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1
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Shadmani A, Wu AY. Navigating the path to corneal healing success and challenges: a comprehensive overview. Eye (Lond) 2025; 39:1047-1055. [PMID: 39939391 PMCID: PMC11978883 DOI: 10.1038/s41433-025-03619-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 12/16/2024] [Accepted: 01/14/2025] [Indexed: 02/14/2025] Open
Abstract
The cornea serves to protect the eye from external insults and refracts light to the retina. Maintaining ocular homeostasis requires constant epithelial renewal and an efficient healing process following injury. Corneal wound healing is a dynamic process involving several key cell populations and molecular pathways. Immediately after a large corneal epithelial injury involving limbal stem cells, conjunctival epithelial cells migrate toward the center of the wound guided by the newly formed electrical field (EF). Proliferation and transdifferentiation play a critical role in corneal epithelial regeneration. Corneal nerve endings migrate through the EF, connect with the migrating epithelial cells, and provide them with multiple growth factors. Finally, the migrated epithelial cells undergo differentiation, which is also regulated by corneal nerve endings. All these processes require energy and effective cellular cross-talk between different cell lines and extracellular matrix molecules. We provide an overview of the roles and interactions between corneal wound regeneration components that may help develop fascinating new targeted therapeutic strategies to enhance corneal wound healing with less injury-related corneal opacity and neovascularization.
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Affiliation(s)
- Athar Shadmani
- Bascom Palmer Eye Institute, University of Miami, Naples, FL, USA
- Omid Salmat Clinic, Firozabad, Shiraz University of Medical Sciences, Firozabad, Iran
| | - Albert Y Wu
- Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA.
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2
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Yang YCSH, Tsai CC, Yang YN, Liu FC, Lee SY, Yang JC, Crawford DR, Chiu HC, Lu MC, Li ZL, Chen YC, Chu TY, Whang-Peng J, Lin HY, Wang K. Heteronemin suppresses EGF‑induced proliferation through the PI3K/PD‑L1 signaling pathways in cholangiocarcinoma. Oncol Rep 2025; 53:32. [PMID: 39791224 DOI: 10.3892/or.2025.8865] [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: 04/17/2024] [Accepted: 09/17/2024] [Indexed: 01/12/2025] Open
Abstract
Epidermal growth factor (EGF) binds with its surface receptor to stimulate gene expression and cancer cell proliferation. EGF stimulates cancer cell growth via phosphoinositide 3‑kinase (PI3K) and programmed cell death ligand 1 (PD‑L1) pathways. As an integrin αvβ3 antagonist, heteronemin exhibits potent cytotoxic effects against cancer cells. It inhibits critical signal transduction pathways promoted by the EGF. In the current study, EGF‑induced signal activation and proliferative effects were investigated in cholangiocarcinoma cells and its molecular targets using qPCR and western blotting analyses. In addition, cell viability assays were performed to assess the growth effects of EGF and heteronemin. Heteronemin reversed the effects of EGF and was further enhanced by blockage of PI3K's activity. In summary, EGF stimulates cholangiocarcinoma cell growth. On the other hand, heteronemin inhibited PI3K activation and PD‑L1 expression to reverse the stimulative effects of EGF‑induced gene expression and proliferation in cholangiocarcinoma cells.
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Affiliation(s)
- Yu-Chen S H Yang
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
| | - Chung-Che Tsai
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
| | - Yung-Ning Yang
- School of Medicine, College of Medicine, I‑Shou University, Kaohsiung 84001, Taiwan, R.O.C
| | - Feng-Cheng Liu
- Division of Rheumatology, Immunology and Allergy, Tri‑Service General Hospital, Taipei 11490, Taiwan, R.O.C
| | - Sheng-Yang Lee
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
| | - Jen-Chang Yang
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
| | - Dana R Crawford
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Hsien-Chung Chiu
- Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri‑Service General Hospital, Taipei 11490, Taiwan, R.O.C
| | - Mei-Chin Lu
- National Museum of Marine Biology and Aquarium, Pingtung 94450, Taiwan, R.O.C
| | - Zi-Lin Li
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
| | - Yi-Chen Chen
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
| | - Tin-Yi Chu
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
| | - Jacqueline Whang-Peng
- Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
| | - Hung-Yun Lin
- Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
| | - Kuan Wang
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
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3
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Zhao M, Jankovic D, Link VM, Souza COS, Hornick KM, Oyesola O, Belkaid Y, Lack J, Loke P. Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically. Nat Commun 2025; 16:1030. [PMID: 39863579 PMCID: PMC11762786 DOI: 10.1038/s41467-025-56379-8] [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: 01/03/2024] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
How macrophages in the tissue environment integrate multiple stimuli depends on the genetic background of the host, but this is still poorly understood. We investigate IL-4 activation of male C57BL/6 and BALB/c strain specific in vivo tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with induced genes associated with more super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals C57BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated C57BL/6 TRMs demonstrate an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeras indicates that transcriptional differences and synergy are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure.
