Mostafa Hamada’s research while affiliated with Kansas City University and other places

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Publications (4)


Schematic of the enzymatic processing of uPA. uPA is secreted as a 411-amino-acid-long inactive protein containing growth factor, kringle, and serine protease domains. Activation of uPA occurs through a proteolytic cleavage between K158 and I159 followed by linkage of the two peptides by a disulfide bond. A second round of proteolytic cleavage between K135 and K136 results in a catalytically inactive amino terminal fragment and a catalytically active soluble low-molecular-weight serine protease. uPA—urokinase-type plasminogen activator; uPAR—uPA receptor.
Schematic of the uPA receptor (uPAR). uPAR has three domains: D1, D2, and D3. D1 binds uPA and D3 is linked by GPI to the outer cell membrane. GPI—glycophosphatidyl inositol; uPA—urokinase-type plasminogen activator.
The urokinase-type plasminogen activator receptor (uPAR) modifies intracellular and extracellular pathways. uPAR is a GPI-linked membrane protein that modifies intracellular downstream pathway responses via protein-to-protein interactions in a large lipid raft of associated membrane proteins. uPAR modifies intracellular activation through interactions with integrins and GPCRs, as illustrated here. Mammalian serpin PAI-1 binding to the uPA/uPAR complex inhibits uPA/uPAR activity and can also be internalized, further modifying and altering intracellular activity pathways. uPA/uPAR also modifies extracellular activity via activation of plasminogen to form plasmin, with subsequent activation of MMPs and growth factors that alter cellular invasion into the extracellular matrix surrounding adjacent cells. The virus-derived serpin Serp-1 also binds and inhibits uPA and the uPAR as well as plasmin. MMP—matrix metalloproteinases; GPCR—G protein-coupled receptor; PAI—plasminogen activator inhibitor; C—complement; Vn—vitronectin; GPI—glycophosphatidyl inostitol; ECM—extracellular matrix; Serp-1—virus-derived serpin.
Urokinase-Type Plasminogen Activator Receptor (uPAR) in Inflammation and Disease: A Unique Inflammatory Pathway Activator
  • Literature Review
  • Full-text available

May 2024

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65 Reads

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7 Citations

Mostafa Hamada

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Kyle Steven Varkoly

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Omer Riyadh

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[...]

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The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a 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. The uPA/uPAR complex has a multifaceted central role in both normal physiological and also pathological responses. uPAR is expressed as a glycophosphatidylinositol (GPI)-linked receptor interacting with vitronectin, integrins, G protein-coupled receptors, and growth factor receptors within a large lipid raft. Through protein-to-protein interactions, cell surface uPAR modulates intracellular signaling, altering cellular adhesion and migration. The uPA/uPAR also modifies extracellular activity, activating plasminogen to form plasmin, which breaks down fibrin, dissolving clots and activating matrix metalloproteinases that lyse connective tissue, allowing immune and cancer cell invasion and releasing growth factors. uPAR is now recognized as a biomarker for inflammatory diseases and cancer; uPAR and soluble uPAR fragments (suPAR) are increased in viral sepsis (COVID-19), inflammatory bowel disease, and metastasis. Here, we provide a comprehensive overview of the structure, function, and current studies examining uPAR and suPAR as diagnostic markers and therapeutic targets. Understanding uPAR is central to developing diagnostic markers and the ongoing development of antibody, small-molecule, nanogel, and virus-derived immune-modulating treatments that target uPAR.

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Fig. 1 Transthoracic echocardiography revealing severe pulmonic regurgitation. a Parasternal short axis of the tricuspid valve inflow tract showing severe tricuspid regurgitation by color flow doppler. b Parasternal short-axis view with broad color flow jet covering the total diameter of the right ventricular outflow tract and showing severe pulmonic regurgitation. c Continuous-wave doppler through the tricuspid valve showing a peak gradient of 93 mmHg suggesting severe pulmonary hypertension in the apical view
Fig. 2 CT scan showing severe pulmonary arterial dilatation indicative of pulmonary hypertension (a) with severe RV dilatation (b)
Surgically repaired tetralogy of Fallot in the 7th decade: a late presentation of severe pulmonic regurgitation

April 2024

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36 Reads

The Egyptian Heart Journal

Background Surgically repaired tetralogy of Fallot (TOF) is a congenital heart disease with a cumulative survival rate of 72% in the 4th decade of life in longitudinal single-cohort studies. Debate surrounds conservative versus surgical management in adults with TOF once pulmonary regurgitation occurs. Case presentation A 73-year-old male with surgically corrected TOF presented with heart failure symptoms. He underwent ToF repair with a classic right Blalock–Taussig shunt at 2 years of age with transannular patching at 18 years of age. Echocardiography revealed elevated right ventricular systolic pressures, severe right ventricular dilatation, and pulmonary regurgitation. Our patient’s new-onset right-sided heart failure was managed medically with diuresis. He received a new pulmonic valve via percutaneous approach on a later planned hospitalization with resolution of symptoms and improved tricuspid regurgitation. Conclusion It is a class I recommendation for pulmonic valve intervention once greater than moderate PR occurs; however, medical optimization should take place first. Following adequate RV load optimization, our patient underwent successful transcatheter pulmonic valve implantation with resolution of symptoms and cessation of diuretic.


