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Ershov PV, Yablokov EO, Mezentsev YV, Ivanov AS. Human prostacyclin and thromboxane synthases: Molecular interactions, regulation, and pharmacology. Biochimie 2025; 234:76-88. [PMID: 40222477 DOI: 10.1016/j.biochi.2025.04.003] [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: 01/14/2025] [Revised: 03/26/2025] [Accepted: 04/11/2025] [Indexed: 04/15/2025]
Abstract
Prostanoids are lipid mediators of the human body that are involved in the inflammation and platelet aggregation. Prostacyclin is a vasodilator and inhibitor of platelet aggregation, and a product of the enzymatic reaction catalyzed by prostacyclin synthase (PTGIS). Thromboxane is a vasoconstrictor and synthesized by thromboxane synthase (TBXAS1). An imbalance of prostanoids can accompany cardio-/cerebrovascular diseases and cancers. PTGIS and TBXAS1 are clinically relevant membrane-bound enzymes of the multigene family of cytochromes P450 (CYPs), also known as CYP8A1 and CYP5A1, respectively. Particular studies of these functional antagonists will contribute to the elucidation of pathogenic mechanisms. The purpose of this work was to analyze the literature landscape over a period of 2020-2024 in the field of biological, pharmacogenomic, and pharmacological features of PTGIS and TBXAS1 as well as to explore the potential of their regulation at the post-transcriptional and post-translational levels using systems biological analysis. The review discusses recent findings on the novel aspects of both synthases established in gene knockout and overexpression experiments, current preclinical pharmacology, and potential ways of gene expression regulation. Identification of protein-protein interactions and post-translational modifications appear to be the main options for modulating PTGIS and TBXAS1 activity. The microsomal CYPs are known to form complexes with each other and direct interactions of CYP2E1 with both synthases can probably lead to modulation of their activity. Progress in the preclinical development of low molecular weight compounds as inhibitors of TBXAS1 is more prospective than PTGIS that is applied as gene therapy biologicals for in vivo production of prostacyclin due to its noticeable anticancer and vasodilator effects.
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Affiliation(s)
- Pavel V Ershov
- Institute of Biomedical Chemistry, 10, Pogodinskaya Street, 119121, Moscow, Russia.
| | - Evgeniy O Yablokov
- Institute of Biomedical Chemistry, 10, Pogodinskaya Street, 119121, Moscow, Russia
| | - Yuri V Mezentsev
- Institute of Biomedical Chemistry, 10, Pogodinskaya Street, 119121, Moscow, Russia
| | - Alexis S Ivanov
- Institute of Biomedical Chemistry, 10, Pogodinskaya Street, 119121, Moscow, Russia
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2
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Li XF, Shen GZ, Gong PF, Yang Y, Tuerxun P. Mechanisms of action of the proline hydroxylase-adenosine pathway in regulating apoptosis and reducing myocardial ischemia-reperfusion injury. Clin Hemorheol Microcirc 2025:13860291241310148. [PMID: 39973430 DOI: 10.1177/13860291241310148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Objective: The aim of this study is to explore the protective mechanism of proline hydroxylase (PHD) in reducing myocardial ischemia-reperfusion injury (MIRI) through the hypoxia-inducible factor (HIF)-1α-adenosine-MAPK/ERK signaling pathway, with the goal of identifying potential drug targets and therapeutic strategies for the clinical management of MIRI. Methods: A rat model of MIRI was established using 45 male Sprague-Dawley (SD) rats, which were randomly divided into the following three groups: sham operation (n = 15), MIRI model (n = 15), and MIRI + FG-4592 preconditioning (n = 15) groups. Cardiac function was assessed by echocardiographic measurements of the left ventricular end-diastolic diameter (LVIDd), left ventricular contractile diameter (LVIDs), left ventricular shortening fraction (FS), and left ventricular ejection fraction (EF). Cardiomyocyte apoptosis was evaluated using hematoxylin-eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Myocardial infarct size was determined with 23,5-triphenyltetrazolium chloride (TTC) staining, while levels of inflammatory factors such as interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) were quantified using enzyme-linked immunosorbent assays (ELISA). Western blot (WB) analysis was performed to assess the expression of apoptotic proteins ERK1/2, phosphorylated-ERK1/2 (p-ERK1/2), AKT, phosphorylated-AKT (p-AKT), caspase-3, BCL-2, and BAX in the infarct boundary area. Adenosine levels within myocardial tissue were also measured. Results: FG-4592 preconditioning significantly improved cardiac function, lowered cardiomyocyte apoptosis and myocardial infarction size, reduced myocardial tissue damage, and inhibited inflammation. Additionally, FG-4592 increased the expression of anti-apoptotic proteins and enhanced adenosine levels in myocardial tissue in the treatment group compared with the MIRI model group. Conclusions: Inhibition of HIF-1α degradation plays a significant role in enhancing extracellular adenosine levels and reducing MIRI, possibly regulating apoptosis through the MAPK/ERK signaling pathway. These findings highlight the potential of targeting the PHD-HIF-adenosine axis in developing treatment strategies for MIRI, meriting future exploration.
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Affiliation(s)
- Xiu-Fen Li
- Department of Cardiology, Xinjiang Medical University Affiliated Traditional Chinese Medicine Hospital, Urumqi, China
| | - Gu-Zhuo Shen
- Department of Cardiology, The Fourth Clinical Medical College of Xinjiang Medical University, Urumqi, China
| | - Peng-Fei Gong
- Department of Cardiology, Xinjiang Medical University Affiliated Traditional Chinese Medicine Hospital, Urumqi, China
| | - Yan Yang
- Department of Cardiology, Xinjiang Medical University Affiliated Traditional Chinese Medicine Hospital, Urumqi, China
| | - Paerhati Tuerxun
- Department of Cardiology, Xinjiang Medical University Affiliated Traditional Chinese Medicine Hospital, Urumqi, China
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3
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Vilahur G, Fuster V. Interplay between platelets and coagulation: from protective haemostasis to pathological arterial thrombosis. Eur Heart J 2025; 46:413-423. [PMID: 39673717 DOI: 10.1093/eurheartj/ehae776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/28/2024] [Accepted: 10/27/2024] [Indexed: 12/16/2024] Open
Abstract
Haemostasis refers to the physiological process aimed at repairing vessel injury and preventing bleeding. It involves four interlinked stages culminating in the formation of a platelet-fibrin haemostatic plug that is eventually dissolved once the vessel heals. In contrast, arterial thrombosis is a pathological condition resulting from atheroma exposure, triggering the formation of a platelet-rich thrombus that may obstruct blood flow, leading to the clinical manifestations of ischaemic cardiovascular disease. The following review will provide a comprehensive overview of the finely regulated endogenous antithrombotic mechanisms responsible for maintaining the haemostatic balance and preventing intravascular thrombosis. Thereafter, it will further detail the different stages and mechanisms governing the intricate interplay between the vessel, platelets, and the coagulation cascade in haemostasis, highlighting the most recent advances in platelet biology and function, to further elucidate the differential traits and players contributing to pathological arterial thrombus growth. The review will also delve into the impact of emerging cardiovascular risk factors on tilting the haemostatic balance towards a pro-thrombotic state, thereby increasing the patient's vulnerability to thrombotic events. Finally, it will underscore the importance of early screening for subclinical atherosclerosis through advanced imaging technologies capable of quantifying plaque burden and metabolic activity since they may set the stage for an increased thrombotic risk. Implementing proactive interventions to halt atherosclerosis progression or inducing its regression at early stages is crucial for preserving haemostasis and reducing the likelihood of ischaemic atherothrombotic disease.
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Affiliation(s)
- Gemma Vilahur
- Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Carrer Sant Quintí 77-79, Barcelona 08041, Spain
- CiberCV, Institute Carlos III, Madrid 28029, Spain
| | - Valentin Fuster
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Szymczyk P, Majewska M, Nowak J. Proteins and DNA Sequences Interacting with Tanshinones and Tanshinone Derivatives. Int J Mol Sci 2025; 26:848. [PMID: 39859562 PMCID: PMC11765770 DOI: 10.3390/ijms26020848] [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: 12/20/2024] [Revised: 01/14/2025] [Accepted: 01/19/2025] [Indexed: 01/27/2025] Open
Abstract
Tanshinones, biologically active diterpene compounds derived from Salvia miltiorrhiza, interact with specific proteins and DNA sequences, influencing signaling pathways in animals and humans. This study highlights tanshinone-protein interactions observed at concentrations achievable in vivo, ensuring greater physiological relevance compared to in vitro studies that often employ supraphysiological ligand levels. Experimental data suggest that while tanshinones interact with multiple proteomic targets, only a few enzymes are significantly affected at biologically relevant concentrations. This apparent paradox may be resolved by tanshinones' ability to bind DNA and influence enzymes involved in gene expression or mRNA stability, such as RNA polymerase II and human antigen R protein. These interactions trigger secondary, widespread changes in gene expression, leading to complex proteomic alterations. Although the current understanding of tanshinone-protein interactions remains incomplete, this study provides a foundation for deciphering the molecular mechanisms underlying the therapeutic effects of S. miltiorrhiza diterpenes. Additionally, numerous tanshinone derivatives have been developed to enhance pharmacokinetic properties and biological activity. However, their safety profiles remain poorly characterized, limiting comprehensive insights into their medicinal potential. Further investigation is essential to fully elucidate the therapeutic and toxicological properties of both native and modified tanshinones.
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Affiliation(s)
- Piotr Szymczyk
- Department of Biology and Pharmaceutical Botany, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland
| | - Małgorzata Majewska
- Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland;
| | - Jadwiga Nowak
- Department of Pharmacology and Therapeutics, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala P.O. Box 7062, Uganda;
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Osete JM, García-Candel F, Fernández-Gómez FJ, Blanquer M, Atucha NM, García-Estañ J, Iyú D. TRAP-Induced Platelet Reactivity Is Inhibited by Omega-3 Fatty Acid-Derived Prostaglandin E3 (PGE3). Biomedicines 2024; 12:2855. [PMID: 39767761 PMCID: PMC11673155 DOI: 10.3390/biomedicines12122855] [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: 11/16/2024] [Revised: 12/05/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Prostaglandins are naturally occurring local mediators that can participate in the modulation of the cardiovascular system through their interaction with Gs/Gi-coupled receptors in different tissues and cells, including platelets. Thrombin is one of the most important factors that regulates platelet reactivity and coagulation. Clinical trials have consistently shown that omega-3 fatty acid supplementation lowers the risk for cardiovascular mortality and morbidity. Since omega-3 fatty acids are the main precursors of PGE3 in vivo, it would be relevant to investigate the effects of PGE3 on Thrombin Receptor Activating Peptide (TRAP-6)-induced platelet reactivity to determine the receptors and possible mechanisms of action of these compounds. Methods: We have measured platelet aggregation, P-selectin expression, and vasodilator-stimulated phosphoprotein (VASP) phosphorylation to evaluate platelet reactivity induced by TRAP-6 to determine the effects of PGE3 on platelet function. Results: We assessed the ability of DG-041, a selective prostanoid EP3 receptor antagonist, and of ONO-AE3-208, a selective prostanoid EP4 receptor antagonist, to modify the effects of PGE3. PGE3 inhibited TRAP-6-induced platelet aggregation and activation. This inhibition was enhanced in the presence of a Gi-coupled EP3 receptor antagonist and abolished in the presence of a Gs-coupled EP4 receptor antagonist. The effects of PGE3 were directly related to changes in cAMP, assessed by VASP phosphorylation. Conclusions: The general effects of PGE3 on human platelet reactivity are the consequence of a balance between activatory and inhibitory effects at receptors that have contrary effects on adenylate cyclase. These results indicate a potential mechanism by which omega-3 fatty acids underlie cardioprotective effects.
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Affiliation(s)
- José-Miguel Osete
- Department of Physiology, University of Murcia, 30120 Murcia, Spain; (J.-M.O.); (N.M.A.); (J.G.-E.)
| | - Faustino García-Candel
- Servicio de Hematología, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain;
- Instituto Murciano de Investigación Biosanitaria (IMIB)—Arrixaca, Unidad de Trasplante Hematopoyético y Terapia Celular, 30120 Murcia, Spain;
| | | | - Miguel Blanquer
- Instituto Murciano de Investigación Biosanitaria (IMIB)—Arrixaca, Unidad de Trasplante Hematopoyético y Terapia Celular, 30120 Murcia, Spain;
- Department of Medicine, University of Murcia, 30120 Murcia, Spain
| | - Noemí M. Atucha
- Department of Physiology, University of Murcia, 30120 Murcia, Spain; (J.-M.O.); (N.M.A.); (J.G.-E.)
- Instituto Murciano de Investigación Biosanitaria (IMIB)—Arrixaca, Unidad de Trasplante Hematopoyético y Terapia Celular, 30120 Murcia, Spain;
| | - Joaquín García-Estañ
- Department of Physiology, University of Murcia, 30120 Murcia, Spain; (J.-M.O.); (N.M.A.); (J.G.-E.)
- Instituto Murciano de Investigación Biosanitaria (IMIB)—Arrixaca, Unidad de Trasplante Hematopoyético y Terapia Celular, 30120 Murcia, Spain;
| | - David Iyú
- Department of Physiology, University of Murcia, 30120 Murcia, Spain; (J.-M.O.); (N.M.A.); (J.G.-E.)
