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Pilard M, Babran S, Martel C. Regulation of Platelet Function by HDL. Arterioscler Thromb Vasc Biol 2025; 45:e184-e200. [PMID: 40207365 DOI: 10.1161/atvbaha.124.318260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
Over the past decade, increasing the capacity of HDL (high-density lipoprotein) cholesterol to mediate macrophage reverse cholesterol transport has been a target of interest in the treatment of cardiovascular diseases (CVDs). However, clinical studies reporting the limited efficacy of HDL or its main apolipoprotein, APOA1, in reducing cardiovascular events have emerged. Although HDL cholesterol is unlikely to play a direct causal role in CVD, its inverse, albeit modest, association with CVD risk, consistently observed in large population studies, suggests it may influence alternative pathways beyond cholesterol metabolism. Given the diverse functions of HDL and its components, it is conceivable that its impact on CVD occurs through less direct mechanisms. A potential hypothesis is that HDL modulates platelet function, a crucial player in the initiation and progression of atherothrombosis, which may contribute to its observed relationship with CVD risk. In this review, we focus on how HDL and its components, with an emphasis on APOA1, interact with platelets (and their precursors or activation products) to modulate atherothrombotic responses.
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Affiliation(s)
- Marion Pilard
- Department of Medicine, Faculty of Medicine, Université de Montréal, Canada
- Montreal Heart Institute, Canada
| | - Sara Babran
- Department of Medicine, Faculty of Medicine, Université de Montréal, Canada
- Montreal Heart Institute, Canada
| | - Catherine Martel
- Department of Medicine, Faculty of Medicine, Université de Montréal, Canada
- Montreal Heart Institute, Canada
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Chen T, Xiao C, Chen X, Yang Z, Zhao J, Bao B, Zeng Q, Jiang L, Huang X, Yang Y, Lin Q, Gong W, Zhu L. Covalently reactive microparticles imbibe blood to form fortified clots for rapid hemostasis and prevention of rebleeding. Nat Commun 2025; 16:3705. [PMID: 40251193 PMCID: PMC12008190 DOI: 10.1038/s41467-025-58204-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 03/13/2025] [Indexed: 04/20/2025] Open
Abstract
Owing to the inherently gradual nature of coagulation, the body fails in covalently crosslinking to stabilize clots rapidly, even with the aid of topical hemostats, thus inducing hemostatic failure and potential rebleeding. Although recently developed adhesives confer sealing bleeding sites independently of coagulation, interfacial blood hampers their adhesion and practical applications. Here, we report a covalently reactive hemostat based on blood-imbibing and -crosslinking microparticles. Once contacting blood, the microparticles automatically mix with blood via imbibition and covalently crosslink with blood proteins and the tissue matrix before natural coagulation operates, rapidly forming a fortified clot with enhanced mechanical strength and tissue adhesion. In contrast to commercial hemostats, the microparticles achieve rapid hemostasis (within 30 seconds) and less blood loss (approximately 35 mg and 1 g in the rat and coagulopathic pig models, respectively), while effectively preventing blood-pressure-elevation-induced rebleeding in a rabbit model. This work advances the development and clinical translation of hemostats for rapid hemostasis and rebleeding prevention.
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Affiliation(s)
- Ting Chen
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Chaonan Xiao
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xianjun Chen
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Ziyi Yang
- Department of General Surgery, Xinhua Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
| | - Jingwei Zhao
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
- Department of General Surgery, Xinhua Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
| | - Bingkun Bao
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Qingmei Zeng
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Li Jiang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xinyi Huang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yi Yang
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Qiuning Lin
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
| | - Wei Gong
- Department of General Surgery, Xinhua Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
| | - Linyong Zhu
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
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Knauss EA, Guci J, Luc N, Disharoon D, Huang GH, Gupta AS, Nieman MT. Mice with reduced protease-activated receptor 4 reactivity show decreased venous thrombosis and platelet procoagulant activity. J Thromb Haemost 2025; 23:1278-1288. [PMID: 39798922 PMCID: PMC11992619 DOI: 10.1016/j.jtha.2024.12.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/15/2025]
Abstract
BACKGROUND Hypercoagulation and thrombin generation are major risk factors for venous thrombosis. Sustained thrombin signaling through protease-activated receptor (PAR) 4 promotes platelet activation, phosphatidylserine exposure, and subsequent thrombin generation. A single nucleotide polymorphism in PAR4 (rs2227376) changes proline to leucine extracellular loop 3, which decreases PAR4 reactivity and is associated with a lower risk for venous thromboembolism (VTE) in a genome wide association studies meta-analysis. OBJECTIVES The goal of this study was to determine the mechanism for the association of rs2227376 with a reduced risk of VTE using mice with a homologous mutation (PAR4-P322L). METHODS Venous thrombosis was examined using our recently generated PAR4-P322L mice in the inferior vena cava stasis and stenosis models. Coagulation and clot stability were measured using rotational thromboelastometry. Thrombin-generating potential was measured in platelet-rich plasma. Phosphatidylserine surface expression and platelet-neutrophil aggregates were analyzed using flow cytometry. RESULTS Mice heterozygous (PAR4P/L) or homozygous (PAR4L/L) at position 310 had reduced sizes of venous clots at 48 hours. PAR4P/L and PAR4L/L platelets had progressively decreased phosphatidylserine in response to thrombin and convulxin, in addition to decreased thrombin generation and decreased PAR4-mediated platelet-neutrophil aggregation. CONCLUSION The leucine allele in extracellular loop 3, PAR4-322L, leads to fewer procoagulant platelets, decreased endogenous thrombin potential, and reduced platelet-neutrophil aggregation. This decreased ability to generate thrombin and bind to neutrophils offers a mechanism for PAR4's role in VTE, highlighting a key role for PAR4 signaling.
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Affiliation(s)
- Elizabeth A Knauss
- Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Johana Guci
- Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Norman Luc
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Dante Disharoon
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Grace H Huang
- Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Anirban Sen Gupta
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Marvin T Nieman
- Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
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Liu Z, Xu J, Wang X. Bioactive hemostatic materials: a new strategy for promoting wound healing and tissue regeneration. MedComm (Beijing) 2025; 6:e70113. [PMID: 40123833 PMCID: PMC11928890 DOI: 10.1002/mco2.70113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 01/09/2025] [Accepted: 01/21/2025] [Indexed: 03/25/2025] Open
Abstract
Wound healing remains a critical global healthcare challenge, with an annual treatment cost exceeding $50 billion worldwide. Over the past decade, significant advances in wound care have focused on developing sophisticated biomaterials that promote tissue regeneration and prevent complications. Despite these developments, there remains a crucial need for multifunctional wound healing materials that can effectively address the complex, multiphase nature of wound repair while being cost effective and easily applicable in various clinical settings. This review systematically analyzes the latest developments in wound healing materials, examining their chemical composition, structural design, and therapeutic mechanisms. We comprehensively evaluate various bioactive components, including natural polymers, synthetic matrices, and hybrid composites, along with their different forms, such as hydrogels, powders, and smart dressings. Special attention is given to emerging strategies in material design that integrate multiple therapeutic functions, including sustained drug delivery, infection prevention, and tissue regeneration promotion. The insights provided in this review illuminate the path toward next-generation wound healing materials, highlighting opportunities for developing more effective therapeutic solutions that can significantly improve patient outcomes and reduce healthcare burden.
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Affiliation(s)
- Zhengyuan Liu
- Beijing National Laboratory for Molecular SciencesInstitute of ChemistryChinese Academy of SciencesBeijingChina
- Sino‐Danish CollegeUniversity of Chinese Academy of Sciences (UCAS)BeijingChina
- Nano‐Science CenterUniversity of CopenhagenCopenhagenDenmark
| | - Junnan Xu
- Department of Urologythe Third Medical Center of PLA General HospitalBeijingChina
| | - Xing Wang
- Beijing National Laboratory for Molecular SciencesInstitute of ChemistryChinese Academy of SciencesBeijingChina
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Pham DT, Thuy NTN, Thao NTP, Nhi LT, Thuy BTP. Naturally derived hydrogels for wound healing. Ther Deliv 2025; 16:349-363. [PMID: 39871586 PMCID: PMC11970767 DOI: 10.1080/20415990.2025.2457928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 01/21/2025] [Indexed: 01/29/2025] Open
Abstract
Natural hydrogels have garnered increasing attention due to their natural origins and beneficial roles in wound healing. Hydrogel water-retaining capacity and excellent biocompatibility create an ideal moist environment for wound healing, thereby enhancing cell proliferation and tissue regeneration. For this reason, naturally derived hydrogels formulated from biomaterials such as chitosan, alginate, gelatin, and fibroin are highly promising due to their biodegradability and low immunogenic responses. Recent integrated approaches to utilizing new technologies with bioactive agents have significantly improved the mechanical properties of hydrogels and the controlled release and delivery of active compounds, thereby increasing the efficiency of the treatment processes. Herein, this review highlights the advantages and the challenges of natural hydrogels in wound healing, focusing on their mechanical strength, controlled degradation rates, safety and efficiency validation, and the potential for incorporating advanced technologies such as tissue engineering and gene therapy for utilization in personalized medicine.
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Affiliation(s)
- Duy Toan Pham
- Department of Health Sciences, College of Natural Sciences, Can Tho University, Can Tho, Vietnam
| | - Ngo Thi Ngoc Thuy
- Institute of Tropical Biology, Vietnam Academy of Science and Technology, Ho Chi Minh City, Vietnam
| | - Nguyen Thi Phuong Thao
- Institute of Tropical Biology, Vietnam Academy of Science and Technology, Ho Chi Minh City, Vietnam
| | - Le Thi Nhi
- Faculty of Materials Science, University of Science, Vietnam National University, Ho Chi Minh City, Vietnam
| | - Bui Thi Phuong Thuy
- Faculty of Fundamental Sciences, Van Lang University, Ho Chi Minh City, Vietnam
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Zhong B, Zhang W, Ming L, Fan Q, Zhang L, Lai H, Huang G, Liu H, Dong Z. Innovative Application of Medicinal Insects: Employing UHPLC-MS, Bioinformatics, In Silico Studies and In Vitro Experiments to Elucidate the Multi-Target Hemostatic Mechanism of Glenea cantor (Coleoptera: Cerambycidae) Charcoal-Based Medicine. Pharmaceuticals (Basel) 2025; 18:479. [PMID: 40283916 PMCID: PMC12030305 DOI: 10.3390/ph18040479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 03/22/2025] [Accepted: 03/24/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Longhorn beetles, a widely recognized group of Chinese traditional medicinal insects, are characterized by their notable hemostatic properties. However, the comprehensive understanding of their medicinal potential has been hindered by the limitations of current research methodologies. Methods: This study focuses on the species Glenea cantor (Fabricius), which can produce several generations per year, and introduces a novel method using microwave carbonization techniques. By employing an in vitro coagulation test, UHPLC-MS, network pharmacology, molecular docking, and molecular dynamics simulation, the hemostatic efficacy and mechanism of action of Glenea cantor charcoal medicine (GC-CM) were thoroughly studied. Results: In vitro coagulation tests showed that GC-CM significantly reduced the activated partial thromboplastin time (APTT) and prothrombin time (PT), indicating its ability to enhance the coagulation cascade and preliminarily confirming its hemostatic efficacy (p < 0.01 vs. blank control group). The analysis revealed that GC-CM comprises 453 components, including 137 bioactive components with high human utilization. After predictions via databases such as SwissTargetPrediction and deduplication, 215 targets linked to hemostatic specificity were identified. These targets regulate signaling pathways such as platelet activation, complement and coagulation cascades, and cGMP-PKG. Molecular docking demonstrated strong affinities between key targets such as SRC and PIK3R1 and compounds such as 2',6'-dihydroxy 4'-methoxydihydrochalcone, and 1-monolinoleoyl-rac-glycerol (binding energy < -5 kcal/mol). Molecular dynamics simulations show good binding capacity between core components and targets Conclusions: The aim of this study was to elucidate the material basis and mechanism of the hemostatic efficacy of GC-CM, offering a model for exploring other insect-based medicinal resources.
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Affiliation(s)
- Bangyu Zhong
- National Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (B.Z.); (W.Z.); (L.M.); (Q.F.); (L.Z.); (H.L.); (G.H.)
- Research Center for Differention and Development of TCM Basic Theory, Jiangxi University of Chinese Medicine, Nanchang 330004, China
- College of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Wen Zhang
- National Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (B.Z.); (W.Z.); (L.M.); (Q.F.); (L.Z.); (H.L.); (G.H.)
- Research Center for Differention and Development of TCM Basic Theory, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Liangshan Ming
- National Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (B.Z.); (W.Z.); (L.M.); (Q.F.); (L.Z.); (H.L.); (G.H.)
- Research Center for Differention and Development of TCM Basic Theory, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Qimeng Fan
- National Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (B.Z.); (W.Z.); (L.M.); (Q.F.); (L.Z.); (H.L.); (G.H.)
- Research Center for Differention and Development of TCM Basic Theory, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Lei Zhang
- National Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (B.Z.); (W.Z.); (L.M.); (Q.F.); (L.Z.); (H.L.); (G.H.)
- Research Center for Differention and Development of TCM Basic Theory, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Hongyu Lai
- National Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (B.Z.); (W.Z.); (L.M.); (Q.F.); (L.Z.); (H.L.); (G.H.)
- Research Center for Differention and Development of TCM Basic Theory, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Genwang Huang
- National Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (B.Z.); (W.Z.); (L.M.); (Q.F.); (L.Z.); (H.L.); (G.H.)
- Research Center for Differention and Development of TCM Basic Theory, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Hongning Liu
- National Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (B.Z.); (W.Z.); (L.M.); (Q.F.); (L.Z.); (H.L.); (G.H.)
- Research Center for Differention and Development of TCM Basic Theory, Jiangxi University of Chinese Medicine, Nanchang 330004, China
- Advanced Research Institute, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Zishu Dong
- National Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (B.Z.); (W.Z.); (L.M.); (Q.F.); (L.Z.); (H.L.); (G.H.)