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Affiliation(s)
- Mingming Zhao
- Type 2 Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Dragana Jankovic
- Type 2 Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Verena M Link
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Camila Oliveira Silva Souza
- Type 2 Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Katherine M Hornick
- NIAID Collaborative Bioinformatics Resource, Integrated Data Sciences Section, Research Technology Branch, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA
| | - Oyebola Oyesola
- Type 2 Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Yasmine Belkaid
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Justin Lack
- NIAID Collaborative Bioinformatics Resource, Integrated Data Sciences Section, Research Technology Branch, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA
| | - Png Loke
- Type 2 Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
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4
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Calligaris M, Spanò DP, Puccio MC, Müller SA, Bonelli S, Lo Pinto M, Zito G, Blobel CP, Lichtenthaler SF, Troeberg L, Scilabra SD. Development of a Proteomic Workflow for the Identification of Heparan Sulphate Proteoglycan-Binding Substrates of ADAM17. Proteomics 2024; 24:e202400076. [PMID: 39318062 DOI: 10.1002/pmic.202400076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 09/26/2024]
Abstract
Ectodomain shedding, which is the proteolytic release of transmembrane proteins from the cell surface, is crucial for cell-to-cell communication and other biological processes. The metalloproteinase ADAM17 mediates ectodomain shedding of over 50 transmembrane proteins ranging from cytokines and growth factors, such as TNF and EGFR ligands, to signalling receptors and adhesion molecules. Yet, the ADAM17 sheddome is only partly defined and biological functions of the protease have not been fully characterized. Some ADAM17 substrates (e.g., HB-EGF) are known to bind to heparan sulphate proteoglycans (HSPG), and we hypothesised that such substrates would be under-represented in traditional secretome analyses, due to their binding to cell surface or pericellular HSPGs. Thus, to identify novel HSPG-binding ADAM17 substrates, we developed a proteomic workflow that involves addition of heparin to solubilize HSPG-binding proteins from the cell layer, thereby allowing their mass spectrometry detection by heparin-treated secretome (HEP-SEC) analysis. Applying this methodology to murine embryonic fibroblasts stimulated with an ADAM17 activator enabled us to identify 47 transmembrane proteins that were shed in response to ADAM17 activation. This included known HSPG-binding ADAM17 substrates (i.e., HB-EGF, CX3CL1) and 14 novel HSPG-binding putative ADAM17 substrates. Two of these, MHC-I and IL1RL1, were validated as ADAM17 substrates by immunoblotting.
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Affiliation(s)
- Matteo Calligaris
- Department of Research IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Proteomics Group of Ri.MED Foundation, Palermo, Italy
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | - Donatella Pia Spanò
- Department of Research IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Proteomics Group of Ri.MED Foundation, Palermo, Italy
- STEBICEF (Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche), Università degli Studi di Palermo, Palermo, Italy
| | - Maria Chiara Puccio
- Department of Research IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Proteomics Group of Ri.MED Foundation, Palermo, Italy
| | - Stephan A Müller
- Neuroproteomics Department, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Simone Bonelli
- Department of Research IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Proteomics Group of Ri.MED Foundation, Palermo, Italy
- STEBICEF (Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche), Università degli Studi di Palermo, Palermo, Italy
| | - Margot Lo Pinto
- Department of Research IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Proteomics Group of Ri.MED Foundation, Palermo, Italy
| | - Giovanni Zito
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Palermo, Italy
| | - Carl P Blobel
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, USA
- School of Medicine, Technical University Munich, Munich, Germany
- Department of Biochemistry, Cell and Molecular Biology, Weill Cornell Medicine, New York, USA
| | - Stefan F Lichtenthaler
- Neuroproteomics Department, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- School of Medicine, Technical University Munich, Munich, Germany
- Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Linda Troeberg
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Simone Dario Scilabra
- Department of Research IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Proteomics Group of Ri.MED Foundation, Palermo, Italy
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5
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Zhang Y, Tang L, Liu H, Cheng Y. The Multiple Functions of HB-EGF in Female Reproduction and Related Cancer: Molecular Mechanisms and Targeting Strategies. Reprod Sci 2024; 31:2588-2603. [PMID: 38424408 DOI: 10.1007/s43032-024-01454-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 01/03/2024] [Indexed: 03/02/2024]
Abstract
Heparin-binding growth factor (HB-EGF) is a member of the epidermal growth factor (EGF) ligand family which has a crucial role in women's health. However, there is a lack of comprehensive review to summarize the significance of HB-EGF. Therefore, this work first described the expression patterns of HB-EGF in the endometrium and ovary of different species and gestational time. Then, the focus was on exploring how it promotes the successful implantation and regulates the process of decidualization and the function of ovarian granulosa cells as an intermediate molecule. Otherwise, we also focused on the clinical and prognostic significance of HB-EGF in female-related cancers (including ovarian cancer, cervical cancer, and endometrial cancer) and breast cancer. Lastly, the article also summarizes the current drugs targeting HB-EGF in the treatment of ovarian cancer and breast cancer. Overall, these studies found that the expression of HB-EGF in the endometrium is spatiotemporal and species-specific. And it mediates the dialogue between the blastocyst and endometrium, promoting synchronous development of the blastocyst and endometrium as an intermediate molecule. HB-EGF may serve as a potentially valuable prognostic clinical indicator in tumors. And the specific inhibitor of HB-EGF (CRM197) has a certain anti-tumor ability, which can exert synergistic anti-tumor effects with conventional chemotherapy drugs. However, it also suggests that more research is needed in the future to elucidate its specific mechanisms and to accommodate clinical studies with a larger sample size to clarify its clinical value.
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Affiliation(s)
- Yuwei Zhang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, Hubei, 430060, People's Republic of China
| | - Lujia Tang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, Hubei, 430060, People's Republic of China
| | - Hua Liu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, Hubei, 430060, People's Republic of China.
| | - Yanxiang Cheng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, Hubei, 430060, People's Republic of China.
