Critical interplay between PAF receptor and PKCδ is involved in dopaminergic insult evoked by methamphetamine in mice.

Platelet-activating factor induces ferroptosis by binding to ATF3 and inhibiting the SLC7A11/GPX4 axis to suppress the progression of endometrial carcinoma.

Rupatadine is a modern, long-acting, non-sedating antihistamine that targets the H1 receptor and exhibits additional strong antagonist activity toward platelet-activating factor (PAF) receptors as well as exerting other anti-inflammatory effects. All these properties have positioned rupatadine as a remarkable treatment option for adults and children with various allergic and skin disorders, including allergic rhinitis and urticaria of different causes. This case series shows the real-world effectiveness and safety of off-label rupatadine use in paediatric patients with clinically relevant complex allergy-related and dermatology-related conditions, whose underlying pathogenetic mechanisms were successfully addressed by the pharmacological profile of rupatadine.

Evidence for keratinocyte-derived microvesicle particles as carriers for the potent lipid mediator platelet-activating factor as effectors for systemic effects associated with many environmental stressors.

Neutrophils, key effector cells of the innate immune system, combat pathogens through mechanisms including the production of reactive oxygen species (ROS) and the release of neutrophil extracellular traps (NETs). While these responses are critical for host defense, prolonged elevation of ROS and dysregulated NETosis mediated by neutrophils have been implicated in autoimmune diseases, chronic inflammation, and cancer. In pancreatic ductal adenocarcinoma (PDAC), a highly aggressive and inflammatory malignancy, an increase in neutrophils infiltrating the tumor microenvironment promotes cancer progression and metastasis through increased ROS production and NET release. Using bioluminescence imaging with the reporter L-012 and NET assays, we assessed ROS and NET release, respectively, induced by phorbol myristate acetate and platelet-activating factor in bone-marrow-isolated neutrophils from wild-type and syngeneic myeloperoxidase (MPO)-deficient mice ex vivo. MPO deficiency impaired both ROS generation and NET release, establishing a positive correlation between these processes. In vivo analyses using subcutaneous and spontaneous murine PDAC models revealed elevated ROS in tumors, which were significantly reduced upon genetic deletion of host MPO or peptidyl arginine deiminase 4, an essential enzyme for NET formation, or after treatment with hydroxychloroquine, a NET inhibitor. Furthermore, luminol and 4-[18F]fluoro-1-naphthol ([18F]4FN), functional L-012 analogs, also enabled non-invasive detection of intratumoral ROS by bioluminescence and PET imaging in vivo, respectively; [18F]4FN PET showed a three-fold increased uptake in PDAC tumors versus muscle. PDAC tissues and blood-isolated neutrophils obtained from PDAC patients exhibited elevated ROS compared to controls ex vivo. Importantly, ROS levels correlated strongly with NET formation in patient samples. These findings reveal a bidirectional relationship between ROS and NETs and highlight the potential utility of L-012- and [18F]4FN-based PET imaging for monitoring NET-associated inflammation in PDAC in vivo.

The critical events that trigger sepsis progression into life-threatening septic shock remain unclear. In agreement with reports that link a drop in platelet count to a complicated clinical course in sepsis patients, here we report that, during sepsis, mouse platelets become activated, deposit systemically on vascular walls, and stimulate perivascular mast cells (MC) by releasing platelet activating factor (PAF). In mouse models and patient samples, MC activation correlates with the development of shock in sepsis and is mechanistically linked to shock by inducing systemic hypotension, vascular leakage and microvascular perfusion abnormalities. Preventing platelet or MC activation, or inhibiting the activity of the major MC granule constituent chymase, averts progression from sepsis to shock and reduces mortality of septic mice. Thus, our work establishes that, during sepsis progression, platelet microvascular adhesion leads to MC-mediated vascular changes to culminate in septic shock and septic shock-associated mortality.

Antagonizing epigenetically controlled PAF/PAF-R pathway improves liver function during experimental cirrhosis.

Psychotropic and neurodegenerative drugs modulate platelet activity via the PAF pathway.

Disruption of the actin cytoskeleton with latrunculin A controls ATP-induced NADPH oxidase activity and the recruitment of G proteins by neutrophil Gαq-coupled receptors.

