International Journal of Molecular Sciences

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Open AccessEditorial

Molecular Research on Platelet Activity in Health and Disease 2.0

by Maria Valeria Catani, Isabella Savini, Valentina Tullio and Valeria Gasperi

Int. J. Mol. Sci. 2021, 22(9), 4968; https://doi.org/10.3390/ijms22094968 - 7 May 2021

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Abstract

Hsia and collaborators [...] Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

Research

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17 pages, 2384 KiB

Open AccessArticle

Plasmin-Induced Activation of Human Platelets Is Modulated by Thrombospondin-1, Bona Fide Misfolded Proteins and Thiol Isomerases

by Claudia Pielsticker, Martin F. Brodde, Lisa Raum, Kerstin Jurk and Beate E. Kehrel

Int. J. Mol. Sci. 2020, 21(22), 8851; https://doi.org/10.3390/ijms21228851 - 23 Nov 2020

Cited by 4 | Viewed by 2197

Abstract

Inflammatory processes are triggered by the fibrinolytic enzyme plasmin. Tissue-type plasminogen activator, which cleaves plasminogen to plasmin, can be activated by the cross-β-structure of misfolded proteins. Misfolded protein aggregates also represent substrates for plasmin, promoting their degradation, and are potent platelet agonists. However, [...] Read more.

Inflammatory processes are triggered by the fibrinolytic enzyme plasmin. Tissue-type plasminogen activator, which cleaves plasminogen to plasmin, can be activated by the cross-β-structure of misfolded proteins. Misfolded protein aggregates also represent substrates for plasmin, promoting their degradation, and are potent platelet agonists. However, the regulation of plasmin-mediated platelet activation by misfolded proteins and vice versa is incompletely understood. In this study, we hypothesize that plasmin acts as potent agonist of human platelets in vitro after short-term incubation at room temperature, and that the response to thrombospondin-1 and the bona fide misfolded proteins Eap and SCN⁻-denatured IgG interfere with plasmin, thereby modulating platelet activation. Plasmin dose-dependently induced CD62P surface expression on, and binding of fibrinogen to, human platelets in the absence/presence of plasma and in citrated whole blood, as analyzed by flow cytometry. Thrombospondin-1 pre-incubated with plasmin enhanced these plasmin-induced platelet responses at low concentration and diminished them at higher dose. Platelet fibrinogen binding was dose-dependently induced by the C-terminal thrombospondin-1 peptide RFYVVMWK, Eap or NaSCN-treated IgG, but diminished in the presence of plasmin. Blocking enzymatically catalyzed thiol-isomerization decreased plasmin-induced platelet responses, suggesting that plasmin activates platelets in a thiol-dependent manner. Thrombospondin-1, depending on the concentration, may act as cofactor or inhibitor of plasmin-induced platelet activation, and plasmin blocks platelet activation induced by misfolded proteins and vice versa, which might be of clinical relevance. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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13 pages, 2286 KiB

Open AccessArticle

Cyclin Y Is Expressed in Platelets and Modulates Integrin Outside-in Signaling

by Anastasia Kyselova, Mauro Siragusa, Julian Anthes, Fiorella Andrea Solari, Stefan Loroch, René P. Zahedi, Ulrich Walter, Ingrid Fleming and Voahanginirina Randriamboavonjy

Int. J. Mol. Sci. 2020, 21(21), 8239; https://doi.org/10.3390/ijms21218239 - 3 Nov 2020

Cited by 4 | Viewed by 2471

Abstract

Diabetes is associated with platelet hyper-reactivity and enhanced risk of thrombosis development. Here we compared protein expression in platelets from healthy donors and diabetic patients to identify differentially expressed proteins and their possible function in platelet activation. Mass spectrometry analyses identified cyclin Y [...] Read more.

Diabetes is associated with platelet hyper-reactivity and enhanced risk of thrombosis development. Here we compared protein expression in platelets from healthy donors and diabetic patients to identify differentially expressed proteins and their possible function in platelet activation. Mass spectrometry analyses identified cyclin Y (CCNY) in platelets and its reduced expression in platelets from diabetic patients, a phenomenon that could be attributed to the increased activity of calpains. To determine the role of CCNY in platelets, mice globally lacking the protein were studied. CCNY^-/- mice demonstrated lower numbers of circulating platelets but platelet responsiveness to thrombin and a thromboxane A₂ analogue were comparable with that of wild-type mice, as was agonist-induced α and dense granule secretion. CCNY-deficient platelets demonstrated enhanced adhesion to fibronectin and collagen as well as an attenuated spreading and clot retraction, indicating an alteration in “outside in” integrin signalling. This phenotype was accompanied by a significant reduction in the agonist-induced tyrosine phosphorylation of β3 integrin. Taken together we have shown that CCNY is present in anucleated platelets where it is involved in the regulation of integrin-mediated outside in signalling associated with thrombin stimulation. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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15 pages, 5846 KiB