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6
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Piszczatowski RT, Bülow HE, Steidl U. Heparan sulfates and heparan sulfate proteoglycans in hematopoiesis. Blood 2024; 143:2571-2587. [PMID: 38639475 PMCID: PMC11830984 DOI: 10.1182/blood.2023022736] [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: 10/04/2023] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 04/20/2024] Open
Abstract
ABSTRACT From signaling mediators in stem cells to markers of differentiation and lineage commitment to facilitators for the entry of viruses, such as HIV-1, cell surface heparan sulfate (HS) glycans with distinct modification patterns play important roles in hematopoietic biology. In this review, we provide an overview of the importance of HS and the proteoglycans (HSPGs) to which they are attached within the major cellular subtypes of the hematopoietic system. We summarize the roles of HSPGs, HS, and HS modifications within each main hematopoietic cell lineage of both myeloid and lymphoid arms. Lastly, we discuss the biological advances in the detection of HS modifications and their potential to further discriminate cell types within hematopoietic tissue.
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Affiliation(s)
- Richard T. Piszczatowski
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
- Department of Pediatrics, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY
| | - Hannes E. Bülow
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY
- Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY
| | - Ulrich Steidl
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
- Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY
- Departments of Oncology, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY
- Blood Cancer Institute, Albert Einstein College of Medicine, Bronx, NY
- Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY
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7
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Patel AS, Ludwinski FE, Kerr A, Farkas S, Kapoor P, Bertolaccini L, Fernandes R, Jones PR, McLornan D, Livieratos L, Saha P, Smith A, Modarai B. A subpopulation of tissue remodeling monocytes stimulates revascularization of the ischemic limb. Sci Transl Med 2024; 16:eadf0555. [PMID: 38896604 DOI: 10.1126/scitranslmed.adf0555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 05/30/2024] [Indexed: 06/21/2024]
Abstract
Despite decades of effort aimed at developing clinically effective cell therapies, including mixed population mononuclear cells, to revascularize the ischemic limb, there remains a paucity of patient-based studies that inform the function and fate of candidate cell types. In this study, we showed that circulating proangiogenic/arteriogenic monocytes (PAMs) expressing the FcγIIIA receptor CD16 were elevated in patients with chronic limb-threatening ischemia (CLTI), and these amounts decreased after revascularization. Unlike CD16-negative monocytes, PAMs showed large vessel remodeling properties in vitro when cultured with endothelial cells and smooth muscle cells and promoted salvage of the ischemic limb in vivo in a mouse model of hindlimb ischemia. PAMs showed a propensity to migrate toward and bind to ischemic muscle and to secrete angiogenic/arteriogenic factors, vascular endothelial growth factor A (VEGF-A) and heparin-binding epidermal growth factor. We instigated a first-in-human single-arm cohort study in which autologous PAMs were injected into the ischemic limbs of five patients with CLTI. Greater than 25% of injected cells were retained in the leg for at least 72 hours, of which greater than 80% were viable, with evidence of enhanced large vessel remodeling in the injected muscle area. In summary, we identified up-regulation of a circulatory PAM subpopulation as an endogenous response to limb ischemia in CLTI and tested a potentially clinically relevant therapeutic strategy.
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Affiliation(s)
- Ashish S Patel
- Academic Department of Vascular Surgery, South Bank Section, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Excellence, King's College London, London SE1 7EH, UK
- Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 7EH, UK
| | - Francesca E Ludwinski
- Academic Department of Vascular Surgery, South Bank Section, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Excellence, King's College London, London SE1 7EH, UK
- Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 7EH, UK
| | - Alexander Kerr
- Academic Department of Vascular Surgery, South Bank Section, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Excellence, King's College London, London SE1 7EH, UK
- Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 7EH, UK
| | - Simon Farkas
- Academic Department of Vascular Surgery, South Bank Section, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Excellence, King's College London, London SE1 7EH, UK
- Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 7EH, UK
| | - Puja Kapoor
- Academic Department of Vascular Surgery, South Bank Section, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Excellence, King's College London, London SE1 7EH, UK
- Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 7EH, UK
| | - Laura Bertolaccini
- Academic Department of Vascular Surgery, South Bank Section, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Excellence, King's College London, London SE1 7EH, UK
- Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 7EH, UK
| | - Ramon Fernandes
- Academic Department of Vascular Surgery, South Bank Section, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Excellence, King's College London, London SE1 7EH, UK
- Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 7EH, UK
| | - Paul R Jones
- Academic Department of Vascular Surgery, South Bank Section, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Excellence, King's College London, London SE1 7EH, UK
- Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 7EH, UK
| | - Donal McLornan
- Department of Haematology, Guy's & St Thomas' NHS Foundation Trust, London SE1 7EH, UK
| | - Lefteris Livieratos
- Department of Biomedical Engineering, School of Biomedical Engineering & Imaging Sciences, King's College London, London SE1 7EH, UK
- Department of Nuclear Medicine, Guy's & St Thomas' NHS Foundation Trust, London SE1 7EH, UK
| | - Prakash Saha
- Academic Department of Vascular Surgery, South Bank Section, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Excellence, King's College London, London SE1 7EH, UK
- Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 7EH, UK
| | - Alberto Smith
- Academic Department of Vascular Surgery, South Bank Section, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Excellence, King's College London, London SE1 7EH, UK
- Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 7EH, UK
| | - Bijan Modarai
- Academic Department of Vascular Surgery, South Bank Section, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Excellence, King's College London, London SE1 7EH, UK
- Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 7EH, UK
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8
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Adrain C, Badenes M. Can the HB-EGF/EGFR pathway restore injured neurons? FEBS J 2024; 291:2094-2097. [PMID: 38680125 DOI: 10.1111/febs.17143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 04/11/2024] [Indexed: 05/01/2024]
Abstract
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a transmembrane protein that, when cleaved by metalloproteases through a process called ectodomain shedding, binds to the EGF receptor (EGFR), activating downstream signaling. The HB-EGF/EGFR pathway is crucial in development and is involved in numerous pathophysiological processes. In this issue of The FEBS Journal, Sireci et al. reveal a previously unexplored function of the HB-EGF/EGFR pathway in promoting neuronal progenitor proliferation and sensory neuron regeneration in the zebrafish olfactory epithelium in response to injury.
