Search Results (68)

Inorganic polyphosphate is highly conserved, critical, yet poorly understood polymer that regulates diverse cellular functions in mammals. Its importance is well established in coagulation, inflammation, mitochondrial function, and stress responses, though the molecular mechanisms for these effects remain only partly understood. Fundamental questions also persist regarding its physiological concentration, chain-length distributions, and the mechanisms that regulate its behavior in specific cellular compartments. Progress is limited by the absence of a known mammalian polyphosphate-synthesizing enzyme. Despite this, recent studies have broadened the scope of polyphosphate biology, suggesting roles in protein phase separation, ATP-independent chaperone activity, metabolic regulation, and intracellular signaling. Polyphosphate modulates the mitochondrial permeability transition pore through calcium-dependent regulation and activates factor XII in coagulation. Findings have also introduced potential connections between polyphosphate and processes such as neurodegeneration, cancer, and tissue regeneration. Despite this expanding landscape, many biological effects remain difficult to interpret due to incomplete mapping of protein targets and longstanding technical limitations in detecting and quantifying polyP. This review integrates molecular protein-interaction mechanisms with compartment-specific functions and disease physiology, providing a clearer mechanistic framework while identifying key conceptual and methodological gaps and outlining priorities for advancing polyphosphate research in mammalian systems. Full article

Background: Recurrent pregnancy loss (RPL) is a multifactorial condition in which genetic variants associated with thrombophilia may contribute to altered coagulation and adverse pregnancy outcomes. Objective: This study aimed to investigate the association between thrombophilia-related single nucleotide variants (SNVs) and coagulation-related metabolites in a cohort of Mexican women with RPL. Methods: A retrospective and descriptive design was conducted including 105 women with at least two consecutive miscarriages and with a multidisciplinary approach that included a thrombophilia-associated SNVs panel. Peripheral blood samples were collected after fasting for biochemical and molecular analyses. Genotyping of thrombophilia-associated SNVs was performed using real-time PCR with custom-designed TaqMan probes on a Rotor-Gene Q platform, including variants in AGT (rs4762, rs699), F7 (rs6046), FGB (rs1800790), MTR (rs1805087), MTRR (rs1801394), MTHFR (rs1801133, rs1801131), F2 (rs1799963), F5 (rs6025), SERPINE1 (rs1799889), F12 (rs1801020), and F13A1 (rs5985) genes. Coagulation parameters evaluated were folic acid, cobalamin, fibrinogen, D-dimer, homocysteine, antithrombin III activity, thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), and Factor XII activity. Results: Significant differences were found in INR values across F7-rs6046 genotypes (p = 0.006), with an additive model showing a mean difference of 0.05 (p = 0.0009). The F12-rs1801020 variant was strongly associated with Factor XII activity (p = 0.002) and aPTT (p = 0.045). Conclusions: These findings indicate that F7-rs6046 and F12-rs1801020 genotypes influence specific coagulation parameters, suggesting that certain thrombophilia-associated SNVs may modulate the hemostatic profile in Mexican women with RPL and contribute to personalized risk assessment in reproductive medicine. Full article

This review reappraises the anti-inflammatory potential of the contact activation system (CAS) in intensive care through an evolutionary lens. The authors propose that coagulation factor XII (FXII) and related components evolved in terrestrial animals as a “foreign-surface sensing–immunothrombosis” module, helping to explain the minimal bleeding phenotype of FXII deficiency and the secondary loss of F12 in marine mammals. CAS shares components with the kallikrein–kinin system (KKS): alpha-coagulation factor XIIa (α-FXIIa) drives coagulation factor XI (FXI) activation to amplify coagulation, whereas betacoagulation factor XIIa (β-FXIIa) activates the KKS to generate bradykinin, promoting vasodilation and vascular leak. Beyond proteolysis, zymogen FXII signals via urokinase-type plasminogen activator receptor (uPAR) to induce neutrophil extracellular trap formation (NETosis), thereby amplifying immunothrombosis. Clinically, the relevance spans sepsis and extracorporeal organ support: pathogens can hijack CAS/KKS to facilitate invasion, and artificial surfaces such as extracorporeal membrane oxygenation (ECMO) circuits chronically trigger contact activation. In animal models, selective inhibition of FXII/FXI prolongs circuit life and attenuates pulmonary edema and inflammation without materially increasing bleeding. The review also catalogs “non-coagulation” roles of CAS members: Activated coagulation factor XI (FXIa) modulates endothelial permeability and smooth-muscle migration, and the FXII heavy chain exhibits direct antimicrobial activity—underscoring CAS as a nexus for coagulation, inflammation, and host defense. Overall, CAS inhibitors may couple “safe anticoagulation” with “cascade-level anti-inflammation,” offering a testable translational path for organ protection in the ICU alongside infection control and informing combined, precision strategies for anticoagulation and anti-inflammatory therapy. Full article

