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Custodia A, Aramburu-Núñez M, Rodríguez-Arrizabalaga M, Pías-Peleteiro JM, Vázquez-Vázquez L, Camino-Castiñeiras J, Aldrey JM, Castillo J, Ouro A, Sobrino T, Romaus-Sanjurjo D. Biomarkers Assessing Endothelial Dysfunction in Alzheimer's Disease. Cells 2023; 12:cells12060962. [PMID: 36980302 PMCID: PMC10047803 DOI: 10.3390/cells12060962] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/07/2023] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
Alzheimer's disease (AD) is the most common degenerative disorder in the elderly in developed countries. Currently, growing evidence is pointing at endothelial dysfunction as a key player in the cognitive decline course of AD. As a main component of the blood-brain barrier (BBB), the dysfunction of endothelial cells driven by vascular risk factors associated with AD allows the passage of toxic substances to the cerebral parenchyma, producing chronic hypoperfusion that eventually causes an inflammatory and neurotoxic response. In this process, the levels of several biomarkers are disrupted, such as an increase in adhesion molecules that allow the passage of leukocytes to the cerebral parenchyma, increasing the permeability of the BBB; moreover, other vascular players, including endothelin-1, also mediate artery inflammation. As a consequence of the disruption of the BBB, a progressive neuroinflammatory response is produced that, added to the astrogliosis, eventually triggers neuronal degeneration (possibly responsible for cognitive deterioration). Recently, new molecules have been proposed as early biomarkers for endothelial dysfunction that can constitute new therapeutic targets as well as early diagnostic and prognostic markers for AD.
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Affiliation(s)
- Antía Custodia
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Marta Aramburu-Núñez
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Mariña Rodríguez-Arrizabalaga
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
| | - Juan Manuel Pías-Peleteiro
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Laura Vázquez-Vázquez
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Javier Camino-Castiñeiras
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - José Manuel Aldrey
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - José Castillo
- Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
| | - Alberto Ouro
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Tomás Sobrino
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Daniel Romaus-Sanjurjo
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Panda A, Halder K, Debnath D, De S, Dasgupta S. Thermodynamics of the Association of Aminoglycoside Antibiotics with Human Angiogenin. Protein Pept Lett 2023; 30:92-101. [PMID: 36281865 DOI: 10.2174/0929866530666221021111823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/12/2022] [Accepted: 04/13/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND The body needs to maintain a firm balance between the inducers and inhibitors of angiogenesis, the process of proliferation of blood vessels from pre-existing ones. Human angiogenin (hAng), being a potent inducer of angiogenesis, is a cause of tumor cell proliferation, therefore its inhibition becomes a vital area of research. Aminoglycosides are linked ring systems consisting of amino sugars and an aminocyclitol ring and are in use in clinical practices for a long time. These compounds have found clinical uses as antibacterial agents that inhibit bacterial protein synthesis. OBJECTIVE Gentamycin C1, Kanamycin A, Neomycin B, Paromomycin I, and Streptomycin A are commonly used aminoglycoside antibiotics that have been used for the present study. Among these, Neomycin has reported inhibitory activity against angiogenin-induced angiogenesis on the chicken chorioallantoic membrane. This study focuses on the thermodynamic parameters involved in the interactions of these antibiotics with hAng. METHODS Agarose gel-based assay, Fluorescence quenching studies and Docking studies. RESULTS Anti-ribonucleolytic effect of the antibiotics was observed qualitatively using an agarose gelbased assay, which shows that Neomycin exhibits the most efficient inhibition of hAng. Fluorescence quenching studies at different temperatures, using Stern-Volmer and van't Hoff equations provide information about the thermodynamics of binding, which furthermore highlights the higher binding constant of Neomycin. Docking studies showed that the antibiotics preferably interact with the nuclear translocation site, except Streptomycin, which shows affinity towards the ribonucleolytic site of the protein with very less affinity value. CONCLUSION The study has shown the highly spontaneous formation of Neomycin-hAng complex, giving an exothermic reaction with increase in the degree of freedom of the protein-ligand complex.