- Instituto Murciano de Investigación Biosanitaria (IMIB)—Arrixaca, Unidad de Trasplante Hematopoyético y Terapia Celular, 30120 Murcia, Spain;
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Ryu MH, Hur SA, Afshar T, Kolmert J, Zurita J, Wheelock CE, Carlsten C. Impact of Short-Term Diesel Exhaust Exposure on Prothrombotic Markers in Chronic Obstructive Pulmonary Disease: A Randomized, Double-Blind, Crossover Study. Ann Am Thorac Soc 2024; 21:1715-1722. [PMID: 39167788 DOI: 10.1513/annalsats.202311-955oc] [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: 11/10/2023] [Accepted: 08/21/2024] [Indexed: 08/23/2024] Open
Abstract
Rationale: Growing evidence suggests that air pollution exposure is a major risk factor in chronic obstructive pulmonary disease (COPD) that is associated with an increased prothrombotic state and adverse cardiovascular outcomes. However, much of this work is based on observational data or human exposure studies involving younger participants. The biological causality and mechanism of air pollution-induced prothrombotic response in patients with COPD remain to be explored. Objectives: The main aim of this work was to investigate the impact of short-term diesel exhaust (DE) exposure on circulating prothrombotic markers-fibrinogen and plasminogen activator inhibitor-1 (PAI-1)-and urinary eicosanoids in patients with COPD. Methods: Twenty-nine research participants were recruited in this randomized, double-blind, crossover, controlled human exposure study to DE. Participants included former smokers with and without mild or moderate COPD (ex-smokers [ES] and COPD group) and healthy never-smokers without COPD (nonsmoker [NS] group). Each participant was exposed to DE (300 μg/m3 of particulate matter with an aerodynamic diameter ≤2.5 μm) and filtered air for 2 hours on different occasions, in randomized order, separated by a 4-week washout. Blood and urine samples were collected before and 24 hours after each exposure. Plasma fibrinogen and serum PAI-1 concentrations were quantified using enzyme-linked immunosorbent assays. Urinary eicosanoid concentrations were quantified using ultraperformance liquid chromatography coupled to tandem mass spectrometry. Linear mixed-effects models were used for statistical comparisons. Results: Participants with COPD showed an increase in plasma fibrinogen (effect estimate, 1.27 [1.06-1.53]; P = 0.01) after DE relative to filtered air, but no significant DE-associated change in serum PAI-1 (0.95 [0.87-1.04]; P = 0.26). In never-smokers and ex-smokers without COPD, fibrinogen (NS group, 1.10 [0.99-1.23]; P = 0.08; ES group, 0.86 [0.68-1.09]; P = 0.08] and PAI-1 (NS group, 1.12 [0.96-1.32]; P = 0.15; ES group, 0.90 [0.79-1.03]; P = 0.13) were not changed after DE exposure. Participants with COPD showed a DE-attributable increase in urinary thromboxane B2 (TXB2) metabolite concentrations as follows: 11-dehydro-TXB2 (1.45 [1.02-2.08]; P = 0.04) and 2,3-dinor-TXB2 (1.45 [1.05-2.00]; P = 0.03). Conclusions: Participants with COPD had increased plasma fibrinogen and urinary TXB2 metabolites after short-term DE exposure, suggesting they may be more susceptible to a pollution-attributable prothrombotic response than healthy control subjects or ex-smokers without COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02236039).
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Affiliation(s)
- Min Hyung Ryu
- Air Pollution Exposure Laboratory, Division of Respiratory Medicine, Department of Medicine, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Seo Am Hur
- Air Pollution Exposure Laboratory, Division of Respiratory Medicine, Department of Medicine, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tina Afshar
- Air Pollution Exposure Laboratory, Division of Respiratory Medicine, Department of Medicine, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Johan Kolmert
- Unit of Integrative Metabolomics, Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden; and
| | - Javier Zurita
- Unit of Integrative Metabolomics, Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden; and
| | - Craig E Wheelock
- Unit of Integrative Metabolomics, Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden; and
- Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
| | - Christopher Carlsten
- Air Pollution Exposure Laboratory, Division of Respiratory Medicine, Department of Medicine, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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Tian J, Gao M, Zhu J, Xu H, Ji H, Xia D, Wang X. Platelets camouflaged nanovehicle improved bladder cancer immunotherapy by triggering pyroptosis. Theranostics 2024; 14:6692-6707. [PMID: 39479459 PMCID: PMC11519802 DOI: 10.7150/thno.99040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 10/01/2024] [Indexed: 11/02/2024] Open
Abstract
The regulation of immunosuppressive microenvironments in tumors through targeted drug delivery shows promise for immunochemotherapy in bladder cancer. Drawing inspiration from stealth tactics, a nano-vehicle camouflaged with platelets (PLTs) was developed to enable precise delivery and trigger pyroptosis for tumor immunotherapy. Methods: Erdafitinib (Erda) was nano-sized and encapsulated in PLTs to construct nano-Erda@PLT. Characterization of the PLTs camouflaged nano-vehicle was conducted using Zetasizer, SEM, and confocal laser scanning microscopy. The excellent targeted delivery property of the PLTs nano-vehicle was investigated through intravital imaging, three-dimensional microspheres, and SEM. Validation of pyroptosis in bladder cancer cells via the caspase-3/GSDME pathway was performed using western blot, immunofluorescence, and ELISA tests. Immunotherapy by nano-Erda@PLT treatment in vivo was confirmed using H&E, immunohistochemical, and flow cytometry. Lastly, the side effects of nano-Erda@PLT were assessed. Results: Proteomic analysis revealed that the activation of p-selectin on platelets facilitated the identification of nano-Erda@PLT targeted therapies. Nanoscale of Erda released in response to adenosine diphosphate, facilitated intratumoral permeation. This could contribute to an upregulation of the key proteins of pyroptosis, caspase-3 and GSDME, in bladder cancer cells due to nano-Erda@PLT accumulation. Additionally, the burst release of numerous inflammatory factors may enhance the system's adaptive immune response. In a bladder cancer animal model, this treatment was found to regulate the immunosuppressive microenvironment, resulting in effective tumor immunotherapy and the induction of a long-lasting, robust immune memory. Conclusion: PLTs-camouflaged nano-vehicles enable nano-Erda-mediated tumor immunotherapy through the induction of pyroptosis. These findings introduce a novel approach in exploring nanomaterial-mediated pyroptosis for cancer immunotherapy.
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Affiliation(s)
| | | | | | | | | | - Donglin Xia
- Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University & School of Public Health of Nantong University, Nantong, 226000, P. R. China
| | - Xiaolin Wang
- Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University & School of Public Health of Nantong University, Nantong, 226000, P. R. China
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Stabile J, Fürstenau CR. Platelets isolation and ectonucleotidase assay: Revealing functional aspects of the communication between the vasculature and the immune system. J Immunol Methods 2024; 533:113746. [PMID: 39181235 DOI: 10.1016/j.jim.2024.113746] [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: 02/10/2024] [Revised: 08/17/2024] [Accepted: 08/19/2024] [Indexed: 08/27/2024]
Abstract
Platelets are enucleated fragments of cells with a diversity of internal granules. They are responsible for functions related to hemostasis, coagulation, and inflammation. The activation of these processes depends on a cascade coordinated by cytokines, chemokines, and components of purinergic signaling, such as ATP, ADP, and adenosine. Platelets express distinct components of the purinergic system: P2X1, P2Y1, PY12, and P2Y14 receptors; and the ectonucleotidases NTPDase, NPP, and 5NTE (ecto-5'-nucleotidase). Except for P2Y14, which has not yet exhibited a known function, all other components relate to the biological processes mentioned before. Platelets are known to display specific responses to microorganisms, being capable of recognizing pathogen-associated molecular patterns (PAMPs), engulfing certain classes of viruses, and participating in NETosis. Platelet function dysregulation implicates various pathophysiological processes, including cardiovascular diseases (CVDs) and infections. In COVID-19 patients, platelets exhibit altered purinergic signaling and increased activation, contributing to inflammation. Excessive platelet activation can lead to complications from thrombosis, which can affect the circulation of vital organs. Therefore, controlling the activation is necessary to end the inflammatory process and restore homeostasis. Ectonucleotidases, capable of hydrolyzing ATP, ADP, and AMP, are of fundamental importance in activating platelets, promising pharmacological targets for clinical use as cardiovascular protective drugs. In this review, we revisit platelet biology, the purinergic receptors and ectonucleotidases on their surface, and their importance in platelet activity. Additionally, we describe methods for isolating platelets in humans and murine, as well as the main techniques for detecting the activity of ectonucleotidases in platelets. Considering the multitude of functions revealed by platelets and their potential use as potent bioreactors able to secrete and present molecules involved in the communication of the vasculature with the immune system, it is crucial to deeply understand platelet biology and purinergic signaling participation to contribute to the developing of therapeutic strategies in diseases of the cardiovascular, inflammatory, and immune systems.
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Affiliation(s)
- Jeferson Stabile
- Laboratory of Vascular Biochemistry, Center for Natural and Human Sciences, Federal University of ABC, Santo André, SP, Brazil
| | - Cristina Ribas Fürstenau
- Laboratory of Vascular Biochemistry, Center for Natural and Human Sciences, Federal University of ABC, Santo André, SP, Brazil.
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Allen MF, Hutchinson JL, Keith M, Mallah S, Corey RA, Trory JS, Jing C, Fang H, Wei L, Bennett SH, Aggarwal VK, Mundell SJ, Hers I. Difluorinated thromboxane A 2 reveals crosstalk between platelet activatory and inhibitory pathways by targeting both the TP and IP receptors. Br J Pharmacol 2024; 181:3685-3699. [PMID: 38840293 DOI: 10.1111/bph.16435] [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: 10/10/2023] [Revised: 12/21/2023] [Accepted: 01/17/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND AND PURPOSE Thromboxane A2 (TXA2) is a prostanoid produced during platelet activaton, important in enhancing platelet reactivity by activation of TP receptors. However, due to the short half-life, studying TXA2 signalling is challenging. To enhance our understanding of TP receptor-mediated platelet biology, we therefore synthesised mono and difluorinated TXA2 analogues and explored their pharmacology on heterologous and endogenously expressed TP receptor function. EXPERIMENTAL APPROACH Platelet functional and signalling responses were studied using aggregometry, Ca2+ mobilisation experiments and immunoblotting and compared with an analogue of the TXA2 precursor prostaglandin H2, U46619. Gαq/Gαs receptor signalling was determined using a bioluminescence resonance energy transfer (BRET) assay in a cell line overexpression system. KEY RESULTS BRET studies revealed that F-TXA2 and F2-TXA2 promoted receptor-stimulated TP receptor G-protein activation similarly to U46619. Unexpectedly, F2-TXA2 caused reversible aggregation in platelets, whereas F-TXA2 and U46619 induced sustained aggregation. Blocking the IP receptor switched F2-TXA2-mediated reversible aggregation into sustained aggregation. Further BRET studies confirmed F2-TXA2-mediated IP receptor activation. F2-TXA2 rapidly and potently stimulated platelet TP receptor-mediated protein kinase C/P-pleckstrin, whereas IP-mediated protein kinase A/P-vasodilator-stimulated phosphoprotein was more delayed. CONCLUSION AND IMPLICATIONS F-TXA2 is a close analogue to TXA2 used as a selective tool for TP receptor platelet activation. In contrast, F2-TXA2 acts on both TP and IP receptors differently over time, resulting in an initial wave of TP receptor-mediated platelet aggregation followed by IP receptor-induced reversibility of aggregation. This study reveals the potential difference in the temporal aspects of stimulatory and inhibitory pathways involved in platelet activation.
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Affiliation(s)
- Megan F Allen
- School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, UK
| | - James L Hutchinson
- School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, UK
| | - Michael Keith
- School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, UK
| | - Shahida Mallah
- School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, UK
| | - Robin A Corey
- School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, UK
| | - Justin S Trory
- School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, UK
| | | | - Huaquan Fang
- School of Chemistry, University of Bristol, Bristol, UK
| | - Liang Wei
- School of Chemistry, University of Bristol, Bristol, UK
| | | | | | - Stuart J Mundell
- School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, UK
| | - Ingeborg Hers
- School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, UK
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Krüger-Genge A, Harb K, Braune S, Jung CHG, Westphal S, Bär S, Mauger O, Küpper JH, Jung F. Effects of Arthrospira platensis on Human Umbilical Vein Endothelial Cells. Life (Basel) 2024; 14:1253. [PMID: 39459553 PMCID: PMC11508656 DOI: 10.3390/life14101253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/03/2024] [Accepted: 09/12/2024] [Indexed: 10/28/2024] Open
Abstract
Atherosclerosis is initiated by injury or damage to the vascular endothelial cell monolayer. Therefore, the early repair of the damaged vascular endothelium by a proliferation of neighbouring endothelial cells is important to prevent atherosclerosis and thrombotic events. Arthrospira platensis (AP) has been used as a dietary supplement, mainly due to its high content of vitamins, minerals, amino acids, and pigments such as chlorophylls, carotenoids, and phycocyanin, ingredients with antioxidant, anti-inflammatory, and anti-thrombotic properties. Therefore, in this prospective, placebo-controlled, data-driven, sample-size-estimated in vitro study, we tested whether an aqueous extract of AP at different concentrations (50, 100, and 200 µg/mL) had an effect on the different cellular parameters of human umbilical vein endothelial cells. Therefore, cell impedance measurement and cell proliferation were measured to investigate the monolayer formation. In addition, cell viability, integrity, and metabolism were analysed to evaluate singular cellular functions, especially the antithrombotic state. Furthermore, cell-cell and cell-substrate interactions were observed. The highest proliferation was achieved after the addition of 100 µg/mL. This was consistently confirmed by two independent optical experiments in cell cultures 48 h and 85 h after seeding and additionally by an indirect test. At this concentration, the activation or dysfunction of HUVECs was completely prevented, as confirmed by prostacyclin and interleukin-6 levels. In conclusion, in this study, AP induced a significant increase in HUVEC proliferation without inducing an inflammatory response but altered the hemostasiological balance in favour of prostacyclin over thromboxane, thereby creating an antithrombotic state. Thus, APE could be applied in the future as an accelerator of endothelial cell proliferation after, e.g., stent placement or atherosclerosis.
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Affiliation(s)
- Anne Krüger-Genge
- Life Science and Bioprocesses, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany; (K.H.); (S.W.); (S.B.); (O.M.)
| | - Kudor Harb
- Life Science and Bioprocesses, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany; (K.H.); (S.W.); (S.B.); (O.M.)
| | - Steffen Braune
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany (J.-H.K.); (F.J.)
- Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
| | - Conrad H. G. Jung
- Carbon Biotech, Social Enterprise Stiftungs AG, 01968 Senftenberg, Germany
| | - Sophia Westphal
- Life Science and Bioprocesses, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany; (K.H.); (S.W.); (S.B.); (O.M.)
| | - Stefanie Bär
- Life Science and Bioprocesses, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany; (K.H.); (S.W.); (S.B.); (O.M.)
| | - Olivia Mauger
- Life Science and Bioprocesses, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany; (K.H.); (S.W.); (S.B.); (O.M.)
| | - Jan-Heiner Küpper
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany (J.-H.K.); (F.J.)
- Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
- Carbon Biotech, Social Enterprise Stiftungs AG, 01968 Senftenberg, Germany
| | - Friedrich Jung
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany (J.-H.K.); (F.J.)
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11
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Chen L, Brustad N, Kim M, Luo Y, Wang T, Ali M, Prince N, Chen Y, Chu S, Begum S, Mendez K, Kelly RS, Schoos AM, Rasmussen MA, Zurita J, Kolmert J, Stokholm J, Litonjua A, Weiss ST, Bønnelykke K, Wheelock CE, Lasky-Su J, Chawes B. Urinary eicosanoid levels in early life and risk of atopic disease in childhood. J Allergy Clin Immunol 2024; 154:670-678. [PMID: 38825025 PMCID: PMC12042789 DOI: 10.1016/j.jaci.2024.05.022] [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: 11/17/2023] [Revised: 05/23/2024] [Accepted: 05/30/2024] [Indexed: 06/04/2024]
Abstract
BACKGROUND Eicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs), and leukotrienes with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. This study aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease. METHODS This study quantified the levels of 21 eicosanoids in urine from children from the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) (age 1 year, n = 450) and VDAART (Vitamin D Antenatal Asthma Reduction Trial) (age 3 years, n = 575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of type-2 inflammation, applying false discovery rate of 5% (FDR5%) multiple testing correction. RESULTS In both cohorts, analyses adjusted for environmental determinants showed that higher TXA2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P < FDR5%) and type-2 inflammation (P < .05). In VDAART, lower PGE2 and PGI2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P < FDR5%). For wheeze/asthma, analyses in COPSAC2010 showed that lower isoprostanes and PGF2 eicosanoids and higher PGD2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (P < .05), whereas analyses in VDAART showed that lower PGE2 and higher TXA2 eicosanoids at age 3 years associated with an increased risk at 6 years (P < FDR5%). CONCLUSIONS This study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases.