Thrombosis remains a leading preventable cause of global morbidity and mortality, with conditions like venous thromboembolism and atrial fibrillation affecting millions worldwide. Traditional anticoagulants (heparins, vitamin K antagonists) require careful monitoring due to narrow therapeutic windows. Direct oral anticoagulants (DOACs) greatly improved convenience and reduced certain hemorrhagic complications (notably intracranial hemorrhage) compared to warfarin, but bleeding, drug–drug interactions, and unmet needs in special populations persist. This review highlights emerging strategies to decouple antithrombotic efficacy from bleeding risk. Novel agents targeting factor XI or XII (small molecules, antibodies, antisense oligonucleotides) have shown in early trials robust thromboembolism prevention with low bleeding. Advances in pharmacogenomics, biomarker-guided dosing, artificial intelligence risk prediction, and digital monitoring promise to personalize therapy. We discuss optimized approaches for high-risk subgroups (cancer-associated thrombosis, extremes of body weight, renal/hepatic dysfunction, pregnancy, perioperative care, and COVID-19) with citations to current evidence. Finally, we outline critical systems-level considerations, including drug accessibility, cost-effectiveness, and educational strategies, that are necessary to realize precision anticoagulation. Our synthesis is grounded in recent peer-reviewed literature and emphasizes innovations likely to improve safety and efficacy of thromboprophylaxis. Full article

Venoms of the Palearctic vipers in the Macrovipera genus cause severe procoagulant clinical effects, yet the precise molecular targets remain incompletely defined. To fill this toxicological knowledge gap, we tested five Macrovipera venoms—M. lebetina cernovi, M. l. obtusa, M. l. turanica (Turkmenistan and Uzbekistan localities), and M. schweizeri—using plasma clotting assays, Factors VII, X, XI, and XII and prothrombin zymogen activation assays, and SDS-PAGE to visualise Factor V (FV) cleavage. All venoms induced extremely rapid clot formation (10.5–12.5 s) compared with the negative control (spontaneous clotting) of 334.6 ± 3.6 s) and the positive control (kaolin trigger) of 55.8 ± 1.9 s. Activation of FVII or FXI was negligible, whereas consistent FX activation and species-variable FXII activation, both moderate, were observed. Prothrombin remained inert in the absence of cofactors, but the presence of FV or FVa elicited potent thrombin generation. SDS-PAGE confirmed proteolytic conversion of the 330 kDa FV zymogen into the ~105 kDa heavy and ~80 kDa light chains of FVa by the venoms of all species. This data demonstrates that Macrovipera venoms rely on a dual enzyme strategy: (i) activation of FV to FVa by serine proteases and (ii) FVa-dependent prothrombin activation by metalloproteases. These results reveal that prothrombin activation is the dominant procoagulant pathway and overshadows the historically emphasised FX activation. This mechanism mirrors, yet is evolutionarily independent from, the FXa:FVa prothrombinase formation seen in Australian elapid venoms, highlighting convergent evolution of cofactor-hijacking strategies among snakes. The discovery of potent FVa-mediated prothrombin activation in Macrovipera challenges existing paradigms of viperid venom action, prompts re-evaluation of related genera (e.g., Daboia), and underpins the design of targeted antivenom and therapeutic interventions. Full article

