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Ophthalmic Surgery, Lasers & Imaging... Dec 2023Michael T. Trese, MD (1946-2022), a vitreoretinal surgeon, made significant contributions to the field of retina. Although most known for his work in pediatric retina... (Review)
Review
Michael T. Trese, MD (1946-2022), a vitreoretinal surgeon, made significant contributions to the field of retina. Although most known for his work in pediatric retina surgery, he was a pioneer in areas such as medical retina, translational research, and telemedicine. This article reviews his major contributions to spread his knowledge more widely to vitreoretinal trainees and specialists. We discuss six areas where Trese made a lasting impact: lens-sparing vitrectomy, familial exudative vitreoretinopathy, congenital X-linked retinoschisis, autologous plasmin enzyme, regenerative medicine, and telemedicine. .
Topics: Male; Child; Humans; Fellowships and Scholarships; Retina; Familial Exudative Vitreoretinopathies; Vitreous Body; Retinoschisis; Vitrectomy
PubMed: 38113364
DOI: 10.3928/23258160-20231020-01 -
Thrombosis Research Jan 2024Growing evidence supports the importance of factor (F) XI activation for thrombosis and hemostasis as well as inflammation and complement systems. In this study, we...
INTRODUCTION
Growing evidence supports the importance of factor (F) XI activation for thrombosis and hemostasis as well as inflammation and complement systems. In this study, we evaluated the effect of activated FXI (FXIa) on the detection of factor deficiencies by global hemostasis assays of thrombin generation (TG), plasmin generation (PG), and clot formation and lysis (CFL).
MATERIALS AND METHODS
An absorbance and fluorescence microplate assay was used to simultaneously observe TG, PG, and CFL in FV-, FVII-, FVIII-, and FIX-deficient plasmas supplemented with purified factors. Coagulation was initiated with tissue factor with or without FXIa in the presence of tissue plasminogen activator. Thrombin and plasmin peak heights (TPH and PPH), maximal clot density (MCD), times to clotting (CT), thrombin and plasmin peaks (TPT and PPT) and clot lysis (LyT) and a new parameter, clot lifetime (LiT), were evaluated.
RESULTS
TG/CFL were elevated by the FXIa at low FV (below 0.1 IU/mL), and at FVIII and FIX above 0.01 IU/mL. FXIa affected PG only at low FV and FVII. At high factor concentrations, FXIa reduced MCD. Thrombin and plasmin substrates had effect on CT, LyT, LiT and MCD parameters.
CONCLUSIONS
FXIa reveals new relationships between TG, PG and CFL parameters in factor deficiencies suggesting potential benefits for discrimination of bleeding phenotypes.
Topics: Humans; Thrombin; Factor XIa; Fibrinolysin; Tissue Plasminogen Activator; Blood Coagulation Tests; Thrombosis
PubMed: 38101192
DOI: 10.1016/j.thromres.2023.11.024 -
Colloids and Surfaces. B, Biointerfaces Aug 2024Residual plasmin activity in whole ultra-instantaneous UHT (UI-UHT) milk causes rapid fat rise during storage, seriously affecting consumers' purchase intentions. In...
New insights into the destabilization of fat globules in ultra-instantaneous UHT milk induced by added plasmin: Molecular mechanisms and the effect of membrane structure on plasmin action.
