Platelet-activating Factor Levels Research Articles

Role of Platelet-Activating Factor in the Pathogenesis of Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is a debilitating condition characterized by mast cell activation. Platelet-activating factor (PAF) is produced by various immune cells, including mast cells, basophils, lymphocytes, and eosinophils, which play crucial roles in CSU pathogenesis. It induces mast cell degranulation, increases vascular permeability, and promotes the chemotaxis of inflammatory cells. These effects result in the release of inflammatory mediators, the development of edema, and the persistence of inflammation, which are key features of CSU. Notably, elevated PAF levels have been linked to heightened disease activity and resistance to antihistamine treatment in CSU patients. Despite these findings, the precise role of PAF in CSU pathogenesis remains unclear. Rupatadine, an antihistamine, and heat shock protein 10, a natural anti-inflammatory peptide that selectively inhibits PAF-induced mast cell degranulation, have demonstrated anti-PAF activity. Furthermore, with the molecular structure of the PAF receptor now identified, several experimental PAF receptor antagonists have been synthesized. However, there remains a significant need for the development of therapeutic options targeting PAF in CSU management.

An immune-adrenergic pathway induces lethal levels of platelet-activating factor in mice

Acute immune responses with excess production of cytokines, lipid/chemical mediators, or coagulation factors, often result in lethal damage. In addition, the innate immune system utilizes multiple types of receptors that recognize neurotransmitters as well as pathogen-associated molecular patterns, making immune responses complex and clinically unpredictable. We here report an innate immune and adrenergic link inducing lethal levels of platelet-activating factor. Injecting mice with toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS), cell wall N-glycans of Candida albicans, and the α2-adrenergic receptor (α2-AR) agonist medetomidine induces lethal damage. Knocking out the C-type lectin Dectin-2 prevents the lethal damage. In spleen, large amounts of platelet-activating factor (PAF) are detected, and knocking out lysophospholipid acyltransferase 9 (LPLAT9/LPCAT2), which encodes an enzyme that converts inactive lyso-PAF to active PAF, protects mice from the lethal damage. These results reveal a linkage/crosstalk between the nervous and the immune system, possibly inducing lethal levels of PAF.

Associations between food groups and biomarkers of inflammation: Are some foods groups more protective than others?

The consumption of healthy foods such as whole grains, vegetables, fruits, nuts, legumes, dairy, and fish is associated with decreased risk of cardiovascular disease (CVD). CVD is an inflammatory disease caused by atherosclerosis. Inflammation is measured clinically using hsCRP, however hsCRP is not specific to CVD. Novel pro-inflammatory markers, such as platelet-activating factor (PAF) and lipoprotein-associated phospholipase A2 (Lp-PLA2), have garnered attention due to their specific roles in endothelial dysfunction and CVD risk. During the COVID 19 outbreak research highlighted a potential interaction between PAF and Lp-PLA2 and the SARS COVID 19 virus(1-3) and related adenovirus-vector and mRNA vaccines.4 This cross-sectional study investigated the association between PAF, Lp-PLA2, hsCRP, and intake of healthy food groups including fruit, cruciferous and other vegetables, grains, meat and poultry, fish and seafood, nuts and legumes, and dairy in 100 adults (49 ± 13 years, 31% male) with variable CVD risk. Data were collected across four groups during May and July 2021 (Groups 1 and 2 - CVD risk factors) and January and April 2022 (Groups 3 and 4 - no CVD risk factors). Fasting PAF, Lp-PLA2 and hsCRP and usual dietary intake (food frequency questionnaire) were measured. Food intake was converted into serves and classified into food groups. Correlations and multiple regressions were performed. Contrary to expectations, mean PAF was lower for groups 1 and 2 (n = 46, mean PAF 3.31 ± 1.66 ng/mL) compared to groups 3 and 4 (n = 54, mean PAF 19.82 ± 12.95 ng/mL) p < 0.001 with a large effect size (eta squared 0.665). Cruciferous vegetables were associated with lower levels of PAF (β = -.27, CI [−0.41, −0.14], p < .001) with a one serve increase in cruciferous vegetables per day associated with an 24% reduction in PAF. Nuts and legumes were associated with lower levels of hsCRP (β = -.51, CI [−0.81, −0.22], p<.001) with an increase of one serve per day associated with a 40% reduction in hsCRP. There were small inverse associations between cheese and both PAF (β = -.15, CI [−0.27, −0.03], p = .017) and Lp-PLA2 (β = -.26, CI [−0.47, −0.04], p = .024), however these were not significant at the Bonferroni-adjusted P<.005 level. In conclusion, cruciferous vegetables and nut and legume consumption were associated with lower levels of inflammation. The lack of associations between PAF and Lp-PLA2 and other healthy foods may be due to confounding by COVID-19 infection and vaccination programs which prevents any firm conclusion on the relationship between PAF, Lp-PLA2 and food groups. Future research should aim to examine the relationship with these novel markers and healthy food groups in a non-pandemic setting.