Open AccessArticle

Extracellular Matrix-Specific Platelet Activation Leads to a Differential Translational Response and Protein De Novo Synthesis in Human Platelets

by Bjoern F. Kraemer, Marc Geimer, Mirita Franz-Wachtel, Tobias Lamkemeyer, Hanna Mannell and Stephan Lindemann

Int. J. Mol. Sci. 2020, 21(21), 8155; https://doi.org/10.3390/ijms21218155 - 31 Oct 2020

Cited by 7 | Viewed by 2252

Abstract

Platelets are exposed to extracellular matrix (ECM) proteins like collagen and laminin and to fibrinogen during acute vascular events. However, beyond hemostasis, platelets have the important capacity to migrate on ECM surfaces, but the translational response of platelets to different extracellular matrix stimuli [...] Read more.

Platelets are exposed to extracellular matrix (ECM) proteins like collagen and laminin and to fibrinogen during acute vascular events. However, beyond hemostasis, platelets have the important capacity to migrate on ECM surfaces, but the translational response of platelets to different extracellular matrix stimuli is still not fully characterized. Using 2D-gel electrophoresis, confocal microscopy, polysome analysis and protein sequencing by mass spectrometry, we demonstrate that platelets show a differential expression profile of newly synthesized proteins on laminin, collagen or fibrinogen. In this context, we observed a characteristic, ECM-dependent translocation phenotype of translation initiation factor eIF4E to the ribosomal site. eIF4E accumulated in polysomes with increased binding of mRNA and co-localization with vinculin, leading to de novo synthesis of important cytoskeletal regulator proteins. As the first study, we included a proteome analysis of laminin-adherent platelets and interestingly identified upregulation of essentially important proteins that mediate cytoskeletal regulation and mobility in platelets, such as filamin A, talin, vinculin, gelsolin, coronin or kindlin-3. In summary, we demonstrate that platelet activation with extracellular matrix proteins results in a distinct stimulus-specific translational response of platelets that will help to improve our understanding of the regulation of platelet mobility and migration. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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15 pages, 2226 KiB

Open AccessArticle

Cholesterol-Rich Microdomains Contribute to PAR1 Signaling in Platelets Despite a Weak Localization of the Receptor in These Microdomains

by Vahideh Rabani, Jennifer Lagoutte-Renosi, Jennifer Series, Benoit Valot, Jean-Marie Xuereb and Siamak Davani

Int. J. Mol. Sci. 2020, 21(21), 8065; https://doi.org/10.3390/ijms21218065 - 29 Oct 2020

Cited by 3 | Viewed by 2209

Abstract

Platelet protease-activated receptor 1 (PAR1) is a cell surface G-protein-coupled receptor (GPCR) that acts as a thrombin receptor promoting platelet aggregation. Targeting the PAR1 pathway by vorapaxar, a PAR1 antagonist, leads to a reduction in ischemic events in cardiovascular patients with a history [...] Read more.

Platelet protease-activated receptor 1 (PAR1) is a cell surface G-protein-coupled receptor (GPCR) that acts as a thrombin receptor promoting platelet aggregation. Targeting the PAR1 pathway by vorapaxar, a PAR1 antagonist, leads to a reduction in ischemic events in cardiovascular patients with a history of myocardial infarction or with peripheral arterial disease. In platelets, specialized microdomains highly enriched in cholesterol act as modulators of the activity of several GPCRs and play a pivotal role in the signaling pathway. However, their involvement in platelet PAR1 function remains incompletely characterized. In this context, we aimed to investigate whether activation of PAR1 in human platelets requires its localization in the membrane cholesterol-rich microdomains. Using confocal microscopy, biochemical isolation, and proteomics approaches, we found that PAR1 was not localized in cholesterol-rich microdomains in resting platelets, and only a small fraction of the receptor relocated to the microdomains following its activation. Vorapaxar treatment increased the level of PAR1 at the platelet surface, possibly by reducing its endocytosis, while its colocalization with cholesterol-rich microdomains remained weak. Consistent with a cholesterol-dependent activation of Akt and p38 MAP kinase in thrombin receptor-activating peptide (TRAP)-activated platelets, the proteomic data of cholesterol-rich microdomains isolated from TRAP-activated platelets showed the recruitment of proteins contributing to these signaling pathways. In conclusion, contrary to endothelial cells, we found that PAR1 was only weakly present in cholesterol-rich microdomains in human platelets but used these microdomains for efficient activation of downstream signaling pathways following TRAP activation. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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23 pages, 1351 KiB

