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The function of the fibrinolytic system was first identified to dissolve fibrin to maintain vascular patency. Connections between the fibrinolytic system and many other physiological and pathological processes have been well established. Dysregulation of the fibrinolytic system is closely associated with multiple pathological conditions, including thrombosis, inflammation, cancer progression, and neuropathies. Thus, molecules in the fibrinolytic system are potent therapeutic and diagnostic targets. This review summarizes the currently used agents targeting this system and the development of novel therapeutic strategies in experimental studies. Future directions for the development of modulators of the fibrinolytic system are also discussed.Fibirinolytic system: an old system as new therapeutic targetsThe fibrinolytic system was originally identified to dissolve blood clots, and is shown to have important roles in other pathological processes, including cancer progression, inflammation, and thrombosis. Molecules or therapeutics targeting fibrinolytic system have been successfully used in the clinical treatments of cancer and thrombotic diseases. The clinical studies and experimental models targeting fibrinolytic system are reviewed by Haili Lin at Sanming First Hosipital, Mingdong Huang at Fuzhou University in China, and Peng Xu at A*STAR in Singapore to demonstrate fibrinolytic system as novel therapeutic targets. As an example, the inhibition of fibrinolytic system protein can be used to suppress cancer prolifieration and metastasis. This review also discusses the potential therapeutic effects of inhibitiors of fibrinolytic system on inflammatory disorders.

Receptor dimerization of urokinase-type plasminogen activator receptor (uPAR) was previously identified at protein level and on cell surface. Recently, a dimeric form of mouse uPAR isoform 2 was proposed to induce kidney disease. Here, we report the crystal structure of human uPAR dimer at 2.96 Å. The structure reveals enormous conformational changes of the dimer compared to the monomeric structure: D1 of uPAR opens up into a large expanded ring that captures a β-hairpin loop of a neighboring uPAR to form an expanded β-sheet, leading to an elongated, highly intertwined dimeric uPAR. Based on the structure, we identify E49P as a mutation promoting dimer formation. The mutation increases receptor binding to the amino terminal fragment of its primary ligand uPA, induces the receptor to distribute to the basal membrane, promotes cell proliferation, and alters cell morphology via β1 integrin signaling. These results reveal the structural basis for uPAR dimerization, its effect on cellular functions, and provide a basis to further study this multifunctional receptor. The structural basis for urokinase-type plasminogen activator receptor (uPAR) dimerization is not understood. Here, the authors solve the crystal structure of soluble uPAR dimers, identifying substantial structural changes compared to the monomer.

Vascular thiol isomerases (VTIs) encompass proteins such as protein disulfide isomerase (PDI), endoplasmic reticulum protein 5 (ERp5), ERp46, ERp57, ERp72, thioredoxin-related transmembrane protein 1 (TMX1), and TMX4, and play pivotal functions in platelet aggregation and formation of thrombosis. Investigating vascular thiol isomerases, their substrates implicated in thrombosis, the underlying regulatory mechanisms, and the development of inhibitors targeting these enzymes represents a rapidly advancing frontier within vascular biology. In this review, we summarize the structural characteristics and functional attributes of VTIs, describe the associations between these enzymes and thrombosis, and outline the progress in developing inhibitors of VTIs for potential antithrombotic therapeutic applications.

ObjectivesThe current tooth bleaching materials are associated with adverse effect. Photodynamic method based on a novel photosensitizer alone, without combining with peroxides, is evaluated for tooth bleaching application.Materials and methodsTeeth samples were randomly divided into 3 groups with different treatment schemes, including negative control group (group A, physiological saline), experimental group (group B, ZnPc(Lys)5), and the positive control group (group C, hydrogen peroxide). Tooth color, surface microhardness, and roughness were determined at baseline, right after the first and second phase of bleaching, as well as 1 week and 1 month post-bleaching. Four samples in each group was randomly selected to evaluate the changes in surface morphology using the scanning electron microscope.ResultsThe color change values (ΔE) in group B (7.10 ± 1.03) and C (12.22 ± 2.35) were significantly higher than that in group A (0.93 ± 0.30, P < 0.05). Additionally, surface microhardness and roughness were significantly affected in group C, but not in the group A and B. Furthermore, the scanning electron microscope images showed no adverse effect of enamel in the group A and B while the group C demonstrated corrosive changes.ConclusionsZnPc(Lys)5 had a satisfactory bleaching effect and is promising to be a new type of tooth bleaching agent.Clinical relevanceThe current tooth bleaching materials give a satisfactory clinical outcome and long-term stability, but associated with some adverse reactions. Photosenstizer ZnPc(Lys)5 eliminated the main side effects observed in hydrogen peroxide-based agents on the enamel, and also had a satisfactory bleaching effect and provide a novel selective bleaching scheme for clinical use.