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Affiliation(s)
- Liang Chen
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
| | - Nicklas Brustad
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Min Kim
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - Yang Luo
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tingting Wang
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Mina Ali
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Nicole Prince
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
| | - Yulu Chen
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
| | - Su Chu
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
| | - Sofina Begum
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
| | - Kevin Mendez
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
| | - Rachel S Kelly
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
| | - Ann-Marie Schoos
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Slagelse Hospital, Slagelse, Denmark
| | - Morten A Rasmussen
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Section of Microbiology and Fermentation, Department of Food Science, University of Copenhagen, Slagelse, Denmark
| | - Javier Zurita
- Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
| | - Johan Kolmert
- Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
| | - Jakob Stokholm
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Slagelse Hospital, Slagelse, Denmark; Section of Microbiology and Fermentation, Department of Food Science, University of Copenhagen, Slagelse, Denmark
| | - Augusto Litonjua
- Division of Pediatric Pulmonary Medicine, Golisano Children's Hospital, University of Rochester Medical Center, Rochester, NY
| | - Scott T Weiss
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
| | - Klaus Bønnelykke
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Craig E Wheelock
- Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
| | - Jessica Lasky-Su
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
| | - Bo Chawes
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
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12
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Petry J, Weiser T, Griesbaum L, Schröder K, Hoch CC, Bashiri Dezfouli A, Shoykhet M, Wollenberg B. 1.8-cineole prevents platelet activation and aggregation by activating the cAMP pathway via the adenosine A 2A receptor. Life Sci 2024; 350:122746. [PMID: 38810792 DOI: 10.1016/j.lfs.2024.122746] [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: 04/15/2024] [Revised: 05/16/2024] [Accepted: 05/22/2024] [Indexed: 05/31/2024]
Abstract
AIMS Dysregulated platelet aggregation is a fatal condition in many bacterial- and virus-induced diseases. However, classical antithrombotics cannot completely prevent immunothrombosis, due to the unaddressed mechanisms towards inflammation. Thus, targeting platelet hyperactivation together with inflammation might provide new treatment options in diseases, characterized by immunothrombosis, such as COVID-19 and sepsis. The aim of this study was to investigate the antiaggregatory effect and mode of action of 1.8-cineole, a monoterpene derived from the essential oil of eucalyptus leaves, known for its anti-inflammatory proprieties. MAIN METHODS Platelet activity was monitored by measuring the expression and release of platelet activation markers, i.e., P-selectin, CD63 and CCL5, as well as platelet aggregation, upon treatment with 1.8-cineole and stimulation with several classical stimuli and bacteria. A kinase activity assay was used to elucidate the mode of action, followed by a detailed analysis of the involvement of the adenylyl-cyclase (AC)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway by Western blot and ELISA. KEY FINDINGS 1.8-cineole prevented the expression and release of platelet activation markers, as well as platelet aggregation, upon induction of aggregation with classical stimuli and immunological agonists. Mechanistically, 1.8- cineole influences the activation of the AC-cAMP-PKA pathway, leading to higher cAMP levels and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Finally, blocking the adenosine A2A receptor reversed the antithrombotic effect of 1.8-cineole. SIGNIFICANCE Given the recognized anti-inflammatory attributes of 1.8-cineole, coupled with our findings, 1.8-cineole might emerge as a promising candidate for treating conditions marked by platelet activation and abnormal inflammation.
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Affiliation(s)
- Julie Petry
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Tobias Weiser
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Lena Griesbaum
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Kathrin Schröder
- Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich, Munich, Germany
| | - Cosima C Hoch
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Ali Bashiri Dezfouli
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany; Central Institute for Translational Cancer Research, Technical University of Munich (TranslaTUM), Department of Radiation Oncology, Klinikum Rechts der Isar, Munich, Germany
| | - Maria Shoykhet
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Barbara Wollenberg
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany.
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Qiu D, He Y, Feng Y, Lin M, Lin Z, Zhang Z, Xiong Y, Hu Z, Ma S, Jin H, Liu J. Tumor perfusion enhancement by microbubbles ultrasonic cavitation reduces tumor glycolysis metabolism and alleviate tumor acidosis. Front Oncol 2024; 14:1424824. [PMID: 39091919 PMCID: PMC11291205 DOI: 10.3389/fonc.2024.1424824] [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: 04/28/2024] [Accepted: 06/25/2024] [Indexed: 08/04/2024] Open
Abstract
The tumor microenvironment is increasingly acknowledged as a critical contributor to cancer progression, mediating genetic and epigenetic alterations. Beyond diverse cellular interactions from the microenvironment, physicochemical factors such as tumor acidosis also significantly affect cancer dynamics. Recent research has highlighted that tumor acidosis facilitates invasion, immune escape, metastasis, and resistance to therapies. Thus, noninvasive measurement of tumor acidity and the development of targeted interventions represent promising strategies in oncology. Techniques like contrast-enhanced ultrasound (CEUS) can effectively assess blood perfusion, while ultrasound-stimulated microbubble cavitation (USMC) has proven to enhance tumor blood perfusion. We therefore aimed to determine whether CEUS assesses tumor acidity and whether USMC treatment can modulate tumor acidity. Firstly, we tracked CEUS perfusion parameters in MCF7 tumor models and compared them with in vivo tumor pH recorded by pH microsensors. We found that the peak intensity and area under curve of tumor contrast-enhanced ultrasound correlated well with tumor pH. We further conducted USMC treatment on MCF7 tumor-bearing mice, tracked changes of tumor blood perfusion and tumor pH in different perfusion regions before and after the USMC treatment to assess its impact on tumor acidity and optimize therapeutic ultrasound pressure. We discovered that USMC with 1.0 Mpa significantly improved tumor blood perfusion and tumor pH. Furthermore, tumor vascular pathology and PGI2 assays indicated that improved tumor perfusion was mainly due to vasodilation rather than angiogenesis. More importantly, analysis of glycolysis-related metabolites and enzymes demonstrated USMC treatment can reduce tumor acidity by reducing tumor glycolysis. These findings support that CEUS may serve as a potential biomarker to assess tumor acidity and USMC is a promising therapeutic modality for reducing tumor acidosis.
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Affiliation(s)
- Danxia Qiu
- Department of Medical Ultrasound, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yangcheng He
- Department of Medical Ultrasound, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yuyi Feng
- Department of Medical Ultrasound, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Minhua Lin
- Department of Medical Ultrasound, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Zekai Lin
- Department of Radiology, The Second Clinical College, Guangzhou Medical University, Guangzhou, China
| | - Zhiyi Zhang
- Department of Medical Ultrasound, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Ying Xiong
- Department of Medical Ultrasound, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Zhiwen Hu
- Department of Medical Ultrasound, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Suihong Ma
- Department of Medical Ultrasound, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Hai Jin
- Department of Medical Ultrasound, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jianhua Liu
- Department of Medical Ultrasound, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
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14
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Wang Z, Zhang G, Hu S, Fu M, Zhang P, Zhang K, Hao L, Chen S. Research progress on the protective effect of hormones and hormone drugs in myocardial ischemia-reperfusion injury. Biomed Pharmacother 2024; 176:116764. [PMID: 38805965 DOI: 10.1016/j.biopha.2024.116764] [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: 02/21/2024] [Revised: 05/05/2024] [Accepted: 05/17/2024] [Indexed: 05/30/2024] Open
Abstract
Ischemic heart disease (IHD) is a condition where the heart muscle does not receive enough blood flow, leading to cardiac dysfunction. Restoring blood flow to the coronary artery is an effective clinical therapy for myocardial ischemia. This strategy helps lower the size of the myocardial infarction and improves the prognosis of patients. Nevertheless, if the disrupted blood flow to the heart muscle is restored within a specific timeframe, it leads to more severe harm to the previously deprived heart tissue. This condition is referred to as myocardial ischemia/reperfusion injury (MIRI). Until now, there is a dearth of efficacious strategies to prevent and manage MIRI. Hormones are specialized substances that are produced directly into the circulation by endocrine organs or tissues in humans and animals, and they have particular effects on the body. Hormonal medications utilize human or animal hormones as their active components, encompassing sex hormones, adrenaline medications, thyroid hormone medications, and others. While several studies have examined the preventive properties of different endocrine hormones, such as estrogen and hormone analogs, on myocardial injury caused by ischemia-reperfusion, there are other hormone analogs whose mechanisms of action remain unexplained and whose safety cannot be assured. The current study is on hormones and hormone medications, elucidating the mechanism of hormone pharmaceuticals and emphasizing the cardioprotective effects of different endocrine hormones. It aims to provide guidance for the therapeutic use of drugs and offer direction for the examination of MIRI in clinical therapy.
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Affiliation(s)
- Zhongyi Wang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Gaojiang Zhang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Shan Hu
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Meilin Fu
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Pingyuan Zhang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Kuo Zhang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Liying Hao
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China.
| | - Sichong Chen
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China.
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15
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Parchem K, Letsiou S, Petan T, Oskolkova O, Medina I, Kuda O, O'Donnell VB, Nicolaou A, Fedorova M, Bochkov V, Gladine C. Oxylipin profiling for clinical research: Current status and future perspectives. Prog Lipid Res 2024; 95:101276. [PMID: 38697517 DOI: 10.1016/j.plipres.2024.101276] [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: 12/12/2023] [Revised: 04/24/2024] [Accepted: 04/29/2024] [Indexed: 05/05/2024]
Abstract
Oxylipins are potent lipid mediators with increasing interest in clinical research. They are usually measured in systemic circulation and can provide a wealth of information regarding key biological processes such as inflammation, vascular tone, or blood coagulation. Although procedures still require harmonization to generate comparable oxylipin datasets, performing comprehensive profiling of circulating oxylipins in large studies is feasible and no longer restricted by technical barriers. However, it is essential to improve and facilitate the biological interpretation of complex oxylipin profiles to truly leverage their potential in clinical research. This requires regular updating of our knowledge about the metabolism and the mode of action of oxylipins, and consideration of all factors that may influence circulating oxylipin profiles independently of the studied disease or condition. This review aims to provide the readers with updated and necessary information regarding oxylipin metabolism, their different forms in systemic circulation, the current limitations in deducing oxylipin cellular effects from in vitro bioactivity studies, the biological and technical confounding factors needed to consider for a proper interpretation of oxylipin profiles.
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Affiliation(s)
- Karol Parchem
- Department of Food Chemistry, Technology and Biotechnology, Faculty of Chemistry, Gdańsk University of Technology, 11/12 Gabriela Narutowicza St., 80-233 Gdańsk, Poland; Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 53210 Pardubice, Czech Republic.
| | - Sophia Letsiou
- Department of Biomedical Sciences, University of West Attica, Ag. Spiridonos St. Egaleo, 12243 Athens, Greece.
| | - Toni Petan
- Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova cesta 39, SI-1000 Ljubljana, Slovenia.
| | - Olga Oskolkova
- Institute of Pharmaceutical Sciences, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria.
| | - Isabel Medina
- Instituto de Investigaciones Marinas-Consejo Superior de Investigaciones Científicas (IIM-CSIC), Eduardo Cabello 6, E-36208 Vigo, Spain.
| | - Ondrej Kuda
- Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 14200 Prague, Czech Republic.
| | - Valerie B O'Donnell
- Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
| | - Anna Nicolaou
- School of Health Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK.
| | - Maria Fedorova
- Center of Membrane Biochemistry and Lipid Research, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, 01307 Dresden, Germany.
| | - Valery Bochkov
- Institute of Pharmaceutical Sciences, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria.
| | - Cécile Gladine
- Université Clermont Auvergne, INRAE, UNH, Clermont-Ferrand, France.
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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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17
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Lin YE, Chen MC. Dextran-40 Reduces Partial Flap Failure: A Systematic Review and Meta-analysis for Antithrombotics after Free Flaps. PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2024; 12:e5812. [PMID: 38752217 PMCID: PMC11095965 DOI: 10.1097/gox.0000000000005812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/22/2024] [Indexed: 05/18/2024]
Abstract
Background Antithrombotic agents are used after free-flap surgery to prevent thrombus formation and improve flap outcomes. However, the reports vary. Therefore, this meta-analysis aimed to elucidate the need for antithrombotic agents in this context. Methods We searched for studies that compared the outcomes of patients undergoing free-flap surgery with or without postoperative antithrombotic agents in the PubMed, Cochrane, and ClinicalTrials.gov databases. The primary outcome was total flap failure, with secondary outcomes including partial flap failure, pedicle thrombosis, and bleeding/hematoma. The relative risks (RRs) of outcomes with or without antithrombotic use were evaluated. Results Fifteen studies (n = 6755 cases) were included. Antithrombotic agents did not reduce flap failure or pedicle thrombosis risks but increased bleeding and hematoma risks (RR, 1.535). Subgroup analyses by antiplatelet and anticoagulant use demonstrated results similar to those of antithrombotic use. The RR of bleeding/hematoma was 1.761 and 2.740 in the antiplatelet and anticoagulant groups, respectively. Postoperative dextran-40 administration reduced the risk of partial flap failure, with an RR of 0.535. Conclusions Postoperative antithrombotic, antiplatelet, or anticoagulant use did not change the risk of total/partial flap failure or pedicle thrombosis but increased the risk of hematoma/bleeding. Postoperative use of dextran-40 reduced the risk of partial flap failure. Increased intraflap blood flow may decrease the risk of partial flap failure. However, dextran-40 may cause severe pulmonary distress. Further prospective studies are required to evaluate the effects of these agents on thrombus formation, intraflap blood flow, and partial flap failure risk.