Residual plasmin activity in whole ultra-instantaneous UHT (UI-UHT) milk causes rapid fat rise during storage, seriously affecting consumers' purchase intentions. In this work, the molecular mechanisms underlying fat destabilization in whole UI-UHT milk by added plasmin were investigated based on the hydrolysis behavior of interfacial proteins. By using SDS-PAGE and peptidomic analysis, we found that the hydrolysis of interfacial proteins by plasmin led to a decrease in the amount and coverage of interfacial proteins and an increase in zeta-potential value, causing the flocculation and coalescence of fat globules. Moreover, the hydrolysis pattern varied in different categories of interfacial proteins by plasmin. In total, 125 peptides in all samples were identified. Plasmin tended to hydrolyze most major milk fat globule membrane (MFGM) proteins into protein fragments (>10 kDa) rather than peptides (<10 kDa). In contrast, peptides derived from caseins were more preferentially identified within a relatively short incubation time. It was the co-hydrolysis of caseins and some major MFGM proteins as anchors that destroyed the stability of MFGM. Furthermore, studies on the effect of trilayer membrane structure remaining at the interface on the hydrolysis rate of major MFGM proteins by plasmin revealed that ADPH and BTN were very sensitive to plasmin action, while PAS 7 was very resistant to plasmin action. Overall, membrane structure reduced the susceptibility of some major MFGM proteins to plasmin and provided protective effects. Therefore, this study provided important insights into the hydrolysis behavior of interfacial proteins in whole UI-UHT milk induced by plasmin.
Topics: Fibrinolysin; Animals; Glycoproteins; Milk; Lipid Droplets; Glycolipids; Hydrolysis
PubMed: 38795586
DOI: 10.1016/j.colsurfb.2024.113987 -
Food Chemistry Dec 2023This study investigated the effect of heating (63°C/30 min or 75°C/15 s) and drying (spray-drying or freeze-drying) on plasmin, cathepsin D, and elastase activities...
This study investigated the effect of heating (63°C/30 min or 75°C/15 s) and drying (spray-drying or freeze-drying) on plasmin, cathepsin D, and elastase activities in bovine, ovine, and caprine milk, compared to non-dried raw milk counterparts. Protease activities and protein hydrolysis were assessed before and after in vitro infant digestion with or without gastric and pancreatic enzymes. At 75°C/15 s, plasmin activity in caprine and ovine milk decreased (69-75%, p<0.05), while cathepsin D activity in spray-dried bovine milk heated increased (2.8-fold, p<0.05). Plasmin and cathepsin D activities increased (<1.2-fold, p<0.05) after in vitro digestion with pancreatin, regardless of milk species. Endogenous milk enzymes hydrolyzed more proteins than gastric enzymes during gastric digestion and contributed to small intestinal digestion. In summary, milk proteases remained active after processing with effects dependent on the species of milk, and they contributed to in vitro protein hydrolysis in the stomach and small intestine.
Topics: Humans; Infant; Animals; Sheep; Goats; Milk; Ruminants; Milk Proteins; Proteolysis; Digestion; Hot Temperature; Cathepsin D
PubMed: 37506658
DOI: 10.1016/j.foodchem.2023.136979 -
Trends in Molecular Medicine May 2024Calcific aortic valve disease (CAVD) is a widely prevalent heart disorder in need of pharmacological interventions. Calcified areas in aortic valves often contain... (Review)
Review
Calcific aortic valve disease (CAVD) is a widely prevalent heart disorder in need of pharmacological interventions. Calcified areas in aortic valves often contain amyloid fibrils that promote calcification in vitro. This opinion paper suggests that amyloid contributes to CAVD development; amyloid-assisted nucleation can accelerate hydroxyapatite deposition onto collagen matrix. Notably, acidic arrays in amyloid match calcium-calcium spacing in the amorphous hydroxyapatite precursor, while oscillating hemodynamic perturbations promote amyloid deposition in the valve. Lipoprotein(a), a genetic risk factor for CAVD, augments calcification via several mechanisms, wherein hydrolysis of oxidized phospholipids (oxPLs) by Lp(a)-associated enzymes helps generate orthophosphate, and apolipoprotein(a) blocks plasmin-induced fibril degradation. Current studies of amyloid-calcium-collagen interactions in solution and in fibrillar complexes allow deeper insight into the role of amyloid in calcification.
PubMed: 38845326
DOI: 10.1016/j.molmed.2024.04.015 -
Brain : a Journal of Neurology Nov 2023Intracerebral haemorrhage is an unmet medical need affecting more than 3 million people worldwide every year and leading to the formation of an intracerebral haematoma....
