Search Results (2,721)

Thrombosis is a cardiovascular disease characterized by the pathological formation of a fibrin clot in blood vessels. Currently available fibrinolytic enzymes have some limitations, including severe side effects, high cost, short half-life, and low fibrin specificity. Proteins from microalgae and cyanobacteria have various biological effects and are emerging as promising sources for fibrinolytic enzymes. In this study, bioinformatics tools were used to evaluate the intrinsic disorder predisposition of microalgal fibrinolytic proteins, their capability to undergo liquid–liquid phase separation (LLPS), and the presence of disorder-based functional regions, and short linear motifs (SLiMs). Analysis revealed that these proteins are predominantly hydrophilic and exhibit acidic (pI 3.96–6.49) or basic (pI 8.05–11.0) isoelectric points. Most of them are expected to be moderately (61.4%) or highly disordered proteins (6.8%) and associated with LLPS, with nine proteins being predicted to behave as droplet drivers (i.e., being capable of spontaneous LLPS), and twenty-five proteins being expected to be droplet clients. These observations suggest that LLPS may be related to the regulation of the functionality of microalgal fibrinolytic proteins. The majority of these proteins belong to the blood coagulation inhibitor (disintegrin) 1 hit superfamily, which can inhibit fibrinogen binding to integrin receptors, preventing platelet aggregation. Furthermore, the SLiM-centered analysis indicated that the main motifs found in these proteins are MOD_GlcNHglycan and CLV_PCSK_SKI1_1, which can also play different roles in thrombolytic activity. Finally, Fisher and conservation analysis indicated that CLV_NRD_NRD_1, CLV_PCSK_FUR_1, CLV_PCSK_PC7_1, and MOD_Cter_Amidation motifs are enriched in intrinsically disordered regions (IDRs) of these proteins, showing significant conservation and suggesting compatibility with proteolytic activation and post-translational processing. These data provide important information regarding microalgal proteins with potential thrombolytic effects, which can be realized through protein–protein interactions mediated by SLiMs present in intrinsically disordered regions (IDRs). Additional analyses should be conducted to confirm these observations using experimental in vitro and in vivo approaches. Full article

The efficacy of platelet-rich plasma (PRP) has long been associated with platelet concentration, yet clinical outcomes remain highly variable and frequently inconsistent. This review challenges the assumption that platelet count alone defines PRP efficacy, proposing instead that functional platelet quality and growth-factor bioactivity are equally critical determinants of therapeutic outcomes. Platelets act as carriers of bioactive molecules stored within alpha granules, including growth factors such as platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), and insulin-like growth factor (IGF), which orchestrate the cellular and molecular events of tissue repair. Variations in donor biology, age, metabolic status, and oxidative stress profoundly influence platelet functionality and growth-factor release. Likewise, centrifugation parameters, temperature control, and activation methods dictate whether these mediators are preserved or prematurely exhausted. Collectively, these findings reveal that platelet number alone cannot predict regenerative potency. The future of PRP standardization requires the integration of platelet quality indices, growth-factor quantification, and patient optimization protocols into clinical practice. By shifting focus from platelet enumeration to bioactivity assessment, regenerative medicine can achieve more consistent, personalized, and scientifically accurate outcomes. Full article

Background: Inflammatory activity in rheumatoid arthritis can be determined by normal blood count ratios such as Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Systemic Immune Inflammation Index (SII), and C-reactive Protein (CRP). Objective: The aim of this research is to determine how these markers change after therapy and whether their pre- and post-treatment differences follow patterns that allow for simple parametric analyses. Methods: A prospective cohort of 52 RA patients (30 females and 22 males) was examined. The patients’ blood samples were tested at baseline and at the end of their 6-month Infliximab treatment. Hematologic markers such as NLR, PLR, and SII were calculated from the complete blood count (CBC), and CRP levels were measured. The statistical methods of Shapiro–Wilk (SW), Kolmogorov–Smirnov (KS), and Anderson–Darling (AD) were used, and later, paired t-tests were used to generate statistics where necessary. Results: Post-treatment measurements were consistently lower for all four biomarkers. QQ-plots and formal tests revealed that the differences between findings were essentially normal, allowing for paired t-tests. The mean decreases were as follows: NLR −1.10 (95% CI −1.48 to −0.71), PLR −43.0 (−55.4 to −30.7), SII −299 (−388 to −211), and CRP −11.36 (−13.18 to −9.54), all p < 0.001. CRP showed the greatest drop, with significant decreases in PLR and SII and a moderate decline in NLR, indicating therapy-related attenuation of systemic inflammation. Conclusions: The study shows that six months of infliximab therapy results in a consistent post-treatment decrease in all four biomarkers: NLR, PLR, SII, and CRP. Because the pre-post differences were roughly normal, CRP revealed the greatest decrease, with significant decreases in PLR and SII and a moderate decrease in NLR, consistent with systemic inflammation reduction. When combined, the CBC-derived indices track with CRP and can serve as practical, low-cost markers for monitoring therapy response in RA, despite the single-arm design. Full article