Open AccessArticle

Increased Pro-Thrombotic Platelet Activity Associated with Thrombin/PAR1-Dependent Pathway Disorder in Patients with Secondary Progressive Multiple Sclerosis

by Angela Dziedzic, Elzbieta Miller, Michal Bijak, Lukasz Przyslo and Joanna Saluk-Bijak

Int. J. Mol. Sci. 2020, 21(20), 7722; https://doi.org/10.3390/ijms21207722 - 19 Oct 2020

Cited by 13 | Viewed by 2950

Abstract

Epidemiological studies confirm the high risk of ischemic events in multiple sclerosis (MS) that are associated with increased pro-thrombotic activity of blood platelets. The most potent physiological platelet agonist is thrombin, which activates platelets via cleavage of specific protease-activated receptors (PARs). Our current [...] Read more.

Epidemiological studies confirm the high risk of ischemic events in multiple sclerosis (MS) that are associated with increased pro-thrombotic activity of blood platelets. The most potent physiological platelet agonist is thrombin, which activates platelets via cleavage of specific protease-activated receptors (PARs). Our current study is aimed to determine the potential genetics and proteomic abnormalities of PAR1 in both platelets and megakaryocytes, which may have thromboembolic consequences in the course of MS. The obtained results were correlated with the expression level of platelet and megakaryocyte transcripts for APOA1 and A2M genes encoding atherosclerosis biomarkers: apolipoprotein A1 (ApoA1) and α-2-macroglobulin (α2M), respectively. Moreover, PAR1 functionality in MS platelets was assessed by flow cytometry, determining the level of platelet–platelet and platelet–leukocyte aggregates, platelet microparticles and surface expression of P-selectin. As a PAR1 agonist, the synthetic TRAP-6 peptide was used, which made it possible to achieve platelet activation in whole blood without triggering clotting. Comparative analyses showed an elevated level of platelet activation markers in the blood of MS patients compared to controls. The mRNA expression of gene coding α2M was upregulated, whilst ApoA1 was down-regulated, both in platelets and megakaryocytes from MS patients. Furthermore, we observed an increase in both mRNA expression and surface density of PAR1 in platelets and megakaryocytes in MS compared to controls. Both the level of platelet activation markers and PAR1 expression showed a high correlation with the expression of transcripts for APOA1 and A2M genes. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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17 pages, 4429 KiB

Open AccessArticle

PAK1 Regulates MEC-17 Acetyltransferase Activity and Microtubule Acetylation during Proplatelet Extension

by Juliette van Dijk, Guillaume Bompard, Gabriel Rabeharivelo, Julien Cau, Claude Delsert and Nathalie Morin

Int. J. Mol. Sci. 2020, 21(20), 7531; https://doi.org/10.3390/ijms21207531 - 13 Oct 2020

Cited by 7 | Viewed by 2865

Abstract

Mature megakaryocytes extend long processes called proplatelets from which platelets are released in the blood stream. The Rho GTPases Cdc42 and Rac as well as their downstream target, p21-activated kinase 2 (PAK2), have been demonstrated to be important for platelet formation. Here we [...] Read more.

Mature megakaryocytes extend long processes called proplatelets from which platelets are released in the blood stream. The Rho GTPases Cdc42 and Rac as well as their downstream target, p21-activated kinase 2 (PAK2), have been demonstrated to be important for platelet formation. Here we address the role, during platelet formation, of PAK1, another target of the Rho GTPases. PAK1 decorates the bundled microtubules (MTs) of megakaryocyte proplatelets. Using a validated cell model which recapitulates proplatelet formation, elongation and platelet release, we show that lack of PAK1 activity increases the number of proplatelets but restrains their elongation. Moreover, in the absence of PAK1 activity, cells have hyperacetylated MTs and lose their MT network integrity. Using inhibitors of the tubulin deacetylase HDAC6, we demonstrate that abnormally high levels of MT acetylation are not sufficient to increase the number of proplatelets but cause loss of MT integrity. Taken together with our previous demonstration that MT acetylation is required for proplatelet formation, our data reveal that MT acetylation levels need to be tightly regulated during proplatelet formation. We identify PAK1 as a direct regulator of the MT acetylation levels during this process as we found that PAK1 phosphorylates the MT acetyltransferase MEC-17 and inhibits its activity. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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17 pages, 4212 KiB