- Research Center for Differention and Development of TCM Basic Theory, Jiangxi University of Chinese Medicine, Nanchang 330004, China
- Advanced Research Institute, Jiangxi University of Chinese Medicine, Nanchang 330004, China
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Zhang YM, Luo Q, Lu M, Gong X, Guo YW, Zeng XB, Zhu Y, Shu D, Lin YL, Guo XR, Ming ZY. Pharmacological effects and mechanism of Ilexsaponin A1 in modulating platelet function. JOURNAL OF ETHNOPHARMACOLOGY 2025; 344:119564. [PMID: 40015536 DOI: 10.1016/j.jep.2025.119564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 02/21/2025] [Accepted: 02/24/2025] [Indexed: 03/01/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ilex pubescens Hook. & Arn. is a traditional Chinese medicine for promoting blood circulation. Ilexsaponin A1 (IsA), a monomer of the compound, exhibits pro-angiogenic, anti-apoptotic and anti-inflammatory activities. Nevertheless, the pharmacological effects and specific mechanisms by which IsA affects platelets remain unknown. AIM OF THE STUDY This study aims to investigate the antiplatelet effects of IsA and the underlying molecular mechanisms. MATERIALS AND METHODS Platelet aggregation and ATP release were assessed using platelet aggregometry. Flow cytometry was employed to evaluate the exposure of P-selectin, integrin αⅡbβ3 activation and calcium mobilization. Fluorescence microscopy was applied to observe platelet spreading. Clot retraction was imaged by digital camera. Protein phosphorylation regulation of major signaling pathways in platelets was determined by immunoblotting analysis. Doppler flowmetry was used to investigate the in vivo effect of IsA on FeCl3-induced carotid artery injury model. Tail vein transection was used to measure bleeding time. RESULTS IsA dose-dependently inhibited platelet aggregation and ATP release induced by collagen, U46619, thrombin and ADP. It also suppressed thrombin-induced P-selectin exposure and PAC-1 binding. Furthermore, IsA inhibited intracellular Ca2+ mobilization and the inward flow of extracellular Ca2+. It also influenced integrin αⅡbβ3 outside-in signaling pathways, including the inhibition of platelet spreading, clot retraction and phosphorylation of outside-in signaling molecules. In addition, IsA suppressed the phosphorylation of Syk-PLCγ2, PI3K-Akt-GSK3β and MAPKs proteins, which are downstream effectors of the collagen and thrombin receptors. CONCLUSION IsA inhibited platelet function and thrombus formation. This has potential to be developed into a novel therapeutic agent for the treatment of thrombotic diseases.
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Affiliation(s)
- Yu-Min Zhang
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China
| | - Qi Luo
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China
| | - Meng Lu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China
| | - Xue Gong
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China
| | - Ya-Wei Guo
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China
| | - Xiang-Bin Zeng
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China
| | - Ying Zhu
- Department of Pharmacy, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dan Shu
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Yue-Ling Lin
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China
| | - Xu-Ran Guo
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China
| | - Zhang-Yin Ming
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China; Tongji-Rongcheng Center for Biomedicine, Huazhong University of Science and Technology, Wuhan, China.
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Josefsson EC. Platelets and megakaryocytes in cancer. J Thromb Haemost 2025; 23:804-816. [PMID: 39742972 DOI: 10.1016/j.jtha.2024.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 12/03/2024] [Accepted: 12/16/2024] [Indexed: 01/04/2025]
Abstract
Platelets have important roles in hemostasis but also actively participate in cancer metastasis and inflammatory processes. They are produced by large precursor cells, the megakaryocytes, residing mainly in the bone marrow. Clinically, elevated platelet counts and/or increased platelet-to-lymphocyte ratio are being explored as biomarkers of metastatic disease and to predict survival or response to therapy in certain cancers. Multiple mechanisms have been put forward on how platelets promote hematogenous metastasis stemming mainly from murine experimental models. Research is now beginning to explore the potential roles of megakaryocytes in solid cancer, myeloma, and lymphoma. Here, we review mechanisms on how platelets and megakaryocytes contribute to cancer progression and metastasis but also discuss potential cancer-suppressing functions mainly related to the regulation of vascular intratumor integrity. Recent developments in cancer immune checkpoint therapy are reviewed with a focus on the potential roles of platelets. Moreover, we review studies exploring platelets for targeted drug delivery systems in cancer therapy.
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Affiliation(s)
- Emma C Josefsson
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, The University of Gothenburg, Gothenburg, Sweden.
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Zhou Y, Feng Y, Xin N, Lu J, Xu X. Assessing Stroke Recurrence Risk by Using a Lipoprotein-Associated Phospholipase A2 and Platelet Count-Based Nomogram. Mol Neurobiol 2025; 62:2835-2845. [PMID: 39177733 DOI: 10.1007/s12035-024-04439-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 08/10/2024] [Indexed: 08/24/2024]
Abstract
Stroke recurrence remains a critical challenge in clinical neurology, necessitating the identification of reliable predictive markers for better management and treatment strategies. This study investigates the interaction between lipoprotein-associated phospholipase A2 (Lp-PLA2) and platelets as a potential predictor for stroke recurrence, aiming to refine risk assessment and therapeutic approaches. In a retrospective cohort of 580 ischemic stroke patients, we analyzed clinical data with a focus on Lp-PLA2 and platelet levels. By using multivariable logistic regression, we identified independent predictors of stroke recurrence. These predictors were then used to develop a comprehensive nomogram. The study established diabetes mellitus, hypertension, low-density lipoprotein (LDL), Lp-PLA2 levels, and platelet counts as independent predictors of stroke recurrence. Crucially, the interaction parameter Lp-PLA2 * platelet (multiplication of Lp-PLA2 and platelet count) exhibited superior predictive power over each factor considered separately. Our nomogram incorporated diabetes mellitus, cerebral infarction causes, hypertension, LDL, and the Lp-PLA2 * platelet count interaction and demonstrated enhanced accuracy in predicting stroke recurrence compared to traditional risk models. The interaction between Lp-PLA2 and platelets emerged as a significant predictor for stroke recurrence when integrated with traditional risk factors. The developed nomogram offers a novel and practical tool in molecular neurobiology for assessing individual risks, facilitating personalized treatment strategies. This approach underscores the importance of multifactorial assessment in stroke management and opens avenues for targeted interventions to mitigate recurrence risks.
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Affiliation(s)
- Yanlong Zhou
- Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou, 215000, China
- Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221600, China
| | - Yu Feng
- Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221600, China
| | - Ning Xin
- Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221600, China.
| | - Jun Lu
- Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221600, China
| | - Xingshun Xu
- Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou, 215000, China.
- Institute of Neuroscience, Soochow University, Suzhou, 215123, China.
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215123, Jiangsu, China.
- Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
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10
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Pirabe A, Schrottmaier WC, Mehic D, Hackl H, Frühwirth S, Schmuckenschlager A, Beck S, Gebhart J, Gleixner K, Sperr W, Assinger A. Impaired hemostatic and immune functions of platelets after acute thrombocytopenia. J Thromb Haemost 2025; 23:1052-1065. [PMID: 39675567 DOI: 10.1016/j.jtha.2024.11.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Platelets are pivotal in maintaining vascular integrity, hemostasis, and immune modulation, with newly generated, immature platelets being the most responsive in fulfilling these tasks. Therefore, the immature platelet fraction provides insights into thrombopoiesis dynamics and clinical prognostication. However, it is currently unclear how immature platelet functions change in settings of acute thrombocytopenia. OBJECTIVES We aimed to investigate the functional consequences of acute thrombocytopenia on newly generated immature platelets in various mouse models and human subjects. METHODS To examine platelet functionality after acute thrombocytopenia, we depleted either megakaryocytes using a platelet factor 4-specific inducible diphtheria toxin receptor transgenic mouse model or platelets via antibody-mediated depletion in mice, and collected blood from acute myeloid leukemia (AML) patients before and after consolidation or induction chemotherapy. Chemotherapy treatment was further repeated in an animal model. We assessed surface receptor expression of activation markers (CD62P, active GPIIb/IIIa, CD40L, CD63, CD107a) and toll-like receptors (TLR2, TLR4, TLR9) on immature and mature platelets following activation. Additionally, we investigated procoagulant platelet formation and platelet-leukocyte interactions in mouse models and patients with AML. RESULTS In murine models, acute thrombocytopenia led to impaired hemostatic function and altered surface receptor expression in newly generated immature platelets. Similarly, AML patients during regeneration post chemotherapy exhibited reduced platelet activation and procoagulant function, alongside altered receptor expression and diminished platelet-leukocyte interactions. CONCLUSION After acute thrombocytopenia platelet-mediated hemostasis and immune modulation by newly generated platelets are impaired, underscoring the clinical relevance of understanding platelet function alterations in (post)thrombocytopenic conditions for therapeutic optimization.
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Affiliation(s)
- Anita Pirabe
- Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Waltraud C Schrottmaier
- Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria. https://twitter.com/WaltraudSchrottmaier
| | - Dino Mehic
- Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Hubert Hackl
- Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Sabine Frühwirth
- Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Anna Schmuckenschlager
- Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Sarah Beck
- Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-University of Wuerzburg, Wuerzburg, Germany; Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Johanna Gebhart
- Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Karoline Gleixner
- Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Sperr
- Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Alice Assinger
- Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
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11
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Lu C, Li C, Gu N, Yang F. Emerging Elastic Micro-Nano Materials for Diagnosis and Treatment of Thrombosis. RESEARCH (WASHINGTON, D.C.) 2025; 8:0614. [PMID: 40028043 PMCID: PMC11868703 DOI: 10.34133/research.0614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/14/2025] [Accepted: 01/24/2025] [Indexed: 03/05/2025]
Abstract
Thrombus is a blood clot that forms in a blood vessel at the point of flaking. Thrombosis is closely associated with cardiovascular diseases caused by different sources and factors. However, the current clinical methods of thrombus diagnosis and treatment still have problems with targeting, permeability, stability, and biosafety. Therefore, in recent years, based on the development of micro/nano technology, researchers have tried to develop some new strategies for the diagnosis and treatment of thrombosis. Due to the unique structural characteristics, the micro-nano materials in physiological environments show excellent transport and delivery properties such as better in vivo circulation, longer life span, better targeting ability, and controllable cellular internalization. Especially, elasticity and stiffness are inherent mechanical properties of some well-designed micro-nano materials, which can make them better adapted to the needs of thrombosis diagnosis and treatment. Herein, this review first introduces the thrombotic microenvironment to characterize the thrombus development process. Then, to fine-tune the pathological occurrence and development of thrombosis, the role of elastic micro-nano materials for thrombus diagnosis and treatment is summarized. The properties, preparation methods, and biological fate of these materials have been discussed in detail. Following, the applications of elastic micro-nano materials in biomedical imaging, drug delivery, and therapy of thrombosis are highlighted. Last, the shortcomings and future design strategies of elastic micro-nano materials in diagnosis and treatment of clinical thrombosis are discussed. This review will provide new ideas for the use of nanotechnology in clinical diagnosis and treatment of thrombus in the future.
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Affiliation(s)
- Chenxin Lu
- State Key Laboratory of Digital Medical Engineering, Jiangsu Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering,
Southeast University, Nanjing 210096, P. R. China
| | - Chunjian Li
- Department of Cardiology,
The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, P. R. China
| | - Ning Gu
- Nanjing Key Laboratory for Cardiovascular Information and Health Engineering Medicine, Institute of Clinical Medicine, Nanjing Drum Tower Hospital, Medical School,
Nanjing University, Nanjing 210093, P. R. China
| | - Fang Yang
- State Key Laboratory of Digital Medical Engineering, Jiangsu Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering,
Southeast University, Nanjing 210096, P. R. China
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12
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Kliuchnikov E, Peshkova AD, Vo MQ, Marx KA, Litvinov RI, Weisel JW, Purohit PK, Barsegov V. Exploring effects of platelet contractility on the kinetics, thermodynamics, and mechanisms of fibrin clot contraction. NPJ BIOLOGICAL PHYSICS AND MECHANICS 2025; 2:6. [PMID: 40012560 PMCID: PMC11850289 DOI: 10.1038/s44341-025-00011-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 01/22/2025] [Indexed: 02/28/2025]
Abstract
Mechanisms of blood clot contraction - platelet-driven fibrin network remodeling, are not fully understood. We developed a detailed computational ClotDynaMo model of fibrin network with activated platelets, whose clot contraction rate for normal 450,000/µl human platelets depends on serum viscosity η, platelet filopodia length l, and weakly depends on filopodia traction force f and filopodia extension-retraction speed v. Final clot volume is independent of η, but depends on v, f and l. Analysis of ClotDynaMo output revealed a 2.24 TJ/mol clot contraction free energy change, with ~67% entropy and ~33% internal energy changes. The results illuminate the "optimal contraction principle" that maximizes volume change while minimizing energy cost. An 8-chain continuum model of polymer elasticity containing platelet forces, captures clot contractility as a function of platelet count, η and l. The ClotDynaMo and continuum models can be extended to include red blood cells, variable platelet properties, and mechanics of fibrin network.
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Affiliation(s)
| | - Alina D. Peshkova
- Departments of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA
| | - Minh Quan Vo
- Department of Mechanical Engineering and Applied Mechanics, University of Pennsylvania, Philadelphia, PA USA
| | - Kenneth A. Marx
- Department of Chemistry, University of Massachusetts, Lowell, MA USA
| | - Rustem I. Litvinov
- Departments of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA
| | - John W. Weisel
- Departments of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA
| | - Prashant K. Purohit
- Department of Mechanical Engineering and Applied Mechanics, University of Pennsylvania, Philadelphia, PA USA
| | - Valeri Barsegov
- Department of Chemistry, University of Massachusetts, Lowell, MA USA
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13
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Setarehaseman A, Mohammadi A, Maitta RW. Thrombocytopenia in Sepsis. Life (Basel) 2025; 15:274. [PMID: 40003683 PMCID: PMC11857489 DOI: 10.3390/life15020274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/05/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Platelets, traditionally known for their role in hemostasis, have emerged as key players in immune response and inflammation. Sepsis, a life-threatening condition characterized by systemic inflammation, often presents with thrombocytopenia, which at times, can be significant. Platelets contribute to the inflammatory response by interacting with leukocytes, endothelial cells, and the innate immune system. However, excessive platelet activation and consumption can lead to thrombocytopenia and exacerbate the severity of sepsis. Understanding the multifaceted roles of platelets in sepsis is crucial for developing effective therapeutic strategies. Targeting platelet-mediated inflammatory responses and promoting platelet production may offer potential avenues for improving outcomes in septic patients with thrombocytopenia. Future research should focus on elucidating the mechanisms underlying platelet dysfunction in sepsis and exploring novel therapeutic approaches to optimize platelet function and mitigate inflammation. This review explores the intricate relationship between platelets, inflammation, and thrombosis in the context of sepsis.
