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Background: While dengue NS1 antigen has been shown to be associated with disease pathogenesis in some studies, it has not been linked in other studies, with the reasons remaining unclear. NS1 antigen levels in acute dengue are often associated with increased disease severity, but there has been a wide variation in results based on past dengue infection and infecting dengue virus (DENV) serotype. As NS1 engages with many host lipids, we hypothesize that the type of NS1-lipid interactions alters its pathogenicity. Methods: Primary human monocyte derived macrophages (MDMs) were co-cultured with NS1 alone or with HDL, LDL, LPS and/or platelet activating factor (PAF) from individuals with a history of past dengue fever (DF = 8) or dengue haemorrhagic fever (DHF = 8). IL-1β levels were measured in culture supernatants, and gene expression analysis carried out in MDMs. Monocyte subpopulations were assessed by flow cytometry. Hierarchical cluster analysis with Euclidean distance calculations were used to differentiate clusters. Differentially expressed variables were extracted and a classifier model was developed to differentiate between past DF and DHF. Results: Significantly higher levels of IL-1β were seen in culture supernatants when NS1 was co-cultured with LDL (p = 0.01, median = 45.69 pg/ml), but lower levels when NS1 was co-cultured with HDL (p = 0.05, median = 4.617 pg/ml). MDMs of those with past DHF produced higher levels of IL-1β when NS1 was co-cultured with PAF (p = 0.02). MDMs of individuals with past DHF, were significantly more likely to down-regulate RPLP2 gene expression when macrophages were co-cultured with either PAF alone, or NS1 combined with PAF, or NS1 combined with LDL. When NS1 was co-cultured with PAF, HDL or LDL two clusters were detected based on IL10 expression, but these did not differentiate those with past DF or DHF. Conclusions: As RPLP2 is important in DENV replication, regulating cellular stress responses and immune responses and IL-10 is associated with severe disease, it would be important to further explore how differential expression of RPLP2 and IL-10 could lead to disease pathogenesis based on NS1 and lipid interactions. [ABSTRACT FROM AUTHOR]

Inflammation and thrombosis are implicated in several chronic disorders. Recent studies have outlined the way in which several compounds can offer protection against inflammation. Within this comprehensive review the so-far reported anti-inflammatory health-promoting effects of several metal-based complexes, both in vitro and in vivo, are thoroughly presented. These metal-based compounds usually interfere with various biochemical processes associated with the inflammatory response and thrombus formation and become capable of inhibiting these biochemical pathways with proposed health benefits. Emphasis is given to the multifaceted actions of metal-based complexes that have exhibited potent anti-inflammatory and antithrombotic activities against the inflammatory mediator, platelet-activating factor (PAF), and its thrombo-inflammatory signaling, as well as on their anti-platelet and antitumor health promoting properties. Furthermore, the enhancement of the anti-inflammatory potency of well-established bioactive compounds by their incorporation as ligands in several metal-based complexes is discussed. Metal-based complexes bearing natural anti-inflammatory bioactives are also outlined. Characteristic examples of both free and metal-based porphyrins are explored. These compounds are recognized to have anti-inflammatory and antithrombotic assets, in addition to other pleiotropic advantages including antibacterial or anticancer actions. Additionally, applications of metal complexes in various models of inflammatory and thrombotic complications are demonstrated. The combined results of this study show that further research is required towards the preparation of several metal-based complexes with improved pharmacological profiles. Finally, restrictions on the application of these metal-based compounds are also covered, along with their prospects for the future and the need for additional study in order to improve their efficacy and safety. [ABSTRACT FROM AUTHOR]

The presence of neutrophil extracellular traps (NETs) in thrombotic diseases has been extensively studied. The exact mechanism of NET formation in deep venous thrombosis (DVT) has not been largely studied. This study is aimed to explore the role of NETs and their interaction with platelet factor 4 (PF4) in DVT. In plasma samples from 51 healthy volunteers and 52 DVT patients, NET markers and PF4 were measured using enzyme-linked immunosorbent assays (ELISA). NET generation in blood samples from healthy subjects and DVT patients was analyzed by confocal microscopy and flow cytometry. The plasma levels of NETs were significantly elevated in DVT patients, and neutrophils from patients showed a stronger ability to generate NETs after treatment. PF4 was upregulated in plasma samples from DVT patients and mediated NET formation. NETs enhanced procoagulant (PCA) via tissue factor and activating platelets to induce procoagulant activity. In addition, we established an inferior vena cava ligation (IVC) model to examine the role of NETs in thrombogenicity in DVT. In conclusion, NET formation was mediated by PF4 and enhance the procoagulant activity in DVT. • NETs are abundant in plasma and thrombi from DVT patients. • PF4 mediates NET formation through autophagy in DVT. • NETs contribute to PCA through tissue factor and activated platelets. • PF4 promotes thrombosis in the IVC model by regulating NET formation. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression levels of small dense low-density lipoprotein cholesterol (sdLDLC), serum amyloid A (SAA), and platelet-activating factor (PAF) in acute coronary syndrome (ACS) and their relationship with vulnerable plaques. Methods A total of 136 patients with coronary heart disease were divided into stable angina pectoris (SAP) group (n=45) and ACS group (n=91) . Based on plaque stability, they were further divided into stable plaque group (n=53) and vulnerable plaque group (n=83) . Differences in sdLDLC, SAA, PAF levels, and plaque characteristics were measured. Results Compared with the SAP group, the ACS group had a higher proportion of male gender, smoking history, levels of white blood cell (WBC), triglyceride (TG), uric acid, creatinine, sdLDLC, SAA, and PAF, and lower level of HDL-C (P＜0.05) . The ACS group showed significantly larger necrotic core (NC), lipid pool area (LPA), plaque lipid ratio (PLR), eccentric index (EI), remodeling index (RI), plaque burden (PB) compared to the SAP group (P＜0.05) . There were statistically significant differences in the expression levels of sdLDLC, SAA, and PAF between the stable plaque group and the vulnerable plaque group (P＜0.05) . Pearson correlation analysis showed that sdLDLC, SAA, and PAF were positively correlated with NT, LPA, PLR, EI, RI, PB (P＜0.05) . Multivariate logistic regression analysis revealed that sdLDLC, SAA, and PAF were independent predictors of vulnerable plaques (P＜0.05) .Conclusion Levels of sdLDLC, SAA, and PAF are significantly elevated in ACS patients and are closely related to vulnerable plaques. [ABSTRACT FROM AUTHOR]

