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International Journal of Nanomedicine 2023In addition to hemostasis and coagulation, years of studies have proved that platelets are involved in the whole process of tumor progression, including tumor invasion,... (Review)
Review
In addition to hemostasis and coagulation, years of studies have proved that platelets are involved in the whole process of tumor progression, including tumor invasion, intravasation, extravasation, and so on. It means that this property of platelets can be used in anti-tumor therapy. However, traditional platelet-based antitumor drugs often cause autologous platelet damage due to lack of targeting, resulting in serious side effects. Therefore, the researchers designed a variety of anti-tumor drug delivery systems based on platelets by targeting platelets or platelet membrane coating. The drug delivery systems have special response modes, which is crucial in the design of nanoparticles. These modes enhance the targeting and improve the anti-tumor effect. Here, we present a review of recent discoveries in the field of the crosstalk between platelets and tumors and the progress of platelet-based anti-tumor nanoparticles.
Topics: Humans; Blood Platelets; Antineoplastic Agents; Cell Membrane; Neoplasms; Drug Delivery Systems; Nanoparticles
PubMed: 37954456
DOI: 10.2147/IJN.S436373 -
Arteriosclerosis, Thrombosis, and... Aug 2023Blood flow-induced hemodynamic changes result in mechanical stress on blood cells and vessel walls. Increased shear stress can activate platelets and other circulating... (Review)
Review
Blood flow-induced hemodynamic changes result in mechanical stress on blood cells and vessel walls. Increased shear stress can activate platelets and other circulating cells, triggering the rapid activation of receptors, calcium channels, and related signaling mechanisms. Shear stress can also modify the folding of extracellular molecules and directly activate mechanosensitive receptors and calcium channels. The mechanical movement of the extracellular matrix and the intracellular cortical actin cytoskeleton can change the conformation of platelet receptors and gate channel pores in the plasma membrane. Mechanosensitive platelet receptors and their downstream signaling events and metabolic products can also indirectly activate calcium channels. While the molecular composite of mechanotransduction pathways has been described in mammals, shear stress-induced platelet receptors and their cross talk with calcium channels have been incompletely characterized. In this review, we discuss current knowledge about the role of mechanosensitive platelet receptors and calcium channels in shear-dependent platelet activation and arterial thrombus formation.
Topics: Animals; Blood Platelets; Calcium Channels; Mechanotransduction, Cellular; Platelet Activation; Signal Transduction; Calcium; Stress, Mechanical; Mammals
PubMed: 37345523
DOI: 10.1161/ATVBAHA.123.318341 -
Genes Aug 2023The goal of regenerative medicine is to achieve tissue regeneration. In the past, commonly used techniques included autologous or allogeneic transplantation and stem... (Review)
Review
The goal of regenerative medicine is to achieve tissue regeneration. In the past, commonly used techniques included autologous or allogeneic transplantation and stem cell therapy, which have limitations, such as a lack of donor sites in the case of autologous transplantation and the invasiveness of stem cell harvesting. In recent years, research has, therefore, focused on new and less invasive strategies to achieve tissue regeneration. A step forward in this direction has been made with the development of autologous platelet concentrates (APCs), which are derived from the patient's own blood. They can be classified into three generations: platelet-rich plasma (PRP), platelet-rich fibrin (PRF), and concentrated growth factors (CGFs). These APCs have different structural characteristics, depending on the distinctive preparation method, and contain platelets, leukocytes, and multiple growth factors, including those most involved in regenerative processes. The purpose of this review is to clarify the most used techniques in the field of regenerative medicine in recent years, comparing the different types of APCs and analyzing the preparation protocols, the composition of the growth factors, the level of characterization achieved, and their clinical applications to date.
Topics: Humans; Regenerative Medicine; Blood Platelets; Leukocytes; Platelet-Rich Plasma; Stem Cell Transplantation
PubMed: 37761809
DOI: 10.3390/genes14091669 -
Circulation Research Apr 2024While platelets have well-studied hemostatic functions, platelets are immune cells that circulate at the interface between the vascular wall and white blood cells. The...
