Platelet-activating Factor Levels Research Articles

Effect of Edaravone Combined with Anticoagulant Therapy on the Serum hs-CRP, IL-6, and TNF-α Levels and Activity of Daily Living in Patients with Acute Cerebral Infarction.

Objective To explore the effect of edaravone combined with anticoagulant therapy on the serum hs-CRP, IL-6, and TNF-α levels and the activity of daily living (ADL) in patients with acute cerebral infarction (ACI). Methods The clinical data of 84 ACI patients treated in our hospital from August 2020 to August 2021 were retrospectively analyzed, and they were divided into the routine group (n = 42) and the combined group (n = 42) according to the order of admission. Both groups were treated with routine clinical treatment, and the combined group was additionally treated with edaravone combined with anticoagulant therapy. Serum samples were collected from both groups after treatment. ELISA was used to detect the serum inflammatory factor levels, and the modified Barthel index score was used to evaluate the ADL of patients. Results Compared with the routine group, the combined group achieved obviously lower levels of PMA, CD62p, and serum inflammatory factors after treatment (P < 0.001), higher modified Barthel score after treatment (P < 0.001), lower plasma viscosity, platelet aggregation rate, and plasma fibrinogen level after treatment (P < 0.001), and higher clinical overall efficacy (P < 0.05). Conclusion Edaravone combined with anticoagulant therapy is a reliable method to enhance ADL and reduce the inflammatory response of ACI patients. This strategy greatly reduces the platelet-activating factor levels of patients and improves the comprehensive clinical efficacy, and its further research will help to establish a better solution for these patients.

Therapeutic effect of rupatadine against l-arginine-induced acute pancreatitis in rats: role of inflammation.

Acute pancreatitis (AP) is an abrupt inflammatory disorder causing high morbidity and mortality. As AP is an insidious medical emergency, a curative modality is required instead of a preventive measure. Thus, we investigated the possible curative effect of rupatadine on a rat model of AP. Rupatadine is a potent histamine receptor 1 (H1R) and platelet-activating factor (PAF) blocker. We used four groups of six Wistar rats as follows: the control group received vehicle; the rupatadine control group received rupatadine as 6mg/kg orally; the AP group received l-arginine intraperitoneally, and the treatment group received rupatadine at 1, 6, and 24h after l-arginine injection. The levels of serum amylase, pancreatic oxidative parameters, and pancreatic cytokines were measured. PAF, histamine, and myeloperoxidase levels were determined in the pancreas. Histopathological and immunohistochemical examinations were performed to determine nuclear factor kappa-B (NF-κB) and caspase 3 expressions. Oxidative damage and severe inflammation were detected in the pancreas of the AP group. Rupatadine reduced the oxidative damage and the levels of proinflammatory cytokines, PAF, histamine, myeloperoxidase, NF-κB, and caspase 3 expressions. It restored the pancreatic acini to almost normal condition. Rupatadine induced important anti-inflammatory and antiapoptotic effects against l-arginine-induced AP.

Effect of butylphthalide combined with ozagrel sodium on cerebral perfusion and oxidative stress indexes in patients with transient ischemic attack

