Search Results (397)

Diabetes mellitus (DM) is a complex metabolic disorder associated with a heightened risk of cardiovascular events, largely driven by a hypercoagulable and hypofibrinolytic state. The pathophysiological interplay between chronic hyperglycemia, oxidative stress, insulin resistance, and systemic inflammation fosters profound alterations in the coagulation cascade, endothelial function, and platelet activity. This narrative review synthesizes evidence from studies published between 2008 and 2026, focusing on coagulation and platelet-related biomarkers selected based on their biological relevance to thrombosis, endothelial dysfunction, and inflammation, as well as the availability of clinical and interventional data across different forms of DM. Although there are numerous biomarkers involved in the pathogenesis of various forms of diabetes, this narrative review critically examines key coagulation biomarkers—including D-dimer, fibrinogen, prothrombin, tissue thromboplastin or tissue factor, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, plasminogen activator inhibitor-1, von Willebrand factor, and β-thromboglobulin—across distinct diabetes subtypes, including type 1, type 2, gestational, and secondary forms linked to endocrinopathies and pancreatic diseases. The literature reveals substantial subtype-specific heterogeneity in hemostatic alterations. For instance, Type 1 DM is characterized by early endothelial dysfunction and platelet activation, while Type 2 DM presents with elevated coagulation factors, impaired fibrinolysis, and a proinflammatory milieu. Gestational DM exhibits pregnancy-specific changes in coagulation, yet distinguishing them from obesity-related effects remains challenging. Secondary diabetes forms, such as those associated with Cushing’s syndrome or pancreatitis, further underscore the diversity in thrombotic risk profiles. Among the coagulation and platelet activation biomarkers reviewed, fibrinogen, P-selectin, and plasminogen activator inhibitor-1 demonstrate the most consistent associations with glycemic control, vascular dysfunction, and therapeutic modulation, particularly in type 2 diabetes, suggesting greater potential for clinical translation. In contrast, evidence for markers such as D-dimer, tissue factor or tissue thromboplastin, and soluble urokinase plasminogen activator receptor remains heterogeneous and insufficient for routine clinical application. By synthesizing mechanistic insights and clinical data, this review highlights the urgent need for subtype-tailored coagulation assessment in diabetes management. A better understanding of the dynamic alterations in coagulation pathways may facilitate earlier detection of vascular complications and inform personalized antithrombotic strategies. Full article

Purpose: To explore the correlation between radiologic patterns on high-resolution computed tomography (HRCT) and circulating biomarkers of inflammation and endothelial activation in patients with COVID-19 pneumonia, with the aim of identifying imaging-biomarker phenotypes that may offer insights for clinical stratification. Materials and Methods: This prospective single-center study included 84 consecutive patients hospitalized with PCR-confirmed SARS-CoV-2 infection and respiratory failure. All underwent baseline HRCT, along with parallel biohumoral profiling, including inflammatory (IL-1Ra, IL-6, IL-10) and endothelial (Angiopoietin-2, sVCAM-1, sE-Selectin) biomarkers. HRCT scans were reviewed for parenchymal and vascular abnormalities (vascular tree-in-bud [TIB], vascular enlargement pattern [VEP]). Semi-quantitative scores were assigned for parenchymal (PS) and vascular (VS) involvement. Results: Patients with higher PS had significantly prolonged hospital stay (35 vs. 17 days; p = 0.014), increased ICU admission rates (68.8% vs. 21.4%; p = 0.003), and elevated serum levels of IL-1Ra, IL-6, and IL-10 (p < 0.05). At multivariable analysis, PS remained independently associated with ICU admission after adjustment for age, inflammatory burden, and comorbidities (p = 0.014). A high VS was associated with significantly increased Angiopoietin-2 levels (p = 0.036), although it did not directly correlate with ICU admission or mortality. A significant positive correlation was observed between PS and VS (r =0.392; p < 0.001). Conclusions: in this study, HRCT-based parenchymal and vascular patterns appear significantly correlated with biological processes occurring in severe COVID-19 pneumonia. These observations, although preliminary, may offer a conceptual basis for future studies exploring radiologic and biomarker-based stratification in severe respiratory infections. Full article

