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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. [ABSTRACT FROM AUTHOR]

Cigarette smoking is known to be the leading cause of chronic obstructive pulmonary disease (COPD). However, the detailed mechanisms have not been elucidated. PAF (platelet-activating factor), a potent inflammatory mediator, is involved in the pathogenesis of various respiratory diseases such as bronchial asthma and COPD. We focused on LPLAT9 (lysophospholipid acyltransferase 9), a biosynthetic enzyme of PAF, in the pathogenesis of COPD. LPLAT9 gene expression was observed in excised COPD lungs and single-cell RNA sequencing data of alveolar macrophages (AMs). LPLAT9 was predominant and upregulated in AMs, particularly monocyte-derived AMs, in patients with COPD. To identify the function of LPLAT9/PAF in AMs in the pathogenesis of COPD, we exposed systemic LPLAT9-knockout (LPALT9−/−) mice to cigarette smoke (CS). CS increased the number of AMs, especially the monocyte-derived fraction, which secreted MMP12 (matrix metalloprotease 12). Also, CS augmented LPLAT9 phosphorylation/activation on macrophages and, subsequently, PAF synthesis in the lung. The LPLAT9−/− mouse lung showed reduced PAF production after CS exposure. Intratracheal PAF administration accumulated AMs by increasing MCP1 (monocyte chemoattractant protein-1). After CS exposure, AM accumulation and subsequent pulmonary emphysema, a primary pathologic change of COPD, were reduced in LPALT9−/− mice compared with LPLAT9+/+ mice. Notably, these phenotypes were again worsened by LPLAT9+/+ bone marrow transplantation in LPALT9−/− mice. Thus, CS-induced LPLAT9 activation in monocyte-derived AMs aggravated pulmonary emphysema via PAF-induced further accumulation of AMs. These results suggest that PAF synthesized by LPLAT9 has an important role in the pathogenesis of COPD. [ABSTRACT FROM AUTHOR]

The off-label use of second-generation antihistamines, used outside of the formal indications authorized by regulatory authorities, in different age groups, doses or in special populations, is very common for many allergic, autoimmune and dermatological diseases. The off-label use of rupatadine (a second-generation antihistamine with PAF antagonist activity) in these conditions is reviewed here, including in combination with immunotherapy in the treatment of food allergy or allergic rhinitis, at high doses in chronic urticaria, and with prescriptions of less common but challenging conditions such as skin pruritus or mast cell activation disorders like mastocytosis. Rupatadine use is reviewed herein to confirm if its off-label management is supported by well-designed clinical trials or by published real-world cases. This review will contribute to increasing compliance and achieving better results in clinical practice. Off-label use of rupatadine should be left to the discretion of the prescribing healthcare professional after careful clinical evaluation.

Background: The Platelet-Activating Factor (PAF)/receptor (PAFR) system is involved in asthma and allergic rhinitis; however, its role in chronic rhinosinusitis (CRS) is still unclear. This study aimed to assess the expression of PAFR and the concentration of Lyso-PAF isoforms in the nasal polyps (NP) of patients suffering from CRS with/without comorbidities such as asthma and NSAID-exacerbated respiratory disease (N-ERD) compared to healthy nasal mucosa (NM) from control subjects. Methods: NM (n = 8) and NP tissues were obtained from patients undergoing surgery for septal deviation/turbinate hypertrophy or endoscopic sinus surgery, respectively. Three phenotypes were studied: CRSwNP with no asthma (n = 6), CRSwNP with non-steroidal anti-inflammatory drug (NSAID)-tolerant asthma (n = 6), and CRSwNP with NSAID-exacerbated respiratory disease (n = 6). PAFR protein and mRNA were assessed via immunochemistry, immunofluorescence, Western blot, and real-time quantitative PCR. Lyso-PAF isoforms (C16, C18, and C18:1) were quantified via mass spectrometry. Results: PAFR protein was expressed in the NM and NP, concretely in epithelial cells and submucosal glands. Compared to NM, PAFR mRNA expression was higher in all NP phenotypes (p < 0.05) while all Lyso-PAF isoform concentrations were higher in the NP from asthmatic patients (p < 0.05). Lyso-PAF C16 and C18 concentrations were higher in the NP from asthmatic patients than in the NP from patients without asthma. Conclusions: The PAF/PAFR system could play a pathophysiological role in CRSwNP pathogenesis. [ABSTRACT FROM AUTHOR]

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

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

Antioxidants are known to play a crucial role in maintaining cellular health by neutralizing harmful free radicals. Among various dietary sources of antioxidants, wheat-based products, particularly flours, have gained significant attention due to their potential health benefits. Durum wheat, a widely cultivated species, serves as a primary ingredient in numerous food products. However, limited research has been conducted to assess the antioxidant activity of flours obtained from durum wheat varieties. In this study, we aimed to comparatively evaluate the antioxidant and antiplatelet potential of flours from 22 selected durum wheat varieties cultivated in Greece. We focused on three major parameters for antioxidant activity measurement: total phenolic content, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and ferric-reducing antioxidant power (FRAP). The total phenolic content was determined using the Folin–Ciocalteu method, while DPPH and FRAP assays were employed to assess the ability of flours to scavenge free radicals and reduce ferric ions, respectively. The antiplatelet activity was evaluated using a platelet-activating factor inhibition assay (PAF) in platelet-rich plasma. Analysis of the data revealed notable differences in the total phenolics and antioxidant and antiplatelet activities among the tested samples. The total phenolic content ranged from 624.0 ± 3.5 to 950.0 ± 5.3 μg of gallic acid equivalent/g flour with the variety Zeta E having the highest content. The antioxidant activities based on the DPPH and FRAP assays ranged from 0.56 ± 0.02 to 2.26 ± 0.08 and 1.93 ± 0.02 to 3.65 ± 0.03 μmol of Trolox equivalent/g flour, respectively, with the varieties Marco Aurelio and Zeta E exerting the highest antioxidant activities in the DPPH and FRAP tests, respectively. In addition, the IC50 values for the antiplatelet activity ranged from 0.72 ± 0.21 to 3.06 ± 0.17 in mg of flour, with the variety of Zoi exhibiting the highest antiplatelet activity. Overall, this comparative evaluation highlights the differences in the antioxidant and antiplatelet activities among flours obtained from 22 different durum wheat varieties cultivated in Greece. The results from this study aid in the selection of wheat varieties with superior antioxidant and antiplatelet capacities for use in bakery food formulation and dietary recommendations. [ABSTRACT FROM AUTHOR]