This study has been undertaken to evaluate the effect of butylphthalide combined with ozagrel sodium on cerebral perfusion and oxidative stress indexes in patients with transient ischemic attack. In this study, a total of 116 patients diagnosed as transient ischemic attack in our hospital (February 2018-February 2020) have been selected and divided into two groups according to the treatment methods.58 cases in the control group have been treated with ozagrel sodium, 58 cases in the observation group have been treated with butylphthalide combined with ozagrelsodium. The CT perfusion imaging parameters, oxidative stress indexes, plaque area, and the levels of platelet activating factor (PAF), α-granule membrane protein-140 (GMP-140), fibrinogen (FIB), platelet aggregation rate (PAgT), neuron-specific enolase (NSE), oxygen-inducible factor-1α ( HIF-1α ), and matrix metalloproteinases-9 ( MMP-9) in the two groups have been recorded, and the total effective rate and adverse reaction rate have been counted. The results shown that the total effective rate of the observation group is higher than that of the control group, and the difference is statistically significant (χ2 = 4.640, P = 0.031). The average time (MTT) required for the two groups of contrast agents to pass through the local brain tissue and the time (TTP) required starting the injection of contrast agents to reach the peak concentration decreased compared to that with before treatment. After treatment, the MTT and TTP of the observation group are shorter than those of the control group (P &lt; 0.05). Compared with before treatment, superoxide dismutase (SOD) in the two groups has higher than that in the control group, PAF, GMP-140, FIB, PAgT, NSE, HIF-1α, MMP-9, malondialdehyde (MDA) and plaque area has decreased. After treatment, the levels of related factors in the observation group are better than those in the control group, and the plaque area is less than that in the control group (P &lt; 0.05).There has been no significant difference in the adverse reaction rate between the observation group and the control group (χ2 = 0.438, P = 0.508).

Characterization of antipsychotic medications, amino acid signatures, and platelet-activating factor in first-episode psychosis

First-episode psychosis refers to individuals early in the course of psychotic illness. Identifying the underlying biological processes, including biomarkers, is essential for improving diagnosis and treatment. We performed metabolomics profiling of plasma from a group of first-episode psychosis patients and matched neurotypical controls. Using global metabolomics profiling, we identified antipsychotic or antidepressant medication in 22 individuals diagnosed with first-episode psychosis, closely matching the drug prescription history. There were significant differences in levels of amino acids or their derivatives, including decreases in D L -arginine, L -histidine, DL-serine and threonine as well as increases in L -glutamic acid, ornithine, and proline. Using targeted metabolomics profiling of 408 compounds in plasma samples we identified significant differences in six compounds including decreases in serotonin and arginine as well as increased levels of sarcosine, proline, cis-4-hydroxyproline and trans-4-hydroxyproline. Platelet-activating factor levels were significantly elevated in the FEP cohort. These findings suggest potential biomarkers that require validation in independent cohorts, and in several cases provide supporting evidence for previously reported observations.

Investigating platelet-activating factor as a potent proinflammatory mediator in coronary atherosclerotic patients.

The inflammatory reaction is one of the complications in patients with coronary atherosclerosis. This study aimed to determine the diagnostic value of platelet-activating factor (PAF) compared with high sensitivity C reactive protein (hs-CRP) in coronary atherosclerotic patients. Fifty patients with coronary atherosclerosis and 30 subjects with normal angiography were considered as the control group attending Cardiac Center-Surgical Specialty Hospital - in Erbil city / Iraq. The levels of PAF and hs-CRP were estimated quantitatively using a sandwich enzyme-linked immunosorbent assay and a particle-enhanced immune turbid metric assay, respectively. Lipid profiles and some hematological indexes were also used in this study. The levels of the inflammatory biomarkers of PAF and hs-CRP increased significantly in the patients group compared with controls (p<0.05). Although the patients group showed the highest level of low-density lipoprotein (LDL), the difference was not significant (p>0.05) compared with the healthy control. However, the incidence of risk factors such as smoking and obesity showed a significant difference (p<0.05) in the patients group. Additionally, the PAF level correlated positively and significantly with hs-CRP (p<0.05), and negatively with high-density lipoprotein (HDL) (p>0.05). Although hs-CRP was a valuable diagnostic marker for coronary atherosclerosis, the PAF level showed to be a better prognostic indicator than hs-CRP in coronary atherosclerosis patients.