Open AccessArticle

Platelets Boost Recruitment of CD133⁺ Bone Marrow Stem Cells to Endothelium and the Rodent Liver—The Role of P-Selectin/PSGL-1 Interactions

by Nadja Lehwald, Constanze Duhme, Iryna Pinchuk, Julian Kirchner, Kristina Wieferich, Moritz Schmelzle, Kerstin Jurk, Beatrice A. Windmöller, Wolfgang Hübner, Bernhard Homey, Johannes Bode, Ralf Kubitz, Tahar Benhidjeb, Martin Krüger, Simon C. Robson, Wolfram T. Knoefel, Beate E. Kehrel and Jan Schulte am Esch

Int. J. Mol. Sci. 2020, 21(17), 6431; https://doi.org/10.3390/ijms21176431 - 3 Sep 2020

Cited by 6 | Viewed by 3844

Abstract

We previously demonstrated that clinical administration of mobilized CD133⁺ bone marrow stem cells (BMSC) accelerates hepatic regeneration. Here, we investigated the potential of platelets to modulate CD133⁺BMSC homing to hepatic endothelial cells and sequestration to warm ischemic livers. Modulatory effects [...] Read more.

We previously demonstrated that clinical administration of mobilized CD133⁺ bone marrow stem cells (BMSC) accelerates hepatic regeneration. Here, we investigated the potential of platelets to modulate CD133⁺BMSC homing to hepatic endothelial cells and sequestration to warm ischemic livers. Modulatory effects of platelets on the adhesion of CD133⁺BMSC to human and mouse liver-sinusoidal- and micro- endothelial cells (EC) respectively were evaluated in in vitro co-culture systems. CD133⁺BMSC adhesion to all types of EC were increased in the presence of platelets under shear stress. This platelet effect was mostly diminished by antagonization of P-selectin and its ligand P-Selectin-Glyco-Ligand-1 (PSGL-1). Inhibition of PECAM-1 as well as SDF-1 receptor CXCR4 had no such effect. In a model of the isolated reperfused rat liver subsequent to warm ischemia, the co-infusion of platelets augmented CD133⁺BMSC homing to the injured liver with heightened transmigration towards the extra sinusoidal space when compared to perfusion conditions without platelets. Extravascular co-localization of CD133⁺BMSC with hepatocytes was confirmed by confocal microscopy. We demonstrated an enhancing effect of platelets on CD133⁺BMSC homing to and transmigrating along hepatic EC putatively depending on PSGL-1 and P-selectin. Our insights suggest a new mechanism of platelets to augment stem cell dependent hepatic repair. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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10 pages, 2348 KiB

Open AccessArticle

Rocuronium Has a Suppressive Effect on Platelet Function via the P2Y12 Receptor Pathway In Vitro That Is Not Reversed by Sugammadex

by Yutaka Murata, Shuji Kawamoto and Kazuhiko Fukuda

Int. J. Mol. Sci. 2020, 21(17), 6399; https://doi.org/10.3390/ijms21176399 - 3 Sep 2020

Cited by 3 | Viewed by 3685

Abstract

Rocuronium is an aminosteroid nondepolarizing neuromuscular blocker that is widely used for anesthesia and intensive care. In this study, we investigated the effect of rocuronium on human platelet functions in vitro. The effects of rocuronium on platelet aggregation, P-selectin expression, and cyclic adenosine [...] Read more.

