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Varanasi SM, Gulani Y, Rachamala HK, Mukhopadhyay D, Angom RS. Neuropilin-1: A Multifaceted Target for Cancer Therapy. Curr Oncol 2025; 32:203. [PMID: 40277760 PMCID: PMC12025621 DOI: 10.3390/curroncol32040203] [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: 01/02/2025] [Revised: 03/10/2025] [Accepted: 03/23/2025] [Indexed: 04/26/2025] Open
Abstract
Neuropilin-1 (NRP1), initially identified as a neuronal guidance protein, has emerged as a multifaceted regulator in cancer biology. Beyond its role in axonal guidance and angiogenesis, NRP1 is increasingly recognized for its significant impact on tumor progression and therapeutic outcomes. This review explores the diverse functions of NRP1 in cancer, encompassing its influence on tumor cell proliferation, migration, invasion, and metastasis. NRP1 interacts with several key signaling pathways, including vascular endothelial growth factor (VEGF), semaphorins, and transforming growth factor-beta (TGF-β), modulating the tumor microenvironment and promoting angiogenesis. Moreover, NRP1 expression correlates with poor prognosis in various malignancies, underscoring its potential as a prognostic biomarker. Therapeutically, targeting NRP1 holds promise as a novel strategy to inhibit tumor growth and enhance the efficacy of regular treatments such as chemotherapy and radiotherapy. Strategies involving NRP1-targeted therapies, including monoclonal antibodies, small molecule inhibitors, and gene silencing techniques, are being actively investigated in preclinical and clinical settings. Despite challenges in specificity and delivery, advances in understanding NRP1 biology offer new avenues for personalized cancer therapy. Although several types of cancer cells can express NRPs, the role of NRPs in tumor pathogenesis is largely unknown. Future investigations are needed to enhance our understanding of the effects and mechanisms of NRPs on the proliferation, apoptosis, and migration of neuronal, endothelial, and cancer cells. The novel frameworks or multi-omics approaches integrate data from multiple databases to better understand cancer's molecular and clinical features, develop personalized therapies, and help identify biomarkers. This review highlights the pivotal role of NRP1 in cancer pathogenesis and discusses its implications for developing targeted therapeutic approaches to improve patient outcomes, highlighting the role of OMICS in targeting cancer patients for personalized therapy.
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Affiliation(s)
| | | | | | - Debabrata Mukhopadhyay
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (S.M.V.); (Y.G.); (H.K.R.)
| | - Ramcharan Singh Angom
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (S.M.V.); (Y.G.); (H.K.R.)
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Terrian L, Thompson JM, Bowman DE, Panda V, Contreras GA, Rockwell C, Sather L, Fink GD, Lauver DA, Nault R, Watts SW, Bhattacharya S. Single-nucleus analysis of thoracic perivascular adipose tissue reveals critical changes in cell composition, communication, and gene regulatory networks induced by a high fat hypertensive diet. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.13.636878. [PMID: 39990347 PMCID: PMC11844537 DOI: 10.1101/2025.02.13.636878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide, with hypertension being its primary causal factor. Most blood vessels are surrounded by perivascular adipose tissue (PVAT), which regulates blood vessel tone through the secretion of vasoactive factors. PVAT is recognized as a key mediator of vascular function and dysfunction in CVD, although the underlying mechanisms remain poorly understood. To investigate PVAT's mechanistic role in hypertension, we performed single nucleus RNA-Sequencing analysis of thoracic aortic PVAT from Dahl SS rats fed a high-fat, hypertensive diet. Computational analysis revealed extensive diet-induced changes in cell-type composition, cell-type specific gene expression, cell-cell communication pathways, and intracellular gene regulatory networks within PVAT. Furthermore, we identified key transcription factors mediating these networks and demonstrated through virtual knock-out experiments that these factors could serve as potential therapeutic targets for preventing or reversing PVAT's hypertensive state.
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Affiliation(s)
- Leah Terrian
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
- Denotes individuals contributed equally as first authors to this work
| | - Janice M. Thompson
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
- Denotes individuals contributed equally as first authors to this work
| | - Derek E. Bowman
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA
- College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA
| | - Vishal Panda
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA
| | - G. Andres Contreras
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA
| | - Cheryl Rockwell
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Lisa Sather
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Gregory D. Fink
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - D. Adam Lauver
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Rance Nault
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
| | - Stephanie W. Watts
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
- Denotes lead investigators/funding
| | - Sudin Bhattacharya
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
- Denotes lead investigators/funding
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Lachowicz-Radulska J, Widelski J, Nowaczyński F, Serefko A, Sobczyński J, Ludwiczuk A, Kasica N, Szopa A. Zebrafish as a Suitable Model for Utilizing the Bioactivity of Coumarins and Coumarin-Based Compounds. Int J Mol Sci 2025; 26:1444. [PMID: 40003910 PMCID: PMC11855297 DOI: 10.3390/ijms26041444] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/03/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
The aim of this review is to summarize the current knowledge on the use of coumarin-derived compounds in the zebrafish (Danio rerio) model. Coumarins, a class of naturally occurring compounds with diverse biological activities, including compounds such as coumarin, angelicin, and warfarin, have attracted considerable attention in the study of potential therapeutic agents for cancer, central nervous system disorders, and infectious diseases. The capabilities of coumarins as active compounds have led to synthesizing various derivatives with their own properties. While such variety is certainly promising, it is also cumbersome due to the large amount of research needed to find the most optimal compounds. The zebrafish model offers unique advantages for such studies, including high genetic and physiological homology to mammals, optical transparency of the embryos, and rapid developmental processes, facilitating the assessment of compound toxicity and underlying mechanisms of action. This review provides an in-depth analysis of the chemical properties of coumarins, their mechanisms of biological activity, and the results of previous studies evaluating the toxicity and efficacy of these compounds in zebrafish assays. The zebrafish model allows for a holistic assessment of the therapeutic potential of coumarin derivatives, offering valuable insights for advancing drug discovery and development.
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Affiliation(s)
- Joanna Lachowicz-Radulska
- Department of Clinical Pharmacy and Pharmaceutical Care, Medical University of Lublin, 7 Chodźki Street, 20-093 Lublin, Poland; (J.L.-R.); (F.N.); (A.S.); (J.S.)
| | - Jarosław Widelski
- Department of Pharmacognosy with Medicinal Plants Garden, Medical University of Lublin, 1 Chodźki Street, 20-093 Lublin, Poland; (J.W.); (A.L.)
| | - Filip Nowaczyński
- Department of Clinical Pharmacy and Pharmaceutical Care, Medical University of Lublin, 7 Chodźki Street, 20-093 Lublin, Poland; (J.L.-R.); (F.N.); (A.S.); (J.S.)
- Department of Pharmacognosy with Medicinal Plants Garden, Medical University of Lublin, 1 Chodźki Street, 20-093 Lublin, Poland; (J.W.); (A.L.)
| | - Anna Serefko
- Department of Clinical Pharmacy and Pharmaceutical Care, Medical University of Lublin, 7 Chodźki Street, 20-093 Lublin, Poland; (J.L.-R.); (F.N.); (A.S.); (J.S.)
| | - Jan Sobczyński
- Department of Clinical Pharmacy and Pharmaceutical Care, Medical University of Lublin, 7 Chodźki Street, 20-093 Lublin, Poland; (J.L.-R.); (F.N.); (A.S.); (J.S.)
| | - Agnieszka Ludwiczuk
- Department of Pharmacognosy with Medicinal Plants Garden, Medical University of Lublin, 1 Chodźki Street, 20-093 Lublin, Poland; (J.W.); (A.L.)
| | - Natalia Kasica
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland;
| | - Aleksandra Szopa
- Department of Clinical Pharmacy and Pharmaceutical Care, Medical University of Lublin, 7 Chodźki Street, 20-093 Lublin, Poland; (J.L.-R.); (F.N.); (A.S.); (J.S.)
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Arppo A, Barker H, Parkkila S. Bioinformatic characterization of ENPEP, the gene encoding a potential cofactor for SARS-CoV-2 infection. PLoS One 2024; 19:e0307731. [PMID: 39661628 PMCID: PMC11633960 DOI: 10.1371/journal.pone.0307731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 11/21/2024] [Indexed: 12/13/2024] Open
Abstract
Research on SARS-CoV-2, the viral pathogen that causes COVID-19, has identified angiotensin converting enzyme 2 (ACE2) as the primary viral receptor. Several genes that encode viral cofactors, such as TMPRSS2, NRP1, CTSL, and possibly KIM1, have since been discovered. Glutamyl aminopeptidase (APA), encoded by the gene ENPEP, is another cofactor candidate due to similarities in its biological role and high correlation with ACE2 and other human coronavirus receptors, such as aminopeptidase N (APN) and dipeptidyl peptidase 4 (DPP4). Recent studies have proposed a role for ENPEP as a viral receptor in humans, and ENPEP and ACE2 are both closely involved in the renin-angiotensin-aldosterone system proposed to play an important role in SARS-CoV-2 pathophysiology. We performed bioinformatic analyses using publicly available bulk (>17,000 samples from 49 distinct tissues) and single-cell (>2.5 million cells) RNA-Seq gene expression datasets to evaluate the expression and function of the ENPEP gene. We also investigated age- and sex-related changes in ENPEP expression. Overall, expression of ENPEP was highest in the small intestine enterocyte brush border and the kidney cortex. ENPEP is widely expressed in a subset of vascular smooth muscle cells (likely pericytes) in systemic vasculature, the heart, and the brain. ENPEP is expressed at low levels in the lower respiratory epithelium. In the lung, ENPEP is most highly expressed in para-alveolar fibroblasts. Single-cell data revealed ENPEP expression in a substantial fraction of ependymal cells, a finding not reported before in humans. Age increases ENPEP expression in skeletal muscle and the prostate, while decreasing it in the heart and aorta. Angiogenesis was found to be a central biological function associated with the ENPEP gene. Tissue-specific roles, such as protein digestion and fat metabolism, were also identified in the intestine. In the liver, the gene is linked to the complement system, a connection that has not yet been thoroughly investigated. Expression of ENPEP and ACE2 is strongly correlated in the small intestine and renal cortex. Both overall and in blood vessels, ENPEP and ACE2 have a stronger correlation than many other genes associated with SARS-CoV-2, such as TMPRSS2, CTSL, and NRP1. Possible interaction between glutamyl aminopeptidase and SARS-CoV-2 should be investigated experimentally.
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Affiliation(s)
- Antti Arppo
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Harlan Barker
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Clinical Chemistry, Fimlab Laboratories PLC, Tampere University Hospital, Tampere, Finland
- Disease Networks Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Seppo Parkkila
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Clinical Chemistry, Fimlab Laboratories PLC, Tampere University Hospital, Tampere, Finland
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Liu J, Geng Y, Jiang S, Guan L, Gao J, Niu MM, Li J. Discovery of novel PARP1/NRP1 dual-targeting inhibitors with strong antitumor potency. Front Pharmacol 2024; 15:1454957. [PMID: 39679370 PMCID: PMC11637875 DOI: 10.3389/fphar.2024.1454957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 11/15/2024] [Indexed: 12/17/2024] Open
Abstract
Given that overexpression of Poly (ADP-ribose) polymerase-1 (PARP1) and Neuropilin-1 (NRP1) is implicated in the pathogenesis of human breast cancer, the design of dual PARP1/NRP1 inhibitors has wide therapeutic prospect. However, there have been no reports of such inhibitors so far. Herein, we discovered novel small molecule inhibitors that simultaneously target PARP1 and NRP1 using structure-based virtual screening for the treatment of breast cancer. Notably, PPNR-4 was the most potent inhibitor targeting PARP1 (IC50 = 7.71 ± 0.39 nM) and NRP1 (IC50 = 24.48 ± 2.16 nM). PPNR-4 showed high affinity and binding stability to PARP1 and NRP1. The cytotoxicity assays showed that PPNR-4 demonstrated significant antiproliferative activity on MDA-MB-231 cells (IC50 = 0.21 μM) without effect on normal human cells. In vivo experiments exhibited that PPNR-4 showed more effective than the positive controls in inhibiting the growth of tumors. Overall, these data suggest that PPNR-4 is an effective antitumor candidate and deserves further research.
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Affiliation(s)
- Juanjuan Liu
- Department of Pharmacy, Taizhou School of Clinical Medicine, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Yifei Geng
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
| | - Su Jiang
- Department of Pharmacy, Taizhou School of Clinical Medicine, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Lixia Guan
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
| | - Junyi Gao
- Department of Pharmacy, Taizhou School of Clinical Medicine, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Miao-Miao Niu
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
| | - Jindong Li
- Department of Pharmacy, Taizhou School of Clinical Medicine, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
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Matilla L, Martín-Núñez E, Navarro A, Garaikoetxea M, Fernández-Celis A, Goñi-Olóriz M, Gainza A, Fernández-Irigoyen J, Santamaría E, Tamayo I, Álvarez V, Sádaba R, Jover E, López-Andrés N. Neuropilin-1 sex-dependently modulates inflammatory, angiogenic and osteogenic phenotypes in the calcifying valve interstitial cell. Biochem Pharmacol 2024; 226:116336. [PMID: 38844264 DOI: 10.1016/j.bcp.2024.116336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 05/29/2024] [Accepted: 06/03/2024] [Indexed: 06/10/2024]
Abstract
The pathological mechanisms underlying the sex-dependent presentation of calcific aortic stenosis (AS) remain poorly understood. We aim to analyse sex-specific responses of valve interstitial cells (VICs) to calcific environments and to identify new pathological and potentially druggable targets. First, VICs from stenotic patients were modelled using pro-calcifying media (HP). Both male and female VICs were inflamed upon calcific HP challenge, although the inflammatory response was higher in female VICs. The osteogenic and calcification responses were higher in male VICs. To identify new players involved in the responses to HP, proteomics analyses were performed on additional calcifying VICs. Neuropilin-1 (NRP-1) was significantly up-regulated in male calcifying VICs and that was confirmed in aortic valves (AVs), especially nearby neovessels and calcifications. Regardless of the sex, NRP-1 expression was correlated to inflammation, angiogenesis and osteogenic markers, but with stronger associations in male AVs. To further evidence the role of NRP-1, in vitro experiments of silencing or supplementation with soluble NRP-1 (sNRP-1) were performed. NRP-1 silencing or addition of sNRP-1 reduced/mended the expression of any sex-specific response triggered by HP. Moreover, NRP-1 regulation contributed to significantly diminish the baseline enhanced expression of pro-inflammatory, pro-angiogenic and pro-osteogenic markers mainly in male VICs. Validation studies were conducted in stenotic AVs. In summary, pharmacologic targeting of NRP-1 could be used to target sex-specific phenotypes in AS as well as to exert protective effects by reducing the basal expression of pathogenic markers only in male VICs.
