Figure - available from: Frontiers in Cardiovascular Medicine
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The thrombotic and thrombolytic cascades and primordial immune response. The thrombotic pathways (intrinsic and extrinsic) and the thrombolytic (fibrinolysis) pathway involve a complex cascade of protease activation. Solid arrows indicate the conversion to an active protease, while dotted line arrows indicate the activity of the activating upstream protease. A variety of inhibitors are shown, with serpin inhibitors denoted by a serpin protein structural image. Examples of early primordial immune response origins are noted in context of the pathways. MYA, million years ago.
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The making and breaking of clots orchestrated by the thrombotic and thrombolytic serine protease cascades are critical determinants of morbidity and mortality during infection and with vascular or tissue injury. Both the clot forming (thrombotic) and the clot dissolving (thrombolytic or fibrinolytic) cascades are composed of a highly sensitive and...
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The balance between proteases and protease inhibitors plays a critical role in tissue remodeling during cardiovascular diseases. Different serine protease inhibitors termed serpins, which are expressed in the cardiovascular system, can exert a fine-tuned regulation of protease activities. Among them, protease nexin-1 (PN-1, encoded by SERPINE2 ) is...
Tick saliva has been extensively studied in the context of tick-host interactions because it is involved in host homeostasis modulation and microbial pathogen transmission to the host. Accumulated knowledge about the tick saliva composition at the molecular level has revealed that serine protease inhibitors play a key role in the tick-host interact...
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... The fibrinolysis starts with converting plasminogen to its active form plasmin which solubilizes the blood clot [7]. Dysregulation of these proteases involved in the coagulation pathway leads to blood-related disorders, chronic lung disease and neurodegenerative diseases [5]. The aetiology of vascular disorders such as atherosclerosis, thrombosis, and aneurysms are also linked to protease activity [8]. ...
Thrombosis is the formation of abnormal blood clots in the blood vessels that obstruct blood flow and lead to thrombosis. Current treatments for thrombosis are associated with serious side effects. Therefore there is a need for alternative natural therapy. A fibrinolytic protease was isolated from fresh leaves of Moringa oleifera Lam. and characterized for its potential to solubilize blood clots and hydrolyse fibrin under in-vitro conditions. The isolated protease showed a single protein band on native-PAGE. It showed optimum fibrinolytic activity at pH 8.0, 37 oC with 50 µg protein. The fibrinolytic activity of isolated protease was also confirmed by fibrin zymography. Km and Vmax of isolated protease were determined by the Lineweaver Burk plot. The isolated protease could solubilize 96.41% of blood clots by 96 h under in-vitro conditions. In-vitro fibrin hydrolysis and blood clot solubilization activities shown by an isolated protease from leaves of Moringa oleifera Lam. suggest its fibrinolytic potential to dissolve blood clots. Being a natural molecule and from a dietary plant it can be explored as an alternative natural therapy against thrombosis.
... In addition to its Food and Drug Administrationapproved use for the management of HAE, C1-INH has been investigated to various degrees of therapeutic efficacy in bacterial sepsis, ischemia-reperfusion, and ongoing studies involving transplant applications for C1-INH, including hyperacute rejection and improving organ viability in transport (33,9093). Furthermore, there has long been interest in the therapeutic design of SERPINs with enhanced specificity for applications in an array of diseases where plasma proteases are implicated (32,94,95). Development of this field has primarily leveraged the archetype of SERPIN activity/function, A1AT, which has favorable drug-like properties such as ease of production, bioavailability, and, importantly, its approval for clinical use in the treatment of A1AT deficiency (53,94,96). ...