Rocuronium is an aminosteroid nondepolarizing neuromuscular blocker that is widely used for anesthesia and intensive care. In this study, we investigated the effect of rocuronium on human platelet functions in vitro. The effects of rocuronium on platelet aggregation, P-selectin expression, and cyclic adenosine monophosphate (cAMP) levels in platelets were measured using an aggregometer, an enzyme immunoassay, and flow cytometry, respectively. Rocuronium inhibited ADP-induced platelet aggregation, P-selectin expression and suppression of cAMP production. These effects were not antagonized by equimolar sugammadex, a synthetic γ-cyclodextrin derivative that antagonizes rocuronium-induced muscle relaxation by encapsulating the rocuronium molecule. Morpholine, which constitutes a part of the rocuronium molecule but is not encapsulated by sugammadex, inhibited ADP-induced platelet aggregation. Vecuronium, which has a molecular structure similar to that of rocuronium but does not possess a morpholine ring, had no significant effect on ADP-induced platelet aggregation. These results indicate that rocuronium has a suppressive effect on platelet functions in vitro that is not reversed by sugammadex and suggest that this effect is mediated by blockade of the P2Y12 receptor signaling pathway via the morpholine ring of rocuronium. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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16 pages, 2995 KiB

Open AccessArticle

Platelet Lysate Induces in Human Osteoblasts Resumption of Cell Proliferation and Activation of Pathways Relevant for Revascularization and Regeneration of Damaged Bone

by Van Thi Nguyen, Marta Nardini, Alessandra Ruggiu, Ranieri Cancedda, Fiorella Descalzi and Maddalena Mastrogiacomo

Int. J. Mol. Sci. 2020, 21(14), 5123; https://doi.org/10.3390/ijms21145123 - 20 Jul 2020

Cited by 11 | Viewed by 2882

Abstract

To understand the regenerative effect of platelet-released molecules in bone repair one should investigate the cascade of events involving the resident osteoblast population during the reconstructive process. Here the in vitro response of human osteoblasts to a platelet lysate (PL) stimulus is reported. [...] Read more.

To understand the regenerative effect of platelet-released molecules in bone repair one should investigate the cascade of events involving the resident osteoblast population during the reconstructive process. Here the in vitro response of human osteoblasts to a platelet lysate (PL) stimulus is reported. Quiescent or very slow dividing osteoblasts showed a burst of proliferation after PL stimulation and returned to a none or very slow dividing condition when the PL was removed. PL stimulated osteoblasts maintained a differentiation capability in vitro and in vivo when tested in absence of PL. Since angiogenesis plays a crucial role in the bone healing process, we investigated in PL stimulated osteoblasts the activation of hypoxia-inducible factor 1-alpha (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) pathways, involved in both angiogenesis and bone regeneration. We observed phosphorylation of STAT3 and a strong induction, nuclear translocation and DNA binding of HIF-1α. In agreement with the induction of HIF-1α an enhanced secretion of vascular endothelial growth factor (VEGF) occurred. The double effect of the PL on quiescent osteoblasts, i.e., resumption of proliferation and activation of pathways promoting both angiogenesis and bone formation, provides a rationale to the application of PL as therapeutic agent in post-traumatic bone repair. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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14 pages, 5278 KiB

Open AccessArticle

Regulation of Human Platelet Activation and Prevention of Arterial Thrombosis in Mice by Auraptene through Inhibition of NF-κB Pathway

by Chih-Wei Hsia, Ming-Ping Wu, Ming-Yi Shen, Chih-Hsuan Hsia, Chi-Li Chung and Joen-Rong Sheu

Int. J. Mol. Sci. 2020, 21(13), 4810; https://doi.org/10.3390/ijms21134810 - 7 Jul 2020

Cited by 9 | Viewed by 2898

Abstract

Platelets are major players in the occurrence of cardiovascular diseases. Auraptene is the most abundant coumarin derivative from plants, and it has been demonstrated to possess a potent capacity to inhibit platelet activation. Although platelets are anucleated cells, they also express the transcription [...] Read more.

Platelets are major players in the occurrence of cardiovascular diseases. Auraptene is the most abundant coumarin derivative from plants, and it has been demonstrated to possess a potent capacity to inhibit platelet activation. Although platelets are anucleated cells, they also express the transcription factor, nuclear factor-κB (NF-κB), that may exert non-genomic functions in platelet activation. In the current study, we further investigated the inhibitory roles of auraptene in NF-κB-mediated signal events in platelets. MG-132 (an inhibitor of proteasome) and BAY11-7082 (an inhibitor of IκB kinase; IKK), obviously inhibited platelet aggregation; however, BAY11-7082 exhibited more potent activity than MG-132 in this reaction. The existence of NF-κB (p65) in platelets was observed by confocal microscopy, and auraptene attenuated NF-κB activation such as IκBα and p65 phosphorylation and reversed IκBα degradation in collagen-activated platelets. To investigate cellular signaling events between PLCγ2-PKC and NF-κB, we found that BAY11-7082 abolished PLCγ2-PKC activation; nevertheless, neither U73122 nor Ro31-8220 had effect on NF-κB activation. Furthermore, both auraptene and BAY11-7082 significantly diminished HO• formation in activated platelets. For in vivo study, auraptene prolonged the occlusion time of platelet plug in mice. In conclusion, we propose a novel inhibitory pathway of NF-κB-mediated PLCγ2-PKC activation by auraptene in human platelets, and further supported that auraptene possesses potent activity for thromboembolic diseases. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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Review

