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1
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Chiang B, Chung YG, Prausnitz MR. Suprachoroidal Drug Delivery for VEGF Suppression in Wet AMD and Other Diseases With Choroidal Neovascularization. Am J Ophthalmol 2025:S0002-9394(25)00196-5. [PMID: 40280278 DOI: 10.1016/j.ajo.2025.04.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 04/15/2025] [Accepted: 04/20/2025] [Indexed: 04/29/2025]
Abstract
PURPOSE Choroidal neovascularization caused by age-related macular degeneration, among other diseases, causes significant visual impairment. Intravitreal therapeutics inhibiting vascular endothelial growth factor (VEGF) signaling have shown excellent safety and efficacy in regressing choroidal neovascularization and improving vision. Current US Food and Drug Administration (FDA)-approved treatments deliver these drugs into the vitreous cavity, even though choroidal neovascularization originates from aberrant signaling in the choroid. DESIGN Systematic review. METHODS A literature search was conducted across PubMed and Google Scholar from inception up to December 31, 2024, focusing on studies investigating suprachoroidal delivery of anti-VEGF therapy. Randomized controlled trials, cohort studies, and case-control studies were included, whereas case reports and review articles were excluded. RESULTS A total of 15 peer-reviewed articles, 3 press releases, 6 conference abstracts and presentations, and 8 clinical trials were identified that were relevant to the topic of suprachoroidal delivery of anti-VEGF therapy. CONCLUSIONS The suprachoroidal space is a potential space between the sclera and the choroid, which has recently become a route of delivery in an FDA-approved treatment. Notably, suprachoroidal delivery results in higher choroidal drug concentrations than intravitreal delivery. Promising results thus far have been seen with suprachoroidal delivery of VEGF-targeting therapies in clinical and preclinical studies; however, future work is needed to more fully demonstrate safety and efficacy.
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Affiliation(s)
- Bryce Chiang
- From the Wilmer Eye Institute (B.C.), Johns Hopkins University, Baltimore, Maryland, USA.
| | - Yooree Grace Chung
- Wallace Coulter Department of Biomedical Engineering at Georgia Tech and Emory University (Y.G.C., M.R.P.), Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Mark R Prausnitz
- School of Chemical & Biomolecular Engineering (M.R.P.), Georgia Institute of Technology, Atlanta, Georgia, USA.
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2
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Clemens MS, Tyree MF, Stenhouse C. Utero-placental adaptations in response to intrauterine growth restriction in swine. Domest Anim Endocrinol 2025; 91:106917. [PMID: 39862557 PMCID: PMC11850212 DOI: 10.1016/j.domaniend.2025.106917] [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: 11/01/2024] [Revised: 12/24/2024] [Accepted: 01/15/2025] [Indexed: 01/27/2025]
Abstract
Intrauterine growth restriction (IUGR) is a common condition in swine associated with high piglet mortality and morbidity that develops in early gestation. This review article explores differences in uterine and placental tissues associated with IUGR fetuses compared to their normally-grown littermates at different stages of gestation. Specifically, we will review the available knowledge to date describing differences in 1) structure, 2) cellular apoptosis and proliferation, 3) adhesion, and 4) angiogenesis in endometrial and placental tissues associated with IUGR fetuses across gestation. Improved understanding of the mechanisms regulating IUGR is essential for the development of strategies to minimize the impact of IUGR in swine operations, thus improving reproductive efficiency and animal welfare.
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Affiliation(s)
- Morgan S Clemens
- Department of Animal Science, Pennsylvania State University, University Park, PA, 16802, USA
| | - Maria F Tyree
- Department of Animal Science, Pennsylvania State University, University Park, PA, 16802, USA
| | - Claire Stenhouse
- Department of Animal Science, Pennsylvania State University, University Park, PA, 16802, USA.
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3
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Yan S, Zhao Y, Yang Y, Liu B, Xu W, Ma Z, Yang Q. Progress of ADAM17 in Fibrosis-Related Diseases. Mediators Inflamm 2025; 2025:9999723. [PMID: 40224489 PMCID: PMC11986189 DOI: 10.1155/mi/9999723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Accepted: 01/09/2025] [Indexed: 04/15/2025] Open
Abstract
Fibrosis leads to structural damage and functional decline and is characterized by an accumulation of fibrous connective tissue and a reduction in parenchymal cells. Because of its extremely poor prognosis, organ fibrosis poses a significant economic burden. In order to prevent and treat fibrosis more effectively, potential mechanisms need to be investigated. A disintegrin and metalloprotease 17 (ADAM17) is a membrane-bound protein. It regulates intracellular signaling and membrane protein degradation. Fibrosis mediated by ADAM17 has been identified as an important contributor, although the specific relationship between its multiple regulatory functions and the pathogenesis is unclear. This article describes ADAM17 activation, function, and regulation, as well as the role of ADAM17 mediated fibrosis injury in kidney, liver, heart, lung, skin, endometrium, and retina. To develop new therapeutic approaches based on ADAM17 related signal pathways.
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Affiliation(s)
- Suyan Yan
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Yaqi Zhao
- Department of Rheumatology and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, China
| | - Yuyu Yang
- UCL School of Pharmacy, University College London, London, UK
| | - Baocheng Liu
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Wei Xu
- Department of Rheumatology and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, China
| | - Zhenzhen Ma
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
- Shandong University of Traditional Chinese Medicine, Jinan 250021, Shandong, China
| | - Qingrui Yang
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
- Department of Rheumatology and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, China
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4
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Dey S, Ghosh M, Dev A. Signalling and molecular pathways, overexpressed receptors of colorectal cancer and effective therapeutic targeting using biogenic silver nanoparticles. Gene 2025; 936:149099. [PMID: 39557372 DOI: 10.1016/j.gene.2024.149099] [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: 08/15/2024] [Revised: 10/18/2024] [Accepted: 11/13/2024] [Indexed: 11/20/2024]
Abstract
Increasing morbidity and mortality in CRC is a potential threat to human health. The major challenges for better treatment outcomes are the heterogeneity of CRC cases, complicated molecular pathway cross-talks, the influence of gut dysbiosis in CRC, and the lack of multimodal target-specific drug delivery. The overexpression of many receptors in CRC cells may pave the path for targeting them with multiple ligands. The design of a more target-specific drug-delivery device with multiple ligand-functionalized, green-synthesized silver nanoparticles is highly promising and may also deliver other approved chemotherapeutic agents. This review presents the various aspects of colorectal cancer and over-expressed receptors that can be targeted with appropriate ligands to enhance the specific drug delivery potency of green synthesised silver nanoparticles. This review aims to broaden further research into this multi-ligand functionalised, safer and effective silver nano drug delivery system.
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Affiliation(s)
- Sandip Dey
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India
| | - Manik Ghosh
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India
| | - Abhimanyu Dev
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India.
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5
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Alvarez-Olmedo D, Kamaliddin C, Verhey TB, Ho M, De Vinney R, Chaconas G. Transendothelial migration of the Lyme disease spirochete involves spirochete internalization as an intermediate step through a transcellular pathway that involves Cdc42 and Rac1. Microbiol Spectr 2025; 13:e0222124. [PMID: 39727396 PMCID: PMC11792520 DOI: 10.1128/spectrum.02221-24] [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: 09/04/2024] [Accepted: 11/22/2024] [Indexed: 12/28/2024] Open
Abstract
Despite its importance in pathogenesis, the hematogenous dissemination pathway of Borrelia burgdorferi is still largely uncharacterized. To probe the molecular details of transendothelial migration more easily, we studied this process using cultured primary or telomerase-immortalized human microvascular endothelial cells in a medium that maintains both the human cells and the spirochetes. In B. burgdorferi-infected monolayers, we observed ~55% of wild-type spirochetes crossing the monolayer. Microscopic characterization revealed entrance points across the cellular surface rather than at cellular junctions, supporting a transcellular route. In support of this pathway, locking the endothelial junctions using a vascular endothelial protein tyrosine phosphatase (VE-PTP) inhibitor did not reduce transendothelial migration. We also used inhibitors to block the most common endocytic pathways to elucidate effectors that might be involved in B. burgdorferi uptake and/or transmigration. Directly inhibiting Cdc42 reduced spirochete transmigration by impeding internalization. However, blocking Rac1 alone dramatically reduced transmigration by ~84% and resulted in a concomitant doubling in spirochete accumulation in the cell. Our combined results support that B. burgdorferi internalization is an intermediate step in the transendothelial migration process, which requires both Cdc42 and Rac1; Cdc42 is needed for spirochete internalization, while Rac1 is required for cellular egress. These are the first two host proteins implicated in B. burgdorferi transmigration across endothelial cells.IMPORTANCELyme borreliosis is caused by Borrelia burgdorferi and related bacteria. It is the most common tick-transmitted illness in the Northern Hemisphere. The ability of this pathogen to spread to a wide variety of locations results in a diverse set of clinical manifestations, yet little is known regarding vascular escape of the spirochete, an important pathway for dissemination. Our current work has studied the traversal of B. burgdorferi across a monolayer of microvascular endothelial cells grown using a new culture system. We show that this occurs by passage of the spirochetes directly through cells rather than at cellular junctions and that internalization of B. burgdorferi is an intermediate step in transmigration. We also identify the first two host proteins, Cdc42 and Rac1, that are used by the spirochetes to promote traversal of the cellular monolayer. Our new experimental system also provides a new avenue for further studies of this important process.
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Affiliation(s)
- Daiana Alvarez-Olmedo
- Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Claire Kamaliddin
- Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, The University of Calgary, Calgary, Alberta, Canada
| | - Theodore B. Verhey
- Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - May Ho
- Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, The University of Calgary, Calgary, Alberta, Canada
| | - Rebekah De Vinney
- Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, The University of Calgary, Calgary, Alberta, Canada
| | - George Chaconas
- Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, The University of Calgary, Calgary, Alberta, Canada
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6
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Azahaf S, Spit KA, de Blok CJM, Nanayakkara PWB. Increased FGF-19 levels following explantation in women with breast implant illness. Sci Rep 2025; 15:3652. [PMID: 39880914 PMCID: PMC11779942 DOI: 10.1038/s41598-025-88013-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 01/23/2025] [Indexed: 01/31/2025] Open
Abstract
Breast Implant Illness (BII) is characterized by a cluster of systemic and local symptoms affecting a subset of women with silicone breast implants. While symptom improvement is frequently observed following implant removal, the underlying mechanisms remain poorly understood, and the absence of reliable biomarkers complicates clinical decision-making. Here, we investigate inflammatory protein profiles in 43 women with BII, comparing pre- and post-explantation levels using the Olink Target 96 Inflammation panel and Meso Scale Discovery technology for absolute quantification. Sixteen inflammatory proteins, including MCP-1, CD8A, and CCL11, were elevated post-explantation, with FGF-19 showing the most pronounced increase (64%). FGF-19 levels increased from a median of 136 pg/mL to 195 pg/mL (p = 0.001), comparable to levels in women with silicone breast implants but no BII. We propose that explantation may alleviate FGF-19 signaling disruption, restoring its metabolic benefits. These findings suggest FGF-19 as a potential diagnostic and therapeutic marker for BII, warranting further investigation.
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Affiliation(s)
- S Azahaf
- Section General Internal Medicine, Department of Internal Medicine, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - K A Spit
- Section General Internal Medicine, Department of Internal Medicine, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - C J M de Blok
- Section General Internal Medicine, Department of Internal Medicine, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - P W B Nanayakkara
- Section General Internal Medicine, Department of Internal Medicine, Amsterdam University Medical Centres, Amsterdam, The Netherlands.
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7
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Abtahi MS, Fotouhi A, Rezaei N, Akalin H, Ozkul Y, Hossein-Khannazer N, Vosough M. Nano-based drug delivery systems in hepatocellular carcinoma. J Drug Target 2024; 32:977-995. [PMID: 38847573 DOI: 10.1080/1061186x.2024.2365937] [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: 03/12/2024] [Revised: 05/22/2024] [Accepted: 06/02/2024] [Indexed: 06/19/2024]
Abstract
The high recurrence rate of hepatocellular carcinoma (HCC) and poor prognosis after medical treatment reflects the necessity to improve the current chemotherapy protocols, particularly drug delivery methods. Development of targeted and efficient drug delivery systems (DDSs), in all active, passive and stimuli-responsive forms for selective delivery of therapeutic drugs to the tumour site has been extended to improve efficacy and reduce the severe side effects. Recent advances in nanotechnology offer promising breakthroughs in the diagnosis, treatment and monitoring of cancer cells. In this review, the specific design of DDSs based on the different nano-particles and their surface engineering is discussed. In addition, the innovative clinical studies in which nano-based DDS was used in the treatment of HCC were highlighted.
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Affiliation(s)
- Maryam Sadat Abtahi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Biotechnology, School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran
| | - Alireza Fotouhi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Niloufar Rezaei
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hilal Akalin
- Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Yusuf Ozkul
- Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Nikoo Hossein-Khannazer
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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8
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Susman S, Santoso B, Makary MS. Locoregional Therapies for Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease. Biomedicines 2024; 12:2226. [PMID: 39457538 PMCID: PMC11504147 DOI: 10.3390/biomedicines12102226] [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: 09/01/2024] [Revised: 09/17/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide with an average five-year survival rate in the US of 19.6%. With the advent of HBV and HCV treatment and prevention, along with the rising rates of obesity, nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome are set to overtake infectious causes as the most common cause of HCC. While surgical resection and transplantation can be curative when amenable, the disease is most commonly unresectable on presentation, and other treatment approaches are the mainstay of therapy. In these patients, locoregional therapies have evolved as a vital tool in both palliation for advanced disease and as a bridge to surgical resection and transplantation. In this review, we will be exploring the primary locoregional therapies for HCC in patients with NAFLD, including transarterial chemoembolization (TACE), bland transarterial embolization (TAE), transarterial radioembolization (TARE), and percutaneous ablation.