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Affiliation(s)
- Yi-En Lin
- From Taipei Veterans General Hospital, Taipei, Taiwan
| | - Mei-Chun Chen
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
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18
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Baucom MR, Price AD, Weissman N, England L, Schuster RM, Pritts TA, Goodman MD. Desmopressin, Misoprostol, nor Carboprost Affect Platelet Aggregability Following Traumatic Brain Injury and Aspirin. J Surg Res 2024; 296:643-653. [PMID: 38359679 DOI: 10.1016/j.jss.2024.01.027] [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: 05/18/2023] [Revised: 12/26/2023] [Accepted: 01/16/2024] [Indexed: 02/17/2024]
Abstract
INTRODUCTION Desmopressin (DDAVP) has been utilized clinically in patients taking aspirin (ASA) to improve drug-induced platelet dysfunction. Misoprostol and carboprost, prostaglandin analogs commonly used for postpartum hemorrhage, may also induce platelet aggregation. The aim of this study was to determine the effects of DDAVP, misoprostol, and carboprost administration on platelet aggregability following traumatic brain injury (TBI) in mice treated with ASA. METHODS Male C57BL/6 mice were randomized into seven groups (n = 5 each): untouched, ASA only, Saline/TBI, ASA/TBI, ASA/TBI/DDAVP 0.4 μg/kg, ASA/TBI/misoprostol 1 mg/kg, and ASA/TBI/carboprost 100 μg/kg. TBI was induced via a weight drop model 4-h after ASA (50 mg/kg) gavage. Mice were given an intraperitoneal injection of DDAVP, misoprostol, or carboprost 10 minutes after TBI. In vivo testing was completed utilizing tail vein bleed. Mice were sacrificed 30-min posttreatment and blood was collected via cardiac puncture. Whole blood was analyzed via Multiplate impedance aggregometry, rotational thromboelastometry, and TEG6s. RESULTS Mice receiving misoprostol after ASA/TBI demonstrated decreased tail vein bleeding times compared to ASA only treated mice. However, mice treated with misoprostol following ASA and TBI demonstrated decreased platelet aggregability compared to untouched mice and TBI only mice within the arachidonic acid agonist pathway. By contrast, DDAVP and carboprost did not significantly change platelet aggregability via adenosine diphosphate or arachidonic acid following ASA and TBI. However, DDAVP did decrease the platelet contribution to clot via rotational thromboelastometry. CONCLUSIONS Reversal of medication-induced platelet inhibition has become increasingly controversial after TBI. Based on these results, DDAVP, misoprostol, nor carboprost consistently improve platelet aggregability following TBI in those also treated with ASA.
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Affiliation(s)
- Matthew R Baucom
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | - Adam D Price
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | | | - Lisa England
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | | | - Timothy A Pritts
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
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Mruthunjaya AKV, Torriero AAJ. Electrochemical Monitoring in Anticoagulation Therapy. Molecules 2024; 29:1453. [PMID: 38611733 PMCID: PMC11012951 DOI: 10.3390/molecules29071453] [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: 02/23/2024] [Revised: 03/16/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open
Abstract
The process of blood coagulation, wherein circulating blood transforms into a clot in response to an internal or external injury, is a critical physiological mechanism. Monitoring this coagulation process is vital to ensure that blood clotting neither occurs too rapidly nor too slowly. Anticoagulants, a category of medications designed to prevent and treat blood clots, require meticulous monitoring to optimise dosage, enhance clinical outcomes, and minimise adverse effects. This review article delves into the various stages of blood coagulation, explores commonly used anticoagulants and their targets within the coagulation enzyme system, and emphasises the electrochemical methods employed in anticoagulant testing. Electrochemical sensors for anticoagulant monitoring are categorised into two types. The first type focuses on assays measuring thrombin activity via electrochemical techniques. The second type involves modified electrode surfaces that either directly measure the redox behaviours of anticoagulants or monitor the responses of standard redox probes in the presence of these drugs. This review comprehensively lists different electrode compositions and their detection and quantification limits. Additionally, it discusses the potential of employing a universal calibration plot to replace individual drug-specific calibrations. The presented insights are anticipated to significantly contribute to the sensor community's efforts in this field.
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Affiliation(s)
| | - Angel A. J. Torriero
- School of Life and Environmental Sciences, Deakin University, Burwood 3125, Australia
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20
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Yang M, Silverstein RL. Targeting Cysteine Oxidation in Thrombotic Disorders. Antioxidants (Basel) 2024; 13:83. [PMID: 38247507 PMCID: PMC10812781 DOI: 10.3390/antiox13010083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 12/29/2023] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
Oxidative stress increases the risk for clinically significant thrombotic events, yet the mechanisms by which oxidants become prothrombotic are unclear. In this review, we provide an overview of cysteine reactivity and oxidation. We then highlight recent findings on cysteine oxidation events in oxidative stress-related thrombosis. Special emphasis is on the signaling pathway induced by a platelet membrane protein, CD36, in dyslipidemia, and by protein disulfide isomerase (PDI), a member of the thiol oxidoreductase family of proteins. Antioxidative and chemical biology approaches to target cysteine are discussed. Lastly, the knowledge gaps in the field are highlighted as they relate to understanding how oxidative cysteine modification might be targeted to limit thrombosis.
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Affiliation(s)
- Moua Yang
- Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-924, Boston, MA 02115, USA
| | - Roy L. Silverstein
- Department of Medicine, Medical College of Wisconsin, Hub 8745, 8701 W Watertown Plank Rd., Milwaukee, WI 53226, USA
- Versiti Blood Research Institute, Milwaukee, WI 53226, USA
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21
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Gogilashvili N, Tsinamdzgvrishvili B, Momtselidze N, Jung F, Plantl L, Urdulashvili T, Mantskava M. Study of some components of the influence and formation of blood flow in patients with "slow flow". Clin Hemorheol Microcirc 2024; 88:325-336. [PMID: 39031348 DOI: 10.3233/ch-249104] [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: 07/22/2024]
Abstract
BACKGROUND "Slow flow" is one very important concept in modern fundamental and clinical biomedicine. Slow coronary flow is indicative of delayed filling of the terminal coronary artery vessels, occurring in the absence of significant coronary stenosis. This group patient of patients exhibits a high incidence of disability and represents a significant financial and material burden for the state and the healthcare system in general. OBJECTIVE The primary objective of our study was to examine patients with slow coronary flow. METHODS We studied the standard parameters recommended by the international health care system (electrocardiography (by Medica QRS-12, Germany), through the electrical activity of a patient's heart by the electrical impulses (beating) of the heart; HC1(Germany); coagulogramma by Coatron M1 (Germany), troponin by AQT 90 (Germany); general blood test we used automatic human counting device HC1(Germany). Also, we investigate the original parameters (non-standard parameters, which we use in this pilot study) that we were first studied for this diagnosis and non-standard parameters. RESULTS A general blood test showed that patients with slow flow had a higher blood leukocyte count than the control group, but the amount of hemoglobin was normal, the hematocrit was much higher than in the control group, and the platelet count was close to the lower limit of clinical standards.We obtained details of blood flow by coagulation situation, such as prothrombin time, prothrombin index, international normalized ratio, activated partial thromboplastin time, thrombin time, fibrinogen, and rheological properties such as index of erythrocyte aggregability, index of erythrocyte deformability, plasma viscosity, in silico blood rheological index. CONCLUSSION Blood flow can be considered as a superposition of vortices with similar frequencies and wave vectors that change after bifurcations or other obstacles in the vascular network. These factors together determine the conditions for structuring the flow of moving blood. Disruption or alteration of these factors results in slow flow. It has been found that the speed of blood flow in the coronary arteries depends on changes in the number and function of red blood cells. Slow flow is directly influenced by the aggregation and deformation of red blood cells, their number, and plasma viscosity. Consequently, the rheological status plays a crucial role in determining blood flow and its velocity.
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Affiliation(s)
| | | | - Nana Momtselidze
- Ivane Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
- UNIK-Kutaisi University, Kutaisi, Georgia
| | - Friedrich Jung
- Brandenburg University of Technology Gottbus-Senftenberg, Cottbus, Germany
| | - Lukas Plantl
- University Hospital Regensburg, Regensburg, Germany
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Ma Y, Du J, Wang XX, Deng T, Qi JL, Cheng H, Li L. Impact of low-to moderate-intensity exercise training on the mRNA expression of purine receptors across various vessels in SHR. Clin Hemorheol Microcirc 2024; 88:463-474. [PMID: 39093066 DOI: 10.3233/ch-242366] [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: 08/04/2024]
Abstract
OBJECTIVE In this study, we developed an exercise training protocol for assessing both blood pressure dynamics and mRNA expression levels of purine receptors in various vascular tissues during physical activity. The objective is to assess the impact of exercise training on blood pressure regulation in spontaneously hypertensive rats (SHR) and purine receptors in vascular tissues. METHODS Wistar Kyoto (WKY) and SHR rats were randomly allocated into sedentary (Sed) and exercise training (ExT) groups. Rats in the Sed groups were allowed unrestricted movement, whereas those in the ExT groups underwent a 16-week regimen of low- to moderate-intensity treadmill exercise. Throughout the intervention period, blood pressure measurements and body weight recordings were conducted. Additionally, mRNA expressions of purine receptors P2X1, P2Y1, and P2Y2 in renal artery (RA), internal carotid artery (Int), thoracic aorta (Aor), and caudal artery (Cau) tissues were assessed. RESULTS In the Sed group, body weight of SHR rats was observed to be lower compared to the three other groups. Over the course of the exercise regimen, blood pressure in the ExT group of SHR rats reduced gradually, converging towards levels similar to those observed in WKY rats by the conclusion of the exercise period. Regarding mRNA expression patterns of P2X1 receptors across the four blood vessels, WKY and SHR rats demonstrated similar sequences, consistently displaying the highest expression levels in the Cau. Conversely, mRNA expressions of P2Y1 and P2Y2 receptors exhibited distinct sequences across the four blood vessels in both WKY and SHR rats. Notably, compared to the Sed group of WKY rats, mRNA expression of P2X1 receptor in the Int of SHR rats revealed an increase, while expressions in the Aor of WKY rats and the Cau of SHR rats decreased following exercise. Expression of P2Y1 receptor mRNA decreased across all four types of blood vessels in SHR rats. Post-exercise, P2Y1 receptor mRNA expression increased in the Aor, decreased in the Cau of WKY rats, and increased in the Int and renal artery (RA) of SHR rats. Conversely, expressions of P2Y2 receptor mRNA decreased in the Int and Aor of SHR rats. Except for the Aor of WKY rats, expressions of P2Y2 receptor mRNA increased in the other arteries of both rat types following exercise. CONCLUSION Differences in the distribution of purine receptor subtypes among distinct arterial segments in both WKY and SHR rats were observed. Exercise training was found to enhance mRNA expression levels of P2Y receptors in these rat models. This finding implies that exercise training might reduce hypertension in SHR rats by bolstering the purinergic relaxation response.
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Affiliation(s)
- Yue Ma
- Department of Anesthesiology, Affiliated Hospital of Hebei University, Baoding, China
| | - Jin Du
- Department of Anesthesiology, Affiliated Hospital of Hebei University, Baoding, China
| | - Xin-Xin Wang
- Department of Anesthesiology, Affiliated Hospital of Hebei University, Baoding, China
| | - Tong Deng
- Department of Anesthesiology, Affiliated Hospital of Hebei University, Baoding, China
| | - Jia-Li Qi
- Department of Anesthesiology, Affiliated Hospital of Hebei University, Baoding, China
| | - Hong Cheng
- Department of Anesthesiology, Affiliated Hospital of Hebei University, Baoding, China
| | - Lu Li
- Department of Anesthesiology, Affiliated Hospital of Hebei University, Baoding, China
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23
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Sun J, Dahiya N, Schmitt T, Stewart C, Anderson J, MacGregor S, Maclean M, Beger RD, Atreya CD. Metabolomics evaluation of the photochemical impact of violet-blue light (405 nm) on ex vivo platelet concentrates. Metabolomics 2023; 19:88. [PMID: 37855954 DOI: 10.1007/s11306-023-02050-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 09/08/2023] [Indexed: 10/20/2023]
Abstract
INTRODUCTION Microbicidal violet-blue light in the visible spectrum (405 nm) has been under evaluation for pathogen inactivation in ex vivo human plasma and platelets (PLTs) stored in plasma. Results to date have demonstrated that several blood-borne infectious disease-causing pathogens can be successfully reduced to significantly low levels in the light-treated plasma and PLTs. METHOD In order to evaluate whether the microbicidal 405 nm light is safe for the treatment of PLT concentrates for pathogen inactivation, LC/MS-based metabolomics analyses were performed to evaluate the overall impact of 405 nm violet-blue light treatment on ex vivo PLT concentrates suspended in plasma and on plasma itself, and to identify metabolome changes in intra-platelet and extra-cellular medium (i.e., plasma). RESULTS The metabolomics data identified that platelet activating factors (PAFs), agonists and prostaglandins, which can influence PLT basic functions such as integrity, activation, and aggregation potential were unaltered, suggesting that 405 nm light illumination is safe regarding PLT basic functions. Distinct increases in hydroxyl fatty acids and aldehydes, as well as decreases in antioxidant metabolites indicated that reactive oxygen species (ROS) were generated at high levels after only one hour of exposure to 405 nm light. Distinctly changed endogenous photosensitizer metabolites after 1 h of light exposure provided good evidence that 405 nm light was an effective microbicide acting through ROS mechanism and no external additive photosensitizers were required.
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Affiliation(s)
- Jinchun Sun
- Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
| | - Neetu Dahiya
- Office of Blood Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA
| | - Thomas Schmitt
- Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA
| | - Caitlin Stewart
- The Robertson Trust Laboratory for Electronic Sterilization Technologies, Department of Electronic and Electrical Engineering, University of Strathclyde, Glasgow, UK
| | - John Anderson
- The Robertson Trust Laboratory for Electronic Sterilization Technologies, Department of Electronic and Electrical Engineering, University of Strathclyde, Glasgow, UK
| | - Scott MacGregor
- The Robertson Trust Laboratory for Electronic Sterilization Technologies, Department of Electronic and Electrical Engineering, University of Strathclyde, Glasgow, UK
| | - Michelle Maclean
- The Robertson Trust Laboratory for Electronic Sterilization Technologies, Department of Electronic and Electrical Engineering, University of Strathclyde, Glasgow, UK
- Department of Biomedical Engineering, University of Strathclyde, Glasgow, UK
| | - Richard D Beger
- Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA
| | - Chintamani D Atreya
- Office of Blood Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA
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24
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Yang M, Smith BC. Cysteine and methionine oxidation in thrombotic disorders. Curr Opin Chem Biol 2023; 76:102350. [PMID: 37331217 PMCID: PMC10527720 DOI: 10.1016/j.cbpa.2023.102350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/19/2023] [Accepted: 05/22/2023] [Indexed: 06/20/2023]
Abstract
Thrombosis is the leading cause of death in many diseased conditions. Oxidative stress is characteristic of these conditions. Yet, the mechanisms through which oxidants become prothrombotic are unclear. Recent evidence suggests protein cysteine and methionine oxidation as prothrombotic regulators. These oxidative post-translational modifications occur on proteins that participate in the thrombotic process, including Src family kinases, protein disulfide isomerase, β2 glycoprotein I, von Willebrand factor, and fibrinogen. New chemical tools to identify oxidized cysteine and methionine proteins in thrombosis and hemostasis, including carbon nucleophiles for cysteine sulfenylation and oxaziridines for methionine, are critical to understanding why clots occur during oxidative stress. These mechanisms will identify alternative or novel therapeutic approaches to treat thrombotic disorders in diseased conditions.