Abstract 5526: Activation of platelet-activating factor (PAF) in high-risk melanoma patients with nodal metastasis

Abstract Background: Platelet-activating factor (PAF) is one of the lipid mediators in ultraviolet-induced immunosuppression signaling. Sentinel lymph nodes (SLNs) are the first organs to receive lymphatic drainage via afferent lymphatic channels leading directly from the primary melanoma. In patients with nodal metastasis, it has been shown that the SLN has a profoundly immunotolerant microenvironment. We sought to determine whether lymphatic fluid signals, including PAF, may be involved in modulating the SLN immune microenvironment to favor melanoma metastasis. Hypothesis: Upregulation of PAF can bind to its receptor on monocytes and activate downstream immunosuppressive chemokines, resulting in an immunosuppressed environment in SLNs that permits nodal metastasis and melanoma progression. Methods: Lymphatic fluids, plasma samples, and SLN samples were collected from patients undergoing surgical excision of melanoma with SLN biopsy under an IRB-approved protocol. Metabolic analyses were performed on lymphatic fluids from high- versus low-risk patients by two-dimensional liquid chromatography system coupled with mass spectrometry (2D LC-MS). Single cell sequencing was done on single cell suspensions from SLN samples. Protein array was used to compare the cytokine and chemokine levels in plasma samples from high- versus low-risk melanoma patients. We compared two groups: low-risk (no SLN metastasis) and high-risk (with SLN metastasis). Results: Lymphatic fluid PAF levels were 3-fold greater in high-risk melanoma patients compared with low-risk patients (p=0.0039). Macrophages were identified as the cell type with greatest PTAFR (platelet-activating factor receptor) expression by single cell sequencing. CCL17 levels in plasma samples from high-risk patients were significantly lower than in low-risk patients (p<0.05). These results suggest that increased PAF in lymphatic fluid may bind to PTAFR in SLN macrophages, inhibit chemokines (such as CCL17), and result in an immunosuppressive SLN environment to favor nodal metastasis and melanoma progression. Conclusion: Lymphatic fluid PAF signaling may contribute to an immunotolerant microenvironment in the SLN that allows nodal metastasis and melanoma progression through downregulation of CCL17. Further studies will investigate whether this pathway can be exploited to therapeutic advantage. Citation Format: Austin McMasters, Julia Chariker, Jae Yeon Hwang, Xinmin Yin, Xipeng Ma, Raobo Xu, Xiang Zhang, Juw Won Park, Kelly M. McMasters, Hongying Hao. Activation of platelet-activating factor (PAF) in high-risk melanoma patients with nodal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5526.

Differential expression of serum TM, PAF, and CD62P in patients with autologous arteriovenous fistula and the correlation with vascular access function.

