Search

Background: Activation of endothelial cells and platelets in atherothrombosis is characterized by upregulation of P-selectin. As a consequence, P-selectin represents a potential target for molecular imaging to identify thrombosis at an early stage. Fucoidan is a polysaccharide ligand extracted from brown algae with nanomolar affinity for P-selectin. This first-in-human study evaluated in healthy volunteers the safety, whole-body biodistribution, and dosimetry of 99mTc-fucoidan (Good Manufacturing Practices grade). We also investigated whether we could observe binding of 99mTc-fucoidan to human thrombi ex vivo and in vivo. In ten healthy volunteers, conjugate whole-body scans were performed up to 24 h following intravenous injection of 99mTc-fucoidan (370 MBq). Moreover, 99mTc-fucoidan uptake in ex vivo human thrombi (n = 11) was measured by gamma counting. Additionally, three patients with a newly diagnosed deep vein thrombosis (DVT) were subjected to 99mTc-fucoidan SPECT/CT imaging. Results: 99mTc-fucoidan was well tolerated in all participants without any drug-related adverse events. The total-body absorbed dose in males was comparable to females (0.012 ± 0.004 vs. 0.011 ± 0.005 mSv/MBq; p = 0.97). Gamma counting experiments demonstrated binding of tracer to ex vivo human thrombi that was 16% lower after blocking with a natural P-selectin ligand, Sialyl Lewis X. 99mTc-fucoidan demonstrated specific uptake at the thrombus site in one out of three scanned patients with DVT. Conclusions: 99mTc-Fucoidan has a favorable biodistribution and safety profile. 99mTc-fucoidan exhibited specific binding to human thrombi in both in vivo and ex vivo settings. Nonetheless, the in vivo results do not support further clinical investigation of 99mTc-fucoidan as an imaging modality for DVT. Other clinical implementations of a technetium− 99m-labeled P-selectin tracer should be considered. Trial registration: Clinicaltrials,NCT03422055.Registered 01/15/2018. URL: https://clinicaltrials.gov/study/NCT03422055Landelijk Trial Register, NL7739. Registered 4/2/2019. https://onderzoekmetmensen.nl/en/trial/26785 [ABSTRACT FROM AUTHOR]

Increased platelet activity is a risk factor of thrombotic events in cardiovascular patients. We studied the relationship between platelet function, platelet size, and the content of reticulated platelets (RP) in patients with coronary heart disease (CHD, n = 55) and acute coronary syndrome (ACS, n = 95) receiving acetylsalicylic acid + clopidogrel or ticagrelor, respectively. The control group consisted of patients with risk factors for CHD, but with no CHD/ACS and free of antiplatelet drugs (n = 66). Platelet function was evaluated by the exposure of activated glycoprotein (GP) IIb-IIIa and P-selectin. In the control group, platelets were activated by TRAP (Thrombin Receptor Activating Peptide) 10 µM, and ADP 20, 5, 2.5 µM, and in the CHD/ACS groups, by TRAP 10 µM, and ADP 20 5 µM (±epinephrine 20 µM). Platelet size was assessed by the mean volume, % large forms, and forward scattering. RP were stained by thiazole orange. In the control group, activated GP IIb-IIIa and P-selectin correlated with platelet size and RP content after platelet activation by all agonists. Despite the decrease in platelet activity by antiplatelet drugs, most correlations (primarily for activated GP IIb-IIIa) were preserved in the CHD/ACS patients. In conclusion, increased platelet size and RP content are associated with increased platelet activity and the reduced efficacy of antiplatelet therapy. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to demonstrate the discriminating predictive indicators in peripheral blood and left atrium blood for predicting the risk of left atrial spontaneous echo contrast (LASEC) in atrial fibrillation patients underwent catheter ablation. Methods: A total of 108 consecutive AF patients treated with radiofrequency ablation between July 2022 and July 2023 were enrolled and divided into two groups based on preprocedural transesophageal echocardiography: the non LASEC group (n = 71) and the LASEC group (n = 37). Circulating platelet and endothelial- derived MPs (PMPs and EMPs) in peripheral blood and left atrial blood were detected. Plasma soluble P-selectin (sP-selectin) and von Willebrand factor (vWF) were observed. Diagnostic efficiency was measured using receiver operating characteristic (ROC) curve. Results: Peripheral sP-selectin, vWF and EMPs expressions elevated in all subjects when compared to those in left atrium blood. Levels of sP-selectin and vWF were significantly higher in peripheral blood of LASEC group than those of non LASEC group (p = 0.0018,p = 0.0271). Significant accumulations of peripheral PMPs and EMPs were documented in LASEC group by comparison with non LASEC group (p = 0.0395,p = 0.018). The area under curve(AUC) of combined PMPs and sP-selectin in predicting LASEC was 0.769 (95%CI: 0.678–0.845, sensitivity: 86.49%, specificity: 59.15%), significantly larger than PMPs or sP-selectin alone. Conclusions: Expressions of PMPs, sP-selectin, EMPs and vWF Increased in NVAF patients with LASEC and that might be potential biomarkers for LASEC prediction. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although plateletpheresis donation is commonly accepted as a safe procedure, its influence on platelet function, coagulation system and fibrinolysis is not completely elucidated. OBJECTIVES: In this study, we tried to assess the effects of plateletpheresis on donor's hemostasis system by measuring platelet activation, development of platelet-leukocyte aggregates, and coagulation activation. STUDY DESIGN: Prospective observational study. METHODS: We used flow cytometry to determine the levels of platelet-monocyte complexes (PMC) and platelet-neutrophil complexes (PNC). sP-selectin and prothrombin fragment (PF) 1 + 2 values were determined by ELISA. RESULTS: The PMC levels increased significantly seven days after apheresis in comparison with just after apheresis and 24 h after apheresis (p < 0.05). The PNC levels increased significantly seven days after apheresis compared to immediately after apheresis (p < 0.05). sP-selectin values decreased significantly immediately after apheresis (p < 0.05). While sP-selectin values increased seven days after apheresis in comparison with immediately after apheresis and 24 h after apheresis, but there were not statistically significant differences for sP-selectin levels (p > 0.05). PF1 + 2 levels decreased significantly immediately after apheresis compared to pre-apheresis (p < 0.05) and increased 24 h after apheresis and seven days after apheresis, but these differences were not statistically significant. CONCLUSION: We concluded that plateletpheresis affects platelet activation but does not cause any change in coagulation activation. [ABSTRACT FROM AUTHOR]

Introduction Thirdhand smoke (THS) is associated with many public health and disease concerns, such as respiratory illness, cancer, lipidemia, and cardiovascular disease (CVD). We have previously shown that a moderate to long-term exposure to THS increases the risk of thrombosis. However, whether short-term exposure to THS would produce any effects remains to be discovered. Therefore, this study investigated the impact of 1-month THS exposure on platelet function, in vivo and in vitro, and on cytokine response, in a sex-dependent manner. Aims and Methods Secondhand smoke or clean air (CA) exposed upholstery materials for 1 week were kept in cages housed with 5–6 mice, and the procedure was repeated for 4 weeks. These THS-exposed mice were evaluated for thrombogenesis and platelet function assays. In addition, cytokines expression was evaluated from pooled serum. Results Compared to the CA group, THS exposure significantly shortened the tail bleeding time and carotid artery thrombus formation. Moreover, the female mice appeared more sensitive to THS exposure than males. Furthermore, platelet aggregation, dense granule secretion, and P-selectin activation markers were significantly elevated due to THS exposure. In addition, high-throughput screening showed at least 30 cytokines differentially modulated by THS in females relative to 26 in male mice. Conclusions Collectively, these results demonstrate that 1 month of THS exposure represents a high health risk, in part, by triggering a prothrombotic phenotype that appears to be more significant in females, who are at a much higher risk for occlusive CVD. Additionally, changes in cytokine levels mediate some of the THS-induced occlusive effects. Implications This study revealed that THS exposure for 1 month is detrimental to the cardiovascular health of both sexes; however, females could be more aggressively affected than males. In addition, interleukins and chemokines could be critical factors for initiating prothrombotic activity due to THS exposure. [ABSTRACT FROM AUTHOR]

This study investigated the roles of P‐selectin and Clara cell secretory protein 16 (CC16) levels in the pathogenesis of severe adenovirus (ADV) pneumonia in children and evaluated their ability to predict disease. Fifty‐one children (age, 1–5 years) with ADV pneumonia who were admitted to Xiamen Children's Hospital were included in this study and divided into the mild group (24 patients) and severe group (27 patients). A control group comprising healthy children of the same age who underwent routine physical examinations during the same period (30 patients) was also included. The univariate analysis demonstrated that the levels of the white blood cell count and C‐reactive protein, procalcitonin, d‐dimer, and P‐selectin were increased in a severe group compared with a mild group, while CC16 levels were significantly decreased (p < 0.05). The logistic regression analysis revealed that P‐selectin and CC16 levels were independent risk factors for severe ADV pneumonia in children. The areas under the ROC curves suggested that P‐selectin and CC16 exhibited high predictive value for severe ADV pneumonia. P‐selectin values more than 898.58 pg/mL and CC16 values less than 11.355 ng/mL predicted severe ADV pneumonia. P‐selectin and CC16 levels are correlated with the severity of ADV pneumonia in children. [ABSTRACT FROM AUTHOR]