Intracerebral haemorrhage is an unmet medical need affecting more than 3 million people worldwide every year and leading to the formation of an intracerebral haematoma. Updated guidelines (2022) for the management of intracerebral haemorrhage patients recognize that minimally invasive approaches for the evacuation of supratentorial intracerebral haemorrhage have demonstrated reductions in mortality compared with medical management alone. However, improvement of functional outcome with a procedure involving thrombolytic therapy was neutral in the last large phase 3 clinical trial and requires a more effective and safer thrombolytic agent than those currently available. Here, we demonstrate that O2L-001 allows for the extended release of W253R/R275S recombinant tissue-type plasminogen activator (rtPA). A new rtPA variant, called optimized tPA (OptPA), offers improved efficacy for haematoma evacuation as well as improved safety. OptPA was produced in a Chinese hamster ovary cell line before purification, nanoprecipitation using the NANOp2Lysis® technological platform followed by suspension in a solution of 17% poloxamer 407 to obtain O2L-001. Plasmin generation assays were performed to demonstrate O2L-001 safety. Ex vivo haematoma models using human blood were used to demonstrate O2L-001 thrombolysis properties and efficacy. For the best translational significance, a clinical sized haematoma was used to ensure catheter placement and to allow administration of the thrombolytic agent into the core of the haematoma via a minimally invasive procedure. The capacity of OptPA to convert plasminogen into plasmin is strongly decreased compared to rtPA, thereby reducing potential bleeding events. However, a clot lysis assay showed that OptPA had the same fibrinolytic activity as rtPA. We demonstrated that long-term exposure to a thrombolytic agent was essential to achieve high thrombolysis efficacy. Indeed, 24 h continuous exposure to 0.1 µg/ml rtPA had similar efficacy than repeated short exposure to 30 µg/ml rtPA. This finding led to the development of O2L-001, allowing the extended release of OptPA in the first 6 h following injection. An ex vivo model using human blood was used to demonstrate O2L-001 efficacy. Interestingly, unlike rtPA, O2L-001 was able to induce the complete lysis of the 5 ml haematoma. In clinical sized haematomas (obtained from 30 ml of human blood), a single injection of O2L-001 at 1 mg/ml into the core of the haematoma led to a 44% increase in thrombolysis compared to rtPA. Taken together, these results demonstrate that O2L-001 provides new hope for haematoma evacuation and the treatment of patients with intracerebral haemorrhage.
Topics: Animals; Cricetinae; Humans; Fibrinolytic Agents; Fibrinolysin; CHO Cells; Cricetulus; Tissue Plasminogen Activator; Cerebral Hemorrhage; Thrombolytic Therapy; Hematoma
PubMed: 37450572
DOI: 10.1093/brain/awad237 -
Diagnostics (Basel, Switzerland) Nov 2023Polymorphisms in the 3' untranslated region of STAT3 mRNA can derange STAT3 gene expression via modifying the microRNA-binding site. This study aimed to examine the...
Relation of STAT3 rs1053005 Variation and miR-452-3p with Osteoarthritis Susceptibility and Severity and the Clinical Response to High-Molecular-Weight Hyaluronic Acid Injection in Osteoarthritis Patients.