End-stage renal disease (ESRD) is the final stage of chronic kidney disease (CKD). We aimed to analyze the expression differences of serum thrombomodulin (TM), platelet-activating factor (PAF), and P-selectin (CD62P) in patients with autologous arteriovenous fistula (AVF) and the correlation with vascular access function. The case data were retrospectively analyzed. Moreover, 160 patients with AVF maintenance hemodialysis were selected as the AVF group, and 150 healthy participants were selected as the healthy control group. According to the function of vascular access, patients in the AVF group were divided into Group A (n = 50, after the first establishment of AVF), Group B (n = 64, normal vascular access function after hemodialysis treatment), and Group C (n = 46, vascular access failure). Pearson analysis was conducted to explore the correlation between serum TM, PAF, CD62P content, and vascular pathological examination indicators, to evaluate the value of TM, PAF, and CD62P levels in predicting vascular access failure in patients with AVF. The serum levels of TM, PAF, and CD62P were positively correlated with the expressions of CD68 and MCP-1, respectively (p < .001). Serum TM was positively correlated with the levels of PAF and CD62P (p < .001), and PAF was positively correlated with the levels of CD62P (p < .001), respectively. Serum levels of TM, PAF and CD62P were risk factors for vascular access failure in AVF patients (p < .05). The area under the curve of serum TM, PAF and CD62P levels in predicting vascular access failure in AVF patients was 0.879. The serum levels of TM, PAF, and CD62P in AVF patients were correlated with the vascular access function of AVF patients, which was very important for maintaining the stability of vascular access function, and had certain value in predicting vascular access failure/disorder in AVF patients, and could be popularized and applied.

Evidence for the involvement of keratinocyte-derived microvesicle particles in the photosensitivity associated with xeroderma pigmentosum type A deficiency.

Photosensitivity can be due to numerous causes. The photosensitivity associated with deficiency of xeroderma pigmentosum type A (XPA) has been previously shown to be associated with excess levels of the lipid mediator platelet-activating factor (PAF) generated by the keratinocyte. As PAF has been reported to trigger the production of subcellular microvesicle particles (MVP) due to the enzyme acid sphingomyelinase (aSMase), the goal of these studies was to discern if PAF and aSMase could serve as therapeutic targets for the XPA deficiency photosensitivity. HaCaT keratinocytes lacking XPA generated greater levels of MVP in comparison to control cells. Mice deficient in XPA also generated enhanced MVP levels in skin and in plasma in response to UV radiation. Use of a genetic strategy with mice deficient in both XPA and PAF receptors revealed that these mice generated less MVP release as well as decreased skin erythema and cytokine release compared to XPA knockout mice alone. Finally, the aSMase inhibitor imipramine blocked UV-induced MVP release in HaCaT keratinocytes, as well as XPA knockout mice. These studies support the concept that the photosensitivity associated with XPA involves PAF- and aSMase-mediated MVP release and provides a potential pharmacologic target in treating this form of photosensitivity.

Investigation of the involvement of platelet-activating factor in the control of hypertension by aerobic training. A randomized controlled trial.

Although studies have demonstrated the effectiveness of exercise in controlling systemic arterial hypertension (SAH), the mechanisms involved in this effect are still poorly understood. Thus, this study investigated the impact of aerobic training on the relationship between platelet-activating factor (PAF) circulating levels and blood pressure in hypertensives. Seventy-seven hypertensive subjects were enrolled in this randomized controlled trial (age 66.51 ± 7.53 years, body mass 76.17 ± 14.19 kg). Participants were randomized to two groups: the intervention group (IG, n = 36), composed of hypertensive individuals submitted to an aerobic training protocol, and the control group (CG, n = 41), composed of non-exercised hypertensives. Body mass index, arterial blood pressure, quality of life, respiratory muscle strength, and functional capacity were assessed before and after 12 weeks. PAF and plasma cytokine levels were also evaluated respectively by liquid chromatography coupled with mass spectrometry and enzyme-linked immunosorbent assay. Aerobic training promoted a significant reduction in blood pressure while functional capacity, expiratory muscle strength, and quality of life, PAFC16:0 and PAFC18:1 plasma levels were increased in comparison to the CG (p < 0.05). In addition, multiple correlation analysis indicated a positive correlation [F (3.19) = 6.322; p = 0.001; R2adjusted = 0.499] between PAFC16:0 levels and expiratory muscle strength after aerobic training. Taken together, our findings indicate that PAF may be involved in the indirect mechanisms that control SAH, being mainly associated with increased respiratory muscle strength in hypertensive subjects undergoing aerobic training.