Inflammatory mediators constitute a recently coined term in the field of metal-based complexes with antiplatelet activities. Our strategy targets Platelet-Activating Factor (PAF) and its receptor, which is the most potent lipid mediator of inflammation. Thus, the antiplatelet (anti-PAF) potency of any substance could be exerted by inhibiting the PAF-induced aggregation in washed rabbit platelets (WRPs), which internationally is a well-accepted methodology. Herein, a series of mononuclear (mer-[Cr(pqx)Cl3(H2O]) (1), [Co(pqx)Cl2(DMF)] (2) (DMF = N,N′-dimethyl formamide), [Cu(pqx)Cl2(DMSO)] (3) (DMSO = dimethyl sulfoxide), [Zn(pqx)Cl2] (4)) and dinuclear complexes ([Mn(pqx)(H2O)2Cl2]2 (5), [Fe(pqx)Cl2]2 (6) and [Ni(pqx)Cl2]2 (7)) incorporating the 2-(2′-pyridyl)quinoxaline ligand (pqx), were biologically evaluated as inhibitors of the PAF- and thrombin-induced aggregation in washed rabbit platelets (WRPs). The molecular structure of the five-co-ordinate analog (3) has been elucidated by single-crystal X-ray diffraction revealing a trigonal bipyramidal geometry. All complexes are potent inhibitors of the PAF-induced aggregation in WRPs in the micromolar range. Complex (6) displayed a remarkable in vitro dual inhibition against PAF and thrombin, with IC50 values of 1.79 μM and 0.46 μM, respectively. Within the series, complex (5) was less effective (IC50 = 39 μM) while complex (1) was almost 12-fold more potent against PAF, as opposed to thrombin-induced aggregation. The biological behavior of complexes 1, 6 and 7 on PAF's basic metabolic enzymatic pathways reveals that they affect key biosynthetic and catabolic enzymes of PAF underlying the anti-inflammatory properties of the relevant complexes. The in vitro cytotoxic activities of all complexes in HEK293T (human embryonic kidney cells) and HeLa cells (cervical cancer cells) are described via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The results reveal that complex 3 is the most potent within the series. [ABSTRACT FROM AUTHOR]

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

Glioblastoma multiforme (GBM) is an aggressive, highly proliferative, invasive brain tumor with a poor prognosis and low survival rate. The current standard of care for GBM is chemotherapy combined with radiation following surgical intervention, altogether with limited efficacy, since survival averages 18 months. Improvement in treatment outcomes for patients with GBM requires a multifaceted approach due to the dysregulation of numerous signaling pathways. Recently emerging therapies to precisely modulate tumor angiogenesis, inflammation, and oxidative stress are gaining attention as potential options to combat GBM. Using a mouse model of GBM, this study aims to investigate Avastin (suppressor of vascular endothelial growth factor and anti-angiogenetic treatment), LAU-0901 (a platelet-activating factor receptor antagonist that blocks pro-inflammatory signaling), Elovanoid; ELV, a novel pro-homeostatic lipid mediator that protects neural cell integrity and their combination as an alternative treatment for GBM. Female athymic nude mice were anesthetized with ketamine/xylazine, and luciferase-modified U87MG tumor cells were stereotactically injected into the right striatum. On post-implantation day 13, mice received one of the following: LAU-0901, ELV, Avastin, and all three compounds in combination. Bioluminescent imaging (BLI) was performed on days 13, 20, and 30 post-implantation. Mice were perfused for ex vivo MRI on day 30. Bioluminescent intracranial tumor growth percentage was reduced by treatments with LAU-0901 (43%), Avastin (77%), or ELV (86%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 72, 92, and 96%, respectively. Additionally, tumor reduction was confirmed by MRI on day 30, which shows a decrease in tumor volume by treatments with LAU-0901 (37%), Avastin (67%), or ELV (81.5%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 69, 78.7, and 88.6%, respectively. We concluded that LAU-0901 and ELV combined with Avastin exert a better inhibitive effect in GBM progression than monotherapy. To our knowledge, this is the first study that demonstrates the efficacy of these novel therapeutic regimens in a model of GBM and may provide the basis for future therapeutics in GBM patients.

Glioblastoma multiforme (GBM) is an aggressive, highly proliferative, invasive brain tumor with a poor prognosis and low survival rate. The current standard of care for GBM is chemotherapy combined with radiation following surgical intervention, altogether with limited efficacy, since survival averages 18 months. Improvement in treatment outcomes for patients with GBM requires a multifaceted approach due to the dysregulation of numerous signaling pathways. Recently emerging therapies to precisely modulate tumor angiogenesis, inflammation, and oxidative stress are gaining attention as potential options to combat GBM. Using a mouse model of GBM, this study aims to investigate Avastin (suppressor of vascular endothelial growth factor and anti-angiogenetic treatment), LAU-0901 (a platelet-activating factor receptor antagonist that blocks pro-inflammatory signaling), Elovanoid; ELV, a novel pro-homeostatic lipid mediator that protects neural cell integrity and their combination as an alternative treatment for GBM. Female athymic nude mice were anesthetized with ketamine/xylazine, and luciferase-modified U87MG tumor cells were stereotactically injected into the right striatum. On post-implantation day 13, mice received one of the following: LAU-0901, ELV, Avastin, and all three compounds in combination. Bioluminescent imaging (BLI) was performed on days 13, 20, and 30 post-implantation. Mice were perfused for ex vivo MRI on day 30. Bioluminescent intracranial tumor growth percentage was reduced by treatments with LAU-0901 (43%), Avastin (77%), or ELV (86%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 72, 92, and 96%, respectively. Additionally, tumor reduction was confirmed by MRI on day 30, which shows a decrease in tumor volume by treatments with LAU-0901 (37%), Avastin (67%), or ELV (81.5%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 69, 78.7, and 88.6%, respectively. We concluded that LAU-0901 and ELV combined with Avastin exert a better inhibitive effect in GBM progression than monotherapy. To our knowledge, this is the first study that demonstrates the efficacy of these novel therapeutic regimens in a model of GBM and may provide the basis for future therapeutics in GBM patients.

IntroductionPhase 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.MethodsIn 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.ResultsLp-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).ConclusionPA 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.

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

Traditionally cardiovascular disease (CVD) risk has been assessed through blood lipids and inflammatory marker C‐reactive protein (hsCRP). Recent clinical interest in novel pro‐inflammatory markers platelet‐activating factor (PAF) and lipoprotein‐associated phospholipase A2 (Lp‐PLA2) recognizes that vascular damage can exist in the absence of traditional risk factors. This cross‐sectional study investigated the potential relationship between circulating PAF, Lp‐PLA2, hsCRP, and traditional risk factors for CVD. One hundred adults (49 ± 13 years, 31% male) with variable CVD risk were recruited. Fasting inflammatory markers PAF, Lp‐PLA2 and hsCRP and total, high‐density lipoprotein (HDL), low‐density lipoprotein (LDL) cholesterol, and triglycerides were measured. Blood pressure, body mass index, and waist circumference were measured. Medical and physical activity data were self‐reported. Linear and multiple regressions were performed. PAF, Lp‐PLA2, and hsCRP independently correlated with several CVD risk factors. PAF was correlated significantly with risk factors in an unexpected way; there was a medium positive correlation between PAF and HDL cholesterol (r = 0.394, p < 0.001) and medium negative correlations with Total:HDL cholesterol; (r = −0.436, p < 0.001) systolic blood pressure; (r = −0.307, p = 0.001); BMI (r = −0.381, p < 0.001); and waist circumference (r = −0.404, p < 0.001). There were large positive correlations between Lp‐PLA2 and LDL (r = 0.525, p < 0.001) and non‐HDL cholesterol (r = 0.508, p < 0.001). There were large positive correlations between hsCRP and Total:HDL cholesterol (r = 0.524, p < 0.001); BMI (r = 0.668, p < 0.001); and waist circumference (r = 0.676, p < 0.001). PAF, Lp‐PLA2, and hsCRP are implicated in the pathophysiology of inflammation in CVD; however, the relationships between each marker and traditional risk factors were different suggesting they may be involved in different atherogenic pathways. [ABSTRACT FROM AUTHOR]