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Affiliation(s)
- Alireza Setarehaseman
- University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA;
| | - Abbas Mohammadi
- Department of Internal Medicine, Valley Health System, Las Vegas, NV 89119, USA;
| | - Robert W. Maitta
- University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA;
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14
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Banaszak LG, Clark PA, Peterson CG, Sheehan J. Acquired Bernard-Soulier-like syndrome due to a plasma-based inhibitor treated successfully with rituximab. Res Pract Thromb Haemost 2025; 9:102727. [PMID: 40264939 PMCID: PMC12013485 DOI: 10.1016/j.rpth.2025.102727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 02/20/2025] [Accepted: 03/06/2025] [Indexed: 04/24/2025] Open
Abstract
Background Bernard-Soulier syndrome (BSS) is an autosomal recessive disorder caused by deficient platelet glycoprotein Ib-IX-V expression resulting in abnormal bleeding, thrombocytopenia, giant platelets, and reduced platelet aggregation response to ristocetin that manifests in childhood. Acquired BSS is a rare disorder characterized by Bernard-Soulier (BS)-like platelet dysfunction in a patient without a history consistent with a bleeding disorder. Key Clinical Question Can acquired BSS respond to immune-directed therapy? Clinical Approach We describe a case of a 79-year-old man presenting with refractory epistaxis found to have an isolated BS-like platelet function defect due to a plasma-based inhibitor. He was treated with rituximab with immediate cessation of bleeding and normalization of platelet function studies. Conclusion To our knowledge, this is the first case of acquired BS-like syndrome described in the absence of systemic illness due to a presumed autoantibody, and we report the successful use of rituximab for treatment of this rare disorder.
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Affiliation(s)
- Lauren G. Banaszak
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
- University of Wisconsin Health Special Coagulation Lab, Madison, Wisconsin, USA
| | - Paula A. Clark
- University of Wisconsin Health Special Coagulation Lab, Madison, Wisconsin, USA
| | | | - John Sheehan
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
- University of Wisconsin Health Special Coagulation Lab, Madison, Wisconsin, USA
- University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
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15
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Wang Y, Mulder IA, Westendorp WF, Coutinho JM, van de Beek D. Immunothrombosis in Acute Ischemic Stroke. Stroke 2025; 56:553-563. [PMID: 39479751 DOI: 10.1161/strokeaha.124.048137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Ischemic stroke is one of the leading causes of disability and mortality worldwide. Thrombosis is the main pathological process of stroke and is therefore an important therapeutic target in stroke prevention. In recent years, with the development of endovascular treatment and therefore retrieving the thrombus for further investigation, evidence is accumulating that immune cells are inextricably linked to stroke pathogenesis. Circulating immune cells have been found to induce immunothrombosis, and they actively participate in the formation of the thrombus by promoting platelet recruitment and thrombin activation. Additionally, the formation of thromboinflammation leads to increased instability of atherosclerotic plaques. We review the concepts of stroke immunothrombosis and thromboinflammation and the effect of immune cells on vessel recanalization and patient outcome. In addition, we elaborate on the possible mechanism of immune cells being activated and participating in thrombosis in ischemic stroke.
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Affiliation(s)
- Yan Wang
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Inge A Mulder
- Department of Biomedical Engineering and Physics (I.A.M.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Microcirculation, the Netherlands (I.A.M.)
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Willeke F Westendorp
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Jonathan M Coutinho
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Diederik van de Beek
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
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16
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Xu F, Gao Y, Xin H, Cao C, Ma W, Sun W, Ma Q. A review on multifunctional calcium alginate fibers for full-time and multipurposed wound treatment: From fundamentals to advanced applications. Int J Biol Macromol 2025; 290:139133. [PMID: 39722391 DOI: 10.1016/j.ijbiomac.2024.139133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 12/09/2024] [Accepted: 12/22/2024] [Indexed: 12/28/2024]
Abstract
Recent progress in wound healing has highlighted the need for more effective treatment strategies capable of addressing the complex biological and physiological challenges of wound repair. Traditional wound dressings often fail to address the complex and evolving needs of chronic, acute, and burn wounds, particularly in terms of promoting healing, preventing infection, and supporting tissue regeneration. In response to these challenges, calcium alginate fibers (CAFs) have emerged as promising materials, characterized by their exceptional structural properties and diverse biological functions, offering significant commercial potential for the development of advanced wound dressings and therapeutic solutions. Here, a brief review of the CAFs for promoting wound healing is presented, with specific discussions of the fundamental characteristics of CAFs and its feasibility to be applied for adjusting physiological and pathological processes involved in wound healing. Then, a comprehensive and in-depth depiction of emerging representative fabrication techniques for generating CAFs is categorized and reviewed. Moreover, emerging applications benefits from the CAFs are reviewed, highlighting the multifunctional roles and benefits of CAFs in facilitating wound repair. Finally, the challenges and perspectives for further advancing CAFs toward a more powerful and versatile therapeutic strategy are discussed, particularly regarding new opportunities in biomedical research and clinical applications.
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Affiliation(s)
- Fenglan Xu
- Department of Clinical Pharmacy, The Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang 212001, China; School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Yang Gao
- Department of Pharmacy, Weifang People's Hospital, Weifang 261041, China; School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Huan Xin
- School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Chenxi Cao
- School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Wenyuan Ma
- School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Wentao Sun
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266113, China.
| | - Qingming Ma
- School of Pharmacy, Qingdao University, Qingdao 266071, China.
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17
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Peng Y, Zheng X, Zhang S, Luo Z, Song L, Chen H, Yao X. Advances in the activity of resveratrol and its derivatives in cardiovascular diseases. Arch Pharm (Weinheim) 2025; 358:e2400865. [PMID: 39956927 DOI: 10.1002/ardp.202400865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/29/2024] [Accepted: 01/14/2025] [Indexed: 02/18/2025]
Abstract
Cardiovascular diseases (CVDs), the leading cause of human death worldwide, are diseases that affect the heart and blood vessels and include arrhythmias, coronary atherosclerotic heart disease, hypertension, and so on. Resveratrol (RSV) is a natural nonflavonoid phenolic compound with antioxidant, anti-inflammatory, anticancer, and cardiovascular protection functions. RSV has shown significant protective effects against CVD. However, RSV's clinical application is limited by its tendency to be oxidized and metabolized easily. Therefore, it is necessary to optimize the RSV structure. This review will introduce the activity, synthesis, and structure-activity relationships of RSV derivatives, and the mechanism of the action of RSV in CVDs in recent years.
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Affiliation(s)
- Yaling Peng
- Institute of Pharmacy and Pharmacology, Hengyang Medicinal School, University of South China, Hengyang, Hunan, China
| | - Xing Zheng
- Institute of Pharmacy and Pharmacology, Hengyang Medicinal School, University of South China, Hengyang, Hunan, China
- Department of Pharmacy, Hunan Vocational College of Science and Technology, Changsha, Hunan, China
| | - Si Zhang
- Department of Pharmacy, Hunan Vocational College of Science and Technology, Changsha, Hunan, China
| | - Zhongqin Luo
- Shaoyang Hospital of TCM, Shaoyang, Hunan, China
| | - Li Song
- Institute of Pharmacy and Pharmacology, Hengyang Medicinal School, University of South China, Hengyang, Hunan, China
| | - Hongfei Chen
- Institute of Pharmacy and Pharmacology, Hengyang Medicinal School, University of South China, Hengyang, Hunan, China
| | - Xu Yao
- Institute of Pharmacy and Pharmacology, Hengyang Medicinal School, University of South China, Hengyang, Hunan, China
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18
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Méndez D, Tellería F, Alarcón M, Montecino-Garrido H, Molina-Gutiérrez N, Morales-Malvarez L, Deras B, Mansilla S, Castro L, Trostchansky A, Araya-Maturana R, Fuentes E. MITOCDNB DECREASES PLATELET ACTIVATION THROUGH ITS SELECTIVE ACTION ON MITOCHONDRIAL THIOREDOXIN REDUCTASE. Biomed Pharmacother 2025; 183:117840. [PMID: 39842272 DOI: 10.1016/j.biopha.2025.117840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 12/30/2024] [Accepted: 01/09/2025] [Indexed: 01/24/2025] Open
Abstract
Platelet inhibition is a fundamental objective to prevent and treat thrombus formation. Platelet activation depends on mitochondrial function. This study aims to identify a new mitochondria-targeting compound with antiplatelet activity at safe concentrations in vitro. Cytotoxicity and viability tests were performed on human platelets from volunteer donors, together with experiments on aggregation, platelet activation, mitochondrial function, mitochondrial respiration, and thioredoxin reductase 2 (TrxR2) enzymatic activity in isolated platelet mitochondria. The compound MitoCDNB, corresponding to the molecule 5-chloro-2,4-dinitrophenylamino linked with triphenylphosphonium cation (TPP+) by a butyl chain and methanesulfonate as the counterion, was evaluated. MitoCDNB demonstrates potent, high mitochondria-selective antiplatelet effects that provide a novel approach to platelet inhibition with potentially minimized systemic risks. Here, we describe the first compound that inhibits platelet activation by decreasing TrxR2 enzymatic activity and collagen-stimulated maximal mitochondrial respiration, preventing aggregation and platelet activation. These results can be used to develop new antiplatelet drugs targeting mitochondria.
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Affiliation(s)
- Diego Méndez
- Thrombosis and Healthy Aging Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Medical Technology School, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
| | - Francisca Tellería
- Thrombosis and Healthy Aging Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Medical Technology School, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
| | - Marcelo Alarcón
- Thrombosis and Healthy Aging Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Medical Technology School, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
| | - Héctor Montecino-Garrido
- Thrombosis and Healthy Aging Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Medical Technology School, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
| | - Nacim Molina-Gutiérrez
- Thrombosis and Healthy Aging Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Medical Technology School, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
| | - Lisandra Morales-Malvarez
- Thrombosis and Healthy Aging Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Medical Technology School, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile; Instituto de Química de Recursos Naturales, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Universidad de Talca, Talca 3460000, Chile
| | - Bessy Deras
- Thrombosis and Healthy Aging Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Medical Technology School, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
| | - Santiago Mansilla
- Departamento de Métodos Cuantitativos and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
| | - Laura Castro
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
| | - Andrés Trostchansky
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
| | - Ramiro Araya-Maturana
- Instituto de Química de Recursos Naturales, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Universidad de Talca, Talca 3460000, Chile.
| | - Eduardo Fuentes
- Thrombosis and Healthy Aging Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Medical Technology School, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile.
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19
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Rajić J, Grdović N, Marković A, Škoro N, Dinić S, Uskoković A, Arambašić Jovanović J, Đorđević M, Sarić A, Vidaković M, Puač N, Mihailović M. Plasma-Activated Water Improve Wound Healing in Diabetic Rats by Influencing the Inflammatory and Remodelling Phase. Int J Mol Sci 2025; 26:1265. [PMID: 39941031 PMCID: PMC11818764 DOI: 10.3390/ijms26031265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/25/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Diabetic foot ulcers have an enormous impact on patients' quality of life and represent a major economic burden. The cause is delayed and incomplete wound healing due to hyperglycemia, reduced blood flow, infections, oxidative stress and chronic inflammation. Plasma-activated water (PAW) is emerging as a new therapeutic approach in wound treatment, as it has many of the advantages of cold atmospheric plasma but is easier to apply, thus allowing for widespread use. The aim of this study was to investigate the potential of PAW to improve wound healing in diabetic rats, with a focus on uncovering the underlying mechanisms. Two full-thickness wounds in control and diabetic animals were treated with PAW, and healing was monitored for 15 days at five time points. PAW improved wound healing in diabetic rats and mainly affected the inflammatory phase of wound healing. Application of PAW decreased the number of inflammatory cells, myeloperoxidase (MPO) and N-acetyl-b-D-glycosaminidase (NAG) activity, as well as the mRNA expression of proinflammatory genes in diabetic rats. Ten days after injury, PAW treatment increased collagen deposition in the diabetic animals by almost 10% without affecting collagen mRNA expression, and this is in correlation with a decrease in the Mmp-9/Timp-1 ratio. In conclusion, PAW treatment affects wound healing by reducing the inflammatory response and influencing extracellular matrix turnover, suggesting that it has great potential to accelerate the healing of diabetic wounds.
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Affiliation(s)
- Jovana Rajić
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia; (N.G.); (S.D.); (A.U.); (J.A.J.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Nevena Grdović
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia; (N.G.); (S.D.); (A.U.); (J.A.J.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Anđelija Marković
- Center for Non-Equilibrium Processes, Institute of Physics, National Institute of Republic of Serbia, University of Belgrade, Pregrevica 118, 11080 Belgrade, Serbia; (A.M.); (N.Š.)
| | - Nikola Škoro
- Center for Non-Equilibrium Processes, Institute of Physics, National Institute of Republic of Serbia, University of Belgrade, Pregrevica 118, 11080 Belgrade, Serbia; (A.M.); (N.Š.)
| | - Svetlana Dinić
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia; (N.G.); (S.D.); (A.U.); (J.A.J.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Aleksandra Uskoković
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia; (N.G.); (S.D.); (A.U.); (J.A.J.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Jelena Arambašić Jovanović
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia; (N.G.); (S.D.); (A.U.); (J.A.J.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Marija Đorđević
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia; (N.G.); (S.D.); (A.U.); (J.A.J.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Ana Sarić
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia; (N.G.); (S.D.); (A.U.); (J.A.J.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Melita Vidaković
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia; (N.G.); (S.D.); (A.U.); (J.A.J.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Nevena Puač
- Center for Non-Equilibrium Processes, Institute of Physics, National Institute of Republic of Serbia, University of Belgrade, Pregrevica 118, 11080 Belgrade, Serbia; (A.M.); (N.Š.)
| | - Mirjana Mihailović
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia; (N.G.); (S.D.); (A.U.); (J.A.J.); (M.Đ.); (A.S.); (M.V.); (M.M.)