BACKGROUND
While platelets have well-studied hemostatic functions, platelets are immune cells that circulate at the interface between the vascular wall and white blood cells. The physiological implications of these constant transient interactions are poorly understood. Activated platelets induce and amplify immune responses, but platelets may also maintain immune homeostasis in healthy conditions, including maintaining vascular integrity and T helper cell differentiation, meaning that platelets are central to both immune responses and immune quiescence. Clinical data have shown an association between low platelet counts (thrombocytopenia) and immune dysfunction in patients with sepsis and extracorporeal membrane oxygenation, further implicating platelets as more holistic immune regulators, but studies of platelet immune functions in nondisease contexts have had limited study.
METHODS
We used in vivo models of thrombocytopenia and in vitro models of platelet and monocyte interactions, as well as RNA-seq and ATAC-seq (assay for transposase-accessible chromatin with sequencing), to mechanistically determine how resting platelet and monocyte interactions immune program monocytes.
RESULTS
Circulating platelets and monocytes interact in a CD47-dependent manner to regulate monocyte metabolism, histone methylation, and gene expression. Resting platelet-monocyte interactions limit TLR (toll-like receptor) signaling responses in healthy conditions in an innate immune training-like manner. In both human patients with sepsis and mouse sepsis models, thrombocytopenia exacerbated monocyte immune dysfunction, including increased cytokine production.
CONCLUSIONS
Thrombocytopenia immune programs monocytes in a manner that may lead to immune dysfunction in the context of sepsis. This is the first demonstration that sterile, endogenous cell interactions between resting platelets and monocytes regulate monocyte metabolism and pathogen responses, demonstrating platelets to be immune rheostats in both health and disease.
Topics: Mice; Animals; Humans; Monocytes; Thrombocytopenia; Blood Platelets; Immunity; Sepsis; Platelet Activation
PubMed: 38456277
DOI: 10.1161/CIRCRESAHA.123.323662 -
Journal of Thrombosis and Haemostasis :... Jul 2023The circulating form of human endoglin (sEng) is a cleavage product of membrane-bound endoglin present on endothelial cells. Because sEng encompasses an RGD motif...
BACKGROUND
The circulating form of human endoglin (sEng) is a cleavage product of membrane-bound endoglin present on endothelial cells. Because sEng encompasses an RGD motif involved in integrin binding, we hypothesized that sEng would be able to bind integrin αIIbβ3, thereby compromising platelet binding to fibrinogen and thrombus stability.
METHODS
In vitro human platelet aggregation, thrombus retraction, and secretion-competition assays were performed in the presence of sEng. Surface plasmon resonance (SPR) binding and computational (docking) analyses were carried out to evaluate protein-protein interactions. A transgenic mouse overexpressing human sEng (hsEng) was used to measure bleeding/rebleeding, prothrombin time (PT), blood stream, and embolus formation after FeCl-induced injury of the carotid artery.
RESULTS
Under flow conditions, supplementation of human whole blood with sEng led to a smaller thrombus size. sEng inhibited platelet aggregation and thrombus retraction, interfering with fibrinogen binding, but did not affect platelet activation. SPR binding studies demonstrated that the specific interaction between αIIbβ3 and sEng and molecular modeling showed a good fitting between αIIbβ3 and sEng structures involving the endoglin RGD motif, suggesting the possible formation of a highly stable αIIbβ3/sEng. hsEng mice showed increased bleeding time and number of rebleedings compared to wild-type mice. No differences in PT were denoted between genotypes. After FeCl injury, the number of released emboli in hsEng mice was higher and the occlusion was slower compared to controls.
CONCLUSIONS
Our results demonstrate that sEng interferes with thrombus formation and stabilization, likely via its binding to platelet αIIbβ3, suggesting its involvement in primary hemostasis control.