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Affiliation(s)
- Lara Matilla
- Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain
| | - Ernesto Martín-Núñez
- Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain
| | - Adela Navarro
- Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain
| | - Mattie Garaikoetxea
- Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain
| | - Amaya Fernández-Celis
- Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain
| | - Miriam Goñi-Olóriz
- Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain
| | - Alicia Gainza
- Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain
| | - Joaquín Fernández-Irigoyen
- Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain
| | - Enrique Santamaría
- Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain
| | - Ibai Tamayo
- Research Methodology Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
| | - Virginia Álvarez
- Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain
| | - Rafael Sádaba
- Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain
| | - Eva Jover
- Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain.
| | - Natalia López-Andrés
- Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain.
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Gui Z, Ye Y, Li Y, Ren Z, Wei N, Liu L, Wang H, Zhang M. Construction of a novel cancer-associated fibroblast-related signature to predict clinical outcome and immune response in cervical cancer. Transl Oncol 2024; 46:102001. [PMID: 38850798 PMCID: PMC11214323 DOI: 10.1016/j.tranon.2024.102001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/18/2024] [Accepted: 05/19/2024] [Indexed: 06/10/2024] Open
Abstract
This study developed a prognostic signature for cervical cancer using transcriptome profiling and clinical data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and TISCH database, focusing on cancer-associated fibroblasts (CAFs). Through LASSO Cox regression and integrated bioinformatics analyses, we identified 144 differentially expressed genes (DEGs) related to CAFs, from which an 11-gene CAF-related signature (CAFRSig) was constructed. The CAFRSig effectively stratified patients into high- and low-risk categories, demonstrating significant prognostic capability in predicting overall survival. Gene ontology (GO) and gene set variation analysis (GSVA) linked the DEGs to crucial pathways in tumor malignancy, immune response, and fatty acid metabolism. The immune landscape analysis, utilizing the TIMER platform and CIBERSORT algorithm, revealed a positive correlation between immune cell effector functions and CAFRSig scores, highlighting the model's potential to identify patients likely to respond to immune checkpoint blockade (ICB) therapies. Furthermore, neuropilin 1 (NRP1), a key gene in the CAFRSig, was upregulated in cervical cancer tissues and associated with disease progression and differentiation. The downregulation of NRP1 curbed cell proliferation and influenced the epithelial-mesenchymal transition (EMT), implicating the PI3K/AKT pathway and modulating PD-L1 expression. This comprehensive analysis establishes a robust prognostic signature based on CAF-related genes, offering valuable insights for optimizing therapeutic strategies in cervical cancer management.
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Affiliation(s)
- Zhongxuan Gui
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China
| | - Yingquan Ye
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China
| | - Yu Li
- Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, Anhui, PR China
| | - Zhengting Ren
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China
| | - Nan Wei
- Department of Radiation Oncology, Anhui Second People's Hospital, Hefei, Anhui, PR China; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China
| | - Li Liu
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China.
| | - Mei Zhang
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China; The Traditional and Western Medicine (TCM)-Integrated Cancer Center of Anhui Medical University, Hefei, Anhui, PR China; Graduate School of Anhui University of Chinese Medicine, Hefei, China.
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Eberhard D, Balkenhol S, Köster A, Follert P, Upschulte E, Ostermann P, Kirschner P, Uhlemeyer C, Charnay I, Preuss C, Trenkamp S, Belgardt BF, Dickscheid T, Esposito I, Roden M, Lammert E. Semaphorin-3A regulates liver sinusoidal endothelial cell porosity and promotes hepatic steatosis. NATURE CARDIOVASCULAR RESEARCH 2024; 3:734-753. [PMID: 39196233 PMCID: PMC11358038 DOI: 10.1038/s44161-024-00487-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 05/07/2024] [Indexed: 08/29/2024]
Abstract
Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, increases worldwide and associates with type 2 diabetes and other cardiometabolic diseases. Here we demonstrate that Sema3a is elevated in liver sinusoidal endothelial cells of animal models for obesity, type 2 diabetes and MASLD. In primary human liver sinusoidal endothelial cells, saturated fatty acids induce expression of SEMA3A, and loss of a single allele is sufficient to reduce hepatic fat content in diet-induced obese mice. We show that semaphorin-3A regulates the number of fenestrae through a signaling cascade that involves neuropilin-1 and phosphorylation of cofilin-1 by LIM domain kinase 1. Finally, inducible vascular deletion of Sema3a in adult diet-induced obese mice reduces hepatic fat content and elevates very low-density lipoprotein secretion. Thus, we identified a molecular pathway linking hyperlipidemia to microvascular defenestration and early development of MASLD.
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Affiliation(s)
- Daniel Eberhard
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Sydney Balkenhol
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Andrea Köster
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Paula Follert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Eric Upschulte
- Cécile & Oskar Vogt Institute of Brain Research, Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany
- Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany
- Helmholtz AI, Research Center Jülich, Jülich, Germany
| | - Philipp Ostermann
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Philip Kirschner
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Celina Uhlemeyer
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Iannis Charnay
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Christina Preuss
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Sandra Trenkamp
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Bengt-Frederik Belgardt
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Timo Dickscheid
- Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany
- Helmholtz AI, Research Center Jülich, Jülich, Germany
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Computer Science, Düsseldorf, Germany
| | - Irene Esposito
- Institute of Pathology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Michael Roden
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Division of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Eckhard Lammert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany.
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
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9
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Morimoto K, Tabata H, Takahashi R, Nakajima K. Interactions between neural cells and blood vessels in central nervous system development. Bioessays 2024; 46:e2300091. [PMID: 38135890 DOI: 10.1002/bies.202300091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/28/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023]
Abstract
The sophisticated function of the central nervous system (CNS) is largely supported by proper interactions between neural cells and blood vessels. Accumulating evidence has demonstrated that neurons and glial cells support the formation of blood vessels, which in turn, act as migratory scaffolds for these cell types. Neural progenitors are also involved in the regulation of blood vessel formation. This mutual interaction between neural cells and blood vessels is elegantly controlled by several chemokines, growth factors, extracellular matrix, and adhesion molecules such as integrins. Recent research has revealed that newly migrating cell types along blood vessels repel other preexisting migrating cell types, causing them to detach from the blood vessels. In this review, we discuss vascular formation and cell migration, particularly during development. Moreover, we discuss how the crosstalk between blood vessels and neurons and glial cells could be related to neurodevelopmental disorders.
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Affiliation(s)
- Keiko Morimoto
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
| | - Hidenori Tabata
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
- Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai, Japan
| | - Rikuo Takahashi
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
| | - Kazunori Nakajima
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
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10
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Bodakuntla S, Kuhn CC, Biertümpfel C, Mizuno N. Cryo-electron microscopy in the fight against COVID-19-mechanism of virus entry. Front Mol Biosci 2023; 10:1252529. [PMID: 37867557 PMCID: PMC10587472 DOI: 10.3389/fmolb.2023.1252529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 09/20/2023] [Indexed: 10/24/2023] Open
Abstract
Cryogenic electron microscopy (cryo-EM) and electron tomography (cryo-ET) have become a critical tool for studying viral particles. Cryo-EM has enhanced our understanding of viral assembly and replication processes at a molecular resolution. Meanwhile, in situ cryo-ET has been used to investigate how viruses attach to and invade host cells. These advances have significantly contributed to our knowledge of viral biology. Particularly, prompt elucidations of structures of the SARS-CoV-2 spike protein and its variants have directly impacted the development of vaccines and therapeutic measures. This review discusses the progress made by cryo-EM based technologies in comprehending the severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2), the virus responsible for the devastating global COVID-19 pandemic in 2020 with focus on the SARS-CoV-2 spike protein and the mechanisms of the virus entry and replication.
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Affiliation(s)
- Satish Bodakuntla
- Laboratory of Structural Cell Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Christopher Cyrus Kuhn
- Laboratory of Structural Cell Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Christian Biertümpfel
- Laboratory of Structural Cell Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Naoko Mizuno
- Laboratory of Structural Cell Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States
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11
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Schnittman SR, Kolossváry M, Beck-Engeser G, Fitch KV, Ambayec GC, Nance RM, Zanni MV, Diggs M, Chan F, McCallum S, Toribio M, Bamford L, Fichtenbaum CJ, Eron JJ, Jacobson JM, Mayer KH, Malvestutto C, Bloomfield GS, Moore RD, Umbleja T, Saag MS, Aberg JA, Currier JS, Delaney JAC, Martin JN, Lu MT, Douglas PS, Ribaudo HJ, Crane HM, Hunt PW, Grinspoon SK. Biological and Clinical Implications of the Vascular Endothelial Growth Factor Coreceptor Neuropilin-1 in Human Immunodeficiency Virus. Open Forum Infect Dis 2023; 10:ofad467. [PMID: 37869406 PMCID: PMC10590105 DOI: 10.1093/ofid/ofad467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 09/06/2023] [Indexed: 10/24/2023] Open
Abstract
Plasma vascular endothelial growth factor (VEGF) coreceptor neuropilin-1 (NRP-1) had the largest association with coronary plaque in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) proteomics analysis. With little known about NRP-1 in people with human immunodeficiency virus (PWH), we explored its relation to other proteins in REPRIEVE and validated our findings through a Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) case-cohort study by assessing its relation to host factors and incident cardiovascular disease and cancer. Within REPRIEVE, NRP-1 was associated with proteins involved in angiogenesis, signal transduction, immunoregulation, and cell migration/adhesion. Within CNICS, NRP-1 was associated with key host factors, including older age and male sex. NRP-1 was associated with an increased hazard of multiple cancers but a decreased prostate cancer risk. Finally, NRP-1 was most strongly associated with mortality and type 2 myocardial infarction. These data suggest that NRP-1 is part of a clinically relevant immunoregulatory pathway related to multiple comorbidities in PWH. Clinical Trials Registration. NCT02344290.
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Affiliation(s)
- Samuel R Schnittman
- Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Márton Kolossváry
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Gabriele Beck-Engeser
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Kathleen V Fitch
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Gabrielle C Ambayec
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Robin M Nance
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Markella V Zanni
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Marissa Diggs
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Fay Chan
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Sara McCallum
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Mabel Toribio
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Laura Bamford
- Division of Infectious Diseases and Global Public Health, University of California, San Diego, San Diego, California, USA
| | - Carl J Fichtenbaum
- Division of Infectious Diseases, University of Cincinnati, Cincinnati, Ohio, USA
| | - Joseph J Eron
- Division of Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Jeffrey M Jacobson
- Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio, USA
| | - Kenneth H Mayer
- Fenway Health and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Carlos Malvestutto
- Division of Infectious Diseases, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Gerald S Bloomfield
- Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA
| | - Richard D Moore
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Triin Umbleja
- Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
| | - Michael S Saag
- Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Judith A Aberg
- Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Judith S Currier
- Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, California, USA
| | - Joseph A C Delaney
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
- College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Jeffrey N Martin
- Department of Epidemiology and Biostatistics, University of California, San Francisco School of Medicine, San Francisco, California, USA
| | - Michael T Lu
- Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Pamela S Douglas
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Heather J Ribaudo
- Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Heidi M Crane
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Peter W Hunt
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Steven K Grinspoon
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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12
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Izci M, Maksoudian C, Gonçalves F, Pérez Gilabert I, Rios Luci C, Bolea-Fernandez E, Vanhaecke F, Manshian BB, Soenen SJ. The Efficacy of Nanoparticle Delivery to Hypoxic Solid Tumors by ciRGD Co-Administration Depends on Neuropilin-1 and Neutrophil Levels. Adv Healthc Mater 2023; 12:e2300594. [PMID: 37247322 DOI: 10.1002/adhm.202300594] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/02/2023] [Indexed: 05/31/2023]
Abstract
The ability to improve nanoparticle delivery to solid tumors is an actively studied domain, where various mechanisms are looked into. In previous work, the authors have looked into nanoparticle size, tumor vessel normalization, and disintegration, and here it is aimed to continue this work by performing an in-depth mechanistic study on the use of ciRGD peptide co-administration. Using a multiparametric approach, it is observed that ciRGD can improve nanoparticle delivery to the tumor itself, but also to tumor cells specifically better than vessel normalization strategies. The effect depends on the level of tumor perfusion, hypoxia, neutrophil levels, and vessel permeability. This work shows that upon characterizing tumors for these parameters, conditions can be selected that can optimally benefit from ciRGD co-administration as a means to improve NP delivery to solid tumors.
