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Gong R, Tan JL, Liu G, Liu XF, Ma L, Shi S. Mechanism of disturbed endothelial cell function on angiogenesis following ischemic brain stroke (Review). Exp Ther Med 2025; 29:61. [PMID: 39991719 PMCID: PMC11843205 DOI: 10.3892/etm.2025.12811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 01/10/2025] [Indexed: 02/25/2025] Open
Abstract
The present study focused on the mechanisms of post-ischemic stroke (IS) angiogenesis from the perspective of endothelial cells (ECs) dysfunction. First, it emphasized the importance of hypoxia-inducible factor-1α in the function of ECs under hypoxic conditions, particularly in promoting angiogenesis and improving cerebral blood supply. Secondly, inflammatory cytokines and adhesion factors (for example, selectins, the immunoglobulin superfamily and integrins) influence the function and angiogenesis of ECs through various mechanisms and signaling pathways following IS. In addition, the effects of oxidative stress on ECs function and angiogenesis were explored, along with the potential of antioxidant strategies to improve EC function and promote angiogenesis. Based on these insights, the present study proposed new therapeutic strategies to ameliorate endothelial dysfunction and promote angiogenesis following IS, including small-molecule drugs targeting specific molecules, gene therapy and traditional Chinese medicine treatments. Finally, the importance of translating these laboratory findings into clinical applications was emphasized, alongside the need for advanced imaging techniques to monitor the dynamic processes of post-IS angiogenesis and evaluate the efficacy of novel therapeutic interventions. These explorations aimed at providing a more comprehensive understanding of EC function and the regulatory mechanisms of a deeper understanding of angiogenesis following IS, offering new intervention strategies for IS treatment.
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Affiliation(s)
- Rui Gong
- Department of Rehabilitation of Chinese Medicine, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Jin-Lang Tan
- Department of Rehabilitation of Chinese Medicine, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Gang Liu
- Department of Acupuncture, Moxibustion and Tuina, The Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Xiao-Fang Liu
- Department of Acupuncture, Moxibustion and Tuina, The Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Le Ma
- Department of Rehabilitation of Chinese Medicine, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Shuai Shi
- Department of Acupuncture, Moxibustion and Tuina, The Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
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2
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Suk TR, Part CE, Zhang JL, Nguyen TT, Heer MM, Caballero-Gómez A, Grybas VS, McKeever PM, Nguyen B, Ali T, Callaghan SM, Woulfe JM, Robertson J, Rousseaux MWC. A stress-dependent TDP-43 SUMOylation program preserves neuronal function. Mol Neurodegener 2025; 20:38. [PMID: 40149017 PMCID: PMC11951803 DOI: 10.1186/s13024-025-00826-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: 06/13/2024] [Accepted: 03/09/2025] [Indexed: 03/29/2025] Open
Abstract
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in TDP-43 are rare, indicating that the progressive accumulation of exogenous factors - such as cellular stressors - converge on TDP-43 to play a key role in disease pathogenesis. Post translational modifications such as SUMOylation play essential roles in response to such exogenous stressors. We therefore set out to understand how SUMOylation may regulate TDP-43 in health and disease. We find that TDP-43 is regulated dynamically via SUMOylation in response to cellular stressors. When this process is blocked in vivo, we note age-dependent TDP-43 pathology and sex-specific behavioral deficits linking TDP-43 SUMOylation with aging and disease. We further find that SUMOylation is correlated with human aging and disease states. Collectively, this work presents TDP-43 SUMOylation as an early physiological response to cellular stress, disruption of which may confer a risk for TDP-43 proteinopathy.
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Affiliation(s)
- Terry R Suk
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Eric Poulin Center for Neuromuscular Diseases, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada
| | - Caroline E Part
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Eric Poulin Center for Neuromuscular Diseases, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada
| | - Jenny L Zhang
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Eric Poulin Center for Neuromuscular Diseases, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada
| | - Trina T Nguyen
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Eric Poulin Center for Neuromuscular Diseases, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada
| | - Meghan M Heer
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Eric Poulin Center for Neuromuscular Diseases, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada
| | - Alejandro Caballero-Gómez
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Eric Poulin Center for Neuromuscular Diseases, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada
| | - Veronica S Grybas
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Eric Poulin Center for Neuromuscular Diseases, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada
| | - Paul M McKeever
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
| | - Benjamin Nguyen
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Eric Poulin Center for Neuromuscular Diseases, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada
| | - Tahir Ali
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Eric Poulin Center for Neuromuscular Diseases, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada
| | - Steve M Callaghan
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Eric Poulin Center for Neuromuscular Diseases, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada
| | - John M Woulfe
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- The Ottawa Hospital Research Institute, the Ottawa Hospital, Ottawa, ON, Canada
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Janice Robertson
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
| | - Maxime W C Rousseaux
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada.
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
- Eric Poulin Center for Neuromuscular Diseases, Ottawa, ON, Canada.
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada.
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3
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Smadja DM, Berkane Y, Bentounes NK, Rancic J, Cras A, Pinault C, Ouarne M, Paucod E, Rachidi W, Lellouch AG, Jeljeli M. Immune-privileged cord blood-derived endothelial colony-forming cells: advancing immunomodulation and vascular regeneration. Angiogenesis 2025; 28:19. [PMID: 40047974 PMCID: PMC11885380 DOI: 10.1007/s10456-025-09973-9] [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: 12/11/2024] [Accepted: 02/25/2025] [Indexed: 03/09/2025]
Abstract
Cord blood-derived endothelial colony-forming cells (CB-ECFCs) hold significant promise for regenerative medicine due to their unique vasculogenic and immunomodulatory properties. These cells exhibit a superior proliferative capacity, robust ability to form vascular networks, and lower immunogenicity compared to adult and embryonic stem cell-derived counterparts. The immune-privileged characteristics of CB-ECFCs, including reduced expression of pro-inflammatory mediators and tolerance-inducing molecules such as HLA-G, further enhance their therapeutic potential. Their low immunogenicity minimizes the risk of immune rejection, making them suitable for allogenic cell therapies. Their application extends to complex tissue engineering and organ revascularization, where their ability to integrate into three-dimensional scaffolds and support vascular tree formation represents a significant advancement. Moreover, CB-ECFCs' capability to adapt to inflammatory stimuli and retain immunological memory highlights their functional versatility in dynamic microenvironments. This review highlights the remarkable ontogeny of ECFCs while unveiling the unparalleled potential of CB-ECFCs in revolutionizing regenerative medicine. From pre-vascularizing engineered tissues and organoids to pioneering cell-based therapies for cardiovascular, dermatological, and degenerative diseases, CB-ECFCs stand at the forefront of cutting-edge biomedical advancements, offering unprecedented opportunities for therapeutic innovation. By leveraging their vasculogenic, immune-regulatory, and regenerative capacities, CB-ECFCs offer a robust alternative for addressing the challenges of vascular repair and organ engineering. Future research should focus on unraveling their transcriptomic and functional profiles to optimize clinical applications and advance the field of regenerative medicine.
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Affiliation(s)
- David M Smadja
- Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.
- Hematology Department, AP-HP, Georges Pompidou European Hospital, Paris, F-75015, France.
| | - Yanis Berkane
- Department of Plastic, Reconstructive and Aesthetic Surgery, Hôpital Sud, CHU Rennes, University of Rennes, Rennes, France
- SITI Laboratory, UMR INSERM 1236, Rennes University Hospital, Rennes, France
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Nun K Bentounes
- Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France
- Hematology Department, AP-HP, Georges Pompidou European Hospital, Paris, F-75015, France
| | - Jeanne Rancic
- Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France
- Hematology Department, AP-HP, Georges Pompidou European Hospital, Paris, F-75015, France
| | - Audrey Cras
- Cell Therapy Department, AP-HP, Saint-Louis Hospital, Paris, F-75010, France
| | - Cécile Pinault
- Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France
- Hematology Department, AP-HP, Georges Pompidou European Hospital, Paris, F-75015, France
| | - Marie Ouarne
- Univ. Grenoble Alpes, CEA, INSERM, IRIG-BGE UA13, Grenoble, 38000, France
| | - Elise Paucod
- Univ. Grenoble Alpes, CEA, INSERM, IRIG-BGE UA13, Grenoble, 38000, France
| | - Walid Rachidi
- Univ. Grenoble Alpes, CEA, INSERM, IRIG-BGE UA13, Grenoble, 38000, France
| | - Alexandre G Lellouch
- Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France
- Hematology Department, AP-HP, Georges Pompidou European Hospital, Paris, F-75015, France
- Department of Plastic, Reconstructive and Aesthetic Surgery, Cedars Sinai Hospital, Los Angeles, USA
| | - Maxime Jeljeli
- Department of Plastic, Reconstructive and Aesthetic Surgery, Cedars Sinai Hospital, Los Angeles, USA
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Gomaa F, Rogers DR, Utter DR, Powers C, Huang IT, Beaudoin DJ, Zhang Y, Cavanaugh C, Edgcomb VP, Bernhard JM. Array of metabolic pathways in a kleptoplastidic foraminiferan protist supports chemoautotrophy in dark, euxinic seafloor sediments. THE ISME JOURNAL 2025; 19:wrae248. [PMID: 39673188 PMCID: PMC11736642 DOI: 10.1093/ismejo/wrae248] [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: 05/22/2024] [Revised: 10/09/2024] [Accepted: 12/13/2024] [Indexed: 12/16/2024]
Abstract
Investigations of the metabolic capabilities of anaerobic protists advances our understanding of the evolution of eukaryotic life on Earth and for uncovering analogous extraterrestrial complex microbial life. Certain species of foraminiferan protists live in environments analogous to early Earth conditions when eukaryotes evolved, including sulfidic, anoxic and hypoxic sediment porewaters. Foraminifera are known to form symbioses as well as to harbor organelles from other eukaryotes (chloroplasts), possibly bolstering the host's independence from oxygen. The full extent of foraminiferal physiological capabilities is not fully understood. To date, evidence for foraminiferal anaerobiosis was gleaned from specimens first subjected to stresses associated with removal from in situ conditions. Here, we report comprehensive gene expression analysis of benthic foraminiferal populations preserved in situ on the euxinic (anoxic and sulfidic) bathyal seafloor, thus avoiding environmental alterations associated with sample recovery, including pressure reduction, sunlight exposure, warming, and oxygenation. Metatranscriptomics, metagenome-assembled genomes, and measurements of substrate uptake were used to study the kleptoplastidic foraminifer Nonionella stella inhabiting sulfur-oxidizing bacterial mats of the Santa Barbara Basin, off California. We show N. stella energy generation under dark euxinia is unusual because it orchestrates complex metabolic pathways for ATP production and carbon fixation through the Calvin cycle. These pathways include extended glycolysis, anaerobic fermentation, sulfide oxidation, and the presence of a membrane-bound inorganic pyrophosphatase, an enzyme that hydrolyzes inorganic pyrophosphate to actively pump protons across the mitochondrial membrane.