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Affiliation(s)
- Stephen Susman
- Department of Radiology, Yale University Medical Center, New Haven, CT 06510, USA
| | - Breanna Santoso
- Heritage College of Osteopathic Medicine, Ohio University, Dublin, OH 43016, USA
| | - Mina S. Makary
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH 43202, USA
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9
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Shekatkar M, Kheur S, Deshpande S, Sakhare S, Sanap A, Kheur M, Bhonde R. Critical appraisal of the chorioallantoic membrane model for studying angiogenesis in preclinical research. Mol Biol Rep 2024; 51:1026. [PMID: 39340708 DOI: 10.1007/s11033-024-09956-x] [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: 03/01/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024]
Abstract
BACKGROUND Angiogenesis, the biological mechanism by which new blood vessels are generated from existing ones, plays a vital role in growth and development. Effective preclinical screening is necessary for the development of medications that may enhance or inhibit angiogenesis in the setting of different disorders. Traditional in vitro and, in vivo models of angiogenesis are laborious and time-consuming, necessitating advanced infrastructure for embryo culture. MAIN BODY A challenge encountered by researchers studying angiogenesis is the lack of appropriate techniques to evaluate the impact of regulators on the angiogenic response. An ideal test should possess reliability, technical simplicity, easy quantifiability, and, most importantly, physiological relevance. The CAM model, leveraging the extraembryonic membrane of the chicken embryo, offers a unique combination of accessibility, low cost, and rapid development, making it an attractive option for angiogenesis assays. This review evaluates the strengths and limitations of the CAM model in the context of its anatomical and physiological properties, and its relevance to human pathophysiological conditions. Its abundant capillary network makes it a common choice for studying angiogenesis. The CAM assay serves as a substitute for animal models and offers a natural setting for developing blood vessels and the many elements involved in the intricate interaction with the host. Despite its advantages, the CAM model's limitations are notable. These include species-specific responses that may not always extrapolate to humans and the ethical considerations of using avian embryos. We discuss methodological adaptations that can mitigate some of these limitations and propose future directions to enhance the translational relevance of this model. This review underscores the CAM model's valuable role in angiogenesis research and aims to guide researchers in optimizing its use for more predictive and robust preclinical studies. CONCLUSION The highly vascularized chorioallantoic membrane (CAM) of fertilized chicken eggs is a cost-effective and easily available method for screening angiogenesis, in comparison to other animal models.
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Affiliation(s)
- Madhura Shekatkar
- Department of Oral Pathology and Microbiology, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India
| | - Supriya Kheur
- Department of Oral Pathology and Microbiology, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India.
| | - Shantanu Deshpande
- Department of Pediatric and Preventive Dentistry, Bharati Vidyapeeth (Deemed to be University), Dental College and Hospital, Navi Mumbai, India
| | - Swapnali Sakhare
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India
| | - Avinash Sanap
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India
| | - Mohit Kheur
- Department of Prosthodontics, M.A. Rangoonwala College of Dental Sciences and Research Centre, Pune, Maharashtra, India
| | - Ramesh Bhonde
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India
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10
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Wen X, Li D, Wang H, Zhang D, Song J, Zhou Z, Huang W, Xia X, Hu X, Liu W, Gonzales J, Via LE, Zhang L, Wang D. IQGAP1 domesticates macrophages to favor mycobacteria survival via modulating NF-κB signal and augmenting VEGF secretion. Int Immunopharmacol 2024; 138:112549. [PMID: 38944950 DOI: 10.1016/j.intimp.2024.112549] [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: 01/15/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 07/02/2024]
Abstract
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), still ranks among the leading causes of annual human death by infectious disease. Mtb has developed several strategies to survive for years at a time within the host despite the presence of a robust immune response, including manipulating the progression of the inflammatory response and forming granulomatous lesions. Here we demonstrate that IQGAP1, a highly conserved scaffolding protein, compartmentalizes and coordinates multiple signaling pathways in macrophages infected with Mycobacterium marinum (Mm or M.marinum), the closest relative of Mtb. Upregulated IQGAP1 ultimately suppresses TNF-α production by repressing the MKK3 signal and reducing NF-κBp65 translocation, deactivating the p38MAPK pathway. Accordingly, IQGAP1 silencing and overexpression significantly alter p38MAPK activity by modulating the production of phosphorylated MKK3 during mycobacterial infection. Pharmacological inhibition of IQGAP1-associated microtubule assembly not only alleviates tissue damage caused by M.marinum infection but also significantly decreases the production of VEGF-a critical player for granuloma-associated angiogenesis during pathogenic mycobacterial infection. Similarly, IQGAP1 silencing in Mm-infected macrophages diminishes VEGF production, while IQGAP1 overexpression upregulates VEGF. Our data indicate that mycobacteria induce IQGAP1 to hijack NF-κBp65 activation, preventing the expression of proinflammatory cytokines as well as promoting VEGF production during infection and granuloma formation. Thus, therapies targeting host IQGAP1 may be a promising strategy for treating tuberculosis, particularly in drug-resistant diseases.
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Affiliation(s)
- Xin Wen
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Dan Li
- Department of Tuberculosis, The Third People's Hospital of Yichang, Yichang 443003, PR China
| | - Hankun Wang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Ding Zhang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Jingrui Song
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Ziwei Zhou
- State Key Laboratory of Genetic Engineering, Institute of Genetics, MOE Engineering Research Center of Gene Technology, School of Life Science, Fudan University, Shanghai 200433, PR China
| | - Weifeng Huang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Xuan Xia
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Xiaohong Hu
- Department of Tuberculosis, The Third People's Hospital of Yichang, Yichang 443003, PR China
| | - Wei Liu
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, PR China; Institute of Digestive Disease, China Three Gorges University, Yichang, PR China; Department of Gastroenterology, Yichang Central People's Hospital, Yichang, PR China
| | - Jacqueline Gonzales
- Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda 20982, MD, USA
| | - Laura E Via
- Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda 20982, MD, USA
| | - Lu Zhang
- State Key Laboratory of Genetic Engineering, Institute of Genetics, MOE Engineering Research Center of Gene Technology, School of Life Science, Fudan University, Shanghai 200433, PR China.
| | - Decheng Wang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China.
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11
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Alvarez-Olmedo D, Kamaliddin C, Verhey TB, Ho M, DeVinney R, Chaconas G. Transendothelial migration of the Lyme disease spirochete involves spirochete internalization as an intermediate step through a transcellular pathway that involves Cdc42 and Rac1. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.10.612329. [PMID: 39314306 PMCID: PMC11419014 DOI: 10.1101/2024.09.10.612329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Despite its importance in pathogenesis, the hematogenous dissemination pathway of B. burgdorferi is still largely uncharacterized. To probe the molecular details of transendothelial migration more easily, we studied this process using cultured primary or telomerase-immortalized human microvascular endothelial cells in a medium that maintains both the human cells and the spirochetes. In B. burgdorferi infected monolayers we observed ∼55% of wild-type spirochetes crossing the monolayer. Microscopic characterization revealed entrance points across the cellular surface rather than at cellular junctions, supporting a transcellular route. In support of this pathway, locking the endothelial junctions using a VE-PTP inhibitor did not reduce transendothelial migration. We also used inhibitors to block the most common endocytic pathways to elucidate effectors that might be involved in B. burgdorferi uptake and/or transmigration. Directly inhibiting Cdc42 reduced spirochete transmigration by impeding internalization. However, blocking Rac1 alone dramatically reduced transmigration and resulted in a concomitant increase in spirochete accumulation in the cell. Our combined results support that B. burgdorferi internalization is an intermediate step in the transendothelial migration process which requires both Cdc42 and Rac1; Cdc42 is needed for spirochete internalization while Rac1 is required for cellular egress. These are the first two host proteins implicated in B. burgdorferi transmigration across endothelial cells. IMPORTANCE Lyme borreliosis is caused by Borrelia burgdorferi and related bacteria. It is the most common tick-transmitted illness in the Northern Hemisphere. The ability of this pathogen to spread to a wide variety of locations results in a diverse set of clinical manisfestations, yet little is known regarding vascular escape of the spirochete, an important pathway for dissemination. Our current work has studied the traversal of B. burgdorferi across a monolayer of microvascular endothelial cells grown in culture. We show that this occurs by passage of the spirochetes directly through these cells rather than at cellular junctions and that internalization of B. burgdorferi is an intermediate step in the transmigration process. We also identify the first two host proteins, Cdc42 and Rac1, that are used by the spirochetes to promote traversal of the cellular monolayer. Our new experimental system also provides a new avenue for further studies of this important process.
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12
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Cozma A, Sitar-Tăuț AV, Orășan OH, Briciu V, Leucuța D, Sporiș ND, Lazăr AL, Mălinescu TV, Ganea AM, Sporiș BM, Vlad CV, Lupșe M, Țâru MG, Procopciuc LM. VEGF Polymorphisms ( VEGF-936 C/T, VEGF-634 G/C and VEGF-2578 C/A) and Cardiovascular Implications in Long COVID Patients. Int J Mol Sci 2024; 25:8667. [PMID: 39201353 PMCID: PMC11354396 DOI: 10.3390/ijms25168667] [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: 07/24/2024] [Revised: 08/02/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
The COVID-19 pandemic has raised awareness of the virus's long-term non-pulmonary consequences. This study examined the relationship between genetic polymorphisms of VEGF and cardiac dysfunction and subclinical atherosclerosis in patients recovering from COVID-19. This study included 67 patients previously diagnosed with COVID-19. VEGF-936C/T, VEGF-634G/C, and VEGF-2578C/A statuses were determined. Conventional echocardiography and arterial parameters assessments were performed at inclusion and at six months after the first assessment. For VEGF-936C/T, dominant and over-dominant models showed a significant increase in ejection fraction at six months after COVID (p = 0.044 and 0.048) and was also a predictive independent factor for the augmentation index (β = 3.07; p = 0.024). The dominant model showed a rise in RV-RA gradient (3.702 mmHg) (p = 0.028 95% CI: 0.040-7.363), with the over-dominant model indicating a greater difference (4.254 mmHg) (p = 0.025 95% CI: 0.624-7.884). The findings for VEGF-634G/C were not statistically significant, except for a difference in TAPSE during initial evaluation, using the codominant model. For VEGF-2578C/A, a difference in ventricular filling pressure (E/E'ratio) was best described under the recessive model. Our research suggests that the VEG-936C/T genotype may impact the baseline level and subsequent changes in cardiac function and subclinical atherosclerosis. These findings offer valuable insights into the complex correlation between genetic polymorphisms and cardiovascular disfunction in long COVID patients.
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Affiliation(s)
- Angela Cozma
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Adela Viviana Sitar-Tăuț
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Olga Hilda Orășan
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Violeta Briciu
- Department of Infectious Diseases and Epidemiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400348 Cluj-Napoca, Romania
| | - Daniel Leucuța
- Department of Medical Informatics and Biostatistics, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Nicolae-Dan Sporiș
- Department of Medical Oncology, Prof. Dr. I. Chiricuța Oncology Institute, 400015 Cluj-Napoca, Romania
| | - Andrada-Luciana Lazăr
- Department of Dermatology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Toma-Vlad Mălinescu
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Andreea-Maria Ganea
- Department of Cardiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Bianca Mihaela Sporiș
- Department of Gastroenterology, Regional Institute of Gastroenterology “Prof. Dr. Octavian Fodor”, 400394 Cluj-Napoca, Romania
| | - Călin Vasile Vlad
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Mihaela Lupșe
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Mădălina-Gabriela Țâru
- Department of Gastroenterology, Regional Institute of Gastroenterology “Prof. Dr. Octavian Fodor”, 400394 Cluj-Napoca, Romania
| | - Lucia Maria Procopciuc
- Department of Medical Biochemistry, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
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13
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Chiba K, Murase T, Yokota K, Tatematsu T, Oda R, Nakamura R, Yobita S, Takano T, Okuda K. Expression of vascular endothelial growth factor receptor in thymic epithelial tumors. Oncol Lett 2024; 28:383. [PMID: 38939624 PMCID: PMC11209869 DOI: 10.3892/ol.2024.14516] [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: 03/01/2024] [Accepted: 05/31/2024] [Indexed: 06/29/2024] Open
Abstract
Thymic epithelial tumors (TETs) are rare and the major symptoms are not obvious until the tumor progresses to a relatively large size and compresses the surrounding organs. As its growth is aggressive and it metastasizes to distant organs, it is important to find novel effective therapies. Lenvatinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, is approved as a drug therapy for thymic carcinoma (TC); however, although it is a molecular targeted therapy, there are no obvious predictors of therapeutic efficacy. The present study aimed to assess the association between clinicopathological factors and the protein expression of VEGFR, which is associated with tumor aggressiveness and the efficacy of VEGFR inhibitors. The VEGFR-2 protein expression was evaluated in 144 patients with TETs who underwent surgical resection. The present study assessed whether the expression of VEGFR-2 protein was associated with TET classification and pathological stage, progression-free survival and overall survival (OS). A total of 94 cases (65.2%) were positive for VEGFR-2 protein. The expression of VEGFR-2 was higher in the more aggressive type B3 thymoma and TC (88.5%) than in types A, AB, B1 and B2 thymoma (60.2%). The 5-year OS rate for the overall population was 53.1%. The 5-year OS rates of patients with negative VEGFR-2 staining score values (66.5%) were significantly longer than in patients with positive VEGFR-2 staining score values (42.5%; P=0.000078). Furthermore, the pathological stage was the only factor significantly associated with OS in multivariate analysis. The results of the present study suggest the possibility that the indications for VEGF inhibitor therapy could be extended to type B3 thymoma.