Polymorphisms in the 3' untranslated region of STAT3 mRNA can derange STAT3 gene expression via modifying the microRNA-binding site. This study aimed to examine the impact of STAT3 rs1053005 variation and miR-452-3p expression on osteoarthritis (OA) susceptibility and severity and the efficacy of intra-articular high-molecular-weight hyaluronic acid (HMW-HA) injection as a therapy option for knee OA. Two hundred and fifty-eight OA patients and 200 healthy controls were enrolled in the study. STAT3 genotyping and STAT3 and miR-452-3p expression were carried out using allelic-discrimination PCR and quantitative real-time PCR. Functional assessment and pain evaluation were performed for all patients. Eighty-three patients received HMW-HA injections, and multiple follow-up visits were performed. STAT3 mRNA was upregulated, and expression was positively associated with plasmin, TNF-α, MMP-3, and STAT3 serum levels, whereas miR-452-3p was downregulated and negatively associated with the previously mentioned parameters in OA patients. Osteoarthritis patients had a lower prevalence of the minor allele of the rs1053005 variant ( < 0.001). Plasmin, TNF, MMP-3, and STAT3 mRNA and protein levels were significantly decreased, and miR-452-3p expression was significantly increased in the GG genotype compared to AG and AA genotypes. HMW-HA injection improved OA patients' clinical scores with concomitant decreased STAT3 levels and enhanced expression of miR-452-3p. More efficient improvement was observed in rs1053005 AG + GG genotype carriers vs. AA genotype carriers. The G allele of STAT3 rs1053005 (A/G) polymorphism was associated with decreased OA susceptibility and severity and enhanced clinical response to HMW-HA injection, possibly via enhancing miR-452-3p binding and a subsequent decrease in STAT3 expression.
PubMed: 38066785
DOI: 10.3390/diagnostics13233544 -
Kardiologia Polska 2024Patients with transient ST-segment elevation myocardial infarction or spontaneous reperfusion, which occurs in approximately 20% of patients with ST-segment elevation... (Review)
Review
Patients with transient ST-segment elevation myocardial infarction or spontaneous reperfusion, which occurs in approximately 20% of patients with ST-segment elevation myocardial infarction (STEMI), have smaller infarcts and more favorable clinical outcomes than patients without spontaneous reperfusion. Understanding the mechanisms underlying spontaneous reperfusion is therefore important since this may identify possible novel therapeutic targets to improve outcomes in patients with STEMI. In this review, we discuss some of the possible determinants of spontaneous reperfusion including pro-thrombotic profile, endogenous fibrinolytic status, lipoprotein(a) (Lp[a]), inflammatory markers, and neutrophil extracellular traps (NETs). Effective (rapid) endogenous fibrinolysis, as assessed in whole blood in vitro, using a point-of-care technique assessment of global thrombotic status, has been strongly linked to spontaneous reperfusion. Lp(a), which has a high degree of homology to plasminogen, may impair fibrinolysis through competitive inhibition of tissue plasminogen activator-mediated plasminogen activation as well as tissue plasminogen activator-mediated clot lysis and contribute to pathogenic clot properties by decreasing fibrin clot permeation. NETs appear to negatively modulate clot lysis by increasing thrombin fiber diameter and inhibiting plasmin-driven lysis of plasma clots. There are limited data that oral anticoagulation may modulate endogenous fibrinolysis but antiplatelet agents currently appear to have no impact. Phase III trials involving subcutaneous P2Y12 or glycoprotein IIb/IIIa inhibitors, oral factor XIa inhibitors, interleukin-6 inhibitors, and apolipoprotein(a) antisense oligonucleotides in patients with cardiovascular disease are ongoing. Future studies will be needed to determine the impact of these novel antithrombotic, anti-inflammatory, and lipid-lowering therapies on endogenous fibrinolysis and spontaneous reperfusion.
Topics: Humans; ST Elevation Myocardial Infarction; Fibrinolysis; Extracellular Traps; Myocardial Reperfusion; Lipoprotein(a)
PubMed: 38493469
DOI: 10.33963/v.phj.99737 -
International Journal of Molecular... Nov 2023Synaptic dysfunction and disrupted communication between neuronal and glial cells play an essential role in the underlying mechanisms of multiple sclerosis (MS). Earlier...