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Affiliation(s)
- Fatma Gomaa
- Department of Geology and Geophysics, Woods Hole Oceanographic Institution, Woods Hole, MA 02543, United States
- Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, United States
| | - Daniel R Rogers
- Chemistry Department, Stonehill College, Easton, MA 02357 United States
| | - Daniel R Utter
- Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA 91125, United States
| | - Christopher Powers
- Department of Cell and Molecular Biology, College of the Environment and Life Sciences, University of Rhode Island, Kingston, RI 02881, United States
| | - I-Ting Huang
- Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, United States
| | - David J Beaudoin
- Department of Biology, Woods Hole Oceanographic Institution, Woods Hole, MA 02543, United States
| | - Ying Zhang
- Department of Cell and Molecular Biology, College of the Environment and Life Sciences, University of Rhode Island, Kingston, RI 02881, United States
| | - Colleen Cavanaugh
- Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, United States
| | - Virginia P Edgcomb
- Department of Geology and Geophysics, Woods Hole Oceanographic Institution, Woods Hole, MA 02543, United States
| | - Joan M Bernhard
- Department of Geology and Geophysics, Woods Hole Oceanographic Institution, Woods Hole, MA 02543, United States
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Emamalipour M, Shamdani S, Mansoori B, Uzan G, Naserian S. The implications of the TNFα-TNFR2 immune checkpoint signaling pathway in cancer treatment: From immunoregulation to angiogenesis. Int J Cancer 2025; 156:7-19. [PMID: 39140321 DOI: 10.1002/ijc.35130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 07/09/2024] [Accepted: 07/12/2024] [Indexed: 08/15/2024]
Abstract
Despite the tremendous advances that have been made in biomedical research, cancer remains one of the leading causes of death worldwide. Several therapeutic approaches have been suggested and applied to treat cancer with impressive results. Immunotherapy based on targeting immune checkpoint signaling pathways proved to be one of the most efficient. In this review article, we will focus on the recently discovered TNFα-TNFR2 signaling pathway, which controls the immunological and pro-angiogenic properties of many immunoregulatory and pro-angiogenic cells such as endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), and regulatory T cells (Tregs). Due to their biological properties, these cells can play a major role in cancer progression and metastasis. Therefore, we will discuss the advantages and disadvantages of an anti-TNFR2 treatment that could carry two faces under one hood. It interrupts the immunosuppressive and pro-angiogenic behaviors of the above-mentioned cells and interferes with tumor growth and survival.
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Affiliation(s)
| | - Sara Shamdani
- CellMedEx, Saint Maur Des Fossés, France
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
| | - Behzad Mansoori
- The Wistar Institute, Molecular & Cellular Oncogenesis Program, Philadelphia, Pennsylvania, USA
| | - Georges Uzan
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
| | - Sina Naserian
- CellMedEx, Saint Maur Des Fossés, France
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
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6
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Fındık DG, Şahin E, Türelik Ö, Güneri G. Epiplakin expression dynamics during colon carcinogenesis: Correlation with proliferation. BIOMOLECULES & BIOMEDICINE 2024; 25:62-70. [PMID: 39052015 PMCID: PMC11647249 DOI: 10.17305/bb.2024.10981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 07/23/2024] [Accepted: 07/23/2024] [Indexed: 07/27/2024]
Abstract
Colorectal cancer poses a significant global health challenge, with a considerable proportion arising from colon adenomas. Understanding the molecules involved in the carcinogenesis process is crucial for improving colon cancer diagnosis and prognosis. While research on the role of epiplakin in cancer remains limited compared to other plakin group proteins, comprehending its expression patterns and correlations can offer valuable insights into colon carcinogenesis. In this study, we analyzed 60 tissue samples, including colon adenocarcinomas, tubular adenomas (low malignancy risk group), tubulovillous adenomas (high malignancy risk group), and adjacent normal colon tissues. Classification and grading were reevaluated by histological examination. Immunohistochemistry was performed to assess epiplakin and Ki67 expression. Epiplakin optical density and the Ki67 proliferation index were calculated using ImageJ. Statistical analyses were conducted to evaluate correlations and significance. Epiplakin expression was significantly decreased in colon adenocarcinomas [optical density median 4.04 (95% CI, 3.98 to 4.24)] and tubulovillous adenomas [4.32 (95% CI, 4.08 to 4.32)] compared to normal colon tissues [4.61 (95% CI, 4.50 to 4.67)] and tubular adenomas [4.87 (95% CI, 4.67 to 4.88)] (P < 0.05). Moreover, adenoma groups exhibited higher proliferation indices (P < 0.05), and a positive correlation was found between epiplakin expression and the Ki67 proliferation index (r = 0.317, P < 0.05). Our study highlights the potential significance of epiplakin in colorectal cancer. Decreased epiplakin expression is associated with colon malignancy progression, suggesting its role as a potential marker.
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Affiliation(s)
- Damla Gül Fındık
- Department of Histology and Embryology, Faculty of Medicine, Bilecik Şeyh Edebali University, Bilecik, Türkiye
| | - Erhan Şahin
- Department of Histology and Embryology, Faculty of Medicine, Bilecik Şeyh Edebali University, Bilecik, Türkiye
| | - Özlem Türelik
- Department of Pathology, Faculty of Medicine, Bilecik Şeyh Edebali University, Bilecik, Türkiye
| | - Gürkan Güneri
- Department of General Surgery, Faculty of Medicine, Bilecik Şeyh Edebali University, Bilecik, Türkiye
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7
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Mussa A, Ismail NH, Hamid M, Al-Hatamleh MAI, Bragoli A, Hajissa K, Mokhtar NF, Mohamud R, Uskoković V, Hassan R. Understanding the role of TNFR2 signaling in the tumor microenvironment of breast cancer. J Exp Clin Cancer Res 2024; 43:312. [PMID: 39609700 PMCID: PMC11603874 DOI: 10.1186/s13046-024-03218-1] [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: 08/21/2024] [Accepted: 10/29/2024] [Indexed: 11/30/2024] Open
Abstract
Breast cancer (BC) is the most frequently diagnosed malignancy among women. It is characterized by a high level of heterogeneity that emerges from the interaction of several cellular and soluble components in the tumor microenvironment (TME), such as cytokines, tumor cells and tumor-associated immune cells. Tumor necrosis factor (TNF) receptor 2 (TNFR2) appears to play a significant role in microenvironmental regulation, tumor progression, immune evasion, drug resistance, and metastasis of many types of cancer, including BC. However, the significance of TNFR2 in BC biology is not fully understood. This review provides an overview of TNFR2 biology, detailing its activation and its interactions with important signaling pathways in the TME (e.g., NF-κB, MAPK, and PI3K/Akt pathways). We discuss potential therapeutic strategies targeting TNFR2, with the aim of enhancing the antitumor immune response to BC. This review provides insights into role of TNFR2 as a major immune checkpoint for the future treatment of patients with BC.
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Affiliation(s)
- Ali Mussa
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu , Kelantan, 16150, Malaysia
- Department of Biology, Faculty of Education, Omdurman Islamic University, P.O. Box 382, Omdurman, Sudan
| | - Nor Hayati Ismail
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu , Kelantan, 16150, Malaysia
| | - Mahasin Hamid
- Department of Pharmaceutics, Xiangya School of Pharmaceutical Sciences, Central South University, Hunan Province, Changsha, 410013, China
- Department of Zoology, Faculty of Sciences and Information Technology, University of Nyala, Nyala, 63311, Sudan
| | - Mohammad A I Al-Hatamleh
- Division of Hematology and Oncology, Department of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Anthony Bragoli
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Khalid Hajissa
- Department of Zoology, Faculty of Science and Technology, Omdurman Islamic University, P.O. Box 382, Omdurman, Sudan
| | - Noor Fatmawati Mokhtar
- Institute for Research in Molecular Medicine (iNFORMM), Universiti Sains Malaysia, Kubang Kerian, Kota Bharu , Kelantan, 16150, Malaysia
| | - Rohimah Mohamud
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu , Kelantan, 16150, Malaysia.
| | - Vuk Uskoković
- TardigradeNano LLC, Irvine, CA, 92604, USA
- Division of Natural Sciences, Fullerton College, Fullerton, CA, 92832, USA
| | - Rosline Hassan
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu , Kelantan, 16150, Malaysia.