Abstract Background Activation of endothelial cells and platelets in atherothrombosis is characterized by upregulation of P-selectin. As a consequence, P-selectin represents a potential target for molecular imaging to identify thrombosis at an early stage. Fucoidan is a polysaccharide ligand extracted from brown algae with nanomolar affinity for P-selectin. This first-in-human study evaluated in healthy volunteers the safety, whole-body biodistribution, and dosimetry of 99mTc-fucoidan (Good Manufacturing Practices grade). We also investigated whether we could observe binding of 99mTc-fucoidan to human thrombi ex vivo and in vivo. In ten healthy volunteers, conjugate whole-body scans were performed up to 24 h following intravenous injection of 99mTc-fucoidan (370 MBq). Moreover, 99mTc-fucoidan uptake in ex vivo human thrombi (n = 11) was measured by gamma counting. Additionally, three patients with a newly diagnosed deep vein thrombosis (DVT) were subjected to 99mTc-fucoidan SPECT/CT imaging. Results 99mTc-fucoidan was well tolerated in all participants without any drug-related adverse events. The total-body absorbed dose in males was comparable to females (0.012 ± 0.004 vs. 0.011 ± 0.005 mSv/MBq; p = 0.97). Gamma counting experiments demonstrated binding of tracer to ex vivo human thrombi that was 16% lower after blocking with a natural P-selectin ligand, Sialyl Lewis X. 99mTc-fucoidan demonstrated specific uptake at the thrombus site in one out of three scanned patients with DVT. Conclusions 99mTc-Fucoidan has a favorable biodistribution and safety profile. 99mTc-fucoidan exhibited specific binding to human thrombi in both in vivo and ex vivo settings. Nonetheless, the in vivo results do not support further clinical investigation of 99mTc-fucoidan as an imaging modality for DVT. Other clinical implementations of a technetium− 99m-labeled P-selectin tracer should be considered. Trial registration: Clinicaltrials,NCT03422055.Registered 01/15/2018. URL: https://clinicaltrials.gov/study/NCT03422055 Landelijk Trial Register, NL7739. Registered 4/2/2019 . https://onderzoekmetmensen.nl/en/trial/26785

Abstract Objectives The purpose of this study was to demonstrate the discriminating predictive indicators in peripheral blood and left atrium blood for predicting the risk of left atrial spontaneous echo contrast (LASEC) in atrial fibrillation patients underwent catheter ablation. Methods A total of 108 consecutive AF patients treated with radiofrequency ablation between July 2022 and July 2023 were enrolled and divided into two groups based on preprocedural transesophageal echocardiography: the non LASEC group (n = 71) and the LASEC group (n = 37). Circulating platelet and endothelial- derived MPs (PMPs and EMPs) in peripheral blood and left atrial blood were detected. Plasma soluble P-selectin (sP-selectin) and von Willebrand factor (vWF) were observed. Diagnostic efficiency was measured using receiver operating characteristic (ROC) curve. Results Peripheral sP-selectin, vWF and EMPs expressions elevated in all subjects when compared to those in left atrium blood. Levels of sP-selectin and vWF were significantly higher in peripheral blood of LASEC group than those of non LASEC group (p = 0.0018,p = 0.0271). Significant accumulations of peripheral PMPs and EMPs were documented in LASEC group by comparison with non LASEC group (p = 0.0395,p = 0.018). The area under curve(AUC) of combined PMPs and sP-selectin in predicting LASEC was 0.769 (95%CI: 0.678–0.845, sensitivity: 86.49%, specificity: 59.15%), significantly larger than PMPs or sP-selectin alone. Conclusions Expressions of PMPs, sP-selectin, EMPs and vWF Increased in NVAF patients with LASEC and that might be potential biomarkers for LASEC prediction.

Integrins were originally identified as receptors for extracellular matrix (ECM) and cell-surface molecules (e.g., VCAM-1 and ICAM-1). Later, we discovered that many soluble growth factors/cytokines bind to integrins and play a critical role in growth factor/cytokine signaling (growth factor-integrin crosstalk). We performed a virtual screening of protein data bank (PDB) using docking simulations with the integrin headpiece as a target. We showed that several growth factors (e.g., FGF1 and IGF1) induce a integrin-growth factor-cognate receptor ternary complex on the surface. Growth factor/cytokine mutants defective in integrin binding were defective in signaling functions and act as antagonists of growth factor signaling. Unexpectedly, several growth factor/cytokines activated integrins by binding to the allosteric site (site 2) in the integrin headpiece, which is distinct from the classical ligand (RGD)-binding site (site 1). Since 25-hydroxycholesterol, a major inflammatory mediator, binds to site 2, activates integrins, and induces inflammatory signaling (e.g., IL-6 and TNFα secretion), it has been proposed that site 2 is involved in inflammatory signaling. We showed that several inflammatory factors (CX3CL1, CXCL12, CCL5, sPLA2-IIA, and P-selectin) bind to site 2 and activate integrins. We propose that site 2 is involved in the pro-inflammatory action of these proteins and a potential therapeutic target. It has been well-established that platelet integrin αIIbβ3 is activated by signals from the inside of platelets induced by platelet agonists (inside-out signaling). In addition to the canonical inside-out signaling, we showed that αIIbβ3 can be allosterically activated by inflammatory cytokines/chemokines that are stored in platelet granules (e.g., CCL5, CXCL12) in the absence of inside-out signaling (e.g., soluble integrins in cell-free conditions). Thus, the allosteric activation may be involved in αIIbβ3 activation, platelet aggregation, and thrombosis. Inhibitory chemokine PF4 (CXCL4) binds to site 2 but did not activate integrins, Unexpectedly, we found that PF4/anti-PF4 complex was able to activate integrins, indicating that the anti-PF4 antibody changed the phenotype of PF4 from inhibitory to inflammatory. Since autoantibodies to PF4 are detected in vaccine-induced thrombocytopenic thrombosis (VIPP) and autoimmune diseases (e.g., SLE, and rheumatoid arthritis), we propose that this phenomenon is related to the pathogenesis of these diseases. P-selectin is known to bind exclusively to glycans (e.g., sLex) and involved in cell-cell interaction by binding to PSGL-1 (CD62P glycoprotein ligand-1). Unexpectedly, through docking simulation, we discovered that the P-selectin C-type lectin domain functions as an integrin ligand. It is interesting that no one has studied whether P-selectin binds to integrins in the last few decades. The integrin-binding site and glycan-binding site were close but distinct. Also, P-selectin lectin domain bound to site 2 and allosterically activated integrins.

Vascular endothelial cells are equipped with numerous specialized granules called Weibel-Palade bodies (WPBs). They contain a cocktail of proteins that can be rapidly secreted (3–5 min) into the vascular lumen after an appropriate stimulus such as thrombin. These proteins are ready without synthesis. Von Willebrand factor (VWF) and P-selectin are the main constituents of WPBs. Upon stimulation, release of ultralarge VWF multimers occurs and assembles into VWF strings on the apical side of endothelium. The VWF A1 domain becomes exposed in a shear-dependent manner recruiting and activating platelets. VWF is able to recruit leukocytes via direct leukocyte binding or via the activated platelets promoting NETosis. Ultralarge VWF strings are ultimately cleaved into smaller pieces by the protease ADAMTS-13 preventing excessive platelet adhesion. Under carefully performed flowing conditions and adequate dose of Shiga toxins, the toxin induces the release of ultralarge VWF multimers from cultured endothelial cells. This basic information allows insight into the pathogenesis of thrombotic thrombocytopenic purpura (TTP) and of STEC-HUS in the diarrhea phase. In TTP, ADAMTS-13 activity is deficient and systemic aggregation of platelets will occur after a second trigger. In STEC-HUS, stimulated release of WPB components in the diarrhea phase of the disease can be presumed to be the first hit in the damage of Gb3 positive endothelial cells. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by severe organ damage and lacking curative treatment. While various immune cell types, especially dysfunctional B and T cells and neutrophils, have been related with disease pathogenesis, limited research has focused on the role of monocytes in SLE. Increased DNA extracellular traps, apoptosis and necrosis have been related to lupus pathogenesis. Our goal is to analyze the contribution of P-selectin glycoprotein ligand 1 (PSGL-1) in SLE monocytes to disease pathogenesis by investigating the control exerted by PSGL-1 on monocyte apoptosis and DNA extrusion in extracellular traps (METs). Monocytes from active disease patients (aSLE) exhibited reduced levels of PSGL-1. Importantly, lower PSGL-1 levels in SLE monocytes associated with several clinical characteristics, including anti-dsDNA autoantibodies, lupus anticoagulant, clinical lung involvement, and anemia. Monocytes from SLE patients showed higher susceptibility to apoptosis than healthy donors (HD) monocytes and PSGL-1/P-selectin interaction decreased secondary necrosis in HD but not in aSLE monocytes. Regarding METs, aSLE monocytes exhibited higher susceptibility to generate METs than HD monocytes. The interaction of HD monocytes with P-selectin induced Syk activation and reduced the levels of DNA extruded in METs. However, in aSLE monocytes, PSGL-1/P-selectin interaction did not activate Syk or reduce the amount of extruded DNA. Our data suggest a dysfunctional PSGL-1/P-selectin axis in aSLE monocytes, unable to reduce secondary necrosis or the amount of DNA released into the extracellular medium in METs, potentially contributing to lupus pathogenesis. [ABSTRACT FROM AUTHOR]