Effect Of Butylphthalide Combined with Ozagrel Sodium on Cerebral Perfusion and Oxidative Stress Indexes in Patients with Transient Ischemic Attack

Background The pathogenesis of transient ischemic attack is not clear. Microthrombosis theory is a theory with high clinical recognition. Microthrombosis of carotid artery and vertebral basilar artery wall occurs shedding and vasospasm, resulting in transient cerebral insufficiency. Microembolic decomposition or distal movement, cerebrovascular dilatation, local collateral circulation after the establishment of symptoms relieved or disappeared. Most patients can be relieved in a short time, but recurrent attacks can gradually damage the structure and function of brain tissue, and increase the risk of acute cerebral infarction. The clinical treatment of this disease is mainly based on the comprehensive control of risk factors, anti thrombosis, and anti-platelet aggregation. Objective To observe the effect of butylphthalide combined with ozagrel sodium on cerebral perfusion and oxidative stress indexes in patients with transient ischemic attack. Methods A total of 116 patients diagnosed as transient ischemic attack in our hospital (February 2018 - February 2020) were selected and divided into two groups according to the treatment methods. 58 cases in the control group were treated with ozagrel sodium, 58 cases in the observation group were treated with butylphthalide combined with ozagrel sodium. The CT perfusion imaging parameters, oxidative stress indexes, plaque area, and the levels of platelet activating factor ( PAF ), α-granule membrane protein-140 ( GMP-140 ), fibrinogen ( FIB ), platelet aggregation rate (PAgT), neuron-specific enolase (NSE), oxygend-inducible factor-1α (HIF-1α), and matrix metalloproteinases 9 (MMP-9) in the two groups were recorded, and the total effective rate and adverse reaction rate were counted. Results The total effective rate of the observation group was higher than that of the control group, and the difference was statistically significant (χ2=4.640, P = 0.031). Compared with before treatment, the average time (MTT) required for the two groups of contrast agents to pass through the local brain tissue and the time (TTP) required to start the injection of contrast agents to reach the peak concentration decreased compared with before treatment. After treatment, the MTT and TTP of the observation group were shorter than those of the control group (P &lt; 0.05). Compared with before treatment, superoxide dismutase ( SOD ) in the two groups was higher than that in the control group, PAF, GMP-140, FIB, PAgT, NSE, HIF-la, MMP-9, malondialdehyde (MDA) and plaque area decreased. After treatment, the levels of related factors in the observation group were better than those in the control group, and the plaque area was less than that in the control group (P &lt; 0.05). There was no significant difference in the adverse reaction rate between the observation group and the control group (χ2 = 0.438, P=0.508). Conclusion Butylphthalide combined with ozagrel sodium in the treatment of transient ischemic attack can improve cerebral perfusion, reduce oxidative stress injury, reduce plaque and improve curative effect.

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.

Introduction: Familial hypercholesterolemia (FH) is characterized by extremely high levels of circulating low-density lipoprotein cholesterol (LDL-C) and is caused by mutations of genes involved in LDL-C metabolism, including LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Accordingly, PCSK9 inhibitors (PCSK9i) are effective in LDL-C reduction. However, no data are available on the pleiotropic effect of PCSK9i. To this end, we performed an untargeted metabolomics approach to gather a global view on changes in metabolic pathways in patients receiving treatment with PCSK9i. Methods: Twenty-five FH patients starting treatment with PCSK-9i were evaluated by an untargeted metabolomics approach at baseline (before PCSK9i treatment) and after 12 weeks of treatment. Results: All the 25 FH subjects enrolled were on maximal tolerated lipid-lowering therapy prior to study entry. After a 12 week treatment with PCSK9i, we observed an expected significant reduction in LDL-cholesterol levels (from 201.0 ± 69.5 mg/dL to 103.0 ± 58.0 mg/dL, p < 0.001). The LDL-C target was achieved in 36% of patients. After peak validation and correction, after 12 weeks of PCSK9i treatment as compared to baseline, we observed increments in creatine (p-value = 0.041), indole (p-value = 0.045), and indoleacrylic acid (p-value= 0.045) concentrations. Conversely, significant decreases in choline (p-value = 0.045) and phosphatidylcholine (p-value < 0.01) together with a reduction in platelet activating factor (p-value = 0.041) were observed. Conclusions: Taking advantage of untargeted metabolomics, we first provided evidence of concomitant reductions in inflammation and platelet activation metabolites in FH patients receiving a 12 week treatment with PCSK9i.

Prolonged Exposure to Platelet Activating Factor Transforms Breast Epithelial Cells.