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31 pages, 1053 KiB

Open AccessReview

Multifaceted Functions of Platelets in Cancer: From Tumorigenesis to Liquid Biopsy Tool and Drug Delivery System

by Melania Dovizio, Patrizia Ballerini, Rosa Fullone, Stefania Tacconelli, Annalisa Contursi and Paola Patrignani

Int. J. Mol. Sci. 2020, 21(24), 9585; https://doi.org/10.3390/ijms21249585 - 16 Dec 2020

Cited by 38 | Viewed by 4810

Abstract

Platelets contribute to several types of cancer through plenty of mechanisms. Upon activation, platelets release many molecules, including growth and angiogenic factors, lipids, and extracellular vesicles, and activate numerous cell types, including vascular and immune cells, fibroblasts, and cancer cells. Hence, platelets are [...] Read more.

Platelets contribute to several types of cancer through plenty of mechanisms. Upon activation, platelets release many molecules, including growth and angiogenic factors, lipids, and extracellular vesicles, and activate numerous cell types, including vascular and immune cells, fibroblasts, and cancer cells. Hence, platelets are a crucial component of cell–cell communication. In particular, their interaction with cancer cells can enhance their malignancy and facilitate the invasion and colonization of distant organs. These findings suggest the use of antiplatelet agents to restrain cancer development and progression. Another peculiarity of platelets is their capability to uptake proteins and transcripts from the circulation. Thus, cancer-patient platelets show specific proteomic and transcriptomic expression patterns, a phenomenon called tumor-educated platelets (TEP). The transcriptomic/proteomic profile of platelets can provide information for the early detection of cancer and disease monitoring. Platelet ability to interact with tumor cells and transfer their molecular cargo has been exploited to design platelet-mediated drug delivery systems to enhance the efficacy and reduce toxicity often associated with traditional chemotherapy. Platelets are extraordinary cells with many functions whose exploitation will improve cancer diagnosis and treatment. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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20 pages, 3013 KiB

Open AccessReview

Effect of Prostanoids on Human Platelet Function: An Overview

by Steffen Braune, Jan-Heiner Küpper and Friedrich Jung

Int. J. Mol. Sci. 2020, 21(23), 9020; https://doi.org/10.3390/ijms21239020 - 27 Nov 2020

Cited by 71 | Viewed by 6280

Abstract

Prostanoids are bioactive lipid mediators and take part in many physiological and pathophysiological processes in practically every organ, tissue and cell, including the vascular, renal, gastrointestinal and reproductive systems. In this review, we focus on their influence on platelets, which are key elements [...] Read more.

Prostanoids are bioactive lipid mediators and take part in many physiological and pathophysiological processes in practically every organ, tissue and cell, including the vascular, renal, gastrointestinal and reproductive systems. In this review, we focus on their influence on platelets, which are key elements in thrombosis and hemostasis. The function of platelets is influenced by mediators in the blood and the vascular wall. Activated platelets aggregate and release bioactive substances, thereby activating further neighbored platelets, which finally can lead to the formation of thrombi. Prostanoids regulate the function of blood platelets by both activating or inhibiting and so are involved in hemostasis. Each prostanoid has a unique activity profile and, thus, a specific profile of action. This article reviews the effects of the following prostanoids: prostaglandin-D₂ (PGD₂), prostaglandin-E₁, -E₂ and E₃ (PGE₁, PGE₂, PGE₃), prostaglandin F_2α (PGF_2α), prostacyclin (PGI₂) and thromboxane-A₂ (TXA₂) on platelet activation and aggregation via their respective receptors. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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19 pages, 3415 KiB

Open AccessReview

Platelets, Thrombocytosis, and Ovarian Cancer Prognosis: Surveying the Landscape of the Literature

by Demetra H. Hufnagel, Gabriella D. Cozzi, Marta A. Crispens and Alicia Beeghly-Fadiel

Int. J. Mol. Sci. 2020, 21(21), 8169; https://doi.org/10.3390/ijms21218169 - 31 Oct 2020

Cited by 41 | Viewed by 3697

Abstract

Platelets are critical components of a number of physiologic processes, including tissue remodeling after injury, wound healing, and maintenance of vascular integrity. Increasing evidence suggests that platelets may also play important roles in cancer. In ovarian cancer, thrombocytosis, both at the time of [...] Read more.

