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1
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Hu DN, Zhang R, Iacob CE, Yao A, Yang SF, Chan CC, Rosen RB. Constitutive and hypoxia-induced VEGF production by cultured uveal melanocytes and retinal pigment epithelial cells. Exp Eye Res 2025; 254:110318. [PMID: 40032151 DOI: 10.1016/j.exer.2025.110318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 02/18/2025] [Accepted: 02/27/2025] [Indexed: 03/05/2025]
Abstract
Constitutive secretion of VEGF is crucial for maintaining ocular circulation while hypoxia-induced VEGF secretion plays an important role in pathological neovascularization. Previous studies have highlighted the critical function of RPE cells in these situations. The role of uveal melanocytes (UM) in VEGF production, however, has not been well described. The aim of this study was to compare VEGF production from human RPE and UM cell lines obtained in pairs from 3 donors to minimize individual variability in cellular function. Cells were subjected to hypoxia, (1% oxygen environment) or chemical hypoxia (cobalt chloride, CoCl2) at different times or dosages, respectively. The effects of these treatments on the cell viability and cell proliferation were tested using MTT and cell counting with trypan blue testing. The production of VEGF and its main upstream factor (hypoxia-inducible factors-1α, HIF-1α) were measured in the conditioned culture medium and cellular extracts, by using ELISA analysis. Additionally, mRNA levels of VEGF and HIF-1α were quantified through real-time PCR analysis. The effects of CoCl2 on the expression of VEGF and HIF-1α in UM and RPE cells were also examined using flow cytometry. Hypoxia and COCL2 exposure did not affect cell viability and cell proliferation. This study revealed that the constitutive production of VEGF by RPE cells is significantly greater than from the UM. However, UM demonstrated a more robust response to high hypoxia or chemical hypoxic stimulation compared to RPE cells. The data suggests that while RPE cells play a critical role in constitutive VEGF production under normal conditions, UM may contribute significantly to the pathological increase in VEGF under severe ocular hypoxia. The observation that intraocular injection of CoCl2 to produce local chemical hypoxia, results in a significant increase of VEGF levels in intraocular fluids and tissues, has not been reported previously. While this model cannot currently test the in vitro results, it may help further our understanding of UM and RPE cells' roles in VEGF production in future studies using more advanced technologies in a well-established in vivo model.
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Affiliation(s)
- Dan-Ning Hu
- New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ruihua Zhang
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Codrin E Iacob
- New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andy Yao
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chi-Chao Chan
- National Eye Institute, National Institutes of Health, Bethesda, MD, USA
| | - Richard B Rosen
- New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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2
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Xu Q, Chen X, Sun S, Zhao C, Shi L, Cheng H, Liu Y, Shi C, Ao X. Vascular Endothelial Growth Factor-Mimetic Peptide and Mitochondria-Targeted Antioxidant-Loaded Hydrogel System Improves Repair of Myocardial Infarction in Mice. J Biomed Mater Res A 2025; 113:e37924. [PMID: 40341794 DOI: 10.1002/jbm.a.37924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 04/10/2025] [Accepted: 04/23/2025] [Indexed: 05/11/2025]
Abstract
Myocardial infarction (MI) is a pathological state characterized by persistent ischemia of the heart. Following MI, the structural and functional remodeling of the myocardium and vasculature involves oxidative stress and mitochondrial dysfunction, which exacerbate myocardial injury. Currently, there are limited effective treatments available to alleviate MI-induced damage. Vascular endothelial growth factor-mimetic (QK) peptides and mitochondria-targeted Szeto-Schiller (SS31) peptides have been extensively investigated for their therapeutic potential in various ischemic cardiomyopathies. However, traditional topical agents used in myocardial ischemia treatment suffer from limitations such as transient retention or undesirable diffusion of the drug. Consequently, a controlled drug delivery system capable of delivering QK and SS31 has gained significant attention for repair. In this study, we constructed self-assembled nanofibrous hydrogels incorporating QK and SS31 with customizable peptide amphiphilic (PA) molecules, resulting in PA1-QK and PA2-SS31 formulations. In vitro experiments demonstrated that both QK and SS31 effectively inhibited mitochondrial damage and apoptosis in a cellular hypoxia/reoxygenation (H/R) model. In vivo studies using a mouse MI model revealed that PA1-QK and PA2-SS31 significantly promoted vascular regeneration, attenuated mitochondrial dysfunction and apoptosis, and facilitated the recovery of cardiac structure and function. These results suggest that PA1-QK and PA2-SS31-loaded self-assembled nanofiber hydrogels represent an effective drug delivery system for promoting regenerative repair of myocardium and blood vessels following MI.
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Affiliation(s)
- Qingling Xu
- School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Xinhui Chen
- School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Shuwei Sun
- School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Chunyige Zhao
- School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Linxin Shi
- School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Han Cheng
- School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Chunying Shi
- School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Xiang Ao
- School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
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Nadora D, Ezzati S, Bol B, Aboud O. Serendipity in Neuro-Oncology: The Evolution of Chemotherapeutic Agents. Int J Mol Sci 2025; 26:2955. [PMID: 40243541 PMCID: PMC11988343 DOI: 10.3390/ijms26072955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 03/01/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
The development of novel therapeutics in neuro-oncology faces significant challenges, often marked by high costs and low success rates. Despite advances in molecular biology and genomics, targeted therapies have had limited impact on improving patient outcomes in brain tumors, particularly gliomas, due to the complex, multigenic nature of these malignancies. While significant efforts have been made to design drugs that target specific signaling pathways and genetic mutations, the clinical success of these rational approaches remains sparse. This review critically examines the landscape of neuro-oncology drug discovery, highlighting instances where serendipity has led to significant breakthroughs, such as the unexpected efficacy of repurposed drugs and off-target effects that proved beneficial. By exploring historical and contemporary cases, we underscore the role of chance in the discovery of impactful therapies, arguing that embracing serendipity alongside rational drug design may enhance future success in neuro-oncology drug development.
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Affiliation(s)
- Denise Nadora
- College of Medicine, California Northstate University, Elk Grove, CA 95757, USA; (S.E.); (B.B.)
| | - Shawyon Ezzati
- College of Medicine, California Northstate University, Elk Grove, CA 95757, USA; (S.E.); (B.B.)
| | - Brandon Bol
- College of Medicine, California Northstate University, Elk Grove, CA 95757, USA; (S.E.); (B.B.)
| | - Orwa Aboud
- Department of Neurology, Comprehensive Cancer Center, University of California, Davis, CA 95616, USA;
- Department of Neurological Surgery, Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
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4
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Zhang S, Wang X, Gao X, Chen X, Li L, Li G, Liu C, Miao Y, Wang R, Hu K. Radiopharmaceuticals and their applications in medicine. Signal Transduct Target Ther 2025; 10:1. [PMID: 39747850 PMCID: PMC11697352 DOI: 10.1038/s41392-024-02041-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/30/2024] [Accepted: 10/28/2024] [Indexed: 01/04/2025] Open
Abstract
Radiopharmaceuticals involve the local delivery of radionuclides to targeted lesions for the diagnosis and treatment of multiple diseases. Radiopharmaceutical therapy, which directly causes systematic and irreparable damage to targeted cells, has attracted increasing attention in the treatment of refractory diseases that are not sensitive to current therapies. As the Food and Drug Administration (FDA) approvals of [177Lu]Lu-DOTA-TATE, [177Lu]Lu-PSMA-617 and their complementary diagnostic agents, namely, [68Ga]Ga-DOTA-TATE and [68Ga]Ga-PSMA-11, targeted radiopharmaceutical-based theranostics (radiotheranostics) are being increasingly implemented in clinical practice in oncology, which lead to a new era of radiopharmaceuticals. The new generation of radiopharmaceuticals utilizes a targeting vector to achieve the accurate delivery of radionuclides to lesions and avoid off-target deposition, making it possible to improve the efficiency and biosafety of tumour diagnosis and therapy. Numerous studies have focused on developing novel radiopharmaceuticals targeting a broader range of disease targets, demonstrating remarkable in vivo performance. These include high tumor uptake, prolonged retention time, and favorable pharmacokinetic properties that align with clinical standards. While radiotheranostics have been widely applied in tumor diagnosis and therapy, their applications are now expanding to neurodegenerative diseases, cardiovascular diseases, and inflammation. Furthermore, radiotheranostic-empowered precision medicine is revolutionizing the cancer treatment paradigm. Diagnostic radiopharmaceuticals play a pivotal role in patient stratification and treatment planning, leading to improved therapeutic outcomes in targeted radionuclide therapy. This review offers a comprehensive overview of the evolution of radiopharmaceuticals, including both FDA-approved and clinically investigated agents, and explores the mechanisms of cell death induced by radiopharmaceuticals. It emphasizes the significance and future prospects of theranostic-based radiopharmaceuticals in advancing precision medicine.
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Grants
- 82372002 National Natural Science Foundation of China (National Science Foundation of China)
- 0104002 Beijing Nova Program
- L248087; L234044 Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)
- Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences (No. 2022-RC350-04), the CAMS Innovation Fund for Medical Sciences (Nos. 2021-I2M-1-026, 2022-I2M-2-002-2, and 2021-I2M-3-001), the National Key Research and Development Program of China (No. 2022YFE0111700),the Fundamental Research Funds for the Central Universities (Nos. 3332023044 and 3332023151), the CIRP Open Fund of Radiation Protection Laboratories (No. ZHYLYB2021005), and the China National Nuclear Corporation Young Talent Program.
- Fundamental Research Funds for the Central Universities,Nos. 3332023044
- Fundamental Research Funds for the Central Universities,Nos. 3332023151
- he Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences,No. 2022-RC350-04;the CAMS Innovation Fund for Medical Sciences,Nos. 2021-I2M-1-026, 2022-I2M-2-002-2, and 2021-I2M-3-001;the National Key Research and Development Program of China,No. 2022YFE0111700
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Affiliation(s)
- Siqi Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Xingkai Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Xin Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Xueyao Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Linger Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Guoqing Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Can Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Yuan Miao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Rui Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China.
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, Lanzhou University, 2019RU066, 730000, Lanzhou, China.
| | - Kuan Hu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China.
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Wang ZY, Mehra A, Wang QC, Gupta S, Ribeiro da Silva A, Juan T, Günther S, Looso M, Detleffsen J, Stainier DYR, Marín-Juez R. flt1 inactivation promotes zebrafish cardiac regeneration by enhancing endothelial activity and limiting the fibrotic response. Development 2024; 151:dev203028. [PMID: 39612288 PMCID: PMC11634031 DOI: 10.1242/dev.203028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 10/22/2024] [Indexed: 12/01/2024]
Abstract
VEGFA administration has been explored as a pro-angiogenic therapy for cardiovascular diseases including heart failure for several years, but with little success. Here, we investigate a different approach to augment VEGFA bioavailability: by deleting the VEGFA decoy receptor VEGFR1 (also known as FLT1), one can achieve more physiological VEGFA concentrations. We find that after cryoinjury, zebrafish flt1 mutant hearts display enhanced coronary revascularization and endocardial expansion, increased cardiomyocyte dedifferentiation and proliferation, and decreased scarring. Suppressing Vegfa signaling in flt1 mutants abrogates these beneficial effects of flt1 deletion. Transcriptomic analyses of cryoinjured flt1 mutant hearts reveal enhanced endothelial MAPK/ERK signaling and downregulation of the transcription factor gene egr3. Using newly generated genetic tools, we observe egr3 upregulation in the regenerating endocardium, and find that Egr3 promotes myofibroblast differentiation. These data indicate that with enhanced Vegfa bioavailability, the endocardium limits myofibroblast differentiation via egr3 downregulation, thereby providing a more permissive microenvironment for cardiomyocyte replenishment after injury.
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Affiliation(s)
- Zhen-Yu Wang
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany
| | - Armaan Mehra
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany
| | - Qian-Chen Wang
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany
| | - Savita Gupta
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany
| | - Agatha Ribeiro da Silva
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany
| | - Thomas Juan
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany
| | - Stefan Günther
- German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany
- Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
| | - Mario Looso
- German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany
- Bioinformatics Core Unit (BCU), Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
| | - Jan Detleffsen
- German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany
- Bioinformatics Core Unit (BCU), Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
| | - Didier Y. R. Stainier
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany
| | - Rubén Marín-Juez
- Centre Hospitalier Universitaire Sainte-Justine Research Center, 3175 Chemin de la Côte-Sainte-Catherine, H3T 1C5 Montréal, QC, Canada
- Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, H3T 1J4 Montréal, QC, Canada
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Mallawarachchi S, Cebecioglu RE, Althumayri M, Beker L, Fernando S, Ceylan Koydemir H. Systematic design and evaluation of aptamers for VEGF and PlGF biomarkers of Preeclampsia. BMC Biotechnol 2024; 24:64. [PMID: 39334133 PMCID: PMC11428563 DOI: 10.1186/s12896-024-00891-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
Preeclampsia is a potentially life-threatening condition for both mother and baby, characterized by hypertension and potential organ damage. Early diagnosis is crucial to mitigate its adverse health effects. Traditional diagnostic methods, which focus on late-manifesting symptoms like hypertension and proteinuria, underscore the need for molecular diagnostic approaches for timely detection. This study successfully designs and evaluates novel aptamers with high specificity and affinity for Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF), biomarkers closely associated with preeclampsia. Using molecular docking, molecular dynamics simulations, and BioLayer Interferometry (BLI), we identified aptamers that demonstrated strong binding affinities, comparable or superior to traditional antibodies. Our findings suggest that these aptamers have the potential to be integrated into cost-effective, point-of-care diagnostic tools, significantly improving early detection and intervention strategies for preeclampsia. The robust performance of these aptamers marks a pivotal step toward the development of more reliable and accessible diagnostic solutions, with implications for better maternal and fetal health outcomes.