Lipid species are known to have various biological functions owing to their structural differences, and each of them possesses a specific role to play depending upon their location and distribution in the cell. Some of these lipids interact with proteins on the cell membrane and acts as second messengers. The level of lipid mediators is generally maintained in the cell by feedback mechanisms; however, their improper degradation or enhanced production leads to their accumulation in the tumor microenvironment and disturbs the homeostasis of the cell. Platelet activating factor (PAF) is a known phospholipid mediator secreted upon immunological challenges by platelets, neutrophils, basophils, and macrophages. PAF, as a potent inflammatory molecule, is well studied, and its role in various cancers and cardiovascular diseases has also been investigated. Interestingly, increased levels of PAF have been found in the blood plasma of smokers, and breast cancer cells have shown the accumulation of PAF in presence of cigarette smoke extract. This accumulation was found to increase tumor cell motility that in turn could promote metastasis. Beyond this, however, the effect of PAF on tumorigenesis has not yet been well explored. Here, we show that the continuous exposure of 3D breast acinar cultures to PAF resulted in the activation of various oncogenic signaling pathways leading to transformation. We also found that the presence of PAF in the micro-environment increased the expression of PAF receptor (PAF-R), which corroborated with the higher expression of PAF-R detected in some epithelial cancers, as per literature. Thus, this study impresses on the fact that the presence of PAF alters the cellular microenvironment and eventually triggers irreversible effects that can cumulatively lead to transformation.

New Insights Into the Pathologic Roles of the Platelet-Activating Factor System.

Described almost 50 years ago, the glycerophosphocholine lipid mediator Platelet-activating factor (PAF) has been implicated in many pathologic processes. Indeed, elevated levels of PAF can be measured in response to almost every type of pathology involving inflammation and cell damage/death. In this review, we provide evidence for PAF involvement in pathologic processes, with focus on cancer, the nervous system, and in photobiology. Importantly, recent insights into how PAF can generate and travel via bioactive extracellular vesicles such as microvesicle particles (MVP) are presented. What appears to be emerging from diverse pathologies in different organ systems is a common theme where pro-oxidative stressors generate oxidized glycerophosphocholines with PAF agonistic effects, which then trigger more enzymatic PAF synthesis via the PAF receptor. A downstream consequence of PAF receptor activation is the generation and release of MVP which provide a mechanism to transmit PAF as well as other bioactive agents. The knowledge gaps which when addressed could result in novel therapeutic strategies are also discussed. Taken together, an enhanced understanding of the PAF family of lipid mediators is essential in our improved comprehension of the relationship amongst the diverse cutaneous, cancerous, neurologic and systemic pathologic processes.

The effect of docosahexaenoic acid supplementation in preterm infants on the incidence of necrotizing enterocolitis and its correlation with the level of platelet activating factor.

Background: Necrotizing Enterocolitis (NEC) is a serious intestinal infection that primarily affects premature and low birth weight babies. Both prematurity and enteral feeding are major risk factors for NEC. This interventional two armed, double blinded randomized controlled clinical trial (IIb) study was to determine the role of Docosahexaenoic Acid (DHA) in preventing or lessening the severity of necrotizing enterocolitis in preterm/low birth weight neonates. Methods: One group (n=20) was assigned to receive DHA and the other received the placebo. Results: Platelets activating factor was significantly higher in neonates who received DHA supplements (p<0.001). As regards the incidence of feeding intolerance, our results demonstrated a significant statistical improvement among neonates of DHA group; regarding abdominal girth, intestinal sound, gastric residual, passage of stool and modified NEC BELL’S criteria (P<0.05). SNAP score for evaluation of sepsis was evaluated initially and 10 days later for both groups where, it increased from 9.6 to 19.2 among patients of group B and decreased from 14.4 to 8.3 among neonates of group A (P<0.001 and 0.001) respectively. Conclusion: DHA has an apparent role in improving growth of preterm neonates, decrease severity and progression of NEC.