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Affiliation(s)
- Mukaddes Izci
- NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven Herestraat 49, Leuven, B3000, Belgium
| | - Christy Maksoudian
- NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven Herestraat 49, Leuven, B3000, Belgium
| | - Filipa Gonçalves
- NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven Herestraat 49, Leuven, B3000, Belgium
| | - Irati Pérez Gilabert
- NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven Herestraat 49, Leuven, B3000, Belgium
| | - Carla Rios Luci
- NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven Herestraat 49, Leuven, B3000, Belgium
| | - Eduardo Bolea-Fernandez
- Atomic & Mass Spectrometry - A&MS research group, Department of Chemistry, Ghent University, Campus Sterre, Krijgslaan 281-S12, Ghent, 9000, Belgium
| | - Frank Vanhaecke
- Atomic & Mass Spectrometry - A&MS research group, Department of Chemistry, Ghent University, Campus Sterre, Krijgslaan 281-S12, Ghent, 9000, Belgium
| | - Bella B Manshian
- Translational Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven Herestraat 49, Leuven, B3000, Belgium
- Leuven Cancer Research Institute, Faculty of Medical Sciences, KU Leuven, Herestraat 49, Leuven, B3000, Belgium
| | - Stefaan J Soenen
- NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven Herestraat 49, Leuven, B3000, Belgium
- Leuven Cancer Research Institute, Faculty of Medical Sciences, KU Leuven, Herestraat 49, Leuven, B3000, Belgium
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13
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Xia X. Identification of host receptors for viral entry and beyond: a perspective from the spike of SARS-CoV-2. Front Microbiol 2023; 14:1188249. [PMID: 37560522 PMCID: PMC10407229 DOI: 10.3389/fmicb.2023.1188249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 07/10/2023] [Indexed: 08/11/2023] Open
Abstract
Identification of the interaction between the host membrane receptor and viral receptor-binding domain (RBD) represents a crucial step for understanding viral pathophysiology and for developing drugs against pathogenic viruses. While all membrane receptors and carbohydrate chains could potentially be used as receptors for viruses, prioritized searches focus typically on membrane receptors that are known to have been used by the relatives of the pathogenic virus, e.g., ACE2 used as a receptor for SARS-CoV is a prioritized candidate receptor for SARS-CoV-2. An ideal receptor protein from a viral perspective is one that is highly expressed in epithelial cell surface of mammalian respiratory or digestive tracts, strongly conserved in evolution so many mammalian species can serve as potential hosts, and functionally important so that its expression cannot be readily downregulated by the host in response to the infection. Experimental confirmation of host receptors includes (1) infection studies with cell cultures/tissues/organs with or without candidate receptor expression, (2) experimental determination of protein structure of the complex between the putative viral RDB and the candidate host receptor, and (3) experiments with mutant candidate receptor or homologues of the candidate receptor in other species. Successful identification of the host receptor opens the door for mechanism-based development of candidate drugs and vaccines and facilitates the inference of what other animal species are vulnerable to the viral pathogen. I illustrate these approaches with research on identification of the receptor and co-factors for SARS-CoV-2.
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Affiliation(s)
- Xuhua Xia
- Department of Biology, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
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14
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Katsi V, Papakonstantinou I, Tsioufis K. Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management. Int J Mol Sci 2023; 24:11786. [PMID: 37511551 PMCID: PMC10381022 DOI: 10.3390/ijms241411786] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/03/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
The involvement of cardiovascular disease in cancer onset and development represents a contemporary interest in basic science. It has been recognized, from the most recent research, that metabolic syndrome-related conditions, ranging from atherosclerosis to diabetes, elicit many pathways regulating lipid metabolism and lipid signaling that are also linked to the same framework of multiple potential mechanisms for inducing cancer. Otherwise, dyslipidemia and endothelial cell dysfunction in atherosclerosis may present common or even interdependent changes, similar to oncogenic molecules elevated in many forms of cancer. However, whether endothelial cell dysfunction in atherosclerotic disease provides signals that promote the pre-clinical onset and proliferation of malignant cells is an issue that requires further understanding, even though more questions are presented with every answer. Here, we highlight the molecular mechanisms that point to a causal link between lipid metabolism and glucose homeostasis in metabolic syndrome-related atherosclerotic disease with the development of cancer. The knowledge of these breakthrough mechanisms may pave the way for the application of new therapeutic targets and for implementing interventions in clinical practice.
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Affiliation(s)
- Vasiliki Katsi
- Department of Cardiology, Hippokration Hospital, 11527 Athens, Greece
| | | | - Konstantinos Tsioufis
- Department of Cardiology, Hippokration Hospital, 11527 Athens, Greece
- School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
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15
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Lu L, Wang L, Zhao L, Liao J, Zhao C, Xu X, Wang F, Zhang X. A Novel Blood-Brain Barrier-Penetrating and Vascular-Targeting Chimeric Peptide Inhibits Glioma Angiogenesis. Int J Mol Sci 2023; 24:ijms24108753. [PMID: 37240099 DOI: 10.3390/ijms24108753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/05/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
The high vascularization of glioma highlights the potential value of anti-angiogenic therapeutics for glioma treatment. Previously, we designed a novel vascular-targeting and blood-brain barrier (BBB)-penetrating peptide, TAT-AT7, by attaching the cell-penetrating peptide TAT to a vascular-targeting peptide AT7, and we demonstrated that TAT-AT7 could target binding to the vascular endothelial growth factor receptor 2 (VEGFR-2) and Neuropilin-1 (NRP-1), which are both highly expressed in endothelial cells. TAT-AT7 has been proven to be a good targeting peptide which could effectively deliver the secretory endostatin gene to treat glioma via the TAT-AT7-modified polyethyleneimine (PEI) nanocomplex. In the current study, we further explored the molecular binding mechanisms of TAT-AT7 to VEGFR-2 and NRP-1 and its anti-glioma effects. Accordingly, TAT-AT7 was proven to competitively bind to VEGFR-2 and NRP-1 and prevent VEGF-A165 binding to the receptors by the surface plasmon resonance (SPR) assay. TAT-AT7 inhibited endothelial cells' proliferation, migration, invasion, and tubule formation, as well as promoted endothelial cells' apoptosis in vitro. Further research revealed that TAT-AT7 inhibited the phosphorylation of VEGFR-2 and its downstream PLC-γ, ERK1/2, SRC, AKT, and FAK kinases. Additionally, TAT-AT7 significantly inhibited angiogenesis of zebrafish embryo. Moreover, TAT-AT7 had a better penetrating ability and could penetrate the BBB into glioma tissue and target glioma neovascularization in an orthotopic U87-glioma-bearing nude mice model, and exhibited the effect of inhibiting glioma growth and angiogenesis. Taken together, the binding and function mechanisms of TAT-AT7 were firstly revealed, and TAT-AT7 was proven to be an effective and promising peptide for the development of anti-angiogenic drugs for targeted treatment of glioma.
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Affiliation(s)
- Lu Lu
- Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Longkun Wang
- Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Lin Zhao
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Jing Liao
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Chunqian Zhao
- Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Xiaohan Xu
- Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Fengshan Wang
- Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Xinke Zhang
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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16
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Folic Acid and Leucovorin Have Potential to Prevent SARS-CoV-2-Virus Internalization by Interacting with S-Glycoprotein/Neuropilin-1 Receptor Complex. Molecules 2023; 28:molecules28052294. [PMID: 36903540 PMCID: PMC10005443 DOI: 10.3390/molecules28052294] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/25/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023] Open
Abstract
The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identified as a potential COVID-19 treatment target. Herein, the effectiveness of folic acid and leucovorin in preventing contact between S-glycoprotein and NRP-1 receptors was investigated using in silico studies and then confirmed in vitro. The results of a molecular docking study showed that leucovorin and folic acid had lower binding energies than EG01377, a well-known NRP-1 inhibitor, and lopinavir. Two hydrogen bonds with Asp 320 and Asn 300 residues stabilized the leucovorin, while interactions with Gly 318, Thr 349, and Tyr 353 residues stabilized the folic acid. The molecular dynamic simulation revealed that the folic acid and leucovorin created very stable complexes with the NRP-1. The in vitro studies showed that the leucovorin was the most active inhibitor of the S1-glycoprotein/NRP-1 complex formation, with an IC75 value of 185.95 µg/mL. The results of this study suggest that folic acid and leucovorin could be considered as potential inhibitors of the S-glycoprotein/NRP-1 complex and, thus, could prevent the SARS-CoV-2 virus' entry into host cells.
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17
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Sarkar M, Saha S. Modeling of SARS-CoV-2 Virus Proteins: Implications on Its Proteome. Methods Mol Biol 2023; 2627:265-299. [PMID: 36959453 DOI: 10.1007/978-1-0716-2974-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2023]
Abstract
COronaVIrus Disease 19 (COVID-19) is a severe acute respiratory syndrome (SARS) caused by a group of beta coronaviruses, SARS-CoV-2. The SARS-CoV-2 virus is similar to previous SARS- and MERS-causing strains and has infected nearly six hundred and fifty million people all over the globe, while the death toll has crossed the six million mark (as of December, 2022). In this chapter, we look at how computational modeling approaches of the viral proteins could help us understand the various processes in the viral life cycle inside the host, an understanding of which might provide key insights in mitigating this and future threats. This understanding helps us identify key targets for the purpose of drug discovery and vaccine development.
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Affiliation(s)
- Manish Sarkar
- Hochschule für Technik und Wirtschaft (HTW) Berlin, Berlin, Germany
- MedInsights SAS, Paris, France
| | - Soham Saha
- MedInsights, Veuilly la Poterie, France.
- MedInsights SAS, Paris, France.
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18
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Abstract
Regulation of the endothelial barrier function is critical to physiological function of the vasculature, which must dynamically change in a number of physiologic and pathologic settings. A new study emphasizes the complex relationship between VE-cadherin phosphorylation , the critical role of YES in this process, and the vascular leak.
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Affiliation(s)
- Michael Simons
- Yale Cardiovascular Research Center and Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06511
| | - Derek Toomre
- Yale Cardiovascular Research Center and Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06511
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19
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Zalpoor H, Aziziyan F, Liaghat M, Bakhtiyari M, Akbari A, Nabi-Afjadi M, Forghaniesfidvajani R, Rezaei N. The roles of metabolic profiles and intracellular signaling pathways of tumor microenvironment cells in angiogenesis of solid tumors. Cell Commun Signal 2022; 20:186. [PMID: 36419156 PMCID: PMC9684800 DOI: 10.1186/s12964-022-00951-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/06/2022] [Indexed: 11/27/2022] Open
Abstract
Innate and adaptive immune cells patrol and survey throughout the human body and sometimes reside in the tumor microenvironment (TME) with a variety of cell types and nutrients that may differ from those in which they developed. The metabolic pathways and metabolites of immune cells are rooted in cell physiology, and not only provide nutrients and energy for cell growth and survival but also influencing cell differentiation and effector functions. Nowadays, there is a growing awareness that metabolic processes occurring in cancer cells can affect immune cell function and lead to tumor immune evasion and angiogenesis. In order to safely treat cancer patients and prevent immune checkpoint blockade-induced toxicities and autoimmunity, we suggest using anti-angiogenic drugs solely or combined with Immune checkpoint blockers (ICBs) to boost the safety and effectiveness of cancer therapy. As a consequence, there is significant and escalating attention to discovering techniques that target metabolism as a new method of cancer therapy. In this review, a summary of immune-metabolic processes and their potential role in the stimulation of intracellular signaling in TME cells that lead to tumor angiogenesis, and therapeutic applications is provided. Video abstract.
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Affiliation(s)
- Hamidreza Zalpoor
- grid.412571.40000 0000 8819 4698Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran ,grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Fatemeh Aziziyan
- grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran ,grid.412266.50000 0001 1781 3962Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahsa Liaghat
- grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran ,Department of Medical Laboratory Sciences, Faculty of Medical Sciences, Islamic Azad University, Kazerun Branch, Kazerun, Iran
| | - Maryam Bakhtiyari
- grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran ,grid.412606.70000 0004 0405 433XDepartment of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Abdullatif Akbari
- grid.412571.40000 0000 8819 4698Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran ,grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mohsen Nabi-Afjadi
- grid.412266.50000 0001 1781 3962Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Razieh Forghaniesfidvajani
- grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran ,grid.411705.60000 0001 0166 0922Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Dr. Gharib St, Keshavarz Blvd, Tehran, Iran ,grid.411705.60000 0001 0166 0922Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Klotz DM, Kuhlmann JD, Link T, Goeckenjan M, Hofbauer LC, Göbel A, Rachner TD, Wimberger P. Clinical impact of soluble Neuropilin-1 in ovarian cancer patients and its association with its circulating ligands of the HGF/c-MET axis. Front Oncol 2022; 12:974885. [PMID: 36338759 PMCID: PMC9635484 DOI: 10.3389/fonc.2022.974885] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 09/05/2022] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND Neuropilin (NRP) is a transmembrane protein, which has been shown to be a pro-angiogenic mediator and implicated as a potential driver of cancer progression. NRP-1 up-regulation in ovarian cancer tissue predicts poor prognosis. However, the clinical relevance of the soluble form of NRP-1 (sNRP-1) as a circulating biomarker in ovarian cancer patients is unknown. METHODS/PATIENTS COHORT sNRP-1 levels were quantified in a cohort of 88 clinically documented ovarian cancer patients by a commercially available sNRP-1 enzyme-linked immunosorbent assay (ELISA) kit (Biomedica, Vienna, Austria). Patients (81.8% with FIGOIII/IV) received primary cytoreductive surgery with the aim of macroscopic complete resection (achieved in 55.7% of patients) and the recommendation of adjuvant chemotherapy in line with national guidelines. RESULTS Higher levels of sNRP-1 reflected more advanced disease (FIGO III/IV) and indicated a trend towards suboptimal surgical outcome, i.e. any residual tumor. sNRP-1 was neither related to the patients' age nor the BRCA1/2 mutational status. Patients with higher sNRP-1 levels at primary diagnosis had a significantly reduced progression-free survival (PFS) (HR = 0.541, 95%CI: 0.304 - 0.963; p = 0.037) and overall survival (OS) (HR = 0.459, 95%CI: 0.225 - 0.936; p = 0.032). Principal component analysis showed that sNRP-1 levels were unrelated to the circulating hepatocyte growth factor (HGF) and the soluble ectodomain of its receptor the tyrosine kinase mesenchymal-epithelial transition (c-MET), suggesting that there is no proportional serological concentration gradient of soluble components of the NRP-1/HGF/c-MET signaling axis. CONCLUSIONS In line with the previously shown tissue-based prognostic role, we demonstrated for the first time that sNRP-1 can also act as a readily accessible, prognostic biomarker in the circulation of patients with ovarian cancer at primary diagnosis. Given its known role in angiogenesis and conferring resistance to the poly ADP-ribose polymerase (PARP) inhibitor olaparib in vitro, our results encourage more detailed investigation into sNRP-1 as a potential predictive biomarker for bevacizumab and/or PARP-inhibitor treatment.