Background/Objectives: Severe COVID-19 is marked by IL-6-driven inflammation, endothelial injury, and dysregulated coagulation. Although IL-6 antagonists improve clinical outcomes, their effects on the temporal evolution of coagulation and fibrinolysis remain insufficiently defined. This study characterizes inflammatory, endothelial, coagulation, and fibrinolytic trajectories following IL-6 receptor blockade in critically ill COVID-19 patients. Methods: In this prospective, exploratory multicenter case series (ClinicalTrials.gov NCT05218369), 15 ICU patients with PCR- or antigen-confirmed COVID-19 received tocilizumab per protocol. Serial sampling at five timepoints (T0–T4) included routine laboratories, comprehensive viscoelastic hemostatic assays (ClotPro^®), and ELISA-based endothelial and fibrinolytic biomarkers. Analyses were primarily descriptive, emphasizing temporal patterns through boxplots; paired Wilcoxon tests with FDR correction contextualized within-patient changes. Results: Patients exhibited marked inflammation, hyperfibrinogenemia, endothelial activation, and delayed fibrinolysis at baseline. IL-6 blockade induced rapid suppression of CRP and PCT, progressive declines in fibrinogen, and modest platelet increases. In contrast, vWF antigen and activity further increased, indicating persistent endothelial dysfunction. Viscoelastic testing showed preserved thrombin generation and sustained high clot firmness, while biochemical markers (rising PAI-1, modest PAP increase, and progressively increasing D-dimer) and VHA indices suggested ongoing antifibrinolytic activity despite resolution of systemic inflammation. Conclusions: IL-6 antagonism was associated with rapid attenuation of systemic inflammation but was not accompanied by normalization of endothelial activation or fibrinolytic resistance. The observed hemostatic profile was consistent with attenuation of inflammation-associated coagulation features, while endothelial and prothrombotic alterations appeared to persist during follow-up, warranting further investigation in larger controlled studies. Full article

Arteriogenesis, the growth of pre-existing arterioles into functional collateral arteries, represents a key adaptive response to severe arterial stenosis. This process is driven by hemodynamic forces and a tightly coordinated inflammatory cascade. Here, we investigated the effects of pharmacological stimulation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling pathway using the phosphodiesterase-5 (PDE5) inhibitor Sildenafil on collateral vessel growth in a murine model of femoral artery ligation (FAL). Flow cytometric analyses revealed that Sildenafil treatment significantly enhanced platelet–leukocyte aggregate formation, a prerequisite for the subsequent initiation of a localized perivascular inflammation. Histological and immunofluorescence analyses further demonstrated a marked increase in mast cell recruitment and degranulation at early time points (days 1 and 3 post-FAL). In addition, Sildenafil promoted perivascular macrophage accumulation on days 3 and 7, with a pronounced shift toward an M2-like pro-regenerative polarization state, ultimately resulting in the enhanced proliferation of vascular cells and the enlargement of collateral diameters. Together, these findings identify Sildenafil as a potent enhancer of arteriogenesis through coordinated immune cell activation, stimulating vascular cell proliferation along with positive collateral outward remodeling. Thus, Sildenafil emerges as a promising therapeutic candidate to promote collateral artery growth in cardiovascular occlusive diseases. Full article