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Affiliation(s)
- Colin Adrain
- Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal
- Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
| | - Marina Badenes
- Veterinary and Animal Research Center (CECAV), Faculty of Veterinary Medicine, Lusófona University-Lisbon University Centre, Portugal
- Superior School of Health, Protection and Animal Welfare, Polytechnic Institute of Lusophony, Lisbon, Portugal
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9
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Upton C, Healey J, Rothnie AJ, Goddard AD. Insights into membrane interactions and their therapeutic potential. Arch Biochem Biophys 2024; 755:109939. [PMID: 38387829 DOI: 10.1016/j.abb.2024.109939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/31/2024] [Accepted: 02/19/2024] [Indexed: 02/24/2024]
Abstract
Recent research into membrane interactions has uncovered a diverse range of therapeutic opportunities through the bioengineering of human and non-human macromolecules. Although the majority of this research is focussed on fundamental developments, emerging studies are showcasing promising new technologies to combat conditions such as cancer, Alzheimer's and inflammatory and immune-based disease, utilising the alteration of bacteriophage, adenovirus, bacterial toxins, type 6 secretion systems, annexins, mitochondrial antiviral signalling proteins and bacterial nano-syringes. To advance the field further, each of these opportunities need to be better understood, and the therapeutic models need to be further optimised. Here, we summarise the knowledge and insights into several membrane interactions and detail their current and potential uses therapeutically.
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Affiliation(s)
- Calum Upton
- School of Biosciences, Health & Life Science, Aston University, Birmingham, B4 7ET, UK
| | - Joseph Healey
- Nanosyrinx, The Venture Centre, University of Warwick Science Park, Coventry, CV4 7EZ, UK
| | - Alice J Rothnie
- School of Biosciences, Health & Life Science, Aston University, Birmingham, B4 7ET, UK
| | - Alan D Goddard
- School of Biosciences, Health & Life Science, Aston University, Birmingham, B4 7ET, UK.
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10
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Sireci S, Kocagöz Y, Alkiraz AS, Güler K, Dokuzluoglu Z, Balcioglu E, Meydanli S, Demirler MC, Erdogan NS, Fuss SH. HB-EGF promotes progenitor cell proliferation and sensory neuron regeneration in the zebrafish olfactory epithelium. FEBS J 2024; 291:2098-2133. [PMID: 38088047 DOI: 10.1111/febs.17033] [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: 11/06/2023] [Revised: 11/15/2023] [Accepted: 12/11/2023] [Indexed: 12/21/2023]
Abstract
Maintenance and regeneration of the zebrafish olfactory epithelium (OE) are supported by two distinct progenitor cell populations that occupy spatially discrete stem cell niches and respond to different tissue conditions. Globose basal cells (GBCs) reside at the inner and peripheral margins of the sensory OE and are constitutively active to replace sporadically dying olfactory sensory neurons (OSNs). In contrast, horizontal basal cells (HBCs) are uniformly distributed across the sensory tissue and are selectively activated by acute injury conditions. Here we show that expression of the heparin-binding epidermal growth factor-like growth factor (HB-EGF) is strongly and transiently upregulated in response to OE injury and signals through the EGF receptor (EGFR), which is expressed by HBCs. Exogenous stimulation of the OE with recombinant HB-EGF promotes HBC expansion and OSN neurogenesis in a pattern that resembles the tissue response to injury. In contrast, pharmacological inhibition of HB-EGF membrane shedding, HB-EGF availability, and EGFR signaling strongly attenuate or delay injury-induced HBC activity and OSN restoration without affecting maintenance neurogenesis by GBCs. Thus, HB-EGF/EGFR signaling appears to be a critical component of the signaling network that controls HBC activity and, consequently, repair neurogenesis in the zebrafish OE.
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Affiliation(s)
- Siran Sireci
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Yigit Kocagöz
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Aysu Sevval Alkiraz
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Kardelen Güler
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Zeynep Dokuzluoglu
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Ecem Balcioglu
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Sinem Meydanli
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Mehmet Can Demirler
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | | | - Stefan Herbert Fuss
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
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11
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O’Neill CE, Sun K, Sundararaman S, Chang JC, Glynn SA. The impact of nitric oxide on HER family post-translational modification and downstream signaling in cancer. Front Physiol 2024; 15:1358850. [PMID: 38601214 PMCID: PMC11004480 DOI: 10.3389/fphys.2024.1358850] [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: 12/20/2023] [Accepted: 02/16/2024] [Indexed: 04/12/2024] Open
Abstract
The human epidermal growth factor receptor (HER) family consists of four members, activated by two families of ligands. They are known for mediating cell-cell interactions in organogenesis, and their deregulation has been associated with various cancers, including breast and esophageal cancers. In particular, aberrant epidermal growth factor receptor (EGFR) and HER2 signaling drive disease progression and result in poorer patient outcomes. Nitric oxide (NO) has been proposed as an alternative activator of the HER family and may play a role in this aberrant activation due to its ability to induce s-nitrosation and phosphorylation of the EGFR. This review discusses the potential impact of NO on HER family activation and downstream signaling, along with its role in the efficacy of therapeutics targeting the family.