Topics: Humans; Animals; Mice; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Endoglin; Endothelial Cells; Blood Platelets; Thrombosis; Fibrinogen
PubMed: 36990159
DOI: 10.1016/j.jtha.2023.03.023 -
International Journal of Molecular... Aug 2023In recent years, several types of platelet concentrates have been investigated and applied in many fields, particularly in the musculoskeletal system. Platelet-rich... (Review)
Review
In recent years, several types of platelet concentrates have been investigated and applied in many fields, particularly in the musculoskeletal system. Platelet-rich fibrin (PRF) is an autologous biomaterial, a second-generation platelet concentrate containing platelets and growth factors in the form of fibrin membranes prepared from the blood of patients without additives. During tissue regeneration, platelet concentrates contain a higher percentage of leukocytes and a flexible fibrin net as a scaffold to improve cell migration in angiogenic, osteogenic, and antibacterial capacities during tissue regeneration. PRF enables the release of molecules over a longer period, which promotes tissue healing and regeneration. The potential of PRF to simulate the physiology and immunology of wound healing is also due to the high concentrations of released growth factors and anti-inflammatory cytokines that stimulate vessel formation, cell proliferation, and differentiation. These products have been used safely in clinical applications because of their autologous origin and minimally invasive nature. We focused on a narrative review of PRF therapy and its effects on musculoskeletal, oral, and maxillofacial surgeries and dermatology. We explored the components leading to the biological activity and the published preclinical and clinical research that supports its application in musculoskeletal therapy. The research generally supports the use of PRF as an adjuvant for various chronic muscle, cartilage, and tendon injuries. Further clinical trials are needed to prove the benefits of utilizing the potential of PRF.
Topics: Humans; Blood Platelets; Cartilage; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Fibrin
PubMed: 37628786
DOI: 10.3390/ijms241612608 -
British Journal of Pharmacology Feb 2024Inflammation is a complex pathophysiological process underlying many clinical conditions. Platelets contribute to the thrombo-inflammatory response. Platelet P2Y... (Review)
Review
Inflammation is a complex pathophysiological process underlying many clinical conditions. Platelets contribute to the thrombo-inflammatory response. Platelet P2Y receptors amplify platelet activation, potentiating platelet aggregation, degranulation and shape change. The contents of platelet alpha granules, in particular, act directly on leucocytes, including mediating platelet-leucocyte aggregation and activation via platelet P-selectin. Much evidence for the role of platelet P2Y receptors in inflammation comes from studies using antagonists of these receptors, such as the thienopyridines clopidogrel and prasugrel, and the cyclopentyltriazolopyrimidine ticagrelor, in animal and human experimental models. These suggest that antagonism of P2Y receptors decreases markers of inflammation with some evidence that this reduces incidence of adverse clinical sequelae during inflammatory conditions. Interpretation is complicated by pleiotropic effects such as those of the thienopyridines on circulating leucocyte numbers and of ticagrelor on adenosine reuptake. The available evidence suggests that P2Y receptors are prominent mediators of inflammation and P2Y receptor antagonism as a potentially powerful strategy in a broad range of inflammatory conditions. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.
Topics: Animals; Humans; Ticagrelor; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Blood Platelets; Inflammation; Platelet Aggregation; Prasugrel Hydrochloride; Thienopyridines; Receptors, Purinergic P2Y12
PubMed: 37771103
DOI: 10.1111/bph.16256 -
International Journal of Molecular... Jul 2023Aside from their key protective roles in hemostasis and innate immunity, platelets are now recognized as having multifaceted, adverse roles in the pathogenesis,... (Review)
Review
Aside from their key protective roles in hemostasis and innate immunity, platelets are now recognized as having multifaceted, adverse roles in the pathogenesis, progression and outcome of many types of human malignancy. The most consistent and compelling evidence in this context has been derived from the notable association of elevated circulating platelet counts with the onset and prognosis of various human malignancies, particularly lung cancer, which represents the primary focus of the current review. Key topics include an overview of the association of lung cancer with the circulating platelet count, as well as the mechanisms of platelet-mediated, pro-tumorigenic immunosuppression, particularly the role of transforming growth factor beta 1. These issues are followed by a discussion regarding the pro-tumorigenic role of platelet-derived microparticles (PMPs), the most abundant type of microparticles (MPs) in human blood. In this context, the presence of increased levels of PMPs in the blood of lung cancer patients has been associated with tumor growth, invasion, angiogenesis and metastasis, which correlate with disease progression and decreased survival times. The final section of the review addresses, firstly, the role of cancer-related platelet activation and thrombosis in the pathogenesis of secondary cardiovascular disorders and the associated mortality, particularly in lung cancer, which is second only to disease progression; secondly, the review addresses the potential role of antiplatelet agents in the adjunctive therapy of cancer.