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

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

A Novel Adenovirus (Adv)-Vaccinated Murine Model Simulates the Prothrombotic Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT) Clinical Disorder

Background: VITT has emerged as a rare (10 -5 to 10 -6 vaccinated individuals), but life-threatening side-effect of post-AdV-based COVID-19 vaccination, characterized by rapidly progressive catastrophic thrombosis, thrombocytopenia and high levels of platelet-activating anti-platelet factor 4 (PF4) antibodies (Abs). While the disorder resembles heparin-induced thrombocytopenia (HIT) in that both anti-PF4 Abs activate platelets via FcγRIIA in the presence of PF4, the Abs differ in their requirements for heparin, i.e. HIT Abs require heparin, but VITT Abs do not. Moreover, alanine substitutions in PF4 revealed distinct antigenic sites in these two prothrombotic disorders. We observed that the defined VITT antigenic site, unlike the HIT antigenic site, is conserved on a second platelet-specific chemokine structurally similar to PF4, neutrophil activating peptide 2 (NAP2) and its precursor platelet-basic protein (PBP) and proposed that PBP as well as PF4 may be able to induce VITT. Objective: We have now generated a murine model of VITT (mVITT) to better understand the pathogenesis of this immune disorder and to examine whether PBP may be involved in this process. Methods: Transgenic FcγRIIA mice (n&amp;gt;5/group) that lack mPF4 (PF4 KO), but express human (h) PF4 were injected intramuscularly with 5x10 9 viral particles/mouse of ChadOx1-nCoV-19 (“nCoV-19 AdV”) leading to expression of the COVID-19 spike protein or control ChadOx-GFP, (“GFP AdV”) expressing the green fluorescent protein. To augment mVITT Ab production, mice also received CpG oligodeoxynucleotides (ODN 2395 or “ODN”, 10µg/mouse i.p for 5 days) as an adjuvant. In these latter experiments, ODN only- and carrier alone- (physiologic buffered saline, “PBS”) injected mice served as controls. The clinical course, blood counts and ELISA for Abs to spike protein, hPF4 and mPBP/NAP2 were followed once a week and organs were harvested for histology at the endpoint. Results: Only mice that received the nCoV-19 developed anti-spike protein Abs. In the studies without ODN, 1 out of the 20 mice injected with either nCoV-19 or GFP AdV developed progressive thrombocytopenia, massive thrombi in the lungs, heart and brain, and died at day 43, one day after receiving a second dose of GFP. This mouse developed a high titer of anti-mNAP2 Abs, but no significant increase in anti-hPF4 ( Table 1). In the studies with ODN adjuvant, 2 out of the 5 mice injected with nCoV-19 AdV and one of the 5 mice injected with GFP AdV developed thrombocytopenia and died at days 14, 39 and 40 after the 1 st dose and prior to being able to receive a second dose. Gross histology of the brains showed areas of infarction and/or hemorrhage. All three affected mice had raised anti-hPF4 Abs ( Table 1). Further characterization of these mice revealed newly formed anti-hPF4 Abs that were heparin independent. Moreover, two monoclonal (mo) Abs, a humanized version of KKO (G4 KKO) that only binds to the HIT antigenic site and 1E12 shown to bind to the VITT antigenic site, were tested for their ability to block the binding of mVITT Ab to hPF4. Only 1E12 blocked that binding (Figure 1). None of the ODN or PBS control mice developed thrombocytopenia or died ( Table 1). Conclusions: We have developed a murine model to simulate the development of VITT that supports AdV:chemokine complex formation as being key to the development of Abs and the prothrombotic state in VITT. This model indicates that anti-PBP/NAP2 Abs can develop after AdV immunization. We also show that the inclusion of an oligonucleotide adjuvant switched antigenic targeting to hPF4. The anti-hPF4 Ab did not develop when adjuvant alone was given, and the resultant Abs clearly bound as VITT-like Abs and not HIT Abs. The basis for the apparent ability of ODN to switch which chemokine is immunogenic will need future study. This model system may be useful in designing AdV that do not induce VITT as backbone for vaccines in the future as well.

