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Zhong Y, Zhong L, Zhou Y, Liao Y, Deng J. Dynamic neutrophil-to-lymphocyte-platelet ratio trajectories predict 30-day and 1-year mortality in sepsis: a retrospective cohort study based on MIMIC-IV 2.2. BMC Infect Dis 2025; 25:594. [PMID: 40275138 PMCID: PMC12023530 DOI: 10.1186/s12879-025-10987-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 04/16/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND This study investigated the relationship between the neutrophil-to-lymphocyte ratio (N/LPR) and its variability ratio (N/LPRR) with 30-day and 1-year mortality outcomes. METHODS A total of 7,443 patients from the MIMIC-IV 2.2 database were included, with 1,765 having multiple N/LPR measurements. Mortality at 1 year and within 30 days served as the primary endpoints. Patients were stratified into four groups according to baseline N/LPRR quartiles. Receiver operating characteristic (ROC) curves assessed the predictive value of N/LPR and N/LPRR for mortality. Kaplan-Meier analysis estimated the risk of mortality events, while restricted cubic spline (RCS) analysis explored the non-linear associations between N/LPR, N/LPRR, and mortality. Cox proportional hazards regression identified the relationship between N/LPRR and all-cause mortality. RESULTS A total of 792 cases of 1-year mortality (44.9%) were recorded, with 437 deaths (24.8%) occurring within 30 days. ROC analysis revealed that N/LPRR outperformed N/LPR in predicting adverse outcomes. Higher N/LPR and N/LPRR were associated with increased mortality rates. RCS analysis indicated significant non-linear relationships between N/LPR, N/LPRR, and mortality risk (both p-values for nonlinearity < 0.001). Subgroup analyses confirmed the robustness of these findings. CONCLUSION In conclusion, elevated N/LPR and N/LPRR are linked to 30-day and 1-year mortality in patients with sepsis. N/LPRR, with its heightened sensitivity, offers clinicians valuable prognostic information on sepsis severity and progression.
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Affiliation(s)
- Yuting Zhong
- Department of Anesthesiology, Meizhou People's Hospital, 63 Huangtang Road, Meijiang District, Guangdong, Meizhou, China
| | - Liping Zhong
- Department of Anesthesiology, Meizhou People's Hospital, 63 Huangtang Road, Meijiang District, Guangdong, Meizhou, China
| | - Yuanjun Zhou
- Department of Anesthesiology, Meizhou People's Hospital, 63 Huangtang Road, Meijiang District, Guangdong, Meizhou, China
| | - Yilin Liao
- Department of Anesthesiology, Meizhou People's Hospital, 63 Huangtang Road, Meijiang District, Guangdong, Meizhou, China
| | - Jingdan Deng
- Department of Anesthesiology, Meizhou People's Hospital, 63 Huangtang Road, Meijiang District, Guangdong, Meizhou, China.
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Tanzadehpanah H, Nobari S, Hoseini AJ, Ghotbani F, Mehrabzadeh M, Jalili shahri J, Alipour A, Sheykhhasan M, Manoochehri H, Darroudi S, Mahaki H. Effect of platelet-rich plasma on angiogenic and regenerative properties in patients with critical limb ischemia. Regen Ther 2025; 28:517-526. [PMID: 39995496 PMCID: PMC11848493 DOI: 10.1016/j.reth.2025.01.008] [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: 11/30/2024] [Revised: 01/01/2025] [Accepted: 01/10/2025] [Indexed: 02/26/2025] Open
Abstract
Platelet-rich plasma (PRP) is a promising regenerative therapy due to its simplicity, clinical application, safety, and ability to promote angiogenesis. It utilizes various angiogenic growth factors in platelets, including platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), which are integral to the tissue repair. Critical limb ischemia (CLI) is a major symptom of peripheral arterial disease (PAD), and PRP therapy aims to improve blood circulation to the distal limb through the development of blood vessels. This review focuses on the extensive research on the molecular mechanisms of PRPs in treating CLI. A comprehensive search was conducted on Web of Science, PubMed, Google Scholar, and Scopus to find studies published during PRP therapy in critical limb ischemia up to June 2024. Current studies reveal that PRP composition varies by case, affecting preparation methods, storage duration, storage methods, and interaction with other materials. PRP-derived growth factors have shown promising results in treating CLI, but well-controlled human research is scarce despite positive animal studies.
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Affiliation(s)
- Hamid Tanzadehpanah
- Antimicrobial Resistance Research Center, Basic Science Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sima Nobari
- Deputy of Health, Iran University of Medical Science, Tehran, Iran
| | | | - Farzaneh Ghotbani
- Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Mehrabzadeh
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jamal Jalili shahri
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirreza Alipour
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Sheykhhasan
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Hamed Manoochehri
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Susan Darroudi
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanie Mahaki
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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3
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Huang Y, Wang J, Guo Y, Shen L, Li Y. Fibrinogen binding to activated platelets and its biomimetic thrombus-targeted thrombolytic strategies. Int J Biol Macromol 2024; 274:133286. [PMID: 38908635 DOI: 10.1016/j.ijbiomac.2024.133286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 06/18/2024] [Accepted: 06/18/2024] [Indexed: 06/24/2024]
Abstract
Thrombosis is associated with various fatal arteriovenous syndromes including ischemic stroke, myocardial infarction, and pulmonary embolism. However, current clinical thrombolytic treatment strategies still have many problems in targeting and safety to meet the thrombolytic therapy needs. Understanding the molecular mechanism that underlies thrombosis is critical in developing effective thrombolytic strategies. It is well known that platelets play a central role in thrombosis and the binding of fibrinogen to activated platelets is a common pathway in the process of clot formation. Based on this, a concept of biomimetic thrombus-targeted thrombolytic strategy inspired from fibrinogen binding to activated platelets in thrombosis was proposed, which could selectively bind to activated platelets at a thrombus site, thus enabling targeted delivery and local release of thrombolytic agents for effective thrombolysis. In this review, we first summarized the main characteristics of platelets and fibrinogen, and then introduced the classical molecular mechanisms of thrombosis, including platelet adhesion, platelet activation and platelet aggregation through the interactions of activated platelets with fibrinogen. In addition, we highlighted the recent advances in biomimetic thrombus-targeted thrombolytic strategies which inspired from fibrinogen binding to activated platelets in thrombosis. The possible future directions and perspectives in this emerging area are briefly discussed.
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Affiliation(s)
- Yu Huang
- Department of Radiology, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai Sixth People's Hospital, 600 Yi Shan Road, Shanghai 200233, PR China.
| | - Jiahua Wang
- Department of Radiology, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai Sixth People's Hospital, 600 Yi Shan Road, Shanghai 200233, PR China
| | - Yuanyuan Guo
- Department of Radiology, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai Sixth People's Hospital, 600 Yi Shan Road, Shanghai 200233, PR China
| | - Lingyue Shen
- Department of Oral & Maxillofacial-Head & Neck Oncology, Department of Laser and Aesthetic Medicine, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stoma-tology & Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Shanghai 200011, PR China.
| | - Yuehua Li
- Department of Radiology, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai Sixth People's Hospital, 600 Yi Shan Road, Shanghai 200233, PR China.
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Keller DA, Bassan A, Amberg A, Burns Naas LA, Chambers J, Cross K, Hall F, Jahnke GD, Luniwal A, Manganelli S, Mestres J, Mihalchik-Burhans AL, Woolley D, Tice RR. In silico approaches in carcinogenicity hazard assessment: case study of pregabalin, a nongenotoxic mouse carcinogen. FRONTIERS IN TOXICOLOGY 2023; 5:1234498. [PMID: 38026843 PMCID: PMC10679394 DOI: 10.3389/ftox.2023.1234498] [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: 06/04/2023] [Accepted: 10/30/2023] [Indexed: 12/01/2023] Open
Abstract
In silico toxicology protocols are meant to support computationally-based assessments using principles that ensure that results can be generated, recorded, communicated, archived, and then evaluated in a uniform, consistent, and reproducible manner. We investigated the availability of in silico models to predict the carcinogenic potential of pregabalin using the ten key characteristics of carcinogens as a framework for organizing mechanistic studies. Pregabalin is a single-species carcinogen producing only one type of tumor, hemangiosarcomas in mice via a nongenotoxic mechanism. The overall goal of this exercise is to test the ability of in silico models to predict nongenotoxic carcinogenicity with pregabalin as a case study. The established mode of action (MOA) of pregabalin is triggered by tissue hypoxia, leading to oxidative stress (KC5), chronic inflammation (KC6), and increased cell proliferation (KC10) of endothelial cells. Of these KCs, in silico models are available only for selected endpoints in KC5, limiting the usefulness of computational tools in prediction of pregabalin carcinogenicity. KC1 (electrophilicity), KC2 (genotoxicity), and KC8 (receptor-mediated effects), for which predictive in silico models exist, do not play a role in this mode of action. Confidence in the overall assessments is considered to be medium to high for KCs 1, 2, 5, 6, 7 (immune system effects), 8, and 10 (cell proliferation), largely due to the high-quality experimental data. In order to move away from dependence on animal data, development of reliable in silico models for prediction of oxidative stress, chronic inflammation, immunosuppression, and cell proliferation will be critical for the ability to predict nongenotoxic compound carcinogenicity.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Jordi Mestres
- Chemotargets SL, Parc Científic de Barcelona, Barcelona, Spain
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De Giovanni M, Chen H, Li X, Cyster JG. GPR35 and mediators from platelets and mast cells in neutrophil migration and inflammation. Immunol Rev 2023; 317:187-202. [PMID: 36928841 PMCID: PMC10504419 DOI: 10.1111/imr.13194] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
Neutrophil recruitment from circulation to sites of inflammation is guided by multiple chemoattractant cues emanating from tissue cells, immune cells, and platelets. Here, we focus on the function of one G-protein coupled receptor, GPR35, in neutrophil recruitment. GPR35 has been challenging to study due the description of multiple ligands and G-protein couplings. Recently, we found that GPR35-expressing hematopoietic cells respond to the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). We discuss distinct response profiles of GPR35 to 5-HIAA compared to other ligands. To place the functions of 5-HIAA in context, we summarize the actions of serotonin in vascular biology and leukocyte recruitment. Important sources of serotonin and 5-HIAA are platelets and mast cells. We discuss the dynamics of cell migration into inflamed tissues and how multiple platelet and mast cell-derived mediators, including 5-HIAA, cooperate to promote neutrophil recruitment. Additional actions of GPR35 in tissue physiology are reviewed. Finally, we discuss how clinically approved drugs that modulate serotonin uptake and metabolism may influence 5-HIAA-GPR35 function, and we speculate about broader influences of the GPR35 ligand-receptor system in immunity and disease.