Background/Objectives: Watermelon (Citrullus lanatus) processing generates substantial quantities of rind, seeds, and residual pulp that are typically discarded despite being rich in polyunsaturated fatty acids, polar lipids, carotenoids, and phenolic compounds. These amphiphilic bioactives are increasingly recognized for their roles in modulating oxidative stress, inflammation, and platelet activation; however, the lipid fraction of watermelon by-products remains insufficiently characterized. This study examined organic watermelon juice and its by-products to isolate, characterize, and evaluate extracts enriched in amphiphilic and lipophilic bioactives, with emphasis on their in vitro antioxidant, anti-inflammatory, and antithrombotic properties. Methods: total lipids were extracted using a modified Bligh–Dyer method and fractionated into total amphiphilic compounds (TAC) and total lipophilic compounds (TLC) via counter-current distribution. Phenolic and carotenoid levels were quantified, and antioxidant capacity was assessed using DPPH, ABTS, and FRAP assays. Anti-platelet and anti-inflammatory activities were evaluated against ADP- and PAF-induced platelet aggregation. Structural characterization of polar lipids was performed using ATR–FTIR, and LC–MS was used to determine fatty acid composition and phospholipid structures. Results and Discussion: Carotenoids were primarily concentrated in the TLC fractions with high ABTS values for antioxidant activity, while phenolics mostly in the juice, the TACs of which showed the strongest total antioxidant capacity based on DPPH. TAC fractions of both samples showed also higher FRAP values of antioxidant activity, likely due to greater phenolic content. TAC extracts also exhibited notable inhibition of PAF- and ADP-induced platelet aggregation, associated with their enriched ω-3 PUFA profiles and favorable ω-6/ω-3 ratios based on their LC-MS profiles. Conclusions: Overall, watermelon products (juice) and by-products represent a valuable and sustainable source of amphiphilic bioactives with significant antioxidant, anti-inflammatory, and anti-platelet potential, supporting their future use in functional foods, nutraceuticals, and cosmetic applications. Full article

Background: Even though there have been improvements in antimicrobial and supportive therapies, sepsis and septic shock are still major causes of death in intensive care units. Early prognostic stratification is very important for helping doctors make decisions. Platelet-derived indices may provide useful, low-cost indicators that signify both inflammatory activation and coagulation irregularities. This study looked at how well different platelet-based ratios could predict death in the hospital from sepsis. Materials and Methods: We performed a prospective observational study spanning one year in a tertiary ICU, enrolling 114 adult patients diagnosed with sepsis or septic shock. Upon admission, four platelet-related biomarkers were measured: the C-reactive protein-to-platelet ratio (CPR), the platelet-to-lymphocyte ratio (PLR), the platelet-to-white blood cell ratio (PWR), and the platelet-to-creatinine ratio (PCR). Logistic regression models and receiver operating characteristic (ROC) analyses were employed to assess predictive accuracy. Results: Compared to survivors, non-survivors (n = 39) had much higher CRP levels and CPR values, alongside lower platelet and lymphocyte counts. The CPR index showed the best ability in differentiating between non-survivors and survivors (AUC 0.757), with a best cutoff of 0.886. In simplified multivariate models, CPR was still an independent predictor of death in the hospital (OR 1.98; 95% CI 1.22–3.21), whereas PLR and PWR were not. PCR showed a non-significant trend toward lower values in not survivors. Conclusions: CPR is a strong and clinically viable predictor of early mortality in sepsis, outperforming other platelet-based indices. Derived from routine laboratory parameters, CPR serves as a valuable adjunct for initial risk stratification in the ICU. To further confirm its prognostic role and incorporation into current scoring systems, large-scale multicenter studies with longitudinal measurements are warranted to validate its prognostic utility and integration into existing scoring systems. Full article

Coronary artery bypass grafting (CABG) remains the gold standard for patients with advanced multivessel coronary artery disease. Optimal myocardial protection versus ischemia during reversible and controlled cardiac arrest is a cornerstone of successful outcomes. Myocardial ischemia represents a state of reduced coronary perfusion with oxygenated blood, insufficient to meet the metabolic demands of the myocardium. Conventional cardioplegic solutions offer controlled and reversible cardiac arrest while actively modulating the molecular and cellular mechanisms that mediate ischemia–reperfusion injury. Cardioplegia dramatically elongates the reversible period of ischemic injury and restricts cardiomyocyte death by shutting down electromechanical activity, lowering metabolic demand, stabilizing ionic homeostasis, protecting mitochondrial integrity, and slowing oxidative stress and inflammatory signaling. During ischemia, cardiomyocytes shift from aerobic to anaerobic metabolism, resulting in adenosine triphosphate (ATP) depletion, loss of ionic homeostasis and calcium overload that activate proteases, phospholipases and membrane damage. Reperfusion restores oxygen supply and prevents irreversible necrosis but paradoxically initiates additional injury in marginally viable myocardium. The reoxygenation phase induces excessive production of reactive oxygen species (ROS), endothelial dysfunction and a strong inflammatory response mediated by neutrophils, platelets and cytokines. Mitochondrial dysfunction and opening of the mitochondrial permeability transition pore (mPTP) further amplify oxidative stress and inflammation, and trigger apoptosis and necroptosis. Understanding these intertwined cellular and molecular mechanisms remains essential for identifying novel therapeutic targets aimed at reducing reperfusion injury and improving myocardial recovery after ischemic events, particularly in coronary surgery. Full article