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Affiliation(s)
- Samavath Mallawarachchi
- Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Rümeysa E Cebecioglu
- Department of Biomedical Sciences and Engineering, Koç University, Istanbul, 34450, Turkey
- Medical Laboratory Techniques, Health Services of Vocational School, Kent University, Istanbul, 34333, Turkey
| | - Majed Althumayri
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
- Center for Remote Health Technologies and Systems, Texas A&M Engineering Experiment Station, College Station, TX, 77843, USA
| | - Levent Beker
- Department of Mechanical Engineering, Koç University, Istanbul, 34450, Turkey
| | - Sandun Fernando
- Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Hatice Ceylan Koydemir
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA.
- Center for Remote Health Technologies and Systems, Texas A&M Engineering Experiment Station, College Station, TX, 77843, USA.
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7
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Mu Y, Zhang X, Zhang L, Luo R, Zhang Y, Wang M. MSC Exosomes Containing Valproic Acid Promote Wound Healing by Modulating Inflammation and Angiogenesis. Molecules 2024; 29:4281. [PMID: 39275128 PMCID: PMC11397650 DOI: 10.3390/molecules29174281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 08/31/2024] [Accepted: 09/05/2024] [Indexed: 09/16/2024] Open
Abstract
PURPOSE Chronic wounds that are difficult to heal pose a major challenge for clinicians and researchers. Currently, common treatment methods focus on isolating the wound from the outside world, relying on the tissue at the wound site to grow and heal unaided. Umbilical cord mesenchymal stem cell (MSC) exosomes can promote wound healing by enhancing new blood vessel growth at the wound site. Valproic acid (VPA) reduces the inflammatory response and acts on macrophages to accelerate wound closure. In this study, VPA was loaded into umbilical cord MSC exosomes to form a drug carrier exosome (VPA-EXO) with the aim of investigating the effect of VPA-EXO on wound healing. METHODS This study first isolated and obtained umbilical cord MSC exosomes, then added VPA to the exosomes and explored the ability of VPA-EXO to promote the proliferation and migration of human skin fibroblasts (HSFs) and human umbilical vein endothelial cells (HUVECs), as well as the ability to promote the angiogenesis of HUVECs, by using scratch, Transwell, and angiogenesis assays. An in vitro cell model was established and treated with VPA-EXO, and the expression levels of inflammation and pro-angiogenesis-related proteins and genes were examined using Western blot and qRT-PCR. The therapeutic effect of VPA-EXO on promoting wound healing in a whole skin wound model was investigated using image analysis of the wound site, H&E staining, and immunohistochemical staining experiments in a mouse wound model. RESULTS The in vitro model showed that VPA-EXO effectively promoted the proliferation and migration of human skin fibroblast cells and human umbilical vein endothelial cells; significantly inhibited the expression of MMP-9, IL-1β, IL-8, TNF-α, and PG-E2; and promoted the expression of vascular endothelial growth factors. In the mouse wound model, VPA-EXO reduced inflammation at the wound site, accelerated wound healing, and significantly increased the collagen content of tissue at the wound site. CONCLUSIONS As a complex with dual efficacy in simultaneously promoting tissue regeneration and inhibiting inflammation, VPA-EXO has potential applications in tissue wound healing and vascular regeneration. In future studies, we will further investigate the mechanism of action and application scenarios of drug-loaded exosome complexes in different types of wound healing and vascular regeneration.
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Affiliation(s)
- Yujie Mu
- School of Light Industry Science and Engineering, Beijing Technology and Business University, Beijing 100048, China
| | - Xiaona Zhang
- School of Light Industry Science and Engineering, Beijing Technology and Business University, Beijing 100048, China
| | - Linfeng Zhang
- School of Light Industry Science and Engineering, Beijing Technology and Business University, Beijing 100048, China
| | - Ruting Luo
- School of Light Industry Science and Engineering, Beijing Technology and Business University, Beijing 100048, China
| | - Yin Zhang
- School of Light Industry Science and Engineering, Beijing Technology and Business University, Beijing 100048, China
| | - Min Wang
- School of Light Industry Science and Engineering, Beijing Technology and Business University, Beijing 100048, China
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8
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Perez-Gutierrez L, Li P, Ferrara N. Endothelial cell diversity: the many facets of the crystal. FEBS J 2024; 291:3287-3302. [PMID: 36266750 DOI: 10.1111/febs.16660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 10/03/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022]
Abstract
Endothelial cells (ECs) form the inner lining of blood vessels and play crucial roles in angiogenesis. While it has been known for a long time that there are considerable differences among ECs from lymphatic and blood vessels, as well as among arteries, veins and capillaries, the full repertoire of endothelial diversity is only beginning to be elucidated. It has become apparent that the role of ECs is not just limited to their exchange functions. Indeed, a multitude of organ-specific functions, including release of growth factors, regulation of immune functions, have been linked to ECs. Recent years have seen a surge into the identification of spatiotemporal molecular and functional heterogeneity of ECs, supported by technologies such as single-cell RNA sequencing (scRNA-seq), lineage tracing and intersectional genetics. Together, these techniques have spurred the generation of epigenomic, transcriptomic and proteomic signatures of ECs. It is now clear that ECs across organs and in different vascular beds, but even within the same vessel, have unique molecular identities and employ specialized molecular mechanisms to fulfil highly specialized needs. Here, we focus on the molecular heterogeneity of the endothelium in different organs and pathological conditions.
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Affiliation(s)
- Lorena Perez-Gutierrez
- Department of Pathology, Moores Cancer Center, University of California, San Diego, CA, USA
| | - Pin Li
- Department of Pathology, Moores Cancer Center, University of California, San Diego, CA, USA
| | - Napoleone Ferrara
- Department of Pathology, Moores Cancer Center, University of California, San Diego, CA, USA
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9
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Huyan T, Fan L, Zheng ZY, Zhao JH, Han ZR, Wu P, Ma Q, Du YQ, Shi YD, Gu CY, Li XJ, Wang WH, Zhang L, Tie L. ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway. Acta Pharmacol Sin 2024; 45:1477-1491. [PMID: 38538716 PMCID: PMC11192920 DOI: 10.1038/s41401-024-01246-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 02/19/2024] [Indexed: 06/23/2024]
Abstract
Refractory wounds are a severe complication of diabetes mellitus that often leads to amputation because of the lack of effective treatments and therapeutic targets. The pathogenesis of refractory wounds is complex, involving many types of cells. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes, including cell migration, communication, and proliferation. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Our results showed that ROCK1 expression significantly increased in wound granulation tissues in diabetic patients, streptozotocin (STZ)-induced diabetic mice, and db/db diabetic mice. Wound healing and blood perfusion were dose-dependently improved by the ROCK1 inhibitor fasudil in diabetic mice. In endothelial cells, fasudil and ROCK1 siRNA significantly elevated the phosphorylation of adenosine monophosphate-activated protein kinase at Thr172 (pThr172-AMPKα), the activity of endothelial nitric oxide synthase (eNOS), and suppressed the levels of mitochondrial reactive oxygen species (mtROS) and nitrotyrosine formation. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that ROCK1 inhibited pThr172-AMPKα by binding to receptor-interacting serine/threonine kinase 4 (RIPK4). These results suggest that fasudil accelerated wound repair and improved angiogenesis at least partially through the ROCK1/RIPK4/AMPK pathway. Fasudil may be a potential treatment for refractory wounds in diabetic patients.
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Affiliation(s)
- Tianru Huyan
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China
- Department of Wound Healing Center and Interventional Radiology and Vascular Surgery, Peking University Third Hospital, Beijing, 100191, China
| | - Lu Fan
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhong-Yuan Zheng
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China
| | - Jing-Hui Zhao
- Department of Wound Healing Center and Interventional Radiology and Vascular Surgery, Peking University Third Hospital, Beijing, 100191, China
| | - Zhen-Ru Han
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Pin Wu
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China
| | - Qun Ma
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China
| | - Ya-Qin Du
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China
| | - Yun-di Shi
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China
| | - Chun-Yan Gu
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xue-Jun Li
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China
| | - Wen-Hui Wang
- Department of Dermatology, Peking University Third Hospital, Beijing, 100191, China
| | - Long Zhang
- Department of Wound Healing Center and Interventional Radiology and Vascular Surgery, Peking University Third Hospital, Beijing, 100191, China.
| | - Lu Tie
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China.
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10
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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11
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Bartkowiak K, Bartkowiak M, Jankowska-Steifer E, Ratajska A, Kujawa M, Aniołek O, Niderla-Bielińska J. Metabolic Syndrome and Cardiac Vessel Remodeling Associated with Vessel Rarefaction: A Possible Underlying Mechanism May Result from a Poor Angiogenic Response to Altered VEGF Signaling Pathways. J Vasc Res 2024; 61:151-159. [PMID: 38615659 DOI: 10.1159/000538361] [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: 11/15/2023] [Accepted: 03/09/2024] [Indexed: 04/16/2024] Open
Abstract
BACKGROUND Elevated mortality rates in patients with metabolic syndrome (MetS) are partly due to adverse remodeling of multiple organs, which may lead to cardiovascular disease, nonalcoholic fatty liver disease, kidney failure, or other conditions. MetS symptoms, such as obesity, hypertension, hyperglycemia, dyslipidemia, associated with insulin and leptin resistance, are recognized as major cardiovascular risk factors that adversely affect the heart. SUMMARY Pathological cardiac remodeling is accompanied by endothelial cell dysfunction which may result in diminished coronary flow, dysregulated oxygen demand/supply balance, as well as vessel rarefaction. The reduced number of vessels and delayed or inhibited formation of collaterals after myocardial infarction in MetS heart may be due to unfavorable changes in endothelial cell metabolism but also to altered expression of vascular endothelial growth factor molecules, their receptors, and changes in signal transduction from the cell membrane, which severely affect angiogenesis. KEY MESSAGES Given the established role of cardiac vessel endothelial cells in maintaining tissue homeostasis, defining the molecular background underlying vessel dysfunction associated with impaired angiogenesis is of great importance for future therapeutic purposes. Therefore, the aim of this paper was to present current information regarding vascular endothelial growth factor signaling in the myocardium of MetS individuals.
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Affiliation(s)
- Krzysztof Bartkowiak
- Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland
| | - Mateusz Bartkowiak
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Ewa Jankowska-Steifer
- Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland
| | - Anna Ratajska
- Department of Pathology, Medical University of Warsaw, Warsaw, Poland
| | - Marek Kujawa
- Department of Histology and Embryology, Faculty of Medicine, Lazarski University, Warsaw, Poland
| | - Olga Aniołek
- Department of Histology and Embryology, Faculty of Medicine, Lazarski University, Warsaw, Poland
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12
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Baek J, Kim H, Jun J, Kang D, Bae H, Cho H, Hah JM. Discovery of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide as dual CSF-1R/c-Kit Inhibitors with improved stability and BBB permeability. Eur J Med Chem 2024; 268:116253. [PMID: 38401188 DOI: 10.1016/j.ejmech.2024.116253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/29/2024] [Accepted: 02/15/2024] [Indexed: 02/26/2024]
Abstract
This study explores the potential of CSF-1R inhibitors as therapeutic agents for neurodegenerative diseases. CSF-1R, a receptor tyrosine kinase primarily expressed in macrophage lineages, plays a pivotal role in regulating various cellular processes. Recent research highlights the significance of CSF-1R inhibition in mitigating neuroinflammation, particularly in Alzheimer's disease, where microglial overactivation contributes to neurodegeneration. The research reveals a series of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide CSF-1R inhibitors, where compounds 7d, 7e, and 9a exhibit outstanding inhibitory activities and selectivity, with IC50 values of 33, 31, and 64 nM, respectively. These most promising compounds in this series were profiled for cellular potency and subjected to in vitro pharmacokinetic profiling. These inhibitors exhibit minimal cytotoxicity, even at higher concentrations, and possess promising blood-brain barrier permeability, making them potential candidates for central nervous system diseases. The investigation into the in vitro ADME properties, including plasma and microsomal stability, reveals that these CSF-1R inhibitors maintain their structural integrity and plasma concentration. This resilience positions them for further development as therapeutic agents for neurodegenerative diseases.