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Affiliation(s)
- Atashi Panda
- Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Krishna Halder
- Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Debkumar Debnath
- Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Soumya De
- School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Swagata Dasgupta
- Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
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The role of patient characteristics and the effects of angiogenic therapies on the microvasculature of the meniscus: A systematic review. Knee 2022; 38:91-106. [PMID: 35964436 DOI: 10.1016/j.knee.2022.07.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/12/2022] [Accepted: 07/15/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Considerable interindividual variation in meniscal microvascularization has been reported. The purpose of this review was to identify which patient characteristics affect meniscal microvascularization and provide a structured overview of angiogenic therapies that influence meniscal neovascularization. METHODS A systematic literature search was undertaken using PubMed, Embase, Web of Science, Cochrane library and Emcare from inception to November 2021. Studies reporting on (1) Patient characteristics that affect meniscal microvascularization, or (2) Therapies that induce neovascularization in meniscal tissue were included. Studies were graded in quality using the Anatomical Quality Assessment (AQUA) tool. The study was registered with PROSPERO(ID:CRD42021242479). RESULTS Thirteen studies reported on patient characteristics and eleven on angiogenic therapies. The influence of Age, Degenerative knee, Gender, and Race was reported. Age is the most studied factor. The entire meniscus is vascularized around birth. With increasing age, vascularization decreases from the inner to the peripheral margin. Around 11 years, blood vessels are primarily located in the peripheral third of the menisci. There seems to be a further decrease in vascularization with increasing age in adults, yet conflicting literature exists. Degenerative changes of the knee also seem to influence meniscal vascularization, but evidence is limited. Angiogenic therapies to improve meniscal vascularization have only been studied in preclinical setting. The use of synovial flap transplantation, stem cell therapy, vascular endothelial growth factor, and angiogenin has shown promising results. CONCLUSION To decrease failure rates of meniscal repair, a better understanding of patient-specific vascular anatomy is essential. Translational clinical research is needed to investigate the clinical value of angiogenic therapies.
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Sitarek P, Merecz-Sadowska A, Śliwiński T, Zajdel R, Kowalczyk T. An In Vitro Evaluation of the Molecular Mechanisms of Action of Medical Plants from the Lamiaceae Family as Effective Sources of Active Compounds against Human Cancer Cell Lines. Cancers (Basel) 2020; 12:E2957. [PMID: 33066157 PMCID: PMC7601952 DOI: 10.3390/cancers12102957] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/05/2020] [Accepted: 10/09/2020] [Indexed: 12/25/2022] Open
Abstract
It is predicted that 1.8 million new cancer cases will be diagnosed worldwide in 2020; of these, the incidence of lung, colon, breast, and prostate cancers will be 22%, 9%, 7%, and 5%, respectively according to the National Cancer Institute. As the global medical cost of cancer in 2020 will exceed about $150 billion, new approaches and novel alternative chemoprevention molecules are needed. Research indicates that the plants of the Lamiaceae family may offer such potential. The present study reviews selected species from the Lamiaceae and their active compounds that may have the potential to inhibit the growth of lung, breast, prostate, and colon cancer cells; it examines the effects of whole extracts, individual compounds, and essential oils, and it discusses their underlying molecular mechanisms of action. The studied members of the Lamiaceae are sources of crucial phytochemicals that may be important modulators of cancer-related molecular targets and can be used as effective factors to support anti-tumor treatment.
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Affiliation(s)
- Przemysław Sitarek
- Department of Biology and Pharmaceutical Botany, Medical University of Lodz, 90-151 Lodz, Poland
| | - Anna Merecz-Sadowska
- Department of Economic Informatics, University of Lodz, 90-214 Lodz, Poland; (A.M.-S.); (R.Z.)
| | - Tomasz Śliwiński
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
| | - Radosław Zajdel
- Department of Economic Informatics, University of Lodz, 90-214 Lodz, Poland; (A.M.-S.); (R.Z.)