Hang Yin, Anhua Shi, Junzi Wu Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of ChinaCorrespondence: Junzi Wu; Anhua Shi, Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China, Tel/Fax +86 187 8855 7524 ; +86 138 8885 0813, Email xnfz@ynutcm.edu.cn; 2697349858@qq.comAbstract: Non-alcoholic fatty liver disease (NAFLD) is a multifaceted clinicopathological syndrome characterised by excessive hepatic lipid accumulation that causes steatosis, excluding alcoholic factors. Platelet-activating factor (PAF), a biologically active lipid transmitter, induces platelet activation upon binding to the PAF receptor. Recent studies have found that PAF is associated with gamma-glutamyl transferase, which is an indicator of liver disease. Moreover, PAF can stimulate hepatic lipid synthesis and cause hypertriglyceridaemia. Furthermore, the knockdown of the PAF receptor gene in the animal models of NAFLD helped reduce the inflammatory response, improve glucose homeostasis and delay the development of NAFLD. These findings suggest that PAF is associated with NAFLD development. According to reports, patients with NAFLD or animal models have marked platelet activation abnormalities, mainly manifested as enhanced platelet adhesion and aggregation and altered blood rheology. Pharmacological interventions were accompanied by remission of abnormal platelet activation and significant improvement in liver function and lipids in the animal model of NAFLD. These confirm that platelet activation may accompany a critical importance in NAFLD development and progression. However, how PAFs are involved in the NAFLD signalling pathway needs further investigation. In this paper, we review the relevant literature in recent years and discuss the role played by PAF in NAFLD development. It is important to elucidate the pathogenesis of NAFLD and to find effective interventions for treatment.Keywords: non-alcoholic fatty liver disease, platelet-activating factor, oxidative stress, inflammation, insulin resistance

COVID-19 is associated with a dysregulated immune response. Currently, several medicines are licensed for the treatment of this disease. Due to their significant role in inhibiting pro-inflammatory cytokines and lipid mediators, glucocorticoids (GCs) have attracted a great deal of attention. Similarly, the endocannabinoid (eCB) system regulates various physiological processes including the immunological response. Additionally, during inflammatory and thrombotic processes, phospholipids from cell membranes are cleaved to produce platelet-activating factor (PAF), another lipid mediator. Nonetheless, the effect of GCs on this lipid pathway during COVID-19 therapy is still unknown. This is a cross-sectional study involving COVID-19 patients (n = 200) and healthy controls (n = 35). Target tandem mass spectrometry of plasma lipid mediators demonstrated that COVID-19 severity affected eCBs and PAF synthesis. This increased synthesis of eCB was adversely linked with systemic inflammatory markers IL-6 and sTREM-1 levels and neutrophil counts. The use of GCs altered these lipid pathways by reducing PAF and increasing 2-AG production. Corroborating this, transcriptome analysis of GC-treated patients blood leukocytes showed differential modulation of monoacylglycerol lipase and phospholipase A2 gene expression. Altogether, these findings offer a breakthrough in our understanding of COVID-19 pathophysiology, indicating that GCs may promote additional protective pharmacological effects by influencing the eCB and PAF pathways involved in the disease course. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [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]

Experiments were undertaken to identify the nature of a previously identified inhibitor of PAF-induced platelet aggregation (PA) in human saliva. Human saliva fractionated by preparative thin layer chromatography (TLC) yielded a fraction that co-migrated with fatty acids (FAs) and inhibited PAF-induced aggregation of platelets. Synthetic FAs tested for their capacities to inhibit 0.1 nM PAF-induced PA showed that only the cis-unsaturated compounds were inhibitory with activities of some of the polyunsaturated FAs (PUFA) reaching almost 100% at 20 μM. Eicosapentanoic acid (EPA) and 8,11,14-eicosatrienoic acid also deaggregated the PAF-induced aggregates. With the exception of oleic acid (OLA), cis-monounsaturated FAs, and elaidic acid, the trans isomer of OLA, were poor inhibitors. In a direct comparison with other platelet agonists, ADP, thrombin, and ionophore A23187, the active saliva fraction and selected individual FAs inhibited, to greater or lesser extent, PA induced by each of the agonists. EPA, OLA, linoleic acid (LNA), and the active saliva fraction were potent inhibitors of ADP-induced PA, EPA completely inhibited thrombin-induced PA and the saliva fraction showed only weak – moderate inhibitory activity to both thrombin- and ionophore A23187-induced PA. Other reports of endogenous PAF inhibitors in mammalian tissues are compared to the present results. PAF can trigger and amplify inflammatory cascades suggesting a possible modulation role for cis-unsaturated FAs in some diseases.

Inflammatory mediators constitute a recently coined term in the field of metal-based complexes with antiplatelet activities. Our strategy targets Platelet-Activating Factor (PAF) and its receptor, which is the most potent lipid mediator of inflammation. Thus, the antiplatelet (anti-PAF) potency of any substance could be exerted by inhibiting the PAF-induced aggregation in washed rabbit platelets (WRPs), which internationally is a well-accepted methodology. Herein, a series of mononuclear (mer-[Cr(pqx)Cl3(H2O]) (1), [Co(pqx)Cl2(DMF)] (2) (DMF = N,N′-dimethyl formamide), [Cu(pqx)Cl2(DMSO)] (3) (DMSO = dimethyl sulfoxide), [Zn(pqx)Cl2] (4)) and dinuclear complexes ([Mn(pqx)(H2O)2Cl2]2 (5), [Fe(pqx)Cl2]2 (6) and [Ni(pqx)Cl2]2 (7)) incorporating the 2-(2′-pyridyl)quinoxaline ligand (pqx), were biologically evaluated as inhibitors of the PAF- and thrombin-induced aggregation in washed rabbit platelets (WRPs). The molecular structure of the five-co-ordinate analog (3) has been elucidated by single-crystal X-ray diffraction revealing a trigonal bipyramidal geometry. All complexes are potent inhibitors of the PAF-induced aggregation in WRPs in the micromolar range. Complex (6) displayed a remarkable in vitro dual inhibition against PAF and thrombin, with IC50 values of 1.79 μM and 0.46 μM, respectively. Within the series, complex (5) was less effective (IC50 = 39 μM) while complex (1) was almost 12-fold more potent against PAF, as opposed to thrombin-induced aggregation. The biological behavior of complexes 1, 6 and 7 on PAF’s basic metabolic enzymatic pathways reveals that they affect key biosynthetic and catabolic enzymes of PAF underlying the anti-inflammatory properties of the relevant complexes. The in vitro cytotoxic activities of all complexes in HEK293T (human embryonic kidney cells) and HeLa cells (cervical cancer cells) are described via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The results reveal that complex 3 is the most potent within the series.