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Affiliation(s)
- Ciara E. O’Neill
- Lambe Institute for Translational Research, Discipline of Pathology, School of Medicine, University of Galway, Galway, Ireland
| | - Kai Sun
- Houston Methodist Research Institute, Houston, TX, United States
- Dr Mary and Ron Neal Cancer Center, Houston Methodist Hospital, Houston, TX, United States
| | | | - Jenny C. Chang
- Houston Methodist Research Institute, Houston, TX, United States
- Dr Mary and Ron Neal Cancer Center, Houston Methodist Hospital, Houston, TX, United States
| | - Sharon A. Glynn
- Lambe Institute for Translational Research, Discipline of Pathology, School of Medicine, University of Galway, Galway, Ireland
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12
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Kremer M, Burkemper N. Aging Skin and Wound Healing. Clin Geriatr Med 2024; 40:1-10. [PMID: 38000854 DOI: 10.1016/j.cger.2023.06.001] [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] [Indexed: 11/26/2023]
Abstract
Responsible for many essential functions of life, human skin is made up of many components, each of which undergoes significant functional changes with aging and photodamage. Wound healing was previously thought to be defective in the elderly given the higher presence of chronic wounds and the longer time required for re-epithelialization of acute wounds. However, these notions have been challenged in recent research, which has shown that wound healing in the elderly is delayed but not defective. Poor healing of chronic wounds in older populations is more often attributable to comorbid conditions rather than age alone.
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Affiliation(s)
- Michael Kremer
- Department of Dermatology, SSM Saint Louis University Hospital, 1225 South Grand Boulevard 3L, St. Louis, MO 63104, USA
| | - Nicole Burkemper
- Department of Dermatology, SSM Saint Louis University Hospital, 1225 South Grand Boulevard 3L, St. Louis, MO 63104, USA.
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13
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Duggins-Warf M, Ghalali A, Sesen J, Martinez T, Fehnel KP, Pineda S, Zurakowski D, Smith ER. Disease specific urinary biomarkers in the central nervous system. Sci Rep 2023; 13:19244. [PMID: 37935834 PMCID: PMC10630515 DOI: 10.1038/s41598-023-46763-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 11/04/2023] [Indexed: 11/09/2023] Open
Abstract
Urinary biomarkers can diagnose and monitor pathophysiologic conditions in the central nervous system (CNS). However, focus is often on single diseases, with limited data on discriminatory capability of this approach in a general setting. Here, we demonstrate that different classes of CNS disease exhibit distinct biomarker patterns, evidence of disease-specific "fingerprinting." Urine from 218 patients with pathology-confirmed tumors or cerebrovascular disease, controls (n = 33) were collected. ELISA and/or bead-based multiplexing quantified levels of 21 putative urinary biomarkers. Analysis identified biomarkers capable of distinguishing each disease from controls and other diseases. Mann-Whitney U tests identified biomarkers with differential expression between disease types and controls (P ≤ 0.001). Subsequent receiver-operating characteristic (ROC) analyses revealed distinguishing biomarkers with high sensitivity and specificity. Areas under the curve (AUCs) ranged 0.8563-1.000 (P values ≤ 0.0003), sensitivities ranged 80.00-100.00%, and specificities ranged 80.95-100.00%. These data demonstrate proof-of-principle evidence that disease-specific urinary biomarker signatures exist. In contrast to non-specific responses to ischemia or injury, these results suggest that urinary biomarkers accurately reflect unique biological processes distinct to different diseases. This work can be used to generate disease-specific panels for enhancing diagnosis, assisting less-invasive follow-up and herald utility by revealing putative disease-specific therapeutic targets.
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Affiliation(s)
- Micah Duggins-Warf
- Vascular Biology Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
- Department of Neurosurgery, Boston Children's Hospital, Boston, MA, USA
| | - Aram Ghalali
- Vascular Biology Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
- Department of Neurosurgery, Boston Children's Hospital, Boston, MA, USA
| | - Julie Sesen
- Vascular Biology Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
- Department of Neurosurgery, Boston Children's Hospital, Boston, MA, USA
| | - Tyra Martinez
- Vascular Biology Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
- Department of Neurosurgery, Boston Children's Hospital, Boston, MA, USA
| | - Katie P Fehnel
- Vascular Biology Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
- Department of Neurosurgery, Boston Children's Hospital, Boston, MA, USA
| | - Steven Pineda
- Vascular Biology Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
- Department of Neurosurgery, Boston Children's Hospital, Boston, MA, USA
| | - David Zurakowski
- Department of Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Edward R Smith
- Vascular Biology Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA.
- Department of Neurosurgery, Boston Children's Hospital, Boston, MA, USA.