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Affiliation(s)
- Daniel Martin Klotz
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Jan Dominik Kuhlmann
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Theresa Link
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Maren Goeckenjan
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Lorenz C. Hofbauer
- German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany
| | - Andy Göbel
- German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany
| | - Tilman D. Rachner
- German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany
| | - Pauline Wimberger
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
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Regulation of Semaphorin3A in the process of cutaneous wound healing. Cell Death Differ 2022; 29:1941-1954. [PMID: 35347234 PMCID: PMC9525670 DOI: 10.1038/s41418-022-00981-6] [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: 09/03/2021] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 12/13/2022] Open
Abstract
Semaphorin 3A (Sema3A) has been recognized as a crucial regulator of morphogenesis and homeostasis over a wide range of organ systems. However, its function in cutaneous wound healing is poorly understood. In our study, we demonstrated that Sema3A adenovirus plasmids transfection limited keratinocyte proliferation and decreased migrative capacity as assessed by in vitro wound healing assay. Sema3A transduction inhibited TGF-β1-mediated keratinocyte migration and EMT process. Besides, we applied mice with K14-Cre-mediated deletion of Sema3A and found that Sema3A depletion postponed wound closure with decreased re-epithelialization and matrix growth. Contrary to the results obtained with full-length Sema3A plasmids transfection, increased keratinocyte migration with recombinant Sema3A proteins resulted in quicker closure of the wounding area after a scratch. Further, exogenously applied recombinant Sema3A worked with EGF to maintain the activation of EGFR by interacting with NRP1 and thereby regulated the internalization of the EGFR-NRP1 complex. Taken together, these results indicated a paradoxical role of autonomous and non-autonomous Sema3A expression during wound healing. Combined administration of recombinant EGF and Sema3A proteins could accelerate the process of wound repair, thus providing promising treatment prospects in the future.
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22
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Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast. Nat Commun 2022; 13:5511. [PMID: 36127427 PMCID: PMC9489707 DOI: 10.1038/s41467-022-33052-y] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 08/30/2022] [Indexed: 01/03/2023] Open
Abstract
Since a detailed inventory of endothelial cell (EC) heterogeneity in breast cancer (BC) is lacking, here we perform single cell RNA-sequencing of 26,515 cells (including 8433 ECs) from 9 BC patients and compare them to published EC taxonomies from lung tumors. Angiogenic ECs are phenotypically similar, while other EC subtypes are different. Predictive interactome analysis reveals known but also previously unreported receptor-ligand interactions between ECs and immune cells, suggesting an involvement of breast EC subtypes in immune responses. We also identify a capillary EC subtype (LIPEC (Lipid Processing EC)), which expresses genes involved in lipid processing that are regulated by PPAR-γ and is more abundant in peri-tumoral breast tissue. Retrospective analysis of 4648 BC patients reveals that treatment with metformin (an indirect PPAR-γ signaling activator) provides long-lasting clinical benefit and is positively associated with LIPEC abundance. Our findings warrant further exploration of this LIPEC/PPAR-γ link for BC treatment. Tumor blood vessels contribute to cancer growth, invasion and metastasis. Here, by using single cell transcriptomics, the authors report an inventory of endothelial cell heterogeneity in patients with breast cancer, including a subtype that expresses genes involved in lipid processing and is regulated by PPAR-γ.
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Drake KA, Chaney C, Patel M, Das A, Bittencourt J, Cohn M, Carroll TJ. Transcription Factors YAP/TAZ and SRF Cooperate To Specify Renal Myofibroblasts in the Developing Mouse Kidney. J Am Soc Nephrol 2022; 33:1694-1707. [PMID: 35918150 PMCID: PMC9529188 DOI: 10.1681/asn.2021121559] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 05/23/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND The embryonic renal stroma consists of multiple molecularly distinct cell subpopulations, the functional significance of which is largely unknown. Previous work has demonstrated that the transcription factors YAP and TAZ play roles in the development and morphogenesis of the nephrons, collecting ducts, and nephron progenitor cells. METHODS In embryonic mouse kidneys, we identified a subpopulation of stromal cells with enriched activity in YAP and TAZ. To evaluate the function of these cell types, we genetically ablated both Yap and Taz from the stromal progenitor population and examined how gene activity and development of YAP/TAZ mutant kidneys are affected over a developmental time course. RESULTS We found that YAP and TAZ are active in a subset of renal interstitium and that stromal-specific coablation of YAP/TAZ disrupts cortical fibroblast, pericyte, and myofibroblast development, with secondary effects on peritubular capillary differentiation. We also demonstrated that the transcription factor SRF cooperates with YAP/TAZ to drive expression of at least a subset of renal myofibroblast target genes and to specify myofibroblasts but not cortical fibroblasts or pericytes. CONCLUSIONS These findings reveal a critical role for YAP/TAZ in specific embryonic stromal cells and suggest that interaction with cofactors, such as SRF, influence the expression of cell type-specific target genes, thus driving stromal heterogeneity. Further, this work reveals functional roles for renal stroma heterogeneity in creating unique microenvironments that influence the differentiation and maintenance of the renal parenchyma.
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Affiliation(s)
- Keri A Drake
- Division of Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Christopher Chaney
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine (Nephrology), University of Texas Southwestern Medical Center, Dallas, Texas
| | - Mohita Patel
- Division of Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Amrita Das
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine (Nephrology), University of Texas Southwestern Medical Center, Dallas, Texas
| | - Julia Bittencourt
- Department of Molecular Genetics and Microbiology, University of Florida Genetics Institute, University of Florida, Gainesville, Florida
| | - Martin Cohn
- Department of Molecular Genetics and Microbiology, University of Florida Genetics Institute, University of Florida, Gainesville, Florida
| | - Thomas J Carroll
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine (Nephrology), University of Texas Southwestern Medical Center, Dallas, Texas
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Awoyemi T, Iaccarino DA, Motta-Mejia C, Raiss S, Kandzija N, Zhang W, Vatish M. Neuropilin-1 is uniquely expressed on small syncytiotrophoblast extracellular vesicles but not on medium/large vesicles from preeclampsia and normal placentae. Biochem Biophys Res Commun 2022; 619:151-158. [PMID: 35760012 DOI: 10.1016/j.bbrc.2022.06.041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/13/2022] [Indexed: 11/15/2022]
Abstract
Preeclampsia (PE) is a multisystem progressive hypertensive disorder unique to human pregnancy. The placenta is fundamental to its pathogenesis and releases placental factors as well as extracellular vesicles (small and medium/large syncytiotrophoblast extracellular vesicles (STB-EVs)) as a response to syncytiotrophoblast stress such as tissue factor and plasminogen activator inhibitors 1. Neuropilin 1 (NRP-1) is an anti-angiogenic factor involved in development, angiogenesis, arteriogenesis, and vascular permeability. NRP-1 acts as a co-receptor for growth factors such as vascular endothelial growth factor (VEGF), placenta growth factor (PLGF), and epidermal growth factor (EGF). Given the documented pro and anti-angiogenic roles of STB-EVs, we hypothesized that 1) STB-EVs might express NRP-1; and 2) the expression of NRP-1 might differ between normal and preeclampsia STB-EVs. METHODS We isolated STB-EVs (both small and medium/large) from PE and NP placentae using the physiologic ex vivo dual lobe perfusion model. The enriched STB-EVs were characterized by Western blot, transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA) according to the international society of extracellular vesicles (ISEV) guidelines. We assessed for NRP-1 expression with Western blot (placenta and STB-EVs) and immunohistochemistry (placenta). We performed co-expression analysis for placenta alkaline phosphatase (PLAP - a known STB-EV marker) and NRP-1 with immunoprecipitation followed by Western blot. RESULTS We confirmed NRP-1 expression in NP and PE placenta. We showed that NRP-1 Expression was limited to small syncytiotrophoblast membrane extracellular vesicles (S STB-EVs) but not medium/large STB-EVs and that NRP-1 is co-expressed with PLAP. CONCLUSION Neuropilin-1 is uniquely expressed on small syncytiotrophoblast extracellular vesicles but not on medium/large vesicles from preeclampsia and normal placentae.
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Affiliation(s)
- Toluwalase Awoyemi
- Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, United Kingdom
| | - Daniela A Iaccarino
- Vita-Salute San Raffaele University, Obstetrics and Gynecology Department, Genomic Unit for the Diagnosis of Human Pathologies, Italy
| | - Carolina Motta-Mejia
- Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, United Kingdom
| | - Sina Raiss
- S Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden
| | - Neva Kandzija
- Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, United Kingdom
| | - Wei Zhang
- Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, United Kingdom
| | - Manu Vatish
- Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, United Kingdom.
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25
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Gomazkov OA. Neuropilin Is a New Player in the Pathogenesis of COVID-19. NEUROCHEM J+ 2022. [PMCID: PMC9294753 DOI: 10.1134/s1819712422020064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Abstract—A family of glycoproteins called neuropilins is gaining attention as a new contributor to the pathogenesis of COVID-19. The concept of penetration of SARS-CoV-2 into host cells is traditionally associated with the receptor role of the ACE2 protein. New evidence suggests that it is possible to enhance pulmonary viral infection by involvement of neuropilins. Neuropilins have two prominent features: (a) a wide range of participation in cellular and tissue processes; (b) a concomitant enhancement of effects associated with the co-reception of regulatory proteins. These features determine the special role of functionally disseminated neuropilins in the pathogenesis of vascular system damage, immunothrombosis, and organ damage with comorbid manifestations during COVID-19. However, the presentation of neuropilins as a generalized therapeutic target that has a corrective effect on the affected areas is an ambiguous approach and requires a selective strategy.
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Affiliation(s)
- O. A. Gomazkov
- Orekhovich Scientific Research Institute of Biomedical Chemistry, Moscow, Russia
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26
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Huang J, Wang J, Li Y, Wang Z, Chu M, Wang Y. Tuftsin: A Natural Molecule Against SARS-CoV-2 Infection. Front Mol Biosci 2022; 9:859162. [PMID: 35402510 PMCID: PMC8984176 DOI: 10.3389/fmolb.2022.859162] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/07/2022] [Indexed: 01/03/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) continuously progresses despite the application of a variety of vaccines. Therefore, it is still imperative to find effective ways for treating COVID-19. Recent studies indicate that NRP1, an important receptor of the natural peptide tuftsin (released from IgG), facilitates SARS-CoV-2 infection. Here, we found 91 overlapping genes between tuftsin targets and COVID-19-associated genes. We have demonstrated that tuftsin could also target ACE2 and exert some immune-related functions. Molecular docking results revealed that tustin could combine with ACE2 and NRP1 in stable structures, and their interacted regions cover the binding surfaces of S1-protein with the two receptors. Using surface plasmon resonance (SPR) analysis, we confirmed that tuftsin can bind ACE2 and NRP1 directly. Importantly, using SPR-based competition assay we have shown here that tuftsin effectively prevented the binding of SARS-CoV-2 S1-protein to ACE2. Collectively, these data suggest that tuftsin is an attractive therapeutic candidate against COVID-19 and can be considered for translational as well as clinical studies.