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Affiliation(s)
- Marco De Giovanni
- Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Hongwen Chen
- Departments of Molecular Genetics and Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xiaochun Li
- Departments of Molecular Genetics and Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jason G. Cyster
- Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
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Utility of Plasma Protein Biomarkers and Mid-infrared Spectroscopy for Diagnosing Fracture-related Infections: A Pilot Study. J Orthop Trauma 2022; 36:e380-e387. [PMID: 35452050 DOI: 10.1097/bot.0000000000002379] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/14/2022] [Indexed: 02/02/2023]
Abstract
OBJECTIVES To compare a large panel of plasma protein inflammatory biomarkers and mid-infrared (MIR) spectral patterns in patients with confirmed fracture-related infections (FRIs) with those in controls without infection. DESIGN Prospective case-control study. SETTING Academic, Level 1 trauma center. PATIENTS Thirteen patients meeting confirmatory FRI criteria were matched to 13 controls based on age, time after surgery, and fracture region. INTERVENTION Plasma levels of 49 proteins were measured using enzyme-linked immunosorbent assay techniques. Fourier transform infrared spectroscopy of dried films was used to obtain MIR spectra of plasma samples. MAIN OUTCOME MEASUREMENTS The main outcome measurements included plasma protein levels and MIR spectra of samples. RESULTS Multivariate analysis-based predictive model developed using enzyme-linked immunosorbent assay-based biomarkers had sensitivity, specificity, and accuracy of 69.2% ± 0.0%, 99.9% ± 1.0%, and 84.5% ± 0.6%, respectively, with platelet-derived growth factor-AB/BB, C-reactive protein, and MIG selected as the minimum number of variables explaining group differences ( P < 0.05). Sensitivity, specificity, and accuracy of the predictive model based on MIR spectra were 69.9% ± 6.2%, 71.9% ± 5.9%, and 70.9% ± 4.8%, respectively, with 6 wavenumbers as explanatory variables ( P < 0.05). CONCLUSIONS This pilot study demonstrates the feasibility of using a select panel of plasma proteins and Fourier transform infrared spectroscopy to diagnose FRIs. Preliminary data suggest that the measurement of these select proteins and MIR spectra may be potential clinical tools to detect FRIs. Further investigation of these biomarkers in a larger cohort of patients is warranted. LEVEL OF EVIDENCE Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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7
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Kauer J, Märklin M, Pflügler M, Hörner S, Hinterleitner C, Tandler C, Jung G, Salih HR, Heitmann JS. BCR::ABL1 tyrosine kinase inhibitors hamper the therapeutic efficacy of blinatumomab in vitro. J Cancer Res Clin Oncol 2022; 148:2759-2771. [PMID: 35551463 PMCID: PMC9470724 DOI: 10.1007/s00432-022-04039-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 04/22/2022] [Indexed: 10/25/2022]
Abstract
PURPOSE Acute B-lymphoblastic leukemia (B-ALL) is a malignant disease characterized by accumulation of clonal immature lymphocytes in the bone marrow and peripheral blood. The approval of BCR::ABL1 tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, nilotinib and ponatinib marked a milestone in targeted therapy only for a subset of patients carrying the translocation t(9;22)(q34;q11). Immunotherapy with the bispecific antibody (bsAb) blinatumomab targeting CD19xCD3 revolutionized treatment of all B-ALL cases. The combination of both TKI and bsAb, so-called "dual targeting", is currently under clinical investigation, although TKI might influence T cell effects. METHODS We here investigated the combination of different TKI and blinatumomab in BCR::ABL1+ and BCR::ABL1- B-ALL cell lines and primary samples regarding T cell proliferation, differentiation, cytokine release and killing of tumor cells. RESULTS In vitro analysis revealed profound reduction of T cell proliferation, differentiation, cytokine release and killing of tumor cells upon application of BCR::ABL1 TKI with blinatumomab. Inhibition was more pronounced with dasatinib and ponatinib compared to nilotinib and imatinib. T cell signalling after CD3 stimulation was impaired by TKI mirrored by inhibition of LCK phosphorylation. This known off-target effect might influence the efficacy of bsAb therapy when combined with BCR::ABL1 TKI. CONCLUSION In conclusion, we propose that nilotinib and imatinib might also be suitable substances for combination with blinatumomab and suggest evaluation in clinical trials.
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Affiliation(s)
- Joseph Kauer
- Departament of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.,Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
| | - Melanie Märklin
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,DFG Cluster of Excellence 2180 'Image-Guided and Functional Instructed Tumor Therapy' (IFIT), University of Tübingen, Tübingen, Germany
| | - Martin Pflügler
- Departament of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.,Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
| | - Sebastian Hörner
- Departament of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany
| | - Clemens Hinterleitner
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen, Germany.,DFG Cluster of Excellence 2180 'Image-Guided and Functional Instructed Tumor Therapy' (IFIT), University of Tübingen, Tübingen, Germany
| | - Claudia Tandler
- Departament of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.,Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,DFG Cluster of Excellence 2180 'Image-Guided and Functional Instructed Tumor Therapy' (IFIT), University of Tübingen, Tübingen, Germany
| | - Gundram Jung
- Departament of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany
| | - Helmut R Salih
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,DFG Cluster of Excellence 2180 'Image-Guided and Functional Instructed Tumor Therapy' (IFIT), University of Tübingen, Tübingen, Germany
| | - Jonas S Heitmann
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany. .,DFG Cluster of Excellence 2180 'Image-Guided and Functional Instructed Tumor Therapy' (IFIT), University of Tübingen, Tübingen, Germany.
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Biomimetic approaches for targeting tumor inflammation. Semin Cancer Biol 2022; 86:555-567. [DOI: 10.1016/j.semcancer.2022.04.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/31/2022] [Accepted: 04/20/2022] [Indexed: 02/08/2023]
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Satria RD, Jhan MK, Chen CL, Tseng PC, Wang YT, Lin CF. Elevated TNF-α Induces Thrombophagocytosis by Mononuclear Cells in ex vivo Whole-Blood Co-Culture with Dengue Virus. J Inflamm Res 2022; 15:1717-1728. [PMID: 35282270 PMCID: PMC8906901 DOI: 10.2147/jir.s356742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 02/24/2022] [Indexed: 11/23/2022] Open
Abstract
Background Infection with dengue virus (DENV) causes hematological complications in dengue diseases characterized by thrombocytopenia accompanied by macrophage activation syndrome and hemophagocytosis in fatal patients. Methods In this study, we investigate the undefined mechanisms underlying the progression of thrombocytopenia caused by thrombophagocytosis based on an ex vivo whole-blood co-culture model of DENV infection for mimicking the acute febrile phase of infection. Results In this model, complete blood count test showed a decrease in monocytes (p < 0.01), but not neutrophils nor other white blood cells, accompanied by a low thrombocyte count (p < 0.01) in DENV infection with a positive correlation (r = 0.636, p < 0.05). Furthermore, DENV exposure caused significant thrombophagocytosis in mononuclear cells (p < 0.05). Abnormal production of tumor necrosis factor (TNF)-α was highly associated with induction of thrombophagocytosis (r = 0.758, p < 0.01), decreased monocytes (r = −0.758, p < 0.01), and decreased thrombocyte (r = −0.728, p < 0.01). Neutralizing TNF-α considerably (p < 0.05) reversed such DENV-induced effects and was further validated by immunostaining-based flow cytometry analysis on mononuclear CD14 positive monocytes. Exogenous administration of TNF-α effectively caused thrombophagocytosis accompanied by decreased monocytes and thrombocytes, probably causing monocyte activation. Conclusion These results demonstrate the potential pathogenesis of thrombocytopenia caused by TNF-α-induced thrombophagocytosis in monocytes during DENV infection.
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Affiliation(s)
- Rahmat Dani Satria
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
- Department of Clinical Pathology and Laboratory Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
- Clinical Laboratory Installation, Dr. Sardjito Central General Hospital, Yogyakarta, 55281, Indonesia
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Ming-Kai Jhan
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Chia-Ling Chen
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Po-Chun Tseng
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
- Core Laboratory of Immune Monitoring, Office of Research & Development, Taipei Medical University, Taipei, 110, Taiwan
| | - Yung-Ting Wang
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Chiou-Feng Lin
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
- Core Laboratory of Immune Monitoring, Office of Research & Development, Taipei Medical University, Taipei, 110, Taiwan
- Correspondence: Chiou-Feng Lin, Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan, Tel +886 2 27361661 ext. 7156, Email
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10
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Lee YK, Wadhwa P, Cai H, Jung SU, Zhao BC, Rim JS, Kim DH, Jang HS, Lee ES. Micro-CT and Histomorphometric Study of Bone Regeneration Effect with Autogenous Tooth Biomaterial Enriched with Platelet-Rich Fibrin in an Animal Model. SCANNING 2021; 2021:6656791. [PMID: 34055131 PMCID: PMC8133871 DOI: 10.1155/2021/6656791] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 04/12/2021] [Accepted: 04/24/2021] [Indexed: 06/12/2023]
Abstract
The aim of this study was to evaluate the potential of tooth biomaterials as bone graft biomaterials for bone healing in rabbits. We prepared tooth biomaterial and platelet-rich fibrin (PRF) to fill the round-shaped defect in the skull of New Zealand white rabbits. These cranial defects were treated with different conditions as follows: group 1, a mixture of tooth biomaterials and platelet-rich fibrin (PRF); group 2, only tooth biomaterials; group 3, only PRF; and group 4, the unfilled control group. Specimens of the filled sites were harvested for analysis with microscopic computerized tomography (micro-CT) and histomorphology at 4 and 8 weeks. As a result of micro-CT, at 4 weeks, the bone volume percentages in groups 1 and 2 were 50.33 ± 6.35 and 57.74 ± 3.13, respectively, and that in the unfilled control group was 42.20 ± 10.53 (p = 0.001). At 8 weeks, the bone volume percentages in groups 1 and 2 were 53.73 ± 9.60 and 54.56 ± 8.44, respectively, and that in the unfilled control group was 37.86 ± 7.66 (p = 0.002). The difference between the experimental group 3 and the unfilled control group was not statistically significant. Histomorphologically, the total new bone was statistically different.