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20
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Liu L, Jing R, Yao L, Wang Y, Mu L, Hu Y. Hemostasis Strategies and Recent Advances in Hydrogels for Managing Uncontrolled Hemorrhage. ACS APPLIED BIO MATERIALS 2025; 8:42-61. [PMID: 39745272 DOI: 10.1021/acsabm.4c01221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2025]
Abstract
Hemorrhage continues to pose a significant challenge in various medical contexts, underscoring the need for advanced hemostatic materials. Hemostatic hydrogels have gained recognition as innovative tools for addressing uncontrollable bleeding, attributed to their distinctive features including biological compatibility, tunable mechanical properties, and exceptional hemostatic performance. This review provides a comprehensive overview of hemostatic hydrogels that offer rapid and effective bleeding control. Particularly, this review focuses on hemostatic hydrogel design and associated hemostatic mechanisms. Additionally, recent advancements in the application of these materials are discussed in detail, especially in clinical trials. Finally, the challenges and potential advancements of hemostatic hydrogels are analyzed and assessed. This review seeks to emphasize the role of hydrogels in biomedical applications for hemorrhage control and provide perspectives on the innovation of clinically applicable hemostatic materials.
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Affiliation(s)
- Lijun Liu
- Department of Pharmacy, Medical Supplier Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Rui Jing
- Department of Pharmacy, Medical Supplier Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Lei Yao
- Department of Pharmacy, Medical Supplier Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Yanbo Wang
- Department of Pharmacy, Medical Supplier Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Lihua Mu
- Department of Pharmacy, Medical Supplier Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Yuan Hu
- Department of Pharmacy, Medical Supplier Center, Chinese PLA General Hospital, Beijing 100853, China
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21
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Garzon Dasgupta AK, Pongérard A, Mallo L, Eckly A, Lanza F, Boiron O, Knapp Y, Strassel C. Uniform impact on individual megakaryocytes is essential for efficient in vitro platelet production. Sci Rep 2025; 15:1809. [PMID: 39805910 PMCID: PMC11730292 DOI: 10.1038/s41598-024-79949-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 11/13/2024] [Indexed: 01/16/2025] Open
Abstract
Different approaches are being developed to efficiently produce in vitro platelets from cultured megakaryocytes to meet the constant demand of platelet transfusion and serve for research purposes. Recent works have shown that turbulence and periodic stress can significantly enhance platelet yield. Here we have developed and characterized a platelet production device that takes in account these properties. This device is based on the Taylor-Couette reactor in which a suspension is confined and sheared between two concentric cylinders. We have demonstrated that such a system allows obtaining high number of in vitro platelets per megakaryocyte with native-like morphology and functional properties. Using the combination of in silico and in vitro techniques, we claimed that overall turbulent conditions are not sufficient for efficient platelet release, and highlighted the importance of the uniform impact of flow on each megakaryocyte, a property that must be taken into account along with general flow characteristics when designing platelet release bioreactors. In addition, we have demonstrated that our system can be scaled up to large volumes without loss of efficiency, a significant advantage for the industrialization of platelet culture. In conclusion, we have developed a platelet production device with a predictable and highly precise effect on each megakaryocyte.
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Affiliation(s)
- Andrei K Garzon Dasgupta
- Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, Strasbourg, F-67065, France
| | - Anaïs Pongérard
- Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, Strasbourg, F-67065, France
| | - Léa Mallo
- Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, Strasbourg, F-67065, France
| | - Anita Eckly
- Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, Strasbourg, F-67065, France
| | - François Lanza
- Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, Strasbourg, F-67065, France
| | - Olivier Boiron
- CNRS, Université Aix-Marseille, Ecole Centrale Marseille, IRPHE UMR7342, Marseille, F-13000, France
| | - Yannick Knapp
- Université Avignon, LAPEC EA4278, Avignon, F-84000, France
| | - Catherine Strassel
- Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, Strasbourg, F-67065, France.
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22
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Liu C, Liu CJ, Tian WQ, Yao W, Miao Y, Zhang M, Yuan XQ, Deng YL, Lu WQ, Li YF, Zeng Q. Phthalate exposures, blood coagulation function, and assisted reproductive technology outcomes: Results from the TREE cohort study. ENVIRONMENTAL RESEARCH 2025; 264:120412. [PMID: 39577722 DOI: 10.1016/j.envres.2024.120412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/24/2024] [Accepted: 11/20/2024] [Indexed: 11/24/2024]
Abstract
BACKGROUND Phthalate exposures have been shown to be inversely associated with reproductive success among women undergoing assisted reproductive technology (ART). However, the underlying mechanisms are unknown. OBJECTIVES To explore blood coagulation function as the mediating role of associations between exposure to phthalates and ART outcomes. METHODS A total of 735 women from the Tongji Reproductive and Environmental (TREE) study were included. Urine samples collected at recruitment were quantified for 8 phthalate metabolites, and blood clotting time and platelet indices were also determined. Generalized linear regression, logistic regression, weighted quantile sum (WQS) regression, or Bayesian kernel machine regression (BKMR) models were applied to investigate the associations among individual and mixture of phthalate metabolites, blood coagulation parameters, and ART outcomes. The mediation role of blood coagulation parameters was estimated by mediation analysis. RESULTS Mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), monobenzyl phthalate (MBzP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and molar sum of di(2-ethylhexyl) phthalate metabolites (∑DEHP) were positively associated with platelet indices. Phthalate metabolite mixture was also positively associated with platelet count (PLT), mean platelet volume (MPV), and plateletcrit (PCT), whereas inversely associated with international normalized ratio (INR). Meanwhile, PLT and PCT were inversely associated with the odds of implantation success and live birth, while prothrombin time and INR were positively associated with the odds of implantation success. Mediation analyses showed indirect effects of above-mentioned phthalate metabolites and phthalate mixture on the odds of implantation success and live birth through PLT or PCT, with the proportion mediated ranging from 3.44% to 8.96%. CONCLUSIONS Phthalates may increase the risks of ART failure through enhancing blood coagulation function. More studies are warranted to verify the findings.
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Affiliation(s)
- Chong Liu
- Department of Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chang-Jiang Liu
- NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing, China
| | - Wen-Qu Tian
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China
| | - Wen Yao
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China
| | - Yu Miao
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Min Zhang
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiao-Qiong Yuan
- Center for Reproductive Medicine, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan-Ling Deng
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Wen-Qing Lu
- Department of Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing, China
| | - Yu-Feng Li
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China.
| | - Qiang Zeng
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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23
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Yang J, Xiao L, Zhang L, Luo G, Ma Y, Wang X, Zhang Y. Platelets: A Potential Factor that Offers Strategies for Promoting Bone Regeneration. TISSUE ENGINEERING. PART B, REVIEWS 2024; 30:631-643. [PMID: 38482796 DOI: 10.1089/ten.teb.2024.0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/13/2024]
Abstract
Bone defects represent a prevalent category of clinical injuries, causing significant pain and escalating health care burdens. Effectively addressing bone defects is thus of paramount importance. Platelets, formed from megakaryocyte lysis, have emerged as pivotal players in bone tissue repair, inflammatory responses, and angiogenesis. Their intracellular storage of various growth factors, cytokines, and membrane protein receptors contributes to these crucial functions. This article provides a comprehensive overview of platelets' roles in hematoma structure, inflammatory responses, and angiogenesis throughout the process of fracture healing. Beyond their application in conjunction with artificial bone substitute materials for treating bone defects, we propose the potential future use of anticoagulants such as heparin in combination with these materials to regulate platelet number and function, thereby promoting bone healing. Ultimately, we contemplate whether manipulating platelet function to modulate bone healing could offer innovative ideas and directions for the clinical treatment of bone defects. Impact statement Given that 5-10% of fracture patients with delayed bone healing or even bone nonunion, this review explores the potential role of platelets in bone healing (directly/indirectly) and proposes ideas and directions for the future as to whether it is possible to promote bone healing and improve fracture healing rates by modulating platelets.
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Affiliation(s)
- Jingjing Yang
- Department of Hygiene Toxicology, School of Public Health, Zunyi Medical University, Zunyi, China
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Key Laboratory of Maternal and Child Health and Exposure Science of Guizhou Higher Education Institutes, Zunyi Medical University, Zunyi, China
- Guizhou Provincial Key Laboratory of Medicinal Biotechnology in Colleges and Universities, Zunyi Medical University, Zunyi, China
| | - Lan Xiao
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- School of Medicine and Dentistry, Griffith University, Queensland, Australia
| | - Lijia Zhang
- Department of Hygiene Toxicology, School of Public Health, Zunyi Medical University, Zunyi, China
- Key Laboratory of Maternal and Child Health and Exposure Science of Guizhou Higher Education Institutes, Zunyi Medical University, Zunyi, China
| | - Guochen Luo
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yaping Ma
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Xin Wang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Guizhou Provincial Key Laboratory of Medicinal Biotechnology in Colleges and Universities, Zunyi Medical University, Zunyi, China
| | - Yi Zhang
- Department of Hygiene Toxicology, School of Public Health, Zunyi Medical University, Zunyi, China
- Key Laboratory of Maternal and Child Health and Exposure Science of Guizhou Higher Education Institutes, Zunyi Medical University, Zunyi, China
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24
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Schaale D, Laspa Z, Balmes A, Sigle M, Dicenta-Baunach V, Hochuli R, Fu X, Serafimov K, Castor T, Harm T, Müller KAL, Rohlfing AK, Laufer S, Schäffer TE, Lämmerhofer M, Gawaz M. Hemin promotes platelet activation and plasma membrane disintegration regulated by the subtilisin-like proprotein convertase furin. FASEB J 2024; 38:e70155. [PMID: 39530531 DOI: 10.1096/fj.202400863rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 10/14/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
Platelet activation plays a critical role in thrombosis and hemostasis. Several pathophysiological situations lead to hemolysis, resulting in the liberation of free ferric iron-containing hemin. Hemin has been shown to activate platelets and induce thrombo-inflammation. Classical antiplatelet therapy failed to prevent hemin-induced platelet activation. Thus, the aim of the present study was to characterize the mechanism of hemin-induced platelet death (ferroptosis). We evaluated the in vitro effect of hemin on platelet activation, signaling, oxylipins, and plasma membrane destruction using light transmission aggregometry, ex vivo thrombus formation, multiparametric flow cytometry, micro-UHPLC mass spectrometry for oxylipin profiling, and scanning ion conductance microscopy (SICM). We found that hemin induces platelet cell death indicated by increased ROS levels, phosphatidyl serine (PS) exposure, and loss of mitochondrial membrane potential (ΔΨm). Further, hemin causes lipid peroxidation and generation of distinct oxylipins, which strongly affects plasma membrane integrity leading to generation of platelet-derived microvesicles. Interestingly, hemin-dependent platelet death (ferroptosis) is specifically regulated by the subtilisin-like proprotein convertase furin. In summary, platelet undergo a non-apoptotic cell death mediated by furin. Inhibition of furin may offer a therapeutic strategy to control hemin-induced thrombosis and thrombo-inflammation at a site of hemolysis.
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Affiliation(s)
- David Schaale
- Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Zoi Laspa
- Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Aylin Balmes
- Institute of Applied Physics, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Manuel Sigle
- Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Valerie Dicenta-Baunach
- Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Ravi Hochuli
- Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Xiaoqing Fu
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Kristian Serafimov
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Tatsiana Castor
- Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Tobias Harm
- Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Karin Anne Lydia Müller
- Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Anne-Katrin Rohlfing
- Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Stefan Laufer
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Tilman E Schäffer
- Institute of Applied Physics, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Michael Lämmerhofer
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Meinrad Gawaz
- Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany
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25
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Ostilla L, Knopoff K, Myers P, Morocco P. Disorders of Coagulation in the Newborn. Neoreviews 2024; 25:e694-e709. [PMID: 39482239 DOI: 10.1542/neo.25-11-e694] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 06/28/2024] [Accepted: 06/28/2024] [Indexed: 11/03/2024]
Abstract
The coagulation system in newborns varies from that of children and adults, with many circulating hemostatic factors being lower in the newborn. Infants are also susceptible to diseases and conditions in the pregnant person affecting their coagulation system, which can make it difficult to rapidly identify the cause behind coagulopathy in a neonate. Coagulation disorders can result in high levels of infant morbidity and mortality, which makes early diagnosis and prompt treatment critical. This review outlines the clinical characteristics, diagnosis and management, epidemiology, and etiologies of both common and uncommon congenital and acquired forms of neonatal coagulopathy.
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Affiliation(s)
- Lorena Ostilla
- Section of Neonatology, Department of Pediatrics, Northwestern University, Chicago, IL
| | - Karyssa Knopoff
- Section of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, University of Chicago, Chicago, IL
| | - Patrick Myers
- Section of Neonatology, Department of Pediatrics, Northwestern University, Chicago, IL
| | - Perry Morocco
- Section of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, University of Chicago, Chicago, IL
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26
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Knopoff K, Ostilla L, Morocco P, Myers P. Thrombotic Disorders in the Newborn. Neoreviews 2024; 25:e710-e719. [PMID: 39482244 DOI: 10.1542/neo.25-11-e710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 06/28/2024] [Accepted: 06/30/2024] [Indexed: 11/03/2024]
Abstract
The coagulation and thrombotic systems of an infant are fundamentally different from those of adults and older children. Hemostatic factors have inherently lower circulation levels in infants and are also affected prenatally by conditions of pregnancy. The unique physiology of neonates can contribute to a procoagulant state, which can result in a high level of morbidity and mortality. This review outlines the epidemiology, clinical characteristics, diagnosis and management, and etiologies of congenital and acquired forms of thrombotic disorders, with a discussion of the evaluation for hypercoagulation.