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Affiliation(s)
- Kensuke Chiba
- Department of Thoracic and Pediatric Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Takayuki Murase
- Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Keisuke Yokota
- Department of Thoracic and Pediatric Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Tsutomu Tatematsu
- Department of Thoracic and Pediatric Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Risa Oda
- Department of Thoracic and Pediatric Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Ryuji Nakamura
- Department of Thoracic and Pediatric Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Shogo Yobita
- Department of Thoracic and Pediatric Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Takatsugu Takano
- Department of Thoracic and Pediatric Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Katsuhiro Okuda
- Department of Thoracic and Pediatric Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
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Sabatelle RC, Colson YL, Sachdeva U, Grinstaff MW. Drug Delivery Opportunities in Esophageal Cancer: Current Treatments and Future Prospects. Mol Pharm 2024; 21:3103-3120. [PMID: 38888089 PMCID: PMC11331583 DOI: 10.1021/acs.molpharmaceut.4c00246] [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] [Indexed: 06/20/2024]
Abstract
With one of the highest mortality rates of all malignancies, the 5-year survival rate for esophageal cancer is under 20%. Depending on the stage and extent of the disease, the current standard of care treatment paradigm includes chemotherapy or chemoradiotherapy followed by surgical esophagogastrectomy, with consideration for adjuvant immunotherapy for residual disease. This regimen has high morbidity, due to anatomic changes inherent in surgery, the acuity of surgical complications, and off-target effects of systemic chemotherapy and immunotherapy. We begin with a review of current treatments, then discuss new and emerging targets for therapies and advanced drug delivery systems. Recent and ongoing preclinical and early clinical studies are evaluating traditional tumor targets (e.g., human epidermal growth factor receptor 2), as well as promising new targets such as Yes-associated protein 1 or mammalian target of rapamycin to develop new treatments for this disease. Due the function and location of the esophagus, opportunities also exist to pair these treatments with a drug delivery strategy to increase tumor targeting, bioavailability, and intratumor concentrations, with the two most common delivery platforms being stents and nanoparticles. Finally, early results with antibody drug conjugates and chimeric antigenic receptor T cells show promise as upcoming therapies. This review discusses these innovations in therapeutics and drug delivery in the context of their successes and failures, with the goal of identifying those solutions that demonstrate the most promise to shift the paradigm in treating this deadly disease.
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Affiliation(s)
- Robert C. Sabatelle
- Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, 02215, USA
| | - Yolonda L. Colson
- Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Uma Sachdeva
- Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Mark W. Grinstaff
- Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, 02215, USA
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15
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Andriyanto A, Putra HY, Subangkit M, Tarigan E, Nugrahaning Widi L, Irarang Y, Manalu W, Fadholly A. Effect of Curcuma longa maceration treatment on ovarian follicular development, serum oestradiol, uterine growth and vascularisation in female albino rats. J Vet Res 2024; 68:287-294. [PMID: 38947163 PMCID: PMC11210355 DOI: 10.2478/jvetres-2024-0020] [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: 10/03/2023] [Accepted: 03/25/2024] [Indexed: 07/02/2024] Open
Abstract
Introduction Curcuma longa is a well-known medicinal plant with various health benefits. This study was designed to evaluate the administration of Indonesian C. longa maceration for its effect on promoting growth and development of the ovary and uterus before mating in female albino rats. Material and Methods A total of 15 female Sprague Dawley rats in their dioestrous phase were assigned into three different groups: the Control group (mineral water); the Cur-Low group (mineral water with 1% C. longa maceration) and the Cur-High group (mineral water with 5% C. longa maceration). The treatments were given for 20 days. Serum concentrations of follicle-stimulating hormone, oestradiol and progesterone were determined. After the sacrifice of the rats, ovary and uterine relative weight, uterine cornua diameter and length, uterine gland diameter (by histology), the number of primary, secondary, tertiary, and Graafian follicles, the number of corpora lutea and vascular endothelial growth factor (VEGF) expression in the ovary were measured. Uterine vascularisation was also evaluated. Results Administration of C. longa maceration significantly improved the relative weights of the uterus and ovary; uterine cornua diameter, length and vascularisation; uterine gland diameter; and expression of VEGF in the ovary. It also increased the number of tertiary follicles and corpora lutea, albeit not significantly. Follicle-stimulating hormone serum concentrations were lower in the administered rats. Conclusion Oestradiol and progesterone levels rose with C. longa maceration treatment. The maceration improved the reproductive organs of unmated rats and had potential to optimise the uterine environment for supporting pregnancy in order to produce high-quality offspring.
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Affiliation(s)
| | | | | | - Elpita Tarigan
- eLRosa Laboratory, iRATco Group, Dramaga Bogor, 16680West Java, Indonesia
| | | | - Yusa Irarang
- eLRosa Laboratory, iRATco Group, Dramaga Bogor, 16680West Java, Indonesia
| | - Wasmen Manalu
- Division of Physiology, School of Veterinary Medicine and Biomedical Sciences, IPB University, Kampus IPB Dramaga Bogor, 16680West Java, Indonesia
| | - Amaq Fadholly
- Division of Pharmacology and Toxicology, West Java, Indonesia
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16
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Toledo-Guardiola SM, Párraga-Ros E, Seva J, Luongo C, García-Vázquez FA, Soriano-Úbeda C, Matás C. Artificial insemination of all ejaculated sperm fractions accelerates embryo development and increases the uterine vascularity in the pig. Theriogenology 2024; 219:32-38. [PMID: 38382215 DOI: 10.1016/j.theriogenology.2024.02.017] [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: 07/13/2023] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 02/23/2024]
Abstract
The semen of boar is characterized by ejaculation in well-differentiated fractions with specific concentration, composition, and volume. The 'sperm-rich fraction' (SRF), the most concentrated seminal fraction, is habitually collected in insemination centers to make artificial insemination (AI) doses. The absence of the other fractions in AI doses could alter the uterine reaction to AI and not trigger essential responses that could maximize fertility. Thus, there is an urge to ascertain the impact of different ejaculate fractions on the uterus after AI to optimize the semen doses. This work analyzed specific parameters related to fertility in pregnant artificially inseminated sows (n = 15) with ac-cumulative fractions of the semen of boars (n = 6): F1, composed of the sperm-rich fraction (SRF); F2, composed of F1 plus the intermediate fraction; F3, composed of F2 plus the post-SRF. Non-inseminated sows (n = 5) were included as control (C). The different types of seminal dose did not affect the number of ovulated follicles (CL; corpora lutea, p > 0.05) but did affect the embryo development (p < 0.05). The proportion of embryos in morula stages was significantly higher in AI-F1 sows (84.4%, p < 0.05). Morulas and blastocysts were balanced in AI-F2 or AI-F3 (p > 0.05). Independently of the type of seminal dose (F1, F2, or F3), we observed by immunohistochemistry that AI significantly increased uterine vascularization, although with some anatomical differences. The cranial region of the uterine horns was significantly more vascularized in AI-F1 or AI-F2 sows (26.7 ± 2.3 and 28.6 ± 2.0%, respectively), and AI-F3 showed significantly less vascularization at that point (17.8 ± 1.6%, p < 0.05). To summarize, the synergistic effect of all ejaculate fractions accelerates embryo development, at least during the preimplantation period, and increases the uterine reaction to AI in certain parts of the uterus.
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Affiliation(s)
- Santa María Toledo-Guardiola
- Departamento de Fisiología, Facultad de Veterinaria, Campus de Excelencia Mare Nostrum Universidad de Murcia, Murcia, Spain.
| | - Ester Párraga-Ros
- Departamento de Anatomía y Anatomía Patológica Comparadas, Facultad de Veterinaria, Campus de Excelencia Mare Nostrum Universidad de Murcia, Murcia, Spain.
| | - Juan Seva
- Departamento de Anatomía y Anatomía Patológica Comparadas, Facultad de Veterinaria, Campus de Excelencia Mare Nostrum Universidad de Murcia, Murcia, Spain.
| | - Chiara Luongo
- Departamento de Fisiología, Facultad de Veterinaria, Campus de Excelencia Mare Nostrum Universidad de Murcia, Murcia, Spain.
| | - Francisco A García-Vázquez
- Departamento de Fisiología, Facultad de Veterinaria, Campus de Excelencia Mare Nostrum Universidad de Murcia, Murcia, Spain.
| | - C Soriano-Úbeda
- Departamento de Medicina, Cirugía y Anatomía Veterinaria, Facultad de Veterinaria, Universidad de León, León, Spain.
| | - C Matás
- Departamento de Fisiología, Facultad de Veterinaria, Campus de Excelencia Mare Nostrum Universidad de Murcia, Murcia, Spain.
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17
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Li Z, Liu Q, Cai Y, Ye N, He Z, Yao Y, Ding Y, Wang P, Qi C, Zheng L, Wang L, Zhou J, Zhang QQ. EPAC inhibitor suppresses angiogenesis and tumor growth of triple-negative breast cancer. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167114. [PMID: 38447883 DOI: 10.1016/j.bbadis.2024.167114] [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: 11/21/2023] [Revised: 02/29/2024] [Accepted: 03/01/2024] [Indexed: 03/08/2024]
Abstract
AIMS Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and regulates angiogenesis in the retina. High intratumor microvascular densities (MVD) resulting from angiogenesis is responsible for breast cancer development. Downregulation of EPAC1 in tumor cell reduces triple-negative breast cancer (TNBC)-induced angiogenesis. However, whether Epac1 expressed in vascular endothelial cells contributes to angiogenesis and tumor development of TNBC remains elusive. MAIN METHODS We employed NY0123, a previously identified potent EPAC inhibitor, to explore the anti-angiogenic biological role of EPAC1 in vitro and in vivo through vascular endothelial cells, rat aortic ring, Matrigel plug, and chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assays, as well as the in vivo xenograft tumor models of TNBC in both chick embryo and mice. KEY FINDINGS Inhibiting EPAC1 in vascular endothelial cells by NY0123 significantly suppresses angiogenesis and tumor growth of TNBC. In addition, NY0123 possesses a better inhibitory efficacy than ESI-09, a reported specific EPAC inhibitor tool compound. Importantly, inhibiting EPAC1 in vascular endothelia cells regulates the typical angiogenic signaling network, which is associated with not only vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) signaling, but also PI3K/AKT, MEK/ERK and Notch pathway. CONCLUSIONS Our findings support that EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC, and EPAC inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC.
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Affiliation(s)
- Zishuo Li
- School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qiao Liu
- School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yuhao Cai
- School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Na Ye
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Zinan He
- School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yuying Yao
- School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yi Ding
- School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Pingyuan Wang
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Cuiling Qi
- School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Lingyun Zheng
- School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Lijing Wang
- School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jia Zhou
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
| | - Qian-Qian Zhang
- School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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18
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Georgiev GP, Yordanov Y, Gaydarski L, Tubbs RS, Olewnik Ł, Zielinska N, Piagkou M, Ananiev J, Dimitrova IN, Slavchev SA, Terziev I, Suwannakhan A, Landzhov B. Are There Any Differences in the Healing Capacity between the Medial Collateral Ligament's (MCL) Proximal and Distal Parts in the Human Knee? Quantitative and Immunohistochemical Analysis of CD34, α-Smooth Muscle Actin (α-SMA), and Vascular Endothelial Growth Factor (VEGF) Expression Regarding the Epiligament (EL) Theory. Biomedicines 2024; 12:659. [PMID: 38540272 PMCID: PMC10967725 DOI: 10.3390/biomedicines12030659] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 03/01/2024] [Accepted: 03/11/2024] [Indexed: 11/11/2024] Open
Abstract
The human knee is a complex joint that comprises several ligaments, including the medial collateral ligament (MCL). The MCL provides stability to the knee and helps prevent its excessive inward movement. The MCL also has a thin layer of connective tissue known as the epiligament (EL), which adheres to the ligament. This unique feature has drawn attention in the field of ligament healing research, as it may have implications for the recovery process of MCL injuries. According to the EL theory, ligament regeneration relies heavily on the provision of cells, blood vessels, and molecules. The present study sought to compare the expression of vascular endothelial growth factor (VEGF), CD34, and α-smooth muscle actin (α-SMA) in healthy knees' proximal and distal MCL segments to better understand how these proteins affect ligament healing. By improving the EL theory, the current results could lead to more effective treatments for ligament injury. To conduct the present analysis, monoclonal antibodies were used against CD34, α-SMA, and VEGF to examine samples from 12 fresh knee joints' midsubstance MCLs. We identified a higher cell density in the EL than in the ligament connective tissue, with higher cell counts in the distal than in the proximal EL part. CD34 immunostaining was weak or absent in blood vessels and the EL, while α-SMA immunostaining was strongest in smooth muscle cells and the EL superficial layer. VEGF expression was mainly in the blood vessels' tunica media. The distal part showed more SMA-positive microscopy fields and higher cell density than the proximal part (4735 vs. 2680 cells/mm2). Our study identified CD34, α-SMA, and VEGF expression in the MCL EL, highlighting their critical role in ligament healing. Differences in α-SMA expression and cell numbers between the ligament's proximal and distal parts may explain different healing capacities, supporting the validity of the EL theory in ligament recovery.