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Affiliation(s)
- Yoon-Ki Lee
- Department of Oral and Maxillofacial Surgery, Graduate School of Clinical Dentistry, Korea University, Seoul 08308, Republic of Korea
| | - Puneet Wadhwa
- Department of Oral and Maxillofacial Surgery, Graduate School of Clinical Dentistry, Korea University, Seoul 08308, Republic of Korea
| | - HongXin Cai
- The CONVERSATIONALIST Club, School of Stomatology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, Shandong 271016, China
| | - Sung-Uk Jung
- Department of Oral and Maxillofacial Surgery, Graduate School of Clinical Dentistry, Korea University, Seoul 08308, Republic of Korea
| | - Bing Cheng Zhao
- The CONVERSATIONALIST Club, School of Stomatology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, Shandong 271016, China
| | - Jae-Suk Rim
- Department of Oral and Maxillofacial Surgery, Graduate School of Clinical Dentistry, Korea University, Seoul 08308, Republic of Korea
| | - Dong-Hyuck Kim
- Department of Oral and Maxillofacial Surgery, Graduate School of Clinical Dentistry, Korea University, Seoul 08308, Republic of Korea
| | - Hyon-Seok Jang
- Department of Oral and Maxillofacial Surgery, Graduate School of Clinical Dentistry, Korea University, Seoul 08308, Republic of Korea
| | - Eui-Seok Lee
- Department of Oral and Maxillofacial Surgery, Graduate School of Clinical Dentistry, Korea University, Seoul 08308, Republic of Korea
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11
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Petrovic SS, Vasiljevska MM, Obradovic SD, Tarabar DK, Doder RB, Majstorovic IJ, Petrovic MD, Magic ZM, Cikota BM, Perisic NJ, Brcerevic IA, Manojlovic NS, Rancic NK. Antiplatelet agents'-ticagrelol and eptifibatide-safety in experimental colitis in mice. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 31:451-458. [PMID: 32721916 DOI: 10.5152/tjg.2020.19454] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND/AIMS To evaluate the side effects of two antiplatelet agents - ticagrelor and eptifibatide - in mice with experimentally-induced inflammatory bowel disease. METHODS AND MATERIAL This study was designed as a controlled, animal, drug safety investigation. C57Bl/6 mice were used to establish the ulcerative colitis model by exposure to dextran sulfate sodium (DSS), and divided into three experimental groups: eptifibatide-treated (150 µg/day intraperitoneally; n = 10), ticagrelol-treated (1 mg/day via gastric tube; n = 10), and DSS-control (plain drinking water; n = 10). An unmodeled non-DSS group served as the experimental control. Complete blood count was taken for all mice at baseline (day 0, treatment initiation) and after four days of treatment. On day 4, all animals were sacrificed for autopsy. The primary outcome measure was bleeding, and the secondary outcomes were change in platelet count, hemoglobin level, and hematocrit level. RESULTS Neither ticagrelor nor eptifibatide treatment produced a significant effect on DSS colitis mice for the safety parameters measured. Platelet count and hemoglobin and hematocrit levels were statistically similar between the three DSS groups and the non-DSS control group (P > 0.05). Autopsy found no evidence of recent bleeding in liver, spleen, central nervous system or serous cavities. CONCLUSION The antiplatelet agents ticagrelor and eptifibatide were safe in DSS colitis mice, suggesting their potential in humans suffering from ulcerative colitis, and supporting future safety studies.
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Affiliation(s)
- Stanko S Petrovic
- Clinic for Gastroenterology and Hepatology, Military Medical Academy, School of Medicine of the Military Medical Academy, University of Defence Belgrade, Serbia
| | | | - Slobodan D Obradovic
- Clinic for Cardiology, Military Medical Academy, School of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia
| | - Dino K Tarabar
- Clinic for Gastroenterology and Hepatology, Military Medical Academy, School of Medicine of the Military Medical Academy, University of Defence Belgrade, Serbia
| | - Radoje B Doder
- Clinic for Gastroenterology and Hepatology, Military Medical Academy, School of Medicine of the Military Medical Academy, University of Defence Belgrade, Serbia
| | | | - Marijana D Petrovic
- Clinic for Nephrology, Military Medical Academy, School of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia
| | - Zvonko M Magic
- Institute for Medical Research, Military Medical Academy, Belgrade, Serbia
| | - Bojana M Cikota
- Institute for Medical Research, Military Medical Academy, Belgrade, Serbia
| | - Nenad J Perisic
- Clinic for Gastroenterology and Hepatology, Military Medical Academy, School of Medicine of the Military Medical Academy, University of Defence Belgrade, Serbia
| | - Irina A Brcerevic
- Clinic for Gastroenterology and Hepatology, Military Medical Academy, School of Medicine of the Military Medical Academy, University of Defence Belgrade, Serbia
| | - Nebojsa S Manojlovic
- Clinic for Gastroenterology and Hepatology, Military Medical Academy, School of Medicine of the Military Medical Academy, University of Defence Belgrade, Serbia
| | - Nemanja K Rancic
- Centre for Clinical Pharmacology, School of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia
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Li J, Zhao Y, Choi J, Ting KK, Coleman P, Chen J, Cogger VC, Wan L, Shi Z, Moller T, Zheng X, Vadas MA, Gamble JR. Targeting miR-27a/VE-cadherin interactions rescues cerebral cavernous malformations in mice. PLoS Biol 2020; 18:e3000734. [PMID: 32502201 PMCID: PMC7299406 DOI: 10.1371/journal.pbio.3000734] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/17/2020] [Accepted: 05/20/2020] [Indexed: 12/13/2022] Open
Abstract
Cerebral cavernous malformations (CCMs) are vascular lesions predominantly developing in the central nervous system (CNS), with no effective treatments other than surgery. Loss-of-function mutation in CCM1/krev interaction trapped 1 (KRIT1), CCM2, or CCM3/programmed cell death 10 (PDCD10) causes lesions that are characterized by abnormal vascular integrity. Vascular endothelial cadherin (VE-cadherin), a major regulator of endothelial cell (EC) junctional integrity is strongly disorganized in ECs lining the CCM lesions. We report here that microRNA-27a (miR-27a), a negative regulator of VE-cadherin, is elevated in ECs isolated from mouse brains developing early CCM lesions and in cultured ECs with CCM1 or CCM2 depletion. Furthermore, we show miR-27a acts downstream of kruppel-like factor (KLF)2 and KLF4, two known key transcription factors involved in CCM lesion development. Using CD5-2 (a target site blocker [TSB]) to prevent the miR-27a/VE-cadherin mRNA interaction, we present a potential therapy to increase VE-cadherin expression and thus rescue the abnormal vascular integrity. In CCM1- or CCM2-depleted ECs, CD5-2 reduces monolayer permeability, and in Ccm1 heterozygous mice, it restores dermal vessel barrier function. In a neonatal mouse model of CCM disease, CD5-2 normalizes vasculature and reduces vascular leakage in the lesions, inhibits the development of large lesions, and significantly reduces the size of established lesions in the hindbrain. Furthermore, CD5-2 limits the accumulation of inflammatory cells in the lesion area. Our work has established that VE-cadherin is a potential therapeutic target for normalization of the vasculature and highlights that targeting miR-27a/VE-cadherin interaction by CD5-2 is a potential novel therapy for the devastating disease, CCM. Cerebral cavernous malformation (CCM) is a disease for which, hitherto, surgery has been the only option. This study shows that a potential therapeutic, CD5-2, inhibits lesion development and vascular leak in the brains of CCM neonatal mice by targeting the endothelial cell–specific adhesion molecule VE-cadherin and restoring the vascular integrity of CCM lesions.
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Affiliation(s)
- Jia Li
- Centre for the Endothelium, Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney, Australia
- Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia
| | - Yang Zhao
- Centre for the Endothelium, Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney, Australia
| | - Jaesung Choi
- Laboratory of Cardiovascular Signaling, Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney, Australia
| | - Ka Ka Ting
- Centre for the Endothelium, Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney, Australia
| | - Paul Coleman
- Centre for the Endothelium, Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney, Australia
| | - Jinbiao Chen
- Liver Injury and Cancer Program, Centenary Institute, The University of Sydney, Sydney, Australia
| | - Victoria C. Cogger
- Aging and Alzheimers Institute and ANZAC Research Institute and Concord Hospital, Charles Perkins Centre, The University of Sydney, Sydney, Australia
| | - Li Wan
- Centre for the Endothelium, Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney, Australia
| | - Zhongsong Shi
- Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | | | - Xiangjian Zheng
- Laboratory of Cardiovascular Signaling, Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney, Australia
| | - Mathew A. Vadas
- Centre for the Endothelium, Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney, Australia
| | - Jennifer R. Gamble
- Centre for the Endothelium, Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney, Australia
- * E-mail:
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Wang B, Feng C, Dang J, Niu L, Shen C, Yang X, Zhang T, Zhang X. Anti-Adhesive, Platelet Gathering Effects of c-RGD Modified Poly(p-dioxanone-co-l-Phe) Electrospun Membrane and Its Comprehensive Application in Intestinal Anastomosis. Macromol Biosci 2019; 20:e1900344. [PMID: 31854121 DOI: 10.1002/mabi.201900344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/05/2019] [Indexed: 11/06/2022]
Abstract
Intestinal resection and anastomosis are performed in over a million people with various bowel diseases annually. Excessive fibrosis and anastomotic site leakage are the main complications of anastomosis surgery, despite great improvements in operative technique and equipment in recent years. In this study, cRGD modified poly(p-dioxanone-co-l-Phe) (PDPA) membranes are designed and applied in intestinal anastomosis to simultaneously solve the two aforementioned complications. cRGD is modified onto PDPA membranes through both physical absorption and π-π accumulation between d-Phe of cRGD and l-Phe of PDPA. Although cRGD modification enhanced the biocompatibility of PDPA membranes, cRGD modified PDPA membrane suppresses fibroblast proliferation both in vitro and in vivo as a result of degradation and subsequent release of fibroblast suppressive l-Phe from PDPA. Meanwhile, platelets are entrapped by cRGD modified PDPA membranes through the specific binding of cRGD and platelet GPIIbIIIa . cRGD modified PDPA membranes are applied in rat intestinal anastomosis, and both adhesion and stenosis are successfully prevented at anastomotic sites. At the same time, bursting pressure, which represents healing intensity at anastomotic sites, is promoted. The gathering and activation of platelets on PDPA membranes induce secretion of autologous PDGF and VEGF to facilitate angiogenesis and subsequent healing of anastomotic sites.
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Affiliation(s)
- Bing Wang
- Sichuan Key Laboratory of Medical Imaging & Department of Chemistry, School of Preclinical Medicine, North Sichuan Medical College, Nanchong, 637000, China
| | - Chengmin Feng
- Department of Clinical Medicine, North Sichuan Medical College & Department of Otolaryngology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
| | - Jiafeng Dang
- Department of Clinical Medicine, North Sichuan Medical College & Department of Obstetrics and Gynecology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
| | - Lijing Niu
- Department of Pathology, School of Preclinical Medicine, North Sichuan Medical College, Nanchong, 637000, China
| | - Chengyi Shen
- Sichuan Key Laboratory of Medical Imaging & Institute of Morphological Research, North Sichuan Medical College, Nanchong, 637000, China
| | - Xiaomei Yang
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong, 637000, China
| | - Ting Zhang
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong, 637000, China
| | - Xiaoming Zhang
- Sichuan Key Laboratory of Medical Imaging & Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
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Coskun B, Ince O, Erkilinc S, Elmas B, Saridogan E, Coskun B, Doganay M. The feasibility of the platelet count and mean platelet volume as markers of endometriosis and adenomyosis: A case control study. J Gynecol Obstet Hum Reprod 2019; 49:101626. [PMID: 31499283 DOI: 10.1016/j.jogoh.2019.101626] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 06/29/2019] [Accepted: 09/05/2019] [Indexed: 01/24/2023]
Abstract
INTRODUCTION The aim of the study is to investigate the role of platelet count (PC) and mean platelet volume (MPV) in determining adenomyosis and endometriosis. MATERIAL AND METHODS This was a retrospective case control study that included adenomyosis, endometriosis and control groups. The adenomyosis group included 84 women diagnosed between January 2013 and January 2015 based on hysterectomy specimen. The endometriosis group included 102 patients underwent diagnostic laparoscopy and confirmed by histopathologic examination. Lastly, the control group included 88 women had no medical problem and underwent tubal ligation. RESULTS MPV (fl) was significantly lower in adenomyosis group (8.5) compared to endometriosis (9, p<0.05) and control groups (9, p<0.01). Modified platelet activity (MPV/PC) was significantly lower in adenomyosis group compared to control group (p<0.01). Bivariate logistic regression model was used to assess the odds ratio of risk factors and serum markers related to endometriosis and adenomyosis. Variables showing significant differences based on post-hoc Bonferroni test were included in the logistic regression model for comparison of each disease with the control group. MPV was not found to be a risk factor both for presence of endometriosis and adenomyosis after adjusting for demographic and clinical characteristics. DISCUSSION Our study suggested that PC and MPV were not useful diagnostic markers for endometriosis or adenomyosis. Further research on how platelet indices and other inflammatory markers are related to inflammation might help better understand their potential as markers for these diseases.