Systemic Dosing of Virus-derived Serpin Improves Survival and Immunothrombotic Damage in Murine Colitis

January 2024

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58 Reads

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1 Citation

Inflammatory bowel disease (IBD) is potentially life-threatening, with risk of bleeding, clotting, infection, sepsis, cancer and toxic megacolon. Systemic and local immune and coagulation dysfunction increase IBD severity. Current treatments are partially effective, but there is no definitive cure. Ser ine p rotease cascades activate thrombotic, thrombolytic and complement pathways and are regulated by in hibitors, serpins . Viruses encode proteins evolved from endogenous central regulatory pathways. A purified secreted Myxomavirus-derived serpin, Serp-1, dosed as a systemic anti-inflammatory drug, has proven efficacy in vascular and inflammatory disorders. PEGylated Serp-1 protein (PEGSerp-1) has improved efficacy in lupus and SARS-CoV-2 models. We examined PEGSerp-1 treatment in a mouse Dextran Sodium Sulfate (DSS) colitis model. Prophylactic PEGSerp-1 significantly improved survival in acute severe 4-5% DSS colitis, reducing inflammation and crypt damage in acute 4-5% DSS induced colitis and when dosed as a chronic delayed treatment for recurrent 2% DSS colitis. PEGSerp-1 reduced iNOS ⁺ M1 macrophage invasion, damage to crypt architecture and vascular inflammation with decreased uPAR, fXa, fibrinogen and complement activation. This work supports PEGSerp-1 as a tissue targeting serpin therapeutic.


Figure 2. Immune-modulating mechanisms of myxoma poxvirus-derived serpins. Serp-1 operates predominantly extracellularly to inhibit thrombotic, thrombolytic, and complement proteases, reducing leukocyte recruitment. Serp-2 and CrmA operate predominantly intracellularly to inhibit
Cont.
Viral SERPINS—A Family of Highly Potent Immune-Modulating Therapeutic Proteins

September 2023

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69 Reads

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5 Citations

Biomolecules

Serine protease inhibitors, SERPINS, are a highly conserved family of proteins that regulate serine proteases in the central coagulation and immune pathways, representing 2–10% of circulating proteins in the blood. Serine proteases form cascades of sequentially activated enzymes that direct thrombosis (clot formation) and thrombolysis (clot dissolution), complement activation in immune responses and also programmed cell death (apoptosis). Virus-derived serpins have co-evolved with mammalian proteases and serpins, developing into highly effective inhibitors of mammalian proteolytic pathways. Through interacting with extracellular and intracellular serine and cysteine proteases, viral serpins provide a new class of highly active virus-derived coagulation-, immune-, and apoptosis-modulating drug candidates. Viral serpins have unique characteristics: (1) function at micrograms per kilogram doses; (2) selectivity in targeting sites of protease activation; (3) minimal side effects at active concentrations; and (4) the demonstrated capacity to be modified, or fine-tuned, for altered protease targeting. To date, the virus-derived serpin class of biologics has proven effective in a wide range of animal models and in one clinical trial in patients with unstable coronary disease. Here, we outline the known viral serpins and review prior studies with viral serpins, considering their potential for application as new sources for immune-, coagulation-, and apoptosis-modulating therapeutics.

Citations (2)


... The biomarker sCD14ST was suggested as a useful prognostic tool with which to predict SARS-CoV-2 outcomes in association with new-generation makers, such as SuPAR (soluble urokinase plasminogen activator receptor) [2,3]. SuPAR is a soluble molecule that can easily be measured in plasma and serum, reflecting the level of immune system activation [7,8], and recent evidence has suggested its potential role as a predictor of COVID-19 outcomes [9][10][11]. One of the challenging aspects of COVID-19 is its complex disease mechanism; COVID-19 can affect different organs, making it hard to identify biomarkers that capture the full effect of the disease [12,13]. ...

Reference:

The Evaluation of New-Generation Biomarker sCD14ST Provides New Insight into COVID-19’s Effect on Bone Remodeling
Urokinase-Type Plasminogen Activator Receptor (uPAR) in Inflammation and Disease: A Unique Inflammatory Pathway Activator

... A general and non-specific overview of complement evasion strategies employed by viruses to thwart the complement system is illustrated in Figure 2 (see reviews [19][20][21][22][23][24][25][26][27][28]), including the following. ...

Viral SERPINS—A Family of Highly Potent Immune-Modulating Therapeutic Proteins

Biomolecules