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Affiliation(s)
- Jihyun Baek
- Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, Republic of Korea
| | - Hyejin Kim
- Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, Republic of Korea
| | - Joonhong Jun
- Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, Republic of Korea
| | - Dahyun Kang
- Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, Republic of Korea
| | - Hyunah Bae
- Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, Republic of Korea
| | - Hyunwook Cho
- Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, Republic of Korea
| | - Jung-Mi Hah
- Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, Republic of Korea.
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13
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Ceci C, Lacal PM, Barbaccia ML, Mercuri NB, Graziani G, Ledonne A. The VEGFs/VEGFRs system in Alzheimer's and Parkinson's diseases: Pathophysiological roles and therapeutic implications. Pharmacol Res 2024; 201:107101. [PMID: 38336311 DOI: 10.1016/j.phrs.2024.107101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/25/2024] [Accepted: 02/05/2024] [Indexed: 02/12/2024]
Abstract
The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological angiogenesis/lymphangiogenesis and in diseases associated to pathological vessel formation, play multifaceted functions in the central nervous system (CNS). In addition to shaping brain development, by controlling cerebral vasculogenesis and regulating neurogenesis as well as astrocyte differentiation, the VEGFs/VEGFRs axis exerts essential functions in the adult brain both in physiological and pathological contexts. In this article, after describing the physiological VEGFs/VEGFRs functions in the CNS, we focus on the VEGFs/VEGFRs involvement in neurodegenerative diseases by reviewing the current literature on the rather complex VEGFs/VEGFRs contribution to the pathogenic mechanisms of Alzheimer's (AD) and Parkinson's (PD) diseases. Thereafter, based on the outcome of VEGFs/VEGFRs targeting in animal models of AD and PD, we discuss the factual relevance of pharmacological VEGFs/VEGFRs modulation as a novel and potential disease-modifying approach for these neurodegenerative pathologies. Specific VEGFRs targeting, aimed at selective VEGFR-1 inhibition, while preserving VEGFR-2 signal transduction, appears as a promising strategy to hit the molecular mechanisms underlying AD pathology. Moreover, therapeutic VEGFs-based approaches can be proposed for PD treatment, with the aim of fine-tuning their brain levels to amplify neurotrophic/neuroprotective effects while limiting an excessive impact on vascular permeability.
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Affiliation(s)
- Claudia Ceci
- Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | | | - Maria Luisa Barbaccia
- Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Nicola Biagio Mercuri
- Neurology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; IRCCS Santa Lucia Foundation, Department of Experimental Neuroscience, Rome, Italy; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Grazia Graziani
- Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - Ada Ledonne
- Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; IRCCS Santa Lucia Foundation, Department of Experimental Neuroscience, Rome, Italy; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
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14
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Chakraborty MP, Das D, Mondal P, Kaul P, Bhattacharyya S, Kumar Das P, Das R. Molecular basis of VEGFR1 autoinhibition at the plasma membrane. Nat Commun 2024; 15:1346. [PMID: 38355851 PMCID: PMC10866885 DOI: 10.1038/s41467-024-45499-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 01/24/2024] [Indexed: 02/16/2024] Open
Abstract
Ligand-independent activation of VEGFRs is a hallmark of diabetes and several cancers. Like EGFR, VEGFR2 is activated spontaneously at high receptor concentrations. VEGFR1, on the other hand, remains constitutively inactive in the unligated state, making it an exception among VEGFRs. Ligand stimulation transiently phosphorylates VEGFR1 and induces weak kinase activation in endothelial cells. Recent studies, however, suggest that VEGFR1 signaling is indispensable in regulating various physiological or pathological events. The reason why VEGFR1 is regulated differently from other VEGFRs remains unknown. Here, we elucidate a mechanism of juxtamembrane inhibition that shifts the equilibrium of VEGFR1 towards the inactive state, rendering it an inefficient kinase. The juxtamembrane inhibition of VEGFR1 suppresses its basal phosphorylation even at high receptor concentrations and transiently stabilizes tyrosine phosphorylation after ligand stimulation. We conclude that a subtle imbalance in phosphatase activation or removing juxtamembrane inhibition is sufficient to induce ligand-independent activation of VEGFR1 and sustain tyrosine phosphorylation.
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Affiliation(s)
- Manas Pratim Chakraborty
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Diptatanu Das
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Purav Mondal
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Pragya Kaul
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Soumi Bhattacharyya
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Prosad Kumar Das
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Rahul Das
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India.
- Centre for Advanced Functional Materials, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India.
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15
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Li Y, Liu Z, Han X, Liang F, Zhang Q, Huang X, Shi X, Huo H, Han M, Liu X, Zhu H, He L, Shen L, Hu X, Wang J, Wang QD, Smart N, Zhou B, He B. Dynamics of Endothelial Cell Generation and Turnover in Arteries During Homeostasis and Diseases. Circulation 2024; 149:135-154. [PMID: 38084582 DOI: 10.1161/circulationaha.123.064301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 10/06/2023] [Indexed: 01/10/2024]
Abstract
BACKGROUND Endothelial cell (EC) generation and turnover by self-proliferation contributes to vascular repair and regeneration. The ability to accurately measure the dynamics of EC generation would advance our understanding of cellular mechanisms of vascular homeostasis and diseases. However, it is currently challenging to evaluate the dynamics of EC generation in large vessels such as arteries because of their infrequent proliferation. METHODS By using dual recombination systems based on Cre-loxP and Dre-rox, we developed a genetic system for temporally seamless recording of EC proliferation in vivo. We combined genetic recording of EC proliferation with single-cell RNA sequencing and gene knockout to uncover cellular and molecular mechanisms underlying EC generation in arteries during homeostasis and disease. RESULTS Genetic proliferation tracing reveals that ≈3% of aortic ECs undergo proliferation per month in adult mice during homeostasis. The orientation of aortic EC division is generally parallel to blood flow in the aorta, which is regulated by the mechanosensing protein Piezo1. Single-cell RNA sequencing analysis reveals 4 heterogeneous aortic EC subpopulations with distinct proliferative activity. EC cluster 1 exhibits transit-amplifying cell features with preferential proliferative capacity and enriched expression of stem cell markers such as Sca1 and Sox18. EC proliferation increases in hypertension but decreases in type 2 diabetes, coinciding with changes in the extent of EC cluster 1 proliferation. Combined gene knockout and proliferation tracing reveals that Hippo/vascular endothelial growth factor receptor 2 signaling pathways regulate EC proliferation in large vessels. CONCLUSIONS Genetic proliferation tracing quantitatively delineates the dynamics of EC generation and turnover, as well as EC division orientation, in large vessels during homeostasis and disease. An EC subpopulation in the aorta exhibits more robust cell proliferation during homeostasis and type 2 diabetes, identifying it as a potential therapeutic target for vascular repair and regeneration.
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Affiliation(s)
- Yi Li
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, China (Y.L., X. Han, F.L., X.S., H.H., L.S., B.Z., B.H.)
- New Cornerstone Investigator Institute, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China (Y.L., Z.L., X. Han, X. Huang, M.H., X.L., H.Z., B.Z.)
| | - Zixin Liu
- New Cornerstone Investigator Institute, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China (Y.L., Z.L., X. Han, X. Huang, M.H., X.L., H.Z., B.Z.)
| | - Ximeng Han
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, China (Y.L., X. Han, F.L., X.S., H.H., L.S., B.Z., B.H.)
- New Cornerstone Investigator Institute, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China (Y.L., Z.L., X. Han, X. Huang, M.H., X.L., H.Z., B.Z.)
| | - Feng Liang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, China (Y.L., X. Han, F.L., X.S., H.H., L.S., B.Z., B.H.)
| | - Qianyu Zhang
- School of Life Science and Technology, ShanghaiTech University, China (Q.Z., M.H., B.Z.)
| | - Xiuzhen Huang
- New Cornerstone Investigator Institute, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China (Y.L., Z.L., X. Han, X. Huang, M.H., X.L., H.Z., B.Z.)
| | - Xin Shi
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, China (Y.L., X. Han, F.L., X.S., H.H., L.S., B.Z., B.H.)
| | - Huanhuan Huo
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, China (Y.L., X. Han, F.L., X.S., H.H., L.S., B.Z., B.H.)
| | - Maoying Han
- New Cornerstone Investigator Institute, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China (Y.L., Z.L., X. Han, X. Huang, M.H., X.L., H.Z., B.Z.)
- School of Life Science and Technology, ShanghaiTech University, China (Q.Z., M.H., B.Z.)
| | - Xiuxiu Liu
- New Cornerstone Investigator Institute, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China (Y.L., Z.L., X. Han, X. Huang, M.H., X.L., H.Z., B.Z.)
| | - Huan Zhu
- New Cornerstone Investigator Institute, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China (Y.L., Z.L., X. Han, X. Huang, M.H., X.L., H.Z., B.Z.)
| | - Lingjuan He
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China (L.H.)
| | - Linghong Shen
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, China (Y.L., X. Han, F.L., X.S., H.H., L.S., B.Z., B.H.)
| | - Xinyang Hu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China (X.H., J.W.)
| | - Jian'an Wang
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China (X.H., J.W.)
| | - Qing-Dong Wang
- Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (Q.D.W.)
| | - Nicola Smart
- Institute of Developmental and Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, UK (N.S.)
| | - Bin Zhou
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, China (Y.L., X. Han, F.L., X.S., H.H., L.S., B.Z., B.H.)
- New Cornerstone Investigator Institute, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China (Y.L., Z.L., X. Han, X. Huang, M.H., X.L., H.Z., B.Z.)
- School of Life Science and Technology, ShanghaiTech University, China (Q.Z., M.H., B.Z.)
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, China (B.Z.)
| | - Ben He
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, China (Y.L., X. Han, F.L., X.S., H.H., L.S., B.Z., B.H.)
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16
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Tavakoli Pirzaman A, Alishah A, Babajani B, Ebrahimi P, Sheikhi SA, Moosaei F, Salarfar A, Doostmohamadian S, Kazemi S. The Role of microRNAs in Hepatocellular Cancer: A Narrative Review Focused on Tumor Microenvironment and Drug Resistance. Technol Cancer Res Treat 2024; 23:15330338241239188. [PMID: 38634139 PMCID: PMC11025440 DOI: 10.1177/15330338241239188] [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: 11/22/2023] [Revised: 01/26/2024] [Accepted: 02/26/2024] [Indexed: 04/19/2024] Open
Abstract
Globally, hepatic cancer ranks fourth in terms of cancer-related mortality and is the sixth most frequent kind of cancer. Around 80% of liver cancers are hepatocellular carcinomas (HCC), which are the leading cause of cancer death. It is well known that HCC may develop resistance to the available chemotherapy treatments very fast. One of the biggest obstacles in providing cancer patients with appropriate care is drug resistance. According to reports, more than 90% of cancer-specific fatalities are caused by treatment resistance. By binding to the 3'-untranslated region of target messenger RNAs (mRNAs), microRNAs (miRNAs), a group of noncoding RNAs which are around 17 to 25 nucleotides long, regulate target gene expression. Moreover, they play role in the control of signaling pathways, cell proliferation, and cell death. As a result, miRNAs play an important role in the microenvironment of HCC by changing immune phenotypes, hypoxic conditions, and acidification, as well as angiogenesis and extracellular matrix components. Moreover, changes in miRNA levels in HCC can effectively resist cancer cells to chemotherapy by affecting various cellular processes such as autophagy, apoptosis, and membrane transporter activity. In the current work, we narratively reviewed the role of miRNAs in HCC, with a special focus on tumor microenvironment and drug resistance.
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Affiliation(s)
| | - Ali Alishah
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Bahareh Babajani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Pouyan Ebrahimi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Ali Sheikhi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Farhad Moosaei
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | | | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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17
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Dimtsas GS, Tsiogka A, Moschos MM. VEGF levels in the aqueous humor of patients with primary open angle glaucoma: A systematic review and a meta-analysis. Eur J Ophthalmol 2023; 33:2228-2235. [PMID: 37038334 DOI: 10.1177/11206721231168146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
PURPOSE To compare the VEGF levels in the aqueous humor of patients with Primary Open Angle Glaucoma (POAG) and non-glaucomatous eyes and reveal any potential statistically significant correlations. METHODS We searched PubMed, from inception to December 31, 2021. Key search terms included VEGF and Glaucoma. All relevant studies that evaluated the VEGF levels in patients with POAG and in the control group were included in this systematic review. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines were followed. Data were extracted independently by 2 authors. Heterogeneity was statistically quantified by Q, H, and I2 statistics, and a meta-analysis was performed using the random-effects model. RESULTS Seven cross-sectional studies were included in the meta-analysis. 144 eyes were enrolled in the POAG group and 162 eyes in the control group. The random effect model showed no statistically significant difference between the two groups (SMD =0.284, 95% CI = -0.173 to 0.741; P = 0.223), but we noticed a trend towards elevated VEGF levels in the aqueous humor of POAG patients. Significant heterogeneity was detected (I2 = 74.1%, P = 0.001). CONCLUSIONS This systematic review and meta-analysis indicates a trend towards elevated VEGF-A levels in the aqueous humor of patients with POAG and suggests a potential neuroprotective role of VEGF in patients with POAG. Future studies are required to evaluate the exact role of VEGF in POAG.