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Affiliation(s)
- Bugra Coskun
- University of Health Sciences Gülhane Education and Research Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey.
| | - Onur Ince
- Kutahya Health Sciences University, Faculty of Medicine, Department of Obstetrics and Gynecology, 43000, Kutahya, Turkey.
| | - Selcuk Erkilinc
- University of Health Sciences Tepecik Education and Research Hospital, Department of Gynecologic Oncology, İzmir, Turkey.
| | - Burak Elmas
- University of Health Sciences Zekai Tahir Burak Women's Health Education and Research Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey.
| | - Erdinc Saridogan
- University of Health Sciences Zekai Tahir Burak Women's Health Education and Research Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey.
| | - Bora Coskun
- University of Health Sciences Gülhane Education and Research Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey.
| | - Melike Doganay
- University of Health Sciences Zekai Tahir Burak Women's Health Education and Research Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey.
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Lin SL, Yeh JL, Tsai PC, Chang TH, Huang WC, Lee ST, Wassler M, Geng YJ, Sulistyowati E. Inhibition of Neointima Hyperplasia, Inflammation, and Reactive Oxygen Species in Balloon-Injured Arteries by HVJ Envelope Vector-Mediated Delivery of Superoxide Dismutase Gene. Transl Stroke Res 2019; 10:413-427. [PMID: 30191468 PMCID: PMC6647364 DOI: 10.1007/s12975-018-0660-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 08/18/2018] [Accepted: 08/22/2018] [Indexed: 11/19/2022]
Abstract
Extracellular superoxide dismutase (EC-SOD) has been implicated in regulation of vascular function but its underlying molecular mechanism is largely unknown. These two-step experiments investigate whether hemagglutinating virus of Japan envelope (HVJ-E) vector-mediated EC-SOD gene delivery might protect against neointima formation, vascular inflammation, and reactive oxygen species (ROS) generation, and also explore cell growth signaling pathways. The first in-vitro experiment was performed to assess the transfection efficacy and safety of HVJ-E compared to lipofectamine®. Results revealed that HVJ-E has higher transfection efficiency and lower cytotoxicity than those of lipofectamine®. Another in-vivo study initially used balloon denudation to rat carotid artery, then delivered EC-SOD cDNA through the vector of HVJ-E. Arterial section with H&E staining from the animals 14 days after balloon injury showed a significant reduction of intima-to-media area ratio in EC-SOD transfected arteries when compared with control (empty vector-transfected arteries) (p < 0.05). Arterial tissue with EC-SOD gene delivery also exhibited lower levels of ROS, as assessed by fluorescent microphotography with dihydroethidium staining. Quantitative RT-PCR revealed that EC-SOD gene delivery significantly diminished mRNA expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β (p < 0.05 in all comparisons). An immunoblotting assay from vascular smooth muscle cell (VSMC) cultures showed that the EC-SOD transfected group attenuated the activation of MEK1/2, ERK1/2, and Akt signaling significantly. In conclusion, EC-SOD overexpression by HVJ-E vector inhibits neointima hyperplasia, inflammation, and ROS level triggered by balloon injury. The modulation of cell growth-signaling pathways by EC-SOD in VSMCs might play an important role in these inhibitory effects.
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Affiliation(s)
- Shoa-Lin Lin
- Intensive Care Unit, Yuan's General Hospital, 162, Cheng-Kung First Road, Lingya District, Kaohsiung, 80249, Taiwan.
- School of Medicine, National Yang-Ming University, Taipei, Taiwan.
| | - Jwu-Lai Yeh
- Department of Pharmacology and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Pei-Chia Tsai
- Intensive Care Unit, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Tsung-Hsien Chang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - Wei-Chun Huang
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Intensive Care Unit, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Song-Tay Lee
- Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan
| | - Michael Wassler
- Department of Cardiovascular Biology and Atherosclerosis, University of Texas at Houston, Houston, TX, USA
| | - Yong-Jian Geng
- Department of Cardiovascular Biology and Atherosclerosis, University of Texas at Houston, Houston, TX, USA
| | - Erna Sulistyowati
- Department of Pharmacology and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Medicine, Islamic University of Malang, Malang, East Java, Indonesia
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Sills ES, Wood SH. Autologous activated platelet-rich plasma injection into adult human ovary tissue: molecular mechanism, analysis, and discussion of reproductive response. Biosci Rep 2019; 39:BSR20190805. [PMID: 31092698 PMCID: PMC6549090 DOI: 10.1042/bsr20190805] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/09/2019] [Accepted: 05/14/2019] [Indexed: 01/19/2023] Open
Abstract
In clinical infertility practice, one intractable problem is low (or absent) ovarian reserve which in turn reflects the natural oocyte depletion associated with advancing maternal age. The number of available eggs has been generally thought to be finite and strictly limited, an entrenched and largely unchallenged tenet dating back more than 50 years. In the past decade, it has been suggested that renewable ovarian germline stem cells (GSCs) exist in adults, and that such cells may be utilized as an oocyte source for women seeking to extend fertility. Currently, the issue of whether mammalian females possess such a population of renewable GSCs remains unsettled. The topic is complex and even agreement on a definitive approach to verify the process of 'ovarian rescue' or 're-potentiation' has been elusive. Similarities have been noted between wound healing and ovarian tissue repair following capsule rupture at ovulation. In addition, molecular signaling events which might be necessary to reverse the effects of reproductive ageing seem congruent with changes occurring in tissue injury responses elsewhere. Recently, clinical experience with such a technique based on autologous activated platelet-rich plasma (PRP) treatment of the adult human ovary has been reported. This review summarizes the present state of understanding of the interaction of platelet-derived growth factors with adult ovarian tissue, and the outcome of human reproductive potential following PRP treatment.
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Affiliation(s)
- E Scott Sills
- Gen 5 Fertility Center, Office for Reproductive Research, Center for Advanced Genetics; San Diego, CA, U.S.A.
- Applied Biotechnology Research Group, University of Westminster; London W1B 2HW, U.K
| | - Samuel H Wood
- Gen 5 Fertility Center, Office for Reproductive Research, Center for Advanced Genetics; San Diego, CA, U.S.A
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PDGF enhances the protective effect of adipose stem cell-derived extracellular vesicles in a model of acute hindlimb ischemia. Sci Rep 2018; 8:17458. [PMID: 30514962 PMCID: PMC6279818 DOI: 10.1038/s41598-018-36143-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 11/09/2018] [Indexed: 12/14/2022] Open
Abstract
We previously have shown that platelet-derived growth factor (PDGF) modulates the biological activity of extracellular vesicles released by adipose-derived mesenchymal stem cells (ASC-EVs). ASC-EVs may interact with blood and vessel cells by transferring proteins and nucleic acids and regulate their functions. In this study, we investigated immunomodulatory activity and protection from acute hindlimb ischemia of EVs released by PDGF-stimulated ASC (PDGF-EVs). PDGF treatment of ASC changed protein and RNA composition of released EVs by enhancing the expression of anti-inflammatory and immunomodulatory factors. In vitro, control EVs (cEVs) derived from non-stimulated ASC increased the secretion of both the IL-1b, IL-17, IFNγ, TNFα pro-inflammatory factors and the IL-10 anti-inflammatory factor, and enhanced the in vitro peripheral blood mononuclear cell (PBMC) adhesion on endothelium. In contrast, PDGF-EVs enhanced IL-10 secretion and induced TGF-β1 secretion by PBMC. Moreover, PDGF-EVs stimulated the formation of T regulatory cells. In vivo, PDGF-EVs protected muscle tissue from acute ischemia, reduced infiltration of inflammatory cells and increased T regulatory cell infiltration in respect to cEVs. Our results suggest that PDGF-EVs are enriched in anti-inflammatory and immunomodulatory factors and induced in PBMC an enhanced production of IL-10 and TGF-β1 resulting in protection of muscle from acute ischemia in vivo.
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Sills ES, Rickers NS, Li X, Palermo GD. First data on in vitro fertilization and blastocyst formation after intraovarian injection of calcium gluconate-activated autologous platelet rich plasma. Gynecol Endocrinol 2018; 34:756-760. [PMID: 29486615 DOI: 10.1080/09513590.2018.1445219] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
Abstract
Platelets modulate clinically relevant yet incompletely understood tissue regeneration processes, and platelet rich plasma (PRP) has been previously used with some success in various non-reproductive medical contexts. Here, we extended PRP application to ovarian tissue with a view to document impact on ovarian reserve among women attending for infertility treatment. PRP was freshly isolated from patients (n= 4) with diminished ovarian reserve as determined by at least one prior IVF cycle canceled for poor follicular recruitment response or estimated by serum AMH and/or FSH, no menses for ≥1 year. Immediately following substrate isolation and activation with calcium gluconate, approximately 5 mL of autologous PRP was injected into each ovary under direct transvaginal sonogram guidance. For each study subject, AMH, FSH, and serum estradiol data were recorded at two-week intervals post-PRP and compared to baseline (pre-PRP) values. In this pilot group, mean (±SD) patient age was 42 ± 4 years with infertility duration reported as 60 ± 25 months. Following this protocol of intraovarian PRP administration, increases in serum AMH (p = .17), decreases in FSH (p < .01), or both, were observed in all cases, sufficient to permit retrieval of 5.3 ± 1.3 MII oocytes. IVF occurred 78 ± 22 (range = 59-110) days after activated PRP injection, and results appeared independent of patient age, infertility duration, baseline platelet concentration or pretreatment antral follicle count. Each patient had at least one blastocyst suitable for cryopreservation. While autologous PRP has been successfully applied therapeutically to various tissues to accelerate healing and wound repair, this is the first description of direct injection of activated PRP into the human ovary of poor prognosis IVF patients. Evidence of improved ovarian function was noted in all who received intraovarian PRP, possibly as early as two months after treatment. Additional research is needed to clarify (and enhance) which PRP components are responsible for altered ovarian function, and to identify predictive characteristics for patients most likely to benefit from this intervention.