| | - Tomasz Kowalczyk
- Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland;
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Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats. Cells 2020; 9:cells9061435. [PMID: 32527043 PMCID: PMC7348746 DOI: 10.3390/cells9061435] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/30/2020] [Accepted: 06/04/2020] [Indexed: 12/16/2022] Open
Abstract
Intrauterine growth retardation (IUGR), which induces epigenetic modifications and permanent changes in gene expression, has been associated with the development of type 2 diabetes. Using a rat model of IUGR, we performed ChIP-Seq to identify and map genome-wide histone modifications and gene dysregulation in islets from 2- and 10-week rats. IUGR induced significant changes in the enrichment of H3K4me3, H3K27me3, and H3K27Ac marks in both 2-wk and 10-wk islets, which were correlated with expression changes of multiple genes critical for islet function in IUGR islets. ChIP-Seq analysis showed that IUGR-induced histone mark changes were enriched at critical transcription factor binding motifs, such as C/EBPs, Ets1, Bcl6, Thrb, Ebf1, Sox9, and Mitf. These transcription factors were also identified as top upstream regulators in our previously published transcriptome study. In addition, our ChIP-seq data revealed more than 1000 potential bivalent genes as identified by enrichment of both H3K4me3 and H3K27me3. The poised state of many potential bivalent genes was altered by IUGR, particularly Acod1, Fgf21, Serpina11, Cdh16, Lrrc27, and Lrrc66, key islet genes. Collectively, our findings suggest alterations of histone modification in key transcription factors and genes that may contribute to long-term gene dysregulation and an abnormal islet phenotype in IUGR rats.
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Brandhorst H, Brandhorst D, Abraham A, Acreman S, Schive SW, Scholz H, Johnson PR. Proteomic Profiling Reveals the Ambivalent Character of the Mesenchymal Stem Cell Secretome: Assessing the Effect of Preconditioned Media on Isolated Human Islets. Cell Transplant 2020; 29:963689720952332. [PMID: 33150790 PMCID: PMC7784517 DOI: 10.1177/0963689720952332] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 07/23/2020] [Accepted: 08/03/2020] [Indexed: 12/23/2022] Open
Abstract
Previous studies in rodents have indicated that function and survival of transplanted islets can be substantially improved by mesenchymal stem cells (MSC). The few human islet studies to date have confirmed these findings but have not determined whether physical contact between MSC and islets is required or whether the benefit to islets results from MSC-secreted proteins. This study aimed to investigate the protective capacity of MSC-preconditioned media for human islets. MSC were cultured for 2 or 5 days in normoxia or hypoxia before harvesting the cell-depleted media for human islet culture in normoxia or hypoxia for 6-8 or 3-4 days, respectively. To characterize MSC-preconditioned media, proteomic secretome profiling was performed to identify angiogenesis- and inflammation-related proteins. A protective effect of MSC-preconditioned media on survival and in vitro function of hypoxic human islets was observed irrespective of the atmosphere used for MSC preconditioning. Islet morphology changed markedly when media from hypoxic MSC were used for culture. However, PDX-1 and insulin gene expression did not confirm a change in the genetic phenotype of these islets. Proteomic profiling of preconditioned media revealed the heterogenicity of the secretome comprising angiogenic and antiapoptotic as well as angiostatic or proinflammatory mediators released at an identical pattern regardless whether MSC had been cultured in normoxic or hypoxic atmosphere. These findings do not allow a clear discrimination between normoxia and hypoxia as stimulus for protective MSC capabilities but indicate an ambivalent character of the MSC angiogenesis- and inflammation-related secretome. Nevertheless, culture of human islets in acellular MSC-preconditioned media resulted in improved morphological and functional islet integrity suggesting a disbalance in favor of protective factors. Further approaches should aim to eliminate potentially detrimental factors to enable the production of advanced clinical grade islet culture media with higher protective qualities.