Platelets are critical for hemostasis and play an active role in immune responses to infection. While thrombocytopenia in sepsis is associated with poor outcomes, platelet dysfunction remains less explored. This prospective observational pilot study investigated the relationship between platelet dysfunction and sepsis severity using multiple platelet function tests. Ten adults with sepsis or septic shock admitted to the ICU of “Fondazione Policlinico Universitario A. Gemelli” and seven healthy controls were enrolled. Blood samples were collected at admission (T0), after 48 h (T1), and after 7 days (T2). Controls were sampled only at T0. Besides platelet count, hemostatic platelet function was assessed by light transmission aggregometry (LTA), thromboelastography (TEG), and platelet activation markers (P-selectin and PAC-1 expression), whereas immune platelet function was assessed by investigation of platelet–leukocyte aggregates and soluble plasma levels of CD40L. Platelet function was correlated with procalcitonin levels and SOFA scores. While thrombocytopenia developed after 48 h, hemostatic and immune platelet dysfunctions were already evident at T0. Platelet function abnormalities were correlated with sepsis severity, as reflected by higher SOFA scores and elevated procalcitonin levels, particularly at T0. Early platelet dysfunction, preceding thrombocytopenia, may represent a potential early indicator of sepsis severity and support timely intervention for hemostatic and immune platelet-dependent abnormalities in septic patients. Full article

Background/Objectives: During oral and gut microbiota dysbiosis, lipopolysaccharides (LPSs) of major bacteria, such as Porphyromonas gingivalis and Escherichia coli, translocate into the bloodstream and lead to endotoxemia. Cerebral endothelial cells are targets of LPSs that may aggravate inflammation and cerebrovascular disorders. This study aimed to evaluate the protective role of the characterized polyphenol-rich extract of the Dodonaea viscosa medicinal plant and a predominant component, epicatechin, on murine bEnd.3 cerebral endothelial cells exposed to P. gingivalis or E. coli LPSs. Methods: The effects of LPSs and polyphenols were assessed on cell viability (MTT, trypan blue exclusion assays) and inflammatory, redox, vasoactive and permeability markers (RT-qPCR, Western blot, ELISA, FITC-Dextran test). Results: The data show that LPSs activated the TLR2-4/NFĸB signaling pathway and promoted IL-1β, IL-6, TNF-α, MCP-1, COX-2, iNOS, ICAM-1, VCAM-1 and E-selectin production without affecting cell viability. LPSs induced oxidative stress by elevating intracellular ROS levels and altering the expression of genes encoding NOX2-4, SOD, catalase, GPx, HO-1 and Nrf2. LPSs imbalanced NO vasodilator and ET-1 vasoconstrictor levels and reduced the production of occludin and ZO-1 tight junction proteins. Meanwhile, LPSs raised the permeability to FITC-Dextran, suggesting cell integrity loss. The extent of endothelial dysfunction caused by LPSs depended on their bacterial origin. Importantly, plant polyphenols and epicatechin exerted anti-inflammatory and antioxidant effects, and attenuated LPSs’ deleterious action on vasoactive and permeability markers. Conclusions: This study shows that polyphenols limit cerebral endothelial cell dysfunction under inflammatory conditions mediated by LPSs, highlighting their therapeutic potential in protecting brain homeostasis during oral and gut microbiota dysbiosis. Full article

Adult growth hormone deficiency (GHD) is linked to increased cardiovascular and metabolic risk due to oxidative stress (OS), endothelial dysfunction, and unhealthy body composition. Long-term systemic effects of recombinant human growth hormone (rhGH) therapy remain insufficiently defined. This study assessed the impact of 24-month rhGH replacement on OS, vascular markers, body composition, and bone mineral density (BMD) in adults with severe GHD. Fifteen adults with confirmed GHD received rhGH for 24 months. Serum insulin-like growth factor 1 (IGF-1), oxidized LDL (Ox-LDL), thioredoxin (Trx), 8-oxoguanine DNA glycosylase 1 (OGG1), E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured at baseline and 12 and 24 months. Body composition and BMD were evaluated by DXA. IGF-1 increased significantly at 12 and 24 months (p < 0.001). Ox-LDL markedly decreased (p < 0.00001), while Trx and OGG1 increased (p < 0.05). Levels of E-selectin, ICAM-1, and VCAM-1 declined, indicating improved endothelial function. Lean body mass and BMD increased, while body fat parameters showed heterogeneous changes. Lipid profiles were unchanged. Significant correlations were observed between vascular markers and adiposity, and between BMD, triglycerides, and IGF-1. A 24-month course of rhGH therapy improves redox balance, vascular function, and body composition in adults with severe GHD, supporting the use of redox and vascular biomarkers to monitor treatment efficacy. Full article