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Affiliation(s)
- E Scott Sills
- a Office for Reproductive Research , Center for Advanced Genetics , Carlsbad , CA , USA
- b Applied Biotechnology Research Group , University of Westminster , London, UK
| | - Natalie S Rickers
- a Office for Reproductive Research , Center for Advanced Genetics , Carlsbad , CA , USA
| | - Xiang Li
- a Office for Reproductive Research , Center for Advanced Genetics , Carlsbad , CA , USA
- c Data Analytics, Paralian Technology, Inc , Mission Viejo , CA , USA
| | - Gianpiero D Palermo
- d Center for Reproductive Medicine & Infertility, Weill Medical College of Cornell University , New York , NY , USA
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Manne BK, Münzer P, Badolia R, Walker-Allgaier B, Campbell RA, Middleton E, Weyrich AS, Kunapuli SP, Borst O, Rondina MT. PDK1 governs thromboxane generation and thrombosis in platelets by regulating activation of Raf1 in the MAPK pathway. J Thromb Haemost 2018; 16:1211-1225. [PMID: 29575487 PMCID: PMC5984143 DOI: 10.1111/jth.14005] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Indexed: 01/02/2023]
Abstract
Essentials Phosphoinositide 3-kinase and MAPK pathways crosstalk via PDK1. PDK1 is required for adenosine diphosphate-induced platelet activation and thromboxane generation. PDK1 regulates RAF proto-oncogene Ser/Thr kinase (Raf1) activation in the MAPK pathway. Genetic ablation of PDK1 protects against platelet-dependent thrombosis in vivo. SUMMARY Background Platelets are dynamic effector cells with functions that span hemostatic, thrombotic and inflammatory continua. Phosphoinositide-dependent protein kinase 1 (PDK1) regulates protease-activated receptor 4-induced platelet activation and thrombus formation through glycogen synthase kinase3β. However, whether PDK1 also signals through the ADP receptor and its functional importance in vivo remain unknown. Objective To establish the mechanism of PDK1 in ADP-induced platelet activation and thrombosis. Methods We assessed the role of PDK1 on 2MeSADP-induced platelet activation by measuring aggregation, thromboxane generation and phosphorylation events in the presence of BX-795, which inhibits PDK1, or by using platelet-specific PDK1 knockout mice and performing western blot analysis. PDK1 function in thrombus formation was assessed with an in vivo pulmonary embolism model. Results PDK1 inhibition with BX-795 reduced 2-methylthio-ADP (2MeSADP)-induced aggregation of human and murine platelets by abolishing thromboxane generation. Similar results were observed in pdk1-/- mice. PDK1 was also necessary for the phosphorylation of mitogen-activated protein kinase kinase 1/2 (MEK1/2), extracellular signal-regulated kinase 1/2, and cytosolic phospholipase A2, indicating that PDK1 regulates an upstream kinase in the mitogen-activated protein kinase (MAPK) pathway. We next determined that this upstream kinase is Raf-1, a serine/threonine kinase that is necessary for the phosphorylation of MEK1/2, as pharmacological inhibition and genetic ablation of PDK1 were sufficient to prevent Raf1 phosphorylation. Furthermore, in vivo inhibition or genetic ablation of PDK1 protected mice from collagen/epinephrine-induced pulmonary embolism. Conclusion PDK1 governs thromboxane generation and thrombosis in platelets that are stimulated with 2MeSADP by regulating activation of the MAPK pathway.
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Affiliation(s)
- Bhanu Kanth Manne
- Department of Internal Medicine, Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112 USA
| | - Patrick Münzer
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, 72076 Germany
| | - Rachit Badolia
- Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, 19140 USA
| | - Britta Walker-Allgaier
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, 72076 Germany
| | - Robert A Campbell
- Department of Internal Medicine, Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112 USA
| | - Elizabeth Middleton
- Department of Internal Medicine, Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112 USA
| | - Andrew S Weyrich
- Department of Internal Medicine, Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112 USA
| | - Satya P Kunapuli
- Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, 19140 USA
| | - Oliver Borst
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, 72076 Germany
| | - Matthew T. Rondina
- Department of Internal Medicine, Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112 USA
- Department of Internal Medicine, GRECC, George E. Wahlen VAMC, Salt Lake City, UT, 84148
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Jin K, Luo Z, Zhang B, Pang Z. Biomimetic nanoparticles for inflammation targeting. Acta Pharm Sin B 2018; 8:23-33. [PMID: 29872620 PMCID: PMC5985691 DOI: 10.1016/j.apsb.2017.12.002] [Citation(s) in RCA: 239] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 11/28/2017] [Accepted: 11/29/2017] [Indexed: 02/07/2023] Open
Abstract
There have been many recent exciting developments in biomimetic nanoparticles for biomedical applications. Inflammation, a protective response involving immune cells, blood vessels, and molecular mediators directed against harmful stimuli, is closely associated with many human diseases. As a result, biomimetic nanoparticles mimicking immune cells can help achieve molecular imaging and precise drug delivery to these inflammatory sites. This review is focused on inflammation-targeting biomimetic nanoparticles and will provide an in-depth look at the design of these nanoparticles to maximize their benefits for disease diagnosis and treatment.
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Key Words
- Biomimetic nanoparticles
- CAM, cellular adhesion molecule
- CCL5, chemokine (C-C motif) ligand 5
- CD40L, cluster of differentiation 40 ligand
- CTC, circulating tumor cell
- CTL, cytotoxic T cell or CD8+ T cell
- CXCL4, chemokine (C-X-C motif) ligand 4
- CXCR1, chemokine (C-X-C motif) receptor 1
- Cell membrane
- Cell membrane proteins
- Cy7, cyanine 7
- DC, dendritic cell
- DSPE-PEG, distearoyl Phosphoethanolamine-poly(ethylene glycol)
- GPIV, glycoprotein IV
- GPIX, glycoprotein IX
- GPIbα, glycoprotein Ibα
- GPV, glycoprotein V
- GPVI, glycoprotein VI
- HUVEC, umbilical cord vascular endothelial cell
- IBD, inflammatory bowel disease
- ICAM-1, intercellular cellular adhesion molecule-1
- IL, interleukin
- IgG, immunoglobulin G
- Immune cells
- Inflammation targeting
- LFA-1, lymphocyte function associated antigen-1
- LLV, leukocyte-like vector
- LPS, lipopolysaccharide
- MHC, major histocompatibility complex
- MRI, magnetic resonance imaging
- Mac-1, macrophage adhesion molecule-1
- Molecular imaging
- NM-NP, neutrophil membrane-coated nanoparticle
- PECAM-1, platelet-endothelial cellular adhesion molecule-1
- PLA-PEG, poly(lactic acid)-poly(ethylene glycol)
- PLGA, poly(lactic-co-glycolic acid)
- PNP, platelet membrane-cloaked nanoparticle
- PSGL-1, P-selectin glycoprotein ligand-1
- RA, rheumatoid arthritis
- RBC, red blood cell
- SLeX, sialyl lewis X
- SPIO, super paramagnetic iron oxide
- TGF-β, transforming growth factor β
- TNF-α, tumor necrosis factor-α
- Targeting ligands
- Th cell, T-helper cell or CD4+ T cell
- VCAM-1, vascular cellular adhesion molecule-1
- VLA-4, very late antigen-4
- VWF, Von Willebrand factor
- apoE–/– mice, Apolipoprotein e knockout mice
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Affiliation(s)
- Kai Jin
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China
| | - Zimiao Luo
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China
- Biomedical Engineering and Technology Institute, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
| | - Bo Zhang
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China
| | - Zhiqing Pang
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China
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Zhang X, Xia S, Xu Q, Huang J. The cytoprotective effects of Δ-17 fatty acid desaturase on injured HUVECs and its underlying mechanism. Saudi Pharm J 2017; 25:587-594. [PMID: 28579896 PMCID: PMC5447458 DOI: 10.1016/j.jsps.2017.04.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Endothelium toxicity has been involved in early endothelial dysfunction to show the pathogenesis of multiple cardiovascular disease that shows atherosclerosis and its complications. Saturated free fatty acids are the main inducing factors of endothelial cell apoptosis and inflammatory cytokines. In humans, stearoyl-CoA desaturase 1 (SCD-1) is a restriction step to saturation to unsaturated fatty acid desaturation, which plays a beneficial role protecting endothelial cells against lipotoxicity. Δ-17 fatty acid desaturase (FAD) is a newly identified FAD which shares 55% identity at the amino acid level with SCD-1. Whether Δ-17 FAD has similar beneficial effect remains poorly understood. Oxidized low density lipoprotein (ox-LDL) was used to induce lipotoxicity in human umbilical vein endothelial cells (HUVECs) to establish a model of oxidative injury. Then HUVECs were transfected with FAD lentivirus to introduce cytoprotective effects. The alterations in cell proliferation and apoptosis, nitric oxide content, malonyldialdehyde (MDA) content, SOD enzyme content, LDH content, GSH-PX level, vascular growth factor (VEGF) expression were evaluated. Studies showed that ox-LDL-induced excess HUVEC apoptosis can be abrogated by upregulation of Δ-17 FAD. The nitric oxide content, GSH-PX content, and SOD enzyme content were increased and the activity of MDA was suppressed by upregulation of Δ-17 FAD. In addition, upregulation of Δ-17 FAD significantly increased VEGF expression. In vitro tube formation assay showed that Δ-17 FAD promoted angiogenesis to a significant degree. These results suggest that Δ-17 fatty acid desaturase may have beneficial action in the prevention of ox-LDL-induced cellular damage.
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Affiliation(s)
- Xiulan Zhang
- Department of Intravenous Admixture, Weifang Peoples’ Hospital, Weifang 261041, China
| | - Shixin Xia
- Department of Pharmacy, Weifang Peoples’ Hospital, Weifang 261041, China
| | - Qiqi Xu
- Department of Pharmacy, Weifang Peoples’ Hospital, Weifang 261041, China
| | - Jiandong Huang
- Department of Pharmacy, Weifang Peoples’ Hospital, Weifang 261041, China
- Corresponding author.
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Ranneh Y, Ali F, Akim AM, Hamid HA, Khazaai H, Fadel A. Crosstalk between reactive oxygen species and pro-inflammatory markers in developing various chronic diseases: a review. APPLIED BIOLOGICAL CHEMISTRY 2017; 60:327-338. [DOI: 10.1007/s13765-017-0285-9] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
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Abstract
Platelets are small, anucleate circulating cells that possess a dynamic repertoire of functions spanning the hemostatic, inflammatory, and immune continuum. Once thought to be merely cell fragments with responses limited primarily to acute hemostasis and vascular wall repair, platelets are now increasingly recognized as key sentinels and effector cells regulating host responses to many inflammatory and infectious cues. Platelet granules, including α-granules and dense-granules, store hundreds of factors and secrete these mediators in response to activating signals. The cargo packaged and stored within platelet granules orchestrates communication between platelets and other circulating cells, augments host defense mechanisms to invading pathogens and tumor cells, and - in some settings - drives dysregulated and injurious responses. This focused review will highlight several of the established and emerging mechanisms and roles of platelet secretion in inflammatory and infectious diseases.