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8
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Yang J, Xu W, Chen D, Liu Y, Hu X. Evidence from Mendelian randomization analysis combined with meta-analysis for the causal validation of the relationship between 91 inflammatory factors and lumbar disc herniation. Medicine (Baltimore) 2024; 103:e40323. [PMID: 39809179 PMCID: PMC11596353 DOI: 10.1097/md.0000000000040323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 10/11/2024] [Indexed: 01/16/2025] Open
Abstract
Lumbar disc herniation (LDH) is a common spinal disease. In recent years, an increasing number of observational studies have reported the impact of inflammatory factors on LDH. By conducting Mendelian randomization (MR) analysis on 91 inflammatory factors, it is possible to reveal their causal relationship with LDH, providing new insights for prevention and treatment strategies. In this study, a two-sample MR analysis was performed, using 91 inflammatory factors as exposure data, and LDH data from 2 different sources as outcome data. Subsequently, the most significant results from the inverse-variance weighted analysis were subjected to meta-analysis, with multiple corrections applied to the thresholds to ensure result accuracy. Finally, reverse causality MR analysis was conducted to validate the causal relationship between the identified positive inflammatory factors and LDH. Ninety-one cytokines were analyzed in relation to LDH using MR with data from the Finngen and UK Biobank databases. The inverse-variance weighted results from both analyses were then meta-analyzed, and multiple corrections were applied to the significance threshold of the meta-analysis results. Ultimately, only 1 cytokine, tumor necrosis factor-beta levels (genome-wide association study ID: GCST90274840), showed a significant association after the combined MR analysis and multiple corrections, with an odds ratio of 1.073 (95% confidence interval: 1.034-1.113, P = .0154). Furthermore, this positive cytokine did not display any reverse causality with LDH from either data source. Tumor necrosis factor-beta levels are a risk factor for LDH, potentially increasing the risk of developing the condition and exacerbating its symptoms.
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Affiliation(s)
- Jingze Yang
- Department of Orthopaedics, First People’s Hospital of Kunming City & Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Wanxian Xu
- Department of Orthopaedics, First People’s Hospital of Kunming City & Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Daolei Chen
- Department of Orthopaedics, First People’s Hospital of Kunming City & Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yichen Liu
- Kunming Medical University, Kunming, Yunnan, China
| | - Xingbo Hu
- Department of Orthopaedics, First People’s Hospital of Kunming City & Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
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9
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Serio G, Naserian S, Fraj SB, Uzan G, Gentile C. Regenerative and Anti-Senescence Potential of Extracts from Different Parts of Black Persimmon in an In Vitro Model of Vascular Endothelium. Foods 2024; 13:3366. [PMID: 39517149 PMCID: PMC11545823 DOI: 10.3390/foods13213366] [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: 09/18/2024] [Revised: 10/14/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
Antioxidants are essential for mitigating oxidative stress and maintaining vascular health. Endothelial colony-forming cells (ECFCs) are pivotal in endothelial regeneration and angiogenesis and serve as a model to study the diversity of endothelial cells across various organs. This study evaluated the effects of peel, pulp, and seed extracts from Diospyros digyna Jacq. fruit (black persimmon) on human cord blood-derived ECFCs (CB-ECFCs) to determine how the distinct antioxidant profiles of the fruit's different parts influence cellular functions. The extracts did not affect endothelial marker expression, cell proliferation, or nitric oxide production, indicating no cytotoxic or inflammatory effects. However, functional assays revealed that the seed extract significantly enhanced tube formation, increasing closed tubular networks by 1.5-fold. All extracts promoted cell migration, with the seed extract demonstrating the most substantial effect, surpassing even vascular endothelial growth factor (VEGF). Additionally, the seed extract exhibited the strongest reduction in cellular senescence, both before and after oxidative stress induction with H2O2. These findings underscore the potential of black persimmon extracts, especially from the seed, to enhance the regenerative capabilities of CB-ECFCs and reduce cellular senescence without affecting the normal endothelial phenotype. This positions them as promising candidates for developing endothelial cell therapies and advancing vascular regeneration.
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Affiliation(s)
- Graziella Serio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze, 90128 Palermo, Italy;
| | - Sina Naserian
- Institut National de la Santé Et de la Recherche Médicale (INSERM) UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France; (S.N.); (S.B.F.)
| | - Sawssen Ben Fraj
- Institut National de la Santé Et de la Recherche Médicale (INSERM) UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France; (S.N.); (S.B.F.)
| | - Georges Uzan
- Institut National de la Santé Et de la Recherche Médicale (INSERM) UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France; (S.N.); (S.B.F.)
| | - Carla Gentile
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze, 90128 Palermo, Italy;
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10
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Hashemi M, Mohandesi Khosroshahi E, Tanha M, Khoushab S, Bizhanpour A, Azizi F, Mohammadzadeh M, Matinahmadi A, Khazaei Koohpar Z, Asadi S, Taheri H, Khorrami R, Ramezani Farani M, Rashidi M, Rezaei M, Fattah E, Taheriazam A, Entezari M. Targeting autophagy can synergize the efficacy of immune checkpoint inhibitors against therapeutic resistance: New promising strategy to reinvigorate cancer therapy. Heliyon 2024; 10:e37376. [PMID: 39309904 PMCID: PMC11415696 DOI: 10.1016/j.heliyon.2024.e37376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 06/29/2024] [Accepted: 09/02/2024] [Indexed: 09/25/2024] Open
Abstract
Immune checkpoints are a set of inhibitory and stimulatory molecules/mechanisms that affect the activity of immune cells to maintain the existing balance between pro- and anti-inflammatory signaling pathways and avoid the progression of autoimmune disorders. Tumor cells can employ these checkpoints to evade immune system. The discovery and development of immune checkpoint inhibitors (ICIs) was thereby a milestone in the area of immuno-oncology. ICIs stimulate anti-tumor immune responses primarily by disrupting co-inhibitory signaling mechanisms and accelerate immune-mediated killing of tumor cells. Despite the beneficial effects of ICIs, they sometimes encounter some degrees of therapeutic resistance, and thereby do not effectively act against tumors. Among multiple combination therapies have been introduced to date, targeting autophagy, as a cellular degradative process to remove expired organelles and subcellular constituents, has represented with potential capacities to overcome ICI-related therapy resistance. It has experimentally been illuminated that autophagy induction blocks the immune checkpoint molecules when administered in conjugation with ICIs, suggesting that autophagy activation may restrict therapeutic challenges that ICIs have encountered with. However, the autophagy flux can also provoke the immune escape of tumors, which must be considered. Since the conventional FDA-approved ICIs have designed and developed to target programmed cell death receptor/ligand 1 (PD-1/PD-L1) as well as cytotoxic T lymphocyte-associated molecule 4 (CTLA-4) immune checkpoint molecules, we aim to review the effects of autophagy targeting in combination with anti-PD-1/PD-L1- and anti-CTLA-4-based ICIs on cancer therapeutic resistance and tumor immune evasion.
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Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahsa Tanha
- Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, United States
| | - Saloomeh Khoushab
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Anahita Bizhanpour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Farnaz Azizi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahsa Mohammadzadeh
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Arash Matinahmadi
- Department of Cellular and Molecular Biology, Nicolaus Copernicus University, Torun, Poland
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hengameh Taheri
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ramin Khorrami
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Marzieh Ramezani Farani
- Department of Biological Sciences and Bioengineering, Nano Bio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Michuhol-gu, Incheon, 22212, Republic of Korea
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mahdi Rezaei
- Health Research Center, Chamran Hospital, Tehran, Iran
| | - Eisa Fattah
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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11
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Jabermoradi S, Paridari P, Ramawad HA, Gharin P, Roshdi S, Toloui A, Yousefifard M. Stem Cell-Derived Exosomes as a Therapeutic Option for Spinal Cord Injuries; a Systematic Review and Meta-Analysis. ARCHIVES OF ACADEMIC EMERGENCY MEDICINE 2024; 13:e2. [PMID: 39318865 PMCID: PMC11417640 DOI: 10.22037/aaem.v12i1.2261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/26/2024]
Abstract
Introduction Exosomes function as cell signaling carriers and have drawn much attention to the cell-free treatments of regenerative medicine. This meta-analysis aimed to investigate the efficacy of mesenchymal stem cell-derived (MSC-derived) exosomes in animal models of spinal cord injuries (SCI). Method A comprehensive search was conducted in Medline, Embase, Scopus, and Web of Science to attain related articles published by January 31, 2023. The eligible keywords were correlated with the spinal cord injury and MSC-derived exosomes. The evaluated outcomes were locomotion, cavity size, cell apoptosis, inflammation, neuro-regeneration, and microglia activation. A standardized mean difference was calculated for each sample and a pooled effect size was reported. Results 65 papers fully met the inclusion criteria. Treatment with MSC-derived exosomes ultimately improved locomotion and shrunk cavity size (p<0.0001). The administration of MSC-derived exosomes enhanced the expression of beta-tubulin III, NF200, and GAP-43, and increased the number of NeuN-positive and Nissl-positive cells, while reducing the expression of glial fibrillary acidic protein (p<0.0001). The number of apoptotic cells in the treatment group decreased significantly (p<0.0001). Regarding the markers of microglia activation, MSC-derived exosomes increased the number of CD206- and CD68-positive cells (p=0.032 and p<0.0001, respectively). Additionally, MSC-derived exosome administration significantly increased the expression of the anti-inflammatory interleukin (IL)-10 and IL-4 (p<0.001 and p=0.001, respectively) and decreased the expression of the inflammatory IL-1b, IL-6, and TNF-a (p<0.0001). Conclusion MSC-derived exosome treatment resulted in a significantly improved locomotion of SCI animals through ameliorating neuroinflammation, reducing apoptosis, and inducing neuronal regrowth by facilitating a desirable microenvironment.