The ancient arm of innate immunity known as the complement system is a blood proteolytic cascade involving dozens of membrane-bound and solution-phase components. Although many of these components serve as regulatory molecules to facilitate controlled activation of the cascade, C1 esterase inhibitor (C1-INH) is the sole canonical complement regulator belonging to a superfamily of covalent inhibitors known as serine protease inhibitors (SERPINs). In addition to its namesake role in complement regulation, C1-INH also regulates proteases of the coagulation, fibrinolysis, and contact pathways. Despite this, the structural basis for C1-INH recognition of its target proteases has remained elusive. In this study, we present the crystal structure of the Michaelis–Menten (M-M) complex of the catalytic domain of complement component C1s and the SERPIN domain of C1-INH at a limiting resolution of 3.94 Å. Analysis of the structure revealed that nearly half of the protein/protein interface is formed by residues outside of the C1-INH reactive center loop. The contribution of these residues to the affinity of the M-M complex was validated by site-directed mutagenesis using surface plasmon resonance. Parallel analysis confirmed that C1-INH–interfacing residues on C1s surface loops distal from the active site also drive affinity of the M-M complex. Detailed structural comparisons revealed differences in substrate recognition by C1s compared with C1-INH recognition and highlight the importance of exosite interactions across broader SERPIN/protease systems. Collectively, this study improves our understanding of how C1-INH regulates the classical pathway of complement, and it sheds new light on how SERPINs recognize their cognate protease targets.
... Serine protease inhibitors (serpins) are a superfamily of highly conserved proteins that participate in a number of fundamental physiological processes, such as blood coagulation [5,6], fibrinolysis [7], inflammation [7], signaling cascades [8,9], immune responses [10,11], tumor suppression and hormone carriage [12]. In pathogens, serpins are believed to have specifically evolved to limit or modulate their host immune responses [13]. ...
... Serine protease inhibitors (serpins) are a superfamily of highly conserved proteins that participate in a number of fundamental physiological processes, such as blood coagulation [5,6], fibrinolysis [7], inflammation [7], signaling cascades [8,9], immune responses [10,11], tumor suppression and hormone carriage [12]. In pathogens, serpins are believed to have specifically evolved to limit or modulate their host immune responses [13]. ...
Serine protease inhibitors are a superfamily of proteins that regulate various physiological processes including fibrinolysis, inflammation and immune responses. In parasite systems, serpins are believed to play important roles in parasite colonization, inhibition of host immune serine proteases and penetration of defensive barriers. However, serpins are less well characterized in schistosomes. In this study, a Schistosoma mansoni serpin (Smserpin-p46) containing a 1360 base pair open reading frame, was cloned, expressed and functionally characterized. Bioinformatics analysis revealed that Smserpin-p46 contains the key residues, structural domains and motifs characteristic of inhibitory serpins. Gene expression profiling demonstrated stage-specific expression of Smserpin-p46 with the highest expression in adult male worms. Recombinant Smserpin-p46 (rSmserpin-p46) inhibited both human neutrophil cathepsin G and elastase, key serine proteases involved in NETosis, a program for the formation of neutrophil extracellular traps. Using specific rabbit antiserum, Smserpin-p46 was detected in soluble worm antigen preparation and was localized to the adult worm tegument. Cumulatively, the expression of Smserpin-p46 on the parasite tegument and its ability to inhibit proteases involved in NETosis highlights the importance of this serpin in parasite-host interactions and encourages its further investigation as a candidate vaccine antigen for the control of schistosomiasis.
... Enzymes are essential for many cellular processes in bacteria, and by inhibiting specific bacterial enzymes, it can disrupt these processes, which can lead to the inhibition of bacterial growth or other detrimental effects on the bacteria. Serine proteases is a type of enzyme which mainly cause various health problems such as inflammation, thrombosis, and bronchoconstriction [41,42]. Numerous of work on aromatic amidine compounds as inhibitors of protease enzyme have been widely studied previously [43][44][45][46]. ...
Antimicrobial resistance (AMR) is a growing and concerning threat to global public health, necessitating innovative strategies to combat this crisis. Amidine-containing compounds have emerged as promising agents in the battle against AMR. This review gives a summary of recent advances from the past decade in studies of antimicrobial amidine-containing compounds with the aim to feature their structural diversity and the pharmacological relevance of the moiety to antimicrobial activity and their potential use in combating antimicrobial resistance, to the greatest extent possible. Highlighting is put on chemical structure of such compounds in relation to antimicrobial activities such as antibacterial, antifungal, and antiparasitic activities. Researchers commonly modify molecules containing amidine or incorporate amidine into existing antimicrobial agents to enhance their pharmacological attributes and combat antimicrobial resistance. This comprehensive review consolidates the current knowledge on amidine-containing compounds, elucidating their antimicrobial mechanisms and highlighting their promise in addressing the global AMR crisis. By offering a multidisciplinary perspective, we aim to inspire further research and innovation in this critical area of antimicrobial research.