Associations of phase angle with platelet-activating factor metabolism and related dietary factors in healthy volunteers.

Phase angle (PA) is derived from bioelectrical impedance analysis (BIA). It reflects cell membrane function and decreases in disease. It is affected by inflammation, oxidative stress, and diet. Platelet-activating factor (PAF) is a potent inflammatory lipid mediator. Its levels, along with the activity of its metabolic enzymes, including CDP-choline:1-alkyl-2-acetyl-sn-glycerol-cholinephosphotransferase, acetyl-CoA:lyso-PAF-acetyltransferases, and PAF-AH/Lp-PLA2 are also related to dietary factors, such as the dietary antioxidant capacity (DAC). The aim of the study was to estimate whether the PAF metabolic circuit and related dietary factors are associated with PA in healthy volunteers. In healthy subjects, PAF, its metabolic enzyme activity, and erythrocyte fatty acids were measured, while desaturases were estimated. Food-frequency questionnaires and recalls were used, and food groups, macronutrient intake, MedDietScore, and DAC were assessed. Lifestyle and biochemical variables were collected. DXA and BIA measurements were performed. Lp-PLA2 activity was positively associated with PA (rho = 0.651, p < 0.001, total population; rho = 0.780, p < 0.001, women), while PAF levels were negatively associated with PA only in men (partial rho = -0.627, p = 0.012) and inversely related to DAC. Estimated desaturase 6 was inversely associated with PA (rho = -0.404, p = 0.01, total sample). Moreover, the DAC correlated positively with PA (rho = 0.513, p = 0.03, women). All correlations were adjusted for age, body mass index, and sex (if applicable). PA is associated with PAF levels and Lp-PLA2 activity in a gender-dependent fashion, indicating the involvement of PAF in cell membrane impairment. The relationship of PA with DAC suggests a protective effect of antioxidants on cellular health, considering that antioxidants may inhibit PAF generation.

B-cell-activating factor (BAFF) and platelet-activating factor (PAF) in pregnancies complicated by maternal obesity and diabetes: a preliminary study

Objective In pregnancies complicated by maternal obesity and diabetes, a disruption in inflammatory mediators occurs, resulting in endothelial microvascular dysfunction, oxidative stress, tissue damage, and maternal and feto-neonatal complications. To outline this proinflammatory status, an innovative approach is represented by the measurement of proinflammatory cytokines. Among these biomarkers, B-cell-activating factor (BAFF) and platelet-activating factor (PAF) play a key role in metabolic regulation, immune response to infections, tissue homeostasis, and “food-related inflammation.” The aim of the present study is to investigate the blood expression of BAFF and PAF in a cohort of pregnant women affected by obesity and diabetes compared with a control group of healthy pregnant women. Methods A prospective longitudinal cohort study has been conducted on pregnant women referred to Fondazione Policlinico Universitario Gemelli IRCCS in Rome. For each pregnant woman, a capillary sample was collected with a swab in three different consecutive evaluations carried out in the three trimesters of pregnancy. Results A total of 77 pregnant women have been enrolled. No significant differences in BAFF and PAF levels were longitudinally observed between groups. Focusing on the exposed group, in the third trimester of pregnancy, both PAF and BAFF levels were lower than the basal time. Among the selected group of patients who developed Gestational Diabetes, only PAF values were longitudinally lower when compared to other groups. The multivariate analysis showed that BAFF levels were positively correlated with thyroid-stimulating hormone levels. No macrosomia, no shoulder dystocia, no major perineal lacerations at birth, and no intrauterine growth restriction were observed in the whole population. Conclusions This study supports the involvement of metabolic and proinflammatory biomarkers in the mechanisms related to pregnancy complications. Improving a good metabolic environment for obese and diabetic pregnant women could break the vicious cycle connecting inflammation, oxidative stress, and metabolic disorders.

Qushi Huayu decoction ameliorates non-alcoholic fatty liver disease in rats by modulating gut microbiota and serum lipids.