Objective To analyze the changes in important indicators such as P-selectin, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and pH value in platelet-rich plasma (PRP) after short-term cryopreservation at -80 ℃, and to provide a theoretical basis for the low-temperature storage of PRP. Methods Each of PRP samples prepared from the blood from 30 healthy donors was divided into 5 aliquots, with 0.5 mL retained per aliquot. These samples were de-signated as group A (fresh sample) and groups B to E (cryopreservation for 5, 10, 15, and 20 d, respectively). The pH values of the five groups were measured. The concentrations of P-selectin, PDGF, and VEGF in each group were determined by the ELISA method. The effect of groups A and E on the vascular formation capacity of human umbilical vein endothelial cells (HUVEC) was determined by the angiogenesis assay. Results No significant differences were observed in the concentrations of P-selectin, PDGF, and VEGF as well as the pH values between group A and groups B to E (P >0.05). Compared with the fresh sample (group A), the number of vessels formed from HUVECs in the sample frozen for 20 d (group E) was basically the same, with no significant differences (P>0.05). Conclusion The cryopreservation of PRP at -80 ℃ has no significant effects on its pH value and concentrations of P-selectin, VEGF, and PDGF, thus extending the clinical application time of PRP.

Cardiovascular diseases generate high costs for public health systems, making it necessary to develop/discover anticoagulant or antiplatelet agents. In this context, the present study investigated the antithrombotic action of the essential oil of Levisticum officinale W.D.J. Koch in an in vitro experimental model. The oil chemical composition was characterized using gas chromatography coupled to mass spectrometry (GC–MS). The trypan blue exclusion assay in platelets (in vitro) was carried out. Systemic toxicity was studied by an in vivo model of Galleria mellonella larvae. Platelet aggregation assay was performed by turbidimetry in an aggregometer device, using the adenosine receptor agonist, ADP, and epinephrine (EPI). Coagulation was determined by prothrombin activity time (PT) and partially activated thromboplastin time (aPTT) in the coagulation system. Platelet activation was assessed by P-selectin expression and reactive oxygen species (ROS) content by flow cytometry and fluorescence, respectively. The oil is composed of monoterpenes, including α-terpinyl acetate, β-phellandrene, β-myrcene, α-terpineol, and (Z)-β-ocimene. The oil did not show toxicity in vitro and in vivo. The oil significantly reduced platelet aggregation against ADP and EPI. EPI-induced aggregation was most potently inhibited. Treatment of platelets with oil showed a decrease in P-selectin expression and ROS production when compared to vehicle. On the other hand, the oil did not interfere in PT and aPTT. The results demonstrated that the essential oil of Levisticum officinale has antiplatelet action but without anticoagulant effects. [ABSTRACT FROM AUTHOR]

During coronary artery bypass grafting (CABG), the surgical procedure, particularly the manipulation of the major arteries of the heart, induces a significant inflammatory state that may compromise platelet function to the extent that platelet transfusion is required. Given stored platelets as a major source of biological mediators, this study investigates the effects of platelet transfusion on the major pro‐aggregatory, pro‐inflammatory and immunomodulatory markers of platelets. Platelets from 20 patients, 10 who received platelet transfusion and 10 without, were subjected to flow cytometery where P‐selectin and CD40 ligand (CD40L) expressions and PAC‐1 binding (activation‐specific anti GPIIb/GPIIIa antibody) analysed at five‐time points of 24 h before surgery, immediately, 2 h, 24 h and 1 week after surgery. Analysis of intra‐platelet transforming growth factor‐beta‐1 (TGF‐β1) was also conducted using western blotting. Patients with platelet transfusion showed increased levels of P‐selectin, CD40L and intra‐platelet TGF‐β1 2‐h after surgery compared to those without transfusion (p < 0.05). PAC‐1 binding was increased 24 h after surgery in transfused patients (p < 0.05). Given the significant post‐transfusion elevation of platelet TGF‐β1, P‐sel/CD40L reduction in transfused patients a week after was of much interest. This study showed for the first time the significant effects of platelet transfusion on the pro‐inflammatory, pro‐aggeregatory and immunomodulatory state of platelets in CABG patients, which manifested with immediate, midterm and delayed consequences. While the increased pro‐inflammatory conditions manifested as an immediate effect of platelet transfusion, the pro‐aggregatory circumstances emerged 24 h post‐transfusion. A week after surgery, attenuations of pro‐inflammatory markers of platelets in transfused patients were shown, which might be due to the immunomodulatory effects of TGF‐β1. [ABSTRACT FROM AUTHOR]

Studies conducted on animal models have identified several therapeutic targets for myelofibrosis, the most severe of the myeloproliferative neoplasms. Unfortunately, many of the drugs which were effective in pre-clinical settings had modest efficacy when tested in the clinic. This discrepancy suggests that treatment for this disease requires combination therapies. To rationalize possible combinations, the efficacy in the Gata1low model of drugs currently used for these patients (the JAK1/2 inhibitor Ruxolitinib) was compared with that of drugs targeting other abnormalities, such as p27kip1 (Aplidin), TGF-β (SB431542, inhibiting ALK5 downstream to transforming growth factor beta (TGF-β) signaling and TGF-β trap AVID200), P-selectin (RB40.34), and CXCL1 (Reparixin, inhibiting the CXCL1 receptors CXCR1/2). The comparison was carried out by expressing the endpoints, which had either already been published or had been retrospectively obtained for this study, as the fold change of the values in the corresponding vehicles. In this model, only Ruxolitinib was found to decrease spleen size, only Aplidin and SB431542/AVID200 increased platelet counts, and with the exception of AVID200, all the inhibitors reduced fibrosis and microvessel density. The greatest effects were exerted by Reparixin, which also reduced TGF-β content. None of the drugs reduced osteopetrosis. These results suggest that future therapies for myelofibrosis should consider combining JAK1/2 inhibitors with drugs targeting hematopoietic stem cells (p27Kip1) or the pro-inflammatory milieu (TGF-β or CXCL1). [ABSTRACT FROM AUTHOR]

In recent years, substantial advancements have been made in understanding the pathophysiology of ischemic stroke. Despite these developments, therapeutic options for cerebral ischemia remain limited due to stringent time windows and various contraindications. Consequently, there has been a concentrated effort to elucidate the underlying mechanisms of cerebral ischemic injury. Emerging research indicates that neutrophil extracellular traps (NETs) exacerbate inflammation and damage in ischemic brain tissue, contributing to neuronal cell death. The inhibition of NETs has shown potential in preventing thrombosis and the infiltration of immune cells. Central to the formation of NETs are P-selectin and its ligand, P-selectin glycoprotein ligand-1 (PSGL-1), which represent promising therapeutic targets. This review explores the detrimental impact of P-selectin, PSGL-1, and NETs on cerebral ischemia. Additionally, it delineates the processes by which P-selectin and PSGL-1 stimulate NETs production and provides evidence that blocking these molecules reduces NETs formation. This novel insight highlights a potential therapeutic avenue that warrants further investigation by researchers in the field. [ABSTRACT FROM AUTHOR]

Introduction: Buerger's Disease (BD), or thromboangiitis obliterans (TAO), is a vasculoocclusive disorder of unknown etiology. Cigarette smoking is considered to be the main risk factor for the development of TAO. This study aimed to assess the activation of platelets in patients with BD compared to a control group. Materials and methods: Thirty patients (24 men and six women, median age 51.4 years) with TAO were included in the study. In the control group there were 20 healthy adults (16 men and four women, median age 44.0 years). Platelet activation was measured by light aggregometry and flow cytometry methods with and without platelet activators, such as thrombin receptor agonist peptide (TRAP-6) and adenosine diphosphate (ADP). Results: The velocity and intensity of aggregation increased in patients with TAO (p <0.05). MFI (mean fluorescence intensity) of P-selectin, CD63 (GP53-component of lysosomal membrane), and PAC-1 (platelet activation complex-1) on platelets increased in patients (p <0.05). Significantly higher aggregation velocities were noted in smoking patients in response to collagen (Coll) and to arachidonic acid (AA) compared to non-smoking ones. Aggregation velocity in response to AA was higher in heavy smokers compared to all smokers. A significantly higher intensity of aggregation was found in moderate smokers in response to epinephrine (EPI) and AA compared to non-smoking ones. A positive correlation between cholesterol concentrations and its fractions (LGL, TG), and platelet aggregation and the MFI of platelets, was found in patients with an increased cholesterol level. The aggregation velocity with EPI and AA was negatively correlated with HDL level. [ABSTRACT FROM AUTHOR]