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Affiliation(s)
- Georgios S Dimtsas
- 1st Department of Ophthalmology, National and Kapodistrian University of Athens, "G. Gennimatas" General Hospital, Athens, Greece
| | - Anastasia Tsiogka
- 1st Department of Ophthalmology, National and Kapodistrian University of Athens, "G. Gennimatas" General Hospital, Athens, Greece
| | - Marilita M Moschos
- 1st Department of Ophthalmology, National and Kapodistrian University of Athens, "G. Gennimatas" General Hospital, Athens, Greece
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Pérez-Gutiérrez L, Ferrara N. Biology and therapeutic targeting of vascular endothelial growth factor A. Nat Rev Mol Cell Biol 2023; 24:816-834. [PMID: 37491579 DOI: 10.1038/s41580-023-00631-w] [Citation(s) in RCA: 146] [Impact Index Per Article: 73.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/16/2023] [Indexed: 07/27/2023]
Abstract
The formation of new blood vessels, called angiogenesis, is an essential pathophysiological process in which several families of regulators have been implicated. Among these, vascular endothelial growth factor A (VEGFA; also known as VEGF) and its two tyrosine kinase receptors, VEGFR1 and VEGFR2, represent a key signalling pathway mediating physiological angiogenesis and are also major therapeutic targets. VEGFA is a member of the gene family that includes VEGFB, VEGFC, VEGFD and placental growth factor (PLGF). Three decades after its initial isolation and cloning, VEGFA is arguably the most extensively investigated signalling system in angiogenesis. Although many mediators of angiogenesis have been identified, including members of the FGF family, angiopoietins, TGFβ and sphingosine 1-phosphate, all current FDA-approved anti-angiogenic drugs target the VEGF pathway. Anti-VEGF agents are widely used in oncology and, in combination with chemotherapy or immunotherapy, are now the standard of care in multiple malignancies. Anti-VEGF drugs have also revolutionized the treatment of neovascular eye disorders such as age-related macular degeneration and ischaemic retinal disorders. In this Review, we emphasize the molecular, structural and cellular basis of VEGFA action as well as recent findings illustrating unexpected interactions with other pathways and provocative reports on the role of VEGFA in regenerative medicine. We also discuss clinical and translational aspects of VEGFA. Given the crucial role that VEGFA plays in regulating angiogenesis in health and disease, this molecule is largely the focus of this Review.
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Affiliation(s)
- Lorena Pérez-Gutiérrez
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Napoleone Ferrara
- Department of Pathology, University of California San Diego, La Jolla, CA, USA.
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
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19
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Duan W, Xia S, Tang M, Lin M, Liu W, Wang Q. Targeting of endothelial cells in brain tumours. Clin Transl Med 2023; 13:e1433. [PMID: 37830128 PMCID: PMC10570772 DOI: 10.1002/ctm2.1433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/11/2023] [Accepted: 09/30/2023] [Indexed: 10/14/2023] Open
Abstract
BACKGROUND Aggressive brain tumours, whether primary gliomas or secondary metastases, are characterised by hypervascularisation and are fatal. Recent research has emphasised the crucial involvement of endothelial cells (ECs) in all brain tumour genesis and development events, with various patterns and underlying mechanisms identified. MAIN BODY Here, we highlight recent advances in knowledge about the contributions of ECs to brain tumour development, providing a comprehensive summary including descriptions of interactions between ECs and tumour cells, the heterogeneity of ECs and new models for research on ECs in brain malignancies. We also discuss prospects for EC targeting in novel therapeutic approaches. CONCLUSION Interventions targeting ECs, as an adjunct to other therapies (e.g. immunotherapies, molecular-targeted therapies), have shown promising clinical efficacy due to the high degree of vascularisation in brain tumours. Developing precise strategies to target tumour-associated vessels based on the heterogeneity of ECs is expected to improve anti-vascular efficacy.
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Affiliation(s)
- Wenzhe Duan
- Department of Respiratory MedicineThe Second HospitalDalian Medical UniversityDalianChina
| | - Shengkai Xia
- Department of Respiratory MedicineThe Second HospitalDalian Medical UniversityDalianChina
| | - Mengyi Tang
- Department of Respiratory MedicineThe Second HospitalDalian Medical UniversityDalianChina
| | - Manqing Lin
- Department of Respiratory MedicineThe Second HospitalDalian Medical UniversityDalianChina
| | - Wenwen Liu
- Cancer Translational Medicine Research CenterThe Second HospitalDalian Medical UniversityDalianChina
| | - Qi Wang
- Department of Respiratory MedicineThe Second HospitalDalian Medical UniversityDalianChina
- Cancer Translational Medicine Research CenterThe Second HospitalDalian Medical UniversityDalianChina
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20
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Agnihotri TG, Salave S, Shinde T, Srikanth I, Gyanani V, Haley JC, Jain A. Understanding the role of endothelial cells in brain tumor formation and metastasis: a proposition to be explored for better therapy. JOURNAL OF THE NATIONAL CANCER CENTER 2023; 3:222-235. [PMID: 39035200 PMCID: PMC11256543 DOI: 10.1016/j.jncc.2023.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 07/23/2024] Open
Abstract
Glioblastoma is one of the most devastating central nervous system disorders. Being a highly vascular brain tumor, it is distinguished by aberrant vessel architecture. This lends credence to the idea that endothelial cells (ECs) linked with glioblastoma vary fundamentally from ECs seen in the healthy human brain. To effectively design an antiangiogenic treatment, it is crucial to identify the functional and phenotypic characteristics of tumor-associated ECs. The ECs associated with glioblastoma are less prone to apoptosis than control cells and are resistant to cytotoxic treatments. Additionally, ECs associated with glioblastoma migrate more quickly than control ECs and naturally produce large amounts of growth factors such as endothelin-1, interleukin-8, and vascular endothelial growth factor (VEGF). For designing innovative antiangiogenic drugs that particularly target tumor-related ECs in gliomas, it is critical to comprehend these distinctive features of ECs associated with gliomas. This review discusses the process of angiogenesis, other factors involved in the genesis of tumors, and the possibility of ECs as a potential target in combating glioblastoma. It also sheds light on the association of tumor microenvironment and ECs with immunotherapy. This review, thus gives us the hope that neuro endothelial targeting with growth factors and angiogenesis regulators combined with gene therapy would open up new doorways and change our traditional perspective of treating cancer.
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Affiliation(s)
- Tejas Girish Agnihotri
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Sagar Salave
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Tanuja Shinde
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Induri Srikanth
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Vijay Gyanani
- Long Acting Drug Delivery, Celanese Corporation, Irving, United States
| | - Jeffrey C. Haley
- Long Acting Drug Delivery, Celanese Corporation, Irving, United States
| | - Aakanchha Jain
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
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21
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Ferreira I, Oliveira I, Bordon K, Reis M, Wiezel G, Sanchez C, Santos L, Santos-Filho N, Pucca M, Antunes L, Lopes D, Arantes E. Beyond Angiogenesis: The Multitasking Approach of the First PEGylated Vascular Endothelial Growth Factor ( CdtVEGF) from Brazilian Rattlesnake Venom. Toxins (Basel) 2023; 15:483. [PMID: 37624240 PMCID: PMC10467076 DOI: 10.3390/toxins15080483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 08/26/2023] Open
Abstract
A pioneering study regarding the isolation, biochemical evaluation, functional assays and first PEGylation report of a novel vascular endothelial growth factor from Crotalus durissus terrificus venom (CdtVEGF and PEG-CdtVEGF). CdtVEGF was isolated from crude venom using two different chromatographic steps, representing 2% of soluble venom proteins. Its primary sequence was determined using mass spectrometry analysis, and the molecule demonstrated no affinity to heparin. The Brazilian crotalid antivenom recognized CdtVEGF. Both native and PEGylated CdtVEGF were able to induce new vessel formation and migration, and to increase the metabolic activity of human umbilical endothelial vascular cells (HUVEC), resulting in better wound closure (~50% within 12 h) using the native form. CdtVEGF induced leukocyte recruitment to the peritoneal cavity in mice, with a predominance of neutrophil influx followed by lymphocytes, demonstrating the ability to activate the immune system. The molecule also induced a dose-dependent increase in vascular permeability, and PEG-CdtVEGF showed less in vivo inflammatory activity than CdtVEGF. By unraveling the intricate properties of minor components of snake venom like svVEGF, this study illuminates the indispensable significance of exploring these molecular tools to unveil physiological and pathological processes, elucidates the mechanisms of snakebite envenomings, and could possibly be used to design a therapeutic drug.
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Affiliation(s)
- Isabela Ferreira
- Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, Ribeirao Preto 14040-903, SP, Brazil
| | - Isadora Oliveira
- Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, Ribeirao Preto 14040-903, SP, Brazil
| | - Karla Bordon
- Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, Ribeirao Preto 14040-903, SP, Brazil
| | - Mouzarllem Reis
- Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, Ribeirao Preto 14040-903, SP, Brazil
| | - Gisele Wiezel
- Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, Ribeirao Preto 14040-903, SP, Brazil
| | - Caroline Sanchez
- Department of Clinical Analysis, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14040-903, SP, Brazil
| | - Luísa Santos
- Institute Multidisciplinary in Health, Federal University of Bahia, Vitoria da Conquista 40110-909, BA, Brazil
| | - Norival Santos-Filho
- Department of Biochemistry and Organic Chemistry, Chemistry Institute, Sao Paulo State University (UNESP), Araraquara 14800-901, SP, Brazil
| | - Manuela Pucca
- Department of Clinical Analysis, Sao Paulo State University (UNESP) Araraquara 14800-901, SP, Brazil
| | - Lusânia Antunes
- Department of Clinical Analysis, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14040-903, SP, Brazil
| | - Daiana Lopes
- Institute Multidisciplinary in Health, Federal University of Bahia, Vitoria da Conquista 40110-909, BA, Brazil
| | - Eliane Arantes
- Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, Ribeirao Preto 14040-903, SP, Brazil
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22
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Stratton HJ, Boinon L, Gomez K, Martin L, Duran P, Ran D, Zhou Y, Luo S, Perez-Miller S, Patek M, Ibrahim MM, Patwardhan A, Moutal A, Khanna R. Targeting the vascular endothelial growth factor A/neuropilin 1 axis for relief of neuropathic pain. Pain 2023; 164:1473-1488. [PMID: 36729125 PMCID: PMC10277229 DOI: 10.1097/j.pain.0000000000002850] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 11/08/2022] [Indexed: 02/03/2023]
Abstract
ABSTRACT Vascular endothelial growth factor A (VEGF-A) is a pronociceptive factor that causes neuronal sensitization and pain. We reported that blocking the interaction between the membrane receptor neuropilin 1 (NRP1) and VEGF-A-blocked VEGF-A-mediated sensory neuron hyperexcitability and reduced mechanical hypersensitivity in a rodent chronic neuropathic pain model. These findings identified the NRP1-VEGF-A signaling axis for therapeutic targeting of chronic pain. In an in-silico screening of approximately 480 K small molecules binding to the extracellular b1b2 pocket of NRP1, we identified 9 chemical series, with 6 compounds disrupting VEGF-A binding to NRP1. The small molecule with greatest efficacy, 4'-methyl-2'-morpholino-2-(phenylamino)-[4,5'-bipyrimidin]-6(1H)-one, designated NRP1-4, was selected for further evaluation. In cultured primary sensory neurons, VEGF-A enhanced excitability and decreased firing threshold, which was blocked by NRP1-4. In addition, NaV1.7 and CaV2.2 currents and membrane expression were potentiated by treatment with VEGF-A, and this potentiation was blocked by NRP1-4 cotreatment. Neuropilin 1-4 reduced VEGF-A-mediated increases in the frequency and amplitude of spontaneous excitatory postsynaptic currents in dorsal horn of the spinal cord. Neuropilin 1-4 did not bind to more than 300 G-protein-coupled receptors and receptors including human opioids receptors, indicating a favorable safety profile. In rats with spared nerve injury-induced neuropathic pain, intrathecal administration of NRP1-4 significantly attenuated mechanical allodynia. Intravenous treatment with NRP1-4 reversed both mechanical allodynia and thermal hyperalgesia in rats with L5/L6 spinal nerve ligation-induced neuropathic pain. Collectively, our findings show that NRP1-4 is a first-in-class compound targeting the NRP1-VEGF-A signaling axis to control voltage-gated ion channel function, neuronal excitability, and synaptic activity that curb chronic pain.