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. 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 chromatography-mass spectrometry (UPLC-MS) were conducted to elucidate the therapeutic mechanism of NAFLD in QHD. 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_sensu_stricto_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_sensu_stricto_1, and Turicibacter, which were also significantly correlated with the biological parameters of NAFLD. Taken together, QHD may exert beneficial effects by regulating the gut microbiota and thus intervening in serum lipids.

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

Serum Levels of Eosinophil-Derived Neurotoxin, Platelet-Activating Factor and Vascular Endothelial Growth Factor in Adult Patients with Atopic Dermatitis-A Pilot Study.

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.

Assessment of Some Platelet Activating Markers and Secretory Status with Clinical Manifestations in Multiple Sclerosis Iraqi Patients

Patients with Multiple sclerosis (MS) are presented with different degree of disability based on Expanded disability status scale (EDSS). Several studies reported that ABH non-secretors have higher prevalence in different auto-immune diseases, also platelets have a multi-form participation in development of MS. Therefore, this study aimed to assess the correlation of clinical manifestations in patients with platelet-activating factor (PAF), P-Selectin, matrix metalloproteinase-9 (MMP-9) and ABH secretor status. Fifty Iraqi patients with relapsing-remitting multiple sclerosis (RRMS) were enrolled and divided into two subgroups; 36 of them with no disability (D0), their EDSS score ranging between 0-1.5, and the rest 14 patients with different degrees of disability (D+), their EDSS score ≥ 2. Along with patients, 20 healthy subjects were involved to act as a control group. Results showed significant elevation of PAF, P-Selectin, and MMP-9 levels in patients compared with those in the control group. However, only PAF level in D+ patients is significantly higher than D0 and positively correlated with duration of disease and serum level of MMP-9. Moreover, the frequency of non-secretors among RRMS patients is significantly higher than those in the control group and have a higher level of MMP-9, so may act as a risk factor for getting MS disease via increasing the serum level of MMP-9.

Serum Levels of Vascular Endothelial Growth Factor, Platelet Activating Factor and Eosinophil-Derived Neurotoxin in Chronic Spontaneous Urticaria-A Pilot Study in Adult Patients.

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.

New transcriptome and clinical findings of platelet-activating factor in chronic spontaneous urticaria: Pathogenic and treatment relevance.

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.

Platelet augmentation activity of mature leaf juice of Sri Lankan wild type cultivar of Carica papaya L: Insights into potential cellular mechanisms

Ethnopharmacological relevanceCarica papaya L., a common fruit crop of the family Caricaceae and its leaf juice/extract is a traditionally commended preparation against dengue and other thrombocytopenic diseases by many Asian countries. Aim of the studyThe present study posits the potential cellular mechanisms of platelet augmentation activity of mature leaf juice of Sri Lankan wild-type Carica papaya. Materials and methodsC. papaya leaf juice prepared from different cultivar types, maturity of the leaf, agro-climatic region, and preparation methods were orally administered to hydroxyurea-induced thrombocytopenic rats at 0.72 ml/100 g BW dosage to investigate the most potent platelet increasing preparation.The papaya juice doses; low dose (LD-0.18 ml/100 g BW), human equivalent dose (HED-0.36 ml/100 g BW), and high dose (HD-0.72 ml/100 g BW), were administered to thrombocytopenic rats (N = 6/group) daily for three consecutive days and post-treatment plasma levels of interleukin 6 (IL-6), thrombopoietin (TPO), and platelet-activating factor (PAF) were quantified using specific rat ELISA kits. The mature leaf juice of C. papaya induced IL-6 secretion from bone marrow cell (BMC) cultures was quantified using ELISA. The ability of papaya juice to protect the platelet membrane, from the damage caused by the lytic agent was analyzed in vitro using the lactate dehydrogenase (LDH) assay. The effect of the mature leaf juice of C. papaya on secondary hemostasis was investigated using blood coagulation and clot hydrolyzing activity. ResultsThe comparative analysis revealed that the platelet increasing activity of C. papaya leaf did not significantly differ among different types of cultivar, maturity of the leaf, agro-climatic regions and preparation methods (p > 0.05). Both TPO and PAF levels in thrombocytopenic rats diminished when treated with all three doses of the mature leaf juice of C. papaya (p < 0.05), yet IL-6 plasma level was unaltered (p > 0.05). Nevertheless, ex vivo treatment of the mature leaf juice of C. papaya had significantly enhanced IL-6 levels of rat BMC cultures (p < 0.05). Pre-treatment of platelets with the mature leaf juice of C. papaya at different concentrations significantly inhibited LDH leakage from platelets and may have reduced the membrane damage caused by the lytic agent (p < 0.05). Treatment of mature leaf juice of C. papaya also significantly reduced blood clotting time through the extrinsic pathway of the blood coagulation cascade (p < 0.05). Further, prolonged incubation of the plasma clot with different concentrations of the papaya leaf juice revealed dose-dependent hydrolysis of the blood clot, indicating fibrinolysis activity. ConclusionsThe current study exceeded the traditional medicinal claims, and scientifically affirmed the platelet augmentation activity of mature leaf juice of C. papaya. The mechanistic rationale tested herein explicated that the platelet augmentation activity of the papaya leaf juice can be partially attributed to the stimulation of bone marrow megakaryocytes via modulating thrombopoietic cytokines TPO and IL-6, and by inhibiting the secretion of PAF, while reducing the peripheral platelet destruction by stabilizing the platelet membrane. Further, mature leaf juice of C. papaya imparted both pro-coagulation and fibrinolysis activity of secondary hemostasis endorsing its potential against thrombocytopenia.