Platelet activating factor (PAF) is a potent lipid mediator involved in inflammation, among other pathophysiological conditions. Bioactive compounds from foods have been suggested to suppress inflammation as well as regulate PAF biosynthesis. Phenolics, such as resveratrol and tyrosol, and their acetylated derivatives, inhibited PAF biosynthetic enzymes' activity, namely acetyl-coenzyme A: lyso–platelet-activating factor acetyltransferases (lysoPAF-AT), and 1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-CPT) under inflammatory stimuli. This study investigates whether resveratrol and tyrosol lipophilic derivatives are capable of affecting the activity of the two isoforms of lysoPAF-AT along with the activity of PAF-CPT compared with the initial compounds under basal conditions. The derivatives were chemically synthesized and the experiments were conducted either with or without pre-incubation of homogenized U-937 cells and the phenolics and the enzyme activities were determined. Pre-incubation experiments resulted in lower half inhibitory concentration (IC50) than those without pre-incubation, reaching a 5-fold difference between them. Moreover, there were differences among parent compounds and their derivatives, suggesting a dependence on the differently substituted groups of the phenolics. PAF-CPT tends to be less phenolic structure dependent than lysoPAF-ATC, whereas the other isoform, lysoPAF-ATE, was less sensitive in general. Resveratrol and its derivatives were more potent than the tyrosolic compounds, regardless of the enzyme test or the conditions of the experiment. The use of phenolic lipophilic derivatives in pharmaceuticals and in food preparation may overcome the limitations of natural phenolics with regard to their weak solubility and stability in a lipophilic environment. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is an irreversible lung fibrotic disorder of unknown cause. It has been reported that bacterial and viral co-infections exacerbate disease pathogenesis. These pathogens use adhesion molecules such as platelet activating factor receptor (PAFR) and intercellular adhesion molecule-1 (ICAM–1) to gain cellular entry, causing infections. Methods: Immunohistochemical staining was carried out for lung resections from IPF patients (n = 11) and normal controls (n = 12). The quantification of PAFR and ICAM–1 expression is presented as a percentage in the small airway epithelium. Also, type 2 pneumocytes and alveolar macrophages were counted as cells per mm2 of the parenchymal area and presented as a percentage. All image analysis was done using Image Pro Plus 7.0 software. Results: PAFR expression significantly increased in the small airway epithelium (p < 0.0001), type 2 pneumocytes (p < 0.0001) and alveolar macrophages (p < 0.0001) compared to normal controls. Similar trend was observed for ICAM–1 expression in the small airway epithelium (p < 0.0001), type 2 pneumocytes (p < 0.0001) and alveolar macrophages (p < 0.0001) compared to normal controls. Furthermore, the proportion of positively expressed type 2 pneumocytes and alveolar macrophages was higher in IPF than in normal control. Conclusions: This is the first study to show PAFR and ICAM–1 expression in small airway epithelium, type 2 pneumocytes and alveolar macrophages in IPF. These findings could help intervene microbial impact and facilitate management of disease pathogenesis. [ABSTRACT FROM AUTHOR]

Depression is a common emotional disorder. Previous studies have suggested that depression is associated with the central nervous system. Recent studies have suggested that reduced testosterone level is the core inducement of depression. Testis is the vital organ for the synthesis of testosterone. How does testis mediate depression is still unknown. We adopted a classical depression model of mouse caused through chronic mild stress (CMS). The metabolomics liquid chromatography-mass spectrometry was adopted to analyse the influence of CMS on testis metabolism. Then we confirmed the possible abnormal metabolism of the testis in depression mice by pathway analysis and molecular biological technique. Compared with control mice, 16 differential metabolites were found in CMS mice by multivariate statistical analysis. In comparison with control mice, CMS mice showed higher levels for campesterol, ribitol, citric acid, platelet activating factor, guanosine, cytosine and xanthine and lower levels for docosahexaenoic acid, hippuric acid, creatine, testosterone, dehydroepiandrosterone, progesterone, l -carnitine, acetyl carnitine and propionyl carnitine. The pathway analysis indicated that these differential metabolites are associated with steroid hormone synthesis, purine metabolism and phenylalanine metabolism. In addition, we also first discovered that testicular morphology in depression mice was damaged and steroid hormone synthetases (including steroidogenic acute regulatory protein and P450 cholesterol side chain cleavage) were inhibited. These findings may be helpful to parse molecular mechanisms of pathophysiology of depression. It also pointed out the direction to search for potential therapy schedules for male depression and provide novel insights into exploring the pathogenesis of male depression. [Display omitted] • Testis metabolic profiling of depression mice model. • Testicular morphology of depression mice was damaged. • Steroid hormone synthetases were inhibited in depression mice model. [ABSTRACT FROM AUTHOR]

• Mechanisms of histamine release from mast cells beyond the activation of the high activity IgE receptor have been reported in chronic spontaneous urticaria patients. These include. • Activation of the coagulation cascade. • The activation of complement system with hyperproduction of C5a. • The activation of the MRGPRX2 receptor. • Hyperexpression of platelet activating factor. There is growing evidence suggesting that in a subset of patients with severe chronic urticaria [CSU] mast cells are activated via mechanisms that bypass the high affinity IgE receptor. This might explain why some patients do not respond at all to anti-IgE therapy [omalizumab]. The present article reviews the pathogenic mechanisms able to lead to histamine release from mast cells described so far in patients with CSU. These include the activation of the coagulation cascade, the activation of the complement system, the activation of the MRGPRX2 receptor, and the platelet activating factor vicious circle. The article suggests some possible interpretations for the clinical events occurring in this specific subset of patients. [ABSTRACT FROM AUTHOR]

Platelet aggregation is a complicated process mediated by different signaling pathways. As the process is highly complex and apparently redundant, the relationships between these pathways are not yet fully known. The aim of this project was to study the interconnections among seven different aggregation pathways in a group of 53 generally healthy volunteers aged 20 to 66 years. Platelet aggregation was induced with thrombin receptor activating peptide 6 (TRAP), arachidonic acid (AA), platelet activating factor 16 (PAF), ADP, collagen, thromboxane A2 analogue U46619 or ristocetin (platelet agglutination) ex vivo in fasting blood samples according to standardized timetable protocol. Additionally, some samples were pre-treated with known clinically used antiplatelet drugs (vorapaxar, ticagrelor or acetylsalicylic acid (ASA)). Significant correlations among all used inducers were detected (Pearson correlation coefficients (rP): 0.3 to 0.85). Of all the triggers, AA showed to be the best predictor of the response to other inducers with rP ranging from 0.66 to 0.85. Interestingly, the antiplatelet response to ticagrelor strongly predicted the response to unrelated drug vorapaxar (rP = 0.71). Our results indicate that a response to one inducer can predict the response for other triggers or even to an antiplatelet drug. These data are useful for future testing but should be also confirmed in patients. [ABSTRACT FROM AUTHOR]

Copyright of Cirugía y Cirujanos is the property of Publicidad Permanyer SLU and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of African Journal of Biological Sciences is the property of African Journal of Biological Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Phomactin diterpenoids possess a unique bicyclo[9.3.1]pentadecane skeleton with multiple oxidative modifications, and are good platelet‐activating factor (PAF) antagonists that can inhibit PAF‐induced platelet aggregation. In this study, we identified the gene cluster (phm) responsible for the biosynthesis of phomactins from a marine fungus, Phoma sp. ATCC 74077. Despite the complexity of their structures, phomactin biosynthesis only requires two enzymes: a type I diterpene cyclase PhmA and a P450 monooxygenase PhmC. PhmA was found to catalyze the formation of the phomactatriene, while PhmC sequentially catalyzes the oxidation of multiple sites, leading to the generation of structurally diverse phomactins. The rearrangement mechanism of the diterpene scaffold was investigated through isotope labeling experiments. Additionally, we obtained the crystal complex of PhmA with its substrate analogue FGGPP and elucidated the novel metal‐ion‐binding mode and enzymatic mechanism of PhmA through site‐directed mutagenesis. This study provides the first insight into the biosynthesis of phomactins, laying the foundation for the efficient production of phomactin natural products using synthetic biology approaches. [ABSTRACT FROM AUTHOR]