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Affiliation(s)
- Moua Yang
- Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
| | - Brian C Smith
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Program in Chemical Biology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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Zhang Y, Liu Y, Sun J, Zhang W, Guo Z, Ma Q. Arachidonic acid metabolism in health and disease. MedComm (Beijing) 2023; 4:e363. [PMID: 37746665 PMCID: PMC10511835 DOI: 10.1002/mco2.363] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 08/13/2023] [Accepted: 08/17/2023] [Indexed: 09/26/2023] Open
Abstract
Arachidonic acid (AA), an n-6 essential fatty acid, is a major component of mammalian cells and can be released by phospholipase A2. Accumulating evidence indicates that AA plays essential biochemical roles, as it is the direct precursor of bioactive lipid metabolites of eicosanoids such as prostaglandins, leukotrienes, and epoxyeicosatrienoic acid obtained from three distinct enzymatic metabolic pathways: the cyclooxygenase pathway, lipoxygenase pathway, and cytochrome P450 pathway. AA metabolism is involved not only in cell differentiation, tissue development, and organ function but also in the progression of diseases, such as hepatic fibrosis, neurodegeneration, obesity, diabetes, and cancers. These eicosanoids are generally considered proinflammatory molecules, as they can trigger oxidative stress and stimulate the immune response. Therefore, interventions in AA metabolic pathways are effective ways to manage inflammatory-related diseases in the clinic. Currently, inhibitors targeting enzymes related to AA metabolic pathways are an important area of drug discovery. Moreover, many advances have also been made in clinical studies of AA metabolic inhibitors in combination with chemotherapy and immunotherapy. Herein, we review the discovery of AA and focus on AA metabolism in relation to health and diseases. Furthermore, inhibitors targeting AA metabolism are summarized, and potential clinical applications are discussed.
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Affiliation(s)
- Yiran Zhang
- Department of Orthopedic SurgeryOrthopedic Oncology InstituteThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
| | - Yingxiang Liu
- Department of Orthopedic SurgeryOrthopedic Oncology InstituteThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
| | - Jin Sun
- Department of Orthopedic SurgeryOrthopedic Oncology InstituteThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
| | - Wei Zhang
- Department of PathologyThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
| | - Zheng Guo
- Department of Orthopedic SurgeryOrthopedic Oncology InstituteThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
| | - Qiong Ma
- Department of Orthopedic SurgeryOrthopedic Oncology InstituteThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
- Department of PathologyThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
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26
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Wang W, Song L, Yang L, Li C, Ma Y, Xue M, Shi D. Panax quinquefolius saponins combined with dual antiplatelet therapy enhanced platelet inhibition with alleviated gastric injury via regulating eicosanoids metabolism. BMC Complement Med Ther 2023; 23:289. [PMID: 37596586 PMCID: PMC10436642 DOI: 10.1186/s12906-023-04112-7] [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: 10/15/2022] [Accepted: 08/01/2023] [Indexed: 08/20/2023] Open
Abstract
BACKGROUND Panax quinquefolius saponin (PQS) was shown beneficial against platelet adhesion and for gastroprotection. This study aimed to investigate the integrated efficacy of PQS with dual antiplatelet therapy (DAPT) on platelet aggregation, myocardial infarction (MI) expansion and gastric injury in a rat model of acute MI (AMI) and to explore the mechanism regarding arachidonic acid (AA)-derived eicosanoids metabolism. METHODS Wistar rats were subjected to left coronary artery occlusion to induce AMI model followed by treatment with DAPT, PQS or the combined therapy. Platelet aggregation was measured by light transmission aggregometry. Infarct size, myocardial histopathology was evaluated by TTC and H&E staining, respectively. Gastric mucosal injury was examined by scanning electron microscope (SEM). A comprehensive eicosanoids profile in plasma and gastric mucosa was characterized by liquid chromatography-mass spectrometer-based lipidomic analysis. RESULTS PQS+DAPT further decreased platelet aggregation, lessened infarction and attenuated cardiac injury compared with DAPT. Plasma lipidomic analysis revealed significantly increased synthesis of epoxyeicosatrienoic acid (EET) and prostaglandin (PG) I2 (potent inhibitors for platelet adhesion and aggregation) while markedly decreased thromboxane (TX) A2 (an agonist for platelet activation and thrombosis) by PQS+DAPT, relative to DAPT. DAPT induced overt gastric mucosal damage, which was attenuated by PQS co-administration. Mucosal gastroprotective PGs (PGE2, PGD2 and PGI2) were consistently increased after supplementation of PQS+DAPT. CONCLUSIONS Collectively, PQS+DAPT showed synergistic effect in platelet inhibition with ameliorated MI expansion partially through upregulation of AA/EET and AA/PGI2 synthesis while suppression of AA/TXA2 metabolism. PQS attenuated DAPT-induced gastric injury, which was mechanistically linked to increased mucosal PG production.
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Affiliation(s)
- Wenting Wang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
- Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Lei Song
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
- Center of Cardiovascular Disease, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Lin Yang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
- Center of Cardiovascular Disease, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Changkun Li
- Shimadzu (China) Co., LTD Beijing Branch, Beijing, 100020, China
| | - Yan Ma
- Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology & Immunology, Vienna General Hospital, Medical University of Vienna, 1090, Vienna, Austria
| | - Mei Xue
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
- Center of Cardiovascular Disease, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
| | - Dazhuo Shi
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
- Center of Cardiovascular Disease, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
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Krüger-Genge A, Köhler S, Laube M, Haileka V, Lemm S, Majchrzak K, Kammerer S, Schulz C, Storsberg J, Pietzsch J, Küpper JH, Jung F. Anti-Cancer Prodrug Cyclophosphamide Exerts Thrombogenic Effects on Human Venous Endothelial Cells Independent of CYP450 Activation-Relevance to Thrombosis. Cells 2023; 12:1965. [PMID: 37566045 PMCID: PMC10416884 DOI: 10.3390/cells12151965] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/09/2023] [Accepted: 07/13/2023] [Indexed: 08/12/2023] Open
Abstract
Cancer patients are at a very high risk of serious thrombotic events, often fatal. The causes discussed include the detachment of thrombogenic particles from tumor cells or the adverse effects of chemotherapeutic agents. Cytostatic agents can either act directly on their targets or, in the case of a prodrug approach, require metabolization for their action. Cyclophosphamide (CPA) is a widely used cytostatic drug that requires prodrug activation by cytochrome P450 enzymes (CYP) in the liver. We hypothesize that CPA could induce thrombosis in one of the following ways: (1) damage to endothelial cells (EC) after intra-endothelial metabolization; or (2) direct damage to EC without prior metabolization. In order to investigate this hypothesis, endothelial cells (HUVEC) were treated with CPA in clinically relevant concentrations for up to 8 days. HUVECs were chosen as a model representing the first place of action after intravenous CPA administration. No expression of CYP2B6, CYP3A4, CYP2C9 and CYP2C19 was found in HUVEC, but a weak expression of CYP2C18 was observed. CPA treatment of HUVEC induced DNA damage and a reduced formation of an EC monolayer and caused an increased release of prostacyclin (PGI2) and thromboxane (TXA) associated with a shift of the PGI2/TXA balance to a prothrombotic state. In an in vivo scenario, such processes would promote the risk of thrombus formation.
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Affiliation(s)
- Anne Krüger-Genge
- Department of Healthcare, Biomaterials and Cosmeceuticals, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany
| | - Susanne Köhler
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
| | - Markus Laube
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
| | - Vanessa Haileka
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
| | - Sandy Lemm
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, 01069 Dresden, Germany
| | - Karolina Majchrzak
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
| | - Sarah Kammerer
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
| | - Christian Schulz
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
- Brandenburg University of Technology Cottbus-Senftenberg, Fraunhofer Project Group PZ-Syn of the Fraunhofer Institute for Cell Therapy and Immunology, Branch Bioanalytics and Bioprocesses (IZI-BB), 14476 Potsdam, Germany
| | - Joachim Storsberg
- Department of Healthcare, Biomaterials and Cosmeceuticals, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany
- Faculty of Medicine, Private University in the Principality of Liechtenstein (UFL), 9495 Triesen, Liechtenstein
| | - Jens Pietzsch
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, 01069 Dresden, Germany
| | - Jan-Heiner Küpper
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
| | - Friedrich Jung
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
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Muravlev IA, Dobrovolsky AB, Antonova OA, Khaspekova SG, Alieva AK, Pevzner DV, Mazurov AV. Effects of Antiplatelet Drugs on Platelet-Dependent Coagulation Reactions. Biomolecules 2023; 13:1124. [PMID: 37509160 PMCID: PMC10377112 DOI: 10.3390/biom13071124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/07/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Activated platelets are involved in blood coagulation by exposing phosphatidylserine (PS), which serves as a substrate for assembling coagulation complexes. Platelets accelerate fibrin formation and thrombin generation, two final reactions of the coagulation cascade. We investigated the effects of antiplatelet drugs on platelet impact in these reactions and platelet ability to expose PS. Washed human platelets were incubated with acetylsalicylic acid (ASA), ticagrelor, ASA in combination with ticagrelor, ruciromab (glycoprotein IIb-IIIa antagonist), or prostaglandin E1 (PGE1). Platelets were not activated or activated by collagen and sedimented in multiwell plates, and plasma was added after supernatant removal. Fibrin formation (clotting) was monitored in a recalcification assay by light absorbance and thrombin generation in a fluorogenic test. PS exposure was assessed by annexin V staining using flow cytometry. Ticagrelor (alone and in combination with ASA), ruciromab, and PGE1, but not ASA, prolonged the lag phase and decreased the maximum rate of plasma clotting and decreased the peak and maximum rate of thrombin generation. Inhibition was observed when platelets were not treated with exogenous agonists (activation by endogenous thrombin) and pretreated with collagen. Ticagrelor (alone and in combination with ASA), ruciromab, and PGE1, but not ASA, decreased PS exposure on washed platelets activated by thrombin and by thrombin + collagen. PS exposure on activated platelets in whole blood was lower in patients with acute coronary syndrome receiving ticagrelor + ASA in comparison with donors free of medications. These results indicate that antiplatelet drugs are able to suppress platelet coagulation activity not only in vitro but also after administration to patients.
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Affiliation(s)
- Ivan A Muravlev
- Chazov National Medical Research Center of Cardiology, Russian Ministry of Health, Academician Chazov Str., 15a, Moscow 121552, Russia
| | - Anatoly B Dobrovolsky
- Chazov National Medical Research Center of Cardiology, Russian Ministry of Health, Academician Chazov Str., 15a, Moscow 121552, Russia
| | - Olga A Antonova
- Chazov National Medical Research Center of Cardiology, Russian Ministry of Health, Academician Chazov Str., 15a, Moscow 121552, Russia
| | - Svetlana G Khaspekova
- Chazov National Medical Research Center of Cardiology, Russian Ministry of Health, Academician Chazov Str., 15a, Moscow 121552, Russia
| | - Amina K Alieva
- Chazov National Medical Research Center of Cardiology, Russian Ministry of Health, Academician Chazov Str., 15a, Moscow 121552, Russia
| | - Dmitry V Pevzner
- Chazov National Medical Research Center of Cardiology, Russian Ministry of Health, Academician Chazov Str., 15a, Moscow 121552, Russia
| | - Alexey V Mazurov
- Chazov National Medical Research Center of Cardiology, Russian Ministry of Health, Academician Chazov Str., 15a, Moscow 121552, Russia
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Bruno A, Tacconelli S, Contursi A, Ballerini P, Patrignani P. Cyclooxygenases and platelet functions. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2023; 97:133-165. [PMID: 37236757 DOI: 10.1016/bs.apha.2022.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Cyclooxygenase (COX) isozymes, i.e., COX-1 and COX-2, are encoded by separate genes and are involved in the generation of the same products, prostaglandin (PG)G2 and PGH2 from arachidonic acid (AA) by the COX and peroxidase activities of the enzymes, respectively. PGH2 is then transformed into prostanoids in a tissue-dependent fashion due to the different expression of downstream synthases. Platelets present almost exclusively COX-1, which generates large amounts of thromboxane (TX)A2, a proaggregatory and vasoconstrictor mediator. This prostanoid plays a central role in atherothrombosis, as shown by the benefit of the antiplatelet agent low-dose aspirin, a preferential inhibitor of platelet COX-1. Recent findings have shown the relevant role played by platelets and TXA2 in developing chronic inflammation associated with several diseases, including tissue fibrosis and cancer. COX-2 is induced in response to inflammatory and mitogenic stimuli to generate PGE2 and PGI2 (prostacyclin), in inflammatory cells. However, PGI2 is constitutively expressed in vascular cells in vivo and plays a crucial role in protecting the cardiovascular systems due to its antiplatelet and vasodilator effects. Here, platelets' role in regulating COX-2 expression in cells of the inflammatory microenvironment is described. Thus, the selective inhibition of platelet COX-1-dependent TXA2 by low-dose aspirin prevents COX-2 induction in stromal cells leading to antifibrotic and antitumor effects. The biosynthesis and functions of other prostanoids, such as PGD2, and isoprostanes, are reported. In addition to aspirin, which inhibits platelet COX-1 activity, possible strategies to affect platelet functions by influencing platelet prostanoid receptors or synthases are discussed.
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Affiliation(s)
- Annalisa Bruno
- Center for Advanced Studies and Technology (CAST), Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy
| | - Stefania Tacconelli
- Center for Advanced Studies and Technology (CAST), Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy
| | - Annalisa Contursi
- Center for Advanced Studies and Technology (CAST), Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy
| | - Patrizia Ballerini
- Center for Advanced Studies and Technology (CAST), Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, "G.d'Annunzio" University, Chieti, Italy
| | - Paola Patrignani
- Center for Advanced Studies and Technology (CAST), Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy.
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Liu J, Peng B, Steinmetz-Späh J, Idborg H, Korotkova M, Jakobsson PJ. Microsomal prostaglandin E synthase-1 inhibition promotes shunting in arachidonic acid metabolism during inflammatory responses in vitro. Prostaglandins Other Lipid Mediat 2023; 167:106738. [PMID: 37094780 DOI: 10.1016/j.prostaglandins.2023.106738] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/14/2023] [Accepted: 04/21/2023] [Indexed: 04/26/2023]
Abstract
Microsomal Prostaglandin E Synthase 1 (mPGES-1) is the key enzyme for the generation of the pro-inflammatory lipid mediator prostaglandin E2 (PGE2), which contributes to several pathological features of many diseases. Inhibition of mPGES-1 has been shown to be a safe and effective therapeutic strategy in various pre-clinical studies. In addition to reduced PGE2 formation, it is also suggested that the potential shunting into other protective and pro-resolving prostanoids may play an important role in resolution of inflammation. In the present study, we analysed the eicosanoid profiles in four in vitro inflammation models and compared the effects of mPGES-1 inhibition with those of cyclooxygenase-2 (Cox-2) inhibition. Our results showed a marked shift to the PGD2 pathway under mPGES-1 inhibition in A549 cells, RAW264.7 cells and mouse bone marrow-derived macrophages (BMDMs), whereas enhanced prostacyclin production was observed in rheumatoid arthritis synovial fibroblasts (RASFs) treated with an mPGES-1 inhibitor. As expected, Cox-2 inhibition completely suppressed all prostanoids. This study suggests that the therapeutic effects of mPGES-1 inhibition may be mediated by modulation of other prostanoids in addition to PGE2 reduction.