Platelet-activating factor and antiphospholipid antibodies in recurrent implantation failure

Recurrent implantation failure (RIF) refers to cases in which women have had the failure of the embryo implantation after several in vitro fertilization (IVF). The success rate for IVF depends on many different factors. Implantation is a complex step in a successful pregnancy. Antiphospholipid antibodies (aPLs) and platelet-activating factor (PAF) can be considered as effective factors in the embryo implantation. The first purpose of this study is to compare the levels of aPLs and PAF among RIF and fertile control women. The second purpose is evaluating correlations between the blood levels of these factors in this two groups. The levels of twelve types of aPL and PAF in peripheral blood samples of RIF and fertile control women were checked with ELISA method. The results showed that levels of Anti Cardiolipin antibody IgG was above the normal level in 3% of RIF patients. This study examined for the first time the correlation between twelve types of aPLs and PAF in RIF and fertile women. The results of these correlations show that the serum levels of aPLs affects themselves and the serum levels of PAF. The correlation of aPLs levels and PAF levels was different in the two groups. Differences in the correlations of aPLs levels and PAF levels in two groups show that the equal changes in the level of variables examined can have different effects in RIF and the fertile control groups. It is suggested that the correlation between these variables be evaluated in other studies.

Shikonin reduces hepatic fibrosis by inducing apoptosis and inhibiting autophagy via the platelet-activating factor-mitogen-activated protein kinase axis.

Liver fibrosis is a tissue repair process that occurs following various types of chronic liver injury and can develop into liver cirrhosis, portal hypertension or liver cancer without effective treatment. Shikonin has anti-inflammatory, antiviral and antitumor properties. Furthermore, shikonin has an additional effect of antagonizing tissue and organ fibrosis. The aim of the present study was to evaluate the mechanisms of action underlying shikonin against liver fibrosis. Cell viability was assessed using the Cell Counting Kit-8 and EdU incorporation assays. Protein and mRNA expression levels were measured via western blotting and immunofluorescence assays, respectively. Apoptosis was examined via flow cytometry and autophagy via transmission electron microscopy. Compared with the control group, shikonin did not significantly alter LX-2 cell viability at 0.2 µmol/ml, which was used as the intervention concentration. However, shikonin significantly inhibited fibrosis, as indicated by a decrease in the expression of α-smooth muscle actin and collagen-I in the TGF-β + shikonin group compared with the TGF-β group. The results indicated that shikonin potentially inhibited fibrosis via promoting cell apoptosis and inhibiting autophagy. Additionally, the results of the present study indicated that shikonin downregulated the expression levels of platelet-activating factor (PAF) in TGF-β-treated cells, which subsequently activated the MAPK signaling pathway, leading to enhanced cell apoptosis and reduced autophagy. Collectively, the present study indicated that shikonin promoted cell apoptosis and suppressed autophagy via the PAF-MAPK axis in LX-2 cells, thus blocking the development of fibrosis. The results of the present study may provide a potential therapeutic strategy for liver fibrosis.

Effects of Snake-Derived Phospholipase A2 Inhibitors on Acute Pancreatitis: In vitro and in vivo Characterization.

ObjectiveWe aimed to investigate the effects of snake-derived phospholipase A2 inhibitor (PLA2) from Sinonatrix percarinata and Bungarus multicinctus on acute pancreatitis in vivo and in vitro and assess the mechanisms.MethodsThe levels of platelet-activating factor (PAF) and tumor necrosis factor (TNF)-α were detected by ELISA, and the characteristics of autophagy were detected by transmission electron microscopy and Western blotting (LC3, p62, and ATG5).ResultsIn vitro experiments showed that PLA2 treatment caused obvious formation of autophagic bodies. By contrast, Sinonatrix and Bungarus peptides reduced the number of autophagic bodies. The concentrations of PAF and TNF-α, and the expressions of p62, autophagy-related 5 (ATG5), and microtubule-associated protein 1A/1B-light chain 3 (LC3)II/LC3I in the PLA2-treated group were significantly higher than in the control group (P<0.05). The concentrations of PAF and TNF-α, and the expressions of p62, ATG5, and LC3II/LC3I in the Sinonatrix or Bungarus peptide treatment groups were significantly lower than in the PLA2-treated cells (P<0.05). In the pancreatic tissue, autophagic bodies were observed in the model group; autophagic bodies were remarkably reduced in Sinonatrix or Bungarus peptide-treated groups compared with the model group. In vivo experiments also showed that the levels of PAF and TNF-α, and the expressions of p62, ATG5, and LC3II/LC3I were significantly higher in the model group than in the control group (P<0.05). The levels of PAF and TNF-α in the model group, and the expressions of p62, ATG5, and LC3II/LC3I in Sinonatrix or Bungarus peptide-treated groups were significantly lower than in the model group (P<0.05).ConclusionSinonatrix or Bungarus peptide could ameliorate the features of acute pancreatitis, likely through regulating autophagy.

