AAPS PharmSciTech, Год журнала: 2023, Номер 24(8)
Опубликована: Ноя. 21, 2023
Язык: Английский
Biomedicines, Год журнала: 2024, Номер 12(6), С. 1167 - 1167
Опубликована: Май 24, 2024
The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. complex has multifaceted central role both normal physiological also pathological responses. uPAR expressed glycophosphatidylinositol (GPI)-linked interacting with vitronectin, integrins, G protein-coupled receptors, growth factor receptors within large lipid raft. Through protein-to-protein interactions, cell surface modulates intracellular signaling, altering cellular adhesion migration. modifies extracellular activity, activating to form plasmin, which breaks down fibrin, dissolving clots matrix metalloproteinases that lyse connective tissue, allowing immune cancer invasion releasing factors. biomarker for inflammatory diseases cancer; soluble fragments (suPAR) are increased viral sepsis (COVID-19), bowel disease, metastasis. Here, we provide comprehensive overview the structure, function, current examining suPAR diagnostic markers therapeutic targets. Understanding developing ongoing development antibody, small-molecule, nanogel, virus-derived immune-modulating treatments target uPAR.
Язык: Английский
Процитировано
10
Cancers, Год журнала: 2022, Номер 14(3), С. 498 - 498
Опубликована: Янв. 19, 2022
Several studies have ascertained that uPA and uPAR do participate in tumor progression metastasis are involved cell adhesion, migration, invasion survival, as well angiogenesis. Increased levels of tissues, stroma biological fluids correlate with adverse clinic-pathologic features poor patient outcomes. After binding to uPAR, activates plasminogen plasmin, a broad-spectrum matrix- fibrin-degrading enzyme able facilitate dissemination distant sites. Moreover, activated by regulates most cancer activities interacting broad range membrane receptors. These findings make not only promising diagnostic prognostic markers but also attractive targets for developing anticancer therapies. In this review, we debate the uPA/uPAR structure-function relationship give an update on molecules interfere or inhibit functions. Additionally, possible clinical development these compounds is discussed.
Язык: Английский
Процитировано
36
Cancers, Год журнала: 2021, Номер 13(21), С. 5376 - 5376
Опубликована: Окт. 27, 2021
One of the largest challenges to implementation precision oncology is identifying and validating selective tumor-driving targets enhance therapeutic efficacy while limiting off-target toxicity. In this context, urokinase-type plasminogen activator receptor (uPAR) has progressively emerged as a promising target in management aggressive malignancies. By focalizing activation cascade subsequent extracellular proteolysis on cell surface migrating cells, uPAR endows malignant cells with high proteolytic migratory potential dissolve restraining matrix (ECM) barriers metastasize distant sites. also assumed choreograph multiple other neoplastic stages via complex molecular interplay distinct cancer-associated signaling pathways. Accordingly, expression observed virtually all human cancers frequently associated poor patient prognosis survival. The unveiled by pleiotropic nature prompted development targeted intervention strategies. present review will focus recently cytotoxic approaches emphasizing novel technologies related limits hindering their application clinical setting. Finally, future research directions emerging opportunities field targeting are discussed.
Язык: Английский
Процитировано
33
Universal Journal of Pharmaceutical Research, Год журнала: 2025, Номер unknown
Опубликована: Янв. 15, 2025
Background: The liver is a crucial synthesis of blood coagulation factors and anticoagulative serine proteases such as protein C(PC) antithrombin III (ATIII), which exerts key role in the regulation hemostatic balance. Activated C(APC) S complex inactivate activated factor Va VIIIa, thus limiting Xa thrombin formation. excess can drive cancer cellular proliferation cell survival through oncogenic receptor Axl. In presence heparin binding, (ATIII) form an inactive 1:1 molar ratio. ATIII also IXa, Xa, XIa XIIa at slow rate. setting diseases, this reduced dysregulation be attributed to decreased by increased consumption coagulative C ATIII. Methods: current study, using routine detection for parameters 75 patients with diseases. Results: results showed that there exist one or three PT, KPTT, TT abnormal longer. Moreover, intensity was associated severity our 20 cirrhosis, significantly plasma antigen (PC:Ag 0.5501 vs 1.0578 µ/ml) level (ATIII: Ag 21.8 39.8 mg/dl, ATIII:C 40.25 105.04%), respectively. Conclusions: measurement multidispillary analyses system are helpful monitoring diseases might play predictable marker. Peer Review History: Received 13 September 2024; Reviewed November; Accepted 26 December; Available online 15 January 2025 Academic Editor: Dr. Marwa A. Fayed, University Sadat City, Egypt, [email protected] Average review marks initial stage: 6.0/10 publication 7.0/10
Язык: Английский
Процитировано
0
Science Advances, Год журнала: 2025, Номер 11(3)
Опубликована: Янв. 17, 2025
Antibody-drug conjugates (ADCs) hold promise to advance targeted therapy of pancreatic ductal adenocarcinoma (PDAC), where the desmoplastic tumor stroma challenges effective treatment. Here, we explored urokinase plasminogen activator receptor (uPAR) as a candidate ADC target in PDAC, harnessing its massive tumoral and stromal expression this stroma-dense tumor. We generated site-specific offering high-affinity, cross-species reactivity, efficient internalization anti-uPAR monoclonal antibody, FL1, carrying potent anthracycline derivative (PNU-158692). In vitro, FL1-PNU exhibited specific cytotoxicity against uPAR-expressing PDAC cell lines, immune cells, bystander killing uPAR-negative cells. vivo, induced remission or sustained regression extended survival xenograft models. syngeneic orthotopic models, antitumor effect promoted immunomodulation by enhancing infiltrating effectors decreasing immunosuppressive This study lays grounds for further exploring putative clinical candidate, potentially providing promising therapeutic avenue monotherapy combinatorial regimens.