This study aimed to determine whether currently available medications for detrusor overactivity (DO) can inhibit the platelet-activating factor (PAF)-induced increase in the mechanical activity of the urinary bladder smooth muscle (UBSM) in guinea pigs. Ten clinically used DO drugs-oxybutynin, tolterodine, fesoterodine, propiverine, propantheline, solifenacin, imidafenacin, flavoxate, urapidil, and clenbuterol-were tested at a concentration of 10 μM, exceeding typical therapeutic plasma levels. Among these, oxybutynin exerted the most pronounced inhibitory effect, reducing the PAF (1 μM)-induced increase in basal tone by approximately 60%. Furthermore, oxybutynin (10 μM) also decreased 60 mM KCl-induced contractions by a similar extent and nearly abolished acetylcholine (ACh, 10 μM)-induced contractions. These findings suggest that oxybutynin suppresses PAF-induced UBSM hyperactivity through a mechanism distinct from its anticholinergic effect, likely mediated by blockade of voltage-dependent Ca2+ channels (VDCCs).

PurposePsoriasis with blood stasis syndrome (BSS) demonstrates aggravated skin lesions compared to psoriasis alone; however, the underlying mechanism remains unclear. This study aims to elucidate the pathological mechanisms of skin lesion exacerbation in psoriasis from the perspective of platelet activation.MethodsA psoriasis rat model was established by topical application of imiquimod (IMQ), while a psoriasis with BSS model was induced using ice–water baths and epinephrine injection. Skin lesions were assessed via hematoxylin and eosin (H&E) staining. Hemorheology was employed to evaluate BSS characteristics. Western blot (WB) was used to examine CD62P (P-selectin) and platelet-activating factor receptor (PAFR) expression to assess platelet activation. The platelet aggregation inhibitor clopidogrel was administered via oral gavage. The psoriasis area and severity index (PASI) was applied to evaluate clopidogrel’s therapeutic effect, and network pharmacology combined with quantitative reverse transcription PCR (RT–qPCR) was used to clarify its mechanism.ResultsHE staining indicated more severe skin lesions in psoriasis with BSS rats than in psoriasis rats (P<0.01). Hemorheological analysis revealed increased blood viscosity and microvascular proliferation in the psoriasis rats with BSS. WB showed significantly elevated expression of CD62P and PAFR in psoriasis with BSS rats (P<0.05). Clopidogrel reduced epidermal thickening, as assessed by the PASI score. Network pharmacology and RT–qPCR identified P2RY12 and GPIIb/IIIa as key targets through which clopidogrel ameliorates skin lesions in psoriasis with BSS.ConclusionPsoriasis with BSS rats exhibit more severe skin lesions than psoriasis rats, associated with enhanced platelet activation. Clopidogrel improved blood stasis and skin inflammation, confirming that platelet activation contributes critically to skin lesion worsening.

Summary:Atopic dermatitis is an allergic skin disease associated with a profound reorganization of the epidermal lipidome. The effect of the altered lipidome on the skin-resident immune cells that drive disease is unclear. Previous reports identified Fatty acid binding protein 5 (FABP5) as a biomarker for atopic dermatitis, yet how FABP5 might contribute to disease pathogenesis is unknown. Here, we use a murine model of atopic dermatitis, to demonstrate that FABP5 is highly expressed in immune and epithelial cell lineages and that FABP5 protects against skin inflammation. Lipidomic analysis revealed that FABP5 deficiency broadly disrupts the systemic abundance of ether-linked lipids, a minor but important subset of glycerophospholipids. We show that these changes in ether lipid abundance are crucial for the proper regulation of platelet activating factor (PAF), a potent inflammatory ether lipid derivative. Concordantly, we observe elevated PAF in FABP5-deficient mice with dermatitis and that depletion of basophils, a major source of PAF, is sufficient to ameliorate disease in these animals. Altogether, our findings reveal a novel role for FABP5 in the control of allergic inflammation through the modulation of ether lipid and PAF metabolism.