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Affiliation(s)
- Heide Brandhorst
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Daniel Brandhorst
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Anju Abraham
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Samuel Acreman
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Simen W. Schive
- Department of Transplantation Medicine and Institute for Surgical Research, Oslo University Hospital, Oslo, Norway
| | - Hanne Scholz
- Department of Transplantation Medicine and Institute for Surgical Research, Oslo University Hospital, Oslo, Norway
- Hybrid Technology Hub, Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Paul R.V. Johnson
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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Khosroshahi NS, Pouladi N, Shavali M, Ghafouri F, Abdolahi S, Hossinpour Feizi MA. Association of –634 G > C VEGF-A polymorphism in thyroid cancer patients in North West of Iran. Meta Gene 2019. [DOI: 10.1016/j.mgene.2019.100611] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
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Sub-chronic 90-day toxicity of neamine in SD rats and its anti-liver cancer activity in vitro and in vivo. Toxicol Appl Pharmacol 2017; 315:50-59. [PMID: 27940282 DOI: 10.1016/j.taap.2016.12.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 11/25/2016] [Accepted: 12/07/2016] [Indexed: 11/21/2022]
Abstract
Neamine, an inhibitor of angiogenin (ANG), is a new investigative anticancer drug currently in preclinical stage. Here we report the 90-day sub-chronic toxicity of neamine in SD rats and its anti-liver cancer activity in vitro and in vivo. Neamine has a No Observed Adverse Effect Level (NOAEL) of 12 and 16mg·kg-1·d-1 for female and male rats, respectively. No mortality was found. The adverse effects included increased organ coefficients of spleen and kidney, increased BUN in both female and male rats at high dose, increased CR and decreased organ coefficients of heart and liver in male rats at high dose. All of which, except the kidney coefficient and BUN in males, returned to normal levels after 28-day recovery. Histopathological examination revealed vacuolar degeneration of glomerulus, degeneration of renal tubules and cast in the kidneys, which were also recovered except in males of high-dosing group. These results indicate that kidney is the most susceptible organ for neamine toxicity. Tissue microarray analysis validated that ANG is up-regulated in hepatocellular carcinoma accompanied by increased nuclear translocation, suggesting that ANG is a possible target for drug development in liver cancer treatment. Neamine blocked nuclear translocation of ANG in HUVEC and HepG2 cells, and inhibited ANG-stimulated cell proliferation without affecting basal level cell proliferation. Neamine also inhibited progression of HepG2 xenografts in athymic mice accompanied by decreased angiogenesis and cancer cell proliferation. These results suggest that neamine is a specific ANG inhibitor with low toxicity and high anti-liver cancer efficacy.
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Drebert Z, MacAskill M, Doughty-Shenton D, De Bosscher K, Bracke M, Hadoke PWF, Beck IM. Colon cancer-derived myofibroblasts increase endothelial cell migration by glucocorticoid-sensitive secretion of a pro-migratory factor. Vascul Pharmacol 2016; 89:19-30. [PMID: 27717848 PMCID: PMC5328197 DOI: 10.1016/j.vph.2016.10.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 08/08/2016] [Accepted: 10/03/2016] [Indexed: 02/04/2023]
Abstract
Angiogenesis is important in cancer progression and can be influenced by tumor-associated myofibroblasts. We addressed the hypothesis that glucocorticoids indirectly affect angiogenesis by altering the release of pro-angiogenic factors from colon cancer-derived myofibroblasts. Our study shows that glucocorticoids reduced prostanoids, urokinase-type plasminogen activator (uPA) and angiopoietin-like protein-2 (ANGPTL2) levels, but increased angiogenin (ANG) in supernatant from human CT5.3hTERT colon cancer-derived myofibroblasts. Conditioned medium from solvent- (CMS) and dexamethasone (Dex)-treated (CMD) myofibroblasts increased human umbilical vein endothelial cell (HUVEC) proliferation, but did not affect expression of pro-angiogenic factors or tube-like structure formation (by HUVECs or human aortic ECs). In a HUVEC scratch assay CMS-induced acceleration of wound healing was blunted by CMD treatment. Moreover, CMS-induced neovessel growth in mouse aortic rings ex vivo was also blunted using CMD. The latter effect could be ascribed to both Dex-driven reduction of secreted factors and potential residual Dex present in CMD (indicated using a dexamethasone-spiked CMS control). A similar control in the scratch assay, however, revealed that altered levels of factors in the CMD, and not potential residual Dex, were responsible for decreased wound closure. In conclusion, our results suggest that glucocorticoids indirectly alter endothelial cell function during tumor development in vivo.