In arid inland river basins, the upstream runoff generation zones contribute the majority of the basin’s water resources. Global warming and land use changes will produce uncertain impacts on runoff variations in the headwaters of inland rivers in arid regions. Deeply understanding the response mechanisms of runoff to climate and land use changes is fundamental for scientifically developing watershed water resource utilization planning and achieving sustainable socio-economic and ecological development. By integrating meteorological data, hydrological data, and multi-source remote sensing data, this study systematically evaluates the factors influencing changes in watershed hydrological processes. The results show: (1) From 1976 to 2016, the Xiying River runoff exhibited a slight increasing trend, with an increment of 0.213 mm per decade. (2) At the interannual scale, runoff is primarily influenced by precipitation changes, with a trend of further weakening ice and snowmelt effects. (3) The land use types in the Xiying River Basin are predominantly forestland, grassland, and unused land. With increasing forestland and cultivated land and decreasing grassland and construction land area, the watershed’s water conservation capacity has significantly improved. Full article

Coagulation factor XII (FXII), the initiator of the intrinsic coagulation pathway, is not involved in hemostasis but is associated with pathological thrombosis. Bacterial infections activate coagulation cascades, although the underlying mechanisms remain not fully understood. Here, we revealed that FXII exhibits antibacterial activity through its heavy chain (hFXII) against Pseudomonas aeruginosa (P. aeruginosa), a Gram-negative bacterium. We constructed an FXII-deficient (FXII^−/−) mouse model and demonstrated that FXII plays a critical role in antibacterial functions. FXII and hFXII significantly reduced bacterial loads via intravenous injection, confirming their antibacterial activity in FXII^−/−. To further investigate the pathophysiological implications of FXII in the P. aeruginosa-induced disseminated intravascular coagulation (DIC) mouse model, FXII and hFXII effectively reduced DIC-related bacterial infections, alleviated organ damage, and decreased fibrin deposition, consequently improving survival rates. This study indicates that FXII exhibits both in vitro and in vivo antibacterial activity, primarily mediated through its heavy chain. In thrombotic diseases triggered by Gram-negative bacterial infections, the antibacterial functions of FXII may influence the progression of the disease. These results not only redefine the critical role of the intrinsic coagulation pathway in innate immune defense but also provide novel insights into the prevention and treatment of severe infection-related diseases. Full article

Effective prehospital hemostasis is pivotal for improving survival outcomes in arterial hemorrhage. Existing hemostatic materials have limitations in terms of both efficiency and portability, particularly under complex wound conditions. This study engineered a kaolin-reinforced biomimetic adhesive composite powder (DTG-K), which achieved dual hemostatic mechanisms: mechanical occlusion via strong interfacial adhesion (lap-shear strength of 58.3 kPa) and biochemical activation of the intrinsic coagulation pathway through factor XII. In vitro evaluations confirmed its exceptional hemocompatibility, with a 0.93% hemolysis rate. When applied to femoral artery hemorrhage models in Bama swine, DTG-K demonstrated complete hemostasis within 30 s through synergistic physical sealing and biochemical coagulation. These findings demonstrate the potential of DTG-K as an innovative strategy for managing life-threatening arterial hemorrhage in prehospital emergency scenarios. Full article

This study analyzes the factors influencing the proportions of blank and null votes in Brazilian municipalities during the 2018 presidential elections. The behavior of the variable of interest is examined using unit regression models within the Generalized Additive Models for Location, Scale, and Shape (GAMLSS) framework. Specifically, five different unit regression models are explored, beta, simplex, Kumaraswamy, unit Weibull, and reflected unit Burr XII regressions, each incorporating submodels for both indexed distribution parameters. The beta regression model emerges as the best fit through rigorous model selection and diagnostic procedures. The findings reveal that the disaggregated municipal human development index (MHDI), particularly its income, longevity, and education dimensions, along with the municipality’s geographic region, significantly affect voting behavior. Notably, higher income and longevity values are linked to greater proportions of blank and null votes, whereas the educational level exhibits a negative relationship with the variable of interest. Additionally, municipalities in the Southeast region tend to have higher average proportions of blank and null votes. In terms of variability, the ability of a municipality’s population to acquire goods and services is shown to negatively influence the dispersion of vote proportions, while municipalities in the Northeast, North, and Southeast regions exhibit distinct patterns of variation compared to other regions. These results provide valuable insights into electoral participation’s socioeconomic and regional determinants, contributing to broader discussions on political engagement and democratic representation in Brazil. Full article