Introduction: Microbicidal violet-blue light in the visible spectrum (405 nm) 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. Method: In order to evaluate whether the microbicidal 405 nm 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 405 nm 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). Results: 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 405 nm 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 405 nm light. Distinctly changed endogenous photosensitizer metabolites after 1 h of light exposure provided good evidence that 405 nm light was an effective microbicide acting through ROS mechanism and no external additive photosensitizers were required. [ABSTRACT FROM AUTHOR]

Background: Displaced abomasum (DA) is one of the most important metabolic disorders of dairy cattle. In DA, ischaemic damage may occur as a result of impaired perfusion due to abomasal displacement, which may result in gastrointestinal mucosal damage. Objective: Investigation of gastrointestinal tissue damage in cattle with right displacement of the abomasum (RDA) and left displacement of the abomasum (LDA) using intestinal‐related biomarkers. Methods: Forty‐eight DA (24 LDA, 24 RDA) and 15 healthy Holstein dairy cows were enrolled between March 2021 and July 2022. Serum biomarkers including gamma‐enteric smooth muscle actin (ACTG‐2), liver‐fatty acid binding proteins (L‐FABP), platelet activating factor (PAF), trefoil factor‐3 (TFF‐3), leptin, claudin‐3 and interleukin‐8 (IL‐8) concentrations were measured from venous blood samples. Results: L‐FABP concentrations in the LDA group and TFF‐3 concentrations in the RDA group were lower than in the control group. The leptin concentration of the RDA group was higher than that of the other groups. There was a negative correlation between lactate, leptin and IL‐8 concentrations. There was a negative correlation between lactate and TFF‐3, whereas leptin and lactate were positively correlated. Leptin was the more reliable biomarker for discriminating between RDA and LDA cases. Conclusion: Changes in serum L‐FABP, TFF‐3 and leptin concentrations in cattle with DA may reflect acute intestinal injury and the subsequent repair phase. However, these biomarkers had poor diagnostic performance in discriminating between healthy and cattle with DA, while leptin emerged as the most useful marker in differentiating LDA from RDA cases. [ABSTRACT FROM AUTHOR]

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease. As a clinical empirical prescription of traditional Chinese medicine, Qushi Huayu decoction (QHD) has attracted considerable attention for its advantages in multi-target treatment of NAFLD. However, the intervention mechanism of QHD on abnormal lipid levels and gut microbiota in NAFLD has not been reported. Methods: Therefore, we verified the therapeutic effect of QHD on high-fat diet (HFD)-induced NAFLD in rats by physiological parameters and histopathological examination. In addition, studies on gut microbiota and serum lipidomics based on 16S rRNA sequencing and ultra-high performance liquid chromatographymass spectrometry (UPLC-MS) were conducted to elucidate the therapeutic mechanism of NAFLD in QHD. Results: The changes in gut microbiota in NAFLD rats are mainly reflected in their diversity and composition, while QHD treated rats restored these changes. The genera Blautia, Lactobacillus, Allobaculum, Lachnoclostridium and Bacteroides were predominant in the NAFLD group, whereas, Turicibacter, Blautia, Sporosarcina, Romboutsia, Clostridium&lowbar;sensu&lowbar;stricto&lowbar;1, Allobaculum, and Psychrobacter were predominant in the NAFLD+QHD group. Lipid subclasses, including diacylglycerol (DG), triglycerides (TG), phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidic acid (PA), phosphatidylserine (PS), lysophosphatidylinositol (LPI), and phosphatidylglycerol (PG), were significantly different between the NAFLD and the control groups, while QHD treatment significantly altered the levels of DG, TG, PA, lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and platelet activating factor (PAF). Finally, Spearman's correlation analysis showed that NAFLD related differential lipid molecules were mainly associated with the genera of Bacteroides, Blautia, Lachnoclostridium, Clostridium&lowbar;sensu&lowbar;stricto&lowbar;1, and Turicibacter, which were also significantly correlated with the biological parameters of NAFLD. Discussion: Taken together, QHD may exert beneficial effects by regulating the gut microbiota and thus intervening in serum lipids. [ABSTRACT FROM AUTHOR]

COVID-19 vaccines have played a critical role in controlling the COVID-19 pandemic. Although overall considered safe, COVID-19 vaccination has been associated with rare but severe thrombotic events, occurring mainly in the context of adenoviral vectored vaccines. A better understanding of mechanisms underlying vaccine-induced hypercoagulability and prothrombotic state is needed to improve vaccine safety profile. We assessed changes to the biomarkers of endothelial function (endothelin, ET-1), coagulation (thrombomodulin, THBD and plasminogen activator inhibitor, PAI) and platelet activation (platelet activating factor, PAF, and platelet factor 4 IgG antibody, PF4 IgG) within a three-week period after the first (prime) and second (boost) doses of Gam-Covid-Vac, an AdV5/AdV26-vectored COVID-19 vaccine. Blood plasma collected from vaccinees (n = 58) was assayed using ELISA assays. Participants were stratified by prior COVID-19 exposure based on their baseline SARS-CoV-2-specific serology results. We observed a significant post-prime increase in circulating ET-1, with levels sustained after the boost dose compared to baseline. ET-1 elevation following dose 2 was most pronounced in vaccinees without prior COVID-19 exposure. Prior COVID-19 was also associated with a mild increase in post-dose 1 PAI. Vaccination was associated with elevated ET-1 up to day 21 after the second vaccine dose, while no marked alterations to other biomarkers, including PF4 IgG, were seen. A role of persistent endothelial activation following COVID-19 vaccination warrants further investigation. [ABSTRACT FROM AUTHOR]