Ursodeoxycholic acid protects neonatal rats from necrotizing enterocolitis: a biochemical, histopathological, and immunohistochemical study

Background The pathophysiology of necrotizing enterocolitis (NEC) includes the massive production of endogenous cytokines with exaggerated activation of inflammatory pathways. Ursodeoxycholic acid (UDCA) has been used as an anti-inflammatory, antioxidant, and anti-apoptotic agent. We investigated the possible protective effects of UDCA in a neonatal rat pup model of NEC. Methods We randomly divided rat pups into three groups: a control group, a non-treated NEC group, and a UDCA-treated NEC group. We induced NEC by feeding formula enterally and via hypoxia/reoxygenation. Intestinal samples were collected for histopathological and immunohistochemical evaluation. Blood samples were taken for biochemical analyses. Results UDCA significantly reduced the extents of terminal ileal and jejunal injuries compared to the NEC group (p < .01), reduced Bax and caspase-3 immunoreactivities (both p < .01), and lowered serum levels of platelet-activating factor and intestinal fatty acid-binding protein (p < .01, p = .023, respectively). Conclusions In a rat model of NEC, UDCA protects against adverse intestinal histological, immunohistochemical, and biochemical changes. UDCA significantly reduces the effects of NEC on the rat pup intestine.

Fetal Exosomal Platelet-activating Factor Triggers Functional Progesterone Withdrawal in Human Placenta.

In most mammals, labor is heralded by the withdrawal of progesterone. In humans, circulating progesterone levels increase as gestation advances while placental expression of progesterone receptor A (PR-A) declines. As a result of PR-A downregulation, the non-canonical NF-κB pathway is activated, an event implicated in triggering labor. Here, we sought to identify fetal-derived mediator(s) that represses placental PR-A in human placenta leading to activation of pro-labor signaling. Lipidomic profiling demonstrated enrichment of platelet-activating factor (PAF) in exosomes originating from the human fetus. Exposure of primary cytotrophoblasts to fetal exosomes from term pregnancies reduced PR-A expression by > 50%, and PAF also reduced PR-A message levels in a dose-dependent manner. Notably, fetal exosomes from preterm pregnancies had lower PAF levels and no effect on PR-A expression. Synthetic PAF-induced DNA methylation increases by 20% at the PR-A promoter, leading to recruitment of corepressors and downregulation of PR-A in cytotrophoblast. Furthermore, suppression of PR-A by PAF-stimulated expression of the pro-labor genes, corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2), which was reversed by disruption of the DNA methyltransferases 3B and 3L. Taken together, PAF represents a novel fetal-derived candidate for initiation of labor by stimulating methylation and repression of PR-A and activating pro-labor signaling in trophoblast.

