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Journal of Clinical Medicine Apr 2024: The coagulation cascade due to tissue damage is considered to be one of the causes of poor prognostic outcomes in patients with acute exacerbations of interstitial...
Usefulness of Combined Measurement of Surfactant Protein D, Thrombin-Antithrombin III Complex, D-Dimer, and Plasmin-α2 Plasmin Inhibitor Complex in Acute Exacerbation of Interstitial Lung Disease: A Retrospective Cohort Study.
: The coagulation cascade due to tissue damage is considered to be one of the causes of poor prognostic outcomes in patients with acute exacerbations of interstitial lung disease (AE-ILD). This study aimed to confirm coagulopathy in AE-ILD by evaluating the differences in the clinical characteristics of coagulation/fibrinolysis markers between stable ILD and AE-ILD. : Overall, 81 patients were enrolled in this retrospective study and categorized into the following two groups: a chronic ILD group comprising 63 outpatients and an acute ILD group comprising 18 inpatients diagnosed with AE-ILD. Serum markers, including thrombin-antithrombin III complex (TAT), D-dimer, plasmin-α2 plasmin inhibitor complex (PIC), and surfactant protein D (SP-D), were compared between the groups. : Among the 18 patients with acute ILD, 17 did not meet the International Society of Thrombosis and Hemostasis scoring system for disseminated intravascular coagulation. In acute ILD, the SP-D levels were statistically significantly positively correlated with TAT, D-dimer, and PIC levels, while the Krebs von den Lungen 6 (KL-6) levels showed no correlation with any of these coagulation/fibrinolytic markers. A positive correlation was observed between SP-D levels and TAT, D-dimer, and PIC levels in acute ILD. Serum TAT, D-dimer, and PIC all showed good area under the receiver operating characteristic (ROC) curve (AUC) values in ROC analysis for the diagnosis of acute ILD. : In the clinical setting of AE-ILD, it may be important to focus not only on alveolar damage markers such as SP-D but also on coagulation/fibrinolytic markers including TAT, D-dimer, and PIC.
PubMed: 38673700
DOI: 10.3390/jcm13082427 -
Foods (Basel, Switzerland) Apr 2024To investigate the gelation process of direct ultra-high-temperature (UHT) milk, a pilot-scale steam infusion heat treatment was used to process milk samples over a wide...
To investigate the gelation process of direct ultra-high-temperature (UHT) milk, a pilot-scale steam infusion heat treatment was used to process milk samples over a wide temperature of 142-157 °C for 0.116-6 s, followed by storage at 4 °C, 25 °C, and 37 °C. The results of the physicochemical properties of milk showed that the particle sizes and plasmin activities of all milk samples increased during storage at 25 °C, but age gelation only occurred in three treated samples, 147 °C/6 s, 142 °C/6 s, and 142 °C/3 s, which all had lower plasmin activities. Furthermore, the properties of formed gels were further compared and analyzed by the measures of structure and intermolecular interaction. The results showed that the gel formed in the 147 °C/6 s-treated milk with a higher C* value had a denser network structure and higher gel strength, while the 142 °C/6 s-treated milk had the highest porosity. Furthermore, disulfide bonds were the largest contributor to the gel structure, and there were significant differences in disulfide bonds, hydrophobic interaction forces, hydrogen bonds, and electrostatic force among the gels. Our results showed that the occurrence of gel was not related to the thermal load, and the different direct UHT treatments produced different age gels in the milk.
PubMed: 38672908
DOI: 10.3390/foods13081236 -
Toxins Apr 2024Green pit viper bites induce mild toxicity with painful local swelling, blistering, cellulitis, necrosis, ecchymosis and consumptive coagulopathy. Several bite cases of...
Green pit viper bites induce mild toxicity with painful local swelling, blistering, cellulitis, necrosis, ecchymosis and consumptive coagulopathy. Several bite cases of green pit vipers have been reported in several south-east Asian countries including the north-eastern region of India. The present study describes isolation and characterization of a haemostatically active protein from venom responsible for coagulopathy. Using a two-step chromatographic method, a snake venom serine protease erythrofibrase was purified to homogeneity. SDS-PAGE of erythrofibrase showed a single band of ~30 kDa in both reducing and non-reducing conditions. The primary structure of erythrofibrase was determined by ESI LC-MS/MS, and the partial sequence obtained showed 77% sequence similarity with other snake venom thrombin-like enzymes (SVTLEs). The partial sequence obtained had the typical 12 conserved cysteine residues, as well as the active site residues (His57, Asp102 and Ser195). Functionally, erythrofibrase showed direct fibrinogenolytic activity by degrading the Aα chain of bovine fibrinogen at a slow rate, which might be responsible for causing hypofibrinogenemia and incoagulable blood for several days in envenomated patients. Moreover, the inability of Indian polyvalent antivenom (manufactured by Premium Serum Pvt. Ltd., Maharashtra, India) to neutralize the thrombin-like and plasmin-like activity of erythrofibrase can be correlated with the clinical inefficacy of antivenom therapy. This is the first study reporting an α-fibrinogenase enzyme erythrofibrase from venom, which is crucial for the pathophysiological manifestations observed in envenomated victims.