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Affiliation(s)
- Jiahao Huang
- Department of Immunology, School of Basic Medical Sciences, Peking University. NHC Key Laboratory of Medical Immunology(Peking University), Beijing, China
| | - Jing Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Yan Li
- Department of Immunology, School of Basic Medical Sciences, Peking University. NHC Key Laboratory of Medical Immunology(Peking University), Beijing, China
| | - Ziyuan Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University. NHC Key Laboratory of Medical Immunology(Peking University), Beijing, China
| | - Ming Chu
- Department of Immunology, School of Basic Medical Sciences, Peking University. NHC Key Laboratory of Medical Immunology(Peking University), Beijing, China
- *Correspondence: Ming Chu, ; Yuedan Wang,
| | - Yuedan Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University. NHC Key Laboratory of Medical Immunology(Peking University), Beijing, China
- *Correspondence: Ming Chu, ; Yuedan Wang,
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García-Escobar A, Vera-Vera S, Jurado-Román A, Jiménez-Valero S, Galeote G, Moreno R. Calcium Signaling Pathway Is Involved in the Shedding of ACE2 Catalytic Ectodomain: New Insights for Clinical and Therapeutic Applications of ACE2 for COVID-19. Biomolecules 2022; 12:biom12010076. [PMID: 35053224 PMCID: PMC8774087 DOI: 10.3390/biom12010076] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/26/2021] [Accepted: 12/29/2021] [Indexed: 02/04/2023] Open
Abstract
The angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane that exists in two forms: the first is a transmembrane protein; the second is a soluble catalytic ectodomain of ACE2. The catalytic ectodomain of ACE2 undergoes shedding by a disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), in which calmodulin mediates the calcium signaling pathway that is involved in ACE2 release, resulting in a soluble catalytic ectodomain of ACE2 that can be measured as soluble ACE2 plasma activity. The shedding of the ACE2 catalytic ectodomain plays a role in cardiac remodeling and endothelial dysfunction and is a predictor of all-cause mortality, including cardiovascular mortality. Moreover, considerable evidence supports that the ACE2 catalytic ectodomain is an essential entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Additionally, endotoxins and the pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-alpha (TNFα) all enhanced soluble catalytic ectodomain ACE2 shedding from the airway epithelia, suggesting that the shedding of ACE2 may represent a mechanism by which viral entry and infection may be controlled such as some types of betacoronavirus. In this regard, ACE2 plays an important role in inflammation and thrombotic response, and its down-regulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury. Soluble forms of ACE2 have recently been shown to inhibit SARS-CoV-2 infection. Furthermore, given that vitamin D enhanced the shedding of ACE2, some studies reported that vitamin D treatment is associated with prognosis improvement in COVID-19. This is an updated review on the evidence, clinical, and therapeutic applications of ACE2 for COVID-19.
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Affiliation(s)
- Artemio García-Escobar
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-917-27-70-00
| | - Silvio Vera-Vera
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Alfonso Jurado-Román
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Santiago Jiménez-Valero
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Guillermo Galeote
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Raúl Moreno
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Brash JT, Ruhrberg C, Fantin A. Evaluating VEGF-Induced Vascular Leakage Using the Miles Assay. Methods Mol Biol 2022; 2475:289-295. [PMID: 35451766 DOI: 10.1007/978-1-0716-2217-9_21] [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: 06/14/2023]
Abstract
Before the endothelial mitogenic activity of the Vascular Endothelial Growth Factor A (VEGF) was described, VEGF had already been identified for its ability to induce vascular leakage. VEGF-induced vascular leakage has been most frequently studied in vivo using the Miles assay, a simple yet invaluable technique that has allowed researchers to unravel the molecular mechanisms underpinning vascular leakage both for VEGF and other permeability inducing agents. In this protocol, a mouse is intravenously injected with Evans Blue dye before VEGF is administered locally via intradermal injection. VEGF promotes vascular leak of serum proteins in the dermis, enabling Evans Blue-labeled albumin extravasation from the circulation and subsequent accumulation in the skin. As the volume of dye extravasation is proportional to the degree of vascular leak, it can be quantified as a proxy measurement of VEGF-induced vascular leakage.
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Affiliation(s)
- James T Brash
- UCL Institute of Ophthalmology, University College London, London, UK
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Wang S, Yao X, Ma S, Ping Y, Fan Y, Sun S, He Z, Shi Y, Sun L, Xiao S, Song M, Cai J, Li J, Tang R, Zhao L, Wang C, Wang Q, Zhao L, Hu H, Liu X, Sun G, Chen L, Pan G, Chen H, Li Q, Zhang P, Xu Y, Feng H, Zhao GG, Wen T, Yang Y, Huang X, Li W, Liu Z, Wang H, Wu H, Hu B, Ren Y, Zhou Q, Qu J, Zhang W, Liu GH, Bian XW. A single-cell transcriptomic landscape of the lungs of patients with COVID-19. Nat Cell Biol 2021; 23:1314-1328. [PMID: 34876692 PMCID: PMC8650955 DOI: 10.1038/s41556-021-00796-6] [Citation(s) in RCA: 130] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 10/18/2021] [Indexed: 02/08/2023]
Abstract
The lung is the primary organ targeted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), making respiratory failure a leading coronavirus disease 2019 (COVID-19)-related mortality. However, our cellular and molecular understanding of how SARS-CoV-2 infection drives lung pathology is limited. Here we constructed multi-omics and single-nucleus transcriptomic atlases of the lungs of patients with COVID-19, which integrate histological, transcriptomic and proteomic analyses. Our work reveals the molecular basis of pathological hallmarks associated with SARS-CoV-2 infection in different lung and infiltrating immune cell populations. We report molecular fingerprints of hyperinflammation, alveolar epithelial cell exhaustion, vascular changes and fibrosis, and identify parenchymal lung senescence as a molecular state of COVID-19 pathology. Moreover, our data suggest that FOXO3A suppression is a potential mechanism underlying the fibroblast-to-myofibroblast transition associated with COVID-19 pulmonary fibrosis. Our work depicts a comprehensive cellular and molecular atlas of the lungs of patients with COVID-19 and provides insights into SARS-CoV-2-related pulmonary injury, facilitating the identification of biomarkers and development of symptomatic treatments.
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Affiliation(s)
- Si Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Xiaohong Yao
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Shuai Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Yifang Ping
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Yanling Fan
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
| | - Shuhui Sun
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Zhicheng He
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Yu Shi
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Liang Sun
- Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- The NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, China
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatric, Beijing Hospital, National Center of Gerontology, National Health Commission, Beijing, China
| | - Shiqi Xiao
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Moshi Song
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jun Cai
- Department of Pathology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jiaming Li
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Rui Tang
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Liyun Zhao
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Chaofu Wang
- Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qiaoran Wang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Lei Zhao
- Department of Pathology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Huifang Hu
- University of Chinese Academy of Sciences, Beijing, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Xindong Liu
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Guoqiang Sun
- University of Chinese Academy of Sciences, Beijing, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Lu Chen
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Guoqing Pan
- The NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, China
| | - Huaiyong Chen
- Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin Institute of Respiratory Diseases, Haihe Hospital, Tianjin University, Tianjin, China
| | - Qingrui Li
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Peipei Zhang
- Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Intelligent Pathology Institute, The First Hospital Affiliated to University of Science and Technology of China, Hefei, China
| | - Yuanyuan Xu
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Huyi Feng
- Chongqing Renji Hospital, University of Chinese Academy of Sciences, Chongqing, China
| | - Guo-Guang Zhao
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, China
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Tianzi Wen
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Yungui Yang
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xuequan Huang
- Center of Minimally Invasive Intervention, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Wei Li
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Zhenhua Liu
- Department of Ultrasound, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hongmei Wang
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Haibo Wu
- Intelligent Pathology Institute, The First Hospital Affiliated to University of Science and Technology of China, Hefei, China
| | - Baoyang Hu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Yong Ren
- Department of Pathology, General Hospital of Central Theater Command of PLA, Wuhan, China
| | - Qi Zhou
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Jing Qu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
| | - Weiqi Zhang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China.
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatric, Beijing Hospital, National Center of Gerontology, National Health Commission, Beijing, China.
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
| | - Xiu-Wu Bian
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.
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Patel M, Shahjin F, Cohen JD, Hasan M, Machhi J, Chugh H, Singh S, Das S, Kulkarni TA, Herskovitz J, Meigs DD, Chandra R, Hettie KS, Mosley RL, Kevadiya BD, Gendelman HE. The Immunopathobiology of SARS-CoV-2 Infection. FEMS Microbiol Rev 2021; 45:fuab035. [PMID: 34160586 PMCID: PMC8632753 DOI: 10.1093/femsre/fuab035] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 07/16/2021] [Indexed: 11/13/2022] Open
Abstract
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to coronavirus disease 2019 (COVID-19). Virus-specific immunity controls infection, transmission and disease severity. With respect to disease severity, a spectrum of clinical outcomes occur associated with age, genetics, comorbidities and immune responses in an infected person. Dysfunctions in innate and adaptive immunity commonly follow viral infection. These are heralded by altered innate mononuclear phagocyte differentiation, activation, intracellular killing and adaptive memory, effector, and regulatory T cell responses. All of such affect viral clearance and the progression of end-organ disease. Failures to produce effective controlled antiviral immunity leads to life-threatening end-organ disease that is typified by the acute respiratory distress syndrome. The most effective means to contain SARS-CoV-2 infection is by vaccination. While an arsenal of immunomodulators were developed for control of viral infection and subsequent COVID-19 disease, further research is required to enable therapeutic implementation.
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Affiliation(s)
- Milankumar Patel
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
| | - Farah Shahjin
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
| | - Jacob D Cohen
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
| | - Mahmudul Hasan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, NE 68198, USA
| | - Jatin Machhi
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
| | - Heerak Chugh
- Drug Discovery & Development Laboratory, Department of Chemistry, University of Delhi, Delhi-110007, India
| | - Snigdha Singh
- Drug Discovery & Development Laboratory, Department of Chemistry, University of Delhi, Delhi-110007, India
| | - Srijanee Das
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
| | - Tanmay A Kulkarni
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, NE 68198, USA
| | - Jonathan Herskovitz
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
| | - Douglas D Meigs
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
| | - Ramesh Chandra
- Drug Discovery & Development Laboratory, Department of Chemistry, University of Delhi, Delhi-110007, India
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi-110007, India
| | - Kenneth S Hettie
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Department of Otolaryngology –Head & Neck Surgery, Stanford University, Palo Alto, CA 94304, USA
| | - R Lee Mosley
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
| | - Bhavesh D Kevadiya
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
| | - Howard E Gendelman
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, NE 68198, USA
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, NE 68198, USA
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31
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Neurotropism of SARS-CoV-2 and neurological diseases of the central nervous system in COVID-19 patients. Exp Brain Res 2021; 240:9-25. [PMID: 34694467 PMCID: PMC8543422 DOI: 10.1007/s00221-021-06244-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 10/08/2021] [Indexed: 02/06/2023]
Abstract
The devastating COVID-19 pandemic is caused by the SARS-CoV-2 virus. It primarily affects the lung and induces acute respiratory distress leading to a decrease in oxygen supply to the cells. This lung insufficiency caused by SARS-CoV-2 virus contributes to hypoxia which can affect the brain and other organ systems. The heightened cytokine storm in COVID-19 patients leads to an immune reaction in the vascular endothelial cells that compromise the host defenses against the SARS-CoV-2 virus in various organs. The vascular endothelial cell membrane breach allows access for SARS-CoV-2 to infect multiple tissues and organs. The neurotropism of spike protein in SARS-CoV-2 rendered by furin site insertion may increase neuronal infections. These could result in encephalitis and encephalopathy. The COVID-19 patients suffered severe lung deficiency often showed effects in the brain and neural system. The early symptoms include headache, loss of smell, mental confusion, psychiatric disorders and strokes, and rarely encephalitis, which indicated the vulnerability of the nervous system to SARS-CoV-2. Infection of the brain and peripheral nervous system can lead to the dysfunction of other organs and result in multi-organ failure. This review focuses on discussing the vulnerability of the nervous system based on the pattern of expression of the receptors for the SARS-CoV-2 and the mechanisms of its cell invasion. The SARS-CoV-2 elicited immune response and host immune response evasion are further discussed. Then the effects on the nervous system and its consequences on neuro-sensory functions are discussed. Finally, the emerging information on the overall genetic susceptibility seen in COVID-19 patients and its implications for therapy outlook is discussed.
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32
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Jarahian M, Marofi F, Maashi MS, Ghaebi M, Khezri A, Berger MR. Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape. Cancers (Basel) 2021; 13:5203. [PMID: 34680351 PMCID: PMC8534074 DOI: 10.3390/cancers13205203] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/28/2022] Open
Abstract
Glycans linked to surface proteins are the most complex biological macromolecules that play an active role in various cellular mechanisms. This diversity is the basis of cell-cell interaction and communication, cell growth, cell migration, as well as co-stimulatory or inhibitory signaling. Our review describes the importance of neuraminic acid and its derivatives as recognition elements, which are located at the outermost positions of carbohydrate chains linked to specific glycoproteins or glycolipids. Tumor cells, especially from solid tumors, mask themselves by re-expression of hypersialylated neural cell adhesion molecule (NCAM), neuropilin-2 (NRP-2), or synaptic cell adhesion molecule 1 (SynCAM 1) in order to protect themselves against the cytotoxic attack of the also highly sialylated immune effector cells. More particularly, we focus on α-2,8-linked polysialic acid chains, which characterize carrier glycoproteins such as NCAM, NRP-2, or SynCam-1. This characteristic property correlates with an aggressive clinical phenotype and endows them with multiple roles in biological processes that underlie all steps of cancer progression, including regulation of cell-cell and/or cell-extracellular matrix interactions, as well as increased proliferation, migration, reduced apoptosis rate of tumor cells, angiogenesis, and metastasis. Specifically, re-expression of poly/oligo-sialylated adhesion molecules on the surface of tumor cells disrupts their interaction with immune-effector cells and contributes to pathophysiological immune escape. Further, sialylated glycoproteins induce immunoregulatory cytokines and growth factors through interactions with sialic acid-binding immunoglobulin-like lectins. We describe the processes, which modulate the interaction between sialylated carrier glycoproteins and their ligands, and illustrate that sialic acids could be targets of novel therapeutic strategies for treatment of cancer and immune diseases.