In this study, blood cell counts and serum C3, C4, and CH50 values at baseline and after more than 6-month drug use were measured to elucidate changes in blood cells and complements during relapse prevention therapies for aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD). A total of 70 patients with AQP4+ NMOSD (87% female, median age 56 years) were enrolled. They were divided into the following treatment groups: glucocorticoids and/or immunosuppressants (GC/IS, n = 22), inebilizumab/rituximab (anti-CD19/20, n = 13), satralizumab (anti-IL-6R, n = 22), and eculizumab/ravulizumab (anti-C5, n = 13). At baseline, the blood counts and complement levels did not differ among the groups. At follow-up, the neutrophil and platelet counts in the anti-IL-6R group decreased from those at baseline (p < 0.0001 and p < 0.001, respectively). Compared with the GC/IS, anti-CD19/20, and anti-C5 groups, the anti-IL-6R group had lower levels of C3 (p < 0.0001, p < 0.01, and p < 0.05, respectively) and C4 (p < 0.0001, p < 0.01, p < 0.001, respectively). Furthermore, the anti-C5 group had significantly lower CH50 levels than the GC/IS, anti-CD19/20, and anti-IL-6R groups (p < 0.0001, p < 0.0001, p < 0.05, respectively). In addition, the anti-IL-6R group had lower CH50 levels than the GC/IS and anti-CD19/20 groups (p < 0.001 and p < 0.05, respectively). The present study demonstrated that anti-IL-6R therapy broadly and mildly suppressed the complement system and decreased the neutrophil and platelet counts. It also showed that anti-C5 therapy strongly suppressed total complement activity but did not affect the C3 and C4 levels or blood counts. These findings may have implications for the mode of action of the drugs and the risk of adverse drug reactions, including infections. Full article

Pulmonary embolism (PE) is one of the most serious complications of antiphospholipid syndrome (APS), a systemic autoimmune disorder defined by thrombotic events and persistent antiphospholipid antibodies (aPLA). PE occurs in 11–20% of patients and may constitute the initial clinical manifestation. Young and middle-aged women are most frequently affected, and triple-positive aPLA profiles markedly increase the risk of recurrence and long-term morbidity, including chronic thromboembolic pulmonary hypertension (CTEPH). This review article summarizes current evidence on the epidemiology, pathophysiology, diagnostic approach, and management of PE in APS. Key mechanisms include anti-β2-glycoprotein I-mediated endothelial and platelet activation, complement engagement, and neutrophil extracellular trap formation, resulting in immunothrombosis. Diagnostic pathways follow standard PE algorithms; however, chronically elevated D-dimer levels and lupus anticoagulant-related aPTT prolongation require careful interpretation and consideration. Long-term vitamin K antagonist therapy remains the standard of care, whereas direct oral anticoagulants are not recommended in high-risk APS. Future directions include improved risk stratification through detailed aPLA profiling and the use of emerging biomarkers, early screening for CTEPH, and the development of targeted therapies such as complement inhibition and anti-NETosis strategies. Full article

Metastasis is still the leading cause of cancer-related death. It happens when disseminated tumor cells (DTCs) successfully navigate a series of steps and adapt to the unique conditions of distant organs. In this review, key molecular and immune mechanisms that shape metastatic spread, long-term survival, and eventual outgrowth are examined, with a focus on how tumor-intrinsic programs interact with extracellular matrix (ECM) remodeling, angiogenesis, and immune regulation. Gene networks that sustain tumor-cell plasticity and invasion are described, including EMT-linked transcription factors such as SNAIL and TWIST, as well as broader transcriptional regulators like SP1. Also, how epigenetic mechanisms, such as EZH2 activity, DNA methylation, chromatin remodeling, and noncoding RNAs, lock in pro-metastatic states and support adaptation under therapeutic pressure. Finally, proteases and matrix-modifying enzymes that physically and biochemically reshape tissues, including MMPs, uPA, cathepsins, LOX/LOXL2, and heparinase, are discussed for their roles in releasing stored growth signals and building permissive niches that enable seeding and colonization. In parallel, immune-evasion strategies that protect circulating and newly seeded tumor cells are discussed, including platelet-mediated shielding, suppressive myeloid populations, checkpoint signaling, and stromal barriers that exclude effector lymphocytes. A major focus is metastatic dormancy, cellular, angiogenic, and immune-mediated, framed as a reversible survival state regulated by stress signaling, adhesion cues, metabolic rewiring, and niche constraints, and as a key determinant of late relapse. Tumor-specific metastatic programs across mesenchymal malignancies (osteosarcoma, chondrosarcoma, and liposarcoma) and selected high-burden cancers (melanoma, hepatocellular carcinoma, glioblastoma, and breast cancer) are highlighted, emphasizing shared principles and divergent organotropisms. Emerging therapeutic strategies that target both the “seed” and the “soil” are also discussed, including immunotherapy combinations, stromal/ECM normalization, chemokine-axis inhibition, epigenetic reprogramming, and liquid-biopsy-enabled minimal residual disease monitoring, to prevent reactivation and improve durable control of metastatic disease. Full article