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Affiliation(s)
- Georgi P. Georgiev
- Department of Orthopedics and Traumatology, University Hospital Queen Giovanna-ISUL, Medical University of Sofia, 1527 Sofia, Bulgaria
| | - Yordan Yordanov
- Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria;
| | - Lyubomir Gaydarski
- Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria; (L.G.); (B.L.)
| | - Richard Shane Tubbs
- Department of Anatomical Sciences, St. George’s University, St. George 1473, Grenada;
- Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Department of Neurology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Łukasz Olewnik
- Department of Anatomical Dissection and Donation, Medical University of Lodz, 90-419 Lodz, Poland; (Ł.O.); (N.Z.)
| | - Nicol Zielinska
- Department of Anatomical Dissection and Donation, Medical University of Lodz, 90-419 Lodz, Poland; (Ł.O.); (N.Z.)
| | - Maria Piagkou
- Department of Anatomy, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Julian Ananiev
- Department of General and Clinical Pathology, Faculty of Medicine, Trakia University, 6000 Stara Zagora, Bulgaria;
| | - Iva N. Dimitrova
- Department of Cardiology, University Hospital “St. Ekaterina”, Medical University of Sofia, 1431 Sofia, Bulgaria;
| | - Svetoslav A. Slavchev
- University Hospital of Orthopedics “Prof. B. Boychev”, Medical University of Sofia, 1614 Sofia, Bulgaria;
| | - Ivan Terziev
- Department of Pathology, University Hospital Queen Giovanna-ISUL, 1527 Sofia, Bulgaria;
| | - Athikhun Suwannakhan
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
- In Silico and Clinical Anatomy Research Group (iSCAN), Bangkok 10400, Thailand
| | - Boycho Landzhov
- Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria; (L.G.); (B.L.)
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19
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Lund N, Wieboldt H, Fischer L, Muschol N, Braun F, Huber T, Sorriento D, Iaccarino G, Müllerleile K, Tahir E, Adam G, Kirchhof P, Fabritz L, Patten M. Overexpression of VEGFα as a biomarker of endothelial dysfunction in aortic tissue of α-GAL-Tg/KO mice and its upregulation in the serum of patients with Fabry's disease. Front Cardiovasc Med 2024; 11:1355033. [PMID: 38374995 PMCID: PMC10875336 DOI: 10.3389/fcvm.2024.1355033] [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: 12/13/2023] [Accepted: 01/17/2024] [Indexed: 02/21/2024] Open
Abstract
Introduction Fabry's disease is an X-linked lysosomal storage disorder caused by reduced activity of α-galactosidase A (GAL), leading to premature death on account of renal, cardiac, and vascular organ failure. Accumulation of the GAL substrate globotriaosylceramide (Gb3) in endothelial and smooth muscle cells is associated with early vascular cell damage, suggesting endothelial dysfunction as a driver of cardiorenal organ failure. Here, we studied the vascular expression of the key angiogenic factors, VEGFα and its antagonist angiostatin, in Fabry α-GAL-Tg/KO mice and determined circulating VEGFα and angiostatin serum levels in patients with Fabry's disease and healthy controls. Methods Cryopreserved aortic vessels from six α-GAL-Tg/KO and six wild-type (WT) mice were obtained and VEGFα and angiostatin levels were determined by performing Western blot analysis. VEGFα expression was visualized by an immunohistochemical staining of paraffin aortic rings. In addition, VEGFα and angiostatin serum levels were measured by using an enzyme-linked immunosorbent assay in 48 patients with genetically verified Fabry's disease (50% male) and 22 healthy controls and correlated with disease severity markers such as lyso-Gb3, albuminuria, NTproBNP, high-sensitive troponin T (hsTNT), and myocardial wall thickness. Results It was found that there was a significant increase in VEGFα protein expression (1.66 ± 0.35 vs. 0.62 ± 0.16, p = 0.0009) and a decrease in angiostatin expression (0.024 ± 0.007 vs. 0.053 ± 0.02, p = 0.038) in aortic lysates from α-GAL-Tg/KO compared with that from WT mice. Immunohistochemical staining revealed an adventitial VEGFα signal in α-GAL-Tg/KO mice, whereas no VEGFα signal could be detected in WT mice aortas. No differences in aortic angiostatin expression between α-GAL-Tg/KO- and WT mice could be visualized. The serum levels of VEGFα were significantly upregulated in patients with Fabry's disease compared with that in healthy controls (708.5 ± 426.3 vs. 458.5 ± 181.5 pg/ml, p = 0.048) and positively associated with albuminuria (r = 0.82, p < 0.0001) and elevated NTproBNP (r = 0.87, p < 0.0001) and hsTNT values (r = 0.41, p = 0.048) in male patients with Fabry's disease. For angiostatin, no significant difference was found between patients with Fabry's disease and healthy controls (747.6 ± 390.3 vs. 858.8 ± 599.3 pg/ml). Discussion In conclusion, an overexpression of VEGFα and downregulation of its counter player angiostatin in aortic tissue of α-GAL-Tg/KO mice support the hypothesis of an underlying vasculopathy in Fabry's disease. Elevated VEGFα serum levels were also observed in patients with Fabry's disease and were positively associated with elevated markers of organ manifestation in males. These findings suggest that angiogenetic markers, such as VEGFα, may be potentially useful biomarkers for the detection of endothelial dysfunction in classical Fabry's disease.
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Affiliation(s)
- N. Lund
- Department of Cardiology, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Intensive Care Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - H. Wieboldt
- Department of Cardiology, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - L. Fischer
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - N. Muschol
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - F. Braun
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - T. Huber
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - D. Sorriento
- Department of Advanced Biomedical Sciences, Interdepartmental Center of Research on Hypertension and Related Conditions of the Federico II University, Naples, Italy
| | - G. Iaccarino
- Department of Clinical Medicine and Surgery, Interdepartmental Center of Research on Hypertension and Related Conditions of the Federico II University, Naples, Italy
| | - K. Müllerleile
- Department of Cardiology, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - E. Tahir
- Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - G. Adam
- Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - P. Kirchhof
- Department of Cardiology, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - L. Fabritz
- Department of Cardiology, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - M. Patten
- Department of Cardiology, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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20
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Zhao HD, Sun JJ, Liu HL. Potential clinical biomarkers in monitoring the severity of Hantaan virus infection. Cytokine 2023; 170:156340. [PMID: 37607412 DOI: 10.1016/j.cyto.2023.156340] [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: 07/10/2023] [Revised: 08/13/2023] [Accepted: 08/17/2023] [Indexed: 08/24/2023]
Abstract
Hantavirus, which causes hemorrhagic fever with renal syndrome (HFRS) is almost prevalent worldwide. While Hantaan virus (HTNV) causes the most severe form of HFRS with typical clinical manifestations of thrombocytopenia, increased vascular permeability, and acute kidney injury. Although the knowledge of the pathogenesis of HFRS is still limited, immune dysfunction and pathological damage caused by disorders of immune regulation are proposed to play a vital role in the development of the disorder, and the endothelium is considered to be the primary target of hantaviruses. Here, we reviewed the production and function of multiple molecules, mainly focusing on their role in immune response, endothelium, vascular permeability regulation, and platelet and coagulation activation which are closely related to the pathogenesis of HTNV infection. meanwhile, the relationship between these molecules and characteristics of HTNV infection including the hospital duration, immune dysfunction, thrombocytopenia, leukocytosis, and acute kidney injury are also presented, to provide a novel insight into the potential role of these molecules as monitoring markers for HTNV infection.
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Affiliation(s)
- Han-Dong Zhao
- Central Laboratory of Virology, Shaanxi Provincial Hospital of Infectious Diseases, The Eighth Hospital Affiliated to Medical College of Xi'an Jiaotong University, Xi'an 710061, China
| | - Ju-Jun Sun
- Clinical Laboratory Center, XD Group Hospital, Xi'an 710077, China
| | - Hong-Li Liu
- Clinical Laboratory Center, Xi'an People's Hospital (Xi'an Fourth Hospital) Guang-Ren Hospital Affiliated to Xi'an Jiaotong University Health Science Center, Xi'an 710004, China.
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21
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Shen Q, Wu X, Chen J, He C, Wang Z, Zhou B, Zhang H. Immune Regulation of Seminal Plasma on the Endometrial Microenvironment: Physiological and Pathological Conditions. Int J Mol Sci 2023; 24:14639. [PMID: 37834087 PMCID: PMC10572377 DOI: 10.3390/ijms241914639] [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: 09/01/2023] [Revised: 09/23/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Seminal plasma (SP) accounts for more than 90% of semen volume. It induces inflammation, regulates immune tolerance, and facilitates embryonic development and implantation in the female reproductive tract. In the physiological state, SP promotes endometrial decidualization and causes changes in immune cells such as macrophages, natural killer cells, regulatory T cells, and dendritic cells. This leads to the secretion of cytokines and chemokines and also results in the alteration of miRNA profiles and the expression of genes related to endometrial tolerance and angiogenesis. Together, these changes modulate the endometrial immune microenvironment and contribute to implantation and pregnancy. However, in pathological situations, abnormal alterations in SP due to advanced age or poor diet in men can interfere with a woman's immune adaptation to pregnancy, negatively affecting embryo implantation and even the health of the offspring. Uterine pathologies such as endometriosis and endometritis can cause the endometrium to respond negatively to SP, which can further contribute to pathological progress and interfere with conception. The research on the mechanism of SP in the endometrium is conducive to the development of new targets for intervention to improve reproductive outcomes and may also provide new ideas for semen-assisted treatment of clinical infertility.
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Affiliation(s)
- Qiuzi Shen
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Q.S.); (X.W.); (J.C.); (C.H.)
| | - Xiaoyu Wu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Q.S.); (X.W.); (J.C.); (C.H.)
| | - Jin Chen
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Q.S.); (X.W.); (J.C.); (C.H.)
| | - Chao He
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Q.S.); (X.W.); (J.C.); (C.H.)
| | - Zehao Wang
- School of Management, Huazhong University of Science and Technology, Wuhan 430074, China;
| | - Boyan Zhou
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Q.S.); (X.W.); (J.C.); (C.H.)
| | - Huiping Zhang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Q.S.); (X.W.); (J.C.); (C.H.)
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22
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Sharun K, Chandran D, Manjusha KM, Mankuzhy PD, Kumar R, Pawde AM, Dhama K, El-Husseiny HM, Amarpal. Advances and prospects of platelet-rich plasma therapy in veterinary ophthalmology. Vet Res Commun 2023; 47:1031-1045. [PMID: 36607500 DOI: 10.1007/s11259-022-10064-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 12/28/2022] [Indexed: 01/07/2023]
Abstract
In the recent decades, there has been a significant uptick on the use of platelet-rich plasma (PRP) as a better alternative for ophthalmologic therapies in pathologies, primarily of the ocular surface. PRP is a class of liquid platelet concentrate containing a supra-physiological concentration of platelets in a relatively small amount of plasma. Its potential to heal various tissues has piqued interest in its therapeutic application as a biomaterial in regenerative medicine. It is currently a popular therapeutic agent in plastic surgery, cardiothoracic surgery, reconstructive surgery, and even oral and maxillofacial surgery. Based on the data from in vitro and in vivo studies, it can be concluded that PRP possesses adequate therapeutic potential in ocular pathologies, especially those involving cornea. In addition, the high concentrations of growth factors (TGF-β, VEGF, EGF) present in the PRP accelerate the healing of the corneal epithelium. PRP has great therapeutic prospects in veterinary ophthalmology as a regenerative therapeutic modality. However, several variables are yet to be defined and standardized that can directly affect the efficacy of PRP application in different ophthalmic conditions. There is a shortage of research on the use of PRP in ocular surface defects compared to the number of studies and reports on the use of autologous and allogeneic serum eye drops. Therefore, a data-driven approach is required to generate consensus/guidelines for the preparation, characterization, and therapeutic use of PRP in veterinary ophthalmology. This review aims to inform readers of the latest research on PRP, including its preparation methods, physiological and biochemical properties, clinical applications in veterinary ophthalmology, and their safety and efficacy.