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Affiliation(s)
- Jianyang Liu
- Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Bing Peng
- Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Julia Steinmetz-Späh
- Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Helena Idborg
- Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Marina Korotkova
- Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Per-Johan Jakobsson
- Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
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Zhang T, Liu L, Huang X, Gao X, Chen D, Huan X, He C, Li Y. Effect of pathological high shear exposure time on platelet activation and aggregation. Clin Hemorheol Microcirc 2023:CH221567. [PMID: 37066902 DOI: 10.3233/ch-221567] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
Circulating platelets are sometimes exposed to high shear rate environments due to vascular stenosis, and the effect of transiently elevated pathological high shear rates on platelet activation and aggregation function has not been clarified. The aim of this study was to investigate the effect of pathological high shear rate (8302s - 1) exposure time (3.16-25.3 ms) on platelet activation and aggregation function. In addition, by adding active ingredients of antiplatelet drugs such as ASA (an active ingredient of aspirin), Ticagrelor, Tirofiban and GP1BA (platelet membrane protein GPIb inhibitor) in vitro, we studied TXA2, P2Y12-ADP, GPIIb/IIIa-fibrinogen and GPIb /IX/V-vWF receptor pathways to determine platelet activation function mediated by pathological high shear rate. In this study, we designed a set of microfluidic chips with stenosis lengths of 0.5 mm, 1 mm, 2 mm, 3 mm, and 4 mm, all with 80% stenosis, to generate pathological high shear forces that can act at different times. The whole blood flowing through the microchannels was collected by perfusion of sodium citrate anticoagulated whole blood at a physiological arterial shear rate (1500 s - 1), and the expression levels of platelet surface activation markers (P-selectin and GP IIb/IIIa) and the degree of platelet aggregation were analyzed by flow cytometry; platelet aggregation patterns were observed by microscopic examination of blood smears. The results showed that shearing significantly increased platelet activation and aggregation levels compared to un-sheared whole blood, and the activation and aggregation levels increased with increasing duration of pathological high shear rate. In vitro inhibition studies showed that ASA barely inhibited the expression of P-selectin and PAC-1 on the platelet surface; Ticagrelor effectively inhibited the expression of both P-selectin and PAC-1; Tirofiban significantly inhibited the expression of PAC-1 on the platelet surface and slightly inhibited the expression of P-selectin; GP1BA significantly inhibited the expression of both.ur results suggest that transient pathological high shear rate (8302s - 1) exposure can induce platelet activation in a time-dependent manner; however, the mechanism is more complex and may be due to the following reasons: transient elevated pathological high shear rate activates platelets through the GPIb/IX/V-vWF receptor pathway, and after platelet activation, its surface membrane protein GPIIb/IIIa receptors activate platelets through fibrinogen to form platelet-platelet aggregates, and further activation of active substances such as ADP and TXA2 released by platelet alpha particles, which contribute to the formation of irreversible platelet aggregation.
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Affiliation(s)
- Tiancong Zhang
- Central Laboratory of Yong-chuan Hospital, Chongqing Medical University, Chongqing, China
| | - Ling Liu
- Central Laboratory of Yong-chuan Hospital, Chongqing Medical University, Chongqing, China
| | - Xiaojing Huang
- Central Laboratory of Yong-chuan Hospital, Chongqing Medical University, Chongqing, China
| | - Xuemei Gao
- Central Laboratory of Yong-chuan Hospital, Chongqing Medical University, Chongqing, China
| | - Dan Chen
- Central Laboratory of Yong-chuan Hospital, Chongqing Medical University, Chongqing, China
| | - Xuanrong Huan
- Central Laboratory of Yong-chuan Hospital, Chongqing Medical University, Chongqing, China
| | - Cui He
- Department of Blood Transfusion of Yong-chuan Hospital, Chongqing Medical University, Chongqing, China
| | - Yuan Li
- Central Laboratory of Yong-chuan Hospital, Chongqing Medical University, Chongqing, China
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Yang XD, Ju B, Xu J, Xiu NN, Sun XY, Zhao XC. Glucocorticoid-induced thrombotic microangiopathy in paroxysmal nocturnal hemoglobinuria: A case report and review of literature. World J Clin Cases 2023; 11:1799-1807. [PMID: 36970013 PMCID: PMC10037281 DOI: 10.12998/wjcc.v11.i8.1799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/02/2022] [Accepted: 02/08/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND Thrombotic microangiopathy (TMA) is a group of disorders that converge on excessive platelet aggregation in the microvasculature, leading to consumptive thrombocytopenia, microangiopathic hemolysis and ischemic end-organ dysfunction. In predisposed patients, TMA can be triggered by many environmental factors. Glucocorticoids (GCs) can compromise the vascular endothelium. However, GC-associated TMA has rarely been reported, which may be due to the lack of awareness of clinicians. Given the high frequency of thrombocytopenia during GC treatment, particular attention should be given to this potentially fatal complication.
CASE SUMMARY An elderly Chinese man had a 12-year history of aplastic anemia (AA) and a 3-year history of paroxysmal nocturnal hemoglobinuria (PNH). Three months earlier, methylprednisolone treatment was initiated at 8 mg/d and increased to 20 mg/d to alleviate complement-mediated hemolysis. Following GC treatment, his platelet counts and hemoglobin levels rapidly decreased. After admission to our hospital, the dose of methylprednisolone was increased to 60 mg/d in an attempt to enhance the suppressive effect. However, increasing the GC dose did not alleviate hemolysis, and his cytopenia worsened. Morphological evaluation of the marrow smears revealed increased cellularity with an increased percentage of erythroid progenitors without evident dysplasia. Cluster of differentiation (CD)55 and CD59 expression was significantly decreased on erythrocytes and granulocytes. In the following days, platelet transfusion was required due to severe thrombocytopenia. Observation of platelet transfusion refractoriness indicated that the exacerbated cytopenia may have been caused by the development of TMA due to GC treatment because the transfused platelet concentrates had no defects in glycosylphosphatidylinositol-anchored proteins. We examined blood smears and found a small number of schistocytes, dacryocytes, acanthocytes and target cells. Discontinuation of GC treatment resulted in rapidly increased platelet counts and steady increases in hemoglobin levels. The patient’s platelet counts and hemoglobin levels returned to the levels prior to GC treatment 4 weeks after GC discontinuation.
CONCLUSION GCs can drive TMA episodes. When thrombocytopenia occurs during GC treatment, TMA should be considered, and GCs should be discontinued.
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Affiliation(s)
- Xiao-Dong Yang
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Bo Ju
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Jia Xu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Nuan-Nuan Xiu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xiao-Yun Sun
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xi-Chen Zhao
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
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Abstract
Platelet plug formation is critically involved in murine ductus arteriosus closure and thrombocytopenia in preterm infants seems to negatively affect spontaneous and pharmacologically induced ductal closure. Furthermore, platelet dysfunction may contribute to ductal patency, especially in extremely immature infants. Neonatal platelets likely have multifaceted roles during ductal closure, such as secretion of several signaling molecules and facilitation of specific cell-cell interactions. The only available randomized-controlled trial on platelet transfusions in preterm infants with patent ductus arteriosus demonstrated that a liberal transfusion regimen did not promote ductal closure, but was associated with an increased rate of intraventricular hemorrhage. Herein, we discuss the available mechanistic evidence on the role of platelets in ductus arteriosus closure and their potential clinical implications in preterm infants. We further briefly outline future research directions aimed at a better understanding of platelet-endothelial interactions in neonatal health and disease.
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Affiliation(s)
- Hannes Sallmon
- Department of Congenital Heart Disease/Pediatric Cardiology, Deutsches Herzzentrum der Charité (DHZC), Berlin, Germany; Division of Pediatric Cardiology, Graz Medical University, Graz, Austria.
| | - Cassidy A Delaney
- Department of Pediatrics, Section of Neonatology, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora CO, USA
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Tamang HK, Stringham EN, Tourdot BE. Platelet Functional Testing Via High-Throughput Microtiter Plate-Based Assays. Curr Protoc 2023; 3:e668. [PMID: 36786557 PMCID: PMC9983762 DOI: 10.1002/cpz1.668] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
Platelets play a critical role in hemostasis and thrombosis; therefore, in vitro assays that measure platelet reactivity are fundamental tools to gain insight into these physiologic processes, to diagnose platelet disorders, and to develop antithrombotic therapies. However, conventional platelet assays such as aggregometry, the clinical gold standard for assessing platelet function, are low throughput and require specialized equipment. Since platelets have a finite life span ex vivo, processes to miniaturize and multiplex assays allow a much broader overview of platelet function in significantly less time than conventional assays. Several groups have developed simplified, high-throughput approaches to quantify platelet activation with standard laboratory equipment to lower the barrier of entry to study platelet biology. This article describes a panel of optimized and validated high-throughput microplate assays to comprehensively assess platelet functionality, independently or in combination, to increase throughput and reduce costs. Specifically, following stimulation of platelets, a plate reader can be used to measure light transmission aggregation via absorbance; dense-granule secretion based on ATP-dependent luminescence generation; and cytosolic calcium levels with a cell-permeant, fluorescent Ca2+ -sensitive dye. Additionally, platelets are an easily accessible component of the blood that share signaling pathways with other cells, making them ideal for high-throughput drug screens. The highly adaptable and complementary assays presented in this article can be used to decipher the molecular mechanism underlying platelet activation or to identify novel inhibitors. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Microtiter plate-based light transmission aggregometry Basic Protocol 2: Measuring dense-granule secretion in high-throughput microplate assays Basic Protocol 3: Microtiter plate-based calcium mobilization Support Protocol: Platelet isolation and enumeration.
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Affiliation(s)
- Hem Kumar Tamang
- Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center; Cincinnati, OH 45229, USA
| | - Emily N. Stringham
- Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center; Cincinnati, OH 45229, USA
| | - Benjamin E. Tourdot
- Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center; Cincinnati, OH 45229, USA
- University of Cincinnati College of Medicine; Cincinnati, OH 45229, USA
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35
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Revelly E, Scala E, Rosner L, Rancati V, Gunga Z, Kirsch M, Ltaief Z, Rusca M, Bechtold X, Alberio L, Marcucci C. How to Solve the Conundrum of Heparin-Induced Thrombocytopenia during Cardiopulmonary Bypass. J Clin Med 2023; 12:jcm12030786. [PMID: 36769435 PMCID: PMC9918281 DOI: 10.3390/jcm12030786] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Heparin-induced thrombocytopenia (HIT) is a major issue in cardiac surgery requiring cardiopulmonary bypass (CPB). HIT represents a severe adverse drug reaction after heparin administration. It consists of immune-mediated thrombocytopenia paradoxically leading to thrombotic events. Detection of antibodies against platelets factor 4/heparin (anti-PF4/H) and aggregation of platelets in the presence of heparin in functional in vitro tests confirm the diagnosis. Patients suffering from HIT and requiring cardiac surgery are at high risk of lethal complications and present specific challenges. Four distinct phases are described in the usual HIT timeline, and the anticoagulation strategy chosen for CPB depends on the phase in which the patient is categorized. In this sense, we developed an institutional protocol covering each phase. It consisted of the use of a non-heparin anticoagulant such as bivalirudin, or the association of unfractionated heparin (UFH) with a potent antiplatelet drug such as tirofiban or cangrelor. Temporary reduction of anti-PF4 with intravenous immunoglobulins (IvIg) has recently been described as a complementary strategy. In this article, we briefly described the pathophysiology of HIT and focused on the various strategies that can be applied to safely manage CPB in these patients.
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Affiliation(s)
- Etienne Revelly
- Department of Anesthesiology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
- Correspondence:
| | - Emmanuelle Scala
- Department of Anesthesiology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne (UNIL), Rue du Bugnon 21, 1011 Lausanne, Switzerland
| | - Lorenzo Rosner
- Department of Anesthesiology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Valentina Rancati
- Department of Anesthesiology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Ziyad Gunga
- Department of Cardiac Surgery, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Matthias Kirsch
- Faculty of Biology and Medicine, University of Lausanne (UNIL), Rue du Bugnon 21, 1011 Lausanne, Switzerland
- Department of Cardiac Surgery, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Zied Ltaief
- Department of Intensive Care Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Marco Rusca
- Department of Intensive Care Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Xavier Bechtold
- Department of Cardiac Surgery, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Lorenzo Alberio
- Faculty of Biology and Medicine, University of Lausanne (UNIL), Rue du Bugnon 21, 1011 Lausanne, Switzerland
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Carlo Marcucci
- Department of Anesthesiology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne (UNIL), Rue du Bugnon 21, 1011 Lausanne, Switzerland
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Yamanaka T, Ueki T, Mase M, Inoue K. Arbitrary Ca 2+ regulation for endothelial nitric oxide, NFAT and NF-κB activities by an optogenetic approach. Front Pharmacol 2023; 13:1076116. [PMID: 36703743 PMCID: PMC9871596 DOI: 10.3389/fphar.2022.1076116] [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: 10/21/2022] [Accepted: 12/23/2022] [Indexed: 01/12/2023] Open
Abstract
Modern western dietary habits and low physical activity cause metabolic abnormalities and abnormally elevated levels of metabolites such as low-density lipoprotein, which can lead to immune cell activation, and inflammatory reactions, and atherosclerosis. Appropriate stimulation of vascular endothelial cells can confer protective responses against inflammatory reactions and atherosclerotic conditions. This study aims to determine whether a designed optogenetic approach is capable of affecting functional changes in vascular endothelial cells and to evaluate its potential for therapeutic regulation of vascular inflammatory responses in vitro. We employed a genetically engineered, blue light-activated Ca2+ channel switch molecule that utilizes an endogenous store-operated calcium entry system and induces intracellular Ca2+ influx through blue light irradiation and observed an increase in intracellular Ca2+ in vascular endothelial cells. Ca2+-dependent activation of the nuclear factor of activated T cells and nitric oxide production were also detected. Microarray analysis of Ca2+-induced changes in vascular endothelial cells explored several genes involved in cellular contractility and inflammatory responses. Indeed, there was an increase in the gene expression of molecules related to anti-inflammatory and vasorelaxant effects. Thus, a combination of human blue light-activated Ca2+ channel switch 2 (hBACCS2) and blue light possibly attenuates TNFα-induced inflammatory NF-κB activity. We propose that extrinsic cellular Ca2+ regulation could be a novel approach against vascular inflammation.