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Affiliation(s)
- Karyssa Knopoff
- Section of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, University of Chicago, Chicago, IL
| | - Lorena Ostilla
- Section of Neonatology, Department of Pediatrics, Northwestern University, Chicago, IL
| | - Perry Morocco
- Section of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, University of Chicago, Chicago, IL
| | - Patrick Myers
- Section of Neonatology, Department of Pediatrics, Northwestern University, Chicago, IL
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27
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Knauss EA, Guci J, Luc N, Disharoon D, Huang GH, Gupta AS, Nieman MT. Mice with Reduced PAR4 Reactivity show Decreased Venous Thrombosis and Platelet Procoagulant Activity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.14.617127. [PMID: 39463946 PMCID: PMC11507748 DOI: 10.1101/2024.10.14.617127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
Background Hypercoagulation and thrombin generation are major risk factors for venous thrombosis. Sustained thrombin signaling through PAR4 promotes platelet activation, phosphatidylserine exposure, and subsequent thrombin generation. A single-nucleotide polymorphism in PAR4 (rs2227376) changes proline to leucine extracellular loop 3 (P310L), which decreases PAR4 reactivity and is associated with a lower risk for venous thromboembolism (VTE) in a GWAS meta-analysis. Objective The goal of this study is to determine the mechanism for the association of rs2227376 with reduced risk for VTE in using mice with a homologous mutation (PAR4-P322L). Methods Venous thrombosis was examined using our recently generated PAR4-P322L mice in the inferior vena cava stasis and stenosis models. Coagulation and clot stability was measured using rotational thromboelastometry (ROTEM). Thrombin generating potential was measured in platelet-rich plasma. Phosphatidylserine surface expression and platelet-neutrophil aggregates were analyzed using flow cytometry. Results PAR4P/L and PAR4L/L had reduced incidence and size of venous clots at 48 hours. PAR4P/L and PAR4L/L platelets had progressively decreased phosphatidylserine in response to thrombin and convulxin, which led to decreased thrombin generation and decreased PAR4-mediated platelet-neutrophil aggregation. Conclusions The leucine allele in extracellular loop 3, PAR4-322L leads to fewer procoagulant platelets and decreased endogenous thrombin potential. This decreased ability to generate thrombin offers a mechanism for PAR4's role in VTE highlighting a key role for PAR4 signaling.
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Affiliation(s)
- Elizabeth A. Knauss
- Case Western Reserve University, School of Medicine, Department of Pharmacology, Cleveland, OH United States
| | - Johana Guci
- Case Western Reserve University, School of Medicine, Department of Pharmacology, Cleveland, OH United States
| | - Norman Luc
- Case Western Reserve University, Department of Biomedical Engineering, Cleveland, OH United States
| | - Dante Disharoon
- Case Western Reserve University, Department of Biomedical Engineering, Cleveland, OH United States
| | - Grace H. Huang
- Case Western Reserve University, School of Medicine, Department of Pharmacology, Cleveland, OH United States
| | - Anirban Sen Gupta
- Case Western Reserve University, Department of Biomedical Engineering, Cleveland, OH United States
| | - Marvin T. Nieman
- Case Western Reserve University, School of Medicine, Department of Pharmacology, Cleveland, OH United States
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28
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Hwang S, Park MS, Koo AJ, Yoo E, Song SH, Kim HK, Park MH, Kang JS. Compound K Promotes Megakaryocytic Differentiation by NLRP3 Inflammasome Activation. Biomolecules 2024; 14:1257. [PMID: 39456190 PMCID: PMC11506438 DOI: 10.3390/biom14101257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/27/2024] [Accepted: 10/02/2024] [Indexed: 10/28/2024] Open
Abstract
Platelets are essential blood components that maintain hemostasis, prevent excessive bleeding, and facilitate wound healing. Reduced platelet counts are implicated in various diseases, including leukemia, hepatitis, cancer, and Alzheimer's disease. Enhancing megakaryocytic differentiation is a promising strategy to increase platelet production. Compound K (CK), a major bioactive metabolite of ginsenosides from Panax ginseng, has demonstrated anti-cancer and neuroprotective properties. In this study, we investigated the effects of CK on megakaryocytic differentiation and apoptosis in chronic myeloid leukemia (CML) cell lines K562 and Meg-01. CK treatment significantly upregulated the mRNA expression of key megakaryocytic differentiation markers, including CD61, CD41, and CD42a, and promoted the formation of large, multinucleated cells in K562 cells. Additionally, flow cytometry analysis revealed that CK at 5 µM induced apoptosis, a critical process in thrombocytopoiesis, in both K562 and Meg-01 cells. RT2 Profiler PCR array analysis further identified a marked increase in the expression of genes associated with the activation of the NLRP3 inflammasome in CK-treated K562 and Meg-01 cells. This study is the first to demonstrate that CK promotes megakaryocytic differentiation and apoptosis through the activation of the ERK/EGR1 and NLRP3 inflammasome pathways. These findings suggest that CK may enhance platelet production, indicating its potential as a therapeutic candidate for platelet-related disorders and other associated diseases.
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MESH Headings
- Humans
- Megakaryocytes/drug effects
- Megakaryocytes/metabolism
- Megakaryocytes/cytology
- Cell Differentiation/drug effects
- NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
- Inflammasomes/metabolism
- Inflammasomes/drug effects
- K562 Cells
- Apoptosis/drug effects
- Ginsenosides/pharmacology
- Platelet Membrane Glycoprotein IIb/metabolism
- Integrin beta3/metabolism
- Integrin beta3/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
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Affiliation(s)
- Seonhwa Hwang
- College of Pharmacy, Kyungsung University, 309 Suyeong-ro, Busan 48434, Republic of Korea; (S.H.); (M.-S.P.); (S.-H.S.); (H.-K.K.)
- Brain Busan 21 Plus Research Project Group, Kyungsung University, Busan 48434, Republic of Korea
| | - Min-Seo Park
- College of Pharmacy, Kyungsung University, 309 Suyeong-ro, Busan 48434, Republic of Korea; (S.H.); (M.-S.P.); (S.-H.S.); (H.-K.K.)
- Brain Busan 21 Plus Research Project Group, Kyungsung University, Busan 48434, Republic of Korea
| | - Anthony Junhoe Koo
- College of Engineering, North Carolina A&T State University, Greensboro, NC 27411, USA;
| | - Eunsoo Yoo
- Chemical, Biological, and Bioengineering Department, North Carolina A&T State University, Greensboro, NC 27411, USA;
| | - Seh-Hyon Song
- College of Pharmacy, Kyungsung University, 309 Suyeong-ro, Busan 48434, Republic of Korea; (S.H.); (M.-S.P.); (S.-H.S.); (H.-K.K.)
| | - Hye-Kyung Kim
- College of Pharmacy, Kyungsung University, 309 Suyeong-ro, Busan 48434, Republic of Korea; (S.H.); (M.-S.P.); (S.-H.S.); (H.-K.K.)
- Brain Busan 21 Plus Research Project Group, Kyungsung University, Busan 48434, Republic of Korea
| | - Min-Hi Park
- College of Pharmacy, Kyungsung University, 309 Suyeong-ro, Busan 48434, Republic of Korea; (S.H.); (M.-S.P.); (S.-H.S.); (H.-K.K.)
- Brain Busan 21 Plus Research Project Group, Kyungsung University, Busan 48434, Republic of Korea
| | - Jae-Seon Kang
- College of Pharmacy, Kyungsung University, 309 Suyeong-ro, Busan 48434, Republic of Korea; (S.H.); (M.-S.P.); (S.-H.S.); (H.-K.K.)
- Brain Busan 21 Plus Research Project Group, Kyungsung University, Busan 48434, Republic of Korea
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Starodubtseva ES, Karogodina TY, Moskalensky AE. Platelet activation near point-like source of agonist: Experimental insights and computational model. PLoS One 2024; 19:e0308679. [PMID: 39361659 PMCID: PMC11449293 DOI: 10.1371/journal.pone.0308679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 07/29/2024] [Indexed: 10/05/2024] Open
Abstract
Disorders of hemostasis resulting in bleeding or thrombosis are leading cause of mortality in the world. Blood platelets are main players in hemostasis, providing the primary response to the vessel wall injury. In this case, they rapidly switch to the activated state in reaction to the exposed chemical substances such as ADP, collagen and thrombin. Molecular mechanisms of platelet activation are known, and detailed computational models are available. However, they are too complicated for large-scale problems (e.g. simulation of the thrombus growth) where less detailed models are required, which still should take into account the variation of agonist concentration and heterogeneity of platelets. In this paper, we present a simple model of the platelet population response to a spatially inhomogeneous stimulus. First, computational nodes modeling platelets are placed randomly in space. Each platelet is assigned the specific threshold for agonist, which determines whether it becomes activated at a given time. The distribution of the threshold value in a population is assumed to be log-normal. The model was validated against experimental data in a specially designed system, where the photorelease of ADP was caused by localized laser stimulus. In this system, a concentration of ADP obeys 2-dimensional Gaussian distribution which broadens due to the diffusion. The response of platelets to the point-like source of ADP is successfully described by the presented model. Our results advance the understanding of platelet function during hemostatic response. The simulation approach can be incorporated into larger computational models of thrombus formation.
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Affiliation(s)
- Ezhena S. Starodubtseva
- Laboratory of Optics and Dynamics of Biological Systems, Novosibirsk State University, Novosibirsk, Russia
| | - Tatyana Yu. Karogodina
- Laboratory of Optics and Dynamics of Biological Systems, Novosibirsk State University, Novosibirsk, Russia
- Laboratory of Photoactivatable Processes, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, Novosibirsk, Russia
| | - Alexander E. Moskalensky
- Laboratory of Optics and Dynamics of Biological Systems, Novosibirsk State University, Novosibirsk, Russia
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Pawluk H, Tafelska-Kaczmarek A, Sopońska M, Porzych M, Modrzejewska M, Pawluk M, Kurhaluk N, Tkaczenko H, Kołodziejska R. The Influence of Oxidative Stress Markers in Patients with Ischemic Stroke. Biomolecules 2024; 14:1130. [PMID: 39334896 PMCID: PMC11430825 DOI: 10.3390/biom14091130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/27/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Stroke is the second leading cause of death worldwide, and its incidence is rising rapidly. Acute ischemic stroke is a subtype of stroke that accounts for the majority of stroke cases and has a high mortality rate. An effective treatment for stroke is to minimize damage to the brain's neural tissue by restoring blood flow to decreased perfusion areas of the brain. Many reports have concluded that both oxidative stress and excitotoxicity are the main pathological processes associated with ischemic stroke. Current measures to protect the brain against serious damage caused by stroke are insufficient. For this reason, it is important to investigate oxidative and antioxidant strategies to reduce oxidative damage. This review focuses on studies assessing the concentration of oxidative stress biomarkers and the level of antioxidants (enzymatic and non-enzymatic) and their impact on the clinical prognosis of patients after stroke. Mechanisms related to the production of ROS/RNS and the role of oxidative stress in the pathogenesis of ischemic stroke are presented, as well as new therapeutic strategies aimed at reducing the effects of ischemia and reperfusion.
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Affiliation(s)
- Hanna Pawluk
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
| | - Agnieszka Tafelska-Kaczmarek
- Department of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Torun, Poland
| | - Małgorzata Sopońska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
| | - Marta Porzych
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
| | - Martyna Modrzejewska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
| | - Mateusz Pawluk
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
| | - Natalia Kurhaluk
- Institute of Biology, Pomeranian University in Slupsk, Arciszewski 22B, 76-200 Slupsk, Poland
| | - Halina Tkaczenko
- Institute of Biology, Pomeranian University in Slupsk, Arciszewski 22B, 76-200 Slupsk, Poland
| | - Renata Kołodziejska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
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Puspitasari YM, Ministrini S, Han J, Karch C, Prisco F, Liberale L, Bengs S, Akhmedov A, Montecucco F, Beer JH, Lüscher TF, Bongiovanni D, Camici GG. Hutchinson-Gilford progeria syndrome mice display accelerated arterial thrombus formation and increased platelet reactivity. Thromb Res 2024; 241:109100. [PMID: 39032390 DOI: 10.1016/j.thromres.2024.109100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 07/12/2024] [Accepted: 07/17/2024] [Indexed: 07/23/2024]
Abstract
INTRODUCTION Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare premature aging genetic disorder caused by a point mutation in the lamin A gene, LMNA. Children with HGPS display short lifespans and typically die due to myocardial infarction or ischemic stroke, both acute cardiovascular events that are tightly linked to arterial thrombosis. Despite this fact, the effect of the classic HGPS LMNA gene mutation on arterial thrombosis remains unknown. METHODS Heterozygous LmnaG609G knock-in (LmnaG609G/+) mice, yielding an equivalent classic mutation observed in HGPS patients (c.1824C>T; pG608G mutation in the human LMNA gene) and corresponding wild-type (WT) control littermates underwent photochemically laser-induced carotid injury to trigger thrombosis. Coagulation and fibrinolytic factors were measured. Furthermore, platelet activation and reactivity were investigated. RESULTS LmnaG609G/+ mice displayed accelerated arterial thrombus formation, as underlined by shortened time to occlusion compared to WT littermates. Levels of factors involved in the coagulation and fibrinolytic system were comparable between groups, while LmnaG609G/+ animals showed higher plasma levels of thrombin-antithrombin complex and lower levels of antithrombin. Bone marrow analysis showed larger megakaryocytes in progeric mice. Lastly, enhanced platelet activation upon adenosine diphosphate, collagen-related peptide, and thrombin stimulation was observed in LmnaG609G/+ animals compared to the WT group, indicating a higher platelet reactivity in progeric animals. CONCLUSIONS LMNA mutation in HGPS mice accelerates arterial thrombus formation, which is mediated, at least in part, by enhanced platelet reactivity, which consequently augments thrombin generation. Given the wide spectrum of antiplatelet agents available clinically, further investigation is warranted to consider the most suitable antiplatelet regimen for children with HGPS to mitigate disease mortality and morbidity.