Язык: Английский
Процитировано
0
International Journal of Biological Macromolecules, Год журнала: 2025, Номер 303, С. 140694 - 140694
Опубликована: Фев. 4, 2025
Язык: Английский
Процитировано
0
Journal of Cardiovascular and Thoracic Research, Год журнала: 2023, Номер 15(3), С. 154 - 160
Опубликована: Сен. 23, 2023
Cardiovascular diseases are the main cause of death among type 2 diabetic patients. Higher levels plasminogen activator urokinase receptor have been found to predict morbidity and mortality across acute chronic in common populace. This study aims explore role serum as a cardiometabolic risk factor Iraqi patients.Seventy patients (40 male 30 female) (mean age: 46.20±7.56 years) participated this study; 35 were with cardiovascular disease without disease; their ages range was 40-55 years. In addition, individuals who apparently healthy selected control group.There significant increases (P<0.05) glycemic lipid profiles compared those group. The present results reveal high (2500.72±12.36 ρg/mL versus 2255.32±10.15 ρg/mL) OR=1.80, 95%CI 1.2, P=0.0001 respectively (229.00±14.48 ρg/mL).It has concluded that showed higher disease, revealed it's critical cardiac disease. Therefore, it could be considered more sensitive biomarker for detection events at high-risk.
Язык: Английский
Процитировано
6
International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(23), С. 17120 - 17120
Опубликована: Дек. 4, 2023
This comprehensive review addresses the intricate and multifaceted regulation of peptidase activity in human health disease, providing a investigation that extends well beyond boundaries active site. Our focuses on multiple mechanisms highlights important role exosites, allosteric sites, processes involved zymogen activation. These play central shaping complex world function are promising potential targets for development innovative drugs therapeutic interventions. The also briefly discusses influence glycosaminoglycans non-inhibitory binding proteins enzyme activities. Understanding their may be crucial factor strategies. By elucidating web regulatory control activity, this deepens our understanding field provides roadmap various strategies to modulate activity.
Язык: Английский
Процитировано
5
Journal of Gastrointestinal Oncology, Год журнала: 2022, Номер 13(6), С. 3100 - 3111
Опубликована: Дек. 1, 2022
Background: This paper aims to explore the effects of plasminogen activator, urokinase (PLAU) expression on migration, invasion, and proliferation colorectal cancer (CRC) cells preliminarily analyze its possible mechanism, thereby laying a foundation for research potential biological targets CRC.
Язык: Английский
Процитировано
8
Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(8), С. 5415 - 5426
Опубликована: Фев. 28, 2023
Diltiazem and glibenclamide are commonly used hypotensive antidiabetic drugs. This study reports the discovery of potential antitumor antimetastatic effects these two drugs using a structural dynamics-driven virtual screening targeting urokinase receptor (uPAR). Owing to uPAR's high flexibility, currently resolved crystal structures uPAR, all in ligand-bound states, provide limited representations its physiological conformation. To improve accuracy screening, we performed long-timescale molecular dynamics simulation obtained representative conformations apo-uPAR as targets for our screening. Experimentally, demonstrated that diltiazem bound uPAR with KD values micromolar range. In addition, both compounds effectively suppressed tumor growth metastasis uPAR-dependent manner vitro vivo. work not only provides potent inhibitors but also proof-of-concept on off-label uses glibenclamide.
Язык: Английский
Процитировано
4