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Affiliation(s)
- Bhanu K Manne
- a The University of Utah Molecular Medicine Program , Salt Lake City , Utah , USA
| | | | - Matthew T Rondina
- a The University of Utah Molecular Medicine Program , Salt Lake City , Utah , USA.,c Department of Internal Medicine , Salt Lake City , Utah , USA.,d The GRECC, George E. Wahlen Salt Lake City VAMC , Salt Lake City , Utah , USA
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Pini A, Obara I, Battell E, Chazot PL, Rosa AC. Histamine in diabetes: Is it time to reconsider? Pharmacol Res 2016; 111:316-324. [DOI: 10.1016/j.phrs.2016.06.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 06/20/2016] [Accepted: 06/21/2016] [Indexed: 10/21/2022]
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Prasad CK, Resmi KR, Krishnan LK, Vaishnav R. Survival of Endothelial Cells in vitro on Paclitaxel-loaded Coronary Stents. J Biomater Appl 2016; 19:271-86. [PMID: 15788425 DOI: 10.1177/0885328205047397] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Coronary stents that are developed for use with balloon angioplasty are known to cause acute occlusion and long-term stenosis. It is likely that a controlled release of drugs at the site of stent implantation might inhibit the proliferation of vascular smooth muscle cells (VSMC) and reduce restenosis. However, if the drug is necrotic and affects cell survival near the implant, it may interrupt the local tissue regeneration. Different methods have been used for the immobilization of drugs with stents to get an effective concentration that inhibits cell proliferation. The objective of this study is to assess the effectiveness of Paclitaxel-loaded stents by immobilization with a biodegradable polymer, to inhibit cell proliferation. The cells used for the evaluation are human umbilical vein endothelial cells (HUVEC) and the proliferation rate of these cells on the drug-coated stent is compared against an uncoated stent for a 72-h period. Evaluations were also made to differentiate between cell apoptosis and necrosis to prove that the drug released is not deleterious to the surrounding tissue. While a similar initial cell adhesion is observed in bare and coated stents, the proliferation of HUVEC is negligible when grown on a drug-coated stent (p < 0.001). By specific staining techniques, the cells on the drug-coated stents are found to be apoptotic and not necrotic, throughout the evaluation period. In vitro leukocyte adhesion and platelet deposition on the drug-coated stents are found to be low when they are exposed to human blood and platelet-rich plasma (PRP), suggesting that the coated stents may not be thrombogenic in vivo. Therefore, drug coating of stents using the described technique may have a considerable promise for the prevention of neointimal proliferation, restenosis, and associated failure of angioplasty.
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Affiliation(s)
- C Krishna Prasad
- Thrombosis Research Unit, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Trivandrum-695 012, India
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Abstract
The administration of fluconazole is commonly used in both inpatient and outpatient settings for the management of candidiasis infection. Although it is associated with a relatively safe side effect profile, some patients experience adverse effects associated with increased morbidity. We describe 1 such patient, a 42-year-old woman with a history of severe eczema who developed fluconazole-induced type 1 Kounis syndrome. Review of literature indicates that this as the first case reported of fluconazole-induced type 1 Kounis syndrome.
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Hu W, Huang Y. Targeting the platelet-derived growth factor signalling in cardiovascular disease. Clin Exp Pharmacol Physiol 2015; 42:1221-4. [DOI: 10.1111/1440-1681.12478] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 08/03/2015] [Accepted: 08/08/2015] [Indexed: 01/08/2023]
Affiliation(s)
- Weining Hu
- Shenzhen Research Institute; Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong China
| | - Yu Huang
- Shenzhen Research Institute; Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong China
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A tryptophan derivative TD-26 attenuates thrombus formation by inhibiting both PI3K/Akt signaling and binding of fibrinogen to integrin αIIbβ3. Biochem Biophys Res Commun 2015; 465:516-22. [PMID: 26278818 DOI: 10.1016/j.bbrc.2015.08.051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 08/12/2015] [Indexed: 01/08/2023]
Abstract
The incidence and mortality of thrombotic disorders are rapidly increasing worldwide. The existing antithrombotic drugs, however, are associated with side effects, especially bleeding complications. Therefore, there remains a need for the development of more effective and safer antithrombotic agents. In this study, we discovered a new synthetic tryptophan derivative TD-26, producing potent inhibitory effect on platelet aggregation while without causing obvious bleeding risk. It has been shown that TD-26 inhibited platelet aggregation induced by ADP, thrombin, U46619 and collagen in vitro and suppressed the platelet aggregation induced by ADP ex vivo. Mechanism studies indicated that TD-26 inhibited platelet adhesion to fibrinogen-coated surfaces, blocked the binding of fibrinogen to integrin αIIbβ3 and reduced Akt(Ser473) phosphorylation in platelet phosphatidylinositol 3-kinase (PI3K) signaling. Furthermore, TD-26 exhibited potent antithrombotic activity in vivo. In animal models, it decreased death of mice with acute pulmonary thrombosis by 90% and attenuated thrombosis weight by 60.3%, both at a dose of 3 mg/kg. Additionally, TD-26 did not obviously prolong bleeding time in mice. Taken together, our results reveal that TD-26 is a novel antithrombotic compound exhibiting both integrin αIIbβ3 inhibition and PI3K signaling blockage, with a low bleeding risk.
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Abstract
Platelets are anucleate blood cells, long known to be critically involved in hemostasis and thrombosis. In addition to their role in blood clots, increasing evidence reveals significant roles for platelets in inflammation and immunity. However, the notion that platelets represent immune cells is not broadly recognized in the field of Physiology. This article reviews the role of platelets in inflammation and immune responses, and highlights their interactions with other immune cells, including examples of major functional consequences of these interactions.
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Affiliation(s)
- Fong W Lam
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas, USA
- Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
| | - K Vinod Vijayan
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas, USA
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
- Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
| | - Rolando E Rumbaut
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas, USA
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
- Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
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Finkenstaedt-Quinn SA, Ge S, Haynes CL. Cytoskeleton dynamics in drug-treated platelets. Anal Bioanal Chem 2015; 407:2803-9. [PMID: 25701419 DOI: 10.1007/s00216-015-8523-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 01/25/2015] [Accepted: 01/27/2015] [Indexed: 12/15/2022]
Abstract
Platelet activation is a key process in blood clot formation. During activation, platelets go through both chemical and physical changes, including secretion of chemical messengers and cellular shape change. Platelet shape change is mediated by the two major cytoskeletal elements in platelets, the actin matrix and microtubule ring. Most studies to date have evaluated these structures qualitatively, whereas this paper aims to provide a quantitative method of examining changes in these structures by fluorescently labeling the element of interest and performing single cell image analysis. The method described herein tracks the diameter of the microtubule ring and the circumference of the actin matrix as they change over time. Platelets were incubated with a series of drugs that interact with tubulin or actin, and the platelets were observed for variation in shape change dynamics throughout the activation process. Differences in shape change mechanics due to drug incubation were observable in each case.
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Abstract
Despite their small size and anucleate status, platelets have diverse roles in vascular biology. Not only are platelets the cellular mediator of thrombosis, but platelets are also immune cells that initiate and accelerate many vascular inflammatory conditions. Platelets are linked to the pathogenesis of inflammatory diseases such as atherosclerosis, malaria infection, transplant rejection, and rheumatoid arthritis. In some contexts, platelet immune functions are protective, whereas in others platelets contribute to adverse inflammatory outcomes. In this review, we will discuss platelet and platelet-derived mediator interactions with the innate and acquired arms of the immune system and platelet-vessel wall interactions that drive inflammatory disease. There have been many recent publications indicating both important protective and adverse roles for platelets in infectious disease. Because of this new accumulating data, and the fact that infectious disease continues to be a leading cause of death globally, we will also focus on new and emerging concepts related to platelet immune and inflammatory functions in the context of infectious disease.
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Relative increase in lymphocytes from as early as 1 month predicts improved response to dasatinib in chronic-phase chronic myelogenous leukemia. Int J Hematol 2013; 99:41-52. [PMID: 24297450 DOI: 10.1007/s12185-013-1483-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 11/21/2013] [Accepted: 11/21/2013] [Indexed: 10/26/2022]
Abstract
Lymphocytosis in response to dasatinib for chronic myelogenous leukemia (CML) may be associated with favorable response. However, it occurs at varying times and in a limited subset of patients. To identify early clinical markers for favorable responses applicable to all patients with or without lymphocytosis, we prospectively analyzed lymphocyte profiles of 50 Japanese CML patients treated with dasatinib after intolerance/resistance to imatinib. Although absolute lymphocyte counts did not differ significantly until 3 months between patients with complete molecular response (CMR) at 12 months and those without it, relative increases in lymphocyte compared with baselines differed significantly from 1 month. Patients with relative lymphocyte counts >150 % at 1 month or >200 % at 3 months had higher CMR rates at 12 months than others (57.9 vs. 23.3 %, P = 0.015, and 76.5 vs. 16.1 %, P < 0.0001, respectively). A relative increase in lymphocyte subset of CD57(+)CD14(-), CD8(+)T, or NK cells >200 % at 1 month was also significantly associated with a higher CMR rate. There were significant negative correlations between relative lymphocyte increases and BCR/ABL transcript levels. CD57(+)CD14(-) cells were a highly specific focus of proliferation. Relative increases in lymphocyte count and its subsets from 1 month are reliable early markers of favorable responses to dasatinib.
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Laycock H, Valente J, Bantel C, Nagy I. Peripheral mechanisms of burn injury-associated pain. Eur J Pharmacol 2013; 716:169-78. [DOI: 10.1016/j.ejphar.2013.01.071] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Revised: 01/22/2013] [Accepted: 01/29/2013] [Indexed: 12/12/2022]
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Patel SH, Rachchh MA, Jadav PD. Evaluation of anti-inflammatory effect of anti-platelet agent-clopidogrel in experimentally induced inflammatory bowel disease. Indian J Pharmacol 2013. [PMID: 23248405 DOI: 10.4103/0253-7613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
AIM To evaluate the anti-inflammatory effect of antiplatelet agent, clopidogrel, in experimentally induced inflammatory bowel disease (IBD). MATERIALS AND METHODS TNBS induced Crohn's disease model and oxazolone induced ulcerative colitis model were used to evaluate the role of clopidogrel in IBD. Spargue Dawley female and Wistar male rats were used respectively. The colitis was induced by a single intra-colonic application of TNBS (0.25 ml, 120 mg/ml in 50% ethanol) and oxazolone (450 μl 5% oxazolone in 50% ethanol). Rats were divided into four groups (n=6) in each model namely normal control, sham control, test and standard group. Drug treatment was carried out for 21 days. After 21 days, animals were sacrificed and evaluated for weight change, colon mucosal damage index (CMDI), disease activity Index (DAI) and myeloperoxidase (MPO) activity. RESULTS Results showed that clopidogrel provided significant protection against mucosal damage in both the models of IBD. It significantly reduced (P<0.05) the decrease in body weight and CMDI, DAI and MPO scores. CONCLUSION The results indicate that clopidogrel may be effective in treatment of Crohn's disease and ulcerative colitis. Platelet inhibition may be one of the mechanism for effectiveness of clopidogrel in the treatment of IBD.
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Affiliation(s)
- Samir H Patel
- Department of Pharmacology, S. J. Thakkar Pharmacy College, Kalawad Road, Rajkot, Gujarat, India
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Patel SH, Rachchh MA, Jadav PD. Evaluation of anti-inflammatory effect of anti-platelet agent-clopidogrel in experimentally induced inflammatory bowel disease. Indian J Pharmacol 2013; 44:744-8. [PMID: 23248405 PMCID: PMC3523503 DOI: 10.4103/0253-7613.103278] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 07/10/2012] [Accepted: 08/31/2012] [Indexed: 12/12/2022] Open
Abstract
Aim: To evaluate the anti-inflammatory effect of antiplatelet agent, clopidogrel, in experimentally induced inflammatory bowel disease (IBD). Materials and Methods: TNBS induced Crohn's disease model and oxazolone induced ulcerative colitis model were used to evaluate the role of clopidogrel in IBD. Spargue Dawley female and Wistar male rats were used respectively. The colitis was induced by a single intra-colonic application of TNBS (0.25 ml, 120 mg/ml in 50% ethanol) and oxazolone (450 μl 5% oxazolone in 50% ethanol). Rats were divided into four groups (n=6) in each model namely normal control, sham control, test and standard group. Drug treatment was carried out for 21 days. After 21 days, animals were sacrificed and evaluated for weight change, colon mucosal damage index (CMDI), disease activity Index (DAI) and myeloperoxidase (MPO) activity. Results: Results showed that clopidogrel provided significant protection against mucosal damage in both the models of IBD. It significantly reduced (P<0.05) the decrease in body weight and CMDI, DAI and MPO scores. Conclusion: The results indicate that clopidogrel may be effective in treatment of Crohn's disease and ulcerative colitis. Platelet inhibition may be one of the mechanism for effectiveness of clopidogrel in the treatment of IBD.