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Affiliation(s)
- Sajjad Jabermoradi
- Physiology Research Center, Iran University ofMedical Sciences, Tehran, Iran
- The first and second authors have identical contributions
| | - Parsa Paridari
- Physiology Research Center, Iran University ofMedical Sciences, Tehran, Iran
- The first and second authors have identical contributions
| | - Hamzah Adel Ramawad
- Department of EmergencyMedicine, NYC Health + Hospitals, Coney Island, New York, USA
| | - Pantea Gharin
- Physiology Research Center, Iran University ofMedical Sciences, Tehran, Iran
| | - Shayan Roshdi
- Physiology Research Center, Iran University ofMedical Sciences, Tehran, Iran
| | - Amirmohammad Toloui
- Physiology Research Center, Iran University ofMedical Sciences, Tehran, Iran
| | - Mahmoud Yousefifard
- Physiology Research Center, Iran University ofMedical Sciences, Tehran, Iran
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12
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Fathi E, Valipour B, Jafari S, Kazemi A, Montazersaheb S, Farahzadi R. The role of the hematopoietic stem/progenitor cells-derived extracellular vesicles in hematopoiesis. Heliyon 2024; 10:e35051. [PMID: 39157371 PMCID: PMC11327835 DOI: 10.1016/j.heliyon.2024.e35051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 07/20/2024] [Accepted: 07/22/2024] [Indexed: 08/20/2024] Open
Abstract
Hematopoietic stem cells (HSCs) are tightly regulated by specific microenvironments called niches to produce an appropriate number of mature blood cell types. Self-renewal and differentiation are two hallmarks of hematopoietic stem and progenitor cells, and their balance is critical for proper functioning of blood and immune cells throughout life. In addition to cell-intrinsic regulation, extrinsic cues within the bone marrow niche and systemic factors also affect the fate of HSCs. Despite this, many paracrine and endocrine factors that influence the function of hematopoietic cells remain unknown. In hematological malignancies, malignant cells remodel their niche into a permissive environment to enhance the survival of leukemic cells. These events are accompanied by loss of normal hematopoiesis. It is well known that extracellular vehicles (EVs) mediate intracellular interactions under physiological and pathological conditions. In other words, EVs transfer biological information to surrounding cells and contribute not only to physiological functions but also to the pathogenesis of some diseases, such as cancers. Therefore, a better understanding of cell-to-cell interactions may lead to identification of potential therapeutic targets. Recent reports have suggested that EVs are evolutionarily conserved constitutive mediators that regulate hematopoiesis. Here, we focus on the emerging roles of EVs in normal and pathological conditions, particularly in hematological malignancies. Owing to the high abundance of EVs in biological fluids, their potential use as biomarkers and therapeutic tools is discussed.
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Affiliation(s)
- Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Behnaz Valipour
- Department of Basic Sciences and Health, Sarab Faculty of Medical Sciences, Sarab, Iran
| | - Sevda Jafari
- Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abdolhassan Kazemi
- Medical Philosophy and History Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Parasitology and Mycology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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13
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Hu Y, Lou X, Zhang K, Pan L, Bai Y, Wang L, Wang M, Yan Y, Wan J, Yao X, Duan X, Ni C, Qin Z. Tumor necrosis factor receptor 2 promotes endothelial cell-mediated suppression of CD8+ T cells through tuning glycolysis in chemoresistance of breast cancer. J Transl Med 2024; 22:672. [PMID: 39033271 PMCID: PMC11265105 DOI: 10.1186/s12967-024-05472-5] [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: 03/20/2024] [Accepted: 07/03/2024] [Indexed: 07/23/2024] Open
Abstract
BACKGROUND T cells play a pivotal role in chemotherapy-triggered anti-tumor effects. Emerging evidence underscores the link between impaired anti-tumor immune responses and resistance to paclitaxel therapy in triple-negative breast cancer (TNBC). Tumor-related endothelial cells (ECs) have potential immunoregulatory activity. However, how ECs regulate T cell activity during TNBC chemotherapy remains poorly understood. METHODS Single-cell analysis of ECs in patients with TNBC receiving paclitaxel therapy was performed using an accessible single-cell RNA sequencing (scRNA-seq) dataset to identify key EC subtypes and their immune characteristics. An integrated analysis of a tumor-bearing mouse model, immunofluorescence, and a spatial transcriptome dataset revealed the spatial relationship between ECs, especially Tumor necrosis factor receptor (TNFR) 2+ ECs, and CD8+ T cells. RNA sequencing, CD8+ T cell proliferation assays, flow cytometry, and bioinformatic analyses were performed to explore the immunosuppressive function of TNFR2 in ECs. The downstream metabolic mechanism of TNFR2 was further investigated using RNA sequencing, cellular glycolysis assays, and western blotting. RESULTS In this study, we identified an immunoregulatory EC subtype, characterized by enhanced TNFR2 expression in non-responders. By a mouse model of TNBC, we revealed a dynamic reduction in the proportion of the CD8+ T cell-contacting tumor vessels that could co-localize spatially with CD8+ T cells during chemotherapy and an increased expression of TNFR2 by ECs. TNFR2 suppresses glycolytic activity in ECs by activating NF-κB signaling in vitro. Tuning endothelial glycolysis enhances programmed death-ligand (PD-L) 1-dependent inhibitory capacity, thereby inducing CD8+ T cell suppression. In addition, TNFR2+ ECs showed a greater spatial affinity for exhausted CD8+ T cells than for non-exhausted CD8+ T cells. TNFR2 blockade restores impaired anti-tumor immunity in vivo, leading to the loss of PD-L1 expression by ECs and enhancement of CD8+ T cell infiltration into the tumors. CONCLUSIONS These findings reveal the suppression of CD8+ T cells by ECs in chemoresistance and indicate the critical role of TNFR2 in driving the immunosuppressive capacity of ECs via tuning glycolysis. Targeting endothelial TNFR2 may serve as a potent strategy for treating TNBC with paclitaxel.
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Affiliation(s)
- Yu Hu
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xiaohan Lou
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Kaili Zhang
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Longze Pan
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Department of Medicine, Luohe Medical College, Luohe, 462000, China
| | - Yueyue Bai
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Shangqiu Hospital, The First Affiliated Hospital of Henan University of Chinese Medicine, Shangqiu, 476000, China
| | - Linlin Wang
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Ming Wang
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yan Yan
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Jiajia Wan
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xiaohan Yao
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xixi Duan
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Chen Ni
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Zhihai Qin
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Bahar R, Darabi S, Norouzian M, Roustaei S, Torkamani-Dordshaikh S, Hasanzadeh M, Vakili K, Fathi M, Khodagholi F, Kaveh N, Jahanbaz S, Moghaddam MH, Abbaszadeh HA, Aliaghaei A. Neuroprotective effect of human cord blood-derived extracellular vesicles by improved neuromuscular function and reduced gliosis in a rat model of Huntington's disease. J Chem Neuroanat 2024; 138:102419. [PMID: 38609056 DOI: 10.1016/j.jchemneu.2024.102419] [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: 12/15/2023] [Revised: 04/09/2024] [Accepted: 04/09/2024] [Indexed: 04/14/2024]
Abstract
Huntington's disease (HD) is a hereditary condition characterized by the gradual deterioration of nerve cells in the striatum. Recent scientific investigations have revealed the promising potential of Extracellular vesicles (EVs) as a therapy to mitigate inflammation and enhance motor function. This study aimed to examine the impact of administering EVs derived from human umbilical cord blood (HUCB) on the motor abilities and inflammation levels in a rat model of HD. After ultracentrifugation to prepare EVs from HUCB to determine the nature of the obtained contents, the expression of CD markers 81 and 9, the average size and also the morphology of its particles were investigated by DLS and Transmission electron microscopy (TEM). Then, in order to induce the HD model, 3-nitropropionic acid (3-NP) neurotoxin was injected intraperitoneal into the rats, after treatment by HUCB-EVs, rotarod, electromyogram (EMG) and the open field tests were performed on the rats. Finally, after rat sacrifice and the striatum was removed, Hematoxylin and eosin staining (H&E), stereology, immunohistochemistry, antioxidant tests, and western blot were performed. Our results showed that the contents of the HUCB-EVs express the CD9 and CD81 markers and have spherical shapes. In addition, the injection of HUCB-EVs improved motor and neuromuscular function, reduced gliosis, increased antioxidant activity and inflammatory factor, and partially prevented the decrease of neurons. The findings generally show that HUCB-EVs have neuroprotective effects and reduce neuroinflammation from the toxic effects of 3-NP, which can be beneficial for the recovery of HD.