Photodynamic therapy (PDT) is recognized as a powerful method to inactivate cells. However, the photosensitizer (PS), a key component of PDT, has suffered from undesired photobleaching. Photobleaching reduces reactive oxygen species (ROS) yields, leading to the compromise of and even the loss of the photodynamic effect of the PS. Therefore, much effort has been devoted to minimizing photobleaching in order to ensure that there is no loss of photodynamic efficacy. Here, we report that a type of PS aggregate showed neither photobleaching nor photodynamic action. Upon direct contact with bacteria, the PS aggregate was found to fall apart into PS monomers and thus possessed photodynamic inactivation against bacteria. Interestingly, the disassembly of the bound PS aggregate in the presence of bacteria was intensified by illumination, generating more PS monomers and leading to an enhanced antibacterial photodynamic effect. This demonstrated that on a bacterial surface, the PS aggregate photo-inactivated bacteria via PS monomer during irradiation, where the photodynamic efficiency was retained without photobleaching. Further mechanistic studies showed that PS monomers disrupted bacterial membranes and affected the expression of genes related to cell wall synthesis, bacterial membrane integrity, and oxidative stress. The results obtained here are applicable to other types of PSs in PDT.

With the increasing demand for tooth bleaching in esthetic dentistry, its safety has been the focus of a comprehensive body of literature. In this context, the aim of the present study was to evaluate the application effects of pentalysine β-carbonylphthalocyanine zinc (ZnPc(Lys)5)-mediated photodynamic therapy in dentin bleaching and its effects on dentin collagen. We first established a new and reproducible tooth staining model using dentin blocks stained by Orange II and then bleached with ZnPc(Lys)5 (25 μM) and hydrogen peroxide (10% or 30%). Data were analyzed with one- and two-way ANOVA and a significance level of p < 0.05. ZnPc(Lys)5 effectively bleached the dentin samples to an extent comparable to hydrogen peroxide at either 10% or 30% concentrations. Further studies on the dentin morphology, chemical element distribution, and protein constituents, using an electron microscope, energy dispersive spectroscopy, X-ray photoelectron spectroscopy, and SDS-PAGE, demonstrated that treatment with the photosensitizer preserved the dentin structure and, at the same time, the major organic component, collagen type I. For comparison, hydrogen peroxide (10% or 30%) treatment significantly degraded the collagen protein. This work indicated that the photosensitizer exerts potent bleaching effects on dentin staining; importantly, does not damage dentin and its collagen content; and opens up a new strategy to further explore various photosensitizers for the bleaching of both tooth enamel and dentin.

Thrombosis occurs in both macrovasculature and microvasculature, causing various cardio-cerebral vascular diseases. The lack of effective and safe antithrombotic drugs leads to a public health crisis. Mounting evidence suggests that protein disulfide isomerase (PDI) plays a critical role in the initial stage of thrombus formation, motivating the research of the feasibility of PDI inhibitors as novel anti-thrombotics. Rutin, one of the most potent PDI inhibitors, was reported to suppress platelet aggregation and thrombosis in animal models, but further studies and clinical translation were restricted due to its low aqueous solubility and oral bioavailability. In this work, we fabricated rutin-loaded lipid-based nano-formulation (NanoR) and characterized their physical-chemical properties, release profiles, pharmacokinetic process, and pharmacodynamic function against thrombosis in macrovessels and microvessels. NanoR provided increased solubility and dissolution of rutin to achieve earlier T max and higher C max than the sodium salt of rutin (NaR) after oral gavage. Ex vivo studies demonstrated that NanoR significantly inhibited thrombin generation and clot formation in the plasma of mice. Importantly, such effect was reversed by exogenous recombinant PDI, demonstrating the specificity of the NanoR. In direct current-induced arterial thrombosis model and ferric chloride-induced microvascular thrombosis model, NanoR exhibited greatly enhanced antithrombotic activity compared with NaR. NanoR also showed good safety performance according to tail bleeding assay, global coagulation tests, and histological analysis. Overall, our current results indicated that NanoR offers a promising antithrombotic treatment with potential for clinical translation.

