after exudate absorption of gingival crevicular fluid. After sample storage for five minutes, the samples were centrifuged at 13,000 rpm.&#x0D; Results: Test sites showed a greater reduction in bleeding on probing and there was a significant difference in the first month only when compared to control sites (Fisher exact=0.010) but no significant difference at three months. The platelet-activating factor was reduced significantly by ozone gel in the first month with only a p-value (0.000) but no significance at one and three months.&#x0D; Conclusion: In comparison to SRP alone, treatment with ozone gel as an adjuvant therapy yields no statistically significant improvement after three months.

Current trends in epigenetic, cellular and molecular pathways in management of rheumatoid arthritis.

Rheumatoid arthritis is a systemic chronic polyarticular autoimmune disorder of joints and joint membrane mainly affecting feet and hands. The pathological manifestation of the disease includes infiltration of immune cells, hyperplasia of the lining of synovium, formation of pannus and bone and cartilage destruction. If left untreated, the appearance of small focal necrosis, adhesion of granulation, and formation of fibrous tissue on the surface of articular cartilage is noted. The disease primarily affects nearly 1% of the population globally, women being more affected than men with a ratio 2:1 and can initiate regardless of any age. The synovial fibroblast in rheumatoid arthritis individuals exhibits an aggressive phenotype which upregulates the manifestation of protooncogenes, adhesive compounds, inflammatory cytokines and matrix-deteriorating enzymes. Apart from the inflammatory effects of cytokines, chemokines are also noted to induce swelling and pain in arthritic individuals by residing in synovial membrane and forming pannus. The current treatment of rheumatoid arthritis includes treatment with non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, treatment with biologics such as inhibitors of TNF-α, interleukins, platelet activating factor, etc. which provides significant relief from symptoms and aids in management of the disease. The current review highlights the pathogenesis involved in the onset of rheumatoid arthritis and also covers epigenetic, cellular and molecular parameters associated with it to aid better and advanced therapeutic approaches for management of the debilitating disease.

Platelet-activating factor as an endogenous cofactor of food anaphylaxis.

Anaphylaxis is a severe, acute, life-threatening generalized or systemic hypersensitivity reaction. The incidence of anaphylaxis is increasing worldwide, with medications and food contributing to most cases. Physical exercise, acute infections, drugs, alcohol, and menstruation are the external cofactors associated with more severe systemic reaction. The aim of this review is to show that platelet-activating factor contributes to the development of severe anaphylactic reaction, and even to anaphylactic shock.

Antiplatelet, cytotoxic activities and characterization of green-synthesized zinc oxide nanoparticles using aqueous extract of Nephrolepis exaltata.

The goal of the current study was to synthesize zinc oxide nanoparticles (ZnO-NPs) using ZnCl2.2H2O salt precursor and an aqueous extract of Nephrolepis exaltata (N. exaltata), which act as a capping and reducing agent. N. exaltata plant extract-mediated ZnO-NPs were further characterized by various techniques, such as X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transforms infrared spectroscopy (FT-IR), UV-visible (UV-Vis), and energy-dispersive X-ray (EDX) analysis. The nanoscale crystalline phase of ZnO-NPs was analyzed by the XRD patterns. The FT-IR analysis revealed different functional groups of biomolecules involved in the reduction and stabilization of the ZnO-NPs. The light absorption and optical properties of ZnO-NPs were examined by UV-Vis spectroscopy at a wavelength of 380 nm. The spherical shape morphology of ZnO-NPs with mean particle size ranges between 60 and 80 nm was confirmed by SEM images. While the EDX analysis was used to identify the elemental composition of ZnO-NPs. Furthermore, the synthesized ZnO-NPs demonstrate potential antiplatelet activity by inhibiting the platelet aggregation induced by platelet activation factor (PAF) and arachidonic acid (AA). The results showed that synthesized ZnO-NPs were more effective in inhibiting platelet aggregation induced by AA with IC50 (56% and 10 μg/mL) and PAF (63% and 10 μg/mL), respectively. However, the biocompatibility of ZnO-NPs was assessed in human lung cancer cell line (A549) under in vitro conditions. The cytotoxicity of synthesized nanoparticles revealed that cell viability decreased and the IC50 was found to be 46.7% at a concentration of 75 μg/mL. The present work concluded the green synthesis of ZnO-NPs that was achieved by N. exaltata plant extract and showed good antiplatelet and cytotoxic activity, which demonstrates the lack of harmful effects making them more effective for use in pharmaceutical and medical fields to treat thrombotic disorders.

Vaccine-induced immune thrombotic thrombocytopenia: what do we know hitherto?