Activated platelets (PLT) could adhere to tumor cells to promote tumor progression and metastasis. Therefore, inhibiting platelet activation and blocking the interaction between tumor cells and platelets are an effective approach to inhibit distal tumor metastasis. In this study, chondroitin sulfate (CS)–glycyrrhetinic acid (GA) dual ligand-modified liposomes (CS–GA–LIP) were prepared for codelivery of aspirin (ASP) and curcumin (CUR). In order to simulate the tumor microenvironment, we established the "HuH-7 + PLT" in vitro coculture cell model and the "H22 + NIH/3T3" coinjected mice model. Physicochemical analysis showed that the particle size of CUR&ASP/CS–GA–LIP was 133.27 nm with high stability. In vitro studies found that CUR&ASP/CS–GA–LIP could target both hepatocellular carcinoma cells and platelets, enhance drug retention in tumor cells, and effectively inhibit tumor proliferation and migration. In addition, in vivo antitumor results demonstrated that CUR&ASP/CS–GA–LIP could aggregate in tumor tissues, inhibit platelet activation and neoangiogenesis, and down-regulate the expression of matrix metalloproteinase 2 (MMP-2), exhibiting strong antiproliferative and antipulmonary metastatic abilities. Consequently, the combination therapy based on CS–GA–LIP might be a valuable antihepatocellular carcinoma strategy. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is characterized by heterogeneity in terms of injury severity, mechanism, outcome, and pathophysiology. A single biomarker alone is unlikely to capture the heterogeneity of even one injury subtype, necessitating the use of panels of biomarkers. Herein, we focus on traumatic cerebrovascular injury and investigate associations of a panel of 16 vascular injury-related biomarkers with indices of TBI severity and outcomes using data from 159 participants in the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot Study. Associations of individual biomarkers and clusters of biomarkers identified using non-linear principal components analysis with TBI severity and outcomes were assessed using logistic regression models and Spearmans correlations. As individual biomarkers, higher levels of thrombomodulin, angiopoietin (Ang)-2, von Willebrand factor, and P-selectin were associated with more severe injury; higher levels of Ang-1, Tie2, vascular endothelial growth factor (VEGF)-C, and basic fibroblast growth factor (bFGF) were associated with less severe injury (all p  0.05). In conclusion, in this trauma-center based population of acute TBI patients, biomarkers of microvascular injury were associated with TBI severity.

BACKGROUND: COVID-19 has been associated with endothelial injury, resultant microvascular inflammation and thrombosis. Activated endothelial cells release and express P-selectin and von Willebrand factor, both of which are elevated in severe COVID-19 and may be implicated in the disease pathophysiology. We hypothesized that crizanlizumab, a humanized monoclonal antibody to P-selectin, would reduce morbidity and death in patients hospitalized for COVID-19. METHODS: An international, adaptive, randomized controlled platform trial, funded by the National Heart, Lung, and Blood Institute, randomly assigned 422 patients hospitalized with COVID-19 with moderate or severe illness to receive either a single infusion of the P-selectin inhibitor crizanlizumab (at a dose of 5 mg/kg) plus standard of care or standard of care alone in an open-label 1:1 ratio. The primary outcome was organ support-free days, evaluated on an ordinal scale consisting of the number of days alive free of organ support through the first 21 days after trial entry. RESULTS: The study was stopped for futility by the data safety monitoring committee. Among 421 randomized patients with known 21-day outcomes, 163 patients (77%) randomized to the crizanlizumab plus standard-of-care arm did not require any respiratory or cardiovascular organ support compared with 169 (80%) in the standard-of-care-alone arm. The adjusted odds ratio for the effect of crizanlizumab on organ support-free days was 0.70 (95% CI, 0.43-1.16), where an odds ratio >1 indicates treatment benefit, yielding a posterior probability of futility (odds ratio 1] = 0.879). CONCLUSIONS: Crizanlizumab, a P-selectin inhibitor, did not result in improvement in organ support-free days in patients hospitalized with COVID-19. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04505774.

Recognition of integrins by CD62P has not been reported and this motivated a docking simulation using integrin αvβ3 as a target. We predicted that the C-type lectin domain of CD62P functions as a potential integrin ligand and observed that it specifically bound to soluble β3 and β1 integrins. Known inhibitors of the interaction between CD62P-PSGL-1 did not suppress the binding, whereas the disintegrin domain of ADAM-15, a known integrin ligand, suppressed recognition by the lectin domain. Furthermore, an R16E/K17E mutation in the predicted integrin-binding interface located outside of the glycan-binding site within the lectin domain, strongly inhibited CD62P binding to integrins. In contrast, the E88D mutation that strongly disrupts glycan binding only slightly affected CD62P-integrin recognition, indicating that the glycan and integrin-binding sites are distinct. Notably, the lectin domain allosterically activated integrins by binding to the allosteric site 2. We conclude that CD62P-integrin binding may function to promote a diverse set of cell-cell adhesive interactions given that β3 and β1 integrins are more widely expressed than PSGL-1 that is limited to leukocytes.

The combination of inflammation and thrombosis is a hallmark of many cardiovascular diseases. Under such conditions, platelets are recruited to an area of inflammation by forming platelet-leukocyte aggregates via interaction of PSGL-1 on leukocytes and P-selectin on activated platelets, which can bind to the endothelium. While particulate drug carriers have been utilized to passively redirect leukocytes from areas of inflammation, the downstream impact of these carriers on platelet accumulation in thromboinflammatory conditions has yet to be studied. Here, we explore the ability of polymeric particles to divert platelets away from inflamed blood vessels both in vitro and in vivo. We find that untargeted and targeted micron-sized polymeric particles can successfully reduce platelet adhesion to an inflamed endothelial monolayer in vitro in blood flow systems and in vivo in a lipopolysaccharide-induced, systemic inflammation murine model. Our data represent initial work in developing cargo-free, anti-platelet therapeutics specifically for conditions of thromboinflammation.

This review examines the endothelial glycocalyx's role in inflammation and explores its involvement in coagulation. The glycocalyx, composed of proteins and glycosaminoglycans, interacts with von Willebrand Factor and could play a crucial role in anchoring it to the endothelium. In inflammatory conditions, glycocalyx degradation may leave P-selectin as the only attachment point for von Willebrand Factor, potentially leading to uncontrolled release of ultralong von Willebrand Factor in the bulk flow in a shear stress-dependent manner. Identifying specific glycocalyx glycosaminoglycan interactions with von Willebrand Factor and P-selectin can offer insights into unexplored coagulation mechanisms. [ABSTRACT FROM AUTHOR]

Objectives Detecting occult cancer in patients with unprovoked venous thromboembolism (VTE) remains a significant challenge. Our objective was to investigate the potential predictive role of coagulation-related biomarkers in the diagnosis of occult malignancies. Methods We conducted a nested case-control study with a 1-year prospective cohort of 214 patients with unprovoked VTE, with a focus on identifying occult cancer. At the time of VTE diagnosis, we measured various biomarkers, including soluble P-selectin (sP-selectin), dimerized plasmin fragment D (D-dimer), platelets, leukocytes, hemoglobin, total extracellular vesicles (EVs), EVs expressing tissue factor on their surface (TF+EVs), and EVs expressing P-selectin on their surface (Psel+EVs) in all participants. Results We observed statistically significant increased levels of sP-selectin (P =.015) in patients with occult cancer. Despite an increase in Psel+EVs, TF+EVs, D-dimer, and platelets within this group, however, no significant differences were found. When sP-selectin exceeded 62 ng/mL and D-dimer surpassed 10,000 µg/L, the diagnosis of occult cancer demonstrated a specificity of up to 91% (95% CI, 79.9%-96.7%). Conclusions The combination of sP-selectin and D-dimer can be a valuable biomarker in detecting occult cancer in patients with unprovoked VTE. Further research is necessary to ascertain whether easily measurable biomarkers such as sP-selectin and D-dimer can effectively distinguish between patients who have VTE with and without hidden malignancies. [ABSTRACT FROM AUTHOR]