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Affiliation(s)
- Khan Sharun
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, 243122, India.
| | - Deepak Chandran
- Department of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore, Tamil Nadu, 642109, India
| | - K M Manjusha
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, 243122, India
| | - Pratheesh D Mankuzhy
- Department of Physiology, Kerala Veterinary and Animal Sciences University, Pookode, Wayanad, Kerala, India
| | - Rohit Kumar
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, 243122, India
| | - Abhijit M Pawde
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, 243122, India
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, 243122, India
| | - Hussein M El-Husseiny
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology (TUAT), Fuchu, Tokyo, 183-0054, Japan
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Benha University, 13736, Toukh, Egypt
| | - Amarpal
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, 243122, India
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23
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Abhinand CS, Galipon J, Mori M, Ramesh P, Prasad TSK, Raju R, Sudhakaran PR, Tomita M. Temporal phosphoproteomic analysis of VEGF-A signaling in HUVECs: an insight into early signaling events associated with angiogenesis. J Cell Commun Signal 2023; 17:1067-1079. [PMID: 36881336 PMCID: PMC10409921 DOI: 10.1007/s12079-023-00736-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 02/17/2023] [Indexed: 03/08/2023] Open
Abstract
Vascular endothelial growth factor-A (VEGF-A) is one of the primary factors promoting angiogenesis in endothelial cells. Although defects in VEGF-A signaling are linked to diverse pathophysiological conditions, the early phosphorylation-dependent signaling events pertinent to VEGF-A signaling remain poorly defined. Hence, a temporal quantitative phosphoproteomic analysis was performed in human umbilical vein endothelial cells (HUVECs) treated with VEGF-A-165 for 1, 5 and 10 min. This led to the identification and quantification of 1971 unique phosphopeptides corresponding to 961 phosphoproteins and 2771 phosphorylation sites in total. Specifically, 69, 153, and 133 phosphopeptides corresponding to 62, 125, and 110 phosphoproteins respectively, were temporally phosphorylated at 1, 5, and 10 min upon addition of VEGF-A. These phosphopeptides included 14 kinases, among others. This study also captured the phosphosignaling events directed through RAC, FAK, PI3K-AKT-MTOR, ERK, and P38 MAPK modules with reference to our previously assembled VEGF-A/VEGFR2 signaling pathway map in HUVECs. Apart from a significant enrichment of biological processes such as cytoskeleton organization and actin filament binding, our results also suggest a role of AAK1-AP2M1 in the regulation of VEGFR endocytosis. Taken together, the temporal quantitative phosphoproteomics analysis of VEGF signaling in HUVECs revealed early signaling events and we believe that this analysis will serve as a starting point for the analysis of differential signaling across VEGF members toward the full elucidation of their role in the angiogenesis processes. Workflow for the identification of early phosphorylation events induced by VEGF-A-165 in HUVEC cells.
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Affiliation(s)
- Chandran S Abhinand
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, 997-0017, Japan.
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, 575018, India.
| | - Josephine Galipon
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, 997-0017, Japan.
- Graduate School of Media and Governance, Keio University, 5322 Endo, Fujisawa, Kanagawa, 252-0882, Japan.
| | - Masaru Mori
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, 997-0017, Japan
- Graduate School of Media and Governance, Keio University, 5322 Endo, Fujisawa, Kanagawa, 252-0882, Japan
| | - Poornima Ramesh
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, 575018, India
| | | | - Rajesh Raju
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, 575018, India
- Center for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, 575018, India
| | - Perumana R Sudhakaran
- Department of Computational Biology and Bioinformatics, University of Kerala, Thiruvananthapuram, Kerala, 695581, India
| | - Masaru Tomita
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, 997-0017, Japan
- Department of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa, Kanagawa, 252-0882, Japan
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24
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Tawagi E, Ung T, Cheng HLM, Santerre JP. Arrhenius-model-based degradable oligourethane hydrogels for controlled growth factor release. Acta Biomater 2023; 166:167-186. [PMID: 37207744 DOI: 10.1016/j.actbio.2023.05.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/22/2023] [Accepted: 05/12/2023] [Indexed: 05/21/2023]
Abstract
Biodegradable hydrogels are growing in demand to enable the delivery of biomolecules (e.g. growth factors) for regenerative medicine. This research investigated the resorption of an oligourethane/polyacrylic acid hydrogel, a biodegradable hydrogel which supports tissue regeneration. The Arrhenius model was used to characterize the resorption of the polymeric gels in relevant in vitro conditions, and the Flory-Rehner equation was used to correlate the volumetric swelling ratio with the extent of degradation. The study found that the swelling rate of the hydrogel follows the Arrhenius model at elevated temperatures, estimating degradation time in saline solution at 37°C to be between 5 and 13 months, serving as a preliminary approximation of degradation in vivo. The degradation products had low cytotoxicity towards endothelial cells, and the hydrogel supported stromal cell proliferation. Additionally, the hydrogels were able to release growth factors and maintain the biomolecules' bioactivity towards cell proliferation. The study of the vascular endothelial growth factor (VEGF) release from the hydrogel used a diffusion process model, showing that the electrostatic attraction between VEGF and the anionic hydrogel allowed for controlled and sustained VEGF release over three weeks. In a rat subcutaneous implant model, a selected hydrogel with desired degradation rates exhibited minimal foreign body response and supported M2a macrophage phenotype, and vascularization. The low M1 and high M2a macrophage phenotypes within the implants were associated with tissue integration. This research supports the use of oligourethane/polyacrylic acid hydrogels as a promising material for delivering growth factors and supporting tissue regeneration. STATEMENT OF SIGNIFICANCE: There is a need for degradable elastomeric hydrogels that can support the formation of soft tissues and minimize long-term foreign body responses. An Arrhenius model was used to estimate the relative breakdown of hydrogels, in-vitro. The results demonstrate that hydrogels made from a combination of poly(acrylic acid) and oligo-urethane diacrylates can be designed to resorb over defined periods ranging from months to years depending on the chemical formulation prescribed by the model. The hydrogel formulations also provided for different release profiles of growth factors, relevant to tissue regeneration. In-vivo, these hydrogels had minimal inflammatory effects and showed evidence of integration into the surrounding tissue. The hydrogel approach can help the field design a broader range of biomaterials for tissue regeneration.
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Affiliation(s)
- Eric Tawagi
- Institute of Biomedical Engineering, University of Toronto, 661 University Avenue, 14th Floor, Room 1435, Toronto, ON M5G 1M1, Canada; Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, Canada
| | - Trevor Ung
- Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, Canada
| | - Hai-Ling Margaret Cheng
- Institute of Biomedical Engineering, University of Toronto, 661 University Avenue, 14th Floor, Room 1435, Toronto, ON M5G 1M1, Canada; Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, Canada; The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto, ON, Canada
| | - J Paul Santerre
- Institute of Biomedical Engineering, University of Toronto, 661 University Avenue, 14th Floor, Room 1435, Toronto, ON M5G 1M1, Canada; Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, Canada; Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
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25
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Stampone E, Bencivenga D, Capellupo MC, Roberti D, Tartaglione I, Perrotta S, Della Ragione F, Borriello A. Genome editing and cancer therapy: handling the hypoxia-responsive pathway as a promising strategy. Cell Mol Life Sci 2023; 80:220. [PMID: 37477829 PMCID: PMC10361942 DOI: 10.1007/s00018-023-04852-2] [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: 05/02/2023] [Revised: 06/14/2023] [Accepted: 06/29/2023] [Indexed: 07/22/2023]
Abstract
The precise characterization of oxygen-sensing pathways and the identification of pO2-regulated gene expression are both issues of critical importance. The O2-sensing system plays crucial roles in almost all the pivotal human processes, including the stem cell specification, the growth and development of tissues (such as embryogenesis), the modulation of intermediate metabolism (including the shift of the glucose metabolism from oxidative to anaerobic ATP production and vice versa), and the control of blood pressure. The solid cancer microenvironment is characterized by low oxygen levels and by the consequent activation of the hypoxia response that, in turn, allows a complex adaptive response characterized mainly by neoangiogenesis and metabolic reprogramming. Recently, incredible advances in molecular genetic methodologies allowed the genome editing with high efficiency and, above all, the precise identification of target cells/tissues. These new possibilities and the knowledge of the mechanisms of adaptation to hypoxia suggest the effective development of new therapeutic approaches based on the manipulation, targeting, and exploitation of the oxygen-sensor system molecular mechanisms.
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Affiliation(s)
- Emanuela Stampone
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy
| | - Debora Bencivenga
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy
| | - Maria Chiara Capellupo
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy
| | - Domenico Roberti
- Department of the Woman, the Child and of the General and Specialty Surgery, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 2, 80138, Naples, Italy
| | - Immacolata Tartaglione
- Department of the Woman, the Child and of the General and Specialty Surgery, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 2, 80138, Naples, Italy
| | - Silverio Perrotta
- Department of the Woman, the Child and of the General and Specialty Surgery, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 2, 80138, Naples, Italy
| | - Fulvio Della Ragione
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy.
| | - Adriana Borriello
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy.
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26
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Abu-Ghazaleh N, Brennecke S, Murthi P, Karanam V. Association of Vascular Endothelial Growth Factors (VEGFs) with Recurrent Miscarriage: A Systematic Review of the Literature. Int J Mol Sci 2023; 24:ijms24119449. [PMID: 37298399 DOI: 10.3390/ijms24119449] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 05/18/2023] [Accepted: 05/20/2023] [Indexed: 06/12/2023] Open
Abstract
Recurrent miscarriage (RM) can be defined as two or more consecutive miscarriages before 20 weeks' gestation. Vascular endothelial growth factors (VEGFs) play an important role in endometrial angiogenesis and decidualization, prerequisites for successful pregnancy outcomes. We conducted a systematic review of the published literature investigating the role of VEGFs in RM. In particular, we explored the methodological inconsistencies between the published reports on this topic. To our knowledge, this is the first systematic literature review to examine the role of VEGFs in RM. Our systematic search followed PRISMA guidelines. Three databases, Medline (Ovid), PubMed, and Embase, were searched. Assessment-bias analyses were conducted using the Joanna Bigger Institute critical appraisal method for case-control studies. Thirteen papers were included in the final analyses. These studies included 677 cases with RM and 724 controls. Endometrial levels of VEGFs were consistently lower in RM cases compared to controls. There were no consistent significant findings with respect to VEGFs levels in decidua, fetoplacental tissues, and serum when RM cases were compared to controls. The interpretation of studies that explored the relationship between VEGFs and RM is hampered by inconsistencies in defining clinical, sampling, and analytical variables. To clarify the association between VEGF and RM in future studies, researchers ideally should use similarly defined clinical groups, similar samples collected in the same way, and laboratory analyses undertaken using the same methods.
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Affiliation(s)
- Nadine Abu-Ghazaleh
- Department of Maternal-Fetal Medicine, Pregnancy Research Centre, Royal Women's Hospital, Parkville, VIC 3052, Australia
| | - Shaun Brennecke
- Department of Maternal-Fetal Medicine, Pregnancy Research Centre, Royal Women's Hospital, Parkville, VIC 3052, Australia
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia
| | - Padma Murthi
- Department of Maternal-Fetal Medicine, Pregnancy Research Centre, Royal Women's Hospital, Parkville, VIC 3052, Australia
- Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia
| | - Vijaya Karanam
- Department of Maternal-Fetal Medicine, Pregnancy Research Centre, Royal Women's Hospital, Parkville, VIC 3052, Australia
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia
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Włodarczyk L, Cichoń N, Karbownik MS, Saso L, Saluk J, Miller E. Circulating Serum VEGF, IGF-1 and MMP-9 and Expression of Their Genes as Potential Prognostic Markers of Recovery in Post-Stroke Rehabilitation-A Prospective Observational Study. Brain Sci 2023; 13:846. [PMID: 37371326 DOI: 10.3390/brainsci13060846] [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: 04/03/2023] [Revised: 05/19/2023] [Accepted: 05/21/2023] [Indexed: 06/29/2023] Open
Abstract
The key period in post-stroke recovery is the first three months due to the high activity of spontaneous and therapeutic-induced processes related to neuroplasticity, angiogenesis and reperfusion. Therefore, the present study examines the expression of VEGF, IGF-1 and MMP-9 proteins and their genes to identify biomarkers that can prognose brain repair ability and thus estimate the outcome of stroke. It also identifies possible associations with clinical scales, including cognitive assessment and depression scales. The study group comprised 32 patients with moderate ischemic stroke severity, three to four weeks after incident. The results obtained after three-week hospitalization indicate a statistically significant change in clinical parameter estimations, as well as in MMP9 and VEGF protein and mRNA expression, over the rehabilitation process. Our findings indicate that combined MMP9 protein and mRNA expression might be a useful biomarker for cognitive improvement in post-stroke patients, demonstrating 87% sensitivity and 71% specificity (p < 0.0001).
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Affiliation(s)
- Lidia Włodarczyk
- Department of Neurological Rehabilitation, Medical University of Lodz, Milionowa 14, 93-113 Lodz, Poland
| | - Natalia Cichoń
- Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Michał Seweryn Karbownik
- Department of Pharmacology and Toxicology, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University, P. le Aldo Moro 5, 00185 Rome, Italy
| | - Joanna Saluk
- Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Elżbieta Miller
- Department of Neurological Rehabilitation, Medical University of Lodz, Milionowa 14, 93-113 Lodz, Poland
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Guo GX, Wu KY, Zhang XY, Lai FX, Tsim KWK, Qin QW, Hu WH. The extract of Curcumae Longae Rhizoma suppresses angiogenesis via VEGF-induced PI3K/Akt-eNOS-NO pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023; 308:116299. [PMID: 36842721 DOI: 10.1016/j.jep.2023.116299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/10/2023] [Accepted: 02/16/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Curcumae Longae Rhizoma (CLR) is a safe natural herbal medicine, and which has been widely used for centuries as functional food and health products, but its effects on angiogenesis and related underlying mechanism remain unclear. AIM OF THE STUDY The abnormal angiogenesis is closely related with various diseases, and therefore the precise control of angiogenesis is of great importance. The well-known angiogenic factor, vascular endothelial growth factor (VEGF), mediates angiogenesis and induces multiple signalling pathways via binding to VEGF receptor (VEGFR). The attenuation of VEGF-triggered angiogenic-related signalling pathways may relieve various diseases through suppression of angiogenesis. Here, we aimed to elucidate that CLR extract could exert striking anti-angiogenic activities both in vitro and in vivo. MATERIALS AND METHODS The viability of human umbilical vascular endothelial cell (HUVEC) was examined by LDH and MTT assays. Migrative and invasive ability of the endothelial cells were independently evaluated by wound healing and transwell assays. The activities of CLR extract on in vitro angiogenesis was tested by tube formation assay. In vivo vascularization was determined by using zebrafish embryo model in the present of CLR extract. Western blotting was applied to determine the phosphorylated levels of VEGFR2, PI3K, AKT and eNOS. Besides, the levels of nitric oxide (NO) and reactive oxygen species (ROS) were separately evaluated by Griess assay and 2'7'-dichlorofluorescein diacetate reaction. In addition, the cell migrative ability of cancer cell was estimated by using cultured human colon carcinoma cells (HT-29 cell line), and immunofluorescence assay was applied to evaluate the effect of CLR extract on nuclear translocation of NF-κB p65 subunit in the VEGF-treated HT-29 cultures. RESULTS CLR extract significantly suppressed a series of VEGF-mediated angiogenic responses, including endothelial cell proliferation, migration, invasion, and tube formation. Moreover, CLR extract reduced in vivo sub-intestinal vessel formation in zebrafish embryo model. Mechanistically, the extract of CLR attenuated the VEGF-triggered signalling, as demonstrated by decreased level of phosphorylated VEGFR2 and subsequently inactivated its downstream regulators, e.g. phospho-PI3K, phospho-AKT and phospho-eNOS. The production of NO and formation of ROS were markedly inhibited in HUVECs. Furthermore, CLR extract suppressed cell migration and NF-κB translocation in cultured HT-29 cells. CONCLUSIONS These preclinical findings demonstrate that the extract of CLR remarkably attenuates angiogenesis and which has great potential as a natural drug candidate with excellent anti-angiogenic activity.