Food fortification is a strategic approach to enhance the nutritional quality of food by incorporating bioactive compounds derived from food by-products. The objective of this study was to assess the impact on bioactivity of tahini enriched with a 4% (w/w) lyophilized microwave-ultrasound assisted extract of red grape pomace from the Limnio variety and a 6% (w/w) freeze-dried aquafaba obtained from Lemnian chickpeas of the Panagia variety. The evaluation was conducted through in vitro experiments. The samples under study were extracted by the Bligh and Dyer method and analyzed for their polyphenolic content, as well as for their content in total flavonoids. Assessment of the antioxidant capacity of the extracts was determined in vitro by the ABTS, DPPH, CUPRAC, FRAP and human blood plasma oxidation inhibition (hBPOxi) assays, while the antiplatelet activity of the extracts was determined by the Platelet Activating Factor inhibition assay (PAFi). The bioactivity of fortified tahini (LAC) was increased compared to plain tahini (Control sample). Total phenolics and total flavonoids were increased by 76% and 78%, respectively (10.7 ± 0.2 vs. 6.02 ± 0.3 and 8.5 ± 0.14 vs. 4.76 ± 0.1 μmol Trolox/g, respectively). Antioxidant activities based on ABTS, DPPH, CUPRAC, FRAP and hBPOxi were increased by 101%, 65%, 77%, 73% and 110%, respectively (52.8 ± 0.7 vs. 26.3 ± 0.4; 20.1 ± 1.6 vs. 12.2 ± 0.2; 81.9 ± 0.4 vs. 46.1 ± 2.1; 46.4 ± 4.0 vs. 26.8 ± 0.8; and 12.2 ± 0.9 vs. 5.8 ± 0.2 μmol Trolox/g, respectively), and antiplatelet activity based on PAFi was also increased by 41% (0.19 ± 0.01 vs. 0.32 ± 0.02 mg, respectively). Red grape pomace extract and aquafaba boosted tahini's in vitro antioxidant and antiplatelet capabilities. The results indicate that the valorization of grape and chickpea processing residuals may reduce waste and improve the nutritional value of tahini. Due to its antioxidant and antiplatelet activities, fortified tahini may contribute to the prevention of chronic diseases where oxidation and thrombosis play critical roles. This study exemplifies sustainable resource use and waste reduction, as well as the importance of circular economy strategies in enhancing diets and human welfare. [ABSTRACT FROM AUTHOR]

G-coupled protein receptors (GPCRs) comprise the largest class of druggable targets. Signaling by GPCRs is initiated from subcellular hot spots including the plasma membrane, signalosomes, and endosomes to contribute to vascular inflammation. GPCR-G protein signaling at the plasma membrane causes endothelial barrier disruption and also cross-talks with growth factor receptors to promote proinflammatory signaling. A second surge of GPCR signaling is initiated by cytoplasmic NFκB activation mediated by β-arrestins and CARMA-BCL10-MALT1 signalosomes. Once internalized, ubiquitinated GPCRs initiate signaling from endosomes via assembly of the transforming growth factor-β-activated kinase binding protein-1 (TAB1)-TAB2-p38 MAPK complex to promote vascular inflammation. Understanding the complexities of GPCR signaling is critical for development of new strategies to treat vascular inflammation such as that associated with COVID-19.

This letter discusses the implications for the pathogenesis and treatment of thrombosis in patients with paroxysmal nocturnal hemoglobinuria (PNH) based on multiomics analysis. The authors conducted whole exome sequencing, single-cell RNA sequencing, and proteomics on two PNH patients with acute thrombotic events. They identified gene mutations associated with thrombosis and found that platelet activation, coagulation cascades, and leukocyte cell adhesion play important roles in PNH thrombosis. The authors recommend screening PNH patients for mutations and treating high-risk patients with prophylactic anticoagulant therapy. They also suggest monitoring antithrombin III levels and adjusting heparin dose during anticoagulant therapy to improve efficacy and safety. [Extracted from the article]

BackgroundDietary micronutrients may play important roles in the improvement of the immune responses against SARS-CoV-2. This study aimed to assess the effect of micronutrients on platelet activating factor (PAF) and immunity with a special focus on the coronavirus disease 2019 (COVID-19).MethodsAll paper published in English on the effects of micronutrients including fat soluble vitamins, water soluble vitamins, and minerals on PAF, immunity, and COVID-19 were collected from online valid databases.ResultsVitamin A may modulate the expression of PAF-receptor gene in patients with COVID-19. Vitamin D may modulate inflammatory response through influencing PAF pathway. Vitamin E may improve COVID-19 related heart injuries by exert anti-PAF activities. Vitamin C status may have PAF related anti-inflammatory and micro-thrombotic effects in SARS-CoV-2 patients. Furthermore, some trace elements such as copper, selenium, and iron may have key roles in strengthens immunity by inactivate PAF acetyl hydrolase.ConclusionThis narrative review study highlighted the importance of micronutrients in the improvement of immune function through modulation of PAF in patients with COVID-19. Further longitudinal studies are warranted.

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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cytoplasmic phospholipase A2 (cPLA2) is a novel strategy and target for the treatment of spinal cord injury. cPLA2 is regulated by RhoA/Rho kinase and mitogen-activated protein kinase (MEK)/extracellular regulated protein kinases (ERK) signaling pathways. Electroacupuncture can treat spinal cord injury by regulating the RhoA/Rho kinase and MEK/ERK signaling pathways. OBJECTIVE: To investigate the effects of electroacupuncture on the activity of cPLA2 after spinal cord injury by regulating Rho/ROCK (Rho kinase) and MEK/ERK signaling pathways. METHODS: After spinal cord injury modeling and Basso, Beattie, Bresnahan scoring, 72 female Sprague-Dawley rats were randomly divided into model group, electroacupuncture group, U0126 treatment group and Y27632 treatment group, with 18 rats in each group. Another 18 rats were used as sham operation group, in which only laminectomy was performed without spinal cord impingement. In the electroacupuncture group, Dazhui (GV 14), Yaoyangguan (GV 3), bilateral Ciliao (BL 32) and Zusanli (ST 36) were treated with electroacupuncture, once a day, 20 minutes each time, 14 times in total. Rats in the U0126 and Y27632 treatment groups were given U0126 and Y27362 subdural injection every other day, respectively. At the end of treatment, the rats were sacrificed after Basso, Beattie, Bresnahan scoring, and the spinal cord tissue was collected to detect the content of prostaglandin E2 and platelet activating factor by ELISA. TUNEL assay was used to detect the apoptosis rate of spinal cord nerve cells. Western blot was used to detect the protein expression of RhoA, ROCK II, MEK, ERK1/2, p-ERK1/2, cPLA2 and p-cPLA2 in the spinal cord. qRT-PCR was used to detect the mRNA expression of RhoA, ROCK II, MEK, ERK1/2 and cPLA2 in the spinal cord. RESULTS AND CONCLUSION: Compared with the sham operation group, Basso, Beattie, Bresnahan score was significantly decreased in the model group (P < 0.01), while the number of apoptotic cells, the levels of prostaglandin E2 and platelet activating factor, and the expression of p-cPLA2 protein and cPLA2 mRNA in spinal cord tissue were significantly increased in the model group (P < 0.01). After treatment, the above indexes were significantly reversed in all the treatment groups except for the mRNA expression of cPLA2 in the electroacupuncture group (P < 0.01). Compared with the sham operation group, the expression of RhoA, ROCK II, and MEK protein and gene, the mRNA expression of ERK1/2, and the protein expression of p-ERK1/2 were significantly increased in the model group (P < 0.01). After treatment, the above indexes were significantly decreased in the three treatment groups (P < 0.01 or P < 0.05). To conclude, electroacupuncture can down-regulate the expression of factors related to Rho/ROCK and MEK/ERK signaling pathways, inhibit the activity of cPLA2, reduce the apoptosis of nerve cells, alleviate inflammatory responses, and finally achieve the therapeutic effect on spinal cord injury. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Lipids and lipoproteins play a key role in cardiovascular diseases (CVD), mainly in the development of atherosclerosis. It is widely accepted that an elevated concentration of low-density lipoproteins (LDL) in circulation is a risk factor for CVD, whereas high concentrations of high-density lipoproteins (HDL) have been related to cardioprotection. The common point of all these studies is to provide a novel approach to cardiovascular risk, either by analyzing the qualitative characteristics of lipoproteins, evaluating the use of ratios between the different lipoprotein fractions, or using nuclear magnetic resonance (NMR) to obtain more detailed information about the lipoprotein profile. These patients not only have an altered lipoprotein profile, but they also have modifications in the qualitative properties of lipoproteins, including loss of function in HDL [[6]]. [Extracted from the article]