Background: Venous Thrombo Embolism (VTE) is the third most common cause of vascular mortality worldwide and comprises Deep-Vein Thrombosis (DVT) and Pulmonary Embolism (PE). It is also the second most common cause of death among cancer patients. VTE contributes immensely to the morbidity and mortality of cancer patients, with a life threaten PE being 3 times more common in cancer patients compared to non-cancer patients. Cancer patients are said to have a 5 to 7 fold increased risk of developing VTE. P-selectin can serve as a promising marker which could help to increase the precision of predicting the risk of VTE among cancer patients when combine with established validated tools. Aim: This study seeks to unravel the increasing trend of cancer associated VTE and the intricate and multifaceted role of P-selectin in cancer associated VTE. Method: A vigorous literature search was performed via the internet search engines linked to academic databases including PubMed, Google Scholar, Ebsco, Hinari, Scopus, etc. Conclusion: This review underscores the dynamic of cancer associated VTE and context-dependent role of P-selectin in cancer associated VTE respectively. As we poke into the relationship between cancer, VTE and P-selectin, as this will create an insight for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of combining aspirin with clopidogrel on high-sensitivity C-reactive protein (hs-CRP) and P-selectin in patients with acute coronary syndrome (ACS). Methods: The medical records of 198 ACS patients treated at Zhaotong Traditional Chinese Medicine Hospital, Zhaotong, China between January 2022 and January 2023 were analyzed retrospectively. Control group (88 patients) received aspirin (300 mg once, and subsequently a maintenance dose of 100 mg daily for 6 months), while the study group (118 patients) received the same dose of aspirin and clopidogrel (150 mg once, and a maintenance dose of 75 mg daily for 6 months). Levels of P-selectin, interleukin-6 (IL-6), hs-CRP, IL-8, tumor necrosis factor-α (TNF-α), efficacy, and incidence of adverse reactions in both groups were determined. Results: There was no significant difference in P-selectin and hs-CRP levels between the two groups before treatment (p > 0.05). However, P-selectin and hs-CRP levels in the study group decreased significantly compared to control group (p < 0.0001). Similarly, there was no significant difference in IL-8, IL-6 and TNF-α levels between the two groups before treatment (p > 0.05). However, IL-8, IL-6, and TNF-α reduced significantly after treatment (p < 0.0001), with more significantly lower levels observed in the study group (p < 0.001). There was no significant difference in the incidence of adverse reactions between the two groups. Conclusion: Aspirin combined with clopidogrel significantly lowers P- selectin, and hs-CRP, IL-8, IL-6, and TNF-α levels without worsening adverse reactions. A more comprehensive analysis of the combined use of aspirin with clopidogrel including all the associated mechanisms in the treatment of ACS is necessary. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of the present study is to see if the presence of angiotensin- converting enzyme 2 (ACE-2), transmembrane serine protease 2 (TMPRSS), and P-selectin in platelets increases the risk of thrombosis in COVID-19 patients. PATIENTS AND METHODS: This was a cross-sectional study conducted in the COVID-19 isolation center between January and September 2021 and comprised 61 COVID-19-infected patients, 21 of whom were in the intensive care unit (ICU) and 40 of whom were non-ICU patients (non-ICUP) in the isolation center. The coagulation profile, as well as the ACE-2, TMPRES, and P-selectin receptors, were all assessed in addition to the complete blood count (CBC). A questionnaire was also utilized to collect social and demographic data. RESULTS: All platelet indices and coagulation profiles were significantly altered in COVID-19 ICUP and non-ICUP in this research; additionally, there is a significant association between the presence of ACE-2, P-selectin, and TMPRRS2 in COVID-19 patients with coagulation profile and platelet indices leading to hypercoagulable state. CONCLUSIONS: In summary, the interaction of ACE-2, TMPRSS, and P-selectin in platelets appears to be a key element contributing to COVID-19 severity via their impact on thrombus development. Further investigation into these pathways may provide possible treatment targets for reducing the severe consequences of the COVID-19 infection. [ABSTRACT FROM AUTHOR]

The most prevalent form of colon cancer also ranks high among cancer-related deaths globally. Traditional chemotherapy drugs do not provide sufficient therapeutic efficacy, and advanced colon cancer demonstrates considerable resistance to chemotherapy. As an oral kinase inhibitor, sorafenib (SOR) suppresses the growth of tumour cells, the formation of new blood vessels, and the death of cancer cells. Unfortunately, sorafenib's limited bioavailability, rapid metabolism, and poor solubility have severely limited its clinical use. We developed nanoparticles targeting P-selectin and SOR, with fucoidan (FU) as a ligand. The SOR-CS-FU-NPs were developed by coating polylactide-co-glycolide nanoparticles with chitosan and FU through electrostatic interaction. The SOR-CS-FU-NPs exhibited an average particle diameter of 209.98 ± 1.25 nm and a polydisperse index (PDI) of 0.229 ± 0.022. The SOR-CS-FU nanoparticles exhibited a continuous release pattern for up to 120 h. The SOR-CS-FU nanoparticles exhibited cytotoxicity 8 times greater than free SOR in HCT116 colorectal cancer cells. The cellular absorption of Rhodamine-CS-FU-NPs was three times more than that of free Rhodamine and 19 times greater than that of Rhodamine-CS-NPs. Enhanced reactive oxygen species (ROS) generation and mitochondrial membrane potential damage were also shown in SOR-CS-FU-NPs. An investigation of cell death found that SOR-CS-FU-NPs had an apoptosis index that was 7.5 times greater than free SOR. After that, the SOR-CS-FU-NPs demonstrated a more significant inhibition of cell migration, leading to a wound closure of about 5 %. No toxicity was shown in the non-cancer VERO cell line when exposed to the developed NPs. Taken together, these results provide strong evidence that biocompatible SOR-CS-FU-NPs fabricated effective carriers for the targeted delivery of dasatinib to colorectal cancer.

BackgroundFeminizing hormonal therapy (FHT) and HIV potentially alter cardiovascular disease (CVD) risk in transgender women (TW).MethodsTW were enrolled in Los Angeles, California and Houston, Texas and frequency-matched to Multicenter AIDS Cohort Study cisgender men (CM) on age, race, substance use, and abacavir use. Biomarkers of CVD risk and inflammation were assessed via ELISA. Wilcoxon rank sum and Fisher's exact tests compared TW and CM. Multivariable linear regression assessed factors associated with biomarker concentrations.ResultsTW (HIV+ n  = 75, HIV- n  = 47) and CM (HIV+ n  = 40, HIV- n  = 40) had mean age 43-45 years; TW/CM were 90%/91% non-Hispanic Black, Hispanic, or Multiracial, 26%/53% obese, and 34%/24% current smokers; 67% of TW were on FHT. Among people with HIV (PWH), TW had higher median extracellular newly-identified receptor for advanced glycation end-products (EN-RAGE), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), soluble tumor necrosis factor receptor type (sTNFR) I/II, interleukin (IL)-8 and plasminogen activator inhibitor (PAI)-1, but lower soluble CD14, von Willebrand factor (vWF) and endothelin (ET)-1 levels than CM. Findings were similar for participants without HIV (all P

Donor-specific HLA Abs contribute to Ab-mediated rejection (AMR) by binding to HLA molecules on endothelial cells (ECs) and triggering intracellular signaling, leading to EC activation and leukocyte recruitment. The molecular mechanisms involving donor-specific HLA Ab-mediated EC activation and leukocyte recruitment remain incompletely understood. In this study, we determined whether TLRs act as coreceptors for HLA class I (HLA I) in ECs. We found that human aortic ECs express TLR3, TLR4, TLR6, and TLR10, but only TLR4 was detected on the EC surface. Consequently, we performed coimmunoprecipitation experiments to examine complex formation between HLA I and TLR4. Stimulation of human ECs with HLA Ab increased the amount of complex formation between HLA I and TLR4. Reciprocal coimmunoprecipitation with a TLR4 Ab confirmed that the crosslinking of HLA I increased complex formation between TLR4 and HLA I. Knockdown of TLR4 or MyD88 with small interfering RNAs inhibited HLA I Ab-stimulated P-selectin expression, von Willebrand factor release, and monocyte recruitment on ECs. Our results show that TLR4 is a novel coreceptor for HLA I to stimulate monocyte recruitment on activated ECs. Taken together with our previous published results, we propose that HLA I molecules form two separate signaling complexes at the EC surface, that is, with TLR4 to upregulate P-selectin surface expression and capture of monocytes to human ECs and integrin β4 to induce mTOR-dependent firm monocyte adhesion via ICAM-1 clustering on ECs, two processes implicated in Ab-mediated rejection.

Glycosylated RNA molecules that can be bound by lectins have been demonstrated on the surfaces of leukocytes, but their physiologic function(s) was not known. A recent study (PMID 38262409) demonstrates that at least 1 function is to promote capture and rolling of neutrophils in the vasculature. Of interest, the neutrophil glycosylated RNA molecules bind to P-selectin but not E-selectin. [ABSTRACT FROM AUTHOR]

Increased platelet activity is a risk factor of thrombotic events in cardiovascular patients. We studied the relationship between platelet function, platelet size, and the content of reticulated platelets (RP) in patients with coronary heart disease (CHD, n = 55) and acute coronary syndrome (ACS, n = 95) receiving acetylsalicylic acid + clopidogrel or ticagrelor, respectively. The control group consisted of patients with risk factors for CHD, but with no CHD/ACS and free of antiplatelet drugs (n = 66). Platelet function was evaluated by the exposure of activated glycoprotein (GP) IIb-IIIa and P-selectin. In the control group, platelets were activated by TRAP (Thrombin Receptor Activating Peptide) 10 µM, and ADP 20, 5, 2.5 µM, and in the CHD/ACS groups, by TRAP 10 µM, and ADP 20 5 µM (±epinephrine 20 µM). Platelet size was assessed by the mean volume, % large forms, and forward scattering. RP were stained by thiazole orange. In the control group, activated GP IIb-IIIa and P-selectin correlated with platelet size and RP content after platelet activation by all agonists. Despite the decrease in platelet activity by antiplatelet drugs, most correlations (primarily for activated GP IIb-IIIa) were preserved in the CHD/ACS patients. In conclusion, increased platelet size and RP content are associated with increased platelet activity and the reduced efficacy of antiplatelet therapy.