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Affiliation(s)
- Harrison J. Stratton
- Department of Pharmacology, College of Medicine, The University of Arizona; Tucson, Arizona, 85724 United States of America
| | - Lisa Boinon
- Department of Pharmacology, College of Medicine, The University of Arizona; Tucson, Arizona, 85724 United States of America
| | - Kimberly Gomez
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York, United States of America
- NYU Pain Research Center, 433 First Avenue, New York, NY 10010, United States of America
| | - Laurent Martin
- Department of Anesthesiology, College of Medicine, The University of Arizona; Tucson, Arizona, 85724 United States of America
| | - Paz Duran
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York, United States of America
- NYU Pain Research Center, 433 First Avenue, New York, NY 10010, United States of America
| | - Dongzhi Ran
- Department of Pharmacology, College of Medicine, The University of Arizona; Tucson, Arizona, 85724 United States of America
| | - Yuan Zhou
- Department of Pharmacology, College of Medicine, The University of Arizona; Tucson, Arizona, 85724 United States of America
| | - Shizhen Luo
- Department of Pharmacology, College of Medicine, The University of Arizona; Tucson, Arizona, 85724 United States of America
| | - Samantha Perez-Miller
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York, United States of America
- NYU Pain Research Center, 433 First Avenue, New York, NY 10010, United States of America
| | - Marcel Patek
- BrightRock Path, LLC, Tucson, Arizona 85704, United States
| | - Mohab M. Ibrahim
- Department of Anesthesiology, College of Medicine, The University of Arizona; Tucson, Arizona, 85724 United States of America
| | - Amol Patwardhan
- Department of Anesthesiology, College of Medicine, The University of Arizona; Tucson, Arizona, 85724 United States of America
| | - Aubin Moutal
- Saint Louis University - School of Medicine, Department of Pharmacology and Physiology, 1402 S. Grand Blvd., Schwitalla Hall, Room 432, Saint Louis, MO 63104
| | - Rajesh Khanna
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York, United States of America
- NYU Pain Research Center, 433 First Avenue, New York, NY 10010, United States of America
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23
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Qin H, Xiao Q, Xie Y, Li D, Long X, Li T, Yi S, Liu Y, Chen J, Xu F. The relationship between VEGF-460(T>C) polymorphism and cancer risk: A systematic review and meta-analysis based on 46 reports. Medicine (Baltimore) 2023; 102:e34089. [PMID: 37390249 PMCID: PMC10313293 DOI: 10.1097/md.0000000000034089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 06/02/2023] [Indexed: 07/02/2023] Open
Abstract
BACKGROUND Extensive studies on the link between single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) and various malignancy risks produced conflicting results, notably for VEGF-460(T/C). To evaluate this correlation more comprehensively and accurately, we perform a meta-analysis. METHODS Through retrieving 5 databases (Web of Science (WoS), Embase, Pubmed, Wanfang database (Wangfang), and China National Knowledge Infrastructure (CNKI)) and applying hand search, citation search, and gray literature search, 44 papers included 46 reports were enrolled. To evaluate the relationship between VEGF-460 and cancer risk, we pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS Our results indicated that the VEGF-460 polymorphism is not related to malignancy susceptibility (dominant model, OR = 0.98, 95% CI = 0.87-1.09; recessive model, OR = 0.95, 95% CI = 0.82-1.10; heterozygous model, OR = 0.99, 95% CI = 0.90-1.10; homozygous model, OR = 0.92, 95% CI = 0.76-1.10; additive model, OR = 0.98, 95% CI = 0.90-1.07). While, in subgroup analysis, this SNP may reduce the risk of hepatocellular carcinoma. CONCLUSION this meta-analysis indicated that VEGF-460 was irrelevant to overall malignancy risk, but it might be a protective factor for hepatocellular carcinoma.
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Affiliation(s)
- Haoran Qin
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qiang Xiao
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yufen Xie
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Dan Li
- Department of Mammary Diseases, Zhuhai Hospital of Integrated Chinese and Western Medicine, Zhuhai, China
| | - Xiaozhou Long
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Taiping Li
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Siqing Yi
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yiqin Liu
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jian Chen
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Foyan Xu
- General Surgery Department, Zhuhai Hospital of integrated Traditional Chinese and Western Medicine, Guangdong, China
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Chen Q, Chen Z, Li F, Zha H, He W, Jiang F, Wei J, Xu J, Li R, Cai L, Liu X. Discovery of highly potent and selective VEGFR2 kinase inhibitors for the treatment of rheumatoid arthritis. Eur J Med Chem 2023; 257:115456. [PMID: 37216810 DOI: 10.1016/j.ejmech.2023.115456] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/24/2023] [Accepted: 05/03/2023] [Indexed: 05/24/2023]
Abstract
Synovial angiogenesis is essential for the development of rheumatoid arthritis (RA). Human vascular endothelial growth factor receptor 2 tyrosine kinase (VEGFR2) is a direct target gene that is notably elevated in RA synovium. Herein, we report the identification of indazole derivatives as a novel class of potent VEGFR2 inhibitors. The most potent compound, compound 25, displayed single-digit nanomolar potency against VEGFR2 in biochemical assays and achieved good selectivity for other protein kinases in the kinome. In addition, compound 25 dose-dependently inhibited the phosphorylation of VEGFR2 in Human Umbilical Vein Endothelial Cells (HUVECs) and showed an anti-angiogenic effect, as evidenced by the inhibition of capillary-like tube formation in vitro. Moreover, compound 25 reduced the severity and development of adjuvant-induced arthritis in rats by inhibiting synovial VEGFR2 phosphorylation and angiogenesis. Overall, these findings provide evidence that compound 25 is a leading potential drug candidate for anti-arthritic and anti-angiogenic therapy.
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Affiliation(s)
- Qingling Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China
| | - Zhuoying Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China
| | - Feilong Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China
| | - Haoyu Zha
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China
| | - Wei He
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China
| | - Fei Jiang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China
| | - Jiamu Wei
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China
| | - Jiajia Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China
| | - Rong Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230026, Anhui Province, PR China.
| | - Li Cai
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China; Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, Anhui Province, PR China.
| | - Xuesong Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China.
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25
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Zheng SY, Wan XX, Kambey PA, Luo Y, Hu XM, Liu YF, Shan JQ, Chen YW, Xiong K. Therapeutic role of growth factors in treating diabetic wound. World J Diabetes 2023; 14:364-395. [PMID: 37122434 PMCID: PMC10130901 DOI: 10.4239/wjd.v14.i4.364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/16/2023] [Accepted: 03/21/2023] [Indexed: 04/12/2023] Open
Abstract
Wounds in diabetic patients, especially diabetic foot ulcers, are more difficult to heal compared with normal wounds and can easily deteriorate, leading to amputation. Common treatments cannot heal diabetic wounds or control their many complications. Growth factors are found to play important roles in regulating complex diabetic wound healing. Different growth factors such as transforming growth factor beta 1, insulin-like growth factor, and vascular endothelial growth factor play different roles in diabetic wound healing. This implies that a therapeutic modality modulating different growth factors to suit wound healing can significantly improve the treatment of diabetic wounds. Further, some current treatments have been shown to promote the healing of diabetic wounds by modulating specific growth factors. The purpose of this study was to discuss the role played by each growth factor in therapeutic approaches so as to stimulate further therapeutic thinking.
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Affiliation(s)
- Shen-Yuan Zheng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Xin-Xing Wan
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Piniel Alphayo Kambey
- Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Yan Luo
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Xi-Min Hu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Yi-Fan Liu
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Jia-Qi Shan
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Yu-Wei Chen
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
- Key Laboratory of Emergency and Trauma, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, Hainan Province, China
- Hunan Key Laboratory of Ophthalmology, Central South University, Changsha 410013, Hunan Province, China
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Basu D, Pal R, Sarkar M, Barma S, Halder S, Roy H, Nandi S, Samadder A. To Investigate Growth Factor Receptor Targets and Generate Cancer Targeting Inhibitors. Curr Top Med Chem 2023; 23:2877-2972. [PMID: 38164722 DOI: 10.2174/0115680266261150231110053650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 09/20/2023] [Accepted: 10/02/2023] [Indexed: 01/03/2024]
Abstract
Receptor tyrosine kinase (RTK) regulates multiple pathways, including Mitogenactivated protein kinases (MAPKs), PI3/AKT, JAK/STAT pathway, etc. which has a significant role in the progression and metastasis of tumor. As RTK activation regulates numerous essential bodily processes, including cell proliferation and division, RTK dysregulation has been identified in many types of cancers. Targeting RTK is a significant challenge in cancer due to the abnormal upregulation and downregulation of RTK receptors subfamily EGFR, FGFR, PDGFR, VEGFR, and HGFR in the progression of cancer, which is governed by multiple RTK receptor signalling pathways and impacts treatment response and disease progression. In this review, an extensive focus has been carried out on the normal and abnormal signalling pathways of EGFR, FGFR, PDGFR, VEGFR, and HGFR and their association with cancer initiation and progression. These are explored as potential therapeutic cancer targets and therefore, the inhibitors were evaluated alone and merged with additional therapies in clinical trials aimed at combating global cancer.
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Affiliation(s)
- Debroop Basu
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Riya Pal
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, IndiaIndia
| | - Maitrayee Sarkar
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Soubhik Barma
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Sumit Halder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Harekrishna Roy
- Nirmala College of Pharmacy, Vijayawada, Guntur, Andhra Pradesh, India
| | - Sisir Nandi
- Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur, 244713, India
| | - Asmita Samadder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
- Cytogenetics and Molecular Biology Lab., Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
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Regression of Human Breast Carcinoma in Nude Mice after Ad sflt Gene Therapy Is Mediated by Tumor Vascular Endothelial Cell Apoptosis. Cancers (Basel) 2022; 14:cancers14246175. [PMID: 36551660 PMCID: PMC9777034 DOI: 10.3390/cancers14246175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/25/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Two vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that recombinant, soluble VEGF receptor domains interfering with VEGF signaling may inhibit in vivo neoangiogenesis, tumor growth and metastatic spread. We hypothesized that a soluble form of FLT-1 receptor (sFLT-1) could inhibit the growth of pre-established tumors via an anti-angiogenic mechanism. A replication-deficient adenovirus (Ad) vector carrying the sflt-1 cDNA (Adsflt) was used to overexpress the sFLT-1 receptor in a breast cancer animal model. MCF-7 cells, which produce VEGF, were used to establish solid tumors in the mammary fat pads of female nude mice. After six weeks, tumors were injected either with Adsflt or a negative control virus (AdCMV.βgal). After six months, average tumor volume in the Adsflt-infected group (33 ± 22 mm3) decreased by 91% relative to that of the negative control group (388 ± 94 mm3; p < 0.05). Moreover, 10 of 15 Adsflt-infected tumors exhibited complete regression. The vascular density of Adsflt-infected tumors was reduced by 50% relative to that of negative controls (p < 0.05), which is consistent with sFLT-1-mediated tumor regression through an anti-angiogenic mechanism. Moreover, cell necrosis and fibrosis associated with long-term regression of Adsflt−infected tumors were preceded by apoptosis of tumor vascular endothelial cells. Mice treated with Adsflt intratumorally showed no delay in the healing of cutaneous wounds, providing preliminary evidence that Ad-mediated sFLT-1 overexpression may be an effective anti-angiogenic therapy for cancer without the risk of systemic anti-angiogenic effects.
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Ahmad A, Nawaz MI. Molecular mechanism of VEGF and its role in pathological angiogenesis. J Cell Biochem 2022; 123:1938-1965. [PMID: 36288574 DOI: 10.1002/jcb.30344] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 09/12/2022] [Accepted: 10/13/2022] [Indexed: 12/24/2022]
Abstract
Over the last seven decades, a significant scientific contribution took place in the delineation of the implications of vascular endothelial-derived growth factor (VEGF) in the processes of angiogenesis. Under pathological conditions, mainly in response to hypoxia or ischemia, elevated VEGF levels promote vascular damage and the growth of abnormal blood vessels. Indeed, the development of VEGF biology has revolutionized our understanding of its role in pathological conditions. Hence, targeting VEGF or VEGF-mediated molecular pathways could be an excellent therapeutic strategy for managing cancers and intraocular neovascular disorders. Although anti-VEGF therapies, such as monoclonal antibodies and small-molecule tyrosine kinase inhibitors, have limited clinical efficacy, they can still significantly improve the overall survival rate. This thus demands further investigation through the development of alternative strategies in the management of VEGF-mediated pathological angiogenesis. This review article focuses on the recent developments toward the delineation of the functional biology of VEGF and the role of anti-VEGF strategies in the management of tumor and eye pathologies. Moreover, therapeutic angiogenesis, an exciting frontier for the treatment of ischemic disorders, is highlighted in this review, including wound healing.