Disclosure: M. D'silva: None. B. Malachowska: None. Y. Qiu: None. J. Sepulveda: None. R. Chang: None. S. Sidoli: None. J.L. Nadler: None. I.J. Kurland: Scorpion Therapeutics.An important early hallmark of Type I Diabetes Mellitus (T1D) is beta-cell dysfunction, a critical mechanism of which is cytokine mediated. Our exploratory study defined regulatory programs controlling human islet responses to pro-inflammatory cytokines by mapping abundance proteomics , as well as metabolomics and lipidomics from the same islets exposed to inflammation-inducing cytokines TNF-alpha, IL-1β and IFN-γ over the time course at 1,6 and 24 hrs after cytokine exposure. Methods: Pancreatic islets were purchased from Prodo Labs (https://prodolabs.com/). Islet samples were extracted by the Folch method, and targeted mass spectrometric methods employing a Sciex 6500+ QTRAP was used to identified metabolites, neutral and phospholipids and oxylipins/eicosanoids,from the aqueous and chloroform fractions. The Folch protein interface was collected, redissolved and then digested using S-Trap flters (Protif), 5% SDS. Proteome raw files were searched using Proteome Discoverer software. Results: Approximately 3500 proteins were identified, of which approximately 200 were significantly changed with cytokine vs control treatment that were further identified from the RECON genome-scale metabolic reconstruction as potentially important for metabolic network flux determination. ∼100 of these metabolic proteomic changes were seen at 1 hr , and an additional 85 metabolic proteins were significantly changed at 6 hr after cytokine stimulation along 35 proteins that were still changed from 1hr. Overall, cytokine stimulation resulted in an inhibition of metabolic protein expression at these time points, however, the metabolomic analysis indicated that islet metabolism was re-directed to specific pathways rather than simply suppressed. Levels of nucleotides needed for DNA and RNA synthesis could be seen to be increased, as well as pentose and hexosamine pathway intermediates, which depleted glycolytic and TCA cycle intermediates. The inflammatory islet response was reflected by an increase in platelet-activating factor PAF and lyso PAF at 1 and 6 hours, however the brunt of the oxylipin/eicosanoid response was delayed until 24 hours after cytokine stimulation, and secreted (media) oxylipins were composed mainly of cycloxygenase (COX) products of arachidonic (AA) acid, as well as 12- and 15-lipoxygenase (LOX) products of AA and DHA. At 24 hours after cytokine stimulation, the suppression/elevation of the metabolic responses seen at 1 and 6 hrs were largely resolved, along with elevations in HLA proteins and proteosome subunit expression consistent with immune response activation. Conclusion: Interventions for arresting beta cell dysfunction need to consider the pathways which may be activated sequentially and in coordination with immune activation.Presentation: Monday, July 14, 2025

Structural and molecular dynamics insights into the competitive inhibition of the platelet-activating factor receptor by acyl-PAF

This study investigates the development and evaluation of anti-photoaging creams enriched with natural extracts from avocado, apple, and kiwi by-products, with and without nanobubbles (NBs), focusing on their antioxidant, photoprotective, anti-inflammatory, and antiplatelet properties. Extract-containing creams showed significantly higher antioxidant capacity, particularly in the ferric reducing antioxidant power (FRAP) assay (S: 710.4 ± 344.3, NB: 566.3 ± 185.0, X: 202.8 ± 145.6 μmol TE/g DW at production; S: 631.7 ± 277.8, NB: 1019.3 ± 574.0, X: 449.8 ± 43.9 μmol TE/g DW after 1 month; p &lt; 0.05), indicating up to a 250% improvement compared to the base cream and stable antioxidant activity during storage. The sun protection factor (SPF) increased in extract-containing creams after storage (8.7 ± 0.8 → 9.5 ± 0.6; p &lt; 0.05). Attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) with Strat-M® membranes revealed enhanced penetration of active compounds in enriched creams, while NBs did not significantly change absorption profiles. Platelet aggregation assays showed markedly lower half maximal inhibitory concentration (IC50) values in extract-enriched creams compared to the base cream for both the platelet-activating factor (PAF) pathway (S: 300.0 ± 42.0, NB: 258.0 ± 31.0 vs. X: 685.0 ± 35.0; after 1 month S: 325.0 ± 50.0, NB: 275.0 ± 42.0 vs. X: 885.0 ± 112.0; p &lt; 0.05) and the adenosine diphosphate (ADP) pathway (S: 450.0 ± 65.0, NB: 400.0 ± 31.0 vs. X: 880.0 ± 58.0; after 1 month S: 470.0 ± 52.0, NB: 412.0 ± 42.0 vs. X: 1102.0 ± 125.0; p &lt; 0.05). In silico analysis was also performed to demonstrate the ligand/protein complex with the strongest affinity to the PAF receptor. Overall, these findings highlight the potential of fruit by-products as sustainable, multifunctional cosmetic ingredients supporting circular economy principles.