[...]the uPA/uPAR system as a therapeutic target has been proposed to reduce mortality of COVID-19 [3]; therefore, further evaluation of the active form of suPAR plasma levels in different symptom types of COVID-19 patients and asymptomatic carriers could still provide important indications for required early admission and treatment. [...]correlation analyses demonstrated that active suPAR levels are positively correlated with high-sensitivity C-reaction protein (hs-CRP), neutrophil/leukocyte ratio, and lymphocyte counts (Table 1). [...]taken together with the results from Rovina et al., these results demonstrated that the active suPAR as a COVID-19 prognostic biomarker may assist in the early triage of SARS-CoV-2-infected persons to prevent virus transmission. 4th Department of Internal Medicine, ATTIKON University Hospital, 1 Rimini Street, 12462, Athens, Greece Evangelos J. Giamarellos-Bourboulis The urokinase plasminogen activator receptor (uPAR) is an immune cell expressed GPI-linked receptor that may be cleaved from the cell surface generating soluble uPAR (suPAR). [...]our data using the suPARnostic® assays both in a large published cohort of patients [1, 7] and in a recent cohort of mild cases from Greece support that patients with asymptomatic or mild COVID-19 have lower levels of suPAR than severe cases.

The Holliday junction (HJ) is a key intermediate during homologous recombination and DNA double-strand break repair. Timely HJ resolution by resolvases is critical for maintaining genome stability. The mechanisms underlying sequence-specific substrate recognition and cleavage by resolvases remain elusive. The monokaryotic chloroplast 1 protein (MOC1) specifically cleaves four-way DNA junctions in a sequence-specific manner. Here, we report the crystal structures of MOC1 from Zea mays , alone or bound to HJ DNA. MOC1 uses a unique β-hairpin to embrace the DNA junction. A base-recognition motif specifically interacts with the junction center, inducing base flipping and pseudobase-pair formation at the strand-exchanging points. Structures of MOC1 bound to HJ and different metal ions support a two-metal ion catalysis mechanism. Further molecular dynamics simulations and biochemical analyses reveal a communication between specific substrate recognition and metal ion-dependent catalysis. Our study thus provides a mechanism for how a resolvase turns substrate specificity into catalytic efficiency. Crystal structural and biochemical analysis of the chloroplast-localized Holliday junction (HJ) resolvase MOC1 in Zea mays reveals that Zm MOC1 uses a unique β-hairpin structure and a two-metal ion catalysis mechanism to recognize and cleave HJs.

Protein disulfide isomerase (PDI) is an oxidoreductase essential for folding proteins in the endoplasmic reticulum. The domain structure of PDI is a – b – b′ – x – a′ , wherein the thioredoxin-like a and a′ domains mediate disulfide bond shuffling and b and b′ domains are substrate binding. The b′ and a′ domains are connected via the x-linker, a 19-amino-acid flexible peptide. Here we identify a class of compounds, termed bepristats, that target the substrate-binding pocket of b′ . Bepristats reversibly block substrate binding and inhibit platelet aggregation and thrombus formation in vivo . Ligation of the substrate-binding pocket by bepristats paradoxically enhances catalytic activity of a and a′ by displacing the x-linker, which acts as an allosteric switch to augment reductase activity in the catalytic domains. This substrate-driven allosteric switch is also activated by peptides and proteins and is present in other thiol isomerases. Our results demonstrate a mechanism whereby binding of a substrate to thiol isomerases enhances catalytic activity of remote domains. Protein Disulfide Isomerase (PDI) is a prothrombotic, multidomain enzyme with separate substrate binding and catalytic domains. Here, the authors identify a new class of compounds that target the PDI substrate binding site, inducing a conformational change in the catalytic domains and inhibiting thrombosis.