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Affiliation(s)
- Samir H Patel
- Department of Pharmacology, S. J. Thakkar Pharmacy College, Kalawad Road, Rajkot, Gujarat, India
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Research progress in the mechanism of effect of PRP in bone deficiency healing. ScientificWorldJournal 2013; 2013:134582. [PMID: 23710132 PMCID: PMC3654280 DOI: 10.1155/2013/134582] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 02/27/2013] [Indexed: 12/19/2022] Open
Abstract
Platelet-rich plasma (PRP) therapy is a recently developed technique that uses a concentrated portion of autologous blood to try to improve and accelerate the healing of various tissues. There is a considerable interest in using these PRP products for the treatment used in bone deficiency healing. Because PRP products are safe and easy to prepare and administer, there has been increased attention toward using PRP in numerous clinical settings. The benefits of PRP therapy appear to be promising, and many investigators are exploring the ways in which this therapy can be used in the clinical setting. At present, the molecular mechanisms of bone defect repair studies have focused on three aspects of the inflammatory cytokines, growth factors and angiogenic factors. The role of PRP works mainly through these three aspects of bone repair. The purpose of this paper is to review the current evidence on the mechanism of the effect of PRP in bone deficiency healing.
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Kondo R, Yano H, Nakashima O, Tanikawa K, Nomura Y, Kage M. Accumulation of platelets in the liver may be an important contributory factor to thrombocytopenia and liver fibrosis in chronic hepatitis C. J Gastroenterol 2013; 48:526-34. [PMID: 22911171 DOI: 10.1007/s00535-012-0656-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Accepted: 07/25/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Thrombocytopenia is a marked feature of chronic liver disease and cirrhosis. We tried to clarify whether an accumulation of platelets in the liver contributes to thrombocytopenia and liver fibrosis in chronic liver disease. METHODS Thirty-eight patients who underwent hepatectomy for hepatocellular carcinoma (HCC) with hepatitis C virus infection were included. The locations of platelets and Kupffer cells and the expression of platelet-derived growth factor (PDGF) receptor-β and smooth muscle actin (SMA) were identified by immunohistochemistry. Perisinusoidal mesenchymal cells that express PDGF receptor-β and SMA were interpreted as transformed hepatic stellate cells (HSCs). RESULTS Patients with cirrhosis had a more extensive platelet area in the liver compared to controls (5601 ± 5611 vs. 564 ± 361 μm(2), p = 0.02), although the blood platelet count significantly decreased along with the progression of liver fibrosis. In cirrhotic liver, most platelets were present in the sinusoidal space of the periportal area with inflammation, where HSCs expressing PDGF receptor-β were frequently observed. In addition, the platelet and Kupffer cell areas were significantly smaller in cancerous tissue than those in noncancerous tissues (platelet area: 492 ± 823 vs. 3643 ± 4055 μm(2), p = 0.001; Kupffer cell area: 450 ± 841 vs. 3012 ± 3051 μm(2), p = 0.001). CONCLUSIONS The accumulation of platelets in the liver with chronic hepatitis may be involved in thrombocytopenia and liver fibrosis through the activation of HSCs. In addition, our findings also indicate that both platelets and Kupffer cells decrease in HCC tissues.
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Affiliation(s)
- Reiichiro Kondo
- Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.
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Liu S, Ren J, Han G, Wang G, Gu G, Xia Q, Li J. Mean platelet volume: a controversial marker of disease activity in Crohn's disease. Eur J Med Res 2012; 17:27. [PMID: 23058104 PMCID: PMC3519557 DOI: 10.1186/2047-783x-17-27] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Accepted: 10/01/2012] [Indexed: 12/13/2022] Open
Abstract
Background We investigated and compared the capacity of mean platelet volume (MPV) and other inflammatory markers in detecting Crohn’s disease (CD) activity and differentiating CD patients from healthy controls. Methods MPV, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cells were measured in 61 CD patients and 50 healthy subjects. Disease activity was assessed by the Crohn’s Disease Activity Index. Results A significant decrease in MPV was noted in patients with CD compared with healthy controls (P <0.0001), but statistical difference was not found between active and inactive CD groups. In CD, no significant correlation was found between MPV and other inflammatory markers. The overall accuracy of MPV (cutoff: 10.35 fl), CRP (cutoff: 4.85 mg/dl) and ESR (cutoff: 8.5 mm/hour) in differentiating CD patients from healthy controls was 76.6%, 65.8% and 72.1% respectively. The overall accuracy of CRP (cutoff: 4.95 mg/dl) and ESR (cutoff: 16.5 mm/hour) in determination of active CD was 80.3% and 73.8%. Conclusions MPV declined in CD patients compared with healthy subjects. MPV had the best accuracy in determination of CD patients and healthy controls. MPV did not show a discriminative value in disease activity.
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Affiliation(s)
- Song Liu
- Department of Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing 210002, China
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Silva RF, Carmona JU, Rezende CMF. Comparison of the effect of calcium gluconate and batroxobin on the release of transforming growth factor beta 1 in canine platelet concentrates. BMC Vet Res 2012; 8:121. [PMID: 22830991 PMCID: PMC3489850 DOI: 10.1186/1746-6148-8-121] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 07/04/2012] [Indexed: 11/13/2022] Open
Abstract
Background The clinical use of autologous platelet concentrates (also known as platelet-rich plasma) on the field of regenerative therapy, in the last decade has been the subject of several studies especially in equine medicine and surgery. The objectives of this study was: 1) to describe and compare the cellular population in whole blood, lower fraction (A) and upper fraction (B) of platelet concentrates, 2) to measure and compare the transforming growth factor beta 1 (TGF-β1) concentration in plasma and both platelet concentrates after be activated with calcium gluconate or batroxobin plus calcium gluconate and, 3) to determine correlations between cell counts in platelet concentrates and concentrations of TGF-β1. Blood samples were taken from 16 dogs for complete blood count, plasma collection and platelet concentrates preparation. The platelet concentrates (PC) were arbitrarily divided into two fractions, specifically, PC-A (lower fraction) and PC-B (upper fraction). The Platelet concentrates were analyzed by hemogram. After activated with calcium gluconate or batroxobin plus calcium gluconate, TGF-β1 concentration was determined in supernatants of platelet concentrates and plasma. Results There were differences statistically significant (P < 0.05) for the platelet count and leukocyte count and TGF-β1 concentration between whole blood, plasma and both platelet concentrates. A significant correlation was found between the number of platelets in both platelet concentrates and TGF-β1 concentration. Platelet collection efficiency was 46.34% and 28.16% for PC-A and PC-B, respectively. TGF-β1 concentration efficiency for PC activated with calcium gluconate was 47.75% and 31.77%, for PC-A and PC-B, respectively. PC activated with batroxobin plus CG showed 46.87% and 32.24% for PC-A and PC-B, respectively. Conclusions The methodology used in this study allows the concentration of a number of platelets and TGF-β1 that might be acceptable for a biological effect for clinical or experimental use as a regenerative therapy in dogs.
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Affiliation(s)
- Raul F Silva
- Departamento de Clínica e Cirurgia Animal, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
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Criswell KA, Wojcinski Z, Pegg D, Albassam M, Duddy S, Olsen E, Bailie M, Foote S, Anderson T. Key components of the mode of action for hemangiosarcoma induction in pregabalin-treated mice: evidence of increased bicarbonate, dysregulated erythropoiesis, macrophage activation, and increased angiogenic growth factors in mice but not in rats. Toxicol Sci 2012; 128:22-41. [PMID: 22539625 DOI: 10.1093/toxsci/kfs147] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
In carcinogenicity studies, pregabalin increased hemangiosarcoma incidence in mice but not in rats. Investigative studies, ranging in length from 24 h to 12 months, were conducted in mice (1000 or 5000 mg/kg) and rats (900 mg/kg) to evaluate a potential mode-of-action scheme for tumor formation. Three areas were evaluated: (1) hematopoiesis (because endothelial and hematopoietic cells arise from the same precursor and hemangiosarcomas are primarily located in mouse hematopoietic tissues), (2) angiogenic growth factors (because increased angiogenic growth factors may stimulate vascular tumors), and (3) pulmonary/blood gas parameters (because hypoxia is a known driver for endothelial cell proliferation). In mice, pregabalin rapidly increased platelet and megakaryocyte counts, activated platelets and bone marrow erythrophages, decreased the myeloid-to-erythroid (M:E) ratio (49%), and produced bone marrow and splenic congestion and extramedullary hematopoiesis (EMH). Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor immunohistochemical staining were also increased in mouse bone marrow and spleen and vascular endothelial growth factor receptor 2 immunolabeling was increased in liver. Serum bicarbonate was increased within 24 h of pregabalin administration, persisted over time, and was accompanied by decreased respiratory rate (up to 34%) and increased partial pressure of carbon dioxide (pCO(2)), resulting in sustained metabolic alkalosis and elevated blood pH in mice. In contrast, in rats, pregabalin decreased overall bone marrow cellularity, including decreased number of megakaryocytes (24%) with no evidence of erythrophages, no change in M:E ratio, no EMH, and no increase in angiogenic growth factors or blood pH. Persistent alterations in serum bicarbonate, respiratory function, and blood gas parameters in mice, without adequate compensatory mechanisms, has the potential to create chronic tissue hypoxia, an accepted driver of endothelial cell proliferation.
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Affiliation(s)
- Kay A Criswell
- Pfizer Worldwide Research and Development, Drug Safety Research and Development, Groton, Connecticut 06340, USA.
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Shemirani AH, Nagy B, Takáts AT, Zsóri KS, András C, Kappelmayer J, Csiki Z. Increased mean platelet volume in primary Raynaud's phenomenon. Platelets 2011; 23:312-6. [PMID: 21942753 DOI: 10.3109/09537104.2011.618563] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
We hypothesized that mean platelet volume (MPV), a reliable marker of platelet activation, might be elevated in primary Raynaud's phenomenon (PRP) even if there was no thrombotic complication in our subjects. In this retrospective-cohort study, we examined the clinical value of MPV in 200 patients with PRP and 116 clinical controls, and measured MPV and platelet P-selectin (CD62P) in all study participants. We also evaluated the effect of age, gender, and disease duration on these platelet activation markers in PRP. MPV and CD62 positivities were significantly (p<0.001) elevated in patients with PRP compared with controls. These differences retained when patients and controls were analyzed according to age, gender, and the disease duration. In logistic regression analysis, MPV (OR: 15.8, 95% CI: 8.14-30.64, p<0.001) and CD62P (OR: 11.3, 95% CI: 4.85-26.12, p<0.001) were found to be independently associated with PRP. In conclusion, increased MPV is independently related to PRP, and its level was not influenced by age, gender, and the duration of PRP.