PAF signaling axis functions as biomarker or target for esophageal squamous cell carcinoma diagnosis or treatment.

BackgroundEpidemiological evidence suggests health risks arise from intake of food additives. This study aims to investigate the mechanisms linking food additives to childhood asthma through a metabolomics strategy.MethodsA total of 120 children with asthma and 120 control subjects were recruited. Serum concentrations of ten food additives - including cyclamate, neotame, aspartame, sodium saccharin, acesulfame, sucralose, benzoic acid, dehydroacetic acid, sunset yellow, and ponceau 4R - were quantified using UPLC-MS/MS. The associations between food additives and asthma were evaluated by logistic regression and chi-square tests. Serum metabolic profiling was performed by UPLC-MS. Identified asthma-associated metabolites were subsequently analyzed for pathway enrichment and mediation effects. In murine studies, acesulfame, sodium saccharin, sodium benzoate, or their mixtures were co-administered with OVA to C57BL/6 mice. Airway inflammation, IgE, IL-4, IL-17A, immune cell differentiation, and CD4+ T cell metabolomics profiles were assessed.ResultsThe detection rates for dehydroacetic acid, benzoic acid and sodium cyclamate exceeded 60%. Benzoic acid, dehydroacetic acid and acesulfame were significantly associated with asthma. Mediation analysis identified fourteen metabolites as mediators in the relationship between benzoic acid and dehydroacetic acid, and childhood asthma, including PC(14:0/14:0), LysoPC(17:0), glycerophosphocholine, PC(18:1(9Z)e/2:0), PE(18:2(9Z,12Z)/14:0), glutamic acid, glutamine, GlcCer(d18:1/16:0), sphingosine, sphingosine-1-phosphate, spermine, spermidine, histidine, and acetylcholine. These metabolites were enriched in glycerophospholipid metabolism, β-alanine metabolism, glutathione metabolism, sphingolipid metabolism, arginine and proline metabolism, arginine biosynthesis, and histidine metabolism pathways. In murine models, food additives significantly exacerbated lung tissue inflammation and elevated levels of IgE, IL-4, and IL-17A in both BALF and serum, and also increased eosinophil percentages in BALF. Furthermore, flow cytometry showed significant alterations in Th1/Th2, Th17/Treg and allergic DC/tolerogenic DC balance within the mesenteric lymph node (MLN) and the lung tissue. Metabolomic profiling of CD4+ T-cells from the MLN demonstrated that food additives primarily disrupted phenylalanine, tyrosine, and tryptophan biosynthesis, and glycerophospholipid metabolism pathways. This disruption involved key metabolites including PC(36:4), platelet-activating factor, LysoPE(P-16:0), PS(14:0/5-iso PGF2VI), PE(14:1(9Z)/15:0), Na,Na-dimethylhistamine, docosadienoic acid, cyclohexaneundecanoic acid, L-acetylcarnitine, phosphorycholine, Cer(d18:2/20:0), DG(22:1n9/0:0/20:4n6), 5’-methylthioadenosine, L-tyrosine, and N-palmitoyl leucine.ConclusionFood additives may aggravate asthma by metabolically dysregulating the homeostasis of helper T-cells and antigen-presenting cells, thereby disrupting immune tolerance.