Dietary bioactive compounds are increasingly explored as complementary cardioprotective strategies, and the nitration of unsaturated fatty acids has emerged as a process capable of enhancing antiplatelet properties. This study investigated whether Phaseolus vulgaris L. extracts can generate nitrated fatty acids under gastric-like conditions and evaluated their effects on human platelet function. Bean extracts and major fatty acids were nitrated in vitro and tested using washed platelets to assess cytotoxicity, TRAP-6 and collagen-induced aggregation, activation markers (P-selectin, CD63), and mitochondrial responses including membrane potential, ROS production, and Ca²⁺ dynamics. Nitrated extracts markedly inhibited TRAP-6 induced aggregation (IC₅₀ ≈ 1.8 mg/mL), whereas non-nitrated extracts showed minimal activity; this effect was reversed by β-mercaptoethanol, indicating dependence on electrophilic nitroalkenes. Fractionation revealed that the lipidic fraction accounted for most of the antiplatelet effect, and isolated nitrated fatty acids (NO₂-LN, NO₂-LA, NO₂-OA) displayed stronger inhibition than their native counterparts without increasing cytotoxicity. Nitrated species additionally reduced mitochondrial membrane potential and granule secretion without elevating ROS. These findings identify Phaseolus vulgaris L. as a natural source of bioactive nitrated fatty acids and support their potential as nutraceutical agents capable of modulating platelet activation and contributing to cardiovascular risk reduction. Full article

Hypoglycemia is associated with cardiovascular events reflected by platelet abnormalities. We hypothesized that sequential endothelial changes may occur during hypoglycemia that may enhance cardiovascular risk. In type 2 diabetes (T2D) (n = 23) and controls (n = 23), blood SOMAscan proteomic analysis of endothelial proteins at baseline, insulin-induced hypoglycemia and post hypoglycemia to 24 h were examined using repeated-measures linear mixed modeling with a prospective parallel study design. Most endothelial proteins that changed over time did not differ between groups. Baseline levels of P-selectin, plasminogen activator inhibitor-1 (PAI-1; serpine-1), E-selectin and angiopoietin-1 (ANGPT1) were significantly higher, whilst cadherin-5 was lower in T2D. Several proteins exhibited changes versus baseline in both T2D and controls. Under hypoglycemia, decreases in cadherin-5 and soluble angiopoietin-1 receptor (sTie-2) were observed, with increased P-selectin, intercellular adhesion molecule-3 (ICAM3), ANGPT1 and PAI-1. Post hypoglycemia, decreased cadherin-5 and ICAM5 were observed at 2 h and PAI-1 at 4 h, as well as increases in P-selectin at 30 min, 1 h and 24 h and ICAM3 at 24 h. Post hypoglycemia, E-selectin, P-selectin and ICAM3 were significantly lower in T2D patients at 2 h, while PAI-1 was significantly lower at 4 h and ICAM3 was significantly lower at 24 h. Baseline endothelial proteins differed between T2D and controls, which may suggest local endothelial inflammatory activation leading to a pro-thrombotic, destabilized vascular phenotype characteristic of diabetic vasculopathy. Hypoglycemia may exacerbate this towards a pro-adhesive and pro-thrombotic phenotype, worsening endothelial dysfunction. Full article

