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Drug Discovery and Novel Platelet Signaling in Thrombogenesis
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Drug Discovery and Novel Platelet Signaling in Thrombogenesis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 15872

Special Issue Editor

Dr. Fadi Khasawneh

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences Irma Lerma Rangel College of Pharmacy, Texas A&M University, 1010 West Avenue B, Kingsville, TX 78363-8202, USA
Interests: platelet; thrombosis; hemostasis; drug discovery; signaling; occlusive disease; cardiovascular disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiovascular disease remains the number world killer, worldwide. Despite signficant progress in understanding platelet signaling in the last decade, much remains unknown or poorly understood. Furthermore, drug discovery research has lagged far behind, with the majority of efforts focused on known/existing drug targets. Indeed, aside from drug discovery in the context of the protease-activated receptor, there has not been any new targets with drugs that have been successfully approved by the Food and Drug Administartion. This issue will focus on novel/new platelets signaling pathways or molecules that could serve as potential therapeutic targets and/or on drug discovery/rediscovery and development efforts for managing thromboembolic disorders. This Special Issue should be interest to the general readership of the journal and is expected to serve as the foundation for guiding the discovery of the next generation of antithrombotic agents.

Dr. Fadi Khasawneh
Guest Editor

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Keywords

  • platelet
  • thrombosis
  • hemostasis
  • drug discovery
  • signaling
  • occlusive disease
  • cardiovascular disease

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Published Papers (6 papers)