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Affiliation(s)
- Ajmal Ahmad
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Abdulaziz University Hospital, Riyadh, Saudi Arabia
| | - Mohd Imtiaz Nawaz
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Abdulaziz University Hospital, Riyadh, Saudi Arabia
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Zmudzka M, Zoladz JA, Majerczak J. The impact of aging and physical training on angiogenesis in the musculoskeletal system. PeerJ 2022; 10:e14228. [PMID: 36348663 PMCID: PMC9637352 DOI: 10.7717/peerj.14228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/22/2022] [Indexed: 11/06/2022] Open
Abstract
Angiogenesis is the physiological process of capillary growth. It is strictly regulated by the balanced activity of agents that promote the formation of capillaries (pro-angiogenic factors) on the one hand and inhibit their growth on the other hand (anti-angiogenic factors). Capillary rarefaction and insufficient angiogenesis are some of the main causes that limit blood flow during aging, whereas physical training is a potent non-pharmacological method to intensify capillary growth in the musculoskeletal system. The main purpose of this study is to present the current state of knowledge concerning the key signalling molecules implicated in the regulation of skeletal muscle and bone angiogenesis during aging and physical training.
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Affiliation(s)
- Magdalena Zmudzka
- Chair of Exercise Physiology and Muscle Bioenergetics, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
| | - Jerzy A. Zoladz
- Chair of Exercise Physiology and Muscle Bioenergetics, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
| | - Joanna Majerczak
- Chair of Exercise Physiology and Muscle Bioenergetics, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
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Signaling pathways and targeted therapies in lung squamous cell carcinoma: mechanisms and clinical trials. Signal Transduct Target Ther 2022; 7:353. [PMID: 36198685 PMCID: PMC9535022 DOI: 10.1038/s41392-022-01200-x] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/03/2022] [Accepted: 09/18/2022] [Indexed: 11/08/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related death across the world. Unlike lung adenocarcinoma, patients with lung squamous cell carcinoma (LSCC) have not benefitted from targeted therapies. Although immunotherapy has significantly improved cancer patients' outcomes, the relatively low response rate and severe adverse events hinder the clinical application of this promising treatment in LSCC. Therefore, it is of vital importance to have a better understanding of the mechanisms underlying the pathogenesis of LSCC as well as the inner connection among different signaling pathways, which will surely provide opportunities for more effective therapeutic interventions for LSCC. In this review, new insights were given about classical signaling pathways which have been proved in other cancer types but not in LSCC, including PI3K signaling pathway, VEGF/VEGFR signaling, and CDK4/6 pathway. Other signaling pathways which may have therapeutic potentials in LSCC were also discussed, including the FGFR1 pathway, EGFR pathway, and KEAP1/NRF2 pathway. Next, chromosome 3q, which harbors two key squamous differentiation markers SOX2 and TP63 is discussed as well as its related potential therapeutic targets. We also provided some progress of LSCC in epigenetic therapies and immune checkpoints blockade (ICB) therapies. Subsequently, we outlined some combination strategies of ICB therapies and other targeted therapies. Finally, prospects and challenges were given related to the exploration and application of novel therapeutic strategies for LSCC.
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Romero R, Jung E, Chaiworapongsa T, Erez O, Gudicha DW, Kim YM, Kim JS, Kim B, Kusanovic JP, Gotsch F, Taran AB, Yoon BH, Hassan SS, Hsu CD, Chaemsaithong P, Gomez-Lopez N, Yeo L, Kim CJ, Tarca AL. Toward a new taxonomy of obstetrical disease: improved performance of maternal blood biomarkers for the great obstetrical syndromes when classified according to placental pathology. Am J Obstet Gynecol 2022; 227:615.e1-615.e25. [PMID: 36180175 PMCID: PMC9525890 DOI: 10.1016/j.ajog.2022.04.015] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 04/11/2022] [Accepted: 04/13/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known. OBJECTIVE To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion. STUDY DESIGN This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion. RESULTS 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions. CONCLUSION Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders.
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Affiliation(s)
- Roberto Romero
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI; Detroit Medical Center, Detroit, MI.
| | - Eunjung Jung
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
| | - Tinnakorn Chaiworapongsa
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
| | - Offer Erez
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Faculty of Health Sciences, Division of Obstetrics and Gynecology, Maternity Department "D," Soroka University Medical Center, School of Medicine, Ben-Gurion University of the Negev, Beersheba, Israel; Department of Obstetrics and Gynecology, HaEmek Medical Center, Afula, Israel
| | - Dereje W Gudicha
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
| | - Yeon Mee Kim
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Pathology, Wayne State University School of Medicine, Detroit, MI; Department of Pathology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Jung-Sun Kim
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Pathology, Wayne State University School of Medicine, Detroit, MI; Department of Pathology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Bomi Kim
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Pathology, Wayne State University School of Medicine, Detroit, MI; Department of Pathology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Juan Pedro Kusanovic
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; División de Obstetricia y Ginecología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro de Investigación e Innovación en Medicina Materno-Fetal, Unidad de Alto Riesgo Obstétrico, Hospital Sotero Del Rio, Santiago, Chile
| | - Francesca Gotsch
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
| | - Andreea B Taran
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
| | - Bo Hyun Yoon
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sonia S Hassan
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Office of Women's Health, Integrative Biosciences Center, Wayne State University, Detroit, MI; Department of Physiology, Wayne State University School of Medicine, Detroit, MI
| | - Chaur-Dong Hsu
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Physiology, Wayne State University School of Medicine, Detroit, MI; Department of Obstetrics and Gynecology, University of Arizona, College of Medicine - Tucson, Tucson, AZ
| | - Piya Chaemsaithong
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Faculty of Medicine, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nardhy Gomez-Lopez
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI
| | - Lami Yeo
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
| | - Chong Jai Kim
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Pathology, Wayne State University School of Medicine, Detroit, MI; Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Adi L Tarca
- Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Department of Computer Science, Wayne State University College of Engineering, Detroit, MI
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Anterior Mandibular Displacement in Growing Rats—A Systematic Review. Animals (Basel) 2022; 12:ani12162059. [PMID: 36009649 PMCID: PMC9405253 DOI: 10.3390/ani12162059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/06/2022] [Accepted: 08/07/2022] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Mandibular deficiency is a very common orthodontic problem. Many different types of appliances have been utilized to correct such malocclusions. Most are appliances that alter the function of the mandible resulting in a more forward positioning of the lower jaw. Many researchers state that such an alteration results in a different rate of mandibular growth, due to condyle endochondral ossification, thus correcting the orthodontic anomaly. Their effect though remains controversial. The aim of the present study was to investigate the effect of such functional appliances in the mandible of growing rats by reviewing the existing literature up to March of 2022. Most of them stated that true condylar growth is observed, although there are many limitations due to the nature of such experiments. Abstract Skeletal Class II malocclusion is the most common skeletal anomaly in orthodontics. Growth in the body of the deficient mandible is induced by periosteal apposition and endochondral ossification in the condyle. Functional appliances have been used in the correction of Class II malocclusions by inducing mandibular growth. Despite their utilization though, their effect still remains controversial. The aim of the present study is to review the existing literature regarding the effects of mandibular protrusion in mandibular growth of growing rats. A protocol was followed according to the guidelines of the Cohrane Handbook for Systematic Reviews. Databases were searched using a specific algorithm. From the ten studies finally analyzed, we conclude that the use of a functional appliance in growing rats induces cell proliferation and bone formation in their condyles, resulting in mandibular growth.
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Suppression of VEGFD expression by S-nitrosylation promotes the development of lung adenocarcinoma. J Exp Clin Cancer Res 2022; 41:239. [PMID: 35941690 PMCID: PMC9358865 DOI: 10.1186/s13046-022-02453-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/28/2022] [Indexed: 11/18/2022] Open
Abstract
Background Vascular endothelial growth factor D (VEGFD), a member of the VEGF family, is implicated in angiogenesis and lymphangiogenesis, and is deemed to be expressed at a low level in cancers. S-nitrosylation, a NO (nitric oxide)-mediated post-translational modification has a critical role in angiogenesis. Here, we attempt to dissect the role and underlying mechanism of S-nitrosylation-mediated VEGFD suppression in lung adenocarcinoma (LUAD). Methods Messenger RNA and protein expression of VEGFD in LUAD were analyzed by TCGA and CPTAC database, respectively, and Assistant for Clinical Bioinformatics was performed for complex analysis. Mouse models with urethane (Ure)–induced LUAD or LUAD xenograft were established to investigate the role of S-nitrosylation in VEGFD expression and of VEGFD mutants in the oncogenesis of LUAD. Molecular, cellular, and biochemical approaches were applied to explore the underlying mechanism of S-nitrosylation-mediated VEGFD suppression. Tube formation and wound healing assays were used to examine the role of VEGFD on the angiogenesis and migration of LUAD cells, and the molecular modeling was applied to predict the protein stability of VEGFD mutant. Results VEGFD mRNA and protein levels were decreased to a different extent in multiple primary malignancies, especially in LUAD. Low VEGFD protein expression was closely related to the oncogenesis of LUAD and resultant from excessive NO-induced VEGFD S-nitrosylation at Cys277. Moreover, inhibition of S-nitrosoglutathione reductase consistently decreased the VEGFD denitrosylation at Cys277 and consequently promoted angiogenesis of LUAD. Finally, the VEGFDC277S mutant decreased the secretion of mature VEGFD by attenuating the PC7-dependent proteolysis and VEGFDC277S mutant thus reversed the effect of VEGFD on angiogenesis of LUAD. Conclusion Low-expression of VEGFD positively correlates with LUAD development. Aberrant S-nitrosylation of VEGFD negates itself to induce the tumorigenesis of LUAD, whereas normal S-nitrosylation of VEGFD is indispensable for its secretion and repression of angiogenesis of LUAD. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02453-8.
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Okada Y, Kawashima N, Noda S, Murano H, Han P, Hashimoto K, Kaneko T, Okiji T. VEGFA promotes odonto/osteoblastic differentiation in dental pulp stem cells via ERK/p38 signaling. J Dent Sci 2022. [DOI: 10.1016/j.jds.2022.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Jeong J, Tanaka M, Iwakiri Y. Hepatic lymphatic vascular system in health and disease. J Hepatol 2022; 77:206-218. [PMID: 35157960 PMCID: PMC9870070 DOI: 10.1016/j.jhep.2022.01.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/13/2022] [Accepted: 01/31/2022] [Indexed: 02/07/2023]
Abstract
In recent years, significant advances have been made in the study of lymphatic vessels with the identification of their specific markers and the development of research tools that have accelerated our understanding of their role in tissue homeostasis and disease pathogenesis in many organs. Compared to other organs, the lymphatic system in the liver is understudied despite its obvious importance for hepatic physiology and pathophysiology. In this review, we describe fundamental aspects of the hepatic lymphatic system and its role in a range of liver-related pathological conditions such as portal hypertension, ascites formation, malignant tumours, liver transplantation, congenital liver diseases, non-alcoholic fatty liver disease, and hepatic encephalopathy. The article concludes with a discussion regarding the modulation of lymphangiogenesis as a potential therapeutic strategy for liver diseases.
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Affiliation(s)
- Jain Jeong
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Masatake Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.
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Abstract
Karaman et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20210565) examined the differential effects of the conditional deletion of genes encoding each VEGF receptor, VEGFR1, VEGFR2 and VEGFR 3, as well as combinations thereof in mice. The results highlight the crosstalk between receptors in different organs and emphasize the importance of VEGF receptor expression and interplay in vascular heterogeneity.
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Affiliation(s)
- Pin Li
- Department of Pathology, University of California, San Diego, La Jolla, CA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Napoleone Ferrara
- Department of Pathology, University of California, San Diego, La Jolla, CA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA
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Ye X, Gaucher JF, Vidal M, Broussy S. A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics. Molecules 2021; 26:6759. [PMID: 34833851 PMCID: PMC8625919 DOI: 10.3390/molecules26226759] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 12/27/2022] Open
Abstract
The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed.
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Affiliation(s)
- Xiaoqing Ye
- Faculté de Pharmacie de Paris, Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, 75006 Paris, France; (X.Y.); (M.V.)
| | - Jean-François Gaucher
- Laboratoire de Cristallographie et RMN Biologiques, Faculté de Pharmacie de Paris, Université de Paris, CiTCoM, 8038 CNRS, 75006 Paris, France;
| | - Michel Vidal
- Faculté de Pharmacie de Paris, Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, 75006 Paris, France; (X.Y.); (M.V.)
- Service Biologie du Médicament, Toxicologie, AP-HP, Hôpital Cochin, 75014 Paris, France
| | - Sylvain Broussy
- Faculté de Pharmacie de Paris, Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, 75006 Paris, France; (X.Y.); (M.V.)