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Affiliation(s)
- Zuzanna Drebert
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology & Experimental Cancer Research, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Mark MacAskill
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Dahlia Doughty-Shenton
- Edinburgh Phenotypic Assay Centre, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Karolien De Bosscher
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Receptor Research Laboratories, Nuclear Receptor Lab (NRL), VIB Department of Medical Protein Research, Ghent University, Ghent, Belgium
| | - Marc Bracke
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology & Experimental Cancer Research, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Patrick W F Hadoke
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
| | - Ilse M Beck
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology & Experimental Cancer Research, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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Lankford L, Selby T, Becker J, Ryzhuk V, Long C, Farmer D, Wang A. Early gestation chorionic villi-derived stromal cells for fetal tissue engineering. World J Stem Cells 2015; 7:195-207. [PMID: 25621120 PMCID: PMC4300931 DOI: 10.4252/wjsc.v7.i1.195] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 11/04/2014] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the potential for early gestation placenta-derived mesenchymal stromal cells (PMSCs) for fetal tissue engineering. METHODS PMSCs were isolated from early gestation chorionic villus tissue by explant culture. Chorionic villus sampling (CVS)-size tissue samples (mean = 35.93 mg) were used to test the feasibility of obtaining large cell numbers from CVS within a clinically relevant timeframe. We characterized PMSCs isolated from 6 donor placentas by flow cytometry immunophenotyping, multipotency assays, and through immunofluorescent staining. Protein secretion from PMSCs was examined using two cytokine array assays capable of probing for over 70 factors in total. Delivery vehicle compatibility of PMSCs was determined using three common scaffold systems: fibrin glue, collagen hydrogel, and biodegradable nanofibrous scaffolds made from a combination of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA). Viral transduction of PMSCs was performed using a Luciferase-GFP-containing lentiviral vector and efficiency of transduction was tested by fluorescent microscopy and flow cytometry analysis. RESULTS We determined that an average of 2.09 × 10(6) (SD ± 8.59 × 10(5)) PMSCs could be obtained from CVS-size tissue samples within 30 d (mean = 27 d, SD ± 2.28), indicating that therapeutic numbers of cells can be rapidly expanded from very limited masses of tissue. Immunophenotyping by flow cytometry demonstrated that PMSCs were positive for MSC markers CD105, CD90, CD73, CD44, and CD29, and were negative for hematopoietic and endothelial markers CD45, CD34, and CD31. PMSCs displayed trilineage differentiation capability, and were found to express developmental transcription factors Sox10 and Sox17 as well as neural-related structural proteins NFM, Nestin, and S100β. Cytokine arrays revealed a robust and extensive profile of PMSC-secreted cytokines and growth factors, and detected 34 factors with spot density values exceeding 10(3). Detected factors had widely diverse functions that include modulation of angiogenesis and immune response, cell chemotaxis, cell proliferation, blood vessel maturation and homeostasis, modulation of insulin-like growth factor activity, neuroprotection, extracellular matrix degradation and even blood coagulation. Importantly, PMSCs were also determined to be compatible with both biological and synthetic material-based delivery vehicles such as collagen and fibrin hydrogels, and biodegradable nanofiber scaffolds made from a combination of PLA and PLGA. Finally, we demonstrated that PMSCs can be efficiently transduced (> 95%) with a Luciferase-GFP-containing lentiviral vector for future in vivo cell tracking after transplantation. CONCLUSION Our findings indicate that PMSCs represent a unique source of cells that can be effectively utilized for in utero cell therapy and tissue engineering.
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Affiliation(s)
- Lee Lankford
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - Taryn Selby
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - James Becker
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - Volodymyr Ryzhuk
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - Connor Long
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - Diana Farmer
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - Aijun Wang
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
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Pyatibratov MG, Kostyukova AS. New insights into the role of angiogenin in actin polymerization. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2012; 295:175-98. [PMID: 22449490 DOI: 10.1016/b978-0-12-394306-4.00011-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Angiogenin is a potent stimulator of angiogenesis. It interacts with endothelial cells and induces a wide range of cellular responses initiating a process of blood vessel formation. One important target of angiogenin is endothelial cell-surface actin, and their interaction might be one of crucial steps in angiogenin-induced neovascularization. Recently, it was shown that angiogenin inhibits polymerization of G-actin and changes the physical properties of F-actin. These observations suggest that angiogenin may cause changes in the cell cytoskeleton. This chapter reviews the current state of the literature regarding angiogenin structure and function and discusses the relationship between the angiogenin and actin and possible functional roles of their interaction.