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Affiliation(s)
- Reza Bahar
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahram Darabi
- Cellular and Molecular Research Center, Research Institute for Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohsen Norouzian
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Susan Roustaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shayesteh Torkamani-Dordshaikh
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maral Hasanzadeh
- Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Vakili
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Neda Kaveh
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shima Jahanbaz
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Meysam Hassani Moghaddam
- Department of Anatomical Sciences, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Hojjat-Allah Abbaszadeh
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Abbas Aliaghaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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15
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Li S, Liu W, Liu J, Yang Z, Zhang L, Nie F, Yang P, Guo H, Yang C. Low-dose TNF-α promotes angiogenesis of oral squamous cell carcinoma cells via TNFR2/Akt/mTOR axis. Oral Dis 2024; 30:3004-3017. [PMID: 37964399 DOI: 10.1111/odi.14802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 10/08/2023] [Accepted: 10/23/2023] [Indexed: 11/16/2023]
Abstract
OBJECTIVES To assess the role of TNF-α/TNFR2 axis on promoting angiogenesis in oral squamous cell carcinoma (OSCC) cells and uncover the underlying mechanisms. MATERIALS AND METHODS The expression of TNFR2 and CD31 in OSCC tissues was examined; gene expression relationship between TNF-α/TNFR2 and angiogenic markers or signaling molecules was analyzed; the expression of angiogenic markers, signaling molecules, TNFR1, and TNFR2 in TNF-α-stimulated OSCC cells treated with or without TNFR2 neutralizing antibody (TNFR2 Nab) were assessed; the concentration of angiogenic markers in the supernatant of OSCC cells was detected; conditioned mediums of OSCC cells treated with TNF-α or TNF-α + TNFR2 Nab were applied to human umbilical vein endothelial cells (HUVECs), followed by tube formation and cell migration assays. RESULTS Significantly elevated expression of TNFR2 and CD31 in OSCC tissues was observed. A positive gene expression correlation was identified between TNF-α/TNFR2 and angiogenic markers or signaling molecules. TNFR2 Nab inhibited the effects of TNF-α on enhancing the expression of angiogenic factors and TNFR2, the phosphorylation of the Akt/mTOR signaling pathway, HUVECs migration, and tube formation. CONCLUSIONS TNFR2 Nab counteracts the effect of TNF-α on OSCC cells through the TNFR2/Akt/mTOR axis, indicating that blocking TNFR2 might be a promising strategy against cancer.
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Affiliation(s)
- Shutong Li
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Wenchuan Liu
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Junze Liu
- School of Information and Computer Sciences, Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, California, USA
| | - Zongcheng Yang
- Division of Life Sciences and Medicine, Department of Stomatology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China
| | - Liguo Zhang
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Fujiao Nie
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Pishan Yang
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Hongmei Guo
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Chengzhe Yang
- Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Institute of Stomatology, Shandong University, Jinan, Shandong, China
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Moghassemi S, Dadashzadeh A, Sousa MJ, Vlieghe H, Yang J, León-Félix CM, Amorim CA. Extracellular vesicles in nanomedicine and regenerative medicine: A review over the last decade. Bioact Mater 2024; 36:126-156. [PMID: 38450204 PMCID: PMC10915394 DOI: 10.1016/j.bioactmat.2024.02.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 02/15/2024] [Accepted: 02/19/2024] [Indexed: 03/08/2024] Open
Abstract
Small extracellular vesicles (sEVs) are known to be secreted by a vast majority of cells. These sEVs, specifically exosomes, induce specific cell-to-cell interactions and can activate signaling pathways in recipient cells through fusion or interaction. These nanovesicles possess several desirable properties, making them ideal for regenerative medicine and nanomedicine applications. These properties include exceptional stability, biocompatibility, wide biodistribution, and minimal immunogenicity. However, the practical utilization of sEVs, particularly in clinical settings and at a large scale, is hindered by the expensive procedures required for their isolation, limited circulation lifetime, and suboptimal targeting capacity. Despite these challenges, sEVs have demonstrated a remarkable ability to accommodate various cargoes and have found extensive applications in the biomedical sciences. To overcome the limitations of sEVs and broaden their potential applications, researchers should strive to deepen their understanding of current isolation, loading, and characterization techniques. Additionally, acquiring fundamental knowledge about sEVs origins and employing state-of-the-art methodologies in nanomedicine and regenerative medicine can expand the sEVs research scope. This review provides a comprehensive overview of state-of-the-art exosome-based strategies in diverse nanomedicine domains, encompassing cancer therapy, immunotherapy, and biomarker applications. Furthermore, we emphasize the immense potential of exosomes in regenerative medicine.
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Affiliation(s)
- Saeid Moghassemi
- Pôle de Recherche en Physiopathologie de La Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Arezoo Dadashzadeh
- Pôle de Recherche en Physiopathologie de La Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Maria João Sousa
- Pôle de Recherche en Physiopathologie de La Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Hanne Vlieghe
- Pôle de Recherche en Physiopathologie de La Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Jie Yang
- Pôle de Recherche en Physiopathologie de La Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Cecibel María León-Félix
- Pôle de Recherche en Physiopathologie de La Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Christiani A. Amorim
- Pôle de Recherche en Physiopathologie de La Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
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Emami Meybodi SM, Moradi Moraddahande F, Dehghani Firoozabadi A. Immunogenic cell death mediated TLR3/4-activated MSCs in U87 GBM cell line. Heliyon 2024; 10:e29858. [PMID: 38698968 PMCID: PMC11064142 DOI: 10.1016/j.heliyon.2024.e29858] [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: 02/17/2024] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 05/05/2024] Open
Abstract
Background and aims Glioblastoma (GBM) is an aggressive primary brain cancer with no promising curative therapies. It has been indicated that MSCs can interact with the tumour microenvironment (TME) through the secretion of soluble mediators regulating intercellular signalling within the TME. TLRs are a multigene family of pattern recognition receptors with evolutionarily conserved regions and are widely expressed in immune and other body cells. MSCs by TLRs can recognize conserved molecular components (DAPMPs and PAPMPs) and activate signalling pathways, which regulate immune and inflammatory responses. MSCs may exert immunomodulatory functions through interaction with their expressed toll-like receptors (TLRs) and exert a protective effect against tumour antigens. As an emerging approach, we aimed to monitor the U87 cell line growth, migration and death markers following specific TLR3/4-primed-MSCs-CMs treatment. Methods and results We investigated the phenotypic and functional outcomes of primed-CMs and glioma cell line co-culture following short-term, low-dose TLR3/4 priming. The gene expression profile of target genes, including apoptotic markers and related genes, was analyzed by qRT-PCR. MicroRNA-Seq examined the miRNA expression patterns, and flow cytometry evaluated the cell viability and cycle stages. The results showed significant changes in apoptosis and likely necroptosis-related markers following TLR3/4-primed-MSCs-CMs exposure in the glioma cell line. Notably, we observed a considerable induction of selective pro-apoptotic markers and both the early and late stages of apoptosis in treated U87 cell lines. Additionally, the migration rate of glioma cells significantly decreased following MSCs-CM treatment. Conclusion Our findings confirmed that the exposure of TLR3/4-activated-MSCs-CMs with glioma tumour cells possibly changes the immunogenicity of the tumour microenvironment and induces immunogenic programmed cell death. Our results can support the idea that TLR3/4-primed-MSCs can lead to innate immune-mediated cell death and modify tumour cell biology in invasive and metastatic cancers.
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Affiliation(s)
- Seyed Mahdi Emami Meybodi
- Yazd Cardiovascular Research Center, Non-Communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Moradi Moraddahande
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Dehghani Firoozabadi
- Yazd Cardiovascular Research Center, Non-Communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Sun X, Wu L, Du L, Xu W, Han M. Targeting the organelle for radiosensitization in cancer radiotherapy. Asian J Pharm Sci 2024; 19:100903. [PMID: 38590796 PMCID: PMC10999375 DOI: 10.1016/j.ajps.2024.100903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/29/2023] [Accepted: 01/16/2024] [Indexed: 04/10/2024] Open
Abstract
Radiotherapy is a well-established cytotoxic therapy for local solid cancers, utilizing high-energy ionizing radiation to destroy cancer cells. However, this method has several limitations, including low radiation energy deposition, severe damage to surrounding normal cells, and high tumor resistance to radiation. Among various radiotherapy methods, boron neutron capture therapy (BNCT) has emerged as a principal approach to improve the therapeutic ratio of malignancies and reduce lethality to surrounding normal tissue, but it remains deficient in terms of insufficient boron accumulation as well as short retention time, which limits the curative effect. Recently, a series of radiosensitizers that can selectively accumulate in specific organelles of cancer cells have been developed to precisely target radiotherapy, thereby reducing side effects of normal tissue damage, overcoming radioresistance, and improving radiosensitivity. In this review, we mainly focus on the field of nanomedicine-based cancer radiotherapy and discuss the organelle-targeted radiosensitizers, specifically including nucleus, mitochondria, endoplasmic reticulum and lysosomes. Furthermore, the organelle-targeted boron carriers used in BNCT are particularly presented. Through demonstrating recent developments in organelle-targeted radiosensitization, we hope to provide insight into the design of organelle-targeted radiosensitizers for clinical cancer treatment.