Cancer invasion and metastasis are critical factors that influence patient prognosis. Carbonic anhydrase IX (CA IX) and carbonic anhydrase XII (CA XII) are key regulators of hypoxia and pH homeostasis in the tumor microenvironment (TME). It has been verified that both CA IX and CA XII play significant roles in promoting tumor metastasis in recent years, but most of the literature tends to treat them as separate entities rather than exploring their synergistic effects. This review provides a comprehensive overview of the roles of CA IX and CA XII in tumor invasion and metastasis, along with their clinical applications, including their spatial distribution characteristics, molecular mechanisms that facilitate tumor metastasis, and their potential for clinical translation. Moreover, this review incorporates the classical tumor core–invasive front model to propose a metabolic coupling model of CA IX and CA XII, offering a fresh perspective on precision therapies that target tumor metabolism. By emphasizing the metabolic coupling between these two molecules, this review offers new insights distinct from previous studies and highlights the clinical therapeutic potential of simultaneously targeting both during treatment. It sheds new light on future research and clinical applications, aiming to enhance the prognosis of cancer patients through innovative therapeutic strategies. Full article

The swim bladder of Chu’s croaker (Nibea coibor) is an expensive food with high texture requirements. In this study, we found that male swim bladder had better toughness than female. To explore the main determining factor affecting texture properties of swim bladder, a comparison of proximate composition, collagen microstructure, and proteomics was carried out between male and female swim bladders. Results indicated that it should be collagen microstructure mainly affecting the texture characteristics of swim bladder, rather than the composition. The collagen fibers in male swim bladder were significantly more uniform and regular than female. By proteomics analysis, it was further discovered that collagen XII was the most significantly up-regulated protein in the male swim bladder and may be crucial in morphology of collagen fibers. In summary, collagen XII was identified to be a potential key molecule affecting the texture of the swim bladder, mainly through regulating properties of collagen fibers. This study contributes to a deeper understanding of the structural characteristics of swim bladder collagen and provides critical molecular targets for the regulation of texture in swim bladder. Full article

Echis species (saw-scaled vipers) are WHO Category 1 medically significant venomous snakes with potent procoagulant venoms, which cause lethal venom-induced consumptive coagulopathy in human victims. Despite clinical presentations of bites varying significantly between individuals within the same species, the contribution of age-related changes in the venom biochemistry has not been investigated. This study investigated the ontogenetic changes in Echis pyramidum pyramidum venom and its impact on therapeutic efficacy. The efficacy of various antivenoms (Echitab, Echitab+ ICP, Inosan MENA, Inosan Pan African, and SAVP-Echis) was tested against both venom phenotypes. While both neonate and adult venoms were procoagulant, there were differences in the underlying biochemistry. Neonate venom was found to potently pathophysiologically activate Factor VII and Factor X, and to a lesser degree Factor XII. In contrast, adult venom was a slower clotter, less potent in activating FVII, equipotent with neonate venom on FXII, and inactive on FX. This is the first documentation of FVII and FXII activation for any Echis venom. The significant ontogenetic toxicological variations in Echis species were shown to impact antivenom efficacy. Among the tested antivenoms, SAVP-Echis was the most effective against both venom phenotypes, with adult venom being better neutralized. These findings suggest the need for a reconsideration of venom mixture selection in antivenom production through the inclusion of neonate venom. Additionally, the results indicate differential ontogenetic predatory ecology, providing a foundation for future natural history investigations. Full article