Synaptic dysfunction and disrupted communication between neuronal and glial cells play an essential role in the underlying mechanisms of multiple sclerosis (MS). Earlier studies have revealed the importance of glutamate receptors, particularly the N-methyl-D-aspartate (NMDA) receptor, in excitotoxicity, leading to abnormal synaptic transmission and damage of neurons. Our study aimed to determine whether antibodies to the NR2 subunit of NMDAR are detected in MS patients and evaluate the correlation between antibody presence and clinical outcome. Furthermore, our focus extended to examine a possible link between NR2 reactivity and anti-coagulant antibody levels as pro-inflammatory molecules associated with MS. A cross-sectional study was carried out, including 95 patients with MS and 61 age- and gender-matched healthy controls (HCs). The enzyme-linked immunosorbent assay was used to detect anti-NR2 antibodies in serum samples of participants along with IgG antibodies against factor (F)VIIa, thrombin, prothrombin, FXa, and plasmin. According to our results, significantly elevated levels of anti-NR2 antibodies were detected in MS patients compared to HCs ( < 0.05), and this holds true when we compared the Relapsing-Remitting MS course with HCs ( < 0.05). A monotonically increasing correlation was found between NR2 seropositivity and advanced disability (r = 0.30; < 0.01), anti-NR2 antibodies and disease worsening (r = 0.24; < 0.05), as well as between antibody activity against NR2 and thrombin (r = 0.33; < 0.01). The presence of anti-NR2 antibodies in MS patients was less associated with anti-plasmin IgG antibodies [OR:0.96 (95%CI: 0.92-0.99); < 0.05]; however, such an association was not demonstrated when analyzing only RRMS patients. In view of our findings, NR2-reactive antibodies may play, paving the way for further research into their potential as biomarkers and therapeutic targets in MS.
Topics: Humans; Receptors, N-Methyl-D-Aspartate; Cross-Sectional Studies; Thrombin; Immunoglobulin G; Biomarkers; Autoantibodies
PubMed: 38003360
DOI: 10.3390/ijms242216170 -
Archives of Toxicology Dec 2023Occupational and environmental exposure of various toxins or cigarette smoke causes non-small cell lung carcinoma (NSCLC); a devastating disease with a very low survival...
Occupational and environmental exposure of various toxins or cigarette smoke causes non-small cell lung carcinoma (NSCLC); a devastating disease with a very low survival rate after metastasis. Increased activity of plasmin is a hallmark in NSCLC metastasis. It is accepted that metastatic cells exhibit higher plasmin activity than cells from primary tumors. Mechanisms behind this elevation, however, are barely understood. We compared plasmin activity and cell migration of A549 cells derived from a primary lung tumor with metastatic H1299 lung cells isolated from lymph nodes. Surprisingly, we found higher plasmin activity and migration for A549 cells. mRNA levels of the plasminogen activator inhibitor-1 (PAI-1) were higher in H1299 cells and activity of extracellular-regulated kinases-1/2 (ERK-1/2) was increased. An inhibitor of ERK-1/2 decreased PAI-1 mRNA levels and increased plasmin activity or cell migration in H1299 cells. Transforming growth factor-β (TGF-β) decreased plasmin activity and migration in A549 cells but enhanced both in H1299 cells. The cytokine massively increased PAI-1 and decreased urokinase plasminogen activator (uPA) levels in A549 cells but strongly induced uPA and only weakly PAI- 1 expression in H1299 cells. Consequently, TGF-β enhanced plasmin activity and cell migration in H1299. Additionally, TGF-β activated ERK-1/2 stronger in H1299 than in A549 cells. Accordingly, an ERK-1/2 inhibitor completely reversed the effects of TGF-β on uPA expression, plasmin activity and migration in H1299 cells. Hence, we provide first data indicating TGF-β-promoted increased plasmin activity and suggest that blocking TGF-β-promoted ERK-1/2 activity might be a straightforward approach to inhibit NSCLC metastasis.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Plasminogen Activator Inhibitor 1; Fibrinolysin; Urokinase-Type Plasminogen Activator; Lung Neoplasms; Cell Movement; RNA, Messenger; Transforming Growth Factor beta
PubMed: 37712947
DOI: 10.1007/s00204-023-03600-6