Platelets are critical components of a number of physiologic processes, including tissue remodeling after injury, wound healing, and maintenance of vascular integrity. Increasing evidence suggests that platelets may also play important roles in cancer. In ovarian cancer, thrombocytosis, both at the time of initial diagnosis and at recurrence, has been associated with poorer prognosis. This review describes current evidence for associations between thrombocytosis and ovarian cancer prognosis and discusses the clinical relevance of platelet count thresholds and timing of assessment. In addition, we discuss several mechanisms from in vitro, in vivo, and clinical studies that may underlie these associations and recommend potential approaches for novel therapeutic targets for this lethal disease. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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26 pages, 1881 KiB

Open AccessReview

Molecular Drivers of Platelet Activation: Unraveling Novel Targets for Anti-Thrombotic and Anti-Thrombo-Inflammatory Therapy

by Madhumita Chatterjee, Agnes Ehrenberg, Laura Mara Toska, Lisa Maria Metz, Meike Klier, Irena Krueger, Friedrich Reusswig and Margitta Elvers

Int. J. Mol. Sci. 2020, 21(21), 7906; https://doi.org/10.3390/ijms21217906 - 24 Oct 2020

Cited by 23 | Viewed by 5648

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death globally—partly a consequence of increased population size and ageing—and are major contributors to reduced quality of life. Platelets play a major role in hemostasis and thrombosis. While platelet activation and aggregation are essential for [...] Read more.

Cardiovascular diseases (CVDs) are the leading cause of death globally—partly a consequence of increased population size and ageing—and are major contributors to reduced quality of life. Platelets play a major role in hemostasis and thrombosis. While platelet activation and aggregation are essential for hemostasis at sites of vascular injury, uncontrolled platelet activation leads to pathological thrombus formation and provokes thrombosis leading to myocardial infarction or stroke. Platelet activation and thrombus formation is a multistage process with different signaling pathways involved to trigger platelet shape change, integrin activation, stable platelet adhesion, aggregation, and degranulation. Apart from thrombotic events, thrombo-inflammation contributes to organ damage and dysfunction in CVDs and is mediated by platelets and inflammatory cells. Therefore, in the past, many efforts have been made to investigate specific signaling pathways in platelets to identify innovative and promising approaches for novel antithrombotic and anti-thrombo-inflammatory strategies that do not interfere with hemostasis. In this review, we focus on some of the most recent data reported on different platelet receptors, including GPIb-vWF interactions, GPVI activation, platelet chemokine receptors, regulation of integrin signaling, and channel homeostasis of NMDAR and PANX1. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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33 pages, 1691 KiB

Open AccessReview

Depression and Cardiovascular Disease: The Viewpoint of Platelets

by Patrizia Amadio, Marta Zarà, Leonardo Sandrini, Alessandro Ieraci and Silvia Stella Barbieri

Int. J. Mol. Sci. 2020, 21(20), 7560; https://doi.org/10.3390/ijms21207560 - 13 Oct 2020

Cited by 40 | Viewed by 4446

Abstract

Depression is a major cause of morbidity and low quality of life among patients with cardiovascular disease (CVD), and it is now considered as an independent risk factor for major adverse cardiovascular events. Increasing evidence indicates not only that depression worsens the prognosis [...] Read more.

Depression is a major cause of morbidity and low quality of life among patients with cardiovascular disease (CVD), and it is now considered as an independent risk factor for major adverse cardiovascular events. Increasing evidence indicates not only that depression worsens the prognosis of cardiac events, but also that a cross-vulnerability between the two conditions occurs. Among the several mechanisms proposed to explain this interplay, platelet activation is the more attractive, seeing platelets as potential mirror of the brain function. In this review, we dissected the mechanisms linking depression and CVD highlighting the critical role of platelet behavior during depression as trigger of cardiovascular complication. In particular, we will discuss the relationship between depression and molecules involved in the CVD (e.g., catecholamines, adipokines, lipids, reactive oxygen species, and chemokines), emphasizing their impact on platelet activation and related mechanisms. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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28 pages, 1845 KiB