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Affiliation(s)
| | - Stefano Ministrini
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; Internal Medicine, Angiology and Atherosclerosis, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Jiaying Han
- Department of Internal Medicine I, School of Medicine, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany
| | - Caroline Karch
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Francesco Prisco
- Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Switzerland
| | - Luca Liberale
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
| | - Susan Bengs
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Alexander Akhmedov
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
| | - Jürg H Beer
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; Department of Cardiology, Royal Brompton & Harefield Hospitals, National Heart & Lung Institute, Imperial College, London, United Kingdom
| | - Dario Bongiovanni
- Department of Internal Medicine I, Cardiology, University Hospital Augsburg, University of Augsburg, Augsburg, Germany; Department of Cardiovascular Medicine, Humanitas Clinical and Research Center IRCCS and Humanitas University, Rozzano, Milan, Italy
| | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; Department of Research and Education, University Hospital Zurich, Zurich, Switzerland.
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Huang Y, Wang J, Guo Y, Shen L, Li Y. Fibrinogen binding to activated platelets and its biomimetic thrombus-targeted thrombolytic strategies. Int J Biol Macromol 2024; 274:133286. [PMID: 38908635 DOI: 10.1016/j.ijbiomac.2024.133286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 06/18/2024] [Accepted: 06/18/2024] [Indexed: 06/24/2024]
Abstract
Thrombosis is associated with various fatal arteriovenous syndromes including ischemic stroke, myocardial infarction, and pulmonary embolism. However, current clinical thrombolytic treatment strategies still have many problems in targeting and safety to meet the thrombolytic therapy needs. Understanding the molecular mechanism that underlies thrombosis is critical in developing effective thrombolytic strategies. It is well known that platelets play a central role in thrombosis and the binding of fibrinogen to activated platelets is a common pathway in the process of clot formation. Based on this, a concept of biomimetic thrombus-targeted thrombolytic strategy inspired from fibrinogen binding to activated platelets in thrombosis was proposed, which could selectively bind to activated platelets at a thrombus site, thus enabling targeted delivery and local release of thrombolytic agents for effective thrombolysis. In this review, we first summarized the main characteristics of platelets and fibrinogen, and then introduced the classical molecular mechanisms of thrombosis, including platelet adhesion, platelet activation and platelet aggregation through the interactions of activated platelets with fibrinogen. In addition, we highlighted the recent advances in biomimetic thrombus-targeted thrombolytic strategies which inspired from fibrinogen binding to activated platelets in thrombosis. The possible future directions and perspectives in this emerging area are briefly discussed.
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Affiliation(s)
- Yu Huang
- Department of Radiology, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai Sixth People's Hospital, 600 Yi Shan Road, Shanghai 200233, PR China.
| | - Jiahua Wang
- Department of Radiology, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai Sixth People's Hospital, 600 Yi Shan Road, Shanghai 200233, PR China
| | - Yuanyuan Guo
- Department of Radiology, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai Sixth People's Hospital, 600 Yi Shan Road, Shanghai 200233, PR China
| | - Lingyue Shen
- Department of Oral & Maxillofacial-Head & Neck Oncology, Department of Laser and Aesthetic Medicine, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stoma-tology & Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Shanghai 200011, PR China.
| | - Yuehua Li
- Department of Radiology, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai Sixth People's Hospital, 600 Yi Shan Road, Shanghai 200233, PR China.
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Guo CY, Mo R, Kim H. Surface topography modulates initial platelet adhesion to titanium substrata. J Oral Biol Craniofac Res 2024; 14:471-477. [PMID: 38962718 PMCID: PMC11220530 DOI: 10.1016/j.jobcr.2024.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 01/04/2024] [Accepted: 02/23/2024] [Indexed: 07/05/2024] Open
Abstract
The clinical success of implanted biomaterials such as dental implants is largely determined by the molecular signaling that occurs at the tissue-implant interface. The modification of surface topography is a widely-employed strategy for optimizing tissue integration with dental implants. However, little is known regarding the direct, cellular-level effects of substratum topography on platelet signaling and adhesion, despite these cells being the first to encounter the implant surface during surgical placement. Here we compared platelet adhesion and secretion on four (4) different titanium surfaces, notably, the modifications applied to commercially available dental implants: smooth (S) titanium; acid-etched (AE), sandblasted (SB) and a combined acid-etching/sandblasting procedure (SLA). Platelets were isolated from human blood, washed, and seeded on to the 4 test surfaces; platelet adhesion was quantified by microscopy. In addition, the secretion of critical molecules stored in platelet granules (platelet factor 4, PF4; soluble P-selectin, sCD62P; transforming growth factor-beta1, TGF-β1; platelet-derived growth factor-AB, PDGF-AB) was measured by enzyme-linked immunosorbent assay (ELISA) analysis of the supernatants. There was greater platelet adhesion to the rougher AE and SB surfaces, however, the concentration of the secreted growth factors was comparable on all surfaces. We conclude that while surface topography can be engineered to modulate initial platelet adhesion, granule secretion is likely regulated as a separate and independent process.
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Affiliation(s)
- Cecilia Yan Guo
- Centre for Blood Research, University of British Columbia, Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3
- Department of Oral Biological and Medical Sciences, University of British Columbia, 2199 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3
| | - Raymond Mo
- Centre for Blood Research, University of British Columbia, Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3
- Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3
| | - Hugh Kim
- Centre for Blood Research, University of British Columbia, Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3
- Department of Oral Biological and Medical Sciences, University of British Columbia, 2199 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3
- Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3
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Yoon I, Han JH, Jeon HJ. Advances in Platelet-Dysfunction Diagnostic Technologies. Biomolecules 2024; 14:714. [PMID: 38927117 PMCID: PMC11201885 DOI: 10.3390/biom14060714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
The crucial role of platelets in hemostasis and their broad implications under various physiological conditions underscore the importance of accurate platelet-function testing. Platelets are key to clotting blood and healing wounds. Therefore, accurate diagnosis and management of platelet disorders are vital for patient care. This review outlines the significant advancements in platelet-function testing technologies, focusing on their working principles and the shift from traditional diagnostic methods to more innovative approaches. These improvements have deepened our understanding of platelet-related disorders and ushered in personalized treatment options. Despite challenges such as interpretation of complex data and the costs of new technologies, the potential for artificial-intelligence integration and the creation of wearable monitoring devices offers exciting future possibilities. This review underscores how these technological advances have enhanced the landscape of precision medicine and provided better diagnostic and treatment options for platelet-function disorders.
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Affiliation(s)
- Inkwon Yoon
- Department of Smart Health Science and Technology, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Jong Hyeok Han
- Department of Smart Health Science and Technology, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Hee-Jae Jeon
- Department of Smart Health Science and Technology, Kangwon National University, Chuncheon 24341, Republic of Korea
- Department of Mechanical and Biomedical Engineering, Kangwon National University, Chuncheon 24341, Republic of Korea
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Han X, Knauss EA, Fuente MDL, Li W, Conlon RA, LePage DF, Jiang W, Renna SA, McKenzie SE, Nieman MT. A mouse model of the protease-activated receptor 4 Pro310Leu variant has reduced platelet reactivity. J Thromb Haemost 2024; 22:1715-1726. [PMID: 38508397 PMCID: PMC12036797 DOI: 10.1016/j.jtha.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 02/26/2024] [Accepted: 03/11/2024] [Indexed: 03/22/2024]
Abstract
BACKGROUND Protease-activated receptor 4 (PAR4) mediates thrombin signaling on platelets and other cells. Our recent structural studies demonstrated that a single nucleotide polymorphism in extracellular loop 3 and PAR4-P310L (rs2227376) leads to a hyporeactive receptor. OBJECTIVES The goal of this study was to determine how the hyporeactive PAR4 variant in extracellular loop 3 impacts platelet function in vivo using a novel knock-in mouse model (PAR4-322L). METHODS A point mutation was introduced into the PAR4 gene F2rl3 via CRISPR/Cas9 to create PAR4-P322L, the mouse homolog to human PAR4-P310L. Platelet response to PAR4 activation peptide (AYPGKF), thrombin, ADP, and convulxin was monitored by αIIbβ3 integrin activation and P-selectin translocation using flow cytometry or platelet aggregation. In vivo responses were determined by the tail bleeding assay and the ferric chloride-induced carotid artery injury model. RESULTS PAR4-P/L and PAR4-L/L platelets had a reduced response to AYPGKF and thrombin measured by P-selectin translocation or αIIbβ3 activation. The response to ADP and convulxin was unchanged among genotypes. In addition, both PAR4-P/L and PAR4-L/L platelets showed a reduced response to thrombin in aggregation studies. There was an increase in the tail bleeding time for PAR4-L/L mice. The PAR4-P/L and PAR4-L/L mice both showed an extended time to arterial thrombosis. CONCLUSION PAR4-322L significantly reduced platelet responsiveness to AYPGKF and thrombin, which is in agreement with our previous structural and cell signaling studies. In addition, PAR4-322L had prolonged arterial thrombosis time. Our mouse model provides a foundation to further evaluate the role of PAR4 in other pathophysiological contexts.
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Affiliation(s)
- Xu Han
- Case Western Reserve University School of Medicine, Department of Pharmacology, Cleveland, Ohio, USA
| | - Elizabeth A Knauss
- Case Western Reserve University School of Medicine, Department of Pharmacology, Cleveland, Ohio, USA
| | - Maria de la Fuente
- Case Western Reserve University School of Medicine, Department of Pharmacology, Cleveland, Ohio, USA
| | - Wei Li
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia, USA
| | - Ronald A Conlon
- Case Transgenic and Targeting Facility, Case Western Reserve University, Cleveland, Ohio, USA
| | - David F LePage
- Case Transgenic and Targeting Facility, Case Western Reserve University, Cleveland, Ohio, USA
| | - Weihong Jiang
- Case Transgenic and Targeting Facility, Case Western Reserve University, Cleveland, Ohio, USA
| | - Stephanie A Renna
- Department of Medicine, The Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Steven E McKenzie
- Department of Medicine, The Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Marvin T Nieman
- Case Western Reserve University School of Medicine, Department of Pharmacology, Cleveland, Ohio, USA.
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Yang J, Wang Z, Liang X, Wang W, Wang S. Multifunctional polypeptide-based hydrogel bio-adhesives with pro-healing activities and their working principles. Adv Colloid Interface Sci 2024; 327:103155. [PMID: 38631096 DOI: 10.1016/j.cis.2024.103155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 03/08/2024] [Accepted: 04/08/2024] [Indexed: 04/19/2024]
Abstract
Wound healing is a complex physiological process involving hemostasis, inflammation, proliferation, and tissue remodeling. Therefore, there is an urgent need for suitable wound dressings for effective and systematical wound management. Polypeptide-based hydrogel bio-adhesives offer unique advantages and are ideal candidates. However, comprehensive reviews on polypeptide-based hydrogel bio-adhesives for wound healing are still lacking. In this review, the physiological mechanisms and evaluation parameters of wound healing were first described in detail. Then, the working principles of hydrogel bio-adhesives were summarized. Recent advances made in multifunctional polypeptide-based hydrogel bio-adhesives involving gelatin, silk fibroin, fibrin, keratin, poly-γ-glutamic acid, ɛ-poly-lysine, serum albumin, and elastin with pro-healing activities in wound healing and tissue repair were reviewed. Finally, the current status, challenges, developments, and future trends of polypeptide-based hydrogel bio-adhesives were discussed, hoping that further developments would be stimulated to meet the growing needs of their clinical applications.
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Affiliation(s)
- Jiahao Yang
- School of Materials and Chemistry, University of Shanghai for Science and Technology, No. 516 Jungong Road, Shanghai 200093, P. R. China
| | - Zhengyue Wang
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR 999077, P. R. China
| | - Xiaoben Liang
- Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, P. R. China
| | - Wenyi Wang
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR 999077, P. R. China.
| | - Shige Wang
- School of Materials and Chemistry, University of Shanghai for Science and Technology, No. 516 Jungong Road, Shanghai 200093, P. R. China.
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Bindal P, Kumar V, Kapil L, Singh C, Singh A. Therapeutic management of ischemic stroke. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:2651-2679. [PMID: 37966570 DOI: 10.1007/s00210-023-02804-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 10/19/2023] [Indexed: 11/16/2023]
Abstract
Stroke is the third leading cause of years lost due to disability and the second-largest cause of mortality worldwide. Most occurrences of stroke are brought on by the sudden occlusion of an artery (ischemic stroke), but sometimes they are brought on by bleeding into brain tissue after a blood vessel has ruptured (hemorrhagic stroke). Alteplase is the only therapy the American Food and Drug Administration has approved for ischemic stroke under the thrombolysis category. Current views as well as relevant clinical research on the diagnosis, assessment, and management of stroke are reviewed to suggest appropriate treatment strategies. We searched PubMed and Google Scholar for the available therapeutic regimes in the past, present, and future. With the advent of endovascular therapy in 2015 and intravenous thrombolysis in 1995, the therapeutic options for ischemic stroke have expanded significantly. A novel approach such as vagus nerve stimulation could be life-changing for many stroke patients. Therapeutic hypothermia, the process of cooling the body or brain to preserve organ integrity, is one of the most potent neuroprotectants in both clinical and preclinical contexts. The rapid intervention has been linked to more favorable clinical results. This study focuses on the pathogenesis of stroke, as well as its recent advancements, future prospects, and potential therapeutic targets in stroke therapy.
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Affiliation(s)
- Priya Bindal
- Department of Pharmacology, ISF College of Pharmacy, Moga 142001, Affiliated to I.K Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Vishal Kumar
- Department of Pharmacology, ISF College of Pharmacy, Moga 142001, Affiliated to I.K Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Lakshay Kapil
- Department of Pharmacology, ISF College of Pharmacy, Moga 142001, Affiliated to I.K Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Charan Singh
- Department of Pharmaceutical Sciences, HNB Garhwal University (A Central University), Chauras Campus, Distt. Tehri Garhwal, Uttarakhand, 246174, India
| | - Arti Singh
- Department of Pharmacology, ISF College of Pharmacy, Moga 142001, Affiliated to I.K Gujral Punjab Technical University, Jalandhar, Punjab, India.