Post-cardiac arrest syndrome (PCAS) remains a major cause of mortality and neurological impairment following successful resuscitation, yet the mechanisms linking global ischemia–reperfusion injury to microvascular and systemic dysfunction are not yet completely understood. While prior work has focused on inflammation, endothelial injury, and circulatory collapse, the central role of platelets in coordinating these pathological processes has not been comprehensively examined. This review provides the first integrated framework positioning platelets as core modulators, rather than secondary participants, in PCAS pathophysiology. We synthesize emerging evidence demonstrating that ischemia and reperfusion transform platelets into potent thromboinflammatory effectors through oxidative stress, DAMP-mediated pattern recognition signaling, and mitochondrial dysfunction. Hyperactivated platelets drive cerebral microthrombus formation, coronary no-reflow, and peripheral organ hypoperfusion, while platelet–leukocyte aggregates, neutrophil extracellular traps, and platelet-derived microparticles amplify systemic inflammation and endothelial injury. We further highlight the clinical significance of dynamic platelet dysfunction in coagulopathy, prognostication, and responses to post-arrest therapies including targeted temperature management and ECMO. Finally, we outline a novel, platelet-centered therapeutic paradigm, emphasizing selective interventions, such as GPVI inhibition, P-selectin blockade, FXI/XIa inhibition, and NETosis modulation, that target pathological platelet activity while preserving essential hemostatic function. In this review, by reframing platelets as the central determinants of PCAS, we report new mechanistic insights and therapeutic opportunities that are complementary to the existing post-arrest strategies and have the potential to improve survival and neurological outcomes after cardiac arrest. Full article

Despite antiretroviral therapy, HIV proteins, such as Tat, persist in tissues, driving chronic inflammation. Cervical inflammation in females not only accelerates HIV progression but also increases the risk of other STIs; hence, understanding the underlying factors/regulators is vital. However, Tat-induced cervical inflammation and its regulation are hitherto poorly understood, which we investigated using TZM-bl cells. Tat stimulation in these cervical epithelial cells significantly increased the expression of various inflammatory mediators, including cytokines (IL-1β, TNF-α, IL-6, IL-17a, GM-CSF), chemokines (MIP-1α, MIP-1β), adhesion molecules (ICAM-1, P-Selectin, E-Selectin), and ROS. Further upregulation of inflammatory mediators (NF-κB, IRAK-4) along with TLR7 was observed in Tat-stimulated cells. Interestingly, Tat stimulation decreased miR-204-5p expression in these cells, suggesting a role in regulating Tat-mediated inflammatory processes. Using a gain-of-function approach, we further observed that the overexpression of miR-204-5p reduced the expression of IL-1β, TNF-α, IL-6, MIP-1α, MIP-1β, ICAM-1, P-Selectin, and ROS in the Tat-stimulated TZM-bl cells, along with NF-κB, IRAK-1, and IRAK-4. Using Western blotting and luciferase assays, miR-204-5p was further shown to directly target NF-κB. Here, we report that HIV-1 Tat stimulation in cervical epithelial cells downregulates hsa-miR-204-5p, thereby activating the pro-inflammatory TLR7/NF-κB axis, highlighting its relevance to understanding mechanisms underlying cervical inflammation. Full article

In vitro testing of ventricular assist devices, constructing a mock circulation system that reproduces physiological cardiac function, is critical. However, current ventricular simulators often lack biomimetic fidelity and may introduce hemolysis and coagulation risks during prolonged operation, affecting hemocompatibility assessment. This study proposes a motor-driven torsional 3D-printed left ventricular simulator to reconstruct the hemodynamics of severe heart failure and related pathological conditions. The system integrates a 3D-printed elastic ventricular model with programmable torsional actuation, allowing the simulation of various cardiac conditions by adjusting the motor torsion angle and rotational speed, peripheral resistance and compliance. Fresh porcine blood was circulated for 4 h in a closed-loop system, with periodic measurements of plasma-free hemoglobin (PfHb), thrombin–antithrombin complex (TAT), and P-selectin. The results show that the system successfully reproduces typical hemodynamic features of severe heart failure, while hemolysis and coagulation markers remain low. After 4 h, PfHb was below 20 mg/dL, with no significant platelet activation or thrombosis. This study demonstrates that the proposed system enhances biomimicry while maintaining excellent hemocompatibility, offering a reliable platform for in vitro performance and safety evaluation of ventricular assist devices. Full article