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Affiliation(s)
- Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit Heidelberg, 69120 Heidelberg, Germany;
| | - Faroogh Marofi
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5165665931, Iran;
| | - Marwah Suliman Maashi
- Stem Cells and Regenerative Medicine Unit at King Fahad Medical Research Centre, Jeddah 11211, Saudi Arabia;
| | - Mahnaz Ghaebi
- Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan 4513956184, Iran;
| | - Abdolrahman Khezri
- Department of Biotechnology, Inland Norway University of Applied Sciences, 2418 Hamar, Norway;
| | - Martin R. Berger
- German Cancer Research Center, Toxicology and Chemotherapy Unit Heidelberg, 69120 Heidelberg, Germany;
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33
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Wei ZZ, Chen D, Lee MJH, Zhao Y, Gu X, Yu SP, Wei L. DL-3-n-butylphthalide Increases Collateriogenesis and Functional Recovery after Focal Ischemic Stroke in Mice. Aging Dis 2021; 12:1835-1849. [PMID: 34631224 PMCID: PMC8460296 DOI: 10.14336/ad.2020.1226] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 12/26/2020] [Indexed: 12/25/2022] Open
Abstract
Recent evidence indicates that collateral circulation is critical for the outcome of ischemic stroke. DL-3-n-butylphthalide (NBP), a synthesized compound based on an extract from seeds of celery Apium graveolens Linn, has been used as a therapeutic drug, showing multiple neuroprotective and regenerative activities. A potential effect of NBP on collateral arterial regulation is unknown. We examined the effects of NBP on arteriogenesis of collateral arteries in vitro and a mouse ischemic stroke model. In cultures of mouse iPS cell-derived vascular progenitors, NBP (10 μM) significantly increased α-smooth muscle actin (αSMA)/CD-31 co-labeled cells and the expression of newly formed vasculature marker PDGFRα. A sensorimotor cortex ischemia was induced in transgenic mice expressing αSMA-GFP that allowed direct observation of arterial vasculatures in brain regions. NBP (80 mg/kg) was intranasally delivered 1 hr after stroke and once daily for 14 days. To label proliferating cells, 5-Bromo-2’-deoxyuridine (BrdU, 50 mg/kg, i.p.) was administrated every day from 3 days after stroke. Western blotting of peri-infarct tissue detected increased expressions of VEGF, Ang-1 and reduced nNOS level in NBP-treated mice. The NBP treatment significantly increased αSMA/BrdU co-labeled cells, the diameter of ipsilateral collaterals, and arterial area in ischemic and peri-infarct regions examined 14 days after stroke. Examined 3 days after stroke, NBP prevented functional deficits in the cylinder test and corner test. The NBP treatment of 14 days improved the local cerebral blood flow (LCBF) and functional performance in multiple tests. Thus, NBP promotes collateriogenesis, short and long-term structural and functional improvements after ischemic stroke.
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Affiliation(s)
- Zheng Zachory Wei
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Dongdong Chen
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Matthew Joong H Lee
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Yingying Zhao
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Xiaohuan Gu
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Shan Ping Yu
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Ling Wei
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
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34
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Sarabipour S, Mac Gabhann F. Targeting neuropilins as a viable SARS-CoV-2 treatment. FEBS J 2021; 288:5122-5129. [PMID: 34185437 PMCID: PMC8420456 DOI: 10.1111/febs.16096] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 06/01/2021] [Accepted: 06/28/2021] [Indexed: 12/21/2022]
Abstract
The SARS-CoV-2 pandemic has significantly impacted global health. Research on viral mechanisms, highly effective vaccines, and other therapies is in progress. Neuropilins have recently been identified as host cell receptors enabling viral fusion. Here, we provide context to neuropilin's tissue-specific role in infection and the potential impact of NRP-based therapeutics. We conclude that the central roles of neuropilins in vascular, neural, and other pathways may render it a less suitable target for treating SARS-CoV-2 than agents that target its binding partner, the viral spike protein.
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Affiliation(s)
- Sarvenaz Sarabipour
- Department of Biomedical EngineeringInstitute for Computational MedicineJohns Hopkins UniversityBaltimoreMDUSA
| | - Feilim Mac Gabhann
- Department of Biomedical EngineeringInstitute for Computational MedicineJohns Hopkins UniversityBaltimoreMDUSA
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35
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Benwell CJ, Taylor JAGE, Robinson SD. Endothelial neuropilin-2 influences angiogenesis by regulating actin pattern development and α5-integrin-p-FAK complex recruitment to assembling adhesion sites. FASEB J 2021; 35:e21679. [PMID: 34314542 DOI: 10.1096/fj.202100286r] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/03/2021] [Accepted: 05/04/2021] [Indexed: 01/02/2023]
Abstract
The ability to form a variety of cell-matrix connections is crucial for angiogenesis to take place. Without stable anchorage to the extracellular matrix (ECM), endothelial cells (ECs) are unable to sense, integrate and disseminate growth factor stimulated responses that drive growth of a vascular bed. Neuropilin-2 (NRP2) is a widely expressed membrane-bound multifunctional non-tyrosine kinase receptor, which has previously been implicated in influencing cell adhesion and migration by interacting with α5-integrin and regulating adhesion turnover. α5-integrin, and its ECM ligand fibronectin (FN) are both known to be upregulated during the formation of neo-vasculature. Despite being descriptively annotated as a candidate biomarker for aggressive cancer phenotypes, the EC-specific roles for NRP2 during developmental and pathological angiogenesis remain unexplored. The data reported here support a model whereby NRP2 actively promotes EC adhesion and migration by regulating dynamic cytoskeletal remodeling and by stimulating Rab11-dependent recycling of α5-integrin-p-FAK complexes to newly assembling adhesion sites. Furthermore, temporal depletion of EC-NRP2 in vivo impairs primary tumor growth by disrupting vessel formation. We also demonstrate that EC-NRP2 is required for normal postnatal retinal vascular development, specifically by regulating cell-matrix adhesion. Upon loss of endothelial NRP2, vascular outgrowth from the optic nerve during superficial plexus formation is disrupted, likely due to reduced FAK phosphorylation within sprouting tip cells.
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Affiliation(s)
- Christopher J Benwell
- Gut Microbes and Health, Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
| | - James A G E Taylor
- Gut Microbes and Health, Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
| | - Stephen D Robinson
- Gut Microbes and Health, Quadram Institute Bioscience, Norwich Research Park, Norwich, UK.,School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, UK
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36
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Douyère M, Chastagner P, Boura C. Neuropilin-1: A Key Protein to Consider in the Progression of Pediatric Brain Tumors. Front Oncol 2021; 11:665634. [PMID: 34277411 PMCID: PMC8281001 DOI: 10.3389/fonc.2021.665634] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 06/10/2021] [Indexed: 12/12/2022] Open
Abstract
Neuropilins are transmembrane glycoproteins that play important roles in cardiovascular and neuronal development, as well as in immunological system regulations. NRP1 functions as a co-receptor, binding numerous ligands, such as SEMA 3 or VEGF and, by doing so, reinforcing their signaling pathways and can also interface with the cytoplasmic protein synectin. NRP1 is expressed in many cancers, such as brain cancers, and is associated with poor prognosis. The challenge today for patients with pediatric brain tumors is to improve their survival rate while minimizing the toxicity of current treatments. The aim of this review is to highlight the involvement of NRP1 in pediatric brain cancers, focusing essentially on the roles of NRP1 in cancer stem cells and in the regulation of the immune system. For this purpose, recent literature and tumor databases were analyzed to show correlations between NRP1 and CD15 (a stem cancer cells marker), and between NRP1 and PDL1, for various pediatric brain tumors, such as high- and low-grade gliomas, medulloblastomas, and ependymomas. Finally, this review suggests a relevant role for NRP1 in pediatric brain tumors progression and identifies it as a potential diagnostic or therapeutic target to improve survival and life quality of these young patients.
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Affiliation(s)
| | - Pascal Chastagner
- Université de Lorraine, CNRS, CRAN, Nancy, France.,Service d'Onco-Hématologie Pédiatrique, CHRU-Nancy, Nancy, France
| | - Cédric Boura
- Université de Lorraine, CNRS, CRAN, Nancy, France
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37
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The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology. Int J Mol Sci 2021; 22:ijms22126364. [PMID: 34198654 PMCID: PMC8232321 DOI: 10.3390/ijms22126364] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/31/2021] [Accepted: 06/01/2021] [Indexed: 11/16/2022] Open
Abstract
Bone morphogenetic proteins (BMPs) were originally identified as the active components in bone extracts that can induce ectopic bone formation. In recent decades, their key role has broadly expanded beyond bone physiology and pathology. Nowadays, the BMP pathway is considered an important player in vascular signaling. Indeed, mutations in genes encoding different components of the BMP pathway cause various severe vascular diseases. Their signaling contributes to the morphological, functional and molecular heterogeneity among endothelial cells in different vessel types such as arteries, veins, lymphatic vessels and capillaries within different organs. The BMP pathway is a remarkably fine-tuned pathway. As a result, its signaling output in the vessel wall critically depends on the cellular context, which includes flow hemodynamics, interplay with other vascular signaling cascades and the interaction of endothelial cells with peri-endothelial cells and the surrounding matrix. In this review, the emerging role of BMP signaling in lymphatic vessel biology will be highlighted within the framework of BMP signaling in the circulatory vasculature.
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Khodajou-Masouleh H, Shahangian SS, Rasti B. Reinforcing our defense or weakening the enemy? A comparative overview of defensive and offensive strategies developed to confront COVID-19. Drug Metab Rev 2021; 53:508-541. [PMID: 33980089 DOI: 10.1080/03602532.2021.1928686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Developing effective strategies to confront coronavirus disease 2019 (COVID-19) has become one of the greatest concerns of the scientific community. In addition to the vast number of global mortalities due to COVID-19, since its outbreak, almost every aspect of human lives has changed one way or another. In the present review, various defensive and offensive strategies developed to confront COVID-19 are illustrated. The Administration of immune-boosting micronutrients/agents, as well as the inhibition of the activity of incompetent gatekeepers, including some host cell receptors (e.g. ACE2) and proteases (e.g. TMPRSS2), are some efficient defensive strategies. Antibody/phage therapies and specifically vaccines also play a prominent role in the enhancement of host defense against COVID-19. Nanotechnology, however, can considerably weaken the virulence of SARS-CoV-2, utilizing fake cellular locks (compounds mimicking cell receptors) to block the viral keys (spike proteins). Generally, two strategies are developed to interfere with the binding of spike proteins to the host cell receptors, either utilizing fake cellular locks to block the viral keys or utilizing fake viral keys to block the cellular locks. Due to their evolutionary conserved nature, viral enzymes, including 3CLpro, PLpro, RdRp, and helicase are highly potential targets for drug repurposing strategy. Thus, various steps of viral replication/transcription can effectively be blocked by their inhibition, leading to the elimination of SARS-CoV-2. Moreover, RNA decoy and CRISPR technologies likely offer the best offensive strategies after viral entry into the host cells, inhibiting the viral replication/assembly in the infected cells and substantially reducing the quantity of viral progeny.
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Affiliation(s)
| | - S Shirin Shahangian
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Behnam Rasti
- Department of Microbiology, Faculty of Basic Sciences, Lahijan Branch, Islamic Azad University (IAU), Lahijan, Guilan, Iran
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Perez-Miller S, Patek M, Moutal A, de Haro PD, Cabel CR, Thorne CA, Campos SK, Khanna R. Novel Compounds Targeting Neuropilin Receptor 1 with Potential To Interfere with SARS-CoV-2 Virus Entry. ACS Chem Neurosci 2021; 12:1299-1312. [PMID: 33787218 PMCID: PMC8029449 DOI: 10.1021/acschemneuro.0c00619] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 03/22/2021] [Indexed: 12/15/2022] Open
Abstract
Neuropilin-1 (NRP-1) is a multifunctional transmembrane receptor for ligands that affect developmental axonal growth and angiogenesis. In addition to a role in cancer, NRP-1 is a reported entry point for several viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19). The furin cleavage product of SARS-CoV-2 Spike protein takes advantage of the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 which accommodates a polybasic stretch ending in a C-terminal arginine. This site has long been a focus of drug discovery efforts for cancer therapeutics. We recently showed that interruption of the VEGF-A/NRP-1 signaling pathway ameliorates neuropathic pain and hypothesize that interference of this pathway by SARS-CoV-2 Spike protein interferes with pain signaling. Here, we report confirmed hits from a small molecule and natural product screen of nearly 0.5 million compounds targeting the VEGF-A binding site on NRP-1. We identified nine chemical series with lead- or drug-like physicochemical properties. Using ELISA, we demonstrate that six compounds disrupt VEGF-A-NRP-1 binding more effectively than EG00229, a known NRP-1 inhibitor. Secondary validation in cells revealed that all tested compounds inhibited VEGF-A triggered VEGFR2 phosphorylation. Further, two compounds displayed robust inhibition of a recombinant vesicular stomatitis virus protein that utilizes the SARS-CoV-2 Spike for entry and fusion. These compounds represent a first step in a renewed effort to develop small molecule inhibitors of the VEGF-A/NRP-1 signaling for the treatment of neuropathic pain and cancer with the added potential of inhibiting SARS-CoV-2 virus entry.