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Affiliation(s)
- Xiaoyan Sun
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
| | - Linjie Wu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
| | - Lina Du
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Wenhong Xu
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Afliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Min Han
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Afliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310058, China
- Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou 310058, China
- Jinhua Institute of Zhejiang University, Jinhua 321299, China
- National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
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Zhou T, Qian H, Zhang D, Fang W, Yao M, Shi H, Chen T, Chai C, Guo B. PGRN inhibits CD8 +T cell recruitment and promotes breast cancer progression by up-regulating ICAM-1 on TAM. Cancer Immunol Immunother 2024; 73:76. [PMID: 38554213 PMCID: PMC10981592 DOI: 10.1007/s00262-024-03655-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: 08/16/2023] [Accepted: 02/11/2024] [Indexed: 04/01/2024]
Abstract
BACKGROUND Tumor microenvironment actually reduces antitumor effect against the immune attack by exclusion of CD8+T cells. Progranulin (PGRN) is a multifunctional growth factor with significant pathological effects in multiple tumors; however, its role in immunity evasion of breast cancer (BCa) is not completely understood. METHODS We depleted GRN (PGRN gene) genetically in mice or specifically in PY8119 murine BCa cell line, and mouse models of orthotopic or subcutaneous transplantation were used. Chimeric mice-deficient of PGRN (Grn-/-) in bone marrow (BM) compartment was also generated. Association of PGRN expression with chemokine production or BCa development was investigated by histological and immunological assays. RESULTS We found PGRN was involved in exhaustion of cytotoxic CD8+T cell in BCa with the increasing expressions of M2 markers and intercellular cell adhesion molecule-1 (ICAM-1) on macrophages. Specifically, ablation of PGRN in PY8119 cells reduced tumor burden, accompanied by the infiltrating of cytotoxic CD8+T cells into tumor nests. Moreover, our result revealed that blockade of PD-1 in PGRN-depleted tumors exhibited better antitumor effect in vivo and significantly decreased tumor burden. CONCLUSION These findings suggest that inhibition of PGRN may act as a potential immune-therapeutic strategy by recovering infiltration of CD8+T cell in BCa tissue and thereby enhancing the response to anti-PD-1 therapy.
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Affiliation(s)
- Ting Zhou
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Husun Qian
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Dian Zhang
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Wenli Fang
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - MengLi Yao
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - He Shi
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Tingmei Chen
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Chengsen Chai
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
| | - Bianqin Guo
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, People's Republic of China.
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20
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He Q, Yu T, Chen J, Liang J, Lin D, Yan K, Xie Z, Song Y, Chen Z. Enhancement of de novo lipogenesis by the IDH1 and IDH2-dependent reverse TCA cycle maintains the growth and angiogenic capacity of bone marrow-derived endothelial progenitor cells under hypoxia. Free Radic Biol Med 2024; 213:327-342. [PMID: 38281628 DOI: 10.1016/j.freeradbiomed.2024.01.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/17/2024] [Accepted: 01/18/2024] [Indexed: 01/30/2024]
Abstract
BACKGROUND Bone marrow-derived endothelial progenitor cells (EPCs) play a dynamic role in maintaining the structure and function of blood vessels. But how these cells maintain their growth and angiogenic capacity under bone marrow hypoxic niche is still unclear. This study aims to explore the mechanisms from a perspective of cellular metabolism. METHODS XFe96 Extracellular Flux Analyzer was used to analyze the metabolic status of EPCs. Gas Chromatography-Mass Spectrometry (GC-MS) was used to trace the carbon movement of 13C-labeled glucose and glutamine under 1 % O2 (hypoxia) and ∼20 % O2 (normoxia). Moreover, RNA interference, targeting isocitrate dehydrogenase-1 (IDH1) and IDH2, was used to inhibit the reverse tricarboxylic acid (TCA) cycle and analyze metabolic changes via isotope tracing as well as changes in cell growth and angiogenic potential under hypoxia. The therapeutic potential of EPCs under hypoxia was investigated in the ischemic hindlimb model. RESULTS Compared with normoxic cells, hypoxic cells showed increased glycolysis and decreased mitochondrial respiration. Isotope metabolic tracing revealed that under hypoxia, the forward TCA cycle was decreased and the reverse TCA cycle was enhanced, mediating the conversion of α-ketoglutarate (α-KG) into isocitrate/citrate, and de novo lipid synthesis was promoted. Downregulation of IDH1 or IDH2 under hypoxia suppressed the reverse TCA cycle, attenuated de novo lipid synthesis (DNL), elevated α-KG levels, and decreased the expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA), eventually inhibiting the growth and angiogenic capacity of EPCs. Importantly, the transplantation of hypoxia-cultured EPCs in a mouse model of limb ischemia promoted new blood vessel regeneration and blood supply recovery in the ischemic area better than the transplantation of normoxia-cultured EPCs. CONCLUSIONS Under hypoxia, the IDH1- and IDH2-mediated reverse TCA cycle promotes glutamine-derived de novo lipogenesis and stabilizes the expression of α-KG and HIF-1α, thereby enhancing the growth and angiogenic capacity of EPCs.
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Affiliation(s)
- Qiwei He
- Neurosurgery Center, Department of Neuro-oncological Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Tiantian Yu
- Metabolic Innovation Center, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, China
| | - Junxiong Chen
- Neurosurgery Center, Department of Neuro-oncological Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Jianli Liang
- Neurosurgery Center, Department of Neuro-oncological Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Dongni Lin
- Neurosurgery Center, Department of Neuro-oncological Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Kaihao Yan
- Neurosurgery Center, Department of Neuro-oncological Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Zijing Xie
- Neurosurgery Center, Department of Neuro-oncological Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Yuqi Song
- Neurosurgery Center, Department of Neuro-oncological Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Zhenzhou Chen
- Neurosurgery Center, Department of Neuro-oncological Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
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Hur JY, Lee S, Shin WR, Kim YH, Ahn JY. The emerging role of medical foods and therapeutic potential of medical food-derived exosomes. NANOSCALE ADVANCES 2023; 6:32-50. [PMID: 38125597 PMCID: PMC10729880 DOI: 10.1039/d3na00649b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 11/08/2023] [Indexed: 12/23/2023]
Abstract
Medical food is consumed for the purpose of improving specific nutritional requirements or disease conditions, such as inflammation, diabetes, and cancer. It involves partial or exclusive feeding for fulfilling unique nutritional requirements of patients and is different from medicine, consisting of basic nutrients, such as polyphenols, vitamins, sugars, proteins, lipids, and other functional ingredients to nourish the patients. Recently, studies on extracellular vesicles (exosomes) with therapeutic and drug carrier potential have been actively conducted. In addition, there have been attempts to utilize exosomes as medical food components. Consequently, the application of exosomes is expanding in different fields with increasing research being conducted on their stability and safety. Herein, we introduced the current trends of medical food and the potential utilization of exosomes in them. Moreover, we proposed Medi-Exo, a exosome-based medical food. Furthermore, we comprehensively elucidate various disease aspects between medical food-derived exosomes (Medi-Exo) and therapeutic natural bionanocomposites. This review highlights the therapeutic challenges regarding Medi-Exo and its potential health benefits.
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Affiliation(s)
- Jin-Young Hur
- Department of Microbiology, Chungbuk National University 1 Chungdae-Ro, Seowon-Gu Cheongju 28644 South Korea +82-43-264-9600 +82-43-261-2301 +82-43-261-3575
| | - SeonHyung Lee
- Department of Bioengineering, University of Pennsylvania 210 S 33rd St. Philadelphia PA 19104 USA
| | - Woo-Ri Shin
- Department of Microbiology, Chungbuk National University 1 Chungdae-Ro, Seowon-Gu Cheongju 28644 South Korea +82-43-264-9600 +82-43-261-2301 +82-43-261-3575
- Department of Bioengineering, University of Pennsylvania 210 S 33rd St. Philadelphia PA 19104 USA
| | - Yang-Hoon Kim
- Department of Microbiology, Chungbuk National University 1 Chungdae-Ro, Seowon-Gu Cheongju 28644 South Korea +82-43-264-9600 +82-43-261-2301 +82-43-261-3575
| | - Ji-Young Ahn
- Department of Microbiology, Chungbuk National University 1 Chungdae-Ro, Seowon-Gu Cheongju 28644 South Korea +82-43-264-9600 +82-43-261-2301 +82-43-261-3575
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22
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Hussen BM, Abdullah ST, Abdullah SR, Younis YM, Hidayat HJ, Rasul MF, Mohamadtahr S. Exosomal non-coding RNAs: Blueprint in colorectal cancer metastasis and therapeutic targets. Noncoding RNA Res 2023; 8:615-632. [PMID: 37767111 PMCID: PMC10520679 DOI: 10.1016/j.ncrna.2023.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is ranked as the world's third-most prevalent cancer, and metastatic CRC considerably increases cancer-related fatalities globally. A number of complex mechanisms that are strictly controlled at the molecular level are involved in metastasis, which is the primary reason for death in people with CRC. Recently, it has become clear that exosomes, which are small extracellular vesicles released by non-tumorous and tumorigenic cells, play a critical role as communication mediators among tumor microenvironment (TME). To facilitate communication between the TME and cancer cells, non-coding RNAs (ncRNAs) play a crucial role and are recognized as potent regulators of gene expression and cellular processes, such as metastasis and drug resistance. NcRNAs are now recognized as potent regulators of gene expression and many hallmarks of cancer, including metastasis. Exosomal ncRNAs, like miRNAs, circRNAs, and lncRNAs, have been demonstrated to influence a number of cellular mechanisms that contribute to CRC metastasis. However, the molecular mechanisms that link exosomal ncRNAs with CRC metastasis are not well understood. This review highlights the essential roles that exosomal ncRNAs play in the progression of CRC metastatic disease and explores the therapeutic choices that are open to patients who have CRC metastases. However, exosomal ncRNA treatment strategy development is still in its early phases; consequently, additional investigation is required to improve delivery methods and find novel therapeutic targets as well as confirm the effectiveness and safety of these therapies in preclinical and clinical contexts.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Biomedical Sciences, College of Science, Cihan University-Erbil, Erbil, Kurdistan Region, 44001, Iraq
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Sara Tharwat Abdullah
- Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Snur Rasool Abdullah
- Medical Laboratory Science, College of Health Sciences, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Yousif Mohammed Younis
- Department of Nursing, College of Nursing, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University-Erbil, Kurdistan Region, Iraq
| | - Mohammed Fatih Rasul
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Sayran Mohamadtahr
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
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Yusupova M, Ankawa R, Yosefzon Y, Meiri D, Bachelet I, Fuchs Y. Apoptotic dysregulation mediates stem cell competition and tissue regeneration. Nat Commun 2023; 14:7547. [PMID: 37985759 PMCID: PMC10662150 DOI: 10.1038/s41467-023-41684-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 09/14/2023] [Indexed: 11/22/2023] Open
Abstract
Since adult stem cells are responsible for replenishing tissues throughout life, it is vital to understand how failure to undergo apoptosis can dictate stem cell behavior both intrinsically and non-autonomously. Here, we report that depletion of pro-apoptotic Bax protein bestows hair follicle stem cells with the capacity to eliminate viable neighboring cells by sequestration of TNFα in their membrane. This in turn induces apoptosis in "loser" cells in a contact-dependent manner. Examining the underlying mechanism, we find that Bax loss-of-function competitive phenotype is mediated by the intrinsic activation of NFκB. Notably, winner stem cells differentially respond to TNFα, owing to their elevated expression of TNFR2. Finally, we report that in vivo depletion of Bax results in an increased stem cell pool, accelerating wound-repair and de novo hair follicle regeneration. Collectively, we establish a mechanism of mammalian cell competition, which can have broad therapeutic implications for tissue regeneration and tumorigenesis.