Background: The goal was to investigate the relationship between serum vascular endothelial growth factor (VEGF), P-selectin, high-density lipoprotein cholesterol (HDL-C), platelet parameters, and coagulation function indexes and postoperative deep vein thrombosis (DVT) in patients with traumatic fracture. Methods: A total of 150 patients with traumatic fractures after DVT were selected as the DVT group, and 150 patients with traumatic fractures without DVT during the same period were selected as the non-DVT group. Serum VEGF, P-selectin, HDL-C, platelet parameters including platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), platelet large cell ratio (P-LCR), and plasma coagulation function indexes including thrombin time (TT), prothrombin time (PT), activated partial thrombin time (APTT), fibrinogen (FIB), and D-dimer (D-D) were measured. Pearson's correlation was performed to analyze the correlation between serum VEGF, P-selectin, and coagulation function indexes, and binary logistic regression was used to analyze the risk factors of DVT. Results: Serum VEGF and P-selectin in the DVT group were higher while HDL-C was lower than those in the non-DVT group (p < 0.05). Serum VEGF and P-selectin were negatively correlated with plasma D-D and FIB (p < 0.05), and serum HDL-C was negatively correlated (p < 0.05). Compared with the non-DVT group, MPV, PDW, and P-LCR in the DVT group were decreased (p < 0.05). Multivariate logistic regression analysis showed that PLCR was a risk factor for postoperative DVT in patients with traumatic fractures (p < 0.05). Conclusions: Serum VEGF and P-selectin are higher and HDL-C is lower in patients with DVT after postoperative traumatic fracture than in patients without DVT. Combined detection of serum VEGF, P-selectin, HDL-C, and coagulation function indexes may help to reduce the risk of DVT. Platelet parameters (MPV, PDW, P-LCR) have certain reference values for the clinical diagnosis and disease evaluation of DVT. [ABSTRACT FROM AUTHOR]

Objective: It is aimed to be a technique that can be used for diagnosis and to prevent maternal deaths in cases where the serum levels of cell adhesion molecules are different in patients with abnormal placentation compared to healthy pregnant women. Materials and methods: Patients between March 2020 and September 2021 were included in the study. While 56 patients, out of 153 cases formed the placental adhesion and/or localization anomaly group, 55 cases without placental adhesion anomaly (placental invasion anomaly and/or previa pathology) constituted the cesarean section group and 42 cases constituted the vaginal birth control group. Demographic characteristics and histories of 153 patients were questioned. I-CAM-1, V-CAM-1, E-Selectin, P-Selectin, LRG-1 levels were studied. The parameters measured by the ELISA method were studied in the Thermo Fisher Scientific Multiscan Go (Finland) device at the Hatay Mustafa Kemal University Medical Faculty Medical Biochemistry USA ELISA Laboratory. Wholehouse and One Way Anova analysis methods were used to compare the results. Results: There were significant differences in E-Selectin, P-Selectin, ICAM-1 and LRG-1 values between the groups (p < 0.05). There was a significant difference between the vaginal birth (VB) and previa/percreata (PP) groups in terms of E-Selectin (p = 0.038). In terms of P-Selectin, there was a significant difference between the C/S and previa/percreata (PP) groups (p < 001). P-Selectin was higher in the previa/percreata (PP) group. There was a significant difference between the Vaginally birth (VB), C/S group (p = 0.041) and the vaginal birth (VB), previa/percreata (PP) group (p = 0.013) in terms of ICAM-1, but there was no significant difference between the C/S and previa/percreata (PP) groups. In terms of LRG-1, there was a significant difference between all 3 groups (p < 0.05). Discussion: A recent study investigated the potential modulatory effects of trans-resveratrol (RSV), arginase and endothelial dysfunction biomarkers in patients with PE. Another reflection of endothelial dysfunction in PE is increased endothelial activation biomarkers such as intercellular adhesion molecule-1 (ICAM-1), von Willebrand factor (vWF), and Caspase-3 (CASP-3). The study, regarding vWF expression, the preeclampsia (PE) group showed higher levels compared to endothelial cells incubated with healty pregnant (HP) plasma [Bueno-Pereira et al 2022 Antioxidants 2111]. From this and similar studies, the hypothesis that the role of cell adhesion molecules in endothelial damage may be the underlying cause of invasion and location anomalies emerges. This hypothesis is the starting point of our study. Conclusions: In our study, all adhesion molecules except V-CAM-1 were found to be significantly higher in the previa/percreata (PP) group. E-Selectin and LRG-1 adhesion molecules were found to be significantly higher even in C/S patients compared to normal delivery. As a result; these adhesion molecules can be studied as a marker in previa/percreata (PP) patients. [ABSTRACT FROM AUTHOR]

Summary: Plasma histamine levels are increased in patients with sickle cell disease (SCD), potentially promoting endothelial P‐selectin expression and vaso‐occlusion via histamine type 2 (H2) receptors. We conducted a prospective, non‐comparative, single‐centre study to determine whether famotidine, a H2 receptor antagonist, reduces P‐selectin expression in SCD children. The median plasma P‐selectin level was significantly reduced after 29 days of oral famotidine (53.2 ng/mL [IQR: 46.7–63.4] vs. 69.9 ng/mL [IQR: 53.6–84.2], median difference −10.2 ng/mL [IQR: −21.8 to −2.7], p = 0.005) in 28 patients. No effect was observed on other adhesion molecules, inflammation or haemolysis markers, except decreased reticulocyte count. No adverse events deemed related to famotidine were observed. Randomized controlled trials are now needed to assess the efficacy of famotidine in preventing vaso‐occlusion in SCD. [ABSTRACT FROM AUTHOR]

Objective To explore the changes and clinical significance of D-dimer (D-D), prothrombin fragment 1+2 (F1+2) and P-selectin in patients with acute deep venous thrombosis of lower extremities (DVT) before and after catheterization and thrombolysis. Methods A total of 186 patients with acute DVT in the Third People's Hospital of Yunnan Province from March 2020 to March 2022 were selected as the study objects. And all of them underwent catheterization and hemolysis and were followed up in the outpatient form 12 months after the surgery. 4 cases were lost to follow-up, and a total of 182 cases completed postoperative follow-up. Postthrombotic syndrome (PTS) was divided into PTS group (n = 27) and non-PTS group (n = 155) according to whether postthrombotic syndrome ( PTS) occurred 12 months after the surgery. The general data of the two groups and the expression of D-D, F1+2, P-selectin in plasma before and after thrombolytic therapy were compared, and the influencing factors of PTS were analyzed by Logistic analysis. Receiver operating characteristic curve (ROC) and area under curve ( AUC) were plotted to analyze the value of plasma D-D, F1+2, P-selectin in predicting the occurrence of PTS, and relative risk (RR) was used to analyze the influence of different plasma D-D, F1+2, Pselectin expression on PTS. Results Age, BMI, venous patency score, and plasma D-D, F1+2, P-selectin expression 1 week and 1 month after thrombolysis in PTS group were higher than those in non-PTS group (P < 0.05). Logistic showed that BMI and plasma D-D, F1+2 and P-selectin 1 week and 1 month after thrombolysis were the influential factors for PTS in acute DVT patients (P < 0.05). ROC curve showed that the combined efficacy of D-D, F1+2 and P-selectin 1 month after thrombolysis was significantly better than that of D-D, F1+2 and P-selectin 1 week after thrombolysis in predicting PTS. One month after thrombolysis, the risk of PTS in patients with high plasma D-D, F1+2, P-selectin expression was 4.211, 2.550 and 3.189 times higher than that in patients with low plasma D-D, F1+2, P-selectin expression. Conclusion The expression of D-D, F1+2 and P-selectin in plasma increases after thrombolysis in acute DVT patients, and the combination of D-D, F1+2 and P-selectin can predict the occurrence of PTS. [ABSTRACT FROM AUTHOR]

Background Agonist-induced platelet activation, with the integrin αIIbβ3 conformational change, is required for fibrinogen binding. This is considered reversible under specific conditions, allowing a second phase of platelet aggregation. The signaling pathways that differentiate between a permanent or transient activation state of platelets are poorly elucidated.

This review examines the endothelial glycocalyx’s role in inflammation and explores its involvement in coagulation. The glycocalyx, composed of proteins and glycosaminoglycans, interacts with von Willebrand Factor and could play a crucial role in anchoring it to the endothelium. In inflammatory conditions, glycocalyx degradation may leave P-selectin as the only attachment point for von Willebrand Factor, potentially leading to uncontrolled release of ultralong von Willebrand Factor in the bulk flow in a shear stress-dependent manner. Identifying specific glycocalyx glycosaminoglycan interactions with von Willebrand Factor and P-selectin can offer insights into unexplored coagulation mechanisms.