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Affiliation(s)
- Samantha Perez-Miller
- Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States
- The Center for Innovation in Brain Sciences, The University of Arizona Health Sciences, Tucson, Arizona, USA
| | - Marcel Patek
- Bright Rock Path Consulting, LLC, Tucson, Arizona
| | - Aubin Moutal
- Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States
| | - Paz Duran de Haro
- Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States
| | - Carly R. Cabel
- Department of Cellular & Molecular Medicine, College of Medicine, The University of Arizona
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona
| | - Curtis A. Thorne
- Department of Cellular & Molecular Medicine, College of Medicine, The University of Arizona
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona
- Bio5 Institute, University of Arizona
| | - Samuel K. Campos
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona
- Bio5 Institute, University of Arizona
- Department of Immunobiology, College of Medicine, University of Arizona
| | - Rajesh Khanna
- Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States
- The Center for Innovation in Brain Sciences, The University of Arizona Health Sciences, Tucson, Arizona, USA
- Regulonix LLC, Tucson, AZ, USA
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Prieto D, González C, Weber L, Realini O, Pino-Lagos K, Bendek MJ, Retamal I, Beltrán V, Riedemann JP, Espinoza F, Chaparro A. Soluble neuropilin-1 in gingival crevicular fluid is associated with rheumatoid arthritis: An exploratory case-control study. J Oral Biol Craniofac Res 2021; 11:303-307. [PMID: 33747759 PMCID: PMC7970360 DOI: 10.1016/j.jobcr.2021.02.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/21/2021] [Accepted: 02/17/2021] [Indexed: 10/22/2022] Open
Abstract
BACKGROUND To explore the soluble Neuropilin-1 (sNRP-1) concentrations in gingival crevicular fluid (GCF) and the periodontal clinical status of patients with Rheumatoid Arthritis (RA). MATERIALS AND METHODS We conducted an exploratory study with 40 study participants, 20 with RA, and 20 healthy controls. Clinical and periodontal data were recorded, and GCF samples were obtained. sNRP-1 levels in GCF were determined by ELISA assay. Descriptive statistics, Mann-Whitney U test, Unpaired t-test, logistic regression model, and Area Under Receiver Operating Characteristic Curve (AUC-ROC) were made to explore the diagnostic performance accuracy. RESULTS RA patients had significantly higher levels of sNRP-1 in GCF (p = 0.0447). The median levels of GCF-sNRP-1 were 208.85 pg/μl (IQR 131.03) in the RA group compared to 81.46 pg/μl (IQR 163.73) in the control group. We observed an association between the GCF-sNRP-1 concentrations and the RA diagnosis (OR:1.009; CI 1.00-1.001; p = 0.047). The diagnosis of chronic periodontitis was also associated with RA (OR: 6.9; CI 1.52-31.37; p = 0.012). Moreover, the AUC-ROC of GCF-sNRP-1 concentrations combined with periodontal clinical parameters such as periodontal probing depth and periodontal inflamed surface area was 0.80. CONCLUSION This exploratory case-control study shows that RA patients had significantly higher levels of sNRP-1 in GCF. New longitudinal studies are necessary to evaluate the role of NRP-1 in periodontal tissues and consider it an oral biomarker with clinical value in RA.
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Affiliation(s)
- Diego Prieto
- Department of Periodontology, Center for Biomedical and Innovation Research, Laboratory of Periodontal Research, Faculty of Dentistry, Universidad de los Andes, Santiago, Chile
| | - Camila González
- Department of Periodontology, Center for Biomedical and Innovation Research, Laboratory of Periodontal Research, Faculty of Dentistry, Universidad de los Andes, Santiago, Chile
| | - Laura Weber
- Department of Periodontology, Center for Biomedical and Innovation Research, Laboratory of Periodontal Research, Faculty of Dentistry, Universidad de los Andes, Santiago, Chile
| | - Ornella Realini
- Department of Periodontology, Center for Biomedical and Innovation Research, Laboratory of Periodontal Research, Faculty of Dentistry, Universidad de los Andes, Santiago, Chile
| | - Karina Pino-Lagos
- Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Maria José Bendek
- Department of Periodontology, Center for Biomedical and Innovation Research, Laboratory of Periodontal Research, Faculty of Dentistry, Universidad de los Andes, Santiago, Chile
| | - Ignacio Retamal
- Department of Periodontology, Center for Biomedical and Innovation Research, Laboratory of Periodontal Research, Faculty of Dentistry, Universidad de los Andes, Santiago, Chile
| | - Víctor Beltrán
- Centre of Investigation and Innovation in Clinical Dentistry, Faculty of Dentistry, Universidad de la Frontera, Temuco, Chile
| | - Juan Pablo Riedemann
- Rheumatology Unit, Faculty of Medicine, Universidad de la Frontera, Temuco, Chile
| | - Francisco Espinoza
- Department of Rheumatology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile
| | - Alejandra Chaparro
- Department of Periodontology, Center for Biomedical and Innovation Research, Laboratory of Periodontal Research, Faculty of Dentistry, Universidad de los Andes, Santiago, Chile
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Rocca C, Grande F, Granieri MC, Colombo B, De Bartolo A, Giordano F, Rago V, Amodio N, Tota B, Cerra MC, Rizzuti B, Corti A, Angelone T, Pasqua T. The chromogranin A 1-373 fragment reveals how a single change in the protein sequence exerts strong cardioregulatory effects by engaging neuropilin-1. Acta Physiol (Oxf) 2021; 231:e13570. [PMID: 33073482 DOI: 10.1111/apha.13570] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/16/2022]
Abstract
AIM Chromogranin A (CgA), a 439-residue long protein, is an important cardiovascular regulator and a precursor of various bioactive fragments. Under stressful/pathological conditions, CgA cleavage generates the CgA1-373 proangiogenic fragment. The present work investigated the possibility that human CgA1-373 influences the mammalian cardiac performance, evaluating the role of its C-terminal sequence. METHODS Haemodynamic assessment was performed on an ex vivo Langendorff rat heart model, while mechanistic studies were performed using perfused hearts, H9c2 cardiomyocytes and in silico. RESULTS On the ex vivo heart, CgA1-373 elicited direct dose-dependent negative inotropism and vasodilation, while CgA1-372 , a fragment lacking the C-terminal R373 residue, was ineffective. Antibodies against the PGPQLR373 C-terminal sequence abrogated the CgA1-373 -dependent cardiac and coronary modulation. Ex vivo studies showed that CgA1-373 -dependent effects were mediated by endothelium, neuropilin-1 (NRP1) receptor, Akt/NO/Erk1,2 pathways, nitric oxide (NO) production and S-nitrosylation. In vitro experiments on H9c2 cardiomyocytes indicated that CgA1-373 also induced eNOS activation directly on the cardiomyocyte component by NRP1 targeting and NO involvement and provided beneficial action against isoproterenol-induced hypertrophy, by reducing the increase in cell surface area and brain natriuretic peptide (BNP) release. Molecular docking and all-atom molecular dynamics simulations strongly supported the hypothesis that the C-terminal R373 residue of CgA1-373 directly interacts with NRP1. CONCLUSION These results suggest that CgA1-373 is a new cardioregulatory hormone and that the removal of R373 represents a critical switch for turning "off" its cardioregulatory activity.
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Affiliation(s)
- Carmine Rocca
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Fedora Grande
- Laboratory of Medicinal and Analytical Chemistry Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Maria Concetta Granieri
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Barbara Colombo
- Division of Experimental Oncology Vita‐Salute San Raffaele University–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute Milan Italy
| | - Anna De Bartolo
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Francesca Giordano
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Vittoria Rago
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine Magna Graecia University of Catanzaro Catanzaro Italy
| | - Bruno Tota
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- Laboratory of Organ and System Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Maria Carmela Cerra
- Laboratory of Organ and System Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Bruno Rizzuti
- CNR‐NANOTEC Licryl‐UOS Cosenza and CEMIF.Cal Department of Physics University of Calabria Rende Italy
| | - Angelo Corti
- Division of Experimental Oncology Vita‐Salute San Raffaele University–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute Milan Italy
| | - Tommaso Angelone
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- National Institute of Cardiovascular Research (INRC) Bologna Italy
| | - Teresa Pasqua
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- "Fondazione Umberto Veronesi" Milan Italy
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Jobe A, Vijayan R. Neuropilins: C-end rule peptides and their association with nociception and COVID-19. Comput Struct Biotechnol J 2021; 19:1889-1895. [PMID: 33815686 PMCID: PMC7997051 DOI: 10.1016/j.csbj.2021.03.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/21/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023] Open
Abstract
Viral internalization is aided by host cell surface receptors. In the case of SARS-CoV-2 and SARS-CoV, the primary host receptor is the angiotensin-converting enzyme 2 (ACE2). Considering the disparities in the transmission rate and viral tropism of the two coronaviruses, additional host factors were suspected. Recently, a novel host factor for SARS-CoV-2 entry, neuropilin-1 (NRP-1) has been identified. These receptors potentiate viral infection in the presence of other host factors like ACE2. Through its C-end rule (CendR) motif exposed following furin processing, the SARS-CoV-2 spike protein binds to the CendR pocket of NRP-1 and achieves cell entry through endocytosis. The binding of SARS-CoV-2 spike protein to the NRP-1 receptor interferes with the docking of its endogenous ligand VEGF-A, signaling that would otherwise promote nociception. This review looks at the function of neuropilins and how it contributes to SARS-CoV-2 infection and nociception.
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Affiliation(s)
- Amie Jobe
- Department of Biology, College of Science, United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates
| | - Ranjit Vijayan
- Department of Biology, College of Science, United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates
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Chen M, Li Y, Huang X, Gu Y, Li S, Yin P, Zhang L, Tang P. Skeleton-vasculature chain reaction: a novel insight into the mystery of homeostasis. Bone Res 2021; 9:21. [PMID: 33753717 PMCID: PMC7985324 DOI: 10.1038/s41413-021-00138-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 11/18/2020] [Accepted: 12/16/2020] [Indexed: 02/01/2023] Open
Abstract
Angiogenesis and osteogenesis are coupled. However, the cellular and molecular regulation of these processes remains to be further investigated. Both tissues have recently been recognized as endocrine organs, which has stimulated research interest in the screening and functional identification of novel paracrine factors from both tissues. This review aims to elaborate on the novelty and significance of endocrine regulatory loops between bone and the vasculature. In addition, research progress related to the bone vasculature, vessel-related skeletal diseases, pathological conditions, and angiogenesis-targeted therapeutic strategies are also summarized. With respect to future perspectives, new techniques such as single-cell sequencing, which can be used to show the cellular diversity and plasticity of both tissues, are facilitating progress in this field. Moreover, extracellular vesicle-mediated nuclear acid communication deserves further investigation. In conclusion, a deeper understanding of the cellular and molecular regulation of angiogenesis and osteogenesis coupling may offer an opportunity to identify new therapeutic targets.
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Affiliation(s)
- Ming Chen
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Yi Li
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Xiang Huang
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Ya Gu
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Shang Li
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Pengbin Yin
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China.
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China.
| | - Licheng Zhang
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China.
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China.
| | - Peifu Tang
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China.
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China.
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Abdelgawad ME, Desterke C, Uzan G, Naserian S. Single-cell transcriptomic profiling and characterization of endothelial progenitor cells: new approach for finding novel markers. Stem Cell Res Ther 2021; 12:145. [PMID: 33627177 PMCID: PMC7905656 DOI: 10.1186/s13287-021-02185-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 01/24/2021] [Indexed: 12/14/2022] Open
Abstract
Background Endothelial progenitor cells (EPCs) are promising candidates for the cellular therapy of peripheral arterial and cardiovascular diseases. However, hitherto there is no specific marker(s) defining precisely EPCs. Herein, we are proposing a new in silico approach for finding novel EPC markers. Methods We assembled five groups of chosen EPC-related genes/factors using PubMed literature and Gene Ontology databases. This shortened database of EPC factors was fed into publically published transcriptome matrix to compare their expression between endothelial colony-forming cells (ECFCs), HUVECs, and two adult endothelial cell types (ECs) from the skin and adipose tissue. Further, the database was used for functional enrichment on Mouse Phenotype database and protein-protein interaction network analyses. Moreover, we built a digital matrix of healthy donors’ PBMCs (33 thousand single-cell transcriptomes) and analyzed the expression of these EPC factors. Results Transcriptome analyses showed that BMP2, 4, and ephrinB2 were exclusively highly expressed in EPCs; the expression of neuropilin-1 and VEGF-C were significantly higher in EPCs and HUVECs compared with other ECs; Notch 1 was highly expressed in EPCs and skin-ECs; MIR21 was highly expressed in skin-ECs; PECAM-1 was significantly higher in EPCs and adipose ECs. Moreover, functional enrichment of EPC-related genes on Mouse Phenotype and STRING protein database has revealed significant relations between chosen EPC factors and endothelial and vascular functions, development, and morphogenesis, where ephrinB2, BMP2, and BMP4 were highly expressed in EPCs and were connected to abnormal vascular functions. Single-cell RNA-sequencing analyses have revealed that among the EPC-regulated markers in transcriptome analyses, (i) ICAM1 and Endoglin were weekly expressed in the monocyte compartment of the peripheral blood; (ii) CD163 and CD36 were highly expressed in the CD14+ monocyte compartment whereas CSF1R was highly expressed in the CD16+ monocyte compartment, (iii) L-selectin and IL6R were globally expressed in the lymphoid/myeloid compartments, and (iv) interestingly, PLAUR/UPAR and NOTCH2 were highly expressed in both CD14+ and CD16+ monocytic compartments. Conclusions The current study has identified novel EPC markers that could be used for better characterization of EPC subpopulation in adult peripheral blood and subsequent usage of EPCs for various cell therapy and regenerative medicine applications.