Arterial baroreflex (ABR) dysfunction has previously been associated with neuroinflammation, the most common pathological feature of neurological disorders. However, the mechanisms mediating ABR dysfunction-induced neuroinflammation are not fully understood. In the present study, we investigated the role of platelet CD40 ligand (CD40L) in neuroinflammation in an in vivo model of ABR dysfunction, and microglia and astrocyte activation in vitro. ABR dysfunction was induced in Sprague‒Dawley rats by sinoaortic denervation (SAD). We used ELSA and immunofluorescence to assess the effect of platelet CD40L on glial cell polarization and the secretion of inflammatory factors. By flow cytometry, we found that rats subjected to SAD showed a high level of platelet microaggregation and upregulation of CD40L on the platelet surface. The promotion of platelet invasion and accumulation was also observed in the brain tissues of rats subjected to SAD. In the animal model and cultured N9 microglia/C6 astrocytoma cells, platelet CD40L overexpression promoted neuroinflammation and activated M1 microglia, A1 astrocytes, and the nuclear factor kappa B (NFκB) signaling pathway. These effects were partially blocked by inhibiting platelet activity with clopidogrel or inhibiting CD40L-mediated signaling. Our results suggest that during ABR dysfunction, CD40L signaling in platelets converts microglia to the M1 phenotype and astrocytes to the A1 phenotype, activating NFκB and resulting in neuroinflammation. Thus, our study provides a novel understanding of the pathogenesis of ABR dysfunction-induced neuroinflammation and indicates that targeting platelet CD40L is beneficial for treating central nervous system (CNS) disorders associated with ABR dysfunction. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Positive allosteric modulators for free fatty acid receptor 2 (FFAR2/GPR43), that affect receptor function through binding to two distinct allosteric binding sites, were used to determine the correlation between the responses induced in neutrophils by two distinct activation modes; FFAR2 was activated either by the orthosteric agonist propionate or by a receptor transactivation mechanism that activated FFAR2 from the cytosolic side of the neutrophil plasma membrane by signals generated by the neutrophil PAFR (receptor for platelet activating factor), P2Y2R (receptor for ATP), FPR1 (receptor for fMLF) and FPR2 (receptor for WKYMVM). We show that the transactivation signals that activate FFAR2 in the absence of any orthosteric agonist were generated downstream of the signaling G protein that couple to PAFR and P2Y2R. This transactivation of allosterically modulated FFAR2s, by signals generated by PAFR/P2Y2R, represents a novel mechanism by which a G protein coupled receptor can be activated. Weak correlations were obtained when the FFAR2 activity was induced by the transactivation signals generated by PAFRs and P2Y2Rs were compared with the FFAR2 activity induced by the orthosteric agonist propionate. Comparison of the responses for each allosteric modulator revealed that the ratio values, calculated from the peak values of the ATP and propionate responses, varied from 0.2 to 1. Depending on the allosteric modulator, the response induced by the two different mechanisms (orthosteric activation and receptor transactivation, respectively), was equal or the propionate response was more pronounced. Importantly, we conclude that FFAR2 activation from outside (orthosteric activation) and inside (receptor cross-talk/transactivation) can be selectively affected by an allosteric FFAR2 modulator. [ABSTRACT FROM AUTHOR]

Although there is increasing evidence that oxidative stress and inflammation induced by COVID-19 may contribute to increased risk and severity of thromboses, the underlying mechanism(s) remain to be understood. The purpose of this review is to highlight the role of blood lipids in association with thrombosis events observed in COVID-19 patients. Among different types of phospholipases A2 that target cell membrane phospholipids, there is increasing focus on the inflammatory secretory phospholipase A2 IIA (sPLA2-IIA), which is associated with the severity of COVID-19. Analysis indicates increased sPLA2-IIA levels together with eicosanoids in the sera of COVID patients. sPLA2 could metabolise phospholipids in platelets, erythrocytes, and endothelial cells to produce arachidonic acid (ARA) and lysophospholipids. Arachidonic acid in platelets is metabolised to prostaglandin H2 and thromboxane A2, known for their pro-coagulation and vasoconstrictive properties. Lysophospholipids, such as lysophosphatidylcholine, could be metabolised by autotaxin (ATX) and further converted to lysophosphatidic acid (LPA). Increased ATX has been found in the serum of patients with COVID-19, and LPA has recently been found to induce NETosis, a clotting mechanism triggered by the release of extracellular fibres from neutrophils and a key feature of the COVID-19 hypercoagulable state. PLA2 could also catalyse the formation of platelet activating factor (PAF) from membrane ether phospholipids. Many of the above lipid mediators are increased in the blood of patients with COVID-19. Together, findings from analyses of blood lipids in COVID-19 patients suggest an important role for metabolites of sPLA2-IIA in COVID-19-associated coagulopathy (CAC). [ABSTRACT FROM AUTHOR]

Purpose: Leishmaniasis, Chagas disease, and sleeping sickness are caused by protozoa Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, respectively. Platelet activating factor acetyl hydrolase (PAF-AH) is an inflammatory protein implicated in pathogenesis of these three infections, thereby making them attractive drug targets. Methods: PAF-AH sequences were retrieved from UniProt and aligned using Clustal Omega. Homologous models of parasitic proteins were built based on crystal structure of human PAF-AH and validated using PROCHECK server. Volumes of substrate-binding channel were calculated using the ProteinsPlus program. High throughput virtual screening using Glide program in Schrodinger was done with ZINC drug library against parasitic PAF-AH enzymes. Complexes with best hits were energy-minimized and subjected to 100 ns molecular dynamic simulation and analyzed. Results: PAF-AH enzyme sequences from protozoa Leishmania donovani, Trypanosoma cruzi, Trypanosoma brucei, and human have a minimum of 34% sequence similarity with each other. Corresponding structures show a globular conformation consisting of twisted β-pleated sheets, flanked by α-helices on either side. Catalytic triad of serine-histidine-aspartate is conserved. Substrate-binding channel residues are conserved to an extent, with a lower channel volume in human as compared to target enzymes. Drug screening resulted in identification of three molecules that had better affinities than the substrate to the target enzymes. These molecules fulfill Lipinski's rules for drug likeness and also bind with less affinity to the human counterpart, thereby establishing a high selective index. Conclusion: Structures of PAF-AH from protozoan parasites and humans belong to the same family of enzymes and have a similar three-dimensional fold. However, they show subtle variations in residue composition, secondary structure composition, substrate-binding channel volume, and conformational stability. These differences result in certain specific molecules being potent inhibitors of the target enzymes while simultaneously having weaker binding to human homologue. [ABSTRACT FROM AUTHOR]