Inflammatory Bowel Disease (IBD) is a group of chronic intestinal diseases, among which Crohn’s disease (CD) and ulcerative colitis (UC) represent the two main types. The differential diagnosis of these two disorders is often a significant challenge, as there is a lack of specific and non-invasive biomarkers. In this study, we assessed the serum profile of proinflammatory mediators (E- and P-selectin, CCL2, IL-1α, IL-12p70, TNF-α) in patients with IBD to identify biomarkers helpful in the differential diagnosis of CD and UC. The conducted statistical analyses revealed a significant increase in E-selectin, P-selectin, IL-1α, and IL-12p70 levels in the serum of CD patients compared to UC. The performed ROC curve analysis identified moderate values of E-selectin (AUC 0.752), P-selectin (AUC 0.733), and IL-1α (AUC 0.731) in differentiating CD from UC, while IL-12p70 presented a satisfactory value (AUC 0.695). Simultaneous measurements of each biomarker with serum calprotectin improved the ability of E-selectin (AUC 0.752 vs. 0.829), P-selectin (AUC 0.733 vs. 0.75), IL-1α (AUC 0.731 vs. 0.778), and IL-12p70 (AUC 0.695 vs. 0.714) to differentiate CD from UC. Moreover, we identified a significant relationship between the concentration of CCL2 (r = 0.566, p < 0.005) and TNF-α (r = 0.431, p < 0.05) and the disease activity expressed as the Mayo score in the UC group. We also identified a significant relationship between the concentration of E-selectin (r = 0.372, p < 0.05), CCL-2 (r = 0.55, p < 0.05), IL-1α (r = 0.637, p < 0.005), and TNF-α in the group of patients with UC. Another significant correlation in the UC group was noted in the case of E-selectin and IL-12p70 (r = 0.542, p < 0.05), as well as between IL1-α and P-selectin (r = 0.514, p < 0.05). The results obtained in this study indicate the potential use of E-selectin, P-selectin, IL-1α, and IL-12p70 serum profiles in differentiating CD from UC. Regarding the significant relationship of CCL2 and TNF-α with the Mayo score, these two biomarkers might be useful in assessing and monitoring the disease activity during UC.

Abstract Thrombotic vascular disorders, specifically thromboembolisms, have a significant detrimental effect on public health. Despite the numerous thrombolytic and antithrombotic drugs available, their efficacy in penetrating thrombus formations is limited, and they carry a high risk of promoting bleeding. Consequently, the current medication dosage protocols are inadequate for preventing thrombus formation, and higher doses are necessary to achieve sufficient prevention. By integrating phototherapy with antithrombotic therapy, this study addresses difficulties related to thrombus-targeted drug delivery. We developed self-assembling nanoparticles (NPs) through the optimization of a co-assembly engineering process. These NPs, called DIP-FU-PPy NPs, consist of polypyrrole (PPy), dipyridamole (DIP), and P-selectin-targeted fucoidan (FU) and are designed to be delivered directly to thrombi. DIP-FU-PPy NPs are proposed to offer various potentials, encompassing drug-loading capability, targeted accumulation in thrombus sites, near-infrared (NIR) photothermal-enhanced thrombus management with therapeutic efficacy, and prevention of rethrombosis. As predicted, DIP-FU-PPy NPs prevented thrombus recurrence and emitted visible fluorescence signals during thrombus clot penetration with no adverse effects. Our co-delivery nano-platform is a simple and versatile solution for NIR-phototherapeutic multimodal thrombus control.

Abstract Background Germinal matrix hemorrhage is a devastating disease of pre-term infancy commonly resulting in post-hemorrhagic hydrocephalus, periventricular leukomalacia, and subsequent neurocognitive deficits. We demonstrate vascular expression of the adhesion molecule P-selectin after GMH and investigate a strategy to specifically target complement inhibition to sites of P-selectin expression to mitigate the pathological sequelae of GMH. Methods We prepared two fusion proteins consisting of different anti-P-selectin single chain antibodies (scFv’s) linked to the complement inhibitor Crry. One scFv targeting vehicle (2.12scFv) blocked the binding of P-selectin to its PSGL-1 ligand expressed on leukocytes, whereas the other targeting vehicle (2.3scFv) bound P-selectin without blocking ligand binding. Post-natal C57BL/6 J mice on day 4 (P4) were subjected to collagenase induced-intraventricular hemorrhage and treated with 2.3Psel-Crry, 2.12Psel-Crry, or vehicle. Results Compared to vehicle treatment, 2.3Psel-Crry treatment after induction of GMH resulted in reduced lesion size and mortality, reduced hydrocephalus development, and improved neurological deficit measurements in adolescence. In contrast, 2.12Psel-Crry treatment resulted in worse outcomes compared to vehicle. Improved outcomes with 2.3Psel-Crry were accompanied by decreased P-selectin expression, and decreased complement activation and microgliosis. Microglia from 2.3Psel-Crry treated mice displayed a ramified morphology, similar to naïve mice, whereas microglia in vehicle treated animals displayed a more ameboid morphology that is associated with a more activated status. Consistent with these morphological characteristics, there was increased microglial internalization of complement deposits in vehicle compared to 2.3Psel-Crry treated animals, reminiscent of aberrant C3-dependent microglial phagocytosis that occurs in other (adult) types of brain injury. In addition, following systemic injection, 2.3Psel-Crry specifically targeted to the post-GMH brain. Likely accounting for the unexpected finding that 2.12Psel-Crry worsens outcome following GMH was the finding that this construct interfered with coagulation in this hemorrhagic condition, and specifically with heterotypic platelet–leukocyte aggregation, which express P-selectin and PSGL-1, respectively. Conclusions GMH induces expression of P-selectin, the targeting of which with a complement inhibitor protects against pathogenic sequelae of GMH. A dual functioning construct with both P-selectin and complement blocking activity interferes with coagulation and worsens outcomes following GMH, but has potential for treatment of conditions that incorporate pathological thrombotic events, such as ischemic stroke.

Objective To investigate the clinical value of serum N-terminal pro B type natriuretic peptide (NT-proBNP) and P-selectin combined with ischemia-modified albumin (IMA) in predicting poor electrocardiographic ST-segment regression (STR) after percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (ASTEMI). Methods 100 patients with ASTEMI who were admitted to the emergency Department of the Second Affiliated Hospital of Nanjing Medical University from January 2020 to July 2022 were selected, and they were divided into STR poor group and STR good group according to electrocardiographic STR after PCI, and 50 healthy volunteers during the same period were selected as control group. Serum NT-proBNP, P-selectin and IMA levels were detected by enzyme-linked immunosorbent assay. Multivariate Logistic regression was used to analyze the influencing factors of poor electrocardiographic STR in patients with ASTEMI after PCI, and the predictive value of serum NT-proBNP, P-selectin and IMA levels in patients with ASTEMI after PCI was analyzed by receiver operating characteristic (ROC) curve. Results Compared with the control group, the serum NT-proBNP, P-selectin and IMA levels in the ASTEMI group before PCI were increased (P＜0.05). According to electrocardiographic STR, patients with ASTEMI were divided into STR poor group of 35 cases and STR good group of 65 cases. The serum NT-proBNP, P-selectin and IMA levels in the STR poor group and STR good group after PCI were lower than those before PCI (P＜0.05). The serum NT-proBNP, P-selectin and IMA levels before PCI and after PCI in the STR poor group were higher than those in the STR good group (P＜0.05). The proportion of Killip grade≥2 grade and troponin I in the STR poor group were higher than those in the STR good group, and the total deviation of ST segment was lower than that in the STR good group (P＜0.05). Multivariate Logistic regression analysis showed that Killip grade≥2 grade and elevated NT-proBNP, P-selectin and IMA were independent risk factors for poor electrocardiographic STR after PCI in patients with ASTEMI (P＜0.05). ROC curve analysis showed that the area under curve (AUC) of serum NT-proBNP, P-selectin combined with IMA in predicting poor electrocardiographic STR after PCI in patients with ASTEMI was greater than that predicted by NT-proBNP, P-selectin and IMA alone. Conclusion Elevated serum NT-proBNP, P-selectin and IMA levels are independently correlated with poor electrocardiographic STR after PCI in patients with ASTEMI, and the combined value of the three is high in predicting poor electrocardiographic STR in patients with ASTEMI after PCI. [ABSTRACT FROM AUTHOR]