Thrombotic cardiovascular diseases are frequent side effects of cancer therapy with cytotoxic drugs such as Doxorubicin. Endothelial cell senescence is emerging as a critical mechanism underlying endothelial dysfunction in this context. Senescent cells, although unable to proliferate, secrete bioactive molecules that alter the tissue microenvironment, a feature known as the senescence-associated secretory phenotype (SASP). Besides soluble molecules, senescent cells also release extracellular vesicles (EVs). Previous studies indicate that senescent endothelial cells produce a secretome that promotes platelet activation; however, the contribution of EVs remains unclear. Here, we show that human microvascular endothelial cells (HMEC-1) exposed to Doxorubicin undergo senescence, display endothelial dysfunction, and release EVs. We found no differences in the concentration or size distribution of EVs from senescent and non-senescent cells. Nevertheless, EVs from senescent HMEC-1 promoted platelet activation more strongly than EVs from control cells. Notably, EVs alone did not induce platelet aggregation, suggesting that soluble factors are also required to support platelet-dependent hemostasis. These findings reveal that EVs from senescent endothelial cells contribute to platelet activation, a process that may favor thrombosis in patients receiving Doxorubicin-based chemotherapy. Full article

Hair loss disorders, particularly androgenetic alopecia (AGA), are common conditions that carry significant psychosocial impact. Current standard therapies, including minoxidil, finasteride, and hair transplantation, primarily slow progression or re-distribute existing follicles and do not regenerate lost follicular structures. In recent years, regenerative medicine has been associated with a gradual shift toward approaches that aim to restore follicular function and architecture. Stem cell-derived conditioned media and exosomes have shown the ability to activate Wnt/β-catenin signaling, enhance angiogenesis, modulate inflammation, and promote dermal papilla cell survival, resulting in improved hair density and shaft thickness with favorable safety profiles. Autologous cell-based therapies, including adipose-derived stem cells and dermal sheath cup cells, have demonstrated the potential to rescue miniaturized follicles, although durability and standardization remain challenges. Adjunctive interventions such as microneedling and platelet-rich plasma (PRP) further augment follicular regeneration by inducing controlled micro-injury and releasing growth and neurotrophic factors. In parallel, machine learning-based diagnostic tools and deep hair phenotyping offer improved severity scoring, treatment monitoring, and personalized therapeutic planning, while robotic Follicular Unit Excision (FUE) platforms enhance surgical precision and graft preservation. Advances in tissue engineering and 3D follicle organoid culture suggest progress toward producing transplantable follicle units, though large-scale clinical translation is still in early development. Collectively, these emerging biological and technological strategies indicate movement beyond symptomatic management toward more targeted, multimodal approaches. Future progress will depend on standardized protocols, regulatory clarity, and long-term clinical trials to define which regenerative approaches can reliably achieve sustainable follicle renewal in routine cosmetic dermatology practice. 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

Platelet-rich fibrin (PRF) is widely used in regenerative dentistry and oral surgery for its ability to promote tissue healing and modulate cellular responses. However, PRF contains not only platelets but also leukocytes and plasma components, complicating efforts to define the specific contribution of platelets to its biological activity. To address this, we used washed, leukocyte-depleted platelets activated with thrombin to generate platelet-released supernatant (PRS), which was applied to gingival fibroblasts. RNA sequencing identified 147 upregulated and 39 downregulated genes (|log₂ fold change| ≥ 2, FDR < 0.001), including cytokines IL11 and CXCL8 previously associated with PRF, as well as mitosis-related genes such as centromere-associated proteins, cell division cycle proteins, kinesin-like proteins, and shugoshins, consistent with gene ontology analyses. Validation by RT-PCR and immunoassays confirmed robust upregulation of IL11 and CXCL8. Functionally, PRS activated TGF-β signaling, indicated by Smad2/3 nuclear translocation, but did not induce NF-κB signaling. These findings demonstrate that platelets are major contributors to PRF’s biological effects, independent of leukocytes and plasma, and elicit a pronounced mitogenic and TGF-β-dominant response in gingival fibroblasts. They also provide insight into the cellular mechanisms underlying PRF-mediated tissue regeneration. Full article