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Affiliation(s)
- Guo-Xia Guo
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China.
| | - Ke-Yue Wu
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China.
| | - Xiao-Yong Zhang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China; University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangzhou, China.
| | - Fu-Xiang Lai
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China.
| | - Karl Wah-Keung Tsim
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China; University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangzhou, China; Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.
| | - Qi-Wei Qin
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China; University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangzhou, China.
| | - Wei-Hui Hu
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China; University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangzhou, China.
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Vassiliou AG, Vrettou CS, Keskinidou C, Dimopoulou I, Kotanidou A, Orfanos SE. Endotheliopathy in Acute COVID-19 and Long COVID. Int J Mol Sci 2023; 24:8237. [PMID: 37175942 PMCID: PMC10179170 DOI: 10.3390/ijms24098237] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 04/28/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023] Open
Abstract
The pulmonary endothelium is a highly regulated organ that performs a wide range of functions under physiological and pathological conditions. Since endothelial dysfunction has been demonstrated to play a direct role in sepsis and acute respiratory distress syndrome, its role in COVID-19 has also been extensively investigated. Indeed, apart from the COVID-19-associated coagulopathy biomarkers, new biomarkers were recognised early during the pandemic, including markers of endothelial cell activation or injury. We systematically searched the literature up to 10 March 2023 for studies examining the association between acute and long COVID-19 severity and outcomes and endothelial biomarkers.
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Affiliation(s)
- Alice G. Vassiliou
- First Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, Evangelismos Hospital, 106 76 Athens, Greece; (C.S.V.); (C.K.); (I.D.); (A.K.)
| | | | | | | | | | - Stylianos E. Orfanos
- First Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, Evangelismos Hospital, 106 76 Athens, Greece; (C.S.V.); (C.K.); (I.D.); (A.K.)
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Gnanasekaran R, Aickareth J, Hawwar M, Sanchez N, Croft J, Zhang J. CmPn/CmP Signaling Networks in the Maintenance of the Blood Vessel Barrier. J Pers Med 2023; 13:jpm13050751. [PMID: 37240921 DOI: 10.3390/jpm13050751] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/19/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
Cerebral cavernous malformations (CCMs) arise when capillaries within the brain enlarge abnormally, causing the blood-brain barrier (BBB) to break down. The BBB serves as a sophisticated interface that controls molecular interactions between the bloodstream and the central nervous system. The neurovascular unit (NVU) is a complex structure made up of neurons, astrocytes, endothelial cells (ECs), pericytes, microglia, and basement membranes, which work together to maintain blood-brain barrier (BBB) permeability. Within the NVU, tight junctions (TJs) and adherens junctions (AJs) between endothelial cells play a critical role in regulating the permeability of the BBB. Disruptions to these junctions can compromise the BBB, potentially leading to a hemorrhagic stroke. Understanding the molecular signaling cascades that regulate BBB permeability through EC junctions is, therefore, essential. New research has demonstrated that steroids, including estrogens (ESTs), glucocorticoids (GCs), and metabolites/derivatives of progesterone (PRGs), have multifaceted effects on blood-brain barrier (BBB) permeability by regulating the expression of tight junctions (TJs) and adherens junctions (AJs). They also have anti-inflammatory effects on blood vessels. PRGs, in particular, have been found to play a significant role in maintaining BBB integrity. PRGs act through a combination of its classic and non-classic PRG receptors (nPR/mPR), which are part of a signaling network known as the CCM signaling complex (CSC). This network couples both nPR and mPR in the CmPn/CmP pathway in endothelial cells (ECs).
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Affiliation(s)
- Revathi Gnanasekaran
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
| | - Justin Aickareth
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
| | - Majd Hawwar
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
| | - Nickolas Sanchez
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
| | - Jacob Croft
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
| | - Jun Zhang
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
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Xiong Y, Fang Z, Dong J, Chen S, Mao J, Zhang W, Hai L, Zhou J, Wang X. Maternal circulating exosomal miR-185-5p levels as a predictive biomarker in patients with recurrent pregnancy loss. J Assist Reprod Genet 2023; 40:553-566. [PMID: 36745296 PMCID: PMC10033820 DOI: 10.1007/s10815-023-02733-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 01/19/2023] [Indexed: 02/07/2023] Open
Abstract
PURPOSE The aim of this study was to explore the predictive role of microRNAs (miRNAs) from maternal serum exosomes in early recurrent pregnancy loss (RPL) and the related mechanism in early pregnancy. METHODS Maternal serum was collected from pregnant women with RPL history or women with ongoing pregnancy (OP); serum exosomes were extracted and identified. Differentially expressed (DE) miRNAs in exosomes were screened by RNA sequencing and further validated by qRT-PCR. Next, the predictive value of exosomal miRNA and the clinical indicators for subsequent miscarriage in RPL patients were evaluated. Additionally, we verified the regulatory relationship between miR-185-5p and vascular endothelial growth factor (VEGF) in decidual natural killer (dNK) cells by overloading or inhibiting the exosomal miR-185-5p level in trophoblast cells. RESULTS The miRNA sequencing revealed 43 DE miRNAs between OP and RPL patients. The five most significant DE miRNAs (miR-22-3p, miR-185-5p, miR-335-3p, miR-362-5p, and miR-378a-3p) were selected for identification, and miR-185-5p was increased in RPL patients. The area under curve (AUC) of the receiver operating characteristic was 0.925 when using miR-185-5p as a biomarker for subsequent miscarriage in RPL patients. In addition, miR-185-5p in exosomes secreted from HTR-8 cells reduces VEGF expression of dNK cells. CONCLUSIONS The current study, for the first time, successfully constructed the correlation between maternal circulating exosomal miR-185-5p expression pattern and RPL, which may be involved in the pathogenesis of RPL by downregulating the VEGFA of dNK cells and perturbing angiogenesis at the maternal-fetal interface.
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Affiliation(s)
- Yujing Xiong
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, 569 Xinyi Road, Baqiao District, Xi'An, Shaanxi Province, China
| | - Zheng Fang
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, 569 Xinyi Road, Baqiao District, Xi'An, Shaanxi Province, China
| | - Jie Dong
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, 569 Xinyi Road, Baqiao District, Xi'An, Shaanxi Province, China
| | - Shuqiang Chen
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, 569 Xinyi Road, Baqiao District, Xi'An, Shaanxi Province, China
| | - Jiaqin Mao
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, 569 Xinyi Road, Baqiao District, Xi'An, Shaanxi Province, China
| | - Wanlin Zhang
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, 569 Xinyi Road, Baqiao District, Xi'An, Shaanxi Province, China
| | - Li Hai
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, 569 Xinyi Road, Baqiao District, Xi'An, Shaanxi Province, China
| | - Jing Zhou
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, 569 Xinyi Road, Baqiao District, Xi'An, Shaanxi Province, China
| | - Xiaohong Wang
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, 569 Xinyi Road, Baqiao District, Xi'An, Shaanxi Province, China.
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Wang Y, Li J, Xia L. Plant-derived natural products and combination therapy in liver cancer. Front Oncol 2023; 13:1116532. [PMID: 36865794 PMCID: PMC9971944 DOI: 10.3389/fonc.2023.1116532] [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: 12/05/2022] [Accepted: 01/31/2023] [Indexed: 02/16/2023] Open
Abstract
Liver cancer is one of the malignant cancers globally and seriously endangers human health because of its high morbidity and mortality. Plant-derived natural products have been evaluated as potential anticancer drugs due to low side effects and high anti-tumor efficacy. However, plant-derived natural products also have defects of poor solubility and cumbersome extraction process. In recent years, a growing numbers of plant derived natural products have been used in combination therapy of liver cancer with conventional chemotherapeutic agents, which has improved clinical efficacy through multiple mechanisms, including inhibition of tumor growth, induction of apoptosis, suppression of angiogenesis, enhancement of immunity, reversal of multiple drug resistance and reduction of side effects. The therapeutic effects and mechanisms of plant-derived natural products and combination therapy on liver cancer are reviewed to provide references for developing anti-liver-cancer strategies with high efficacy and low side effects.
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Affiliation(s)
- Yuqin Wang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, China
| | - Jinyao Li
- *Correspondence: Jinyao Li, ; Lijie Xia,
| | - Lijie Xia
- *Correspondence: Jinyao Li, ; Lijie Xia,
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The Role of Membrane-Type 1 Matrix Metalloproteinase-Substrate Interactions in Pathogenesis. Int J Mol Sci 2023; 24:ijms24032183. [PMID: 36768503 PMCID: PMC9917210 DOI: 10.3390/ijms24032183] [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: 12/31/2022] [Revised: 01/17/2023] [Accepted: 01/20/2023] [Indexed: 01/25/2023] Open
Abstract
A protease is an enzyme with a proteolytic activity that facilitates the digestion of its substrates. Membrane-type I matrix metalloproteinase (MT1-MMP), a member of the broader matrix metalloproteinases (MMP) family, is involved in the regulation of diverse cellular activities. MT1-MMP is a very well-known enzyme as an activator of pro-MMP-2 and two collagenases, MMP-8 and MMP-13, all of which are essential for cell migration. As an anchored membrane enzyme, MT1-MMP has the ability to interact with a diverse group of molecules, including proteins that are not part of the extracellular matrix (ECM). Therefore, MT1-MMP can regulate various cellular activities not only by changing the extra-cellular environment but also by regulating cell signaling. The presence of both intracellular and extra-cellular portions of MT1-MMP can allow it to interact with proteins on both sides of the cell membrane. Here, we reviewed the MT1-MMP substrates involved in disease pathogenesis.
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34
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Vaseghi S, Mostafavijabbari A, Alizadeh MS, Ghaffarzadegan R, Kholghi G, Zarrindast MR. Intricate role of sleep deprivation in modulating depression: focusing on BDNF, VEGF, serotonin, cortisol, and TNF-α. Metab Brain Dis 2023; 38:195-219. [PMID: 36399239 DOI: 10.1007/s11011-022-01124-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 11/06/2022] [Indexed: 11/19/2022]
Abstract
In this review article, we aimed to discuss intricate roles of SD in modulating depression in preclinical and clinical studies. Decades of research have shown the inconsistent effects of SD on depression, focusing on SD duration. However, inconsistent role of SD seems to be more complicated, and SD duration cannot be the only one factor. Regarding this issue, we chose some important factors involved in the effects of SD on cognitive functions and mood including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), serotonin, cortisol, and tumor necrosis factor-alpha (TNF-α). It was concluded that SD has a wide-range of inconsistent effects on BDNF, VEGF, serotonin, and cortisol levels. It was noted that BDNF diurnal rhythm is significantly involved in the modulatory role of SD in depression. Furthermore, the important role of VEGF in blood-brain barrier permeability which is involved in modulating depression was discussed. It was also noted that there is a negative correlation between cortisol and BDNF that modulates depression. Eventually, it was concluded that TNF-α regulates sleep/wake cycle and is involved in the vulnerability to cognitive and behavioral impairments following SD. TNF-α also increases the permeability of the blood-brain barrier which is accompanied by depressive behavior. In sum, it was suggested that future studies should focus on these mechanisms/factors to better investigate the reasons behind intricate roles of SD in modulating depression.