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14
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Younes R, Issa Y, Jdaa N, Chouaib B, Brugioti V, Challuau D, Raoul C, Scamps F, Cuisinier F, Hilaire C. The Secretome of Human Dental Pulp Stem Cells and Its Components GDF15 and HB-EGF Protect Amyotrophic Lateral Sclerosis Motoneurons against Death. Biomedicines 2023; 11:2152. [PMID: 37626649 PMCID: PMC10452672 DOI: 10.3390/biomedicines11082152] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable paralytic disorder caused by the progressive death of upper and lower motoneurons. Although numerous strategies have been developed to slow disease progression and improve life quality, to date only a few therapeutic treatments are available with still unsatisfactory therapeutic benefits. The secretome of dental pulp stem cells (DPSCs) contains numerous neurotrophic factors that could promote motoneuron survival. Accordingly, DPSCs confer neuroprotective benefits to the SOD1G93A mouse model of ALS. However, the mode of action of DPSC secretome on motoneurons remains largely unknown. Here, we used conditioned medium of human DPSCs (DPSCs-CM) and assessed its effect on survival, axonal length, and electrical activity of cultured wildtype and SOD1G93A motoneurons. To further understand the role of individual factors secreted by DPSCs and to circumvent the secretome variability bias, we focused on GDF15 and HB-EGF whose neuroprotective properties remain elusive in the ALS pathogenic context. DPSCs-CM rescues motoneurons from trophic factor deprivation-induced death, promotes axon outgrowth of wildtype but not SOD1G93A mutant motoneurons, and has no impact on the spontaneous electrical activity of wildtype or mutant motoneurons. Both GDF15 and HB-EGF protect SOD1G93A motoneurons against nitric oxide-induced death, but not against death induced by trophic factor deprivation. GDF15 and HB-EGF receptors were found to be expressed in the spinal cord, with a two-fold increase in expression for the GDF15 low-affinity receptor in SOD1G93A mice. Therefore, the secretome of DPSCs appears as a new potential therapeutic candidate for ALS.
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Affiliation(s)
- Richard Younes
- INM, University of Montpellier, INSERM, 34295 Montpellier, France
- LBN, University of Montpellier, 34193 Montpellier, France
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut 6573, Lebanon
| | - Youssef Issa
- INM, University of Montpellier, INSERM, 34295 Montpellier, France
| | - Nadia Jdaa
- INM, University of Montpellier, INSERM, 34295 Montpellier, France
| | - Batoul Chouaib
- LBN, University of Montpellier, 34193 Montpellier, France
- Human Health Department, IRSN, SERAMED, LRMed, 92262 Fontenay-aux-Roses, France
| | | | - Désiré Challuau
- INM, University of Montpellier, INSERM, 34295 Montpellier, France
| | - Cédric Raoul
- INM, University of Montpellier, INSERM, 34295 Montpellier, France
| | | | | | - Cécile Hilaire
- INM, University of Montpellier, INSERM, 34295 Montpellier, France
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15
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Li X, Mo K, Tian G, Zhou J, Gong J, Li L, Huang X. Shikimic Acid Regulates the NF-κB/MAPK Signaling Pathway and Gut Microbiota to Ameliorate DSS-Induced Ulcerative Colitis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023. [PMID: 37257042 DOI: 10.1021/acs.jafc.3c00283] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Shikimic acid (SA) is a compound extracted from the plant anise and has anti-inflammatory effects. However, any impact on intestinal inflammation or mechanisms involved has not been investigated. The present study used a dextran sulfate sodium (DSS)-induced mouse colitis model to investigate the effects of SA on intestinal inflammation. Intragastric administration of SA slowed DSS-induced weight loss, reduced disease activity index (DAI) score, enhanced the intestinal barrier, reduced the destruction of the colonic structure, inhibited the phosphorylation of key proteins in MAPK and NF-κB signaling pathways, inhibited the expression of inflammatory factors TNF-α, IL-1β, and MPO (P < 0.05), decreased IFN-γ expression (P < 0.05), and increased immunoglobulin IgG content (P < 0.05). After 50 mg/kg SA treatment, the content of Bacteroidetes increased and Proteobacteria decreased in the cecal feces of mice with colitis (P < 0.05) and the richness of gut species increased. In conclusion, SA could improve intestinal inflammation and enhance intestinal immunity, indicating its suitability as a therapeutic candidate.
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Affiliation(s)
- Xin Li
- Guangdong Key Laboratory for Veterinary Drug Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Kaibin Mo
- Guangdong Key Laboratory for Veterinary Drug Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Ge Tian
- Guangdong Key Laboratory for Veterinary Drug Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Jiaxin Zhou
- Guangdong Key Laboratory for Veterinary Drug Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Jiongzhou Gong
- Guangdong Key Laboratory for Veterinary Drug Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Li Li
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Xianhui Huang
- Guangdong Key Laboratory for Veterinary Drug Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
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16
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Abstract
Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder with multifaceted neuropathological features, including β-amyloid plaques, neurofibrillary tangles, and neuroinflammation. Over the past decade, emerging evidence has implicated both beneficial and pathological roles for innate immune genes and immune cells, including peripheral immune cells such as T cells, which can infiltrate the brain and either ameliorate or exacerbate AD neuropathogenesis. These findings support a neuroimmune axis of AD, in which the interplay of adaptive and innate immune systems inside and outside the brain critically impacts the etiology and pathogenesis of AD. In this review, we discuss the complexities of AD neuropathology at the levels of genetics and cellular physiology, highlighting immune signaling pathways and genes associated with AD risk and interactions among both innate and adaptive immune cells in the AD brain. We emphasize the role of peripheral immune cells in AD and the mechanisms by which immune cells, such as T cells and monocytes, influence AD neuropathology, including microglial clearance of amyloid-β peptide, the key component of β-amyloid plaque cores, pro-inflammatory and cytotoxic activity of microglia, astrogliosis, and their interactions with the brain vasculature. Finally, we review the challenges and outlook for establishing immune-based therapies for treating and preventing AD.