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Affiliation(s)
- Amir-Houshang Shemirani
- Clinical Research Center, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
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Histamine blood concentration in ischemic heart disease patients. J Biomed Biotechnol 2011; 2011:315709. [PMID: 21687546 PMCID: PMC3114553 DOI: 10.1155/2011/315709] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2010] [Revised: 03/18/2011] [Accepted: 04/14/2011] [Indexed: 11/18/2022] Open
Abstract
The aim of this study was to investigate histamine blood concentration in subjects suffering from different types of ischemic heart diseases during the period of eight days. Our results showed that the histamine blood level was associated with different types of ischemic heart diseases. The blood histamine level in all investigated patients was significantly higher when compared to control subjects (44.87 ± 1.09 ng mL−1), indicating the increase of histamine release in patients suffering from coronary diseases. In patients suffering from ACS-UA and ACS-STEMI, the second day peak of histamine level occurs (90.85 ± 6.34 ng mL−1 and 121.7 ± 6.34 ng mL−1, resp.) probably as the reperfusion event. Furthermore, our data suggest that histamine can be additional parameter of myocardial ischemia along with cardiac specific enzymes and may prove to be an excellent single prognostic marker for multitude of ischemic heart diseases.
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Abstract
Inflammatory mediators, adhesion molecules of neutrophils and monocytes, have been shown to be increased in the plasma of patients presenting with acute coronary syndromes. Anaphylaxis is a systemic, immediate hypersensitivity reaction caused by rapid IgE-mediated release of mediators from mast cells and basophils. Kounis syndrome is the coincidental occurrence of these two distinct conditions accompanied by clinical and laboratory findings of angina pectoris caused by inflammatory mediators released during an allergic insult. Allergic angina can progress to acute myocardial infarction, which is termed 'allergic myocardial infarction'. There are several causes reported to be capable of inducing Kounis syndrome. These include a number of conditions, several drugs, foods and insect stings, among others. In this article, the clinical aspects, diagnosis, pathogenesis, incidence and epidemiology, related conditions and therapeutic management of this important syndrome are discussed.
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Affiliation(s)
- Murat Biteker
- Department of Cardiology, Haydarpaşa Numune Education and Research Hospital, Istanbul, Turkey.
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Cromer WE, Mathis JM, Granger DN, Chaitanya GV, Alexander JS. Role of the endothelium in inflammatory bowel diseases. World J Gastroenterol 2011; 17:578-93. [PMID: 21350707 PMCID: PMC3040330 DOI: 10.3748/wjg.v17.i5.578] [Citation(s) in RCA: 136] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Revised: 06/29/2010] [Accepted: 07/06/2010] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease. At the core of these alterations are endothelial cells, whose continual adjustments in structure and function coordinate vascular supply, immune cell emigration, and regulation of the tissue environment. Expansion of the endothelium in IBD (angiogenesis), mediated by inflammatory growth factors, cytokines and chemokines, is a hallmark of active gut disease and is closely related to disease severity. The endothelium in newly formed or inflamed vessels differs from that in normal vessels in the production of and response to inflammatory cytokines, growth factors, and adhesion molecules, altering coagulant capacity, barrier function and blood cell recruitment in injury. This review examines the roles of the endothelium in the initiation and propagation of IBD pathology and distinctive features of the intestinal endothelium contributing to these conditions.
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Salih J, Hilpert J, Placke T, Grünebach F, Steinle A, Salih HR, Krusch M. The BCR/ABL-inhibitors imatinib, nilotinib and dasatinib differentially affect NK cell reactivity. Int J Cancer 2010; 127:2119-28. [PMID: 20143399 DOI: 10.1002/ijc.25233] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
In chronic myeloid leukemia (CML), BCR/ABL-mediated oncogenic signaling can be targeted with the BCR/ABL-inhibitors Imatinib, Nilotinib and Dasatinib. However, these agents may also affect anti-tumor immunity. Here, we analyzed the effects of the 3 BCR/ABL-inhibitors on natural killer (NK) cell reactivity. Exposure of CML cells (K562, Meg-01) to pharmacological concentrations of Imatinib, Nilotinib and Dasatinib diminished expression of ligands for the activating immunoreceptor NKG2D to a similar extent. This resulted in comparably reduced NK cell cytotoxicity and IFN-gamma production. When direct effects on NK cell responses to K562 and primary CML cells as well as activating cytokines were studied, Dasatinib was found to abrogate NK cytotoxicity and cytokine production. Nilotinib did not alter cytotoxicity but, at high levels, impaired NK cytokine production, while Imatinib had no direct influence on NK cell reactivity. Of note, Nilotinib, but not the other BCR/ABL-inhibitors increased cell death within the preferentially cytokine-secreting CD56(bright)CD16(-) NK cell subset, which may, at least in part, serve to explain the effect of Nilotinib on NK cytokine production. Analysis of NK cell signaling revealed that Dasatinib inhibited proximal signaling events leading to decreased phosphorylation of PI3K and ERK that are crucial for NK cell reactivity. Imatinib and Nilotinib, in contrast, showed no relevant effect on NK cell PI3K or ERK activity. In light of the potential role of NK cells in the immunesurveillance of residual leukemia and for future combinatory immunotherapeutic approaches, our data indicate that choice and dosing of the most suitable BCR/ABL-inhibitor for a given patient require careful consideration.
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Affiliation(s)
- Julia Salih
- Department of Hematology/Oncology, Eberhard-Karls-University, Tuebingen, Germany
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Talaat RM. Soluble angiogenesis factors in sera of Egyptian patients with hepatitis C virus infection: correlation with disease severity. Viral Immunol 2010; 23:151-157. [PMID: 20373995 DOI: 10.1089/vim.2009.0089] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C virus (HCV) infection causes chronic hepatitis, which gradually progresses to liver cirrhosis and subsequently to hepatocellular carcinoma (HCC). Angiogenesis plays a major role in chronic inflammation and may have prognostic value in disease progression. This study was designed to evaluate vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and tumor necrosis factor-alpha (TNF-alpha) as prognostic factors of disease progression in Egyptian patients with different stages of HCV-related cirrhosis and HCC. VEGF, PDGF, and TNF-alpha were measured using enzyme-linked immunosorbent assay (ELISA) in 82 HCV-infected patients (20 mild, 20 moderate, and 20 severe cirrhosis patients, and 22 HCC patients), and 20 healthy controls. Our results showed comparable increases in VEGF and PDGF levels in those with increasing clinical stages of disease, with maximal production seen in HCC patients. A gradual elevation of TNF-alpha levels was seen also in HCV-infected patients at different stages of disease and HCC. A statistically significantly positive correlation between serum levels of VEGF, PDGF, and TNF-alpha, and grade of disease was recorded. Thus assessment of these parameters in those with different stages of disease may be helpful in choosing the best treatment strategy, and indicate that anti-angiogenic therapy may be useful.
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Affiliation(s)
- Roba M Talaat
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), Menofia University, Sadat City, Egypt.
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Lee EH, Kim JY, Kweon HY, Jo YY, Min SK, Park YW, Choi JY, Kim SG. A combination graft of low-molecular-weight silk fibroin with Choukroun platelet-rich fibrin for rabbit calvarial defect. ACTA ACUST UNITED AC 2010; 109:e33-8. [PMID: 20149696 DOI: 10.1016/j.tripleo.2009.12.043] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2009] [Revised: 12/09/2009] [Accepted: 12/28/2009] [Indexed: 10/19/2022]
Abstract
OBJECTIVE The objective of this study was to determine the capabilities of silk fibroin as a biomaterial template for bone formation when mixed with Choukroun platelet-rich fibrin (PRF) in vivo. STUDY DESIGN Ten New Zealand white rabbits were used for this study and bilateral round shaped defects were formed in the parietal bone (diameter 9.0 mm). The silk fibroin was digested by acid and made into powder (molecular weight <1.0 kDa). The right side (experimental group) received the silk fibroin plus platelet-rich fibroin and the left side (control group) did not receive a graft. Animals were killed at 6 weeks and 12 weeks. The specimens were examined by microscopic computerized tomography (micro-CT). Subsequently, they underwent decalcification and were stained for histologic analysis. RESULTS There was no significant difference between groups at 6 weeks after operation. In the micro-CT results, however, tissue mineral content in the experimental group at 12 weeks after operation was 132.09 +/- 4.41 and that in the control group was 126.42 +/- 6.62 (P = .011). Tissue mineral density in the experimental group was 2,088.88 +/- 648.34, and that in the control group was 2,029.72 +/- 668.22 (P = .013). The results of the histomorphometric analysis were in accordance with the micro-CT results. The total new bone was 49.86 +/- 7.49% in the control group at 12 weeks after the operation and 59.83 +/- 10.92% in the experimental group (P = .021). CONCLUSION A combined application of Choukroun PRF with acid-digested silk fibroin showed more rapid bone healing than unfilled control.
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Affiliation(s)
- Eui-Hee Lee
- Department of Oral and Maxillofacial Surgery, Sacred Heart Hospital, Hallym University, Gangneung, Korea
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Yazici S, Yazici M, Erer B, Erer B, Calik Y, Ozhan H, Ataoglu S. The platelet indices in patients with rheumatoid arthritis: Mean platelet volume reflects disease activity. Platelets 2010; 21:122-5. [DOI: 10.3109/09537100903474373] [Citation(s) in RCA: 167] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Graham S, Leonidou A, Lester M, Heliotis M, Mantalaris A, Tsiridis E. Investigating the role of PDGF as a potential drug therapy in bone formation and fracture healing. Expert Opin Investig Drugs 2009; 18:1633-54. [DOI: 10.1517/13543780903241607] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Jancinová V, Nosál R. Increased histamine content in Ca2+-ionophore A23187-activated human blood platelets. Platelets 2009; 9:203-6. [PMID: 16793702 DOI: 10.1080/09537109876690] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
Stimulation of human blood platelets with Ca2+-ionophore A23187 at the concentrations of 0.5, 1, 2 and 3 micromol/ litre increased the total platelet histamine content from 25 ng (resting platelets) to 35, 40, 42 and 47 ng/10(8) platelets, respectively. The maximum rise was 90% , while in the presence of thrombin (0.01-1 NIH U/ml) or phorbol 12-myristate 13-acetate (PMA) (10-100 nmol/l) histamine content rose maximally by 40%. Ionophore induced a histamine increase in the same concentration range as that needed to induce platelet aggregation and liberation of [3H]-arachidonic acid. Decrease of temperature from 37 to 0 degrees C or inhibitors of platelet functions, such as acetylsalicylic acid (1 mmol/litre) or [H1]-histamine receptor antagonist Dithiaden (0.1 mmol/litre), 1 inhibited histamine liberation from A23187- stimulated platelets, but did not affect the total rise in histamine content. The presented results indicate that, similarly as with other stimuli, Ca2+-ionophore A23187 activation of human blood platelets is accompanied by histamine synthesis.
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Affiliation(s)
- V Jancinová
- Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
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