Hypertension and atherosclerosis are debilitating diseases that affect millions each year. Long-term consequences include but are not limited to stroke, myocardial infarction, and kidney failure. Platelet-activating factor (PAF) is a proinflammatory mediator synthesized from a subclass of phosphatidylcholines that increases platelet activation, leukocyte adhesion, infiltration of macrophages, and intracellular lipid accumulation, thereby contributing to atherosclerosis. Magnesium, a key micronutrient and free radical scavenger, is a water-soluble mineral that regulates peripheral vasodilation and calcium, phosphate, and hydroxyapatite homeostasis. Magnesium’s antihypertensive ability stems from its role as a natural calcium antagonist and promoter of vasodilatory mediators, such as nitric oxide. Platelet-activating factor and magnesium share an inverse relationship, and elevated magnesium levels have been shown to have protective effects against plaque formation as well as antihypertensive and antiarrhythmic effects, all of which allow for healthier aging. The purpose of this literature review is to investigate the role of platelet-activating factor and magnesium in the pathophysiology of hypertension, atherosclerosis, cardiovascular disease, stroke, and aging. Since the pathophysiology of the platelet-activating factor biomolecule is underexplored, further research studies are warranted in order to navigate the putative signaling pathways involved in the cardioprotective effects of dietary magnesium as a natural anti-PAF agent.

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 Ovarian cancer is the leading cause of death from gynaecologic illnessed worldwide. Platelet-activating factor acetyl hydrolase IB2 (PAF-AH IB2) is an intracellular serine esterase that hydrolyzes platelet-activating factor, a G-protein-like trimer with two catalytic subunits and one regulatory subunit. The regulatory role of PAF-AH IB2 in the oncogenesis of ovarian cancer is not well understood. Methods In this study, the TCGA dataset and clinical cancer tissue microarray were utilized to investigate abnormal overexpression of PAF-AH IB2 in ovarian cancer. To investigate the impact on the cell proliferation, migration, and tumorigenicity in vitro, PAF-AH IB2 stable knocking down (KD) ovarian cancer cells were established by ShRNA. The whole transcription profiling, tyrosine kinase profiling and standard cell functional assays were integrated to explore the biological importance and mechanism of PAF-AH IB2 modulated in ovarian cancer. Results PAF-AH IB2 was identified significantly overexpression in four subtypes of ovarian cancer. In vitro, PAF-AH IB2 KD significantly inhibited cancer cell proliferation, migration, and tumorigenicity, activated caspases and caused cell cycle arrest, and made the cells more sensitive to PAF. PAF-AH 1B2 KD cells down-regulated several key regulators of the multiple tyrosine kinases-mediated signaling pathway, suggesting a novel interaction network between the growth factor receptors pathway and PAF-AH 1B2 mediated PAF signalling. Conclusions These findings revealed a previously undiscovered role for PAF-AH IB2 as a potenial therapy target and essential signaling mediators in ovarian cancer pathogenesis, as well as new possible preventive and therapeutic strategies to inhibit this enzyme in clinical treatment for ovarian cancer.

Fluorouracil (5-FU) is a widely used chemotherapeutic agent in various malignant tumors. However, intestinal toxicity is considered the irritant unavoidable adverse effect during the course therapy. The aim of the current study was to screen the effect of a new selective histamine receptor 1 blocker and platelet-activating factor (PAF) blocker on 5-FU induced intestinal toxicity. Five groups (6 rats each) of adult male rats (Wistar) were arranged as follows: (1) control group that was treated with carboxymethylcellulose, (2) a group that received rupatadine (higher dose) only, (3) a group that received 5-FU and (4) and (5) groups that received 5-FU plus lower or higher dose rupatadine, respectively. At end of the experiment, we determined intestinal malondialdehyde (MDA), glutathione reduced (GSH), nitric oxide (NO), tumor necrosis factor (TNF-α), interleukin 1β, 6, 10 (IL-1β, IL-6, IL-10), PAF, histamine, myeloperoxidase, cysteine-aspartic acid protease-3 (caspase-3), and nuclear factor kappa B (NF-κB) as well as the histological analysis. 5-FU injection caused marked elevation of MDA, NO, TNF-α, IL-1β, IL-6, PAF, histamine, myeloperoxidase, caspase-3, and NF-κB expressions. The intoxicated animals showed deficient GSH and IL-10 along with significant loss of villi, disorganized crypts, and inflammatory cell infiltration. Rupatadine pretreatment reduced the previously mentioned parameters, preserved a nearly normal intestinal mucosa picture with replenished GSH and elevated IL-10. In conclusion, rupatadine is a dual histamine receptor 1, and a PAF blocker could reduce 5-FU-induced oxidative damage, inflammation, apoptosis, and ulceration of the intestinal epithelium. Rupatadine may be a valuable modality to decrease 5-FU induced intestinal mucositis. [ABSTRACT FROM AUTHOR]

Thermal burn injuries (TBIs) in patients who are alcohol‐intoxicated result in greater morbidity and mortality. The systemic toxicity found in human patients, which includes both immediate systemic cytokine generation with multiple organ failure and a delayed systemic immunosuppression, has previously been replicated in mouse models combining ethanol and localized TBI. Though considerable insights have been provided with these models, the exact mechanisms for these pathologic effects are unclear. In this review, we highlight the roles of the lipid mediator platelet‐activating factor (PAF) and subcellular microvesicle particle (MVP) release in response to intoxicated thermal burn injury (ITBI) as effectors in the pathology. Particularly, MVP is released from keratinocytes in response to PAF receptor (PAFR) activation due to excess PAF produced by ITBI. These subcellular particles carry and thus protect the metabolically labile PAF which enable binding of this potent lipid mediator to several key sites. We hypothesize that PAF carried by MVP can bind to PAFR within the gut, activating myosin light chain kinase (MLCK). The subsequent gut barrier dysfunction in response to MLCK activation then allows bacteria to invade the lymphatic system and, eventually, the bloodstream, resulting in sepsis and resultant dysregulated inflammation in multiple organs. PAF in MVP also activate the skin mast cell PAFR resulting in migration of this key effector cell to the lymph nodes to induce immunosuppression. This review thus provides a mechanism and potential therapeutic approaches for the increased toxicity and immunosuppressive outcomes of TBI in the presence of acute ethanol exposure. [ABSTRACT FROM AUTHOR]