The syndrome “bassess richesses” is a vector-borne disease of sugar beet in Germany. The gammaproteobacterium ‘Candidatus Arsenophonus phytopathogenicus’ causes reduced sugar content and biomass, growth abnormalities, and yellowing. Co-infection with the 16SrXII-P stolbur phytoplasmas often leads to more severe symptoms and a risk of complete economic loss. This yellowing agent of the Mollicutes class had not been described before, so its differences from other stolbur phytoplasmas remained unanswered. The genome of strain GOE was sequenced, providing a resource to analyze its characteristics. Phylogenetic position was revised, genome organization was compared, and functional reconstructions of metabolic and virulence factors were performed. Average nucleotide identity analysis indicates that GOE represents a new ‘Ca. Phytoplasma’ species. Our results show that GOE is also distinct from other stolbur phytoplasmas in terms of smaller genome size and G+C content. Its reductive evolution is reflected in conserved membrane protein repertoire and minimal metabolism. The encoding of a riboflavin kinase indicates a lost pathway of phytoplasmas outside the groups 16SrXII and 16SrXIII. GOE shows a complete tra5 transposon harboring orthologs of SAP11, SAP54, and SAP05 effectors indicating an original phytoplasma pathogenicity island. Our results deepen the understanding of phytoplasma evolution and reaffirm the heterogeneity of stolbur phytoplasmas. Full article

Hemostasis is a mechanism that stops bleeding from an injured vessel, involves multiple interlinked steps, culminating in the formation of a “clot” sealing the damaged area. Moreover, it has long been recognized that inflammation also provokes the activation of the coagulation system. However, there has been an increasing amount of evidence revealing the immune function of the hemostasis system. This review collects and analyzes the results of the experimental studies and data from clinical observations confirming the inflammatory function of hemostasis. Here, we summarize the latest knowledge of the pathways in immune system activation under the influence of coagulation factors. The data analyzed allow us to consider the components of hemostasis as receptors recognizing «foreign» or damaged «self» or/and as «self» damage signals that initiate and reinforce inflammation and affect the direction of the adaptive immune response. To sum up, the findings collected in the review allow us to classify the coagulation factors, such as Damage-Associated Molecular Patterns that break down the conventional concepts of the coagulation system. Full article

The selective inhibition of key enzymes, such as carbonic anhydrases (CAs IX and XII), which are overexpressed in cancer tissues, has emerged as a promising strategy in cancer research. However, a multitarget approach is often preferred to achieve enhanced therapeutic outcomes. In this study, aryl sulfonamides were conjugated with a thiosemicarbazone moiety to enable dual functionality: the inhibition of CAs and the chelation of metal cations. Several structural factors were systematically modified, including the position of the sulfonamido group, the length of the linker, the nature of the aromatic residue, and the type of substituents. Tumor-associated CAs IX and XII inhibition was evaluated using the stopped-flow CO₂ hydrase assay, and the inhibition constants (K_i) were determined. The most promising compounds were further analyzed through molecular docking simulations. Metal chelation capabilities were evaluated using UV–Vis spectroscopy, while antiproliferative activities were measured using the sulforhodamine B (SBR) assay. Additionally, holotomographic 3D microscopy was employed to investigate the mechanisms of cell death. Sulfonamido-derived Schiff bases were synthesized through a three-step procedure that did not require column chromatography purification: (1) isothiocyanation of amino-sulfonamides, (2) nucleophilic addition of hydrazine, and (3) acid-promoted condensation with different aldehydes (benzaldehydes or pyridine-2-carboxaldehyde). The synthesized compounds exhibited inhibition of CAs in the low nanomolar to submicromolar range, with selectivity largely influenced by structural features. Notably, the m-sulfonamide derivative 5b, bearing a pyridin-2-yl residue, demonstrated potent and selective inhibition of CA IX (K_i = 4.9 nM) and XII (K_i = 5.6 nM). Additionally, it efficiently chelated Fe²⁺, Fe³⁺, and Cu²⁺ and showed promising antiproliferative activity (GI₅₀ 4.5–10 µM). Mechanistic studies revealed that apoptosis was involved in its mode of action. Therefore, the synergistic integration of sulfonamides and thiosemicarbazones represents an effective strategy for the development of multimodal anticancer agents. Full article