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Affiliation(s)
- Tomoyasu Yamanaka
- Department of Neurosurgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takatoshi Ueki
- Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Mitsuhito Mase
- Department of Neurosurgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Koichi Inoue
- Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan,*Correspondence: Koichi Inoue,
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Doğan K, Bolat S, Öksüz C, Büyüktuna SA. Leukotriene metabolism and proiflammatory cytokines in Crimean Congo hemorrhagic fever. J Med Virol 2023; 95:e28199. [PMID: 36207793 DOI: 10.1002/jmv.28199] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/14/2022] [Accepted: 10/04/2022] [Indexed: 01/11/2023]
Abstract
Crimean-Congo hemorrhagic fever (CCHF) is an emerging acute viral infection disease, yet its pathophysiology remains largely uncharacterized. Lipid mediators are molecules that play numerous roles in the physiologic and pathophysiologic conditions in certain viral diseases. No previous study evaluated the status of cysteinyl leukotrienes (CYSLT) and 5-lipoxygenase (5-LO) and their relationship with proinflammatory cytokines in CCHF. A total of 90 subjects including 60 CCHF patients and 30 healthy controls were enrolled the study. Serum CYSLT, 5-LO, interleukin-6 (IL-6), and ferritin levels were determined in the study population. Lower median 5-LO level was determined in patients compared to healthy controls (p = 0.0004). Higher ferritin (p < 0.001) and IL-6 (p < 0.001) levels in patients than healthy controls. No statistically significant difference was observed between patients and controls in terms of CYSLT levels. No statistically significant differences were observed between mild, moderate, and severe groups in terms of both 5-LO and CYSLT levels. IL-6 and ferritin levels were higher in severe group compared mild and moderate groups. In conclusion, changes in 5-LO enzyme and increased inflammation are related with the disease molecular mechanism. Higher inflammatory status contributes to the impaired hemostatic balance in CCHF. Thus, treatment strategies to reduce inflammation may help to prevent bleeding and DIC in patients. IL-6 and ferritin can be used to as an additional biomarker in the estmation of the prognosis and diagnosis of the patients.
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Affiliation(s)
- Kübra Doğan
- Department of Biochemistry, Sivas Numune Hospital, Sivas, Turkey
| | - Serkan Bolat
- Department of Biochemistry, School of Medicine, University of Sivas Cumhuriyet, Sivas, Turkey
| | - Caner Öksüz
- Department of Infectious Diseases, School of Medicine, University of Sivas Cumhuriyet, Sivas, Turkey
| | - Seyit Ali Büyüktuna
- Department of Infectious Diseases, School of Medicine, University of Sivas Cumhuriyet, Sivas, Turkey
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The role of PGE2 and EP receptors on lung's immune and structural cells; possibilities for future asthma therapy. Pharmacol Ther 2023; 241:108313. [PMID: 36427569 DOI: 10.1016/j.pharmthera.2022.108313] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 10/06/2022] [Accepted: 11/17/2022] [Indexed: 11/27/2022]
Abstract
Asthma is the most common airway chronic disease with treatments aimed mainly to control the symptoms. Adrenergic receptor agonists, corticosteroids and anti-leukotrienes have been used for decades, and the development of more targeted asthma treatments, known as biological therapies, were only recently established. However, due to the complexity of asthma and the limited efficacy as well as the side effects of available treatments, there is an urgent need for a new generation of asthma therapies. The anti-inflammatory and bronchodilatory effects of prostaglandin E2 in asthma are promising, yet complicated by undesirable side effects, such as cough and airway irritation. In this review, we summarize the most important literature on the role of all four E prostanoid (EP) receptors on the lung's immune and structural cells to further dissect the relevance of EP2/EP4 receptors as potential targets for future asthma therapy.
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Sachdeva S, Saluja H, Mani A, Phadnaik MB, Mani S. Lipoxins in inflammation. Clin Hemorheol Microcirc 2022; 82:201-216. [PMID: 35147530 DOI: 10.3233/ch-211346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Lipoxins and ATL appear to be the first recognized members of a new class of endogenous mediator that are anti-inflammatory or serve for the "pro-resolution" of inflammation. PGE2 can and may display anti-inflammatory properties in certain settings, but in most cases, it enhances inflammation in vivo. This is likely the result of numerous receptor isoforms and differential coupled mechanisms for PGE2 and its diverse role in human physiology. Since the integrated response of the host is essential to health and disease, it is important to achieve a more complete understanding of the molecular and cellular events governing the formation and actions of endogenous mediators of resolution that appear to control the magnitude and duration of inflammation. In view of the present body of evidence, it is not surprising that a protective action for inhibition of COX-2 was found in cardiovascular disease. Characterizing useful experimental systems with clinically relevant endpoints will also take a multidisciplinary approach and require a shift in our current thinking about inflammation and the role of lipid mediators.
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Affiliation(s)
- Shivani Sachdeva
- Department of Periodontology, Pravara Institute of Medical Sciences, Rdc, Loni, Maharashtra, India
| | - Harish Saluja
- Department of Oral and Maxillofacial Surgery, Pravara Institute of Medical Sciences, Rdc, Loni, Maharashtra, India
| | - Ameet Mani
- Department of Periodontology, Pravara Institute of Medical Sciences, Rdc, Loni, Maharashtra, India
| | - M B Phadnaik
- Department of Periodontology, #Government Dental College Nagpur, Maharashtra, India
| | - Shubhangi Mani
- Department of Orthodontics, Pravara Institute of Medical Sciences, Rdc, Loni, Maharashtra, India
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40
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Gao MJ, Cui NH, Liu X, Wang XB. Inhibition of mitochondrial complex I leading to NAD +/NADH imbalance in type 2 diabetic patients who developed late stent thrombosis: Evidence from an integrative analysis of platelet bioenergetics and metabolomics. Redox Biol 2022; 57:102507. [PMID: 36244294 PMCID: PMC9579714 DOI: 10.1016/j.redox.2022.102507] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/05/2022] [Accepted: 10/09/2022] [Indexed: 11/22/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a strong indicator of late stent thrombosis (LST). Platelet bioenergetic dysfunction, although critical to the pathogenesis of diabetic macrovascular complications, remains uncharacterized in T2DM patients who developed LST. Here, we explored the mechanistic link between the alterations in platelet bioenergetics and LST in the setting of T2DM. Platelet bioenergetics, metabolomics, and their interactomes were analyzed in a nested case-control study including 15 T2DM patients who developed LST and 15 matched T2DM patients who did not develop LST (non-LST). Overall, we identified a bioenergetic alteration in T2DM patients with LST characterized by an imbalanced NAD+/NADH redox state resulting from deficient mitochondrial complex I (NADH: ubiquinone oxidoreductase) activity, which led to reduced ATP-linked and maximal mitochondrial respiration, increased glycolytic flux, and platelet hyperactivation compared with non-LST patients. Congruently, platelets from LST patients exhibited downregulation of tricarboxylic acid cycle and NAD+ biosynthetic pathways as well as upregulation of the proximal glycolytic pathway, a metabolomic change that was primarily attributed to compromised mitochondrial respiration rather than increased glycolytic flux as evidenced by the integrative analysis of bioenergetics and metabolomics. Importantly, both bioenergetic and metabolomic aberrancies in LST platelets could be recapitulated ex vivo by exposing the non-LST platelets to a low dose of rotenone, a complex I inhibitor. In contrast, normalization of the NAD+/NADH redox state, either by increasing NAD+ biosynthesis or by inhibiting NAD+ consumption, was able to improve mitochondrial respiration, inhibit mitochondrial oxidant generation, and consequently attenuate platelet aggregation in both LST platelets and non-LST platelets pretreated with low-dose rotenone. These data, for the first time, delineate the specific patterns of bioenergetic and metabolomic alterations for T2DM patients who suffer from LST, and establish the deficiency of complex I-derived NAD+ as a potential pathogenic mechanism in platelet abnormalities.
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Affiliation(s)
- Mi-Jie Gao
- Department of Clinical Laboratory, Key Clinical Laboratory of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Ning-Hua Cui
- Zhengzhou Key Laboratory of Children's Infection and Immunity, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Xia'nan Liu
- Department of Clinical Laboratory, Key Clinical Laboratory of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Xue-Bin Wang
- Department of Clinical Laboratory, Key Clinical Laboratory of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China.
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Siddiqui S, Deshmukh AJ, Mudaliar P, Nalawade AJ, Iyer D, Aich J. Drug repurposing: re-inventing therapies for cancer without re-entering the development pipeline—a review. J Egypt Natl Canc Inst 2022; 34:33. [PMID: 35934727 PMCID: PMC9358112 DOI: 10.1186/s43046-022-00137-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 07/10/2022] [Indexed: 11/25/2022] Open
Abstract
While majority of the current treatment approaches for cancer remain expensive and are associated with several side effects, development of new treatment modalities takes a significant period of research, time, and expenditure. An alternative novel approach is drug repurposing that focuses on finding new applications for the previously clinically approved drugs. The process of drug repurposing has also been facilitated by current advances in the field of proteomics, genomics, and information computational biology. This approach not only provides cheaper, effective, and potentially safer drugs with less side effects but also increases the processing pace of drug development. In this review, we wish to highlight some recent developments in the area of drug repurposing in cancer with a specific focus on the repurposing potential of anti-psychotic, anti-inflammatory and anti-viral drugs, anti-diabetic, antibacterial, and anti-fungal drugs.
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Schanze N, Hamad MA, Nührenberg TG, Bode C, Duerschmied D. Platelets in Myocardial Ischemia/Reperfusion Injury. Hamostaseologie 2022; 43:110-121. [PMID: 35913081 PMCID: PMC10132858 DOI: 10.1055/a-1739-9351] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022] Open
Abstract
Coronary artery disease, including myocardial infarction (MI), remains a leading cause of global mortality. Rapid reperfusion therapy is key to the improvement of patient outcome but contributes substantially to the final cardiac damage. This phenomenon is called "ischemia/reperfusion injury (IRI)." The underlying mechanisms of IRI are complex and not fully understood. Contributing cellular and molecular mechanisms involve the formation of microthrombi, alterations in ion concentrations, pH shifts, dysregulation of osmolality, and, importantly, inflammation. Beyond their known action as drivers of the development of coronary plaques leading to MI, platelets have been identified as important mediators in myocardial IRI. Circulating platelets are activated by the IRI-provoked damages in the vascular endothelium. This leads to platelet adherence to the reperfused endothelium, aggregation, and the formation of microthrombi. Furthermore, activated platelets release vasoconstrictive substances, act via surface molecules, and enhance leukocyte infiltration into post-IR tissue, that is, via platelet-leukocyte complexes. A better understanding of platelet contributions to myocardial IRI, including their interaction with other lesion-associated cells, is necessary to develop effective treatment strategies to prevent IRI and further improve the condition of the reperfused myocardium. In this review, we briefly summarize platelet properties that modulate IRI. We also describe the beneficial impacts of antiplatelet agents as well as their mechanisms of action in IRI beyond classic effects.
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Affiliation(s)
- Nancy Schanze
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany.,Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany
| | - Muataz Ali Hamad
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany.,Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Thomas Georg Nührenberg
- Department of Cardiology and Angiology II, Heart Center, University of Freiburg, Freiburg, Germany.,Institute for Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany
| | - Christoph Bode
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Daniel Duerschmied
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany.,Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany.,European Center for AngioScience (ECAS) and German Center for Cardiovascular Research (DZHK) partner site Heidelberg/Mannheim, Mannheim, Germany
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Kratz D, Wilken-Schmitz A, Sens A, Hahnefeld L, Scholich K, Geisslinger G, Gurke R, Thomas D. Post-mortem changes of prostanoid concentrations in tissues of mice: Impact of fast cervical dislocation and dissection delay. Prostaglandins Other Lipid Mediat 2022; 162:106660. [PMID: 35714920 DOI: 10.1016/j.prostaglandins.2022.106660] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/18/2022] [Accepted: 06/10/2022] [Indexed: 11/29/2022]
Abstract
Prostanoids are potent lipid mediators involved in a wide variety of physiological functions like blood pressure regulation or inflammation as well as cardiovascular and malign diseases. Elucidation of their modes of action is mainly carried out in pre-clinical animal models by quantifying prostanoids in tissues of interest. Unfortunately, prostanoids are prone to post-mortem artifact formation and de novo synthesis can already be caused by external stimuli during the euthanasia of animals like prolonged hypercapnia or ischemia. Therefore, this study investigates the suitability and impact of fast cervical dislocation for the determination of prostanoids (6-keto-PGF1α, TXB2, PGF2α, PGD2, PGE2) in seven tissues of mice (spinal cord, brain, sciatic nerve, kidney, liver, lung, and spleen) to minimize time-dependent effects and approximate physiological concentrations. Tissues were dissected in a standardized sequence directly or after 10 min to investigate the influence of dissection delays. The enzyme inhibitor indomethacin (10 µM) in combination with low processing temperatures was employed to preserve prostanoid concentrations during sample preparation. Quantification of prostanoids was performed via LC-MS/MS. This study shows, that prostanoids are differentially susceptible to post-mortem artifact formation which is closely connected to their physiological function and metabolic stability in the respective tissues. Prostanoids in the brain, spinal cord, and kidney that are not involved in the regulatory response post-mortem, i.e. blood flow regulation (6-keto-PGF1α, PGE2, PGF2α) showed high reproducibility even after dissection delay and could be assessed after fast cervical dislocation if prerequisites like standardized pre-analytical workflows with immediate dissection and inhibition of residual enzymatic activity are in place. However, in tissues with high metabolic activity (liver, lung) more stable prostanoid metabolites should be used. Moreover, prostanoids in the spleen were strongly affected by dissection delays and presumably the method of euthanasia itself.
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Affiliation(s)
- D Kratz
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital of Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - A Wilken-Schmitz
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
| | - A Sens
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital of Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - L Hahnefeld
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital of Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
| | - K Scholich
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital of Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
| | - G Geisslinger
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital of Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
| | - R Gurke
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital of Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
| | - D Thomas
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital of Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
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Shpakova V, Rukoyatkina N, Al Arawe N, Prilepskaya A, Kharazova A, Sharina I, Gambaryan S, Martin E. ML355 Modulates Platelet Activation and Prevents ABT-737 Induced Apoptosis in Platelets. J Pharmacol Exp Ther 2022; 381:164-175. [PMID: 35197320 PMCID: PMC9073945 DOI: 10.1124/jpet.121.000973] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 02/05/2022] [Indexed: 01/14/2023] Open
Abstract
12-lipoxigenase (12-LOX) is implicated in regulation of platelet activation processes and can be a new promising target for antiplatelet therapy. However, investigations of 12-LOX were restricted by the lack of specific and potent 12-LOX inhibitors and by controversial data concerning the role of 12-LOX metabolites in platelet functions. A novel specific 12-LOX inhibitor ML355 was shown to inhibit platelet aggregation without adverse side effects on hemostasis; however, the molecular mechanisms of its action on platelets are poorly understood. Here, we showed that ML355 inhibited platelet activation induced by thrombin or thromboxane A2, but not by collagen-related peptide. ML355 blocked protein kinase B, phosphoinositide 3-kinase, and extracellular signal-regulated kinase, but not p38 kinase, spleen tyrosine kinase (Syk), or phospholipase Cγ2 phosphorylation in activated platelets. The main inhibitory effect of low doses of ML355 (1-20 μM) on thrombin activated platelets was mediated by the decrease in reactive oxygen species level, whereas high doses of ML355 (50 μM) caused cyclic adenosine monophosphate activation. ML355 did not affect the activity of nitric oxide-dependent soluble guanylyl cyclase, nor did it affect the relaxation of preconstricted aortic rings in mice. ML355 itself did not affect platelet viability, but at 50 μM dose blocked caspase-dependent apoptosis induced by B-cell lymphoma II inhibitor ABT-737. SIGNIFICANCE STATEMENT: The current paper provides novel and original data concerning molecular mechanisms of 12-LOX inhibitor ML355 action on platelets. These data reveal antiplatelet and protective effects of ML355 on platelets and may be of importance for both antiplatelet and anticancer therapy.