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Affiliation(s)
- Mikhail G Pyatibratov
- Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, Russia
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Bharadwaj S, Naidu AGT, Betageri GV, Prasadarao NV, Naidu AS. Milk ribonuclease-enriched lactoferrin induces positive effects on bone turnover markers in postmenopausal women. Osteoporos Int 2009; 20:1603-11. [PMID: 19172341 DOI: 10.1007/s00198-009-0839-8] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2008] [Accepted: 12/12/2008] [Indexed: 11/25/2022]
Abstract
UNLABELLED Current treatments for postmenopausal osteoporosis suffer from side effects. Safe and natural milk proteins, ribonuclease, and lactoferrin promote formation of new capillaries and bone formation. A ribonuclease-enriched lactoferrin supplement studied here, demonstrates significant reduction in resorption and increase in formation, towards restoring the balance of bone turnover within 6 months. INTRODUCTION Osteoporosis, a major health issue among postmenopausal women, causes increased bone resorption and reduced bone formation. A reduction in angiogenesis could also contribute to this imbalance. Current treatments such as hormone replacement therapy and bisphosphonates have drawbacks of severe side effects. Milk ribonuclease (RNase) is known to promote angiogenesis and lactoferrin (LF) to stimulate bone formation by osteoblasts. We examine the effect of ribonuclease-enriched lactoferrin supplement on the bone health of postmenopausal women. METHODS A total of 38 healthy, postmenopausal women, aged 45 to 60 years were randomized into placebo or RNAse-enriched-LF (R-ELF) supplement groups. The bone health status was monitored by assessing bone resorption markers, serum N-telopeptides (NTx), and urine deoxypyridinoline (Dpd) crosslinks and serum bone formation markers, bone-specific alkaline phosphatase (BAP), and osteocalcin (OC). RESULTS R-ELF supplementation demonstrated a decrease in urine Dpd levels by 14% (19% increase for placebo) and serum NTx maintained at 24% of the baseline (41% for placebo), while serum BAP and OC levels showed a 45% and 16% elevation (25% and 5% for placebo). CONCLUSIONS R-ELF supplementation demonstrated a statistically significant reduction in bone resorption and increase in osteoblastic bone formation, to restore the balance of bone turnover within a short period.
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Affiliation(s)
- S Bharadwaj
- N-terminus Research Laboratory, 981 Corporate Center Dr., # 110, Pomona, CA 91768, USA
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Chen Y, Zhang S, Chen YP, Lin JY. Increased expression of angiogenin in gastric carcinoma in correlation with tumor angiogenesis and proliferation. World J Gastroenterol 2006; 12:5135-9. [PMID: 16937522 PMCID: PMC4088009 DOI: 10.3748/wjg.v12.i32.5135] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the implication of angiogenin (ANG) in the neovascularizaton and growth of human gastric carcinoma (HGC).
METHODS: ANG mRNA expression in HGC specimens obtained by surgical resection from patients with HGC were examined by RT-PCR. ANG, Ki-67, VEGF protein expression and microvessel density (MVD) in HGC specimens were detected by immunohistochemistry.
RESULTS: RT-PCR showed significantly higher ANG mRNA expression (0.482 ± 0.094) in HGC tissues than in the surrounding nontumorous tissues (0.276 ± 0.019, P = 0.03). MVD within tumorous tissues increased significantly with ANG mRNA expression (r = 0.380, P = 0.001) and ANG protein expression (P < 0.01). The ANG expression levels of cancer tissues were positively correlated with VEGF (P < 0.01) and the proliferation index of cancer cells (P < 0.01).
CONCLUSION: ANG is one of the neovascularization factors of HGC. ANG may work in coordination with VEGF, and promote the proliferation of HGC cells.