P-selectin, a cell adhesion molecule of the selectin family, is expressed on the surface of activated endothelial cells (ECs) and platelets. Binding of P-selectin to P-selectin glycoprotein ligand-1 (PSGL-1) supports the leukocytes capture and rolling on stimulated ECs and increases the aggregation of leukocytes and activated platelets. Cancer cachexia is a systemic inflammation disorder characterized by metabolic disturbances, reduced body weight, loss of appetite, fat depletion, and progressive muscle atrophy. Cachexia status is associated with increased pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), which activates ECs to release P-selectin. Single-nucleotide polymorphisms (SNPs) loci of P-selectin encoding gene SELP are associated with higher level of plasma P-selectin and increase the susceptibility to cachexia in cancer patients. Elevated P-selectin expression has been observed in the hypothalamus, liver, and gastrocnemius muscle in animal models with cancer cachexia. Increased P-selectin may cause excessive inflammatory processes, muscle atrophy, and blood hypercoagulation, thus facilitating the development of cancer cachexia. In this review, physiological functions of P-selectin and its potential roles in cancer cachexia have been summarized. We also discuss the therapeutic potential of P-selectin inhibitors for the treatment of cancer cachexia. [ABSTRACT FROM AUTHOR]

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

Background: Platelets are rapidly deployed to infection sites and respond to pathogenic molecules via pattern recognition receptors (TLR, NLRP). Dickkopf1 (DKK1) is a quintessential Wnt antagonist produced by a variety of cell types including platelets, endothelial cells, and is known to modulate proinflammatory responses in infectious diseases and cancer. Moreover, DKK1 is critical for forming leukocyte-platelet aggregates and induction of type 2 cellmediated immune responses. Our previous publication showed activated platelets release DKK1 following Leishmania major recognition. Results: Here we probed the role of the key surface virulence glycoconjugate lipophosphoglycan (LPG), on DKK1 production using null mutants deficient in LPG synthesis (Dlpg1- and Dlpg2-). Leishmania-induced DKK1 production was reduced to control levels in the absence of LPG in both mutants and was restored upon re-expression of the cognate LPG1 or LPG2 genes. Furthermore, the formation of leukocyte-platelet aggregates was dependent on LPG. LPG mediated platelet activation and DKK1 production occurs through TLR1/2. Conclusion: Thus, LPG is a key virulence factor that induces DKK1 production from activated platelets, and the circulating DKK1 promotes Th2 cell polarization. This suggests that LPG-activated platelets can drive innate and adaptive immune responses to Leishmania infection. [ABSTRACT FROM AUTHOR]

BACKGROUND: Lymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1- phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T-cell activation. Characterizing this biology is relevant for developing much needed therapies. METHODS: Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1-deficient (S1pr1LECKO) mice were generated. Disease progression was quantified by tail-volumetric and -histopathologic measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then cocultured with CD4 T cells, followed by an analysis of CD4 T-cell activation and pathway signaling. Last, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T-cell activation. RESULTS: Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1P receptor 1 (S1PR1). LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T-cell infiltration in mouse lymphedema. LECs, isolated from S1pr1LECKO mice and cocultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs promoted T-helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. Human dermal LECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro, P-selectin blockade reduced the activation and differentiation of Th cells cocultured with shS1PR1-treated human dermal LECs. P-selectin--directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema. CONCLUSIONS: This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T-cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition. [ABSTRACT FROM AUTHOR]

Background and aims: The adhesion molecule P-selectin is expressed by endothelial cells and platelets. It is involved in platelet activation and leukocyte adhesion, both important processes in the pathogenesis of atherosclerosis. Our study was designed to assess the predictive value of soluble P-selectin (sP-selectin) on the progression of peripheral atherosclerosis. Methods: This is an observational, single-center, cohort study that included 443 patients with established cardiovascular disease (CVD) or at least one cardiovascular risk factor. Over a period of 4 years, each patient underwent three-dimensional (3D) ultrasound to assess the plaque volume of the carotid and femoral arteries once per year. In addition, plasma sP-selectin levels were measured at each visit. The association between changes in sP-selectin and peripheral atherosclerotic plaque progression was assessed using growth curve models. Results: 338 patients were available for statistical analysis. Each standard deviation increase in sP-selectin was significantly (p < 0.001) associated with a 46.09 mm3 higher plaque volume. In ROC-analysis, changes in sP-selectin over time showed an optimal cut-off value around Δ 0.0 µg/mL sP-selectin and significantly improved the predictive value of the ESC-SCORE (AUC for the combination of both parameters was 0.75 (95% CI 0.68–0.81, p < 0.001). Patients with increasing sP-selectin showed a significantly higher plaque progression compared to patients with decreasing or stable sP-selectin levels (202 mm3 vs. 110 mm3, p < 0.001). Conclusions: Increasing sP-selectin levels can predict higher atherosclerotic plaque progression as measured by 3D ultrasound. We suggest serial measurements of sP-selectin as an easily measurable biomarker for peripheral atherosclerotic plaque progression. [ABSTRACT FROM AUTHOR]

Background: Excessive neutrophil extracellular traps (NETs) is involved in the progression of acute pancreatitis (AP) but the mechanisms controlling NETs formation in AP are not fully understood. Therefore, our study sought to investigate the mechanism of the highly expressed P-selectin stimulating the formation of NETs in AP. Methods: NETs formation was detected by flow cytometry, immunofluorescence staining, and cf-DNA and MPO-DNA complexes were measured as biomarkers of NETs formation. Neutrophils treated with P-selectin and pharmacological inhibitors were examined by western blot, immunofluorescence staining and flow cytometry. Mouse model of AP was established by caerulein and the effect of inhibiting P-selectin by PSI-697 on the level of NETs and PAD4 in pancreatic tissue was observed. The severity of AP was evaluated by histopathological score and the detection of serum amylase and lipase. Results: Patients with AP had elevated levels of NETs and P-selectin compared with healthy volunteers. Stimulation of P-selectin up-regulated the expression of PSGL-1, increased the phosphorylation of Syk, mediated intracellular calcium signal and led to the activation and expression of PAD4, which modulated NETs formation in neutrophils. Pretreament with PSI-697 blunted NETs formation and PAD4 expression in the pancreatic tissue, and ameliorated the severity of AP in mice. Conclusion: Taken together, these results suggest that P-selectin induces NETs through PSGL-1 and its downstream Syk/Ca2+/PAD4 signaling pathway, and that targeting this pathway might be a promising strategy for the treatment of AP. [ABSTRACT FROM AUTHOR]

BACKGROUND: Epidemiological studies have found that female workers who are exposed to waste sevoflurane for a long time have reduced fertility and increased incidence of abortion and fetal deformity. OBJECTIVE: To imitate the working environment of long-term exposure to waste sevoflurane and investigate the mechanism of embryo implantation disorder induced by low-concentration sevoflurane exposure by observing the expression of intercellular adhesion molecule 1, integrin β1, P-selectin, and matrix metalloproteinase 9 in endometrium of pregnant mice exposed to low concentrations of sevoflurane, attempting to provide a basis for clinical safe drug use and occupational protection and to lay a foundation for further research on the mechanism of inhalation anesthetics on embryo implantation at gene and molecular levels. METHODS: Forty female Kunming mice and sixteen male Kunming mice, aged 6 weeks, weighting (20±2) g, were caged separately. Forty female mice were randomly divided into experimental group and control group. Mice in the experimental group were exposed to 0.1% sevoflurane, 6 hours per day, while those in the control group were exposed to the air. Thirty days later, the female mice in estrus were caged with mature male mice at a rate of 2:1. Whether the female mice were pregnant was observed at 7:00 am on the second day after mating. The pregnant mice were kept independently in the original condition (n ≥ 8 pregnant mice in each group). Mouse uterus on day 4.5 of gestation was removed and sliced for histological observation. The expression of intercellular adhesion molecule 1, integrin β1, P-selectin, and matrix metalloproteinase 9 in endometrial tissue was detected by immunohistochemistry and statistically analyzed. The average integrated absorbance value of positive reactants was calculated. RESULTS AND CONCLUSION: In the experimental and control groups, 17 and 15 female mice were respectively found in estrus; 12 and 10 female mice respectively were found vaginal plugs after mating. Five and two female mice were found pseudopregnant on day 4.5 of gestation in the experimental and control groups, respectively. Therefore, there were 7 and 8 pregnant mice in the experimental and control groups, respectively, and the vacant value in the experimental group was replaced by the average value obtained in the same group, which would be subsequently used in the controlled trial. Immunohistochemical results showed that the endometrium (glandular epithelial cells, luminal epithelial cells and stromal cells) of all pregnant mice were positively stained brownish yellow, but the expressions of intercellular adhesion molecule 1, integrin β1, P-selectin, and matrix metalloproteinase 9 (0.019±0.007, 0.017±0.007, 0.015±0.005, 0.012±0.005) in the experimental group were significantly lower than those in the control group (0.032±0.014, 0.025±0.008, 0.021±0.007, 0.023±0.005) (P < 0.05). All these findings indicate that long-term exposure to 0.1% sevoflurane may affect the adhesion of mouse embryos to endometrium and the embryo implantation, which may be related to the inhibitory effects of sevoflurane on the expressions of intercellular adhesion molecule 1, integrin β1, P-selectin, and matrix metalloproteinase 9, causing the imbalance in endometrial immunoregulation, the invasion of trophoblast cells into the endometrium and the inhibition of endometrial decidualization, and miscarriage and bleeding due to damaged vascular endothelium. [ABSTRACT FROM AUTHOR]