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Affiliation(s)
- Mohamed Essameldin Abdelgawad
- Biochemistry & Molecular Biotechnology Division, Chemistry Department, Faculty of Science; Innovative Cellular Microenvironment Optimization Platform (ICMOP), Helwan University, Cairo, Egypt. .,Inserm UMR-S-MD 1197, Hôpital Paul Brousse - Bâtiment Lavoisier, 12-14 avenue Paul Vaillant Couturier, 94800, Villejuif, France. .,Paris-Saclay University, Villejuif, France.
| | - Christophe Desterke
- Paris-Saclay University, Villejuif, France.,Inserm UMR-S-MD A9, Hôpital Paul Brousse, Villejuif, France
| | - Georges Uzan
- Inserm UMR-S-MD 1197, Hôpital Paul Brousse - Bâtiment Lavoisier, 12-14 avenue Paul Vaillant Couturier, 94800, Villejuif, France.,Paris-Saclay University, Villejuif, France
| | - Sina Naserian
- Inserm UMR-S-MD 1197, Hôpital Paul Brousse - Bâtiment Lavoisier, 12-14 avenue Paul Vaillant Couturier, 94800, Villejuif, France. .,Paris-Saclay University, Villejuif, France. .,CellMedEx, Saint Maur des Fossés, France.
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Prieto D, Maurer G, Sáez M, Cáceres F, Pino-Lagos K, Chaparro A. Soluble Neuropilin-1 in gingival crevicular fluid from periodontitis patients: An exploratory cross-sectional study. J Oral Biol Craniofac Res 2021; 11:84-87. [PMID: 33384917 PMCID: PMC7770967 DOI: 10.1016/j.jobcr.2020.11.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 11/04/2020] [Accepted: 11/21/2020] [Indexed: 10/22/2022] Open
Abstract
BACKGROUND Soluble Neuropilin-1 (sNRP-1) is a glycoprotein with angiogenic and immune regulatory functions, which correspond to processes deeply involved with periodontal diseases. This study's objective was to determine the concentration of sNRP-1 in gingival crevicular fluid (GCF) samples of severe periodontitis (stages III-IV) compared to mild-moderate (stages I-II) periodontitis patients. MATERIALS AND METHODS An exploratory cross-sectional study was conducted, including 36 adults subjected to a complete periodontal exam, which recorded the following periodontal parameters: periodontal probing depth (PPD), clinical attachment loss (CAL), bleeding on probing (BOP), gingival index (GI) and periodontal inflamed surface area (PISA). Periodontitis was defined by two periodontists using the case definition proposed by the 2017 World Workshop for periodontal diseases. GCF samples were collected to determine the levels of sNRP-1 via ELISA. The results were analyzed using descriptive statistics, Mann-Whitney, Kruskal Wallis, and Spearman tests. RESULTS The levels of sNRP-1 in patient's GCF with periodontitis in stages III-IV showed a median of 38.385 ng/mL (iqr 30.98), in comparison with 20.085 ng/mL (iqr 12.74) for stages I-II (p = 0.202). Regardless of the periodontitis stage, we observed a positive correlation between the levels of sNRP-1 in BOP (Rho: 0.45; p = 0.0048), PISA (Rho: 0.50; p = 0.0019), PD (Rho: 0.3; p = 0.015) and GI (Rho: 0.37; p = 0.02). CONCLUSIONS The GCF-sNRP-1 concentration was positively related to periodontal clinical inflammatory parameters and probably could be involved in pro-inflammatory and angiogenic mechanisms observed in periodontitis. Additional studies are necessary to confirm these preliminary results.
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Affiliation(s)
- Diego Prieto
- Departamento de Periodoncia, Facultad de Odontología, Universidad de los Andes, Santiago, Chile
| | - Gloria Maurer
- Departamento de Periodoncia, Facultad de Odontología, Universidad de los Andes, Santiago, Chile
| | - Maximiliano Sáez
- Departamento de Periodoncia, Facultad de Odontología, Universidad de los Andes, Santiago, Chile
| | - Felipe Cáceres
- Departamento de Periodoncia, Facultad de Odontología, Universidad de los Andes, Santiago, Chile
| | - Karina Pino-Lagos
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Alejandra Chaparro
- Departamento de Periodoncia, Facultad de Odontología, Universidad de los Andes, Santiago, Chile
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Kothandaraman N, Rengaraj A, Xue B, Yew WS, Velan SS, Karnani N, Leow MKS. COVID-19 endocrinopathy with hindsight from SARS. Am J Physiol Endocrinol Metab 2021; 320:E139-E150. [PMID: 33236920 PMCID: PMC7816429 DOI: 10.1152/ajpendo.00480.2020] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The current COVID-19 pandemic is probably the worst the world has ever faced since the start of the new millennium. Although the respiratory system is the most prominent target of SARS-CoV-2 (the contagion of COVID-19), extrapulmonary involvement are emerging as important contributors of its morbidity and lethality. This article summarizes the impact of SARS-CoV and SARS-CoV-2 on the endocrine system to facilitate our understanding of the nature of coronavirus-associated endocrinopathy. Although new data are rapidly accumulating on this novel infection, many of the endocrine manifestations of COVID-19 remain incompletely elucidated. We, hereby, summarize various endocrine dysfunctions including coronavirus-induced new onset diabetes mellitus, hypocortisolism, thyroid hormone, and reproductive system aberrations so that clinicians armed with such insights can potentially benefit patients with COVID-19 at the bedside.
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Affiliation(s)
- Narasimhan Kothandaraman
- Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Anantharaj Rengaraj
- Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, A*STAR, Singapore
| | - Bo Xue
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- NUS Synthetic Biology for Clinical and Technological Innovation, National University of Singapore, Singapore
| | - Wen Shan Yew
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- NUS Synthetic Biology for Clinical and Technological Innovation, National University of Singapore, Singapore
| | - S Sendhil Velan
- Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Agency for Science, Technology and Research (A*STAR), Singapore
- Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, A*STAR, Singapore
- Department of Physiology, National University of Singapore, Singapore
| | - Neerja Karnani
- Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Melvin Khee Shing Leow
- Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Agency for Science, Technology and Research (A*STAR), Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Lee Kong Chian School of Medicine, National University of Singapore, Singapore
- Duke-NUS Medical School, Singapore
- Department of Endocrinology, Tan Tock Seng Hospital, Singapore
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47
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Moutal A, Martin LF, Boinon L, Gomez K, Ran D, Zhou Y, Stratton HJ, Cai S, Luo S, Gonzalez KB, Perez-Miller S, Patwardhan A, Ibrahim MM, Khanna R. SARS-CoV-2 spike protein co-opts VEGF-A/neuropilin-1 receptor signaling to induce analgesia. Pain 2021; 162:243-252. [PMID: 33009246 PMCID: PMC7737878 DOI: 10.1097/j.pain.0000000000002097] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/02/2020] [Accepted: 09/02/2020] [Indexed: 12/19/2022]
Abstract
Global spread of severe acute respiratory syndrome coronavirus 2 continues unabated. Binding of severe acute respiratory syndrome coronavirus 2's spike protein to host angiotensin-converting enzyme 2 triggers viral entry, but other proteins may participate, including the neuropilin-1 receptor (NRP-1). Because both spike protein and vascular endothelial growth factor-A (VEGF-A)-a pronociceptive and angiogenic factor, bind NRP-1, we tested whether spike could block VEGF-A/NRP-1 signaling. VEGF-A-triggered sensory neuron firing was blocked by spike protein and NRP-1 inhibitor EG00229. Pronociceptive behaviors of VEGF-A were similarly blocked through suppression of spontaneous spinal synaptic activity and reduction of electrogenic currents in sensory neurons. Remarkably, preventing VEGF-A/NRP-1 signaling was antiallodynic in a neuropathic pain model. A "silencing" of pain through subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals.
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Affiliation(s)
| | - Laurent F. Martin
- Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ, United States
| | | | | | | | | | | | - Song Cai
- Departments of Pharmacology, and
| | | | | | - Samantha Perez-Miller
- Departments of Pharmacology, and
- Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ, United States
| | - Amol Patwardhan
- Departments of Pharmacology, and
- Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ, United States
- Comprehensive Pain and Addiction Center, The University of Arizona, Tucson, AZ, United States
| | - Mohab M. Ibrahim
- Departments of Pharmacology, and
- Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ, United States
- Comprehensive Pain and Addiction Center, The University of Arizona, Tucson, AZ, United States
| | - Rajesh Khanna
- Departments of Pharmacology, and
- Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ, United States
- Comprehensive Pain and Addiction Center, The University of Arizona, Tucson, AZ, United States
- Center for Innovation in Brain Sciences, University of Arizona, Tucson, AZ, United States
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48
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Masre SF, Jufri NF, Ibrahim FW, Abdul Raub SH. Classical and alternative receptors for SARS-CoV-2 therapeutic strategy. Rev Med Virol 2020; 31:1-9. [PMID: 33368788 PMCID: PMC7883063 DOI: 10.1002/rmv.2207] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 01/08/2023]
Abstract
Understanding the molecules that are essential for severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) entry can provide insights into viral infection and dissemination. Recently, it has been identified from several studies that angiotensin‐converting enzyme 2 receptor and transmembrane serine protease 2 are the main entry molecules for the SARS‐CoV‐2, which produced the pandemic of Covid‐19. However, additional evidence showed several other viral receptors and cellular proteases that are also important in facilitating viral entry and transmission in the target cells. In this review, we summarized the types of SARS‐CoV‐2 entry molecules and discussed their crucial roles for virus binding, protein priming and fusion to the cellular membrane important for SARS‐CoV‐2 infection.
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Affiliation(s)
- Siti Fathiah Masre
- Faculty of Health Sciences, Centre for Toxicology and Health Risk Studies, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nurul Farhana Jufri
- Faculty of Health Sciences, Centre for Toxicology and Health Risk Studies, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Farah Wahida Ibrahim
- Faculty of Health Sciences, Centre for Toxicology and Health Risk Studies, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Sayyidi Hamzi Abdul Raub
- Pantai Premier Pathology SDN BHD, Reference Specialised Laboratory, Pantai Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
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49
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Capillary Rarefaction in Obesity and Metabolic Diseases-Organ-Specificity and Possible Mechanisms. Cells 2020; 9:cells9122683. [PMID: 33327460 PMCID: PMC7764934 DOI: 10.3390/cells9122683] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/02/2020] [Accepted: 12/10/2020] [Indexed: 12/11/2022] Open
Abstract
Obesity and its comorbidities like diabetes, hypertension and other cardiovascular disorders are the leading causes of death and disability worldwide. Metabolic diseases cause vascular dysfunction and loss of capillaries termed capillary rarefaction. Interestingly, obesity seems to affect capillary beds in an organ-specific manner, causing morphological and functional changes in some tissues but not in others. Accordingly, treatment strategies targeting capillary rarefaction result in distinct outcomes depending on the organ. In recent years, organ-specific vasculature and endothelial heterogeneity have been in the spotlight in the field of vascular biology since specialized vascular systems have been shown to contribute to organ function by secreting varying autocrine and paracrine factors and by providing niches for stem cells. This review summarizes the recent literature covering studies on organ-specific capillary rarefaction observed in obesity and metabolic diseases and explores the underlying mechanisms, with multiple modes of action proposed. It also provides a glimpse of the reported therapeutic perspectives targeting capillary rarefaction. Further studies should address the reasons for such organ-specificity of capillary rarefaction, investigate strategies for its prevention and reversibility and examine potential signaling pathways that can be exploited to target it.
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50
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Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, van der Meer F, Kallio K, Kaya T, Anastasina M, Smura T, Levanov L, Szirovicza L, Tobi A, Kallio-Kokko H, Österlund P, Joensuu M, Meunier FA, Butcher SJ, Winkler MS, Mollenhauer B, Helenius A, Gokce O, Teesalu T, Hepojoki J, Vapalahti O, Stadelmann C, Balistreri G, Simons M. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 2020; 370:856-860. [PMID: 33082293 PMCID: PMC7857391 DOI: 10.1126/science.abd2985] [Citation(s) in RCA: 1368] [Impact Index Per Article: 273.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 10/12/2020] [Indexed: 12/11/2022]
Abstract
The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells facing the nasal cavity. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.
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Affiliation(s)
- Ludovico Cantuti-Castelvetri
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Ravi Ojha
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
| | - Liliana D Pedro
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Minou Djannatian
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Jonas Franz
- Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
- Campus Institute for Dynamics of Biological Networks, University of Göttingen, Göttingen, Germany
- Max Planck Institute for Experimental Medicine, Göttingen, Germany
| | - Suvi Kuivanen
- Department of Virology, Medicum, University of Helsinki, Helsinki, Finland
| | | | - Katri Kallio
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
| | - Tuğberk Kaya
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
| | - Maria Anastasina
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
- Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Teemu Smura
- Department of Virology, Medicum, University of Helsinki, Helsinki, Finland
| | - Lev Levanov
- Department of Virology, Medicum, University of Helsinki, Helsinki, Finland
| | - Leonora Szirovicza
- Department of Virology, Medicum, University of Helsinki, Helsinki, Finland
| | - Allan Tobi
- Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Hannimari Kallio-Kokko
- Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Pamela Österlund
- Department of Health Security, Finnish Institute for Health and Welfare (THL), Helsinki, Finland
| | - Merja Joensuu
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - Frédéric A Meunier
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - Sarah J Butcher
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
- Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Martin Sebastian Winkler
- Department of Anesthesiology and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany
| | - Brit Mollenhauer
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
- Paracelsus-Elena-Klinik Kassel, Kassel, Germany
| | - Ari Helenius
- Institute of Biochemistry, ETH Zürich, Zürich, Switzerland
| | - Ozgun Gokce
- Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
| | - Tambet Teesalu
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
- Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Center for Nanomedicine and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA
| | - Jussi Hepojoki
- Campus Institute for Dynamics of Biological Networks, University of Göttingen, Göttingen, Germany
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Olli Vapalahti
- Department of Virology, Medicum, University of Helsinki, Helsinki, Finland
- Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
| | - Christine Stadelmann
- Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Giuseppe Balistreri
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland.
- The Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - Mikael Simons
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany.
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Munich Cluster of Systems Neurology (SyNergy), Munich, Germany
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