Studies in human medicine have demonstrated that rotavirus infection can also affect extraintestinal sites due to its systemic effects. However, in veterinary medicine, the injury caused by rotavirus diarrhea is limited to the intestines, and its effects on various systemic structures remain poorly understood. In this observational case–control study, we aimed to determine the effects of HSP-27, Caspase-3, IL-2, γ-H2AX, HMGB-1, SP-D, and GDH (or GLDH) on the pathogenesis of rotavirus infection by using biomarkers for diagnostic purposes in lung and liver injury in neonate diarrheic calves naturally infected with rotavirus, both alive and post-mortem. Fifty-two Simmental calves (1–28 days old) of both sexes, 40 infected with rotavirus and 12 healthy, were studied. Twenty-eight out of 40 survived, while the remainder underwent necropsy for histopathological and immunopathological (HSP-27, Caspase-3, IL-2, γ-H2AX) examination of the lungs and livers. Lung and liver-specific serum E-selectin, glutamate dehydrogenase, surfactant protein-D, and high mobility group box-1 were analyzed by a bovine-specific ELISA kit (Shanghai Coon Koon Biotech Co., Ltd., China). Histopathological and immunohistochemical analyses confirmed lung and liver injury in naturally infected calves. HMGB-1, SP-D, and GDH concentrations were significantly higher in naturally infected calves than in the control group (p < 0.001, p < 0.001, and p < 0.05, respectively), showing an excellent diagnostic predictive capacity for lung and liver injury. Also, IL-2, HSP-27, CASP-3, and γ-H2AX were significantly expressed in the lungs (p < 0.001, p < 0.001, p < 0.001, and p < 0.05, respectively) and liver (p < 0.001, p < 0.001, p < 0.01, and p < 0.01, respectively). All these observations led us to hypothesize that oxidative stress, apoptosis, and DNA damage may underlie the pathogenesis of this condition. Nevertheless, further studies on large populations of rotavirus-infected calves are needed to confirm the data reported in the current study. Full article

We present the case of a Vipera ammodytes ammodytes (Vaa, nose-horned viper)-bitten patient with recurrent thrombocytopenia. A 53-year-old patient envenomated by Vaa experienced three episodes of venom-dependent thrombocytopenia (4, 57 and 11 × 10⁹/L), all of which we managed with antivenom Fab fragments. Despite these three severe episodes of thrombocytopenia within 24 h, platelet function remained intact, as demonstrated by normal thromboelastometry and aggregometry (96, 126, and 150 U) results after antivenom was administered and the platelet count normalized. Furthermore, flow cytometry showed only 0.3–1.7% expression of P-selectin on platelets, indicating that platelets did not activate but remained functional during and after thrombocytopenia. We assessed platelet function using rotational thromboelastometry, which evaluates the overall kinetics of hemostasis, including clot formation and stability. We performed aggregometry, which also reflects platelet function, only when the platelet count was within the normal range. Flow cytometry quantified P-selectin expression as a key marker of platelet activation. This case demonstrates that a component of Vaa venom can repeatedly induce venom-dependent thrombocytopenia, which is reversible by intervention, while platelet function remains intact. Full article

The replacement of ionizable functional groups that are predominantly charged at physiological pH with neutral bioisosteres is a common strategy in medicinal chemistry; however, its impact on binding affinity is often context-dependent. Here, we investigated a series of amide derivatives of a glycomimetic E-selectin ligand, in which the carboxylate group of the lead compound is substituted with a range of amide and isosteric analogs. Despite the expected loss of the salt-bridge interaction with Arg97, several amides retained or even improved the binding affinity. Co-crystal structures revealed conserved binding poses across the series, with consistent interactions involving the carbonyl oxygen of the amide and the key residues Tyr48 and Arg97. High-level quantum chemical calculations ruled out a direct correlation between carbonyl partial charges and affinity. Instead, a moderate correlation was observed between ligand binding and the out-of-plane pyramidality of the amide nitrogen, suggesting a favorable steric adaptation within the binding site. Molecular dynamics (MD) simulations revealed that high-affinity ligands exhibit enhanced solution-phase pre-organization toward the bioactive conformation, likely reducing the entropic penalty upon binding. Further analysis of protein–ligand complexes using Molecular mechanics/Generalized born surface area (MM-GB/SA) decomposition suggested minor lipophilic contributions from amide substituents. Taken together, this work underscores the importance of geometric and conformational descriptors, beyond classical electrostatics, in driving affinity in glycomimetic ligand design and provides new insights into the nuanced role of amides as carboxylate isosteres in protein–ligand recognition. Full article