Serum platelet activating factor levels predicts refractoriness to antihistamine treatment in chronic spontaneous urticaria

This work was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korea government (MSIP) (NRF-2018R1A2B6006199) and a research grant from Ahn-Gook Pharmaceutical Co, Ltd, Seoul, Republic of Korea. Platelet activating factor (PAF) is one of the most potent phospholipid released from platelets as well as various inflammatory cells. PAF has been known to play a role in the regulation of immune responses and allergic inflammation. This study was aimed to compare circulating levels of PAF and PAF-acetylhydrolase (AH) which can catabolize PAF in patients with chronic spontaneous urticarial (CSU) and healthy controls (NC) and to investigate relationships of their levels and urticaria severity and therapeutic response. Serum PAF and PAF-AH levels were measured by ELISA in 283 CSU patients and 111 age- and sex-matched NCs. Urticaria severity was evaluated by urticaria activity score over 7 days (UAS7). Within 3 months after measuring PAF levels, patients whose urticaria was not controlled by antihistamine treatment were classified as histamine receptor 1 antagonist (H1RA) non-responders. Serum PAF levels were higher in CSU patients than in NCs (median 4368.9 [17.0–14768.3] vs. 3256.4 [27.1–13886.7] pg/ml, p = 0.015), while serum PAF-AH levels were lower in CSU patients (105.6 [2.6–296.4] vs. 125.7 [2.0–291.1] ng/ml, p = 0.001). H1RA non-responders had higher levels of PAF (3804.5 [17.0–11716.3] vs. 5426.3 [53.1–14768.3], p < 0.001) in their sera. A generalized linear model revealed that a higher UAS7 score (odds ratio 1.023) and a PAF level ≥ 5000 pg/ml (1.409) were significant predictors of a poor response to H1RA treatment. CSU patients, particularly those with H1RA refractoriness, showed significant increases in serum PAF levels and decreases in PAF-AH as compared with NCs. Therapies modulating PAF and PAF-AH levels could be effective in patients with CSU refractory to antihistamines.

Thermal Burn Injury Generates Bioactive Microvesicles: Evidence for a Novel Transport Mechanism for the Lipid Mediator Platelet-Activating Factor (PAF) That Involves Subcellular Particles and the PAF Receptor.

Thermal burn injuries are an important environmental stressor that can result in considerable morbidity and mortality. The exact mechanism by which an environmental stimulus to skin results in local and systemic effects is an area of active research. One potential mechanism to allow skin keratinocytes to disperse bioactive substances is via microvesicle particles, which are subcellular bodies released directly from cellular membranes. Our previous studies have indicated that thermal burn injury of the skin keratinocyte in vitro results in the production of the lipid mediator platelet-activating factor (PAF). The present studies demonstrate that thermal burn injury to keratinocytes in vitro and human skin explants ex vivo, and mice in vivo generate microvesicle particles. Use of pharmacologic and genetic tools indicates that the optimal release of microvesicles is dependent upon the PAF receptor. Of note, burn injury-stimulated microvesicle particles do not carry appreciable protein cytokines yet contain high levels of PAF. These studies describe a novel mechanism involving microvesicle particles by which a metabolically labile bioactive lipid can travel from cells in response to environmental stimuli.

Rutin ameliorates cigarette smoke mediated lung inflammation in a mouse model of chronic obstructive pulmonary disease via regulating the levels of tumor necrosis factor-α, interleukin-8 and PAF

IntroductionRutin is a plant-derived flavonoid. In the present work we screened the activity of rutin in a cigarette smoke induced lung disease mouse model of chronic obstructive pulmonary disease (COPD).Material and methodsThe mice were subjected to cigarette smoke for two weeks for inducing COPD simulating lung inflammation. Two hours prior to exposure to cigarette smoke, the mice were treated with rutin via the oral route. After treatment, the mice were assessed for profiling of cytokines and infiltration of immune cells in the bronchoalveolar fluid and histological alterations in the lungs. Roflumilast, an anti-COPD drug, was used as a positive control for comparing the efficacy of rutin.ResultsThe results of the study suggested that the treatment with rutin inhibited the inflow of macrophages, lymphocytes and neutrophils significantly in the airway. It was also observed that the treatment with rutin significantly decreased tumor necrosis factor-, interleukin-8 and platelet activating factor levels in the bronchoalveolar lavage fluid compared to the cigarette smoke exposed group. Interestingly, the findings of our study were parallel to the positive control RFL included in the experiment in the treated mice.ConclusionsThe findings suggested that rutin exerts a protective effect against cigarette smoke mediated COPD-like lung inflammation. Hence rutin may be a novel therapeutic agent for treating inflammatory conditions in lungs such as COPD.