Vaccine-induced immune thrombotic thrombocytopenia (VITT), also known as thrombosis with thrombocytopenia syndrome, is a catastrophic and life-threatening reaction to coronavirus disease 2019 (COVID-19) vaccines, which occurs disproportionately in response to vaccination with non-replicating adenovirus vector (AV) vaccines. The mechanism of VITT is not well defined and it has not been resolved why cases of VITT are predominated by vaccination with AV vaccines. However, virtually all VITT patients have positive platelet-activating anti-platelet factor 4 (PF4) antibody titers. Subsequently, platelets are activated and depleted in an Fcγ-receptor IIa (FcγRIIa or CD32a)-dependent manner, but it is not clear why or how the anti-PF4 response is mounted. This review describes the pathogenesis of VITT and provides insight into possible mechanisms that prompt the formation of a PF4/polyanion complex, which drives VITT pathology, as an amalgam of current experimental data or hypotheses.

Ether lipids and a peroxisomal riddle in sperm.

Sperm are terminally differentiated cells that lack most of the membranous organelles, resulting in a high abundance of ether glycerolipids found across different species. Ether lipids include plasmalogens, platelet activating factor, GPI-anchors and seminolipid. These lipids play important roles in sperm function and performance, and thus are of special interest as potential fertility markers and therapeutic targets. In the present article, we first review the existing knowledge on the relevance of the different types of ether lipids for sperm production, maturation and function. To further understand ether-lipid metabolism in sperm, we then query available proteomic data from highly purified sperm, and produce a map of metabolic steps retained in these cells. Our analysis pinpoints the presence of a truncated ether lipid biosynthetic pathway that would be competent for the production of precursors through the initial peroxisomal core steps, but devoid of subsequent microsomal enzymes responsible for the final synthesis of all complex ether-lipids. Despite the widely accepted notion that sperm lack peroxisomes, the thorough analysis of published data conducted herein identifies nearly 70% of all known peroxisomal resident proteins as part of the sperm proteome. In view of this, we highlight open questions related to lipid metabolism and possible peroxisomal functions in sperm. We propose a repurposed role for the truncated peroxisomal ether-lipid pathway in detoxification of products from oxidative stress, which is known to critically influence sperm function. The likely presence of a peroxisomal-derived remnant compartment that could act as a sink for toxic fatty alcohols and fatty aldehydes generated by mitochondrial activity is discussed. With this perspective, our review provides a comprehensive metabolic map associated with ether-lipids and peroxisomal-related functions in sperm and offers new insights into potentially relevant antioxidant mechanisms that warrant further research.

Investigation of anti-PF4 versus anti-PF4/heparin reactivity using fluid-phase enzyme immunoassay for 4 anti-PF4 disorders: classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, vaccine-induced immune thrombotic thrombocytopenia, and spontaneous HIT

BackgroundFour platelet-activating anti-platelet factor 4 (PF4) disorders have been recognized: classic heparin-induced thrombocytopenia (cHIT), autoimmune heparin-induced thrombocytopenia (aHIT), spontaneous heparin-induced thrombocytopenia (SpHIT), and vaccine-induced immune thrombotic thrombocytopenia (VITT). All test immunoglobulin G (IgG) positive using solid-phase enzyme immunoassay (solid-EIA) against PF4/heparin (PF4/H) and/or PF4 alone. Fluid-phase EIA (fluid-EIA) should better discriminate between anti-PF4 and anti-PF4/H antibodies since conformationally altered PF4 bound to solid phase is avoided. ObjectivesTo compare anti-PF4 vs anti-PF4/H antibody profiles for anti-PF4 disorders using solid- and fluid-EIA. MethodsWe developed a novel fluid-EIA to measure anti-PF4 vs anti-PF4/H antibodies. ResultsUsing fluid-EIA, 27 of 27 (100%) cHIT sera tested IgG positive with PF4/H, but only 4 of 27 (14.8%) tested positive against PF4 alone; all 27 exhibited heparin-enhanced binding. In contrast, 17 of 17 (100%) VITT sera tested IgG positive against PF4 alone, with markedly reduced binding against PF4/H; this distinct VITT antibody profile was not evident using solid-EIA. All 15 aHIT sera and all 11 SpHIT sera tested IgG positive against PF4 alone, with variable reactivity in PF4/H-EIA (heparin-enhanced binding in 14 of 15 and 10 of 11 aHIT and SpHIT sera, respectively). Remarkably, 1 SpHIT patient with a VITT-mimicking fluid-EIA profile (PF4 >> PF4/H) also clinically resembled patients with VITT (postviral cerebral vein/sinus thrombosis), with anti-PF4 reactivity correlating inversely with platelet count recovery; moreover, the single aHIT patient with a VITT-mimicking fluid-EIA profile also developed postviral cerebral vein/sinus thrombosis. ConclusioncHIT and VITT sera showed opposite fluid-EIA profiles (cHIT: PF4/H >> PF4, with most testing negative against PF4 alone; VITT: PF4 >> PF4/H, with most testing negative against PF4/H). In contrast, all aHIT and SpHIT sera reacted against PF4 alone but with variable (usually enhanced) reactivity against PF4/H. VITT-mimicking clinical/serologic profiles occurred in only a minority of patients with SpHIT and aHIT.

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.