The aim of the current study is to identify the possible protective effect of rupatadine (RUP) on ovarian ischemia reperfusion (OIR) in rats. RUP was administered in the presence and absence of OIR. Thirty-two adult Wistar albino female rats were randomly arranged into four groups: Sham, RUP (6mg/kg/day) for 14 days, OIR and OIR + RUP groups.The results demonstrated that OIR significantly lowered serum anti-mullerian hormone level and ovarian total antioxidant capacity. Besides, a significant elevation in serum follicle stimulating hormone, lutenizing hormone, ovarian malondialdehyde level, hypoxia-inducible factor-1(HIF-1α), platelet activating factor (PAF), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and interleukin 1beta (IL-1β) levels along with an evident increase in ovarian vascular endothelial growth factor (VEGF) and caspase-3 immunoexpression. While, OIR + RUP pretreated group showed a reversal in OIR damaging effects in a significant manner in all the aforementioned parameters. Based on these findings; RUP has powerful anti-IR actions by lowering oxidative stress, inflammation, and apoptosis via modulation of the PAF/ NF-κB/TNF-α/ IL-1β; HIF-1α/ VEGF / Caspase 3 signaling pathways.

Rupatadine, primarily used for treating allergic rhinitis as a selective histamine H1 receptor and platelet-activating factor antagonist, has potential anticancer properties, specifically through inducing lysosomal membrane permeabilization. The present study explores the efficacy of rupatadine in pancreatic cancer. The study assessed the effects of rupatadine on cell viability in AsPC-1 and MIA PaCa-2 pancreatic cancer cell lines at concentrations ranging from 0.001 to 50 µM. Additionally, a xenograft pancreatic cancer model in mice was used, with rupatadine administered intraperitoneally at 3 mg/kg three times weekly for 3 weeks. Tumor weights were measured 21 days post-treatment. Western blot analysis and immunohistochemical staining were conducted on excised tumor tissues to evaluate the impact on EMT and apoptosis. Rupatadine exhibited a concentration-dependent decrease in cell viability in both pancreatic cancer cell lines (P<0.05). In vivo, rupatadine significantly reduced tumor weight in the xenograft model compared with control groups (P<0.05). Further analysis revealed inhibition of EMT, evidenced by increased E-cadherin and decreased Vimentin and Snail levels. Apoptosis was enhanced, as shown by increased PARP and decreased Mcl-1 levels (P<0.05). Rupatadine shows significant anticancer potential in pancreatic cancer by inhibiting EMT and promoting apoptosis. These findings suggest that rupatadine could be developed as a novel therapeutic agent for pancreatic cancer, meriting further clinical investigation.

Inflammation serves as a protective response to combat cellular and tissue damage. There is currently a wide array of synthetic and traditional therapies available for the treatment of inflammatory diseases. However, it is necessary to create a drug delivery system based on nanotechnology that can improve the solubility, permeability, and bioavailability of current treatments. Mesoporous silica nanoparticles (MSNPs) are inorganic materials known for their organised porous interiors, high pore volumes, substantial surface area, exceptional selectivity, permeability, low refractive index, and customisable pore sizes. This review offers concise insights into the progression of the pathophysiology of inflammation, as well as the inducers, mediators, and effectors that are involved in the inflammatory pathway. This study focuses on the growing significance of MSNPs in the treatment of neuroinflammation, inflammatory bowel disease, arthritic inflammation, lung inflammation, and wound healing applications. This review also presents the latest information on the crucial role of MSNPs in delivering herbal medicines for the treatment of inflammation. A comprehensive literature search was conducted for this aim, utilising the Google Scholar, PubMed, and ScienceDirect databases. A systematic review was undertaken utilising scholarly articles published in peer-reviewed journals from 2000 to 2024. The inflammatory mediators involved in the pathophysiology of inflammation include platelet-activating factor, lipoxygenase, cyclooxygenase, Interferon-α, interleukin-6, interleukin- 1β, matrix metalloproteinases, inducible nitric oxide synthase, nuclear factor-κB, prostaglandins, nitric oxide, and phospholipase A2. MSNPs have the potential to be used in the treatment of neuroinflammation, inflammatory bowel disease, arthritic inflammation, lung inflammation, and wound healing. The investigation of the MSNPs of plant-based compounds such as berberine, tetrahydrocannabinol, curcumin, and resveratrol has shown successful results in recent years for the purpose of managing inflammation. This review demonstrates that MSNPs have a strong potential to play a positive role in delivering synthetic and plant-based therapies for the treatment of inflammatory illnesses.