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Research

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14 pages, 3638 KiB  
Article
Oxidative Stress Induced by Cortisol in Human Platelets
by Maria Grazia Signorello, Silvia Ravera and Giuliana Leoncini
Int. J. Mol. Sci. 2024, 25(7), 3776; https://doi.org/10.3390/ijms25073776 - 28 Mar 2024
Cited by 1 | Viewed by 1626
Abstract
Hypercortisolism is known to affect platelet function. However, few studies have approached the effect of exogenous cortisol on human platelets, and the results obtained are conflicting and unconvincing. In this study, the effect of exogenous cortisol on several parameters indicative of oxidative status [...] Read more.
Hypercortisolism is known to affect platelet function. However, few studies have approached the effect of exogenous cortisol on human platelets, and the results obtained are conflicting and unconvincing. In this study, the effect of exogenous cortisol on several parameters indicative of oxidative status in human platelets has been analysed. We have found that cortisol stimulates ROS production, superoxide anion formation, and lipid peroxidation, with these parameters being in strict correlation. In addition, cortisol decreases GSH and membrane SH-group content, evidencing that the hormone potentiates oxidative stress, depleting platelet antioxidant defence. The involvement of src, syk, PI3K, and AKT enzymes in oxidative mechanisms induced by cortisol is shown. The main sources of ROS in cells can include uncontrolled increase of NADPH oxidase activity and uncoupled aerobic respiration during oxidative phosphorylation. Both mechanisms seem to be involved in ROS formation induced by cortisol, as the NADPH oxidase 1 inhibitor 2(trifluoromethyl)phenothiazine, and rotenone and antimycin A, complex I and III inhibitor, respectively, significantly reduce oxidative stress. On the contrary, the NADPH oxidase inhibitor gp91ds-tat, malate and NaCN, complex II and IV inhibitor, respectively, have a minor effect. It is likely that, in human platelets, oxidative stress induced by cortisol can be associated with venous and arterial thrombosis, greatly contributing to cardiovascular diseases. Full article
(This article belongs to the Special Issue Drug Discovery and Novel Platelet Signaling in Thrombogenesis)
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21 pages, 5367 KiB  
Article
Characterization of the Protein Corona of Three Chairside Hemoderivatives on Melt Electrowritten Polycaprolactone Scaffolds
by T. Fernandez-Medina, C. Vaquette, M. N. Gomez-Cerezo and S. Ivanovski
Int. J. Mol. Sci. 2023, 24(7), 6162; https://doi.org/10.3390/ijms24076162 - 24 Mar 2023
Cited by 2 | Viewed by 1765
Abstract
In tissue engineering, the relationship between a biomaterial surface and the host’s immune response during wound healing is crucial for tissue regeneration. Despite hemoderivative functionalization of biomaterials becoming a common tissue-engineering strategy for enhanced regeneration, the characteristics of the protein–biomaterial interface have not [...] Read more.
In tissue engineering, the relationship between a biomaterial surface and the host’s immune response during wound healing is crucial for tissue regeneration. Despite hemoderivative functionalization of biomaterials becoming a common tissue-engineering strategy for enhanced regeneration, the characteristics of the protein–biomaterial interface have not been fully elucidated. This study characterized the interface formed by the adsorbed proteins from various hemoderivatives with pristine and calcium phosphate (CaP)-coated polycaprolactone (PCL) melt electrowritten scaffolds. PCL scaffolds were fabricated by using melt electrospinning writing (MEW). Three hemoderivatives (pure platelet-rich plasma (P-PRP), leucocyte platelet-rich plasma (L-PRP) and injectable platelet-rich fibrin (i-PRF)) and total blood PLASMA (control) were prepared from ovine blood. Hemoderivatives were characterized via SEM/EDX, cross-linking assay, weight loss, pH and protein quantification. The interface between PCL/CaP and hemoderivative was examined via FTIR, XPS and electrophoresis. i-PRF/PCL-CaP (1653 cm−1), PLASMA/PCL-CaP (1652 cm−1) and i-PRF/PCL (1651 cm−1) demonstrated a strong signal at the Amide I region. PLASMA and i-PRF presented similar N1s spectra, with most of the nitrogen involved in N-C=O bonds (≈400 eV). i-PRF resulted in higher adsorption of low molecular weight (LMW) proteins at 60 min, while PLASMA exhibited the lowest adsorption. L-PRP and P-PRP had a similar pattern of protein adsorption. The characteristics of biomaterial interfaces can be customized, thus creating a specific hemoderivative-defined layer on the PCL surface. i-PRF demonstrated a predominant adsorption of LMW proteins. Further investigation of hemoderivative functionalized biomaterials is required to identify the differential protein corona composition, and the resultant immune response and regenerative capacity. Full article
(This article belongs to the Special Issue Drug Discovery and Novel Platelet Signaling in Thrombogenesis)
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13 pages, 2288 KiB  
Article
D121 Located within the DRY Motif of P2Y12 Is Essential for P2Y12-Mediated Platelet Function
by Carol Dangelmaier, Benjamin Mauri, Akruti Patel, Satya P. Kunapuli and John C Kostyak
Int. J. Mol. Sci. 2022, 23(19), 11519; https://doi.org/10.3390/ijms231911519 - 29 Sep 2022
Cited by 1 | Viewed by 1595
Abstract
Platelets are anucleate cells that mediate hemostasis. This occurs via a primary signal that is reinforced by secreted products such as ADP that bind purinergic receptors (P2Y1 and P2Y12) on the platelet surface. We recently identified a human subject, whom we termed platelet [...] Read more.
Platelets are anucleate cells that mediate hemostasis. This occurs via a primary signal that is reinforced by secreted products such as ADP that bind purinergic receptors (P2Y1 and P2Y12) on the platelet surface. We recently identified a human subject, whom we termed platelet defect subject 25 (PDS25) with a platelet functional disorder associated with the P2Y12 receptor. PDS25 has normal blood cell counts and no history of bleeding diathesis. However, platelets from PDS25 have virtually no response to 2-MeSADP (a stable analogue of ADP). Genetic analysis of P2Y12 from PDS25 revealed a heterozygous mutation of D121N within the DRY motif. Rap1b activity was reduced in platelets from PDS25, while VASP phosphorylation was enhanced, suggesting that signaling from the P2Y12 receptor was interrupted by the heterozygous mutation. To explore this further, we produced knock-in mice that mimic our subject. Bleeding failed to cease in homozygous KI mice during tail bleeding assays, while tail bleeding times did not differ between WT and heterozygous KI mice. Furthermore, occlusions failed to form in most homozygous KI mice following carotid artery injury via FeCl3. These data indicate that the aspartic acid residue found in the DRY motif of P2Y12 is essential for P2Y12 function. Full article
(This article belongs to the Special Issue Drug Discovery and Novel Platelet Signaling in Thrombogenesis)
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13 pages, 1763 KiB  
Article
The Antidepressant Duloxetine Inhibits Platelet Function and Protects against Thrombosis
by Patricia A. Lozano, Ahmed B. Alarabi, Sarah E. Garcia, Erica T. Boakye, Hendreta T. Kingbong, Elie Naddour, Daniel Villalobos-García, Precious Badejo, Medhat S. El-Halawany, Fadi T. Khasawneh and Fatima Z. Alshbool
Int. J. Mol. Sci. 2022, 23(5), 2587; https://doi.org/10.3390/ijms23052587 - 26 Feb 2022
Cited by 3 | Viewed by 3887
Abstract
While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million people worldwide. Interestingly, there is evidence that CVD is more prevalent in people with MDD. It is well [...] Read more.
While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million people worldwide. Interestingly, there is evidence that CVD is more prevalent in people with MDD. It is well established that neurotransmitters, namely serotonin and norepinephrine, are involved in the biochemical mechanisms of MDD, and consequently, drugs targeting serotonin-norepinephrine reuptake, such as duloxetine, are commonly prescribed for MDD. In this connection, serotonin and norepinephrine are also known to play critical roles in primary hemostasis. Based on these considerations, we investigated if duloxetine can be repurposed as an antiplatelet medication. Our results-using human and/or mouse platelets show that duloxetine dose-dependently inhibited agonist-induced platelet aggregation, compared to the vehicle control. Furthermore, it also blocked agonist-induced dense and α-granule secretion, integrin αIIbβ3 activation, phosphatidylserine expression, and clot retraction. Moreover duloxetine-treated mice had a significantly prolonged occlusion time. Finally, duloxetine was also found to impair hemostasis. Collectively, our data indicate that the antidepressant duloxetine, which is a serotonin-norepinephrine antagonist, exerts antiplatelet and thromboprotective effects and inhibits hemostasis. Consequently, duloxetine, or a rationally designed derivative, presents potential benefits in the context of CVD, including that associated with MDD. Full article
(This article belongs to the Special Issue Drug Discovery and Novel Platelet Signaling in Thrombogenesis)
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Review