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Affiliation(s)
- Marianna Yusupova
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | - Roi Ankawa
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
- Augmanity, Rehovot, Israel
| | - Yahav Yosefzon
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | - David Meiri
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | | | - Yaron Fuchs
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
- Augmanity, Rehovot, Israel.
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Tang SQ, Xing T, Lyu ZS, Guo LP, Liang M, Li CY, Zhang YY, Wang Y, Xu LP, Zhang XH, Huang XJ, Kong Y. Repair of dysfunctional bone marrow endothelial cells alleviates aplastic anemia. SCIENCE CHINA. LIFE SCIENCES 2023; 66:2553-2570. [PMID: 37289327 DOI: 10.1007/s11427-022-2310-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 03/07/2023] [Indexed: 06/09/2023]
Abstract
Aplastic anemia (AA) is a life-threatening disease characterized by bone marrow (BM) failure and pancytopenia. As an important component of the BM microenvironment, endothelial cells (ECs) play a crucial role in supporting hematopoiesis and regulating immunity. However, whether impaired BM ECs are involved in the occurrence of AA and whether repairing BM ECs could improve hematopoiesis and immune status in AA remain unknown. In this study, a classical AA mouse model and VE-cadherin blocking antibody that could antagonize the function of ECs were used to validate the role of BM ECs in the occurrence of AA. N-acetyl-L-cysteine (NAC, a reactive oxygen species scavenger) or exogenous EC infusion was administered to AA mice. Furthermore, the frequency and functions of BM ECs from AA patients and healthy donors were evaluated. BM ECs from AA patients were treated with NAC in vitro, and then the functions of BM ECs were evaluated. We found that BM ECs were significantly decreased and damaged in AA mice. Hematopoietic failure and immune imbalance became more severe when the function of BM ECs was antagonized, whereas NAC or EC infusion improved hematopoietic and immunological status by repairing BM ECs in AA mice. Consistently, BM ECs in AA patients were decreased and dysfunctional. Furthermore, dysfunctional BM ECs in AA patients led to their impaired ability to support hematopoiesis and dysregulate T cell differentiation toward proinflammatory phenotypes, which could be repaired by NAC in vitro. The reactive oxygen species pathway was activated, and hematopoiesis- and immune-related signaling pathways were enriched in BM ECs of AA patients. In conclusion, our data indicate that dysfunctional BM ECs with impaired hematopoiesis-supporting and immunomodulatory abilities are involved in the occurrence of AA, suggesting that repairing dysfunctional BM ECs may be a potential therapeutic approach for AA patients.
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Affiliation(s)
- Shu-Qian Tang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Tong Xing
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Zhong-Shi Lyu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Li-Ping Guo
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Mi Liang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Chen-Yuan Li
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Yuan-Yuan Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Yuan Kong
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China.
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Ghafouri-Fard S, Shoorei H, Dong P, Poornajaf Y, Hussen BM, Taheri M, Akbari Dilmaghani N. Emerging functions and clinical applications of exosomal microRNAs in diseases. Noncoding RNA Res 2023; 8:350-362. [PMID: 37250456 PMCID: PMC10209650 DOI: 10.1016/j.ncrna.2023.05.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/07/2023] [Accepted: 05/07/2023] [Indexed: 05/31/2023] Open
Abstract
Exosomes are an important group of extracellular vesicles that transfer several kinds of biomolecules and facilitate cell-cell communication. The content of exosomes, particularly the amounts of microRNA (miRNAs) inside these vesicles, demonstrates a disease-specific pattern reflecting pathogenic processes and may be employed as a diagnostic and prognostic marker. miRNAs may enter recipient cells through exosomes and generate a RISC complex that can cause degradation of the target mRNAs or block translation of their corresponding proteins. Therefore, exosome-derived miRNAs constitute an important mechanism of gene regulation in recipient cells. The miRNA content of exosomes can be used as an important tool in the detection of diverse disorders, particularly cancers. This research field has an important situation in cancer diagnosis. In addition, exosomal microRNAs offer a great deal of promise in the treatment of human disorders. However, there are still certain challenges to be resolved. The most important challenges are as follow: the detection of exosomal miRNAs should be standardized, exosomal miRNAs-associated studies should be conducted in large number of clinical samples, and experiment settings and detection criteria should be consistent across different labs. The goal of this article is to present an overview of the effects of exosome-derived microRNAs on a variety of diseases, including gastrointestinal, pulmonary, neurological, and cardiovascular diseases, with a particular emphasis on malignancies.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Peixin Dong
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yadollah Poornajaf
- Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Bashdar Mahmud Hussen
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nader Akbari Dilmaghani
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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26
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Iqbal F, Johnston A, Wyse B, Rabani R, Mander P, Hoseini B, Wu J, Li RK, Gauthier-Fisher A, Szaraz P, Librach C. Combination human umbilical cord perivascular and endothelial colony forming cell therapy for ischemic cardiac injury. NPJ Regen Med 2023; 8:45. [PMID: 37626067 PMCID: PMC10457300 DOI: 10.1038/s41536-023-00321-3] [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: 10/26/2022] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Cell-based therapeutics are promising interventions to repair ischemic cardiac tissue. However, no single cell type has yet been found to be both specialized and versatile enough to heal the heart. The synergistic effects of two regenerative cell types including endothelial colony forming cells (ECFC) and first-trimester human umbilical cord perivascular cells (FTM HUCPVC) with endothelial cell and pericyte properties respectively, on angiogenic and regenerative properties were tested in a rat model of myocardial infarction (MI), in vitro tube formation and Matrigel plug assay. The combination of FTM HUCPVCs and ECFCs synergistically reduced fibrosis and cardiomyocyte apoptosis, while promoting favorable cardiac remodeling and contractility. These effects were in part mediated by ANGPT2, PDGF-β, and VEGF-C. PDGF-β signaling-dependent synergistic effects on angiogenesis were also observed in vitro and in vivo. FTM HUCPVCs and ECFCs represent a cell combination therapy for promoting and sustaining vascularization following ischemic cardiac injury.
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Affiliation(s)
- Farwah Iqbal
- Create Fertility Centre, Toronto, ON, Canada
- Virginia Tech Carillion School of Medicine, Roanoke, VA, USA
| | | | | | | | | | | | - Jun Wu
- Toronto General Research Institute (TGRI), University Health Network (UHN), Toronto, ON, Canada
| | - Ren-Ke Li
- Toronto General Research Institute (TGRI), University Health Network (UHN), Toronto, ON, Canada
| | | | | | - Clifford Librach
- Create Fertility Centre, Toronto, ON, Canada.
- Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada.
- Institute of Medical Sciences, Department of Physiology, University of Toronto, Toronto, ON, Canada.
- Department of Obstetrics and Gynecology, Women's College Hospital, Toronto, ON, Canada.
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27
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Salybekov AA, Hassanpour M, Kobayashi S, Asahara T. Therapeutic application of regeneration-associated cells: a novel source of regenerative medicine. Stem Cell Res Ther 2023; 14:191. [PMID: 37533070 PMCID: PMC10394824 DOI: 10.1186/s13287-023-03428-y] [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: 12/25/2022] [Accepted: 07/25/2023] [Indexed: 08/04/2023] Open
Abstract
Chronic diseases with comorbidities or associated risk factors may impair the function of regenerative cells and the regenerative microenvironment. Following this consideration, the vasculogenic conditioning culture (VCC) method was developed to boost the regenerative microenvironment to achieve regeneration-associated cells (RACs), which contain vasculogenic endothelial progenitor cells (EPCs) and anti-inflammatory/anti-immunity cells. Preclinical and clinical studies demonstrate that RAC transplantation is a safe and convenient cell population for promoting ischemic tissue recovery based on its strong vasculogenicity and functionality. The outputs of the scientific reports reviewed in the present study shed light on the fact that RAC transplantation is efficient in curing various diseases. Here, we compactly highlight the universal features of RACs and the latest progress in their translation toward clinics.