Platelet‐activating factor (PAF, 1‐alkyl‐2‐acetyl‐sn‐glycero‐3‐phosphorylcholine) was discovered when the mechanisms involved in the deposition of immune complex in tissues were being scrutinized in the experimental model of rabbit serum sickness. The initial adscription of PAF to IgE‐dependent anaphylaxis was soon extended after disclosing its release from phagocytes stimulated by calcium mobilizing agents, formylated peptides, and phagocytosable particles. This explains why ongoing research in the field turned to the analysis of immune cell types and stimuli involved in PAF production with the purpose of establishing its role in pathology. This was spurred by the identification of the chemical structure of PAF and the enzymic mechanisms involved in its biosynthesis and degradation, which showed commonalities with those involved in eicosanoid production and the Lands' cycle of phospholipid fatty acid remodeling. The reassignment of PAF function in immunopathology is explained by the finding that the most robust mechanisms leading to PAF production are associated with opsonic and non‐opsonic phagocytosis, depending on the cell type. While polymorphonuclear leukocytes exhibit opsonic phagocytosis, monocyte‐derived dendritic cells show a marked preference for non‐opsonic phagocytosis associated with C‐type lectin receptors. This is particularly relevant to the defense against fungal invasion and explains why PAF exerts an autocrine feed‐forwarding mechanism required for the selective expression of some cytokines. [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]

Previous publications have reported a potent effect of COVID‐19 on platelet function and that the Spike protein enhances washed human platelet aggregation induced by various agonists. This study aims to evaluate whether mRNA vaccination for COVID‐19 affects human platelet‐rich plasma (hPRP) aggregation response, whether a recombinant Spike protein modulates PAF‐induced aggregation in hPRP and in washed rabbit platelets (WRP), and to investigate the effect of recombinant Spike protein on the PAF production in the U‐937 cell line. Our results showed that PRP from vaccinated individuals exhibited ex vivo lower EC50 values in response to PAF, ADP, and collagen. Platelet incubation with the Spike protein alone did not induce aggregation either in hPRP or in WRP, but resulted in augmentation of in vitro PAF‐induced aggregation in hPRP from non‐vaccinated individuals and in WRP. When PRP from vaccinated individuals was incubated with the Spike protein and PAF was subsequently added, elimination of the secondary wave of the biphasic aggregation curve was recorded compared with the aggregation induced by PAF alone. Collagen‐induced in vitro aggregation was dose‐dependently reduced when platelets were pre‐incubated with the Spike protein in all tested aggregation experiments. Stimulation of U‐937 by the Spike protein induced an increase in intracellular PAF production accompanied by elevation of the activities of all three PAF biosynthetic enzymes. In conclusion, since the Spike protein appears to modulate PAF production and activity, the use of compounds that act as PAF inhibitors, could be considered at least in mild cases of patients infected with SARS‐CoV‐2. [ABSTRACT FROM AUTHOR]

Platelet-activating factor (PAF) is a lipid mediator that interacts with its receptor (PAF-R) to carry out cell signalling. However, under certain conditions the binding of PAF to PAF-R leads to the activation of pro-inflammatory and prothrombotic pathways that have been implicated in the onset and development of atherosclerotic cardiovascular diseases (CVD) and inflammatory diseases. Over the past four decades, research has focused on the identification and development of PAF-R antagonists that target these inflammatory diseases. Research has also shown that dietary factors such as polar lipids, polyphenols, and other nutrient constituents may affect PAF metabolism and PAF-R function through various mechanisms. In this review we focus on the inhibition of PAF-R and how this may contribute to reducing cardiovascular disease risk. We conclude that further development of PAF-R inhibitors and human studies are required to investigate how modulation of the PAF-R may prevent the development of atherosclerotic cardiovascular disease and may lead to the development of novel therapeutics. [ABSTRACT FROM AUTHOR]

Platelet‐activating factor (PAF) is an important lipid mediator of anaphylaxis and therefore can be an anti‐anaphylactic agent target. Recently, we reported that several synthetic biotinylated peptides containing a Tyr‐Lys‐Asp‐Gly sequence markedly inhibited the bioactivities of PAF in vitro and in vivo; it also inhibited anaphylactic reactions such as hypothermia, hypotension, and vascular permeability in vivo. Here, we report the anti‐anaphylactic effects of three biotinylated heptapeptides (peptide 1: H‐Lys(biotinyl)‐Trp‐Tyr‐Lys‐Asp‐Gly‐Asp‐OH, peptide 2: H‐D‐Lys(biotinyl)‐Trp‐Tyr‐Lys‐Asp‐Gly‐Asp‐OH, and peptide 3: H‐D‐Lys(biotinyl)‐Trp‐Tyr‐Lys‐Asp‐Gly‐D‐Asp‐OH). The experiment using tryptophan fluorescence spectroscopy showed that the interaction of peptides 2 and 3 with PAF was larger than that of peptide 1. Experiments using a rat model of hind paw edema showed that peptides 1, 3, and 2 inhibited PAF‐induced edema by 67.9%, 69.3%, and 79.3%, respectively. In a mouse model of anaphylaxis, both peptides 2 and 3 showed inhibitory effects on anaphylactic hypothermia, whereas peptide 1 did not. Furthermore, experiments involving in vitro rat plasma stability of peptides showed that both peptides 3 and 2 were more stable in plasma compared to peptide 1 (84.0%, 51.8%, and 0%, remained after 6 h, respectively). Our results suggest that both peptides 2 and 3 may show systemic and local inhibitory effects as anti‐anaphylactic agents targeting PAF. [ABSTRACT FROM AUTHOR]

Background: There is limited ability to predict the severity of allergic reactions in children. Data derived predominantly from adults have implicated the platelet‐activating factor pathway as a potential contributor to severe anaphylaxis. In this study, we sought to prospectively assess involvement of key components of the platelet‐activating factor pathway in pediatric patients with anaphylaxis. Methods: Forty‐six pediatric patients (<18 years) presenting with acute anaphylaxis were assessed. Anaphylaxis severity was graded and serum anaphylaxis markers were measured acutely and in 36 children who returned for follow‐up >4 weeks after their acute presentation. These markers were compared with pediatric laboratory reference sera. Results: Severe anaphylaxis was experienced by 12/46 (26%) and mild‐moderate anaphylaxis in 34/46 (74%) children. Platelet‐activating factor acetylhydrolase (PAF‐AH) activity was inversely associated with severe anaphylaxis: 9/12 children with severe anaphylaxis had reduced PAF‐AH activity as compared with 14/34 with mild‐moderate anaphylaxis (p <.05). Furthermore, 3/3 children who required intensive care had markedly reduced mean PAF‐AH (nmol/ml/min) (13.73, 95%CI: 7.42–20.03) versus 20/23 who required ward/emergency department care (17.81, 95%CI: 16.80–18.83; p <.05). In children with anaphylaxis, PAF‐AH during acute anaphylaxis was unchanged relative to the child's basal levels (mean, 17.26, 95%CI: 16.10–18.42 vs 17.50, 95%CI: 16.21–18.78, p =.63) and was lower than healthy pediatric controls (mean 19.21; 95%CI:18.21–20.21; p <.05). Conclusion: Decreased serum PAF‐AH activity is a biomarker of severe anaphylaxis. Levels of this enzyme do not change from basal levels during acute anaphylaxis. Our results show that PAF‐AH is a biomarker of anaphylaxis severity in children. This key regulatory enzyme may modulate susceptibility to severe anaphylaxis. [ABSTRACT FROM AUTHOR]