The association between dietary patterns and the novel inflammatory markers platelet-activating factor and lipoprotein-associated phospholipase A2: a systematic review.

ContextAtherosclerosis is a disease of chronic inflammation. Recent research has identified 2 novel inflammatory biomarkers: platelet-activating factor (PAF) and lipoprotein-associated phospholipase A2 (Lp-PLA2). Diet has been proposed as a mediator of inflammation, but to date, the focus for these novel biomarkers has been on individual foods and nutrients rather than overall dietary patterns.ObjectiveTo systematically review the literature on the association between dietary patterns and PAF and Lp-PLA2.Data SourcesThe PubMed, Embase, CINAHL, and Cochrane CENTRAL literature databases were searched.Data AnalysisStudy quality was evaluated using the Quality Criteria Checklist. Sixteen studies (n = 4 observational and n = 12 interventional) were included and assessed for associations between dietary patterns and PAF and Lp-PLA2.ConclusionStudy quality varied from neutral (n = 10) to positive (n = 6). Mediterranean, heart healthy, and vegetarian dietary patterns were associated with improved levels of PAF and Lp-PLA2. Conversely, Western dietary patterns were less favorable. A range of well-established, healthier dietary patterns may lower inflammation and the risk of atherosclerosis. More well-designed studies are needed to confirm these findings and identify other dietary patterns that improve inflammation.

Rupatadine ameliorated ulcerative colitis in rats via modulation of platelet-activatiweng factor/interleukin-6/vascular endothelial growth factor signalling pathway.

This study aimed to analyse the potential effect of rupatadine (RUP) on ulcerative colitis (UC) induced by acetic acid (AA). Forty male adult Wistar rats were divided into five groups: Control group: received vehicles for 14 days; AA model group: received AA at the 13th day; Sulfasalazine (SLZ) + AA group: received SLZ (250mg/kg) for 14 days and AA at the 13th day; RUP-3 + AA group: received RUP (3mg/kg/day) for 14 days and AA at the 13th day; and RUP-6 + AA group: received RUP (6mg/kg/day) for 14 days and AA at the 13th day. Evidence of UC was assessed both macroscopically and microscopically. Oxidative stress markers (total antioxidant capacity and malondialdehyde), antioxidant enzyme (superoxide dismutase), histamine and platelet-activating factor (PAF) were determined. Immunohistochemical estimations of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) were done. The AA group showed evidence of UC that was associated with a significant increase in oxidative stress, histamine and PAF levels with significant elevation in colonic VEGF and IL-6 immuno-expressions. RUP, in a dose-dependent manner, significantly ameliorated UC. RUP protects against UC by reducing oxidative stress and by regulating the PAF/IL-6/VEGF pathway.