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Affiliation(s)
- Yu Chen
- Department of Physiology and Pathophysiology, Fujian Medical University, Fuzhou 350004, Fujian Province, China
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Roiz L, Smirnoff P, Bar-Eli M, Schwartz B, Shoseyov O. ACTIBIND, an actin-binding fungal T2-RNase with antiangiogenic and anticarcinogenic characteristics. Cancer 2006; 106:2295-308. [PMID: 16586499 DOI: 10.1002/cncr.21878] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND ACTIBIND is an Aspergillus niger extracellular ribonuclease (T2-ribonuclease [RNase]) that possesses actin-binding activity. In plants, ACTIBIND inhibits the elongation and alters the orientation of pollen tubes by interfering with the intracellular actin network. The question rose whether ACTIBIND can also affect mammalian cancer development. METHODS Cell colony formation was performed in human colon (HT-29, Caco-2, RSB), breast (ZR-75-1), and ovarian (2780) cancer cells in the presence or absence of 1 muM ACTIBIND. In HT-29 and ZR-75-1 cells, the effect of ACTIBIND on cell migration was studied by microscopic observations and by invasion assay through Matrigel. Tube formation was assessed in human umbilical vein endothelial cells (HUVEC) in the presence of angiogenin or basic fibroblast growth factor (bFGF) (1 microg/mL each) following overnight incubation with 1 or 10 microM ACTIBIND. In an athymic mouse xenograft model, HT-29 cells were injected subcutaneously, followed by subcutaneous (0.4-8 mg/mouse/injection) or intraperitoneal (0.001-1 mg/mouse/injection) injections of ACTIBIND. In a rat dimethylhydrazine (DMH)-colorectal carcinogenesis model, ACTIBIND was released directly into the colon via osmotic micropumps (250 microg/rat/day) or given orally via microcapsules (1.6 mg/rat/day). Aberrant crypt foci, tumors in the distal colon, and tumor blood vessels were examined. RESULTS ACTIBIND had an anticlonogenic effect unrelated to its ribonuclease activity. It also inhibited angiogenin-induced HUVEC tube formation in a dose-responsive manner. ACTIBIND was found to bind actin in vitro. It also bound to cancer cell surfaces, leading to disruption of the internal actin network and inhibiting cell motility and invasiveness through Matrigel-coated filters. In mice, ACTIBIND inhibited HT-29 xenograft tumor development, given either as a subcutaneous or intraperitoneal treatment. In rats, ACTIBIND exerted preventive and therapeutic effects on developing colonic tumors induced by DMH. It also reduced the degree of tumor observation. CONCLUSIONS This study indicated that ACTIBIND is an effective antiangiogenic and anticarcinogenic factor.
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Affiliation(s)
- Levava Roiz
- Institute of Plant Science and Genetics in Agriculture, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot, Israel
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Ostrowski SE, Reilly AA, Collins DN, Ramsingh AI. Progression or resolution of coxsackievirus B4-induced pancreatitis: a genomic analysis. J Virol 2004; 78:8229-37. [PMID: 15254194 PMCID: PMC446102 DOI: 10.1128/jvi.78.15.8229-8237.2004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2004] [Accepted: 04/28/2004] [Indexed: 01/24/2023] Open
Abstract
Group B coxsackieviruses are associated with chronic inflammatory diseases of the pancreas, heart, and central nervous system. Chronic pancreatitis, which can develop from acute pancreatitis, is considered a premalignant disorder because it is a major risk factor for pancreatic cancer. To explore the genetic events underlying the progression of acute to chronic disease, a comparative analysis of global gene expression during coxsackievirus B4-induced acute and chronic pancreatitis was undertaken. A key feature of acute pancreatitis that resolved was tissue regeneration, which was accompanied by increased expression of genes involved in cell growth, inhibition of apoptosis, and embryogenesis and by increased division of acinar cells. Acute pancreatitis that progressed to chronic pancreatitis was characterized by lack of tissue repair, and the expression map highlighted genes involved in apoptosis, acinoductular metaplasia, remodeling of the extracellular matrix, and fibrosis. Furthermore, immune responses appeared skewed toward development of alternatively activated (M2) macrophages and T helper 2 (Th2) cells during disease that resolved and toward classically activated (M1) macrophages and Th1 cells during disease that progressed. Our hypothesis is that growth and differentiation signals coupled with the M2/Th2 milieu favor acinar cell proliferation, while diminished growth signals and the M1/Th1 milieu favor apoptosis of acinar cells and remodeling/proliferation of the extracellular matrix, resulting in fibrosis.
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Affiliation(s)
- Stephanie E Ostrowski
- Departmen tof Biomedical Science, School of Public Health, State University of New York at Albany, Albany, New York 12237, USA
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