Open AccessReview

Revisiting Platelets and Toll-Like Receptors (TLRs): At the Interface of Vascular Immunity and Thrombosis

by Kathryn Hally, Sebastien Fauteux-Daniel, Hind Hamzeh-Cognasse, Peter Larsen and Fabrice Cognasse

Int. J. Mol. Sci. 2020, 21(17), 6150; https://doi.org/10.3390/ijms21176150 - 26 Aug 2020

Cited by 59 | Viewed by 5544

Abstract

While platelet function has traditionally been described in the context of maintaining vascular integrity, recent evidence suggests that platelets can modulate inflammation in a much more sophisticated and nuanced manner than previously thought. Some aspects of this expanded repertoire of platelet function are [...] Read more.

While platelet function has traditionally been described in the context of maintaining vascular integrity, recent evidence suggests that platelets can modulate inflammation in a much more sophisticated and nuanced manner than previously thought. Some aspects of this expanded repertoire of platelet function are mediated via expression of Toll-like receptors (TLRs). TLRs are a family of pattern recognition receptors that recognize pathogen-associated and damage-associated molecular patterns. Activation of these receptors is crucial for orchestrating and sustaining the inflammatory response to both types of danger signals. The TLR family consists of 10 known receptors, and there is at least some evidence that each of these are expressed on or within human platelets. This review presents the literature on TLR-mediated platelet activation for each of these receptors, and the existing understanding of platelet-TLR immune modulation. This review also highlights unresolved methodological issues that potentially contribute to some of the discrepancies within the literature, and we also suggest several recommendations to overcome these issues. Current understanding of TLR-mediated platelet responses in influenza, sepsis, transfusion-related injury and cardiovascular disease are discussed, and key outstanding research questions are highlighted. In summary, we provide a resource—a “researcher’s toolkit”—for undertaking further research in the field of platelet-TLR biology. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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Open AccessReview

Systematic Review—The Potential Implications of Different Platelet-Rich Plasma (PRP) Concentrations in Regenerative Medicine for Tissue Repair

by Pietro Gentile and Simone Garcovich

Int. J. Mol. Sci. 2020, 21(16), 5702; https://doi.org/10.3390/ijms21165702 - 9 Aug 2020

Cited by 84 | Viewed by 5811

Abstract

The number of studies evaluating platelet-rich plasma (PRP) concentration has substantially grown in the last fifteen years. A systematic review on this field has been realized by evaluating in the identified studies the in vitro PRP concentration—also analyzing the platelet amount—and the in [...] Read more.

The number of studies evaluating platelet-rich plasma (PRP) concentration has substantially grown in the last fifteen years. A systematic review on this field has been realized by evaluating in the identified studies the in vitro PRP concentration—also analyzing the platelet amount—and the in vivo PRP effects in tissue regeneration compared to any control. The protocol has been developed in agreement with the Preferred Reporting for Items for Systematic Reviews and Meta-Analyses-Protocols (PRISMA-P) guidelines. Multistep research of the PubMed, MEDLINE, Embase, PreMEDLINE, Ebase, CINAHL, PsycINFO, Clinicaltrials.gov, Scopus database and Cochrane databases has permitted to identify articles on different concentrations of PRP in vitro and related in vivo impact for tissue repair. Of the 965 articles initially identified, 30 articles focusing on PRP concentration have been selected and, consequently, only 15 articles have been analyzed. In total, 40% (n = 6) of the studies were related to the fixed PRP Concentration Group used a fixed PRP concentration and altered the platelet concentration by adding the different volumes of the PRP (lysate) to the culture. This technique led to a substantial decrease in nutrition available at higher concentrations. Sixty percent (n = 9) of the studies were related to the fixed PRP Volume Group that used a fixed PRP-to-media ratio (Vol/Vol) throughout the experiment and altered the concentration within the PRP volume. For both groups, when the volume of medium (nutrition) decreases, a lower rate of cell proliferation is observed. A PRP concentration of 1.0 × 10⁶ plt/μL, appears to be optimal thanks to the constant and plentiful capillary nutrition supply and rapid diffusion of growth factors that happen in vivo and it also respects the blood decree-law. The PRP/media ratio should provide a sufficient nutrition supply to prevent cellular starvation, that is, PRP ≤ 10% (Vol/Vol) and thus best mimic the conditions in vivo. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)

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