Untargeted metabolomics predicts the functional outcome of ischemic stroke

Metabolites in blood have been found associated with the occurrence of vascular diseases, but its role in the functional recovery of stroke is unclear. The aim of this study is to investigate whether the untargeted metabolomics at the acute stage of ischemic stroke is able to predict functional recovery. One hundred and fifty patients with acute ischemic stroke were recruited and followed up for 3 months. Fasting blood samples within 7 days of stroke were obtained, liquid chromatography and mass spectrometry were applied to identify outcome-associated metabolites. The patients' clinical characteristics and identified metabolites were included for constructing the outcome prediction model using machine learning approaches. By using multivariate analysis, 220 differentially expressed metabolites (DEMs) were discovered between patients with favorable outcomes (modified Rankin Scale, mRS≤2at 3 months, n=77) and unfavorable outcomes (mRS≥3at 3 months, n=73). After feature selection, 63 DEMs were chosen for constructing the outcome prediction model. The predictive accuracy was below 0.65 when including patients' clinical characteristics, and could reach 0.80 when including patients' clinical characteristics and 63 selected DEMs. The functional enrichment analysis identified platelet activating factor (PAF) as the strongest outcome-associated metabolite, which involved in proinflammatory mediators release, arachidonic acid metabolism, eosinophil degranulation, and production of reactive oxygen species. Metabolomics is a potential method to explore the blood biomarkers of acute ischemic stroke. The patients with unfavorable outcomes had a lower PAF level compared to those with favorable outcomes.

Role of Low-Density Lipoprotein in Early Vascular Aging Associated With Systemic Lupus Erythematosus.

Patients with systemic lupus erythematosus (SLE) often have atherosclerotic complications at a young age but normal low-density lipoprotein (LDL) levels. This study was undertaken to investigate the role of LDL composition in promoting early vascular aging in SLE patients. Plasma LDL from 45 SLE patients (SLE-LDL) and from 37 normal healthy controls (N-LDL) was chromatographically divided into 5 subfractions (L1-L5), and the subfraction composition was analyzed. Correlations between subfraction levels and signs of early vascular aging were assessed. Mechanisms of lipid-mediated endothelial dysfunction were explored using in vitro assays and experiments in apoE-/- mice. The L5 percentage was increased 3.4 times in the plasma of SLE patients compared with normal controls. This increased percentage of SLE-L5 was positively correlated with the mean blood pressure (r = 0.27, P = 0.04), carotid intima-media thickness (IMT) (right carotid IMT, r = 0.4, P = 0.004; left carotid IMT, r = 0.36, P = 0.01), pulse wave velocity (r = 0.29, P = 0.04), and blood levels of CD16+ monocytes (r = 0.35, P = 0.004) and CX3CL1 cytokines (r = 0.43, P < 0.001) in SLE patients. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analysis revealed that plasma levels of lysophosphatidylcholine (LPC) and platelet-activating factor (PAF) were increased in SLE-LDL and in the SLE-L5 plasma subfraction. Injecting SLE-LDL, SLE-L5, or LPC into young, male apoE-/- mice caused increases in plasma CX3CL1 levels, aortic fatty-streak areas, aortic vascular aging, and macrophage infiltration into the aortic wall, whereas injection of N-LDL or SLE-L1 had negligible effects (n = 3-8 mice per group). In vitro, SLE-L5 lipid extracts induced increases in CX3CR1 and CD16 expression in human monocytes; synthetic PAF and LPC had similar effects. Furthermore, lipid extracts of SLE-LDL and SLE-L5 induced the expression of CX3CL1 and enhanced monocyte-endothelial cell adhesion in assays with bovine aortic endothelial cells. An increase in plasma L5 levels, not total LDL concentration, may promote early vascular aging in SLE patients, leading to premature atherosclerosis.