Platelet-activating factor (PAF) is an important chemical mediator in the field of inflammation, but its function in the skin is unclear. To unravel the role of PAF, we focused on lysophosphatidylcholine acyltransferase 2 (LPCAT2 also called LPLAT9), a biosynthetic enzyme involved in PAF production, and investigated the role of PAF in allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). We measured the amount of PAF in the skin and investigated the ear swelling responses and leukocyte infiltration into the skin following the application of 2,4,6-trinitro-1-chlorobenzene (TNCB) or croton oil in wild-type (WT) and LPCAT2 knockout (LPCAT2-KO) mice. The amount of PAF was increased in the skin of WT mice after TNCB or croton oil application but not detected in LPCAT2-KO mice. The ear swelling response was decreased in LPCAT2-KO mice compared with that in WT mice. In the ACD model, the numbers of lymphocytes, eosinophils, macrophages, mast cells and neutrophils were smaller in LPCAT2-KO mice than in WT mice. In the ICD model, the ear swelling response was also decreased in LPCAT2-KO mice compared with that in WT mice. When double staining of each inflammatory cell type and LPCAT2 was performed in ACD tissue, marked co-staining of the eosinophil marker and LPCAT2 was observed. In addition, LPCAT2 expression was observed in the epidermis. These results indicate that PAF is involved in the infiltration of several cell types into the sites of allergic and non-allergic skin inflammation. Furthermore, eosinophils and keratinocytes are primarily responsible for PAF production in skin inflammation., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A non-suppurative inflammatory disease of the middle ear with middle ear effusion and conductive hearing loss is called otitis media with effusion. Poor eustachian tube function, immunological factors, viral factors, and other factors are primarily involved in its pathophysiology, which has not yet been completely understood. Several researcher scholars have recently studied platelet-activating factor and they found that platelet-activating factor is closely associated to the occurrence, development, and outcome of otitis media with effusion. Platelet-activating factor is a significant element contributing to the extension of otitis media with effusion. In order to give a reference for further investigation into the mechanism and clinical management of this illness, the research status of platelet-activating factor and otitis media with effusion during the past two decades is reviewed in this study, along with the mechanisms of otitis media with effusion leading to otitis media with effusion., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Platelet-activating factor (PAF) is a potent classical lipid mediator that plays a critical role in various diseases such as allergy and nervous system disorders. In the realm of allergy, previous studies suggested that PAF is generated in response to extracellular stimuli and contributes to allergic reactions via PAF receptor (PAFR). However, the sources of endogenous PAF and its pathophysiological dynamics remain largely elusive in vivo. Here, we report that rapid and local PAF generation completely depends on lysophospholipid acyltransferase 9 (LPLAT9, also known as LPCAT2) expressed in mast cells in IgE-mediated passive cutaneous anaphylaxis. However, we found that LPLAT9 knockout (KO) mice did not display attenuated vascular leakage. Additionally, decreased vascular leakage was observed in PAFR KO mice, but not in endothelial cell-specific mice in this model. These divergences highlight a yet unsolved complexity of the biological functions of PAF and PAFR in a pathophysiological process., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The purpose of this literature review is to gain an overview of the role of platelet-activating factor (PAF) within each of the body systems and how it contributes to normal and pathophysiological states. The review showed that there are multiple functions of PAF that are common to several body systems; however, there is little evidence to explain why PAF has this affect across multiple systems. Interestingly, there seems to be conflicting research as to whether PAF is an overall protective or pathogenic pathway. Within this research, it was found that there are different pathways depending on the specific body system, as well as between body systems. However, one universal function reported in the literature is of PAF as a pro-inflammatory molecule. Overall, this review identified five major functions of PAF: vasoconstriction, increased inflammation, vascular remodeling, increased edema, and endothelial permeability.

Bacterial toxins signaling through Toll-like receptors (TLRs) are implicated in the pathogenesis of many inflammatory diseases. Among the toxins, lipopolysaccharide (LPS) exerts its action via TLR-4 while lipoteichoic acid (LTA) and bacterial lipoproteins such as Braun lipoprotein (BLP) or its synthetic analogue Pam3CSK4 act through TLR-2. Part of the TLR mediated pathogenicity is believed to stem from endogenously biosynthesized platelet-activating factor (PAF)- a potent inflammatory phospholipid acting through PAF-receptor (PAF-R). However, the role of PAF in inflammatory diseases like endotoxemia is controversial. In order to test the direct contribution of PAF in TLR-mediated pathogenicity, we intraperitoneally injected PAF to Wistar albino mice in the presence or absence of bacterial toxins. Intraperitoneal injection of PAF (5 μg/mouse) causes sudden death of mice, that can be delayed by simultaneously or pre-treating the animals with high doses of bacterial toxins- a phenomenon known as endotoxin cross-tolerance. The bacterial toxins- induced tolerance to PAF can be reversed by increasing the concentration of PAF suggesting the reversibility of cross-tolerance. We did similar experiments using human platelets that express both canonical PAF-R and TLRs. Although bacterial toxins did not induce human platelet aggregation, they inhibited PAF-induced platelet aggregation in a reversible manner. Using rabbit platelets that are ultrasensitive to PAF, we found bacterial toxins (LPS and LTA) and Pam3CSK4 causing rabbit platelet aggregation via PAF-R dependent way. The physical interaction of PAF-R and bacterial toxins is also demonstrated in a human epidermal cell line having stable PAF-R expression. Thus, we suggest the possibility of direct physical interaction of bacterial toxins with PAF-R leading to cross-tolerance.

Gestational diabetes mellitus (GD) is characterized by glycemic and lipid metabolism alterations in an environment of low-grade inflammation. Our trial aimed to assess the effect of nutraceutical supplements (omega-3 fatty acids, anthocyanins, and alpha-cyclodextrins) in GD patients and evaluate the role of anthropometric, metabolic, and inflammatory parameters as biomarkers to identify subjects who require pharmacological hypoglycemic treatment during gestation. Pregnant women with GD at 24–28 weeks of gestation were enrolled in a double-blind trial and randomized to receive either nutraceutical supplements or a placebo for 12 weeks. No statistically significant differences were observed between the two groups in blood and urine measurements of metabolic, inflammatory, and antioxidant parameters. In the whole cohort, pre-pregnancy BMI and anthropometric measurements were significantly different in patients who required pharmacological intervention. These patients showed higher triglycerides, CRP, and insulin levels and gave birth to newborns with significantly higher weights. Subjects with a greater AA/EPA ratio had higher PAF levels and gave birth four days earlier. In conclusion, one-to-one nutritional coaching and poor compliance with nutraceutical supplementation might have outweighed the impact of this intervention. However, triglyceride concentration and the AA/EPA ratio seems to be a biomarker for higher inflammatory levels and GD candidates for pharmacological treatment. An adequate assumption of omega-3 in women with GD, either by a controlled diet or by nutraceutical supplementation, reduces the need for pharmacological therapy. [ABSTRACT FROM AUTHOR]