... Numerous important physiological processes rely on trypsin-like serine proteases. This includes hemostasis, the immune response system and extracellular matrix remodeling [5][6][7][8]. Dysregulation of these enzymes can lead to severe pathological incidents, which range from cardiovascular disorders to cancer progression or neurodegenerative and inflammation processes [8][9][10]. Moreover, proteases often are virulence factors in infectious diseases. ...
... This includes hemostasis, the immune response system and extracellular matrix remodeling [5][6][7][8]. Dysregulation of these enzymes can lead to severe pathological incidents, which range from cardiovascular disorders to cancer progression or neurodegenerative and inflammation processes [8][9][10]. Moreover, proteases often are virulence factors in infectious diseases. ...
... Computed physicochemical properties, absorption spectra and stability studies are depicted in Supplementary Figures S4 and S5 and Table S1. [8] 2847 ± 844 [47] 14e ...
Trypsin-like serine proteases are involved in many important physiological processes like blood coagulation and remodeling of the extracellular matrix. On the other hand, they are also associated with pathological conditions. The urokinase-pwlasminogen activator (uPA), which is involved in tissue remodeling, can increase the metastatic behavior of various cancer types when overexpressed and dysregulated. Another member of this protease class that received attention during the SARS-CoV 2 pandemic is TMPRSS2. It is a transmembrane serine protease, which enables cell entry of the coronavirus by processing its spike protein. A variety of different inhibitors have been published against both proteases. However, the selectivity over other trypsin-like serine proteases remains a major challenge. In the current study, we replaced the arginine moiety at the P1 site of peptidomimetic inhibitors with different bioisosteres. Enzyme inhibition studies revealed that the phenylguanidine moiety in the P1 site led to strong affinity for TMPRSS2, whereas the cyclohexylguanidine derivate potently inhibited uPA. Both inhibitors exhibited high selectivity over other structurally similar and physiologically important proteases.
... During the healing process, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) convert the fibrin-bound plasminogen to the active enzyme plasmin, which in turn lyses the fibrin network into a degradable form. Freely circulating t-PA and u-PA are inactivated by the plasminogen activator inhibitor (PAI) 1 and 2, and plasmin is blocked by a2 antiplasmin ( Figure 6B) (95,96). Since platelets, leukocytes, and erythrocytes circulate continuously in the blood vessels until they are needed, the B A FIGURE 6 Schematic representation of the coagulation pathways and fibrinolytic pathways. ...
Toll-like receptor 4 (TLR4) are part of the innate immune system. They are capable of recognizing pathogen-associated molecular patterns (PAMPS) of microbes, and damage-associated molecular patterns (DAMPs) of damaged tissues. Activation of TLR4 initiates downstream signaling pathways that trigger the secretion of cytokines, type I interferons, and other pro-inflammatory mediators that are necessary for an immediate immune response. However, the systemic release of pro-inflammatory proteins is a powerful driver of acute and chronic inflammatory responses. Over the past decades, immense progress has been made in clarifying the molecular and regulatory mechanisms of TLR4 signaling in inflammation. However, the most common strategies used to study TLR4 signaling rely on genetic manipulation of the TLR4 or the treatment with agonists such as lipopolysaccharide (LPS) derived from the outer membrane of Gram-negative bacteria, which are often associated with the generation of irreversible phenotypes in the target cells or unintended cytotoxicity and signaling crosstalk due to off-target or pleiotropic effects. Here, optogenetics offers an alternative strategy to control and monitor cellular signaling in an unprecedented spatiotemporally precise, dose-dependent, and non-invasive manner. This review provides an overview of the structure, function and signaling pathways of the TLR4 and its fundamental role in endothelial cells under physiological and inflammatory conditions, as well as the advances in TLR4 modulation strategies.