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Affiliation(s)
- Salar Vaseghi
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran.
| | | | - Mohammad-Sadegh Alizadeh
- Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran
- Department of Cellular and Molecular Sciences, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Reza Ghaffarzadegan
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
| | - Gita Kholghi
- Department of Psychology, Faculty of Human Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Mohammad-Reza Zarrindast
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Arrigo A, Aragona E, Bandello F. VEGF-targeting drugs for the treatment of retinal neovascularization in diabetic retinopathy. Ann Med 2022; 54:1089-1111. [PMID: 35451900 PMCID: PMC9891228 DOI: 10.1080/07853890.2022.2064541] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Diabetic retinopathy (DR) is the most common microangiopathic complication of diabetes mellitus, representing a major cause of visual impairment in developed countries. Proliferative DR (PDR) represents the last stage of this extremely complex retinal disease, characterized by the development of neovascularization induced by the abnormal production and release of vascular endothelial growth factor (VEGF). The term VEGF includes different isoforms; VEGF-A represents one of the most important pathogenic factors of DR. Anti-VEGF intravitreal therapies radically changed the outcome of DR, due to combined anti-angiogenic and anti-edematous activities. Nowadays, several anti-VEGF molecules exist, characterized by different pharmacological features and duration. With respect to PDR, although anti-VEGF treatments represented a fundamental step forward in the management of this dramatic complication, a big debate is present in the literature regarding the role of anti-VEGF as substitute of panretinal photocoagulation or if these two approaches may be used in combination. In the present review, we provided an update on VEGF isoforms and their role in DR pathogenesis, on current anti-VEGF molecules and emerging new drugs, and on the current management strategies of PDR. There is an overall agreement regarding the relative advantage provided by anti-VEGF, especially looking at the management of PDR patients requiring vitrectomy, with respect to laser. Based on the current data, laser approaches might be avoided when a perfectly planned anti-VEGF therapeutic strategy can be adopted. Conversely, laser treatment may have a role for those patients unable to guarantee enough compliance to anti-VEGF injections.Key messagesVEGF increased production, stimulated by retinal hypoperfusion and ischaemia, is a major pathogenic factor of neovascular complication onset in diabetic retinopathy and of DR stages progression.Nowadays, several anti-VEGF molecules are available in clinical practice and other molecules are currently under investigation. Each anti-VEGF molecule is characterized by different targets and may interact with multiple biochemical pathways within the eye.All the data agreed in considering anti-VEGF molecules as a first line choice for the management of diabetic retinopathy. Laser treatments may have a role in selected advanced cases and for those patients unable to guarantee enough compliance to intravitreal treatments schemes.
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Affiliation(s)
- Alessandro Arrigo
- IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Emanuela Aragona
- IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Francesco Bandello
- IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
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Molecular Mechanisms Underlying Twin-to-Twin Transfusion Syndrome. Cells 2022; 11:cells11203268. [PMID: 36291133 PMCID: PMC9600593 DOI: 10.3390/cells11203268] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/14/2022] [Accepted: 10/15/2022] [Indexed: 11/17/2022] Open
Abstract
Twin-to-twin transfusion syndrome is a unique disease and a serious complication occurring in 10–15% of monochorionic multiple pregnancies with various placental complications, including hypoxia, anemia, increased oxidative stress, and ischemia-reperfusion injury. Fetoscopic laser photocoagulation, a minimally invasive surgical procedure, seals the placental vascular anastomoses between twins and dramatically improves the survival rates in twin-to-twin transfusion syndrome. However, fetal demise still occurs, suggesting the presence of causes other than placental vascular anastomoses. Placental insufficiency is considered as the main cause of fetal demise in such cases; however, little is known about its underlying molecular mechanisms. Indeed, the further association of the pathogenic mechanisms involved in twin-to-twin transfusion syndrome placenta with several molecules and pathways, such as vascular endothelial growth factor and the renin–angiotensin system, makes it difficult to understand the underlying pathological conditions. Currently, there are no effective strategies focusing on these mechanisms in clinical practice. Certain types of cell death due to oxidative stress might be occurring in the placenta, and elucidation of the molecular mechanism underlying this cell death can help manage and prevent it. This review reports on the molecular mechanisms underlying the development of twin-to-twin transfusion syndrome for effective management and prevention of fetal demise after fetoscopic laser photocoagulation.
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The role of the Immune System in the Development of Endometriosis. Cells 2022; 11:cells11132028. [PMID: 35805112 PMCID: PMC9265783 DOI: 10.3390/cells11132028] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/19/2022] [Accepted: 06/23/2022] [Indexed: 12/10/2022] Open
Abstract
Endometriosis is a chronic disease that affects about 10% of women of reproductive age. It can contribute to pelvic pain, infertility or other conditions such as asthma, cardiovascular disease, breast or ovarian cancer. Research has shown that one of the conditions for the development of endometrial lesions is the dysfunction of the immune system. It appears that immune cells, such as neutrophils, macrophages, NK cells and dendritic cells, may play a specific role in the angiogenesis, growth and invasion of endometriosis cells. Immune cells secrete cytokines and defensins that also affect the endometriosis environment. This review discusses the various components of the immune system that are involved in the formation of endometrial lesions in women.
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Momha R, Le Bot D, Mosset P, Legrand AB. Anti-Angiogenic and Cytotoxicity Effects of Selachyl Alcohol Analogues. Anticancer Agents Med Chem 2022; 22:1913-1920. [PMID: 34636316 DOI: 10.2174/1871520621666211012090411] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 08/18/2021] [Accepted: 08/26/2021] [Indexed: 01/18/2023]
Abstract
BACKGROUND The active ingredients in the shark liver oil (SLO) mixture were found to be a group of etherlinked glycerol known as alkylglycerols (AKGs). During the last century, initial clinical use of the SLO mixture was for treating leukemias and later preventing radiation sickness from cancer x-ray therapy. Selachyl alcohol is one of the most abundant AKGs in the SLO mixture and it displayed strong activity in reducing lung metastasis number on a model of grafted tumor in mice (Lewis lung carcinoma cells). OBJECTIVES In this study, selachyl alcohol analogue containing methoxyl (7), gem-difluorinated (8), azide (9) and hydroxyl (10) group at the 12 position in the alkyl chain were synthesized and compared regarding their cytotoxicity and anti-migratory effects on Human Umbilical Vein Endothelial Cell line. METHODS AKGs 7-10 were synthesized according to the literature procedure. The cytotoxicity of the studied AKGs was evaluated by the MTT test and Human Umbilical Vein Endothelial Cell line (HUVEC) was used as an in vitro model to evaluate their anti-migratory effects. RESULTS The four AKGs have substantially the same toxicity threshold (≥ 12 μM), whereas they have an anti-migratory activity significantly different on endothelial cells. AKGs 9 and 10 significantly reduce the chemotactic migration induced by VEGF, but analogue (10) containing the hydroxyl group at the 12 position in the alkyl chain was the most potent anti-VEGF inhibitor. CONCLUSION We presented here a series of four synthetic selachyl alcohol analogues, among which AKGs 9 and 10 showed the ability to inhibit endothelial cell migration. The relationship structures and anti-VEGF effects of these analogues were also evaluated and discussed. Unnatural synthesized AKGs could be explored as one new source of anticancer agents.
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Affiliation(s)
- René Momha
- Hauts de France, AGIR, EA 4294, UFR of Pharmacy, Jules Verne University of Picardie, Amiens 80037, France.,Ecole Nationale Supérieure de Chimie de Rennes, Université de Rennes, CNRS, UMR 6226, 11 allée de Beaulieu, Rennes 35708, France
| | - Damien Le Bot
- Laboratoire de Pharmacologie Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes, 2 Avenue du Pr Léon Bernard, Rennes 35043, France
| | - Paul Mosset
- Ile et Vilaine, Université de Rennes, CNRS, ISCR, UMR 6226, Avenue du Général Leclerc, Rennes F-35000, France
| | - Alain Bernard Legrand
- Laboratoire de Pharmacologie Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes, 2 Avenue du Pr Léon Bernard, Rennes 35043, France
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Hagström A, Kal Omar R, Williams PA, Stålhammar G. The rationale for treating uveal melanoma with adjuvant melatonin: a review of the literature. BMC Cancer 2022; 22:398. [PMID: 35413810 PMCID: PMC9006630 DOI: 10.1186/s12885-022-09464-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/28/2022] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Uveal melanoma is a rare form of cancer with high mortality. The incidence of metastases is attributed to early seeding of micrometastases from the eye to distant organs, primarily the liver. Once these seeded clusters of dormant tumor cells grow into larger radiologically detectable macrometastases, median patient survival is about 1 year. Melatonin is an important hormone for synchronizing circadian rhythms. It is also involved in other aspects of human physiology and may offer therapeutic benefits for a variety of diseases including cancer. METHODS Articles involving the physiological effects of melatonin, pharmacokinetics, and previous use in cancer studies were acquired using a comprehensive literature search in the Medline (PubMed) and Web of Science databases. In total, 147 publications were selected and included in the review. RESULTS Melatonin has been observed to suppress the growth of cancer cells, inhibit metastatic spread, enhance immune system functions, and act as an anti-inflammatory in both in vitro and in vivo models. Melatonin may also enhance the efficacy of cancer treatments such as immuno- and chemotherapy. Numerous studies have shown promising results for oral melatonin supplementation in patients with other forms of cancer including cutaneous malignant melanoma. Cell line and animal studies support a hypothesis in which similar benefits may exist for uveal melanoma. CONCLUSIONS Given its low cost, good safety profile, and limited side effects, there may be potential for the use of melatonin as an adjuvant oncostatic treatment. Future avenues of research could include clinical trials to evaluate the effect of melatonin in prevention of macrometastases of uveal melanoma.
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Affiliation(s)
- Anna Hagström
- Department of Medicine, Karolinska Institutet, D1:04, 171 76, Stockholm, Sweden.
| | - Ruba Kal Omar
- Department of Medicine, Karolinska Institutet, D1:04, 171 76, Stockholm, Sweden.
| | - Pete A Williams
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, 171 64, Stockholm, Sweden
| | - Gustav Stålhammar
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, 171 64, Stockholm, Sweden
- St. Erik Eye Hospital, Box 4078, 171 04, Stockholm, Sweden
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Malekan M, Ebrahimzadeh MA. Vascular Endothelial Growth Factor Receptors [VEGFR] as Target in Breast Cancer Treatment: Current Status in Preclinical and Clinical Studies and Future Directions. Curr Top Med Chem 2022; 22:891-920. [PMID: 35260067 DOI: 10.2174/1568026622666220308161710] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 01/11/2022] [Accepted: 01/20/2022] [Indexed: 12/09/2022]
Abstract
Breast cancer [BC] is one of the most common cancers among women, one of the leading causes of a considerable number of cancer-related death globally. Among all procedures leading to the formation of breast tumors, angiogenesis has an important role in cancer progression and outcomes. Therefore, various anti-angiogenic strategies have developed so far to enhance treatment's efficacy in different types of BC. Vascular endothelial growth factors [VEGFs] and their receptors are regarded as the most well-known regulators of neovascularization. VEGF binding to vascular endothelial growth factor receptors [VEGFRs] provides cell proliferation and vascular tissue formation by the subsequent tyrosine kinase pathway. VEGF/VEGFR axis displays an attractive target for anti-angiogenesis and anti-cancer drug design. This review aims to describe the existing literature regarding VEGFR inhibitors, focusing on BC treatment reported in the last two decades.
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Affiliation(s)
- Mohammad Malekan
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Ali Ebrahimzadeh
- Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
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41
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Tian T, Ruan J, Zhang J, Zhao CX, Chen D, Shan J. Nanocarrier-Based Tumor-Targeting Drug Delivery Systems for Hepatocellular Carcinoma Treatments: Enhanced Therapeutic Efficacy and Reduced Drug Toxicity. J Biomed Nanotechnol 2022; 18:660-676. [PMID: 35715919 DOI: 10.1166/jbn.2022.3297] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC), due to the lack of efficient diagnostic methods and short of available treatments, becomes the third main cause of cancer deaths. Novel treatments for HCCs are thus in great need. The fast-growing area of drug delivery provides intriguing possibility to design nanocarriers with unique properties. The nanocarriers performanced as drug deliver vehicles enable the design of diverse drug delivery systems, which could serve multiple purposes, including improved bioavailability, controlled or triggered release and targeted delivery, leading to enhanced drug efficacy and lowered drug toxicity. This paper provides an overview on the types of delivery vehicles, functions of drug nanocarriers and types of ligand-based targeting systems and highlights the advances made towards better HCC treatments.
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Affiliation(s)
- Tian Tian
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, People's Republic of China
| | - Jian Ruan
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, People's Republic of China
| | - Jia Zhang
- College of Energy Engineering and State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310027, Zhejiang Province, People's Republic of China
| | - Chun-Xia Zhao
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia
| | - Dong Chen
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, People's Republic of China
| | - Jianzhen Shan
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, People's Republic of China
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Wysmołek ME, Długosz E, Wiśniewski M. The Immunological Role of Vascular and Lymphatic Endothelial Cells in Filarial Infections. Animals (Basel) 2022; 12:ani12040426. [PMID: 35203133 PMCID: PMC8868237 DOI: 10.3390/ani12040426] [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: 11/30/2021] [Revised: 01/25/2022] [Accepted: 02/07/2022] [Indexed: 11/26/2022] Open
Abstract
Simple Summary The endothelium is a monolayer of cells forming a thin membrane that lines the inside of blood vessels. These cells release molecules that regulate vascular relaxation, contraction, and can control blood clotting and the immune response. During infections with filarial nematodes, common parasites of humans and animals, the endothelium is believed to play a key role in the communication between the host and the parasite, since the embryonic stage of filaroids is distributed in the bloodstream. Therefore, this review aims to gather research from different scientists in order to better understand the host immune response in infections with filarial nematodes. Abstract The embryonic stage of filarial nematodes, or microfilariae (Mf), shows daily and seasonal periodicity that requires their migration through blood vessels into the lungs, where they are sequestered when not circulating in the peripheral blood. Therefore, Mf and the host endothelium are likely in a permanent state of hide and seek. Interestingly, filarial nematodes co-cultured in media with a murine endothelial cell line survive eight times longer than those cultured in media alone. This suggests that the endothelium is an important element of the immune response in filarial nematodes, perversely promoting their survival in the host. In this review, we will focus on potential pathways involved in the relationship between filarial nematodes and the host endothelium, including the role of endothelial ICAM/VCAM/PECAM adhesion molecules, surface markers involved in the passage of Mf through host tissue, anti-thrombolic effects caused by the presence of filarial nematodes (including plasmins), endothelial cell proliferation (VEGF), and other aspects of the immune activation of the endothelium. The aim of this review is to merge the knowledge about the cross-talk between Mf of different filarial nematode species and endothelial cells (EC), thus allowing a better understanding of the mechanism of these parasitic infections.