Topics: Animals; India; Trimeresurus; Crotalid Venoms; Fibrinogen; Serine Proteases; Amino Acid Sequence; Snake Bites
PubMed: 38668626
DOI: 10.3390/toxins16040201 -
Scientific Reports Apr 2024ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13, regulates the length of Von Willebrand factor (VWF) multimers and their...
ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13, regulates the length of Von Willebrand factor (VWF) multimers and their platelet-binding activity. ADAMTS13 is constitutively secreted as an active protease and is not inhibited by circulating protease inhibitors. Therefore, the mechanisms that regulate ADAMTS13 protease activity are unknown. We performed an unbiased proteomics screen to identify ligands of ADAMTS13 by optimizing the application of BioID to plasma. Plasma BioID identified 5 plasma proteins significantly labeled by the ADAMTS13-birA* fusion, including VWF and plasminogen. Glu-plasminogen, Lys-plasminogen, mini-plasminogen, and apo(a) bound ADAMTS13 with high affinity, whereas micro-plasminogen did not. None of the plasminogen variants or apo(a) bound to a C-terminal truncation variant of ADAMTS13 (MDTCS). The binding of plasminogen to ADAMTS13 was attenuated by tranexamic acid or ε-aminocaproic acid, and tranexamic acid protected ADAMTS13 from plasmin degradation. These data demonstrate that plasminogen is an important ligand of ADAMTS13 in plasma by binding to the C-terminus of ADAMTS13. Plasmin proteolytically degrades ADAMTS13 in a lysine-dependent manner, which may contribute to its regulation. Adapting BioID to identify protein-interaction networks in plasma provides a powerful new tool to study protease regulation in the cardiovascular system.
Topics: Fibrinolysin; von Willebrand Factor; ADAMTS13 Protein; ADAM Proteins; Tranexamic Acid; Ligands; Plasminogen
PubMed: 38643218
DOI: 10.1038/s41598-024-59672-6 -
PloS One 2024Our understanding of the specific aspects of vascular contributions to dementia remains unclear.
BACKGROUND
Our understanding of the specific aspects of vascular contributions to dementia remains unclear.
OBJECTIVES
We aim to identify the correlates of incident dementia in a multi-ethnic cardiovascular cohort.
METHODS
A total of 6806 participants with follow-up data for incident dementia were included. Probable dementia diagnoses were identified using hospitalization discharge diagnoses according to the International Classification of Diseases Codes (ICD). We used Random Forest analyses to identify the correlates of incident dementia and cognitive function from among 198 variables collected at the baseline MESA exam entailing demographic risk factors, medical history, anthropometry, lab biomarkers, electrocardiograms, cardiovascular magnetic resonance imaging, carotid ultrasonography, coronary artery calcium and liver fat content. Death and stroke were considered competing events.
RESULTS
Over 14 years of follow-up, 326 dementia events were identified. Beyond age, the top correlates of dementia included coronary artery calcification, high sensitivity troponin, common carotid artery intima to media thickness, NT-proBNP, physical activity, pulse pressure, tumor necrosis factor-α, history of cancer, and liver to spleen attenuation ratio from computed tomography. Correlates of cognitive function included income and physical activity, body size, serum glucose, glomerular filtration rate, measures of carotid artery stiffness, alcohol use, and inflammation indexed as IL-2 and TNF soluble receptors and plasmin-antiplasmin complex.
CONCLUSION
In a deeply phenotyped cardiovascular cohort we identified the key correlates of dementia beyond age as subclinical atherosclerosis and myocyte damage, vascular function, inflammation, physical activity, hepatic steatosis, and history of cancer.
Topics: Humans; Atherosclerosis; Coronary Artery Disease; Risk Factors; Carotid Intima-Media Thickness; Inflammation; Neoplasms; Dementia; Incidence; Cardiovascular Diseases
PubMed: 38635767
DOI: 10.1371/journal.pone.0298952 -
Graefe's Archive For Clinical and... Apr 2024To report the results of invivo generated autologous plasmin enzyme(IVAP) assisted vitrectomy, partial circumferential-oral retinotomy and silicone oil injection for...