... The primary mechanism of haemostasis regulates bleeding which involves the formation of clots and their solubilization [5]. Active serine proteases and their regulation by inhibitors in the circulating blood form the basis for both clot-formation and clot-solubilization cascades [6]. ...
... The brinolysis starts with the conversion of plasminogen to its active form plasmin which solubilizes the blood clot [7]. Dysregulation of these proteases involved in coagulation pathway leads to blood related disorders, chronic lung disease and neurodegenerative diseases [5]. The aetiology of vascular disorders such as atherosclerosis, thrombosis, and aneurysms are also linked to protease activity [8]. ...
Thrombosis is the formation of abnormal blood clots in the blood vessels that obstruct blood flow and lead to cause thrombosis. Current treatments for thrombosis are associated with serious side effects. Therefore there is a need for alternative natural therapy. To isolate and characterize fibrinolytic protease from M.oleifera and evaluation of its fibrinolytic efficiency.
Fresh leaves of Moringa oleifera Lam were taken, fibrinolytic protease was isolated and characterized for its potential to solubilize fibrin under in-vitro conditions and its blood clot solubilization efficiency under ex-vivo experiments. The isolated protease showed a single protein band on native-PAGE. It showed optimum fibrinolytic activity at pH 8.0, 37 oC at 50µg concentration. Its fibrinolytic activity was also confirmed by fibrin zymography. Km and Vmax of isolated protease was determined by the Lineweaver Burk plot. The isolated protease could solubilize 96.41% of blood clot by 96 hrs under ex-vivo conditions. In-vitro fibrin hydrolysis and ex-vivo blood clot solubilization activities shown by isolated protease from leaves of Moringa oleifera Lam suggest its fibrinolytic potential to dissolve blood clots. Being a natural molecule and from a dietary plant it can be explored as an alternative natural therapy against thrombosis.
... The immune system response to SARS-CoV-2 reveals a different point of view on COVID-19 and fibrinolysis. Numerous inflammatory conditions are linked to the elevated circulating suPAR level [11]. ...
... Our finding was consistent with Zhang et al., who examined SERPINE treatment of severe immune-mediated lung damage in SARS-CoV-2 viral infections in mice models and found its effectiveness in preventing disease-mediated damage [29]. It is worth noting that the role of serpins and anti-PLAUR in the fibrinolysis process in COVID-19 is complex, and investigations on the potential therapeutic modulation of these processes with natural, virus-derived, or engineered serpins, expanding the consideration of these proteins beyond only regulation of the fibrinolytic system, may be a valuable pursuit as many of these modulators are already found to be safe and effective, and in some cases, FDA-approved [11]. Designing inhibitors that cross species barriers according to the species-specific residues of uPA and block uPAR-uPA interactions simultaneously would be helpful. ...
Urokinase receptors regulate the interplay between inflammation, immunity, and blood clotting. The soluble urokinase plasminogen activator system is an immunologic regulator affecting endothelial function and its related receptor; the soluble urokinase plasminogen activator receptor (suPAR) has been reported to impact kidney injury. This work aims to measure serum levels of suPAR in COVID-19 patients and correlate the measurements with variable clinicolaboratory parameters and patient outcomes. In this prospective cohort study, 150 COVID-19 patients and 50 controls were included. The circulating suPAR levels were quantified by Enzyme-linked immunosorbent assay (ELISA). Routine COVID-19 laboratory assessments, including CBC, CRP, LDH, serum creatinine, and estimated glomerular filtration rates, were performed. The need for oxygen therapy, CO-RAD score, and survival rates was assessed. Bioinformatic analysis and molecular docking were run to explore the urokinase receptor structure/function and to characterize molecules as potential anti-suPAR therapeutic targets, respectively. We found higher circulating suPAR levels in COVID-19 patients vs. controls (p < 0.001). Circulating suPAR levels positively correlated with COVID-19 severity, the need for O2 therapy, the total leukocytes count, and the neutrophils to lymphocyte ratio, while they were negatively correlated with the O2 saturation level, albumin, blood calcium, lymphocytic count, and GFR. In addition, the suPAR levels were associated with poor prognostic outcomes such as a high incidence of acute kidney injury (AKI) and mortality rate. Kaplan–Meier curves showed a lower survival rate with higher suPAR levels. The logistic regression analysis confirmed the significant association of suPAR levels with the occurrence of AKI related to COVID-19 and with increased mortality probability within three months of COVID-19 follow-up. Some compounds that can act similarly to uPAR were discovered and tested by molecular docking to identify the possible ligand–protein interactions. In conclusion, higher circulating suPAR levels were associated with COVID-19 severity and could be considered a putative predictor of AKI development and mortality.