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17 pages, 1876 KiB  
Review
The Novel Role of Noncoding RNAs in Modulating Platelet Function: Implications in Activation and Aggregation
by Giovanni Cimmino, Stefano Conte, Domenico Palumbo, Simona Sperlongano, Michele Torella, Alessandro Della Corte and Paolo Golino
Int. J. Mol. Sci. 2023, 24(8), 7650; https://doi.org/10.3390/ijms24087650 - 21 Apr 2023
Cited by 1 | Viewed by 3631
Abstract
It is currently believed that plaque complication, with the consequent superimposed thrombosis, is a key factor in the clinical occurrence of acute coronary syndromes (ACSs). Platelets are major players in this process. Despite the considerable progress made by the new antithrombotic strategies (P2Y12 [...] Read more.
It is currently believed that plaque complication, with the consequent superimposed thrombosis, is a key factor in the clinical occurrence of acute coronary syndromes (ACSs). Platelets are major players in this process. Despite the considerable progress made by the new antithrombotic strategies (P2Y12 receptor inhibitors, new oral anticoagulants, thrombin direct inhibitors, etc.) in terms of a reduction in major cardiovascular events, a significant number of patients with previous ACSs treated with these drugs continue to experience events, indicating that the mechanisms of platelet remain largely unknown. In the last decade, our knowledge of platelet pathophysiology has improved. It has been reported that, in response to physiological and pathological stimuli, platelet activation is accompanied by de novo protein synthesis, through a rapid and particularly well-regulated translation of resident mRNAs of megakaryocytic derivation. Although the platelets are anucleate, they indeed contain an important fraction of mRNAs that can be quickly used for protein synthesis following their activation. A better understanding of the pathophysiology of platelet activation and the interaction with the main cellular components of the vascular wall will open up new perspectives in the treatment of the majority of thrombotic disorders, such as ACSs, stroke, and peripheral artery diseases before and after the acute event. In the present review, we will discuss the novel role of noncoding RNAs in modulating platelet function, highlighting the possible implications in activation and aggregation. Full article
(This article belongs to the Special Issue Drug Discovery and Novel Platelet Signaling in Thrombogenesis)
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Other

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9 pages, 1079 KiB  
Brief Report
Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death
by Yan Zhang, Congqing Wu, Lan Li, Ankit Pandeya, Guoying Zhang, Jian Cui, Daniel Kirchhofer, Jeremy P. Wood, Susan S. Smyth, Yinan Wei and Zhenyu Li
Int. J. Mol. Sci. 2022, 23(12), 6800; https://doi.org/10.3390/ijms23126800 - 18 Jun 2022
Cited by 12 | Viewed by 2476
Abstract
Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through [...] Read more.
Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through a tissue-factor (TF)-dependent mechanism. We used a combination of various deficient mice to elucidate the molecular mechanism of histone-induced coagulation. We showed that histones trigger coagulation activation in vivo, as evidenced by coagulation parameters and fibrin deposition in tissues. However, histone-induced coagulopathy was neither dependent on intracellular inflammasome pathways involving caspase 1/11 and gasdermin D (GSDMD), nor on cell surface receptor TLR2- and TLR4-mediated host immune response, as the deficiency of these genes in mice did not protect against histone-induced coagulopathy. The incubation of histones with macrophages induced lytic cell death and phosphatidylserine (PS) exposure, which is required for TF activity, a key initiator of coagulation. The neutralization of TF diminished the histone-induced coagulation. Our findings revealed lytic cell death as a novel mechanism of histone-induced coagulation activation and thrombosis. Full article
(This article belongs to the Special Issue Drug Discovery and Novel Platelet Signaling in Thrombogenesis)
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