The unique processing technology of dry-cured meat products leads to strong proteolysis, which produces numerous peptides. The purpose of this investigation was the systematic isolation, purification, and identification of potentially cardioprotective bioactive peptides from dry-cured pork coppa during processing. According to the results of anti-platelet-activating factor acetyl hydrolase activity and radical scavenging ability in vitro, the inhibitory effect of M1F2 in purified fractions on cardiovascular inflammation was higher than that of M2F2. The peptide of M1F2 was identified by nano-liquid chromatography–tandem mass spectrometry. A total of 30 peptides were identified. Based on bioinformatics methods, including in silico analysis and molecular docking, LTDKPFL, VEAPPAKVP, KVPVPAPK, IPVPKK, and PIKRSP were identified as the most promising potential platelet-activating factor acetyl hydrolase inhibitory peptides. Overall, bioactive peptides produced during dry-cured pork coppa processing demonstrate positive effects on human health. [ABSTRACT FROM AUTHOR]

Previously, we revealed a crucial role of 5-HT degradation system (5DS), consisting of 5-HT2A receptor (5-HT2AR), 5-HT synthases and monoamine oxidase A (MAO-A), in ischemia-reperfusion (IR)-caused organ injury. Whereas, platelet activating factor receptor (PAFR) also mediates myocardial ischemia-reperfusion injury (MIRI). Here, we try to clarify the relationship between 5DS and PAFR in mediating MIRI. H9c2 cell injury and rat MIRI were caused by hypoxia/reoxygenation (H/R) or PAF, and by ligating the left anterior descending coronary artery then untying, respectively. 5-HT 2A R and PAFR antagonists [sarpogrelate hydrochloride (SH) and BN52021], MAO-A, AKT, mTOR and 5-HT synthase inhibitors (clorgyline, perifosine, rapamycin and carbidopa), and gene-silencing PKCε were used in experiments The mitochondrial ROS production, respiratory chain damage, inflammation, apoptosis and myocardial infarction were significantly prevented by BN52021, SH and clorgyline in H/R and PAF-treated cells and in IR myocardium. BN52021 also significantly suppressed the upregulation of PAFR, 5-HT 2A R, 5-HT synthases and MAO-A expression (mRNA and protein), and Gα q and PKCε (in plasmalemma) expression induced by H/R, PAF or IR; the effects of SH were similar to that of BN52021 except for no affecting the expression of PAFR and 5-HT 2A R. Gene-silencing PKCε suppressed H/R and PAF-induced upregulation of 5-HT synthases and MAO-A expression in cells; perifosine and rapamycin had not such effects; however, clorgyline suppressed H/R and PAF-induced phosphorylation of AKT and mTOR. MIRI is probably due to PAFR-mediated 5-HT 2A R activation, which further activates PKCε-mediated 5-HT synthesis and degradation, leading to mitochondrial ROS production. ● MIRI is due to 5DS-caused mitochondrial ROS production, could be prevented by inhibiting 5DS. ● PAFR activated by PAF causes 5DS activation, leading to MIRI. ● PAFR mediates 5-HT 2A R expression at gene level, latter mediates Gq/PKCε pathway activation. ● PKCε mediates 5-HT synthases and MAO-A expression at gene level. ● Phosphorylation of AKT and mTOR is due to mitochondrial ROS induced by 5-HT degradation. [ABSTRACT FROM AUTHOR]

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Abstract Background Postoperative cognitive dysfunction (POCD) are a common complication of the central nervous system following surgery and anesthesia. The specific pathogenesis and effective therapeutics of POCD need to be further studied. Ginkgolide B (GB), a platelet-activating factor receptor-specific antagonist, has been suggested to have strong anti-inflammatory effects. Here we tested the effects and mechanism of GB on POCD of aged rats. Methods Neurobehavioral tests were used to investigate the effect of GB pretreatment on POCD. The hippocampus were harvested to test the expression of proinflammatory cytokines by ELISA. The expression of the microglial marker ionized calcium-binding adaptor molecule-1 (Iba-1) in the hippocampus was evaluated by western blot assay and immunohistochemistry. A Nissl staining experiment was used to detect the neuronal numbers in the hippocampus. Results Surgery might result in the overexpression of platelet activating factor (PAF) in the plasma and hippocampus and might cause hippocampus-dependent memory impairment. GB pretreatment, inhibited the activation of microglia, reduced the levels of IL-1β and TNF-α, decreased the loss of neurons after surgery, and prevented POCD in aged rats. Conclusion Our findings suggested that PAF was involved in the development of POCD. Improvement of POCD by PAF antagonist GB was associated with the inhibition of microgliosis-mediated neuroinflammation and neuronal apoptosis in aged rats.

Background: Hypercoagulable state and thromboembolic complications are potential life-threatening events in COVID-19 patients. Our previous studies demonstrated that SARS-CoV-2 infection as well as viral spike protein expressed epithelial cells exhibit senescence with the release of inflammatory molecules, including alarmins. Findings: We observed extracellular alarmins present in the culture media of SARS-CoV-2 spike expressing cells activate human THP-1 monocytes to secrete pro-inflammatory cytokines to a significant level. The release of THP-1 derived pro-inflammatory cytokine signature correlated with the serum of acute COVID-19 patient, but not in post-COVID-19 state. Our study suggested that the alarmins secreted by spike expressing cells, initiated phagocytosis property of THP-1 cells. The phagocytic monocytes secreted complement component C5a and generated an autocrine signal via C5aR1 receptor. The C5a-C5aR1 signal induced formation of monocyte mediated extracellular trap resulted in the generation of a prothrombogenic stimulus with activating platelets and increased tissue factor activity. We also observed an enhanced C5a level, platelet activating factor, and high tissue factor activity in the serum of acute COVID-19 patients, but not in recovered patients. Conclusion: Our present study demonstrated that SARS-CoV-2 spike protein modulates monocyte responses in a paracrine manner for prothrombogenic stimulus by the generation of C5a complement component. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic, highly pruritic, relapsing–remitting inflammatory skin disease. The etiology of AD has not been fully explained yet and complex interactions of various small molecules are still being taken into account. The aim of this research was to investigate the serum eosinophil-derived neurotoxin (EDN), platelet activating factor (PAF) and vascular endothelial growth factor (VEGF) concentrations in relation to the disease severity and pruritus intensity in adult patients with AD. This pilot study was performed on 30 participants (15 patients with AD and 15 healthy controls). Blood samples were taken to examine the serum levels of EDN, PAF and VEGF using the enzyme-linked immunosorbent assay (ELISA) test. The severity of disease was assessed by the Scoring Atopic Dermatitis (SCORAD) index. The intensity of pruritus, as a subjective symptom, was determined by the Visual Analogue Scale (VAS). Obtained results revealed that the EDN (p = 0.016) and VEGF (p = 0.032), but not PAF (p = 0.841) concentrations were significantly higher in patients with AD compared with those of the control group. There was positive correlation between the EDN level and the SCORAD index in patients with AD (r = −0.9, p = 0.037) which was not found for the PAF and VEGF levels. Circulating EDN, PAF and VEGF levels were not significantly correlated with the severity of pruritus. Our results suggest that the END and VEGF serum levels are significantly increased in patients with AD compared to control group. Moreover, EDN might be useful to reflect the severity of symptoms. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Corals and humans represent two extremely disparate metazoan lineages and are therefore useful for comparative evolutionary studies. Two lipid-based molecules that are central to human immunity, platelet-activating factor (PAF) and Lyso-PAF were recently identified in scleractinian corals. To identify processes in corals that involve these molecules, PAF and Lyso-PAF biosynthesis was quantified in conditions known to stimulate PAF production in mammals (tissue growth and exposure to elevated levels of ultraviolet light) and in conditions unique to corals (competing with neighbouring colonies over benthic space). Similar to observations in mammals, PAF production was higher in regions of active tissue growth and increased when corals were exposed to elevated levels of ultraviolet light. PAF production also increased when corals were attacked by the stinging cells of a neighbouring colony, though only the attacked coral exhibited an increase in PAF. This reaction was observed in adjacent areas of the colony, indicating that this response is coordinated across multiple polyps including those not directly subject to the stress. PAF and Lyso-PAF are involved in coral stress responses that are both shared with mammals and unique to the ecology of cnidarians.