Rotational atherectomy (RA) is an established technique for modifying heavily calcified and fibrotic coronary artery lesions. Despite its efficacy, the use of a high-speed rotating burr can provoke platelet activation and endothelial injury, thereby increasing thrombotic risk, promoting inflammation, and impairing vascular healing. This study investigated the effects of RA and its procedural characteristics on endothelial function and platelet activation by assessing circulating biomarkers. We prospectively analyzed 34 patients undergoing elective RA at a tertiary center. Blood samples were obtained before and 12–24 h after the procedure. Plasma levels of soluble E-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), platelet factor 4 (PF4), P-selectin, and cluster of differentiation 40 ligand (CD40L) were measured. The study population had a mean age of 71 ± 8.9 years, and 73.8% were male. Cardiovascular comorbidities were prevalent, including diabetes (61.9%), hypertension (92.9%), hypercholesterolemia (42.9%), heart failure (45.2%), atrial fibrillation (21.4%), prior PCI (81%), and prior CABG (11.9%). RA significantly increased levels of P-selectin (55.5 ± 26.1 vs. 68.9 ± 26.5, p < 0.001), CD40L (2261.3 ± 2489.9 vs. 3602.0 ± 2428.5, p = 0.01), and PF4 (6054.7 ± 5751.8 vs. 10,877.6 ± 4979.7, p < 0.001). Moreover, mean burr speed correlated with CD40L elevation, while burr-to-artery ratio correlated with E-selectin increase (all p < 0.05). RA induces significant platelet activation and endothelial injury, with biomarker changes suggesting correlation with procedural parameters. These findings highlight the biological impact of RA and may inform strategies to optimize the safety of complex PCI. Full article

In the context of HIV infection, PSGL-1 expression and impact on CD4⁺ T cells remain largely unexplored. Thus, to address these critical gaps in knowledge, blood was sampled from HIV-negative controls and both ART-treated and ART-naïve individuals and stratified according to CD4⁺ T cell counts. PSGL-1 expression on CD4⁺ T cells and CD4⁺ T cell–platelet aggregates, along with PD-1, Bcl-2, and Caspase-3, were assessed with flow cytometry. Levels of IL-12, IFN-γ, LPS, and β-glucan were determined with ELISA. Spearman’s correlation test was used to determine the correlation between PSGL-1 expression on CD4⁺ T cell counts and markers of inflammation/translocation. PSGL-1 was significantly overexpressed in ART-treated individuals (p < 0.0001) and exhibited markedly lower expression in ART-naïve individuals (p ≤ 0.01), consistent with a suppressive influence of HIV VL prior to ART initiation and a proinflammatory environment promoting PSGL-1 overexpression during ART. In both groups, individuals with CD4⁺ T cells < 200 cells/µL exhibited elevated levels of PSGL-1 (p < 0.05) and increased CD4⁺ T cell–platelet aggregates (p < 0.05). In ART-treated individuals only, PSGL-1 expression positively correlated with IFN-γ (r = 0.318, p = 0.021), IL-12 (r = 0.498, p < 0.001), LPS (r = 0.382, p = 0.005), and β-glucan (r = 0.318, p = 0.021), reinforcing the link between inflammatory activation and PSGL-1 overexpression. In this group, those with CD4⁺ T cells < 200 cells/µL had higher Caspase-3 and PD-1 (p < 0.0001) and lower Bcl-2 (p ≤ 0.01). No significant differences in these markers were found across CD4⁺ strata in ART-naïve individuals. PSGL-1 expression is influenced by ART and immune status. PSGL-1 signaling drives CD4⁺ T cell phenotypic changes. Full article