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Affiliation(s)
- Valentina Shpakova
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia (V.S., N.R., S.G.); Saint Petersburg State University, Saint Petersburg, Russia (N.A.A., A.P., A.K.); and Department of Internal Medicine, Division of Cardiology, University of Texas Houston Medical School, Houston, Texas (I.S., E.M.)
| | - Natalia Rukoyatkina
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia (V.S., N.R., S.G.); Saint Petersburg State University, Saint Petersburg, Russia (N.A.A., A.P., A.K.); and Department of Internal Medicine, Division of Cardiology, University of Texas Houston Medical School, Houston, Texas (I.S., E.M.)
| | - Nada Al Arawe
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia (V.S., N.R., S.G.); Saint Petersburg State University, Saint Petersburg, Russia (N.A.A., A.P., A.K.); and Department of Internal Medicine, Division of Cardiology, University of Texas Houston Medical School, Houston, Texas (I.S., E.M.)
| | - Anna Prilepskaya
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia (V.S., N.R., S.G.); Saint Petersburg State University, Saint Petersburg, Russia (N.A.A., A.P., A.K.); and Department of Internal Medicine, Division of Cardiology, University of Texas Houston Medical School, Houston, Texas (I.S., E.M.)
| | - Alexandra Kharazova
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia (V.S., N.R., S.G.); Saint Petersburg State University, Saint Petersburg, Russia (N.A.A., A.P., A.K.); and Department of Internal Medicine, Division of Cardiology, University of Texas Houston Medical School, Houston, Texas (I.S., E.M.)
| | - Iraida Sharina
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia (V.S., N.R., S.G.); Saint Petersburg State University, Saint Petersburg, Russia (N.A.A., A.P., A.K.); and Department of Internal Medicine, Division of Cardiology, University of Texas Houston Medical School, Houston, Texas (I.S., E.M.)
| | - Stepan Gambaryan
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia (V.S., N.R., S.G.); Saint Petersburg State University, Saint Petersburg, Russia (N.A.A., A.P., A.K.); and Department of Internal Medicine, Division of Cardiology, University of Texas Houston Medical School, Houston, Texas (I.S., E.M.)
| | - Emil Martin
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia (V.S., N.R., S.G.); Saint Petersburg State University, Saint Petersburg, Russia (N.A.A., A.P., A.K.); and Department of Internal Medicine, Division of Cardiology, University of Texas Houston Medical School, Houston, Texas (I.S., E.M.)
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Nuñez-Borque E, Fernandez-Bravo S, Yuste-Montalvo A, Esteban V. Pathophysiological, Cellular, and Molecular Events of the Vascular System in Anaphylaxis. Front Immunol 2022; 13:836222. [PMID: 35371072 PMCID: PMC8965328 DOI: 10.3389/fimmu.2022.836222] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/07/2022] [Indexed: 01/10/2023] Open
Abstract
Anaphylaxis is a systemic hypersensitivity reaction that can be life threatening. Mechanistically, it results from the immune activation and release of a variety of mediators that give rise to the signs and symptoms of this pathological event. For years, most of the research in anaphylaxis has focused on the contribution of the immune component. However, approaches that shed light on the participation of other cellular and molecular agents are necessary. Among them, the vascular niche receives the various signals (e.g., histamine) that elicit the range of anaphylactic events. Cardiovascular manifestations such as increased vascular permeability, vasodilation, hypotension, vasoconstriction, and cardiac alterations are crucial in the pathophysiology of anaphylaxis and are highly involved to the development of the most severe cases. Specifically, the endothelium, vascular smooth muscle cells, and their molecular signaling outcomes play an essential role downstream of the immune reaction. Therefore, in this review, we synthesized the vascular changes observed during anaphylaxis as well as its cellular and molecular components. As the risk of anaphylaxis exists both in clinical procedures and in routine life, increasing our knowledge of the vascular physiology and their molecular mechanism will enable us to improve the clinical management and how to treat or prevent anaphylaxis. Key Message Anaphylaxis, the most severe allergic reaction, involves a variety of immune and non-immune molecular signals that give rise to its pathophysiological manifestations. Importantly, the vascular system is engaged in processes relevant to anaphylactic events such as increased vascular permeability, vasodilation, hypotension, vasoconstriction, and decreased cardiac output. The novelty of this review focuses on the fact that new studies will greatly improve the understanding of anaphylaxis when viewed from a vascular molecular angle and specifically from the endothelium. This knowledge will improve therapeutic options to treat or prevent anaphylaxis.
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Affiliation(s)
- Emilio Nuñez-Borque
- Department of Allergy and Immunology, Instituto en Investigación Sanitaria - Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Sergio Fernandez-Bravo
- Department of Allergy and Immunology, Instituto en Investigación Sanitaria - Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Alma Yuste-Montalvo
- Department of Allergy and Immunology, Instituto en Investigación Sanitaria - Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Vanesa Esteban
- Department of Allergy and Immunology, Instituto en Investigación Sanitaria - Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid (UAM), Madrid, Spain.,Faculty of Medicine and Biomedicine, Alfonso X El Sabio University, Madrid, Spain
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Siniarski A, Gąsecka A, Starczyński M, Banaszkiewicz M, Darocha S, Torbicki A, Kurzyna M, Filipiak KJ, Nessler J, Gajos G. Prostacyclin analogues decrease platelet aggregation but have no effect on thrombin generation, fibrin clot structure, and fibrinolysis in pulmonary arterial hypertension: PAPAYA coagulation. Platelets 2022; 33:1065-1074. [DOI: 10.1080/09537104.2022.2042234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Aleksander Siniarski
- Department of Coronary Artery Disease and Heart Failure, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Kraków, Poland
| | - Aleksandra Gąsecka
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Miłosz Starczyński
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Marta Banaszkiewicz
- Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, Poland
| | - Szymon Darocha
- Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, Poland
| | - Adam Torbicki
- Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, Poland
| | - Marcin Kurzyna
- Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, Poland
| | - Krzysztof J. Filipiak
- Department of Clinical Sciences, Maria Sklodowska-Curie Medical Academy, Warsaw, Poland
| | - Jadwiga Nessler
- Department of Coronary Artery Disease and Heart Failure, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Kraków, Poland
| | - Grzegorz Gajos
- Department of Coronary Artery Disease and Heart Failure, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Kraków, Poland
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Reitsma SE, Lakshmanan HHS, Johnson J, Pang J, Parra-Izquierdo I, Melrose AR, Choi J, Anderson DEJ, Hinds MT, Stevens JF, Aslan JE, McCarty OJT, Lo JO. Chronic edible dosing of Δ9-tetrahydrocannabinol (THC) in nonhuman primates reduces systemic platelet activity and function. Am J Physiol Cell Physiol 2022; 322:C370-C381. [PMID: 35080922 PMCID: PMC8858671 DOI: 10.1152/ajpcell.00373.2021] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cannabis usage has steadily increased as acceptance is growing for both medical and recreational reasons. Medical cannabis is administered for treatment of chronic pain based on the premise that the endocannabinoid system signals desensitize pain sensor neurons and produce anti-inflammatory effects. The major psychoactive ingredient of cannabis is Δ9-tetrahydrocannabinol (THC) that signals mainly through cannabinoid receptor-1 (CBr), which is also present on nonneuron cells including blood platelets of the circulatory system. In vitro, CBr-mediated signaling has been shown to acutely inhibit platelet activation downstream of the platelet collagen receptor glycoprotein (GP)VI. The systemic effects of chronic THC administration on platelet activity and function remain unclear. This study investigates the effects of chronic THC administration on platelet function using a nonhuman primate (NHP) model. Our results show that female and male NHPs consuming a daily THC edible had reduced platelet adhesion, aggregation, and granule secretion in response to select platelet agonists. Furthermore, a change in bioactive lipids (oxylipins) was observed in the female cohort after THC administration. These results indicate that chronic THC edible administration desensitized platelet activity and function in response to GPVI- and G-protein coupled receptor-based activation by interfering with primary and secondary feedback signaling pathways. These observations may have important clinical implications for patients who use medical marijuana and for providers caring for these patients.
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Affiliation(s)
- Stéphanie E. Reitsma
- 1Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | | | - Jennifer Johnson
- 1Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Jiaqing Pang
- 1Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Iván Parra-Izquierdo
- 1Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon,2Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon
| | - Alex R. Melrose
- 1Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon,2Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon
| | - Jaewoo Choi
- 3Linus Pauling Institute, Oregon State University, Corvallis, Oregon
| | - Deirdre E. J. Anderson
- 1Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Monica T. Hinds
- 1Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Jan Frederik Stevens
- 3Linus Pauling Institute, Oregon State University, Corvallis, Oregon,4College of Pharmacy, Oregon State university, Corvallis, Oregon
| | - Joseph E. Aslan
- 1Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon,2Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon
| | - Owen J. T. McCarty
- 1Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Jamie O. Lo
- 5Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon
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Roy MC, Nam K, Kim J, Stanley D, Kim Y. Thromboxane Mobilizes Insect Blood Cells to Infection Foci. Front Immunol 2022; 12:791319. [PMID: 34987515 PMCID: PMC8720849 DOI: 10.3389/fimmu.2021.791319] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/18/2021] [Indexed: 01/18/2023] Open
Abstract
Innate immune responses are effective for insect survival to defend against entomopathogens including a fungal pathogen, Metarhizium rileyi, that infects a lepidopteran Spodoptera exigua. In particular, the fungal virulence was attenuated by cellular immune responses, in which the conidia were phagocytosed by hemocytes (insect blood cells) and hyphal growth was inhibited by hemocyte encapsulation. However, the chemokine signal to drive hemocytes to the infection foci was little understood. The hemocyte behaviors appeared to be guided by a Ca2+ signal stimulating cell aggregation to the infection foci. The induction of the Ca2+ signal was significantly inhibited by the cyclooxygenase (COX) inhibitor. Under the inhibitory condition, the addition of thromboxane A2 or B2 (TXA2 or TXB2) among COX products was the most effective to recover the Ca2+ signal and hemocyte aggregation. TXB2 alone induced a microaggregation behavior of hemocytes under in vitro conditions. Indeed, TXB2 titer was significantly increased in the plasma of the infected larvae. The elevated TXB2 level was further supported by the induction of phospholipase A2 (PLA2) activity in the hemocytes and subsequent up-regulation of COX-like peroxinectins (SePOX-F and SePOX-H) in response to the fungal infection. Finally, the expression of a thromboxane synthase (Se-TXAS) gene was highly expressed in the hemocytes. RNA interference (RNAi) of Se-TXAS expression inhibited the Ca2+ signal and hemocyte aggregation around fungal hyphae, which were rescued by the addition of TXB2. Without any ortholog to mammalian thromboxane receptors, a prostaglandin receptor was essential to mediate TXB2 signal to elevate the Ca2+ signal and mediate hemocyte aggregation behavior. Specific inhibitor assays suggest that the downstream signal after binding TXB2 to the receptor follows the Ca2+-induced Ca2+ release pathway from the endoplasmic reticulum of the hemocytes. These results suggest that hemocyte aggregation induced by the fungal infection is triggered by TXB2via a Ca2+ signal through a PG receptor.
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Affiliation(s)
- Miltan Chandra Roy
- Department of Plant Medicals, Andong National University, Andong, South Korea
| | - Kiwoong Nam
- DGIMI, Univ Montpellier, INRAE, Montpellier, France
| | - Jaesu Kim
- Department of Agricultural Convergence Technology, Jeonbuk National University, Jeonju, South Korea
| | - David Stanley
- Biological Control of Insect Research Laboratory, United States Department of Agriculture-Agricultural Research Station (USDA/ARS), Columbia, MO, United States
| | - Yonggyun Kim
- Department of Plant Medicals, Andong National University, Andong, South Korea
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Chirkov YY, Nguyen TH, Horowitz JD. Impairment of Anti-Aggregatory Responses to Nitric Oxide and Prostacyclin: Mechanisms and Clinical Implications in Cardiovascular Disease. Int J Mol Sci 2022; 23:1042. [PMID: 35162966 PMCID: PMC8835624 DOI: 10.3390/ijms23031042] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/10/2022] [Accepted: 01/15/2022] [Indexed: 01/27/2023] Open
Abstract
The propensity towards platelet-rich thrombus formation increases substantially during normal ageing, and this trend is mediated by decreases in platelet responsiveness to the anti-aggregatory nitric oxide (NO) and prostacyclin (PGI2) pathways. The impairment of soluble guanylate cyclase and adenylate cyclase-based signalling that is associated with oxidative stress represents the major mechanism of this loss of anti-aggregatory reactivity. Platelet desensitization to these autacoids represents an adverse prognostic marker in patients with ischemic heart disease and may contribute to increased thrombo-embolic risk in patients with heart failure. Patients with platelet resistance to PGI2 also are unresponsive to ADP receptor antagonist therapy. Apart from ischemia, diabetes and aortic valve disease are also associated with impaired anti-aggregatory homeostasis. This review examines the association of impaired platelet cyclic nucleotide (i.e., cGMP and cAMP) signalling with the emerging evidence of thromboembolic risk in cardiovascular diseases, and discusses the potential therapeutic strategies targeting this abnormality.
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Affiliation(s)
| | | | - John D. Horowitz
- Cardiology Laboratory, Basil Hetzel Institute, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide 5011, Australia; (Y.Y.C.); (T.H.N.)
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Alemán-Jiménez C, Domínguez-Perles R, Fanti F, Gallego-Gómez JI, Simonelli-Muñoz A, Moine E, Durand T, Crauste C, Gil-Izquierdo Á, Medina S. Unravelling the capacity of hydroxytyrosol and its lipophenolic derivates to modulate the H2O2-induced isoprostanoid profile of THP-1 monocytes by UHPLC-QqQ-MS/MS lipidomic workflow. Microchem J 2021. [DOI: 10.1016/j.microc.2021.106703] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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