Corals and humans represent two extremely disparate metazoan lineages and are therefore useful for comparative evolutionary studies. Two lipid-based molecules that are central to human immunity, platelet-activating factor (PAF) and Lyso-PAF were recently identified in scleractinian corals. To identify processes in corals that involve these molecules, PAF and Lyso-PAF biosynthesis was quantified in conditions known to stimulate PAF production in mammals (tissue growth and exposure to elevated levels of ultraviolet light) and in conditions unique to corals (competing with neighbouring colonies over benthic space). Similar to observations in mammals, PAF production was higher in regions of active tissue growth and increased when corals were exposed to elevated levels of ultraviolet light. PAF production also increased when corals were attacked by the stinging cells of a neighbouring colony, though only the attacked coral exhibited an increase in PAF. This reaction was observed in adjacent areas of the colony, indicating that this response is coordinated across multiple polyps including those not directly subject to the stress. PAF and Lyso-PAF are involved in coral stress responses that are both shared with mammals and unique to the ecology of cnidarians.

Abstract Background Sublingual immunotherapy tablets (SLIT-T) are an effective treatment for allergic rhinitis (AR), but some patients experience local allergic reactions (LAR) in the first few weeks of treatment that can lead to treatment discontinuation. Although oral antihistamines are recommended for the treatment and pretreatment of LAR associated with SLIT-T, there are no clinical trial data to support this recommendation. Rupatadine is an H1 antihistamine that also inhibits platelet activating factor activity. The objective of this case series is to describe real-world clinical situations in which rupatadine was used to treat or mitigate SLIT-T–related LAR. Case presentations Five cases are presented by the managing allergist and off-label use of rupatadine is their expert opinion only. Patients in all 5 cases were treated with a SLIT-T (e.g. ragweed, tree, grass, or house dust mites) for the management of allergic rhinitis and experienced bothersome LAR with the first SLIT-T administration. In 3 cases, rupatadine 10 mg was administered for the immediate treatment of LAR (either in-office with the first SLIT-T dose or for subsequent LAR experienced at home) and the symptoms resolved. In 3 cases, pretreatment with other second-generation H1 antihistamines was unable to prevent LAR and the patients discontinued the SLIT-T. In these 3 cases, switching to pretreatment with rupatadine allowed the patients to restart and tolerate SLIT-T treatment with minimal or no LAR. In these patients with an established history of LAR, proactive pretreatment with rupatadine in subsequent seasons or with initiation of a different SLIT-T mitigated the previously experienced LARs. Conclusions In the cases presented, treatment with rupatadine resolved LAR associated with SLIT-T treatment and rupatadine pretreatment appeared to mitigate subsequent LAR. Rupatadine may be an option to treat or improve the tolerability of the SLIT-T, potentially improving early treatment persistence.

Abbreviations Lp-PLA 2 lipoprotein-associated phospholipase A 2 LPS lipopolysaccharides LTA lipoteichoic acid OxPLs oxidized-phospholipids PAF platelet-activating factor SARS severe acute respiratory syndrome This special issue includes papers that address how immunity may be influenced by platelet-activating factor (PAF). PAF was discovered in 1972 and its structure was elucidated in 1979 as a glyceryl-ether lipid (1- I O i -alkyl-2-acetyl- I sn i -glycero-3-phosphocholine).[1] PAF exists in very low concentration and is extremely short-lived due to its degradation and inactivation by PAF acetylhydrolases including lipoprotein-associated phospholipase A SB 2 sb (Lp-PLA SB 2 sb ). IL-1 beta and IL-6 stimulate the production of platelet-activating factor (PAF) by cultured rabbit synovial cells. PAF-induced inflammatory and immuno-allergic ophthalmic diseases and their mitigation with PAF receptor antagonists: cell and nuclear effects. [Extracted from the article]

Platelet‐activating factor (PAF) is a phospholipid‐derived mediator with an established role in multiple inflammatory states. PAF is synthesized and secreted by multiple cell types and is then rapidly hydrolyzed and degraded to an inactive metabolite, lyso‐PAF, by the enzyme PAF acetylhydrolase. In addition to its role in platelet aggregation and activation, PAF contributes to allergic and nonallergic inflammatory diseases such as anaphylaxis, sepsis, cardiovascular disease, neurological disease, and malignancy as demonstrated in multiple animal models and, increasingly, in human disease states. Recent research has demonstrated the importance of the PAF pathway in multiple conditions including the prediction of severe pediatric anaphylaxis, effects on blood–brain barrier permeability, effects on reproduction, ocular diseases, and further understanding of its role in cardiovascular risk. Investigation of PAF as both a biomarker and a therapeutic target continues because of the need for directed management of inflammation. Collectively, studies have shown that therapies focused on the PAF pathway have the potential to provide targeted and effective treatments for multiple inflammatory conditions. [ABSTRACT FROM AUTHOR]

Fatty acids and phospholipid molecules are essential for determining the structure and function of cell membranes, and they hence participate in many biological processes. Platelet activating factor (PAF) and its precursor plasmalogen, which represent two subclasses of ether phospholipids, have attracted increasing research attention recently due to their association with multiple chronic inflammatory, neurodegenerative, and metabolic disorders. These pathophysiological conditions commonly involve inflammatory processes linked to an excess presence of PAF and/or decreased levels of plasmalogens. However, the molecular mechanisms underlying the roles of plasmalogens in inflammation have remained largely elusive. While anti‐inflammatory responses most likely involve the plasmalogen signal pathway; pro‐inflammatory responses recruit arachidonic acid, a precursor of pro‐inflammatory lipid mediators which is released from membrane phospholipids, notably derived from the hydrolysis of plasmalogens. Plasmalogens per se are vital membrane phospholipids in humans. Changes in their homeostatic levels may alter cell membrane properties, thus affecting key signaling pathways that mediate inflammatory cascades and immune responses. The plasmalogen analogs of PAF are also potentially important, considering that anti‐PAF activity has strong anti‐inflammatory effects. Plasmalogen replacement therapy was further identified as a promising anti‐inflammatory strategy allowing for the relief of pathological hallmarks in patients affected by chronic diseases with an inflammatory component. The aim of this Short Review is to highlight the emerging roles and implications of plasmalogens in chronic inflammatory disorders, along with the promising outcomes of plasmalogen replacement therapy for the treatment of various PAF‐related chronic inflammatory pathologies. [ABSTRACT FROM AUTHOR]