Background: Platelet-activating factor (PAF) has been suggested to be a potent inflammatory mediator in Allergic rhinitis (AR) pathogenesis. Vitamin E, an essential nutrient that comprises tocopherol and tocotrienol, is known as a potential therapeutic agent for airway allergic inflammation. This study aimed to investigate the beneficial effects of intranasal Tocotrienol-rich fraction (TRF) on PAF-induced AR in a rat model. Methods: Sprague Dawley rats were randomly assigned into 3 groups: Control, PAF-induced AR and PAF-induced AR with TRF treatment. To induce AR, 50 μl of 16 μg/ml PAF was nasally instilled into each nostril. From day 1 to 7 after AR induction, 10 μl of 16 μg/μl TRF was delivered intranasally to the TRF treatment group. Complete upper skulls were collected for histopathological evaluation on day 8. Results: The average severity scores of AR were significantly higher in the PAF-induced AR rats compared to both control and PAF-induced AR with TRF treatment. The histologic examination of the nasal structures showed moderate degree of inflammation and polymorphonuclear cells infiltration in the lamina propria, mucosa damage and vascular congestion in the PAF-induced AR rats. TRF was able to ameliorate the AR symptoms by restoring the nasal structures back to normal. H&E staining demonstrated a statistically significant benefit upon TRF treatment, where minimal degree of inflammation, and a reduction in the infiltration of polymorphonuclear cells, mucosa damage and vascular congestion were observed. Conclusion: TRF exhibited symptomatic relief action in AR potentially due to its antioxidant, anti-inflammatory and anti-allergic properties. [ABSTRACT FROM AUTHOR]

Context Atherosclerosis 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. Objective To systematically review the literature on the association between dietary patterns and PAF and Lp-PLA2. Data Sources The PubMed, Embase, CINAHL, and Cochrane CENTRAL literature databases were searched. Data Analysis Study 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. Conclusion Study 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. [ABSTRACT FROM AUTHOR]

Experiments were undertaken to identify the nature of a previously identified inhibitor of PAF-induced platelet aggregation (PA) in human saliva. Human saliva fractionated by preparative thin layer chromatography (TLC) yielded a fraction that co-migrated with fatty acids (FAs) and inhibited PAF-induced aggregation of platelets. Synthetic FAs tested for their capacities to inhibit 0.1 nM PAF-induced PA showed that only the cis-unsaturated compounds were inhibitory with activities of some of the polyunsaturated FAs (PUFA) reaching almost 100% at 20 μM. Eicosapentanoic acid (EPA) and 8,11,14-eicosatrienoic acid also deaggregated the PAF-induced aggregates. With the exception of oleic acid (OLA), cis-monounsaturated FAs, and elaidic acid, the trans isomer of OLA, were poor inhibitors. In a direct comparison with other platelet agonists, ADP, thrombin, and ionophore A23187, the active saliva fraction and selected individual FAs inhibited, to greater or lesser extent, PA induced by each of the agonists. EPA, OLA, linoleic acid (LNA), and the active saliva fraction were potent inhibitors of ADP-induced PA, EPA completely inhibited thrombin-induced PA and the saliva fraction showed only weak – moderate inhibitory activity to both thrombin- and ionophore A23187-induced PA. Other reports of endogenous PAF inhibitors in mammalian tissues are compared to the present results. PAF can trigger and amplify inflammatory cascades suggesting a possible modulation role for cis-unsaturated FAs in some diseases. [ABSTRACT FROM AUTHOR]

Abstract The chimera antigen receptor (CAR) T cell therapy is a novel and potential targeted therapy and has achieved satisfactory efficacy in patients with relapsed or refractory multiple myeloma (MM) in recent years. However, cytokine release syndrome (CRS) and clinical efficacy have become the major obstacles which limit the application of CAR-T in clinics. To explore the potential biomarkers in plasma for evaluating CRS and clinical efficacy, we performed metabolomic and lipidomic profiling of plasma samples from 17 relapsed or refractory MM patients received CAR-T therapy. Our study showed that glycerophosphocholine (GPC), an intermediate of platelet-activating factor (PAF)-like molecule, was significantly decreased when the participants underwent CRS, and the remarkable elevation of lysophosphatidylcholines (lysoPCs), which were catalyzed by lysoPC acyltransferase (LPCAT) was a distinct metabolism signature of relapsed or refractory MM patients with prognostic value post-CAR-T therapy. Both GPC and lysoPC are involved in platelet-activating factor (PAF) remodeling pathway. Besides, these findings were validated by LPCAT1 expression, a key factor in the PAF pathway, associated with poor outcome in three MM GEP datasets of MM. In conclusion, CAR-T therapy alters PAF synthesis in MM patients, and targeting PAF remodeling may be a promising strategy to enhance MM CAR-T therapy.

Background and aims: Several studies have reported the positive cardio-metabolic effects of yogurt consumption. The addition of olive oil’s bioactive extracts into yogurt can result to a functional food with pleiotropic properties against cardiovascular diseases. A polar lipid extract of olive pomace (OOPLE) that contains platelet activating factor receptor (PAF-R) antagonists, has been stated not only to inhibit the development of atherosclerotic plaques in hypercholesterolemic rabbits but also to regress the already formed plaques. The present study aims to investigate the effect of the daily intake of an OOPLE-enriched low-fat yogurt, on the metabolic profile, ex vivo platelet aggregation and markers of thrombosis and inflammation, in healthy, mainly overweight volunteers. Methods and results: A randomized, three-arm, double-blind, placebo-controlled, parallel-group, 8 weeks duration, clinical trial was performed in apparently healthy adults (35–65 years old). Group A (control group) consumed at most one yogurt every two weeks, Group B (plain yogurt) consumed one serving of plain yogurt every day and Group C (enriched yogurt) consumed one serving of yogurt, enriched with OOPLE, daily. Enriched yogurt intake resulted in lower levels of IL-10 and to lower platelet sensitivity against PAF, compared to the other two groups (p-values

Platelet-activating factor (PAF) is a potent phospholipid mediator crucial in multiple inflammatory and immune responses through binding and activating the PAF receptor (PAFR). However, drug development targeting the PAFR has been limited, partly due to an incomplete understanding of its activation mechanism. Here, we present a 2.9-Å structure of the PAF-bound PAFR-G i complex. Structural and mutagenesis analyses unveil a specific binding mode of PAF, with the choline head forming cation-π interactions within PAFR hydrophobic pocket, while the alkyl tail penetrates deeply into an aromatic cleft between TM4 and TM5. Binding of PAF modulates conformational changes in key motifs of PAFR, triggering the outward movement of TM6, TM7, and helix 8 for G protein coupling. Molecular dynamics simulation suggests a membrane-side pathway for PAF entry into PAFR via the TM4-TM5 cavity. By providing molecular insights into PAFR signaling, this work contributes a foundation for developing therapeutic interventions targeting PAF signal axis. [Display omitted] • 2.9-Å Cryo-EM structure of the PAFR-G i complex activated by PAF • The choline head of PAF forms cation-π interactions within a hydrophobic pocket in PAFR • A membrane-side pathway for PAF entry into PAFR revealed by computational simulation Fan et al. presents the 2.9-Å cryo-EM structure of platelet-activating factor receptor PAFR-G i complex bound to PAF, which reveals the specific binding mode of PAF within PAFR. Structural and computational analyses provide insights into PAFR activation and a membrane entry pathway for PAF to PAFR via the TM4-TM5 cleft. [ABSTRACT FROM AUTHOR]