Invivo generated autologous plasmin enzyme assisted vitrectomy, partial circumferential-oral retinotomy, silicone oil injection in patients with chronic retinal detachment without posterior vitreous detachment.
PURPOSE
To report the results of invivo generated autologous plasmin enzyme(IVAP) assisted vitrectomy, partial circumferential-oral retinotomy and silicone oil injection for surgical treatment of patients with chronic retinal detachment without posterior vitreous detachment(PVD).
METHODS
Study was performed in retrospective, comparative manner. A total of 16 consecutive eyes with chronic retinal detachment who had intravitreal injection of 50 µgr of t-PA and 0.1 ml of autologous whole blood, 3 days before surgery, underwent lens extraction with phacoemulsification, IVAP assisted vitrectomy, partial circumferential-oral retinotomy, and silicone oil injection(Study Group) were compared to a similar group of 15 eyes who had undergone vitrectomy, with or without lens extraction and silicone oil injection(Control Group) for the treatment of chronic retinal detachment. Primary outcome measures were initial retinal reattachment and number of operations at postoperative 6 months.
RESULTS
Mean age of 16 patients of whom 7 were female, was 39.31 ± 17.76 years in study group and 15 patients of whom 4 were female, was 35.40 ± 11.92 years (p = 0.607). Mean follow-up time was 10.68 ± 7.15 months in study group and 29.13 ± 18.83 months in control group (p = 0.001). Initial retinal reattachment was achieved in 87.50% (14 out of 16 patients) in the study group, whereas it was 46.66% (7 out of 15 patients) in the control group (p = 0.017). The mean number of operations for reattachment in the study group was 1.12 ± 0.34, whereas it was 1.46 ± 0.51 in the control group (p = 0.039) at postoperative 6 months While the preoperative LogMAR visual acuity was 1.25 ± 0.64, it was 0.53 ± 0.37 at postoperative 6 months in study group (p = 0.001). Conversely, in the control group, the preoperative LogMAR visual acuity was 1.22 ± 0.33, it was 1.20 ± 0.89 at postoperative 6 months (p = 0.780). At postoperative 6 months,, epiretinal membrane developed in 2 eyes of the study group, 1 eye in the control group, and phthisis bulbi occurred in 1 eye of control group.
CONCLUSION
IVAP assisted vitrectomy, partial circumferential-oral retinotomy and silicone oil injection is effective and safe for the surgical treatment of chronic retinal detachment without PVD.
PubMed: 38630302
DOI: 10.1007/s00417-024-06466-1 -
Scientific Reports Apr 2024Parkinson's disease (PD) is the second most frequently diagnosed neurodegenerative disease, and it is characterized by the intracellular and extracellular accumulation...
Parkinson's disease (PD) is the second most frequently diagnosed neurodegenerative disease, and it is characterized by the intracellular and extracellular accumulation of α-synuclein (α-syn) and Tau, which are major components of cytosolic protein inclusions called Lewy bodies, in the brain. Currently, there is a lack of effective methods that preventing PD progression. It has been suggested that the plasminogen activation system, which is a major extracellular proteolysis system, is involved in PD pathogenesis. We investigated the functional roles of plasminogen in vitro in an okadaic acid-induced Tau hyperphosphorylation NSC34 cell model, ex vivo using brains from normal controls and methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, and in vivo in a widely used MPTP-induced PD mouse model and an α-syn overexpression mouse model. The in vitro, ex vivo and in vivo results showed that the administered plasminogen crossed the blood‒brain barrier (BBB), entered cells, and migrated to the nucleus, increased plasmin activity intracellularly, bound to α-syn through lysine binding sites, significantly promoted α-syn, Tau and TDP-43 clearance intracellularly and even intranuclearly in the brain, decreased dopaminergic neurodegeneration and increased the tyrosine hydroxylase levels in the substantia nigra and striatum, and improved motor function in PD mouse models. These findings indicate that plasminogen plays a wide range of pivotal protective roles in PD and therefore may be a promising drug candidate for PD treatment.
Topics: Animals; Mice; alpha-Synuclein; Disease Models, Animal; DNA-Binding Proteins; Dopamine; Neurodegenerative Diseases; Parkinson Disease; Plasminogen; Serine Proteases; tau Proteins; Dopaminergic Neurons
PubMed: 38615036
DOI: 10.1038/s41598-024-59090-8 -
International Journal of Molecular... Mar 2024Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells...
Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells (PBMCs) are immunocompetent cells that could orchestrate cell-cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature in the bulk PBMCs of patients with IPF and the effects of anti-fibrotic drugs on these signatures. Differentially expressed genes (DEGs) between "patients with IPF and healthy controls" and "before and after anti-fibrotic treatment" were analyzed. Enrichment analysis suggested that fatty acid elongation interferes with TGF-β/Smad signaling and the production of oxidative stress since treatment with NTD upregulates the fatty acid elongation enzymes . Treatment with PFD downregulates , which produces wound-healing collagens because activated monocyte-derived macrophages participate in the production of collagen, type I, and alpha 1 during tissue damage. Plasminogen activator inhibitor-1 (PAI-1) regulates wound healing by inhibiting plasmin-mediated matrix metalloproteinase activation, and the inhibition of PAI-1 activity attenuates lung fibrosis. DEG analysis suggested that both the PFD and NTD upregulate , which regulates PAI-1 activity. This study embraces a novel approach by using RNA sequencing to examine PBMCs in IPF, potentially revealing systemic biomarkers or pathways that could be targeted for therapy.
Topics: Humans; Plasminogen Activator Inhibitor 1; Leukocytes, Mononuclear; Transcriptome; Idiopathic Pulmonary Fibrosis; Fatty Acids
PubMed: 38612561
DOI: 10.3390/ijms25073750 -
Frontiers in Oncology 2024Our earlier research revealed that the secreted lysyl oxidase-like 4 (LOXL4) that is highly elevated in triple-negative breast cancer (TNBC) acts as a catalyst to lock...
Lysyl oxidase-like 4 promotes the invasiveness of triple-negative breast cancer cells by orchestrating the invasive machinery formed by annexin A2 and S100A11 on the cell surface.
BACKGROUND
Our earlier research revealed that the secreted lysyl oxidase-like 4 (LOXL4) that is highly elevated in triple-negative breast cancer (TNBC) acts as a catalyst to lock annexin A2 on the cell membrane surface, which accelerates invasive outgrowth of the cancer through the binding of integrin-β1 on the cell surface. However, whether this machinery is subject to the LOXL4-mediated intrusive regulation remains uncertain.
METHODS
Cell invasion was assessed using a transwell-based assay, protein-protein interactions by an immunoprecipitation-Western blotting technique and immunocytochemistry, and plasmin activity in the cell membrane by gelatin zymography.
RESULTS
We revealed that cell surface annexin A2 acts as a receptor of plasminogen via interaction with S100A10, a key cell surface annexin A2-binding factor, and S100A11. We found that the cell surface annexin A2/S100A11 complex leads to mature active plasmin from bound plasminogen, which actively stimulates gelatin digestion, followed by increased invasion.
CONCLUSION
We have refined our understanding of the role of LOXL4 in TNBC cell invasion: namely, LOXL4 mediates the upregulation of annexin A2 at the cell surface, the upregulated annexin 2 binds S100A11 and S100A10, and the resulting annexin A2/S100A11 complex acts as a receptor of plasminogen, readily converting it into active-form plasmin and thereby enhancing invasion.
PubMed: 38595825
DOI: 10.3389/fonc.2024.1371342 -
Journal of Chromatography. B,... May 2024D-dimer is a protein fragment generated during the fibrin breakdown by plasmin, and it serves as a mature biomarker for diagnosing thrombotic disorders. A novel...
D-dimer is a protein fragment generated during the fibrin breakdown by plasmin, and it serves as a mature biomarker for diagnosing thrombotic disorders. A novel immunoassay method based on surface plasmon resonance (SPR) has been developed, validated, and successfully applied for the quantification of D-dimer in human plasma with high sensitivity and rapidity. In this methodological study, we investigated the activity and stability of the SPR biosensor, sample pre-processing, washing conditions, intra-day and inter-day precision and accuracy and detection parameters, including a limit of detection of 8.3 ng/mL, a detection range spanning from 31.25 to 4000 ng/mL, and a detection time of 20 min. We compared D-dimer plasma concentration determination results using SPR with a classical latex-enhanced immunoturbidimetric immunoassay in 29 healthy individuals and thrombotic patients, and both methods exhibited consistency. Furthermore, we propose a hypothesis about the relationship between the concentration of D-dimer and its molecular weight. With an increase in the D-dimer concentration in plasma, the D-dimer approaches its simplest form (190 kDa).
Topics: Female; Humans; Male; Fibrin Fibrinogen Degradation Products; Immunoassay; Limit of Detection; Linear Models; Reproducibility of Results; Surface Plasmon Resonance; Thrombosis
PubMed: 38583228
DOI: 10.1016/j.jchromb.2024.124102