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M S M, Samal DB, Amirtraj J V, Subramanian S, Venkatasubbu GD. Enhanced coagulation cascade activation and styptic effects of Zn@SiO 2 nanocomposite. Colloids Surf B Biointerfaces 2024; 239:113927. [PMID: 38714078 DOI: 10.1016/j.colsurfb.2024.113927] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 04/22/2024] [Accepted: 04/23/2024] [Indexed: 05/09/2024]
Abstract
Humans often have bleeding, which exerts substantial selective pressure on the coagulation system to optimize hemostasis in a variety of situations. Uncontrolled hemorrhage due to severe trauma leads to morbidity and mortality. Although nonbiological surfaces such as silicates can activate coagulation factor XII (FXII), the presence of Zn (Zinc) in the material stimulates and activates the various steps in the coagulation cascade. This results in blood clotting. The Zn@SiO2 nanocomposite has an excellent hemostatic property that establishes hemostasis by activating the factors responsible for the formation of a stable clot called fibrin mesh. This can be used as a hemostatic agent during surgeries and in any other trauma condition related to bleeding. Zn@SiO2 was synthesized and characterized with XRD, FTIR and HRTEM. It is analyzed for its RBC (Red Blood Corpuscles) aggregation and Platelet adhesion ability, fibrin formation, thrombus formation and prothrombin time (PT), Activated Partial Thromboplastin Time (aPTT), D-dimer for its ability to activate the coagulation cascade to achieve stable clotting.
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Affiliation(s)
- Marvaan M S
- Department of Nanotechnology, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamilnadu, India
| | - Debashree Banita Samal
- Department of Biotechnology, School of Bioengineering, College of Engineering and technology, SRM Institute of science and technology, Katankulathur, Chengalpattu, Tamilnadu, India; Apollo Specialty Hospitals, OMR, Chennai, Tamilnadu, India
| | | | | | - G Devanand Venkatasubbu
- Department of Nanotechnology, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamilnadu, India.
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Lusardi M, Signorello MG, Russo E, Caviglia D, Ponassi M, Iervasi E, Rosano C, Brullo C, Spallarossa A. Structure-Activity Relationship Studies on Highly Functionalized Pyrazole Hydrazones and Amides as Antiproliferative and Antioxidant Agents. Int J Mol Sci 2024; 25:4607. [PMID: 38731825 PMCID: PMC11083148 DOI: 10.3390/ijms25094607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 04/19/2024] [Accepted: 04/20/2024] [Indexed: 05/13/2024] Open
Abstract
Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure-activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10-22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC50 values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N-acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure-activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives.
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Affiliation(s)
- Matteo Lusardi
- Department of Pharmacy, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; (M.L.); (M.G.S.); (E.R.); (D.C.); (C.B.)
| | - Maria Grazia Signorello
- Department of Pharmacy, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; (M.L.); (M.G.S.); (E.R.); (D.C.); (C.B.)
| | - Eleonora Russo
- Department of Pharmacy, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; (M.L.); (M.G.S.); (E.R.); (D.C.); (C.B.)
| | - Debora Caviglia
- Department of Pharmacy, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; (M.L.); (M.G.S.); (E.R.); (D.C.); (C.B.)
| | - Marco Ponassi
- Proteomics and Mass Spectrometry Unit, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132 Genova, Italy; (M.P.); (E.I.); (C.R.)
| | - Erika Iervasi
- Proteomics and Mass Spectrometry Unit, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132 Genova, Italy; (M.P.); (E.I.); (C.R.)
| | - Camillo Rosano
- Proteomics and Mass Spectrometry Unit, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132 Genova, Italy; (M.P.); (E.I.); (C.R.)
| | - Chiara Brullo
- Department of Pharmacy, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; (M.L.); (M.G.S.); (E.R.); (D.C.); (C.B.)
| | - Andrea Spallarossa
- Department of Pharmacy, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; (M.L.); (M.G.S.); (E.R.); (D.C.); (C.B.)
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Kouwenberg CV, Kuiper JJW, de Boer JH, Kalinina Ayuso V. Serum Biomarkers of Vascular Involvement in Childhood Uveitis. Transl Vis Sci Technol 2024; 13:9. [PMID: 38573655 PMCID: PMC11005069 DOI: 10.1167/tvst.13.4.9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 02/27/2024] [Indexed: 04/05/2024] Open
Abstract
Purpose Nonanterior uveitis frequently involves the retinal vasculature; however, no molecular markers associated with the retinal vascular disease are currently known. In this study, we aimed to identify serum biomarker signatures associated with retinal vascular involvement in noninfectious pediatric uveitis. Methods We performed a 384-plex targeted proteomic analysis of serum samples of 154 noninfectious pediatric uveitis patients diagnosed with nonanterior uveitis (n = 74), idiopathic chronic anterior uveitis (iCAU, n = 36), or juvenile idiopathic arthritis-associated uveitis (JIA-U, n = 44), as well as 22 noninflammatory pediatric controls. Data on retinal vascular involvement (i.e., papillitis, cystoid macular edema, retinal vasculitis, or retinal capillary leakage on optical coherence tomography and/or fluorescein angiography) were used to stratify cases in the nonanterior uveitis group. Results In the analysis of nonanterior uveitis, we identified nine proteins significantly associated with retinal vascular involvement, including F13B, MYOM3, and PTPN9. These proteins were enriched through pathway enrichment analysis for the coagulation cascade. Comparing cases and controls, we identified 63 differentially expressed proteins, notably proteins involved in platelet biology and complement cascades, which could be primarily attributed to differences in serum proteomes between anterior uveitis and nonanterior uveitis groups. Conclusions Serum proteins related to the coagulation and complement cascade are associated with retinal vascular involvement in pediatric uveitis patients. Our results indicate involvement of mediators that could interact with the microcirculation in pediatric uveitis and might serve as potential biomarkers in personalized medicine in the future. Translational Relevance Our targeted proteomics analysis in serum of pediatric uveitis patients indicates involvement of mediators that could interact with the microcirculation in pediatric uveitis and might serve as potential biomarkers in personalized medicine in the future.
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Affiliation(s)
- Carlyn V. Kouwenberg
- Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jonas J. W. Kuiper
- Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Joke H. de Boer
- Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Viera Kalinina Ayuso
- Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands
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Peng C, Wang Y, Zhang H, Chen P. The platelet-related genes associated with the prognosis of HCC by regulating cycling T cell and prolif-TAMs. Heliyon 2024; 10:e26798. [PMID: 38486758 PMCID: PMC10938119 DOI: 10.1016/j.heliyon.2024.e26798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 01/15/2024] [Accepted: 02/20/2024] [Indexed: 03/17/2024] Open
Abstract
Accumulating evidence highlighted the important roles of platelets in the prognosis and progression of various tumors. Nevertheless, the role of platelet-related genes (PRGs) in HCC remains limited. In this work, 92 differentially expressed PRGs were described in HCC using TCGA and ICGC databases. Then, based on the different expressions of PRGs, we explored two subtypes and developed the PRGs prognostic signature in HCC. The PRGs signature was an independent prognosis factor associated with immune cell infiltration in HCC. Furthermore, two external validation sets verified the expression and prognosis of the PRGs signature gene in HCC. Finally, scRNA-seq analysis demonstrated that the signature genes (CENPE and KIF2C) were mainly expressed in cycling T cells and prolif-TAMs. Enrichment analysis showed that CENPE and KIF2C regulated the cell cycle and p53 pathways in these cells. In conclusion, this study builds the PRGs-related risk signature of HCC and reveals the potential mechanism by which these signature genes regulate the immune microenvironment in HCC.
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Affiliation(s)
- Chenjia Peng
- School of Mathematics and Computational Science, Hunan First Normal University, Changsha, 410205, PR China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, PR China
| | - Ying Wang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, PR China
| | - Hengbo Zhang
- Physical Education Department, First Hunan Normal University, Changsha, 410081, PR China
| | - Ping Chen
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, PR China
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Feng M, Zeng X, Lin Q, Wang Y, Wei H, Yang S, Wang G, Chen X, Guo M, Yang X, Hu J, Zhang Y, Yang X, Du Y, Zhao Y. Characterization of Chitosan-Gallic Acid Graft Copolymer for Periodontal Dressing Hydrogel Application. Adv Healthc Mater 2024; 13:e2302877. [PMID: 38041691 DOI: 10.1002/adhm.202302877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/09/2023] [Indexed: 12/03/2023]
Abstract
The postoperative periodontal wound is in a complex physiological environment; the bacteria accumulation, the saliva stimulation, and the food residues retention will aggravate the wound deterioration. Commercial periodontal dressings have been widely used for postoperative periodontal treatment, and there still exists some problems, such as poor biocompatibility, weak adhesion, insufficient antibacterial, and anti-inflammatory properties. In this study, a chitosan-gallic acid graft copolymer (CS-GA) is synthesized as a potential periodontal dressing hydrogel. CS-GA possesses high swelling rate, adjustable degradability, self-healing ability, biocompatibility, strong adhesion ability, high mechanical properties and toughness. Furthermore, CS-GA has good scavenging ability for ·OH, O2 - , and 1 O2. And CS-GA has good inhibition effect on different bacterial through bacterial membranes damage. CS-GA can stop bleeding in a short time and adsorb erythrocytes to form physical blood clots to enhance the hemostatic performance. In addition, CS-GA can reduce inflammatory factors expressions, increase collagen fibers deposition, and neovascularization to promote wounds healing, which makes it as a potential periodontal dressing for postoperative tissue restoration.
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Affiliation(s)
- Mengge Feng
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, P. R. China
| | - Xuelian Zeng
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
| | - Quan Lin
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
| | - Yunxiao Wang
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, P. R. China
| | - Hongjiang Wei
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, P. R. China
| | - Shanyi Yang
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, P. R. China
| | - Guangwei Wang
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
| | - Xingyu Chen
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
| | - Mengqin Guo
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
| | - Xin Yang
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
| | - Jun Hu
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
- Hubei Jiangxia Laboratory, Wuhan, 430200, P. R. China
| | - Yufeng Zhang
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, P. R. China
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
| | - Yangge Du
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, P. R. China
| | - Yanbing Zhao
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
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Zhang B, Wang M, Tian H, Cai H, Wu S, Jiao S, Zhao J, Li Y, Zhou H, Guo W, Qu W. Functional hemostatic hydrogels: design based on procoagulant principles. J Mater Chem B 2024; 12:1706-1729. [PMID: 38288779 DOI: 10.1039/d3tb01900d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2024]
Abstract
Uncontrolled hemorrhage results in various complications and is currently the leading cause of death in the general population. Traditional hemostatic methods have drawbacks that may lead to ineffective hemostasis and even the risk of secondary injury. Therefore, there is an urgent need for more effective hemostatic techniques. Polymeric hemostatic materials, particularly hydrogels, are ideal due to their biocompatibility, flexibility, absorption, and versatility. Functional hemostatic hydrogels can enhance hemostasis by creating physical circumstances conducive to hemostasis or by directly interfering with the physiological processes of hemostasis. The procoagulant principles include increasing the concentration of localized hemostatic substances or establishing a physical barrier at the physical level and intervention in blood cells or the coagulation cascade at the physiological level. Moreover, synergistic hemostasis can combine these functions. However, some hydrogels are ineffective in promoting hemostasis or have a limited application scope. These defects have impeded the advancement of hemostatic hydrogels. To provide inspiration and resources for new designs, this review provides an overview of the procoagulant principles of hemostatic hydrogels. We also discuss the challenges in developing effective hemostatic hydrogels and provide viewpoints.
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Affiliation(s)
- Boxiang Zhang
- Department of Colorectal & Anal Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Min Wang
- Department of Colorectal & Anal Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Heng Tian
- Department of Hand Surgery, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, P. R. China.
| | - Hang Cai
- Department of Pharmacy, The Second Hospital of Jilin University, Changchun, 130041, P. R. China
| | - Siyu Wu
- Department of Hand Surgery, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, P. R. China.
| | - Simin Jiao
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, P. R. China
| | - Jie Zhao
- Key Laboratory of Bionic Engineering, Ministry of Education, Jilin University, Changchun, 130022, P. R. China
| | - Yan Li
- Trauma and Reparative Medicine, Karolinska University Hospital, Stockholm, Sweden
- The Division of Orthopedics and Biotechnology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Huidong Zhou
- Department of Hand Surgery, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, P. R. China.
| | - Wenlai Guo
- Department of Hand Surgery, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, P. R. China.
| | - Wenrui Qu
- Department of Hand Surgery, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, P. R. China.
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Araujo DFD, Holanda BF, Nascimento FLFD, Martins AB, Silva ALM, Pereira MG, Freitas Pires AD, Assreuy AMS. Polysaccharide-rich extract of Genipa americana leaves exerts anti-inflammatory effects modulated by platelet mediators. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117234. [PMID: 37793578 DOI: 10.1016/j.jep.2023.117234] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 09/22/2023] [Accepted: 09/25/2023] [Indexed: 10/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Genipa americana L. (Rubiaceae) leaves are traditionally used to treat fever, pharyngitis, healing, luxation and bruises. AIM OF THE STUDY This study aimed to investigate the anti-inflammatory effect of the polysaccharide-rich extract of G. americana leaves (PE-Ga) in acute inflammation models and underlying mechanisms associated with platelet activity. MATERIALS AND METHODS Rats received PE-Ga (0.3-3.0 mg/kg; IV) 30 min before injection (IP or SC) of zymosan, serotonin, PGE2, PLA2, PAF or L-arginine, and evaluated in the models of paw edema and acute peritonits. The blockage of plasma serotonin reuptake into platelets was performed with fluoxetine (40 mg/kg; IP). RESULTS In vitro, PE-Ga inhibited ADP-induced platelet aggregation up to 49%. In the edema model, PE-Ga reduced (41%) the time-course of the edema induced by zymosan, mainly the last phase (62%), as well as that induced by PLA2 (32%), PAF (35%), L-arginine (36%), PGE2 (49%) or serotonin (54% AUC); and reversed paw hypernociception induced by PGE2 or serotonin. In the peritonitis model, PE-Ga reversed abdominal hypernociception and reduced leukocyte migration induced by zymosan to blood (38%) and peritoneal cavity (55%), mainly neutrophils (70%). PE-GA also decreased leukocyte rolling (32%) and adhesion (47%), and increased the rolling velocity 2.2-fold. In the peritoneal fluid, PE-Ga reversed P-selectin and reduced total proteins (17%), MDA (40%), NO2-/NO3- (27%), and MPO activity (43%) but increased catalase activity 3.3-fold compared to zymosan. In addition, fluoxetine reversed PE-Ga anti-inflammatory effect on leukocyte migration and adhesion. CONCLUSIONS PE-Ga exerts antiplatelet and anti-inflammatory effects in acute inflammation induced by zymosan, being modulated by P-selectin and platelet serotonin, among other inflammatory mediators.