Platelet-activating factor (PAF) plays a significant role in several leucocyte functions, including platelet aggregation and inflammation. Additionally, PAF has a role in the behavioral and physiological changes in mammals. However, the effect of PAF has not been well studied in birds. Therefore, the study aimed to determine if PAF affects feeding behavior, voluntary activity, cloacal temperature, and feed passage through the digestive tract in chicks (Gallus gallus). We also studied the involvement of PAF in the innate immune system induced by lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria. Both intraperitoneal (IP) and intracerebroventricular (ICV) injections of PAF significantly decreased food intake. IP injection of PAF significantly decreased voluntary activity and slowed the feed passage from the crop, whereas ICV injection had no effect. Conversely, ICV injection of PAF significantly increased the cloacal temperature, but IP injection had no effect. The IP injection of LPS significantly reduced the mRNA expression of lysophosphatidylcholine acyltransferase 2, an enzyme responsible for PAF production in the heart and pancreas. On the other hand, LPS significantly increased the mRNA expression of the PAF receptor in the peripheral organs. The present study shows that PAF influences behavioral and physiological responses and is related to the response against bacterial infections in chicks. • IP and ICV injections of PAF suppressed food intake in chicks. • IP injection of PAF decreased activity and feed passage through the digestive tract. • ICV injection of PAF increased body temperature. • LPS affected mRNA of PAF synthesis enzyme and PAF receptor in several organs. • PAF is related to behavior, physiological responses and immune system in chicks. [ABSTRACT FROM AUTHOR]

This study assesses the in vitro antiplatelet properties of polar lipid extracts of two popular beers, a red wine and their 0% equivalents against platelet aggregation. Total lipids (TL) were isolated using the Bligh and Dyer method from each beverage and the total polar lipid (TPL) and total neutral lipid (TNL) fractions were further isolated using counter-current distribution. The lipid profile of each TPL fraction was analysed using LC-MS. Platelet aggregometry was performed to evaluate the TL, TNL, and TPL extracts of each beverage against platelet-activating factor (PAF) induced platelet aggregation. TPL and TL lipid fractions significantly inhibit platelet aggregation, with TPL fractions showing the highest inhibition as evidenced by generally low IC 50 values, ranging from 9 μg to 553 μg. These results indicate that antiplatelet lipid microconstituents are present in beer, wine, and their 0% alcohol counterparts, in low but bioactive amounts. These lipids are characterized by predominance of saturated fatty acids (SFA) and a relatively high ratio of n-6 to n-3 polyunsaturated fatty acids (PUFA) in the TPL composition. The extracts also contained notable levels of phenolic compounds ranging from 0.05 to 0.31 mg/mL. These data provide evidence for the presence of antiplatelet lipid microconstituents that may contribute to the observed epidemiological cardioprotective effects of moderate beer and wine consumption. Furthermore, 0% alcoholic beverages may also provide comparable antiplatelet cardioprotective microconstituents devoid of the risk of ethanol ingestion. • Polar lipids and Total lipids of beer, red wine, and their dealcoholized variants inhibit PAF-induced platelet aggregation. • LC-MS showed that the polar lipid fatty acid composition was characterized by high levels of saturated fatty acids. • Lipid extracts from dealcoholized beverages have comparable antiplatelet activity to their alcoholic counterparts. [ABSTRACT FROM AUTHOR]

Ultraviolet B radiation (UVB) has profound effects on human skin that results in a broad spectrum of immunological local and systemic responses and is the major cause of skin carcinogenesis. One important area of study in photobiology is how UVB is translated into effector signals. As the skin is exposed to UVB light, subcellular microvesicle particles (MVP), a subtype of bioactive extracellular vesicles, are released causing a variety of local and systemic immunological effects. In this review, we highlight keratinocyte MVP release in keratinocytes in response to UVB. Specifically, Platelet-activating factor receptor agonists generated by UVB result in MVP released from keratinocytes. The downstream effects of MVP release include the ability of these subcellular particles to transport agents including the glycerophosphocholine-derived lipid mediator Platelet-activating factor (PAF). Moreover, even though UVB is only absorbed in the epidermis, it appears that PAF release from MVPs also mediates systemic immunosuppression and enhances tumor growth and metastasis. Tumor cells expressing PAF receptors can use this mechanism to evade chemotherapy responses, leading to treatment resistance for advanced cancers such as melanoma. Furthermore, novel pharmacological agents provide greater insight into the UVB-induced immune response pathway and a potential target for pharmacological intervention. This review outlines the need to more clearly elucidate the mechanism linking UVB-irradiation with the cutaneous immune response and its pathological manifestations. An improved understanding of this process can result in new insights and treatment strategies for UVB-related disorders from carcinogenesis to photosensitivity. [ABSTRACT FROM AUTHOR]

Platelet-activating factor (PAF) is an important mediator of allergic reactions such as anaphylaxis, and is therefore an anaphylactic drug target. Previously, we found marked inhibition of anaphylactic reactions by a synthetic N-terminally biotinylated peptide (BP21) capable of specifically binding PAF. In this study, we investigated the effects of 10-hydroxy-2-decenoic acid (10-HDA) and various peptides derived from royalisin, both of which are widely known to be major components of royal jelly from honeybees, on PAF/histamine-induced rat hind-paw edema and mouse anaphylactic hypothermia. In a rat model of hind paw edema, both 10-HDA (50 nmol/paw) and a royalisin-related N-terminally biotinylated peptide, Biotin-RL-Y11, (10 nmol/paw) markedly inhibited PAF-induced paw edema by 95.5±5.0% and 71.9±9.9%, respectively. 10-HDA also inhibited histamine-induced paw edema by 42.7±19.2%. In contrast, three peptides with N-terminal HDA modifications, namely 10-HDA-RL-Y11, 10-HDA-RL-R11, and 10-HDA-P21 only weakly inhibited PAF-induced paw edema. In a mouse model of anaphylaxis, the administration of 10-HDA (100-1000 nmol/mouse) and/or Biotin-RL-Y11 (100 nmol/mouse) showed the inhibitory effects on anaphylactic hypothermia. These results suggest that both 10-HDA and Biotin-RL-Y11 may exert an anti-anaphylactic effect targeting PAF. [ABSTRACT FROM AUTHOR]