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17
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Basu D, Pal R, Sarkar M, Barma S, Halder S, Roy H, Nandi S, Samadder A. To Investigate Growth Factor Receptor Targets and Generate Cancer Targeting Inhibitors. Curr Top Med Chem 2023; 23:2877-2972. [PMID: 38164722 DOI: 10.2174/0115680266261150231110053650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 09/20/2023] [Accepted: 10/02/2023] [Indexed: 01/03/2024]
Abstract
Receptor tyrosine kinase (RTK) regulates multiple pathways, including Mitogenactivated protein kinases (MAPKs), PI3/AKT, JAK/STAT pathway, etc. which has a significant role in the progression and metastasis of tumor. As RTK activation regulates numerous essential bodily processes, including cell proliferation and division, RTK dysregulation has been identified in many types of cancers. Targeting RTK is a significant challenge in cancer due to the abnormal upregulation and downregulation of RTK receptors subfamily EGFR, FGFR, PDGFR, VEGFR, and HGFR in the progression of cancer, which is governed by multiple RTK receptor signalling pathways and impacts treatment response and disease progression. In this review, an extensive focus has been carried out on the normal and abnormal signalling pathways of EGFR, FGFR, PDGFR, VEGFR, and HGFR and their association with cancer initiation and progression. These are explored as potential therapeutic cancer targets and therefore, the inhibitors were evaluated alone and merged with additional therapies in clinical trials aimed at combating global cancer.
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Affiliation(s)
- Debroop Basu
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Riya Pal
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, IndiaIndia
| | - Maitrayee Sarkar
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Soubhik Barma
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Sumit Halder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Harekrishna Roy
- Nirmala College of Pharmacy, Vijayawada, Guntur, Andhra Pradesh, India
| | - Sisir Nandi
- Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur, 244713, India
| | - Asmita Samadder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
- Cytogenetics and Molecular Biology Lab., Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
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18
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Van Hiep N, Sun WL, Feng PH, Lin CW, Chen KY, Luo CS, Dung LN, Van Quyet H, Wu SM, Lee KY. Heparin binding epidermal growth factor-like growth factor is a prognostic marker correlated with levels of macrophages infiltrated in lung adenocarcinoma. Front Oncol 2022; 12:963896. [PMID: 36439487 PMCID: PMC9686304 DOI: 10.3389/fonc.2022.963896] [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: 06/08/2022] [Accepted: 10/27/2022] [Indexed: 11/11/2022] Open
Abstract
Background The interactions between tumor cells and the host immune system play a crucial role in lung cancer progression and resistance to treatment. The alterations of EGFR signaling have the potential to produce an ineffective tumor-associated immune microenvironment by upregulating a series of immune suppressors, including inhibitory immune checkpoints, immunosuppressive cells, and cytokines. Elevated Heparin-binding EGF-like growth factor (HB-EGF) expression, one EGFR ligand correlated with higher histology grading, worse patient prognosis, and lower overall survival rate, acts as a chemotactic factor. However, the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the accumulation of immune cells in the tumor microenvironment remains unclear. Methods The clinical association of HB-EGF expression in lung cancer was examined using the Gene Expression Omnibus (GEO) repository. HB-EGF expression in different cell types was determined using single-cell RNA sequencing (scRNA-seq) dataset. The correlation between HB-EGF expression and cancer-immune infiltrated cells was investigated by performing TIMER and ClueGo pathways analysis from TCGA database. The chemotaxis of HB-EGF and macrophage infiltration was investigated using migration and immunohistochemical staining. Results The high HB-EGF expression was significantly correlated with poor overall survival in patients with lung adenocarcinoma (LUAD) but not lung squamous cell carcinoma (LUSC). Moreover, HB-EGF expression was correlated with the infiltration of monocytes, macrophages, neutrophils, and dendritic cells in LUAD but not in LUSC. Analysis of scRNA-seq data revealed high HB-EGF expression in lung cancer cells and myeloid cells. Results from the pathway analysis and cell-based experiment indicated that elevated HB-EGF expression was associated with the presence of macrophage and lung cancer cell migration. HB-EGF was highly expressed in tumors and correlated with M2 macrophage infiltration in LUAD. Conclusions HB-EGF is a potential prognostic marker and therapeutic target for lung cancer progression, particularly in LUAD.