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Affiliation(s)
- Diego Freitas de Araujo
- Instituto Superior de Ciências Biomédicas, Universidade Estadual Do Ceará, Av. Dr. Silas Munguba 1700, Fortaleza, CE, 60740-000, Brazil
| | - Bianca Feitosa Holanda
- Instituto Superior de Ciências Biomédicas, Universidade Estadual Do Ceará, Av. Dr. Silas Munguba 1700, Fortaleza, CE, 60740-000, Brazil
| | | | - Alice Brito Martins
- Instituto Superior de Ciências Biomédicas, Universidade Estadual Do Ceará, Av. Dr. Silas Munguba 1700, Fortaleza, CE, 60740-000, Brazil; Centro de Ciências da Saúde, Centro Universitário Estácio Do Ceará, Unidade Centro, Av. Duque de Caxias 101, Fortaleza, CE, 60035-111, Brazil
| | - Alefe Lopes Macario Silva
- Faculdade de Educação, Ciências e Letras Do Sertão Central, Universidade Estadual Do Ceará, Rua José de Queiroz 2554, Quixadá, CE, 63900-000, Brazil
| | - Maria Gonçalves Pereira
- Instituto Superior de Ciências Biomédicas, Universidade Estadual Do Ceará, Av. Dr. Silas Munguba 1700, Fortaleza, CE, 60740-000, Brazil; Faculdade de Educação, Ciências e Letras Do Sertão Central, Universidade Estadual Do Ceará, Rua José de Queiroz 2554, Quixadá, CE, 63900-000, Brazil
| | - Alana de Freitas Pires
- Instituto Superior de Ciências Biomédicas, Universidade Estadual Do Ceará, Av. Dr. Silas Munguba 1700, Fortaleza, CE, 60740-000, Brazil; Centro de Ciências da Saúde, Centro Universitário Estácio Do Ceará, Unidade Centro, Av. Duque de Caxias 101, Fortaleza, CE, 60035-111, Brazil
| | - Ana Maria Sampaio Assreuy
- Instituto Superior de Ciências Biomédicas, Universidade Estadual Do Ceará, Av. Dr. Silas Munguba 1700, Fortaleza, CE, 60740-000, Brazil.
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Grzelak A, Hnydka A, Higuchi J, Michalak A, Tarczynska M, Gaweda K, Klimek K. Recent Achievements in the Development of Biomaterials Improved with Platelet Concentrates for Soft and Hard Tissue Engineering Applications. Int J Mol Sci 2024; 25:1525. [PMID: 38338805 PMCID: PMC10855389 DOI: 10.3390/ijms25031525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/19/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Platelet concentrates such as platelet-rich plasma, platelet-rich fibrin or concentrated growth factors are cost-effective autologous preparations containing various growth factors, including platelet-derived growth factor, transforming growth factor β, insulin-like growth factor 1 and vascular endothelial growth factor. For this reason, they are often used in regenerative medicine to treat wounds, nerve damage as well as cartilage and bone defects. Unfortunately, after administration, these preparations release growth factors very quickly, which lose their activity rapidly. As a consequence, this results in the need to repeat the therapy, which is associated with additional pain and discomfort for the patient. Recent research shows that combining platelet concentrates with biomaterials overcomes this problem because growth factors are released in a more sustainable manner. Moreover, this concept fits into the latest trends in tissue engineering, which include biomaterials, bioactive factors and cells. Therefore, this review presents the latest literature reports on the properties of biomaterials enriched with platelet concentrates for applications in skin, nerve, cartilage and bone tissue engineering.
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Affiliation(s)
- Agnieszka Grzelak
- Chair and Department of Biochemistry and Biotechnology, Medical University of Lublin, Chodzki Street 1, 20-093 Lublin, Poland; (A.G.); (A.H.)
| | - Aleksandra Hnydka
- Chair and Department of Biochemistry and Biotechnology, Medical University of Lublin, Chodzki Street 1, 20-093 Lublin, Poland; (A.G.); (A.H.)
| | - Julia Higuchi
- Laboratory of Nanostructures, Institute of High Pressure Physics, Polish Academy of Sciences, Prymasa Tysiaclecia Avenue 98, 01-142 Warsaw, Poland;
| | - Agnieszka Michalak
- Independent Laboratory of Behavioral Studies, Medical University of Lublin, Chodzki 4 a Street, 20-093 Lublin, Poland;
| | - Marta Tarczynska
- Department and Clinic of Orthopaedics and Traumatology, Medical University of Lublin, Jaczewskiego 8 Street, 20-090 Lublin, Poland; (M.T.); (K.G.)
- Arthros Medical Centre, Chodzki 31 Street, 20-093 Lublin, Poland
| | - Krzysztof Gaweda
- Department and Clinic of Orthopaedics and Traumatology, Medical University of Lublin, Jaczewskiego 8 Street, 20-090 Lublin, Poland; (M.T.); (K.G.)
- Arthros Medical Centre, Chodzki 31 Street, 20-093 Lublin, Poland
| | - Katarzyna Klimek
- Chair and Department of Biochemistry and Biotechnology, Medical University of Lublin, Chodzki Street 1, 20-093 Lublin, Poland; (A.G.); (A.H.)
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Walker LE, Stewart A, Pirmohamed SM, Meschia JF, Kinne FB. Stroke Pharmacogenetics. STROKE GENETICS 2024:423-508. [DOI: 10.1007/978-3-031-41777-1_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Chan MH, Sun F, Malakan J. Controversies in Stoppage of Antiplatelet and Anticoagulant Medications Prior to Oral Surgery. Dent Clin North Am 2024; 68:21-45. [PMID: 37951634 DOI: 10.1016/j.cden.2023.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
Dental procedures can pose a risk of bleeding, and it is not uncommon for dentists to consult prescribing physicians regarding a mutual patient's antiplatelet and anticoagulant medication to prevent excessive bleeding during or after an upcoming procedure. However, there has been a growing controversy in the dental community surrounding the stoppage of these medications prior to dental procedures. Some believe that stopping these medications prior to dental procedures is necessary to reduce the risk of bleeding complications, while others argue that stopping them can increase the risk of stroke or other thromboembolic events. The debate has left many dentists and specialists unsure about the best course of action when it comes to managing bleeding risk during dental procedures.In this article, we will review the antithrombotic medications, indications, mechanism of action, and its effects on the coagulation pathway, laboratory testing and reversal agents. Also, we will explore the controversy surrounding the stoppage of novel anitplatelets (eg,: prasurgrel and ticagrelor), dual-antiplatelets, triple-antiplatelet, vitamin K antagonists (eg,: wafarin, coumadin), and direct oral anticoagulants (eg,: dabigatran, rivaroxaban, xarelto and endoxaban) in dentistry and examine the current evidence and guidelines for managing dental patients undergoing oral surgery.
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Affiliation(s)
- Michael H Chan
- Oral & Maxillofacial Surgery, Department of Veterans Affairs, New York Harbor Healthcare System (Brooklyn Campus), 800 Poly Place (Bk-160), Brooklyn, NY 11209, USA; Oral & Maxillofacial Surgery, Department of Oral and Maxillofacial Surgery, The Brooklyn Hospital Center, 121 DeKalb Avenue (Box-187), Brooklyn, NY 11201, USA.
| | - Feiyi Sun
- Oral & Maxillofacial Surgery, Department of Oral and Maxillofacial Surgery, The Brooklyn Hospital Center, 121 DeKalb Avenue, Brooklyn, NY 11201, USA
| | - Jonathan Malakan
- Oral & Maxillofacial Surgery, Department of Oral and Maxillofacial Surgery, The Brooklyn Hospital Center, 121 DeKalb Avenue, Brooklyn, NY 11201, USA
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Inoue M, Ohwada M, Watanabe N. The shear rate promotes pinocytosis of extracellular dextran in platelets. Clin Hemorheol Microcirc 2024; 87:237-247. [PMID: 38393893 PMCID: PMC11307048 DOI: 10.3233/ch-232075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2024]
Abstract
BACKGROUND Several conventional studies focused on platelet pinocytosis for possible utilization as drug delivery systems. Although platelet pinocytosis is important in such utilization, the impact of the shear rate on pinocytosis is unclear. OBJECTIVE Our objective was to investigate the relationship between shear rate and platelet pinocytosis in vitro. In addition, this study addressed the change in platelet aggregation reactivity with adenosine diphosphate (ADP) stimulation after pinocytosis. METHOD Porcine platelet-rich plasma was mixed with fluorescein isothiocyanate (FITC)-conjugated dextran and incubated for 15 min under shear conditions of 0, 500, and 1500 s-1. After incubation, confocal microscopic scanning and three-dimensional rendering were performed to confirm the internalization of FITC-dextran into platelets. The amount of FITC-dextran accumulated via platelet pinocytosis was compared using flow cytometry at each shear rate. In addition, light transmission aggregometry by ADP stimulation was applied to platelets after pinocytosis. RESULTS The amount of intracellular FITC-dextran increased with higher shear rates. Platelets with increased amounts of intracellular FITC-dextran did not show changes in the aggregation reactivity to ADP. CONCLUSIONS A higher shear rate promotes platelet pinocytosis, but enhanced pinocytosis does not affect aggregation sensitivity, which is stimulated by ADP.
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Affiliation(s)
- Masataka Inoue
- Functional Control Systems, Graduate School of Engineering and Science, Shibaura Institute of Technology, Saitama, Japan
| | - Masahiro Ohwada
- Functional Control Systems, Graduate School of Engineering and Science, Shibaura Institute of Technology, Saitama, Japan
| | - Nobuo Watanabe
- Functional Control Systems, Graduate School of Engineering and Science, Shibaura Institute of Technology, Saitama, Japan
- Department of Bio-Science and Engineering, Biofluid Science and Engineering Laboratory, College of Systems Engineering and Science, Shibaura Institute of Technology, Saitama, Japan
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Rotbain Curovic V, Tavenier J, Ferreira-Divino LF, Poulsen CG, Houlind MB, Pedersen OB, Urbak L, Hansen TW, Sillesen H, Frimodt-Møller M, Hvas AM, Rossing P. Soluble urokinase plasminogen activator receptor, platelet aggregation, and carotid plaque thickness in diabetes: A cross-sectional analysis. J Diabetes Complications 2024; 38:108654. [PMID: 38042098 DOI: 10.1016/j.jdiacomp.2023.108654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/14/2023] [Accepted: 11/25/2023] [Indexed: 12/04/2023]
Affiliation(s)
| | - Juliette Tavenier
- Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | | | | | - Morten B Houlind
- Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark; University of Copenhagen, Copenhagen, Denmark
| | - Oliver B Pedersen
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Lærke Urbak
- Department of Vascular Surgery, Rigshospitalet, Copenhagen, Denmark
| | | | - Henrik Sillesen
- Department of Vascular Surgery, Rigshospitalet, Copenhagen, Denmark
| | | | | | - Peter Rossing
- Steno Diabetes Center Copenhagen, Herlev, Denmark; University of Copenhagen, Copenhagen, Denmark
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Biswas R, Boyd EK, Eaton N, Steenackers A, Schulte ML, Reusswig F, Yu H, Drew C, Kahr WHA, Shi Q, Plomann M, Hoffmeister KM, Falet H. PACSIN2 regulates platelet integrin β1 hemostatic function. J Thromb Haemost 2023; 21:3619-3632. [PMID: 37678551 PMCID: PMC10841284 DOI: 10.1016/j.jtha.2023.08.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 08/11/2023] [Accepted: 08/25/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND Upon vessel injury, platelets adhere to exposed matrix constituents via specific membrane receptors, including the von Willebrand factor receptor glycoprotein (GP)Ib-IX-V complex and integrins β1 and β3. In platelets, the Fes/CIP4-homology Bin-Amphiphysin-Rvs protein PACSIN2 associates with the cytoskeletal and scaffolding protein filamin A (FlnA), linking GPIbα and integrins to the cytoskeleton. OBJECTIVES Here we investigated the role of PACSIN2 in platelet function. METHODS Platelet parameters were evaluated in mice lacking PACSIN2 and platelet integrin β1. RESULTS Pacsin2-/- mice displayed mild thrombocytopenia, prolonged bleeding time, and delayed thrombus formation in a ferric chloride-mediated carotid artery injury model, which was normalized by injection of control platelets. Pacsin2-/- platelets formed unstable thrombi that embolized abruptly in a laser-induced cremaster muscle injury model. Pacsin2-/- platelets had hyperactive integrin β1, as evidenced by increased spreading onto surfaces coated with the collagen receptor α2β1-specific peptide GFOGER and increased binding of the antibody 9EG7 directed against active integrin β1. By contrast, Pacsin2-/- platelets had normal integrin αIIbβ3 function and expressed P-selectin normally following stimulation through the collagen receptor GPVI or with thrombin. Deletion of platelet integrin β1 in Pacsin2-/- mice normalized platelet count, hemostasis, and thrombus formation. A PACSIN2 peptide mimicking the FlnA-binding site mediated the pull-down of a FlnA rod 2 construct by integrin β7, a model for integrin β-subunits. CONCLUSIONS Pacsin2-/- mice displayed severe thrombus formation defects due to hyperactive platelet integrin β1. The data suggest that PACSIN2 binding to FlnA negatively regulates platelet integrin β1 hemostatic function.
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Affiliation(s)
- Ratnashree Biswas
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA
| | - Emily K Boyd
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Nathan Eaton
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Agata Steenackers
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA
| | | | - Friedrich Reusswig
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA
| | - Hongyin Yu
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Caleb Drew
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA
| | - Walter H A Kahr
- Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Qizhen Shi
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Children's Research Institute, Children's Wisconsin, Milwaukee, Wisconsin, USA
| | - Markus Plomann
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Karin M Hoffmeister
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA; Departments of Biochemistry and Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Hervé Falet
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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