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Diana D, Di Stasi R, García-Viñuales S, De Rosa L, Isernia C, Malgieri G, Milardi D, D'Andrea LD, Fattorusso R. Structural characterization of the thermal unfolding pathway of human VEGFR1 D2 domain. FEBS J 2021; 289:1591-1602. [PMID: 34689403 PMCID: PMC9299094 DOI: 10.1111/febs.16246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/13/2021] [Accepted: 10/21/2021] [Indexed: 11/27/2022]
Abstract
Folding stability is a crucial feature of protein evolution and is essential for protein functions. Thus, the comprehension of protein folding mechanisms represents an important complement to protein structure and function, crucial to determine the structural basis of protein misfolding. In this context, thermal unfolding studies represent a useful tool to get a molecular description of the conformational transitions governing the folding/unfolding equilibrium of a given protein. Here, we report the thermal folding/unfolding pathway of VEGFR1D2, a member of the immunoglobulin superfamily by means of a high-resolution thermodynamic approach that combines differential scanning calorimetry with atomic-level unfolding monitored by NMR. We show how VEGFR1D2 folding is driven by an oxidatively induced disulfide pairing: the key event in the achievement of its functional structure is the formation of a small hydrophobic core that surrounds a disulfide bridge. Such a 'folding nucleus' induces the cooperative transition to the properly folded conformation supporting the hypothesis that a disulfide bond can act as a folding nucleus that eases the folding process.
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Affiliation(s)
| | | | | | - Lucia De Rosa
- Istituto di Biostrutture e Bioimmagini, CNR, Napoli, Italy
| | - Carla Isernia
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli', Caserta, Italy
| | - Gaetano Malgieri
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli', Caserta, Italy
| | | | - Luca D D'Andrea
- Istituto di Scienze e Tecnologie Chimiche 'Giulio Natta', CNR, Milano, Italy
| | - Roberto Fattorusso
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli', Caserta, Italy
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Shafique QUA, Rehman HM, Zaheer T, Tahir RA, Bhinder MA, Gul R, Saleem M. A Computational Approach to Modeling an Antagonistic Angiogenic VEGFR1-IL2 Fusion Protein for Cancer Therapy. Bioinform Biol Insights 2021; 15:11779322211043297. [PMID: 34566410 PMCID: PMC8458685 DOI: 10.1177/11779322211043297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/13/2021] [Indexed: 11/17/2022] Open
Abstract
In cancer treatment, immunotherapy has great potential for improving the prognosis of patients with hematologic and solid malignancies. In this study, various bioinformatics tools and servers were used to design an antiangiogenic fusion protein. After comprehensive evaluation, an antiangiogenic fusion protein was designed using a soluble extracellular domain of human vascular endothelial growth factor receptor 1 (sVEGFR-1) and human interleukin-2 (IL-2) joined by a flexible linker. The final construct was composed of 875 amino acids. The secondary structure of the fusion protein, obtained by CFSSP, PSIPRED, and SOPMA tools, consisted of 14.17% helices, 29.71% extended strands, 4.69% beta turns and 51.43% random coils. Tertiary structure prediction by Raptor X showed that the fusion protein comprises 3 domains with 875 modeled amino acids, out of which 26 positions (2%) were considered disordered. The Ramachandran plot revealed 89.3%, 7.1%, and 3.6% amino acid residues in favored, allowed, and outlier regions, respectively. Physical features of the Molecular Dynamic (MD) simulated system such as root mean square deviation, root mean square fluctuation, solvent-on hand surface region, and radius of gyration identified the fusion construct as a stable and compact protein with few fluctuations in its overall structure. Docking of the fusion protein showed that interaction between sVEGFR-1/VEGFA and IL-2/IL-2R still exists. In silico analysis revealed that the fusion protein comprising IL-2 and sVEGFR-1 has stable structure and the selected linker can efficiently separate the two domains. These observations may be helpful in determining protein stability prior to protein expression.
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Affiliation(s)
| | - Hafiz Muzzammel Rehman
- Institute of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan.,Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore, Pakistan
| | - Tahreem Zaheer
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Rana Adnan Tahir
- Department of Biosciences, COMSATS University Islamabad, Sahiwal, Pakistan
| | - Munir Ahmad Bhinder
- Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore, Pakistan
| | - Roquyya Gul
- Faculty of Life Sciences, Gulab Devi Educational Complex, Lahore, Pakistan
| | - Mahjabeen Saleem
- Institute of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan
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Uemura A, Fruttiger M, D'Amore PA, De Falco S, Joussen AM, Sennlaub F, Brunck LR, Johnson KT, Lambrou GN, Rittenhouse KD, Langmann T. VEGFR1 signaling in retinal angiogenesis and microinflammation. Prog Retin Eye Res 2021; 84:100954. [PMID: 33640465 PMCID: PMC8385046 DOI: 10.1016/j.preteyeres.2021.100954] [Citation(s) in RCA: 183] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 02/12/2021] [Accepted: 02/19/2021] [Indexed: 12/13/2022]
Abstract
Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, -C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.
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Affiliation(s)
- Akiyoshi Uemura
- Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
| | - Marcus Fruttiger
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
| | - Patricia A D'Amore
- Schepens Eye Research Institute of Massachusetts Eye and Ear, 20 Staniford Street, Boston, MA, 02114, USA.
| | - Sandro De Falco
- Angiogenesis Laboratory, Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", Via Pietro Castellino 111, 80131 Naples, Italy; ANBITION S.r.l., Via Manzoni 1, 80123, Naples, Italy.
| | - Antonia M Joussen
- Department of Ophthalmology, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, and Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Florian Sennlaub
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012, Paris, France.
| | - Lynne R Brunck
- Bayer Consumer Care AG, Pharmaceuticals, Peter-Merian-Strasse 84, CH-4052 Basel, Switzerland.
| | - Kristian T Johnson
- Bayer Consumer Care AG, Pharmaceuticals, Peter-Merian-Strasse 84, CH-4052 Basel, Switzerland.
| | - George N Lambrou
- Bayer Consumer Care AG, Pharmaceuticals, Peter-Merian-Strasse 84, CH-4052 Basel, Switzerland.
| | - Kay D Rittenhouse
- Bayer Consumer Care AG, Pharmaceuticals, Peter-Merian-Strasse 84, CH-4052 Basel, Switzerland.
| | - Thomas Langmann
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Joseph-Stelzmann-Str. 9, 50931, Cologne, Germany.
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A Multifunctional Nanoplatform Made of Gold Nanoparticles and Peptides Mimicking the Vascular Endothelial Growth Factor. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11146333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
In this work, nanobiohybrids of plasmonic gold nanoparticles (AuNP, anti-angiogenic) and a peptide mimicking the vascular endothelial growth factor (VEGF, pro-angiogenic) were assembled and scrutinized in terms of physicochemical characterization, including optical properties, surface charge, surface chemical structure and morphology of the bioengineered metal nanoparticles, for their potential application as multifunctional theranostic (i.e., therapy + sensing) nanoplatform (AuNP/VEGF). Specifically, a peptide sequence encompassing the VEGF cellular receptor domain 73–101 (VEGF73–101) and its single point cysteine mutated were immobilized onto AuNP by physi- and chemi-sorption, respectively. The new hybrid systems were characterized by means of a multitechnique approach, including dynamic light scattering (DLS) analyses, zeta potential (ZP), spectroscopic (UV-Vis, FT-IR, XPS), spectrometric (TOF-SIMS) and microscopic (AFM, SEM) techniques. Proof-of-work cellular experiments in human umbilical vein endothelial cells (HUVEC) upon the treatment with AuNP/VEGF samples, demonstrated no toxicity up to 24 h (MTT assay) as well an effective internalization (laser confocal microscopy, LSM).
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Mushimiyimana I, Tomas Bosch V, Niskanen H, Downes NL, Moreau PR, Hartigan K, Ylä-Herttuala S, Laham-Karam N, Kaikkonen MU. Genomic Landscapes of Noncoding RNAs Regulating VEGFA and VEGFC Expression in Endothelial Cells. Mol Cell Biol 2021; 41:e0059420. [PMID: 33875575 PMCID: PMC8224232 DOI: 10.1128/mcb.00594-20] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/29/2020] [Accepted: 04/03/2021] [Indexed: 12/26/2022] Open
Abstract
Vascular endothelial growth factors (VEGFs) are best known as key regulators of angiogenesis and lymphangiogenesis. Although VEGFs have been promising therapeutic targets for various cardiovascular diseases, their regulatory landscape in endothelial cells remains elusive. Several studies have highlighted the involvement of noncoding RNAs (ncRNAs) in the modulation of VEGF expression. In this study, we investigated the role of two classes of ncRNAs, long ncRNAs (lncRNAs) and enhancer RNAs (eRNAs), in the transcriptional regulation of VEGFA and VEGFC. By integrating genome-wide global run-on sequencing (GRO-Seq) and chromosome conformation capture (Hi-C) data, we identified putative lncRNAs and eRNAs associated with VEGFA and VEGFC genes in endothelial cells. A subset of the identified putative enhancers demonstrated regulatory activity in a reporter assay. Importantly, we demonstrate that deletion of enhancers and lncRNAs by CRISPR/Cas9 promoted significant changes in VEGFA and VEGFC expression. Transcriptome sequencing (RNA-Seq) data from lncRNA deletions showed downstream factors implicated in VEGFA- and VEGFC-linked pathways, such as angiogenesis and lymphangiogenesis, suggesting functional roles for these lncRNAs. Our study uncovers novel lncRNAs and eRNAs regulating VEGFA and VEGFC that can be targeted to modulate the expression of these important molecules in endothelial cells.
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Affiliation(s)
- Isidore Mushimiyimana
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Vanesa Tomas Bosch
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Henri Niskanen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Nicholas L. Downes
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Pierre R. Moreau
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | | | - Seppo Ylä-Herttuala
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
- Heart Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland
| | - Nihay Laham-Karam
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Minna U. Kaikkonen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
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Snake venom vascular endothelial growth factors (svVEGFs): Unravelling their molecular structure, functions, and research potential. Cytokine Growth Factor Rev 2021; 60:133-143. [PMID: 34090786 DOI: 10.1016/j.cytogfr.2021.05.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/18/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023]
Abstract
Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis, a physiological process characterized by the formation of new vessels from a preexisting endothelium. VEGF has also been implicated in pathologic states, such as neoplasias, intraocular neovascular disorders, among other conditions. VEGFs are distributed in seven different families: VEGF-A, B, C, D, and PIGF (placental growth factor), which are identified in mammals; VEGF-E, which are encountered in viruses; and VEGF-F or svVEGF (snake venom VEGF) described in snake venoms. This is the pioneer review of svVEGF family, exploring its distribution among the snake venoms, molecular structure, main functions, and potential applications.
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Heparin-binding VEGFR1 variants as long-acting VEGF inhibitors for treatment of intraocular neovascular disorders. Proc Natl Acad Sci U S A 2021; 118:1921252118. [PMID: 34006633 PMCID: PMC8166142 DOI: 10.1073/pnas.1921252118] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Neovascularization is a key feature of ischemic retinal diseases and the wet form of age-related macular degeneration (AMD), all leading causes of severe vision loss. Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of these disorders. Millions of patients have been treated with these drugs worldwide. However, in real-life clinical settings, many patients do not experience the same degree of benefit observed in clinical trials, in part because they receive fewer anti-VEGF injections. Therefore, there is an urgent need to discover and identify novel long-acting VEGF inhibitors. We hypothesized that binding to heparan-sulfate proteoglycans (HSPG) in the vitreous, and possibly other ocular structures, may be a strategy to promote intraocular retention, ultimately leading to a reduced burden of intravitreal injections. We designed a series of VEGF receptor 1 variants and identified some with strong heparin-binding characteristics and ability to bind to vitreous matrix. Our data indicate that some of our variants have longer duration and greater efficacy in animal models of intraocular neovascularization than current standard of care. Our study represents a systematic attempt to exploit the functional diversity associated with heparin affinity of a VEGF receptor.