The objective of the study was to assess the pathogenic and treatment relevance of Platelet Activating factor (PAF) in chronic spontaneous urticaria (CSU). The expression and cellular location of PAF receptor (PAFR) and serum levels of PAF and PAF acetylhydrolase (PAF‐AH) in patients with moderate/severe CSU (n = 45) and healthy controls (HCs, n = 17) were studied. Skin samples from the active wheal (LS‐CSU, 13 samples for qPCR and 33 for immunohistochemistry) and non‐lesional skin (NLS‐CSU, 13 samples) of CSU patients and HCs (13 samples and 5 for immunohistochemistry) were analyzed. Serum PAF and PAF‐AH levels were measured by ELISA and compared between HC (10 samples) and CSU patients (25 samples) and, among them, between those refractory and non‐refractory to second‐generation H1‐antihistamines (sgAH). PAFR mRNA expression was significantly higher in LS‐CSU versus HCs (p = 0.014). PAFR positive staining in immunohistochemistry was mainly found in the epidermal basal layer in HCs, whereas it was broadly present along the epidermis in LS‐CSU samples. Endothelial cells showed PAFR expression exclusively in LS‐CSU and NLS‐CSU samples. PAFR expression was observed in the nerves of HC, LS‐CSU, and NLS‐CSU samples. Double PAFR/CD43 expression showed that T‐lymphocytes were the main cell type from the wheal inflammatory infiltrate expressing PAFR. A significantly lower PAF‐AH/PAF ratio was observed in sgAH non‐responders versus responders (6.1 vs. 12.6; p = 0.049). Our study confirms that PAF is a mediator of wheal pathogenesis in CSU. The significantly lower PAF‐AH/PAF ratio in sgAH non‐responders vs responders suggests that PAF could be a potential biomarker of sgAH refractoriness. [ABSTRACT FROM AUTHOR]

This study has been undertaken to evaluate the effect of butylphthalide combined with ozagrel sodium on cerebral perfusion and oxidative stress indexes in patients with transient ischemic attack. In this study, a total of 116 patients diagnosed as transient ischemic attack in our hospital (February 2018-February 2020) have been selected and divided into two groups according to the treatment methods.58 cases in the control group have been treated with ozagrel sodium, 58 cases in the observation group have been treated with butylphthalide combined with ozagrelsodium. The CT perfusion imaging parameters, oxidative stress indexes, plaque area, and the levels of platelet activating factor (PAF), α-granule membrane protein-140 (GMP-140), fibrinogen (FIB), platelet aggregation rate (PAgT), neuron-specific enolase (NSE), oxygen-inducible factor-1α ( HIF-1α ), and matrix metalloproteinases-9 ( MMP-9) in the two groups have been recorded, and the total effective rate and adverse reaction rate have been counted. The results shown that the total effective rate of the observation group is higher than that of the control group, and the difference is statistically significant (Χ² = 4.640, P = 0.031). The average time (MTT) required for the two groups of contrast agents to pass through the local brain tissue and the time (TTP) required starting the injection of contrast agents to reach the peak concentration decreased compared to that with before treatment. After treatment, the MTT and TTP of the observation group are shorter than those of the control group (P < 0.05). Compared with before treatment, superoxide dismutase (SOD) in the two groups has higher than that in the control group, PAF, GMP-140, FIB, PAgT, NSE, HIF-1α, MMP-9, malondialdehyde (MDA) and plaque area has decreased. After treatment, the levels of related factors in the observation group are better than those in the control group, and the plaque area is less than that in the control group (P < 0.05).There has been no significant difference in the adverse reaction rate between the observation group and the control group (Χ² = 0.438, P = 0.508). [ABSTRACT FROM AUTHOR]

To study the effect of cilostazol after thrombolytic therapy with recombinant human tissue plasminogen activator (rt-PA) in patients with acute cerebral infarction and its effect on Serum Platelet lysosomal membrane protein (CD63), α Role of granule membrane glycoprotein (CD62P) and platelet activating factor (PAF). 90 patients with acute cerebral infarction treated in our hospital from February 2020 to February 2022, they were randomly divided into observation group and control group, with 45 cases in each group. Both groups were treated with rt-PA thrombolytic therapy, the control group was treated with aspirin after thrombolytic therapy, and the observation group was treated with cilostazol on the basis of the control group, and were treated continuously for 14 days. The clinical efficacy, changes of serum CD62p, CD63, PAF, whole blood viscosity, plasma viscosity, erythrocyte specific volume (HCT), NIHSS score, Barthel scale (Barthel Index) score, and incidence of bleeding events were compared between the two groups. The total effective rate of the observation group was 91.11%, which was higher than 73.33% of the control group, with statistical significance (P<0.05); the serum CD62p, CD63 and PAF in observation group were lower than those in control group, with statistical significance (P<0.05); the whole blood viscosity, plasma viscosity and HCT in observation group were lower than those of control group, with statistical significance (P<0.05); the NIHSS score in observation group was lower than control group, and Barthel index was higher than control group, with statistical significance (P<0.05); comparison of the total incidence of bleeding events between the two groups, with statistical significance (P＞0.05). Cilostazol have a significant effect on acute cerebral infarction patients after rt-PA thrombolytic therapy, which can effectively reduce the expression of serum CD62p, CD63 and PAF and improve platelet function, with good safety and worthy of clinical promotion. [ABSTRACT FROM AUTHOR]

Chronic spontaneous urticaria (CSU) is a skin disease characterized by the presence of wheals, angioedema, or both for at least 6 weeks. Although, CSU is often regarded as autoimmune in nature, its etiology is not fully explained and interactions between various small molecules are still taken under account. The aim of this research was to investigate the mean serum concentration of vascular endothelial growth factor (VEGF), platelet activating factor (PAF), and eosinophil-derived neurotoxin (EDN) in relation to the disease activity and pruritus intensity in adult patients with CSU. Fifteen patients with CSU and 15 healthy subjects participated in this pilot study. Blood samples were taken to examine the mean serum levels of VEGF, PAF, and EDN by the enzyme-linked immunosorbent assay test (ELISA). The Urticaria Activity Score (UAS7) and The Visual Analogue Scale (VAS) were used to assess the disease activity and the pruritus intensity, respectively. Obtained results revealed that VEGF, PAF, and EDN concentrations were higher in patients with CSU compared with those of the control group, but only for VEGF it was statistically significant (p = 0.008). However, levels of all investigated cytokines were not significantly correlated neither with the disease activity nor with the pruritus intensity. Our results showed higher serum levels of VEGF, PAF, and EDN among CSU patients which may highlight a functional role of these cytokines in the disease's pathogenesis. In contrast, VEGF, PAF, or EDN might not be useful to reflect the severity of symptoms. [ABSTRACT FROM AUTHOR]