Topics: Humans; Blood Platelets; Cell-Derived Microparticles; Thrombosis; Lung Neoplasms; Carcinogenesis; Disease Progression
PubMed: 37569299
DOI: 10.3390/ijms241511927 -
Haematologica Jul 2023Integrins are heterodimeric transmembrane receptors composed of α and β chains, with an N-terminal extracellular domain forming a globular head corresponding to the... (Review)
Review
Integrins are heterodimeric transmembrane receptors composed of α and β chains, with an N-terminal extracellular domain forming a globular head corresponding to the ligand binding site. Integrins regulate various cellular functions including adhesion, migration, proliferation, spreading and apoptosis. On platelets, integrins play a central role in adhesion and aggregation on subendothelial matrix proteins of the vascular wall, thereby ensuring hemostasis. Platelet integrins belong either to the β1 family (α2β1, α5β1 and α6β1) or to the β3 family (αIIbβ3 and αvβ3). On resting platelets, integrins can engage their ligands when the latter are immobilized but not in their soluble form. The effects of various agonists promote an inside-out signal in platelets, increasing the affinity of integrins for their ligands and conveying a modest signal reinforcing platelet activation, called outside-in signaling. This outside-in signal ensures platelet adhesion, shape change, granule secretion and aggregation. In this review, we examine the role of each platelet integrin in hemostatic plug formation, hemostasis and arterial thrombosis and also beyond these classical functions, notably in tumor metastasis and sepsis.
Topics: Humans; Blood Platelets; Integrins; Ligands; Hemostasis; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombosis; Platelet Aggregation
PubMed: 36700400
DOI: 10.3324/haematol.2022.282136 -
Platelets Dec 2023Various modifications of proteins and the resulting proteoforms of a protein can associate with many diseases and are also significantly involved in the rapid regulation...
Various modifications of proteins and the resulting proteoforms of a protein can associate with many diseases and are also significantly involved in the rapid regulation of hemostasis and thrombosis. For example, the release of prostacyclin from the intact endothelium and the consequent following phosphorylation of VASP in platelets is a post-translational regulation to keep them in a quiescent state. In Alzheimer's disease, proteoforms arise from the altered cleavage of the amyloid precursor protein, which finally causes amyloid plaques in the brain. This changed processing of the amyloid precursor protein can also be detected in platelets, making them an attractive source of biomarkers for this neurodegenerative disease. Age-related or prothrombotic disorders can have multiple origins, including genomic, transcriptional, and translational factors, which together can be mapped at the proteome level. Hence, recording these dynamic protein changes under physiological and pathophysiological conditions is paramount in platelet proteomics. To effectively study diseases through platelet proteomics, it is crucial to consider platelets' primary regulatory mechanism and thoroughly evaluate the disparities between the two leading proteomics technologies, top-down and bottom-up approaches. This commentary provides insights into the differences between these two technologies, which are particularly noticeable in detecting the different proteoforms of a protein.
Topics: Humans; Proteomics; Neurodegenerative Diseases; Amyloid beta-Protein Precursor; Blood Platelets; Protein Processing, Post-Translational; Proteome
PubMed: 37272536
DOI: 10.1080/09537104.2023.2220046