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Patel SS, Sandur A, El-Kebir M, Gaba RC, Schook LB, Schachtschneider KM. Transcriptional Profiling of Porcine HCC Xenografts Provides Insights Into Tumor Cell Microenvironment Signaling. Front Genet 2021; 12:657330. [PMID: 33995488 PMCID: PMC8118521 DOI: 10.3389/fgene.2021.657330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, representing the most common form of liver cancer. As HCC incidence and mortality continue to increase, there is a growing need for improved translational animal models to bridge the gap between basic HCC research and clinical practice to improve early detection and treatment strategies for this deadly disease. Recently the Oncopig cancer model-a novel transgenic swine model that recapitulates human cancer through Cre recombinase induced expression of KRAS G12D and TP53 R167H driver mutations-has been validated as a large animal translational model for human HCC. Due to the similar size, anatomy, physiology, immunology, genetics, and epigenetics between pigs and humans, the Oncopig has the potential to improve translation of novel diagnostic and therapeutic modalities into clinical practice. Recent studies have demonstrated the importance of tumor cells in shaping its surrounding microenvironment into one that is more proliferative, invasive, and metastatic; however, little is known about the impact of microenvironment signaling on HCC tumor biology and differential gene expression between HCC tumors and its tumor microenvironment (TME). In this study, transcriptional profiling was performed on Oncopig HCC xenograft tumors (n = 3) produced via subcutaneous injection of Oncopig HCC cells into severe combined immunodeficiency (SCID) mice. To differentiate between gene expression in the tumor and surrounding tumor microenvironment, RNA-seq reads originating from porcine (HCC tumor) and murine (microenvironment) cells were bioinformatically separated using Xenome. Principle component analysis (PCA) demonstrated clustering by group based on the expression of orthologous genes. Genes contributing to each principal component were extracted and subjected to functional analysis to identify alterations in pathway signaling between HCC cells and the microenvironment. Altered expression of genes associated with hepatic fibrosis deposition, immune response, and neo angiogenesis were observed. The results of this study provide insights into the interplay between HCC and microenvironment signaling in vivo, improving our understanding of the interplay between HCC tumor cells, the surrounding tumor microenvironment, and the impact on HCC development and progression.
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Affiliation(s)
- Shovik S. Patel
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, United States
| | - Amitha Sandur
- Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Mohammed El-Kebir
- Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Ron C. Gaba
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, United States
| | - Lawrence B. Schook
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, United States
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Kyle M. Schachtschneider
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, United States
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, United States
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Correlationship between Ki67, VEGF, and p53 and Hepatocellular Carcinoma Recurrence in Liver Transplant Patients. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6651397. [PMID: 33954191 PMCID: PMC8064788 DOI: 10.1155/2021/6651397] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/07/2021] [Accepted: 03/30/2021] [Indexed: 12/23/2022]
Abstract
Background and Aims Patients with hepatocellular carcinoma (HCC) who undergo orthotopic liver transplantation (OLT) are at risk for posttransplant tumor recurrence. The aim of this study was to evaluate the correlation between the expression of Ki67, VEGF, and p53 in HCC and clinicopathological characteristics of HCC patients, as well as their predictive value for HCC recurrence after OLT. Methods 60 patients who underwent OLT and were found to have HCC in the liver explant. The expression of Ki67, VEGF, and p53 in HCC was detected by immunohistochemistry. Results Ki67 was associated with the tumor number and the grade of differentiation at baseline. VEGF was associated with the diameter and number of tumors, tumor differentiation, and lymph node metastasis. p53 was associated with the tumor diameter and tumor encapsulation. The expression of Ki67, VEGF, and p53 in HCC was correlated with the tumor recurrence after OLT, respectively. Among them, VEGF was an independent predictor for tumor recurrence after OLT. Conclusion Ki67, VEGF, and p53 are associated with the recurrence of HCC after OLT. VEGF independently predicts the recurrence of HCC.
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Xu AA, Shapero KS, Geibig JA, Ma HWK, Jones AR, Hanna M, Pitts DR, Hillas E, Firpo MA, Peattie RA. Histologic evaluation of therapeutic responses in ischemic myocardium elicited by dual growth factor delivery from composite glycosaminoglycan hydrogels. Acta Histochem 2021; 123:151699. [PMID: 33662819 DOI: 10.1016/j.acthis.2021.151699] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 02/10/2021] [Accepted: 02/23/2021] [Indexed: 01/01/2023]
Abstract
In this project, the ability of dual growth factor-preloaded, silk-reinforced, composite hyaluronic acid-based hydrogels to elicit advantageous histologic responses when secured to ischemic myocardium was evaluated in vivo. Reinforced hydrogels containing both Vascular Endothelial Growth Factor (VEGF) and Platelet-derived Growth Factor (PDGF) were prepared by crosslinking chemically modified hyaluronic acid and heparin with poly(ethylene glycol)-diacrylate around a reinforcing silk mesh. Composite patches were sutured to the ventricular surface of ischemic myocardium in Sprague-Dawley rats, and the resulting angiogenic response was followed for 28 days. The gross appearance of treated hearts showed significantly reduced ischemic area and fibrous deposition compared to untreated control hearts. Histologic evaluation showed growth factor delivery to restore myofiber orientation to pre-surgical levels and to significantly increase elicited microvessel density and maturity by day 28 in infarcted myocardial tissue (p < 0.05). In addition, growth factor delivery reduced cell apoptosis and decreased the density of elicited mast cells and both CD68+ and anti-inflammatory CD163+ macrophages. These findings suggest that HA-based, dual growth factor-loaded hydrogels can successfully induce a series of beneficial responses in ischemic myocardium, and offer the potential for therapeutic improvement of ischemic myocardial remodeling.
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Affiliation(s)
- Alexander A Xu
- Department of Surgery, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA
| | - Kayle S Shapero
- Department of Surgery, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA
| | - Jared A Geibig
- Department of Surgery, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA
| | - Hsiang-Wei K Ma
- Department of Surgery, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA
| | - Alex R Jones
- Department of Surgery, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA
| | - Marina Hanna
- Department of Surgery, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA
| | - Daniel R Pitts
- Department of Surgery, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA
| | - Elaine Hillas
- Department of Surgery, School of Medicine, The University of Utah, 30 N., 1930 E., Salt Lake City, UT, 84132, USA
| | - Matthew A Firpo
- Department of Surgery, School of Medicine, The University of Utah, 30 N., 1930 E., Salt Lake City, UT, 84132, USA
| | - Robert A Peattie
- Department of Surgery, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
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Tirronen A, Downes NL, Huusko J, Laakkonen JP, Tuomainen T, Tavi P, Hedman M, Ylä-Herttuala S. The Ablation of VEGFR-1 Signaling Promotes Pressure Overload-Induced Cardiac Dysfunction and Sudden Death. Biomolecules 2021; 11:452. [PMID: 33802976 PMCID: PMC8002705 DOI: 10.3390/biom11030452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 03/15/2021] [Indexed: 12/28/2022] Open
Abstract
Molecular mechanisms involved in cardiac remodelling are not fully understood. To study the role of vascular endothelial growth factor receptor 1 (VEGFR-1) signaling in left ventricular hypertrophy (LVH) and heart failure, we used a mouse model lacking the intracellular VEGFR-1 tyrosine kinase domain (VEGFR-1 TK-/-) and induced pressure overload with angiotensin II infusion. Using echocardiography (ECG) and immunohistochemistry, we evaluated pathological changes in the heart during pressure overload and measured the corresponding alterations in expression level and phosphorylation of interesting targets by deep RNA sequencing and Western blot, respectively. By day 6 of pressure overload, control mice developed significant LVH whereas VEGFR-1 TK-/- mice displayed a complete absence of LVH, which correlated with significantly increased mortality. At a later time point, the cardiac dysfunction led to increased ANP and BNP levels, atrial dilatation and prolongation of the QRSp duration as well as increased cardiomyocyte area. Immunohistochemical analyses showed no alterations in fibrosis or angiogenesis in VEGFR-1 TK-/- mice. Mechanistically, the ablation of VEGFR-1 signaling led to significantly upregulated mTOR and downregulated PKCα phosphorylation in the myocardium. Our results show that VEGFR-1 signaling regulates the early cardiac remodelling during the compensatory phase of pressure overload and increases the risk of sudden death.
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Affiliation(s)
- Annakaisa Tirronen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland; (A.T.); (N.L.D.); (J.H.); (J.P.L.); (T.T.); (P.T.)
| | - Nicholas L. Downes
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland; (A.T.); (N.L.D.); (J.H.); (J.P.L.); (T.T.); (P.T.)
| | - Jenni Huusko
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland; (A.T.); (N.L.D.); (J.H.); (J.P.L.); (T.T.); (P.T.)
| | - Johanna P. Laakkonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland; (A.T.); (N.L.D.); (J.H.); (J.P.L.); (T.T.); (P.T.)
| | - Tomi Tuomainen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland; (A.T.); (N.L.D.); (J.H.); (J.P.L.); (T.T.); (P.T.)
| | - Pasi Tavi
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland; (A.T.); (N.L.D.); (J.H.); (J.P.L.); (T.T.); (P.T.)
| | - Marja Hedman
- Institute of Clinical Medicine, University of Eastern Finland, 70029 Kuopio, Finland;
- Heart Center and Cardiothoracic Surgery, Kuopio University Hospital, 70029 Kuopio, Finland
| | - Seppo Ylä-Herttuala
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland; (A.T.); (N.L.D.); (J.H.); (J.P.L.); (T.T.); (P.T.)
- Heart Center and Gene Therapy Unit, Kuopio University Hospital, 70029 Kuopio, Finland
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The Role of VEGF Receptors as Molecular Target in Nuclear Medicine for Cancer Diagnosis and Combination Therapy. Cancers (Basel) 2021; 13:cancers13051072. [PMID: 33802353 PMCID: PMC7959315 DOI: 10.3390/cancers13051072] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/13/2021] [Accepted: 02/24/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary The rapid development of diagnostic and therapeutic methods of the cancer treatment causes that these diseases are becoming better known and the fight against them is more and more effective. Substantial contribution in this development has nuclear medicine that enables very early cancer diagnosis and early start of the so-called targeted therapy. This therapeutic concept compared to the currently used chemotherapy, causes much fewer undesirable side effects, due to targeting a specific lesion in the body. This review article discusses the possible applications of radionuclide-labelled tracers (peptides, antibodies or synthetic organic molecules) that can visualise cancer cells through pathological blood vessel system in close tumour microenvironment. Hence, at a very early step of oncological disease, targeted therapy can involve in tumour formation and growth. Abstract One approach to anticancer treatment is targeted anti-angiogenic therapy (AAT) based on prevention of blood vessel formation around the developing cancer cells. It is known that vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFRs) play a pivotal role in angiogenesis process; hence, application of angiogenesis inhibitors can be an effective approach in anticancer combination therapeutic strategies. Currently, several types of molecules have been utilised in targeted VEGF/VEGFR anticancer therapy, including human VEGF ligands themselves and their derivatives, anti-VEGF or anti-VEGFR monoclonal antibodies, VEGF binding peptides and small molecular inhibitors of VEGFR tyrosine kinases. These molecules labelled with diagnostic or therapeutic radionuclides can become, respectively, diagnostic or therapeutic receptor radiopharmaceuticals. In targeted anti-angiogenic therapy, diagnostic radioagents play a unique role, allowing the determination of the emerging tumour, to monitor the course of treatment, to predict the treatment outcomes and, first of all, to refer patients for AAT. This review provides an overview of design, synthesis and study of radiolabelled VEGF/VEGFR targeting and imaging agents to date. Additionally, we will briefly discuss their physicochemical properties and possible application in combination targeted radionuclide tumour therapy.
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Arcucci V, Stacker SA, Achen MG. Control of Gene Expression by Exosome-Derived Non-Coding RNAs in Cancer Angiogenesis and Lymphangiogenesis. Biomolecules 2021; 11:249. [PMID: 33572413 PMCID: PMC7916238 DOI: 10.3390/biom11020249] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/29/2021] [Accepted: 02/04/2021] [Indexed: 12/12/2022] Open
Abstract
Abstract: Tumour angiogenesis and lymphangiogenesis are hallmarks of cancer and have been associated with tumour progression, tumour metastasis and poor patient prognosis. Many factors regulate angiogenesis and lymphangiogenesis in cancer including non-coding RNAs which are a category of RNAs that do not encode proteins and have important regulatory functions at transcriptional and post-transcriptional levels. Non-coding RNAs can be encapsulated in extracellular vesicles called exosomes which are secreted by tumour cells or other cells in the tumour microenvironment and can then be taken up by the endothelial cells of blood vessels and lymphatic vessels. The "delivery" of these non-coding RNAs to endothelial cells in tumours can facilitate tumour angiogenesis and lymphangiogenesis. Here we review recent findings about exosomal non-coding RNAs, specifically microRNAs and long non-coding RNAs, which regulate tumour angiogenesis and lymphangiogenesis in cancer. We then focus on the potential use of these molecules as cancer biomarkers and opportunities for exploiting ncRNAs for the treatment of cancer.
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Affiliation(s)
- Valeria Arcucci
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, 305 Grattan St., Melbourne VIC 3000, Australia; (V.A.); (S.A.S.)
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville VIC 3010, Australia
| | - Steven A. Stacker
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, 305 Grattan St., Melbourne VIC 3000, Australia; (V.A.); (S.A.S.)
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville VIC 3010, Australia
- Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville VIC 3050, Australia
| | - Marc G. Achen
- O’Brien Institute Department, St Vincent’s Institute of Medical Research, 9 Princes Street, Fitzroy VIC 3065, Australia
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy VIC 3065, Australia
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