... Specificity of fibrinolytic protease(s) of selected fungal isolates for different substrates: Coagulation cascade and fibrinolysis are complex processes and are tightly regulated by sequence of events affecting the series of receptors, inhibitors and cofactors 9,39 . There are plentiful proteins present in the blood plasma and all are vital or important for normal functioning of the living system. ...
The diseases related to the cardiovascular system significantly contribute towards global mortality. Dysregulation/malfunctioning of coagulation and fibrinolytic pathways especially under pathophysiological conditions disturbs the homeostasis and causes cardiovascular complications. Thrombosis is one such disorder wherein normal blood flow is obstructed due to an abnormal fibrin clot. Serious issues with the available therapeutics (thrombolytics) viz. fatal side effects, low specificity and efficacy and high cost, motivate the research for discovery of potentially novel, safe, efficacious and cost-effective thrombolytics. In the present study, an effectual fibrin specific fibrinolytic protease (thrombolytic) was produced from a newly isolated fungus Aspergillus flavus SH71 by using low-cost agricultural residues as substrates. Molasses as a sole carbon source and linseed cake as an exclusive nitrogen source supported the protease production of 188.99 U/mL and 215.67 U/mL respectively which were higher than that obtained in control (133.91 U/mL). Also, some other agro-based substrates (orange peel, rice bran, malt, mixed fruit brunch and soymeal) supported higher enzyme titre than control. Furthermore, a bioprocess was developed for fibrinolytic protease production by optimization of process variables i.e. concentration of molasses and linseed cake, medium pH and incubation time based on design of experiments and a substantial yield enhancement was achieved (1.97 folds).
... Under inflammatory conditions, these modulate hyaluronic acid molecules, and these further create serum-derived hyaluronan-associated proteins complex and build tunnels for the leukocytes migrating within the extracellular matrix. 29 Similar to α-2macroglobulin and antithrombin III, ITIH is assigned to proteases inhibitors. However, apart from their inflammatory contribution, ITIH 1 and 2 are also recognized for regulating implantation and placentation. ...
Kidney transplantation remains the therapeutic option for patients with end‐stage kidney disease. Current immunosuppressive regimens are efficient in combating acute kidney rejection. However, insights into chronic kidney allograft injury remains limited. Simultaneously, pregnancy is more common after kidney transplantation than during dialysis treatment. Due to ethical issues, comprehensive studies on the impact of immunosuppressive regimens on pregnancy are challenging. The study aimed to investigate the proteomic status of lymphocytes obtained from pregnant female rats under immunosuppressive treatment. The experiment involved a group of 10 female, pregnant Wistar rats, five of which were treated with tacrolimus, mofetil mycophenolate, and glucocorticosteroids; five were used as control. The lymphocytes were obtained and analyzed with mass spectrometry. Measurements were processed by a database search in the ProteinPilot software with a cutoff of 1% false discovery rate. The outcomes were verified statistically by a t‐test (p value < 0.05) regarding proteins up‐ and downregulation. A total of 2082 proteins were identified in all experiments. Eight hundred five proteins were quantified in an absolute manner in a data‐independent acquisition‐total protein approach analysis. Ninety‐five proteins were recognized as present at different concentrations in analyzed groups and were annotated to intracellular pathways. The proteins involved in nonsense‐mediated decay and L13a‐mediated translational silencing of ceruloplasmin expression were recognized as downregulated. The set of proteins clinically identified as acute phase proteins was upregulated. Despite the blockade of adaptive cellular immunity, the lymphocytes in the analyzed group reveal sustained proinflammatory status with decreased ability to regulate translation. This potentially affects pregnancy and immunity.