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Affiliation(s)
- Nguyen Van Hiep
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan,Oncology Center, Bai Chay Hospital, Quang Ninh, Ha Long, Vietnam,Department of Thoracic and Neurological Surgery, Bai Chay Hospital, Quang Ninh, Ha Long, Vietnam
| | - Wei-Lun Sun
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan,Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan,TMU Research Center for Thoracic Medicine, Taipei Medical University, Taipei, Taiwan
| | - Po-Hao Feng
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan,Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan,TMU Research Center for Thoracic Medicine, Taipei Medical University, Taipei, Taiwan
| | - Cheng-Wei Lin
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan,TMU Research Center for Thoracic Medicine, Taipei Medical University, Taipei, Taiwan,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kuan-Yuan Chen
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan,Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan,TMU Research Center for Thoracic Medicine, Taipei Medical University, Taipei, Taiwan,Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ching-Shan Luo
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan,Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan,TMU Research Center for Thoracic Medicine, Taipei Medical University, Taipei, Taiwan
| | - Le Ngoc Dung
- Department of Thoracic and Neurological Surgery, Bai Chay Hospital, Quang Ninh, Ha Long, Vietnam
| | - Hoang Van Quyet
- Department of Thoracic and Neurological Surgery, Bai Chay Hospital, Quang Ninh, Ha Long, Vietnam
| | - Sheng-Ming Wu
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan,Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan,TMU Research Center for Thoracic Medicine, Taipei Medical University, Taipei, Taiwan,*Correspondence: Kang-Yun Lee, ; Sheng-Ming Wu,
| | - Kang-Yun Lee
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan,Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan,Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan,TMU Research Center for Thoracic Medicine, Taipei Medical University, Taipei, Taiwan,Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan,*Correspondence: Kang-Yun Lee, ; Sheng-Ming Wu,
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19
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Park SH, Yoon SJ, Choi S, Jung J, Park JY, Park YH, Seo J, Lee J, Lee MS, Lee SJ, Son MY, Cho YL, Kim JS, Lee HJ, Jeong J, Kim DS, Park YJ. Particulate matter promotes cancer metastasis through increased HBEGF expression in macrophages. Exp Mol Med 2022; 54:1901-1912. [PMID: 36352257 PMCID: PMC9722902 DOI: 10.1038/s12276-022-00886-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/31/2022] [Accepted: 09/13/2022] [Indexed: 11/11/2022] Open
Abstract
Although many cohort studies have reported that long-term exposure to particulate matter (PM) can cause lung cancer, the molecular mechanisms underlying the PM-induced increase in cancer metastasis remain unclear. To determine whether PM contributes to cancer metastasis, cancer cells were cultured with conditioned medium from PM-treated THP1 cells, and the migration ability of the treated cancer cells was assessed. The key molecules involved were identified using RNA-seq analysis. In addition, metastatic ability was analyzed in vivo by injection of cancer cells into the tail vein and intratracheal injection of PM into the lungs of C57BL/6 mice. We found that PM enhances the expression of heparin-binding EGF-like growth factor (HBEGF) in macrophages, which induces epithelial-to-mesenchymal transition (EMT) in cancer cells, thereby increasing metastasis. Macrophage stimulation by PM results in activation and subsequent nuclear translocation of the aryl hydrocarbon receptor and upregulation of HBEGF. Secreted HBEGF activates EGFR on the cancer cell surface to induce EMT, resulting in increased migration and invasion in vitro and increased metastasis in vivo. Therefore, our study reveals a critical PM-macrophage-cancer cell signaling axis mediating EMT and metastasis and provides an effective therapeutic approach for PM-induced malignancy.
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Affiliation(s)
- Seung-Ho Park
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Sung-Jin Yoon
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Song Choi
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Jaeeun Jung
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Jun-Young Park
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Young-Ho Park
- Futuristic Animal Resource and Research Center, KRIBB, Ochang, Republic of Korea
| | - Jinho Seo
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Jungwoon Lee
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Moo-Seung Lee
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Seon-Jin Lee
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Mi-Young Son
- University of Science and Technology (UST), Daejeon, Republic of Korea
- Stem Cell Convergence Research Center, KRIBB, Daejeon, Republic of Korea
| | - Young-Lai Cho
- Metabolic Regulation Research Center, KRIBB, Daejeon, Republic of Korea
| | - Jang-Seong Kim
- Biotherapeutics Translational Research Center, KRIBB, Daejeon, Republic of Korea
| | - Hyo Jin Lee
- Department of Internal Medicine, Cancer Research Institute and Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Jinyoung Jeong
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
- University of Science and Technology (UST), Daejeon, Republic of Korea.
| | - Dae-Soo Kim
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
- University of Science and Technology (UST), Daejeon, Republic of Korea.
| | - Young-Jun Park
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
- University of Science and Technology (UST), Daejeon, Republic of Korea.
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20
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Cheng JC, Han X, Meng Q, Guo Y, Liu B, Song T, Jia Y, Fang L, Sun YP. HB-EGF upregulates StAR expression and stimulates progesterone production through ERK1/2 signaling in human granulosa-lutein cells. Cell Commun Signal 2022; 20:166. [PMID: 36284301 PMCID: PMC9598000 DOI: 10.1186/s12964-022-00983-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/01/2022] [Indexed: 11/10/2022] Open
Abstract
Background Heparin-binding epidermal growth factor-like growth factor (HB-EGF) belongs to the epidermal growth factor (EGF) family of growth factors. HB-EGF and its receptors, epidermal growth factor receptor (EGFR) and HER4, are expressed in the human corpus luteum. HB-EGF has been shown to regulate luteal function by preventing cell apoptosis. Steroidogenesis is the primary function of the human corpus luteum. Steroidogenic acute regulatory protein (StAR) plays a critical role in steroidogenesis. StAR expression and progesterone (P4) production in human granulosa-lutein (hGL) cells have been shown to be upregulated by a ligand of EGFR, amphiregulin. However, whether HB-EGF can achieve the same effects remains unknown. Methods A steroidogenic human ovarian granulosa-like tumor cell line, KGN, and primary culture of hGL cells obtained from patients undergoing in vitro fertilization treatment were used as experimental models. The underlying molecular mechanisms mediating the effects of HB-EGF on StAR expression and P4 production were explored by a series of in vitro experiments. Results Western blot showed that EGFR, HER2, and HER4 were expressed in both KGN and hGL cells. Treatment with HB-EGF for 24 h induced StAR expression but did not affect the expression of steroidogenesis-related enzymes, P450 side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase, and aromatase. Using pharmacological inhibitors and a siRNA-mediated knockdown approach, we showed that EGFR, HER4, but not HER2, were required for HB-EGF-stimulated StAR expression and P4 production. In addition, HB-EGF-induced upregulations of StAR expression and P4 production were mediated by the activation of the ERK1/2 signaling pathway. Conclusion This study increases the understanding of the physiological role of HB-EGF in human luteal functions.
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