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Pain Relief and Antimicrobial Activity in Alveolar Osteitis after Platelet-Rich Fibrin Application—A Non-Randomized Controlled Study. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12031324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
The objective was to compare pain relief in alveolar osteitis achieved by the application of platelet-rich fibrin (PRF) and aspirin cones, and to assess the influence of both treatments on bacterial concentrations in post-extraction wounds. A split-mouth, single-center, non-randomized controlled trial was conducted in 30 patients. Pain relief was assessed using the visual analog scale at three time points (before, 24 h after, and 48 h after intervention). Bacterial concentrations were evaluated from cultures of swab samples collected at the three time points. A Wilcoxon matched-pairs signed-rank test was performed to detect differences in distributions of scalar variables between treatment with PRF and aspirin cones. Pain relief at 24 h and 48 h after treatment was significantly higher (p = 0.003) with PRF application than with aspirin cone placement. Additionally, PRF application caused a significantly higher reduction in aerobic bacteria concentration, an average increase, instead of a decrease, in lactic acid bacilli concentration in the first 24 h, and a significantly greater increase in streptococci concentration at 48 h follow-up. PRF provides better pain relief than aspirin cones in alveolar osteitis. Bacterial concentrations in the extraction wounds are consistent with the pain relief achieved after PRF or aspirin application.
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Morbidelli L, Donnini S. Introduction. ANTIANGIOGENIC DRUGS AS CHEMOSENSITIZERS IN CANCER THERAPY 2022:1-28. [DOI: 10.1016/b978-0-323-90190-1.00018-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Choo PP, Md Din N, Azmi N, Bastion MLC. Review of the management of sight-threatening diabetic retinopathy during pregnancy. World J Diabetes 2021; 12:1386-1400. [PMID: 34630896 PMCID: PMC8472492 DOI: 10.4239/wjd.v12.i9.1386] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 06/25/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) is a noncommunicable disease reaching epidemic proportions around the world. It affects younger individuals, including women of childbearing age. Diabetes can cause diabetic retinopathy (DR), which is potentially sight threatening when severe nonproliferative DR (NPDR), proliferative DR (PDR), or sight-threatening diabetic macular oedema (STDME) develops. Pregnancy is an independent risk factor for the progression of DR. Baseline DR at the onset of pregnancy is an important indicator of progression, with up to 10% of women with baseline NPDR progressing to PDR. Progression to sight-threatening DR (STDR) during pregnancy causes distress to the patient and often necessitates ocular treatment, which may have a systemic effect. Management includes prepregnancy counselling and, when possible, conventional treatment prior to pregnancy. During pregnancy, closer follow-up is required for those with a long duration of DM, poor baseline control of blood sugar and blood pressure, and worse DR, as these are risk factors for progression to STDR. Conventional treatment with anti-vascular endothelial growth factor agents for STDME can potentially lead to foetal loss. Treatment with laser photocoagulation may be preferred, and surgery under general anaesthesia should be avoided. This review provides a management plan for STDR from the perspective of practising ophthalmologists. A review of strategies for maintaining the eyesight of diabetic women with STDR with emphasis on prepregnancy counselling and planning, monitoring and safe treatment during pregnancy, and management of complications is presented.
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Affiliation(s)
- Priscilla Peixi Choo
- Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Wilayah Persekutuan, Malaysia
| | - Norshamsiah Md Din
- Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Wilayah Persekutuan, Malaysia
| | - Nooraniah Azmi
- Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Wilayah Persekutuan, Malaysia
- Department of Ophthalmology, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Mae-Lynn Catherine Bastion
- Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Wilayah Persekutuan, Malaysia
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Kirschen GW, AlAshqar A, Miyashita-Ishiwata M, Reschke L, El Sabeh M, Borahay MA. Vascular biology of uterine fibroids: connecting fibroids and vascular disorders. Reproduction 2021; 162:R1-R18. [PMID: 34034234 DOI: 10.1530/rep-21-0087] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022]
Abstract
Fibroids are benign tumors caused by the proliferation of myometrial smooth muscle cells in the uterus that can lead to symptoms such as abdominal pain, constipation, urinary retention, and infertility. While traditionally thought of as a disease process intrinsic to the uterus, accumulating evidence suggests that fibroid growth may be linked with the systemic vasculature system, although cell-intrinsic factors are certainly of principal importance in their inception. Fibroids are associated with essential hypertension and preeclampsia, as well as atherosclerosis, for reasons that are becoming increasingly elucidated. Factors such as the renin-angiotensin-aldosterone system, estrogen, and endothelial dysfunction all likely play a role in fibroid pathogenesis. In this review, we lay out a framework for reconceptualizing fibroids as a systemic vascular disorder, and discuss how pharmaceutical agents and other interventions targeting the vasculature may aid in the novel treatment of fibroids.
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Affiliation(s)
- Gregory W Kirschen
- Department of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, Maryland, USA
| | - Abdelrahman AlAshqar
- Department of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Obstetrics and Gynecology, Kuwait University, Kuwait City, Kuwait
| | | | - Lauren Reschke
- Department of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, Maryland, USA
| | - Malak El Sabeh
- Department of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, Maryland, USA
| | - Mostafa A Borahay
- Department of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, Maryland, USA
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Huang Z, Huang S, Song T, Yin Y, Tan C. Placental Angiogenesis in Mammals: A Review of the Regulatory Effects of Signaling Pathways and Functional Nutrients. Adv Nutr 2021; 12:2415-2434. [PMID: 34167152 PMCID: PMC8634476 DOI: 10.1093/advances/nmab070] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/05/2021] [Accepted: 05/11/2021] [Indexed: 12/13/2022] Open
Abstract
Normal placental development and proper angiogenesis are essential for fetal growth during pregnancy. Angiogenesis involves the regulatory action of many angiogenic factors and a series of signal transduction processes inside and outside the cell. The obstruction of placental angiogenesis causes fetal growth restriction and serious pregnancy complications, even leading to fetal loss and pregnancy cessation. In this review, the effects of placental angiogenesis on fetal development are described, and several signaling pathways related to placental angiogenesis and their key regulatory mediators are summarized. These factors, which include vascular endothelial growth factor (VEGF)-VEGF receptor, delta-like ligand 4 (DLL-4)-Notch, Wnt, and Hedgehog, may affect the placental angiogenesis process. Moreover, the degree of vascularization depends on cell proliferation, migration, and differentiation, which is affected by the synthesis and secretion of metabolites or intermediates and mutual coordination or inhibition in these pathways. Furthermore, we discuss recent advances regarding the role of functional nutrients (including amino acids and fatty acids) in regulating placental angiogenesis. Understanding the specific mechanism of placental angiogenesis and its influence on fetal development may facilitate the establishment of new therapeutic strategies for the treatment of preterm birth, pre-eclampsia, or intrauterine growth restriction, and provide a theoretical basis for formulating nutritional regulation strategies during pregnancy.
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Affiliation(s)
- Zihao Huang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Shuangbo Huang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Tongxing Song
- Huazhong Agricultural University, College of Animal Science and Technology, Wuhan, China
| | - Yulong Yin
- National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, China
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Babapoor-Farrokhran S, Gill D, Alzubi J, Mainigi SK. Atrial fibrillation: the role of hypoxia-inducible factor-1-regulated cytokines. Mol Cell Biochem 2021; 476:2283-2293. [PMID: 33575876 DOI: 10.1007/s11010-021-04082-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 01/25/2021] [Indexed: 11/25/2022]
Abstract
Atrial fibrillation (AF) is a common arrhythmia that has major morbidity and mortality. Hypoxia plays an important role in AF initiation and maintenance. Hypoxia-inducible factor (HIF), the master regulator of oxygen homeostasis in cells, plays a fundamental role in the regulation of multiple chemokines and cytokines that are involved in different physiological and pathophysiological pathways. HIF is also involved in the pathophysiology of AF induction and propagation mostly through structural remodeling such as fibrosis; however, some of the cytokines discussed have even been implicated in electrical remodeling of the atria. In this article, we highlight the association between HIF and some of its related cytokines with AF. Additionally, we provide an overview of the potential diagnostic benefits of using the mentioned cytokines as AF biomarkers. Research discussed in this review suggests that the expression of these cytokines may correlate with patients who are at an increased risk of developing AF. Furthermore, cytokines that are elevated in patients with AF can assist clinicians in the diagnosis of suspect paroxysmal AF patients. Interestingly, some of the cytokines have been elevated specifically when AF is associated with a hypercoagulable state, suggesting that they could be helpful in the clinician's and patient's decision to begin anticoagulation. Finally, more recent research has demonstrated the promise of targeting these cytokines for the treatment of AF. While still in its early stages, tools such as neutralizing antibodies have proved to be efficacious in targeting the HIF pathway and treating or preventing AF.
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Affiliation(s)
- Savalan Babapoor-Farrokhran
- Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA, 19141, USA.
| | - Deanna Gill
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Jafar Alzubi
- Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA, 19141, USA
| | - Sumeet K Mainigi
- Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA, 19141, USA
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA
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A 60% Edible Ethanolic Extract of Ulmus davidiana Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis. Molecules 2021; 26:molecules26040781. [PMID: 33546250 PMCID: PMC7913375 DOI: 10.3390/molecules26040781] [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: 12/10/2020] [Revised: 01/27/2021] [Accepted: 01/29/2021] [Indexed: 11/17/2022] Open
Abstract
As abnormal angiogenesis is associated with exacerbation of various diseases, precise control over angiogenesis is imperative. Vascular endothelial growth factor (VEGF), the most well-known angiogenic factor, binds to VEGF receptor (VEGFR), activates various signaling pathways, and mediates angiogenesis. Therefore, blocking the VEGF-induced angiogenic response-related signaling pathways may alleviate various disease symptoms through inhibition of angiogenesis. Ulmus davidiana is a safe natural product that has been traditionally consumed, but its effects on endothelial cells (ECs) and the underlying mechanism of action are unclear. In the present study, we focused on the effect of a 60% edible ethanolic extract of U. davidiana (U60E) on angiogenesis. U60E inhibited the VEGF-mediated proliferation, tube formation, and migration ability of ECs. Mechanistically, U60E inhibited endothelial nitric oxide synthase activation and nitric oxide production by blocking the protein kinase B signaling pathway activated by VEGF and consequently inhibiting proliferation, tube formation, and migration of ECs. These results suggest that U60E could be a potential and safe therapeutic agent capable of suppressing proangiogenic diseases by inhibiting VEGF-induced angiogenesis.
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50
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Iwabuchi T, Ogura K, Tamba K, Tsunekawa Y, Sugano M, Hagiwara K, Kiso A. Cepharanthine induces the proliferation of human dermal papilla cells and stimulates vascular endothelial growth factor expression through increased intracellular calcium mobilization and hypoxia-inducible factor activation. Clin Exp Dermatol 2021; 46:694-703. [PMID: 33296524 DOI: 10.1111/ced.14533] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 11/20/2020] [Accepted: 12/04/2020] [Indexed: 11/26/2022]
Abstract
BACKGROUND Cepharanthine (CEP), a compound extracted from the vine Stephania cephalantha, is commonly prescribed to treat alopecia areata; however, the scientific evidence for its efficacy is limited. AIM To investigate the effect of CEP and its structural analogues on human hair growth in vitro. METHODS The effects of CEP and three of its structural analogues on the proliferation of human dermal papilla cells (hDPCs) and human outer root sheath cells (hORSCs) were investigated. Their effects on vascular endothelial growth factor (VEGF) expression were also assessed by real-time PCR. Activation of pathways leading to VEGF expression, such as intracellular Ca2+ mobilization and hypoxia-inducible factor (HIF) expression, was also characterized. RESULTS CEP and two of its structural analogues significantly stimulated the growth of hDPCs but not hORSCs. Moreover, CEP and all three structural analogues significantly induced the expression of VEGF in hDPCs. CEP increased the intracellular Ca2+ concentration in hDPCs. CEP also increased the expression of HIF-1α and HIF-2α and induced the expression of HIF-responsive genes in hDPCs, even under normoxia. CONCLUSIONS These results suggest that CEP and its structural analogues have the potential to restore hair growth by promoting the proliferation of hDPCs and increasing their expression of VEGF.
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Affiliation(s)
- T Iwabuchi
- Faculty of Bioscience and Biotechnology, Tokyo University of Technology, Hachioji, Tokyo, Japan
| | - K Ogura
- Faculty of Bioscience and Biotechnology, Tokyo University of Technology, Hachioji, Tokyo, Japan
| | - K Tamba
- Faculty of Bioscience and Biotechnology, Tokyo University of Technology, Hachioji, Tokyo, Japan
| | - Y Tsunekawa
- Faculty of Bioscience and Biotechnology, Tokyo University of Technology, Hachioji, Tokyo, Japan
| | - M Sugano
- Faculty of Bioscience and Biotechnology, Tokyo University of Technology, Hachioji, Tokyo, Japan
| | - K Hagiwara
- Faculty of Bioscience and Biotechnology, Tokyo University of Technology, Hachioji, Tokyo, Japan
| | - A Kiso
- Research Center, Maruzen Pharmaceuticals Co. Ltd., Fukuyama, Hiroshima, Japan
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