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Affiliation(s)
- Amankeldi A Salybekov
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Japan.
| | - Mehdi Hassanpour
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Shuzo Kobayashi
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Takayuki Asahara
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Japan
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28
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Ben Fraj S, Naserian S, Lorenzini B, Goulinet S, Mauduit P, Uzan G, Haouas H. Human Umbilical Cord Blood Endothelial Progenitor Cell-Derived Extracellular Vesicles Control Important Endothelial Cell Functions. Int J Mol Sci 2023; 24:9866. [PMID: 37373015 DOI: 10.3390/ijms24129866] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/02/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Circulating endothelial progenitor cells (EPCs) play a pivotal role in the repair of diseases in which angiogenesis is required. Although they are a potentially valuable cell therapy tool, their clinical use remains limited due to suboptimal storage conditions and, especially, long-term immune rejection. EPC-derived extracellular vesicles (EPC-EVs) may be an alternative to EPCs given their key role in cell-cell communication and expression of the same parental markers. Here, we investigated the regenerative effects of umbilical cord blood (CB) EPC-EVs on CB-EPCs in vitro. After amplification, EPCs were cultured in a medium containing an EVs-depleted serum (EV-free medium). Then, EVs were isolated from the conditioned medium with tangential flow filtration (TFF). The regenerative effects of EVs on cells were investigated by analyzing cell migration, wound healing, and tube formation. We also analyzed their effects on endothelial cell inflammation and Nitric Oxide (NO) production. We showed that adding different doses of EPC-EVs on EPCs does not alter the basal expression of the endothelial cell markers nor change their proliferative potential and NO production level. Furthermore, we demonstrated that EPC-EVs, when used at a higher dose than the physiological dose, create a mild inflammatory condition that activates EPCs and boosts their regenerative features. Our results reveal for the first time that EPC-EVs, when used at a high dose, enhance EPC regenerative functions without altering their endothelial identity.
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Affiliation(s)
- Sawssen Ben Fraj
- National Institute of Applied Sciences and Technology (INSAT), Carthage University, Tunis 1080, Tunisia
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France
- LR18ES40, Inflammation, Environment and Signalization Pathologies, Faculty of Medicine, University of Monastir, Monastir 5000, Tunisia
| | - Sina Naserian
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France
- CellMedEx, 94100 Saint Maur Des Fossés, France
| | | | - Sylvie Goulinet
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France
| | - Philippe Mauduit
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France
| | - Georges Uzan
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France
| | - Houda Haouas
- National Institute of Applied Sciences and Technology (INSAT), Carthage University, Tunis 1080, Tunisia
- LR18ES40, Inflammation, Environment and Signalization Pathologies, Faculty of Medicine, University of Monastir, Monastir 5000, Tunisia
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29
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W B Jr M, A S R, P M, F B. Cellular and Natural Viral Engineering in Cognition-Based Evolution. Commun Integr Biol 2023; 16:2196145. [PMID: 37153718 PMCID: PMC10155641 DOI: 10.1080/19420889.2023.2196145] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/23/2023] [Indexed: 05/10/2023] Open
Abstract
Neo-Darwinism conceptualizes evolution as the continuous succession of predominately random genetic variations disciplined by natural selection. In that frame, the primary interaction between cells and the virome is relegated to host-parasite dynamics governed by selective influences. Cognition-Based Evolution regards biological and evolutionary development as a reciprocating cognition-based informational interactome for the protection of self-referential cells. To sustain cellular homeorhesis, cognitive cells collaborate to assess the validity of ambiguous biological information. That collective interaction involves coordinate measurement, communication, and active deployment of resources as Natural Cellular Engineering. These coordinated activities drive multicellularity, biological development, and evolutionary change. The virome participates as the vital intercessory among the cellular domains to ensure their shared permanent perpetuation. The interactions between the virome and the cellular domains represent active virocellular cross-communications for the continual exchange of resources. Modular genetic transfers between viruses and cells carry bioactive potentials. Those exchanges are deployed as nonrandom flexible tools among the domains in their continuous confrontation with environmental stresses. This alternative framework fundamentally shifts our perspective on viral-cellular interactions, strengthening established principles of viral symbiogenesis. Pathogenesis can now be properly appraised as one expression of a range of outcomes between cells and viruses within a larger conceptual framework of Natural Viral Engineering as a co-engineering participant with cells. It is proposed that Natural Viral Engineering should be viewed as a co-existent facet of Natural Cellular Engineering within Cognition-Based Evolution.
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Affiliation(s)
- Miller W B Jr
- Banner Health Systems - Medicine, Paradise Valley, Arizona, AZ, USA
| | - Reber A S
- Department of Psychology, University of British Columbia, Vancouver, BC, Canada
| | - Marshall P
- Department of Engineering, Evolution 2.0, Oak Park, IL, USA
| | - Baluška F
- Institute of Cellular and Molecular Botany, University of Bonn, Bonn, Germany
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30
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Shi X, Seidle KA, Simms KJ, Dong F, Chilian WM, Zhang P. Endothelial progenitor cells in the host defense response. Pharmacol Ther 2023; 241:108315. [PMID: 36436689 PMCID: PMC9944665 DOI: 10.1016/j.pharmthera.2022.108315] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/15/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022]
Abstract
Extensive injury of endothelial cells in blood vasculature, especially in the microcirculatory system, frequently occurs in hosts suffering from sepsis and the accompanied systemic inflammation. Pathological factors, including toxic components derived from invading microbes, oxidative stress associated with tissue ischemia/reperfusion, and vessel active mediators generated during the inflammatory response, are known to play important roles in mediating endothelial injury. Collapse of microcirculation and tissue edema developed from the failure of endothelial barrier function in vital organ systems, including the lung, brain, and kidney, are detrimental, which often predict fatal outcomes. The host body possesses a substantial capacity for maintaining vascular homeostasis and repairing endothelial damage. Bone marrow and vascular wall niches house endothelial progenitor cells (EPCs). In response to septic challenges, EPCs in their niche environment are rapidly activated for proliferation and angiogenic differentiation. In the meantime, release of EPCs from their niches into the blood stream and homing of these vascular precursors to tissue sites of injury are markedly increased. The recruited EPCs actively participate in host defense against endothelial injury and repair of damage in blood vasculature via direct differentiation into endothelial cells for re-endothelialization as well as production of vessel active mediators to exert paracrine and autocrine effects on angiogenesis/vasculogenesis. In recent years, investigations on significance of EPCs in host defense and molecular signaling mechanisms underlying regulation of the EPC response have achieved substantial progress, which promotes exploration of vascular precursor cell-based approaches for effective prevention and treatment of sepsis-induced vascular injury as well as vital organ system failure.
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Affiliation(s)
- Xin Shi
- Department of Integrative Medical Sciences, Northeast Ohio Medical University College of Medicine, Rootstown, OH 44272, United States of America
| | - Kelly A Seidle
- Department of Integrative Medical Sciences, Northeast Ohio Medical University College of Medicine, Rootstown, OH 44272, United States of America
| | - Kevin J Simms
- Department of Integrative Medical Sciences, Northeast Ohio Medical University College of Medicine, Rootstown, OH 44272, United States of America
| | - Feng Dong
- Department of Integrative Medical Sciences, Northeast Ohio Medical University College of Medicine, Rootstown, OH 44272, United States of America
| | - William M Chilian
- Department of Integrative Medical Sciences, Northeast Ohio Medical University College of Medicine, Rootstown, OH 44272, United States of America
| | - Ping Zhang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University College of Medicine, Rootstown, OH 44272, United States of America.
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31
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Yan D, Cui D, Zhu Y, Chan CKW, Choi CHJ, Liu T, Lee NP, Law S, Tsao SW, Ma S, Cheung ALM. M6PR- and EphB4-Rich Exosomes Secreted by Serglycin-Overexpressing Esophageal Cancer Cells Promote Cancer Progression. Int J Biol Sci 2023; 19:625-640. [PMID: 36632458 PMCID: PMC9830512 DOI: 10.7150/ijbs.79875] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 12/13/2022] [Indexed: 01/04/2023] Open
Abstract
Accumulating evidence shows that exosomes participate in cancer progression. However, the functions of cancer cell exosome-transmitted proteins are rarely studied. Previously, we reported that serglycin (SRGN) overexpression promotes invasion and metastasis of esophageal squamous cell carcinoma (ESCC) cells. Here, we investigated the paracrine effects of exosomes from SRGN-overexpressing ESCC cells (SRGN Exo) on ESCC cell invasion and tumor angiogenesis, and used mass spectrometry to identify exosomal proteins involved. Cation-dependent mannose-6-phosphate receptor (M6PR) and ephrin type-B receptor 4 (EphB4) were pronouncedly upregulated in SRGN Exo. Upregulated exosomal M6PR mediated the pro-angiogenic effects of SRGN Exo both in vitro and in vivo, while augmented exosomal EphB4 mediated the pro-invasive effect of SRGN Exo on ESCC cells in vitro. In addition, in vitro studies showed that manipulation of M6PR expression affected the viability and migration of ESCC cells. Both M6PR and EphB4 expression levels were positively correlated with that of SRGN in the serum of patients with ESCC. High level of serum M6PR was associated with poor overall survival rates. Taken together, this study presents the first proof that exosomal M6PR and EphB4 play essential roles in tumor angiogenesis and malignancy, and that serum M6PR is a novel prognostic marker for ESCC patients.
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Affiliation(s)
- Dongdong Yan
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Di Cui
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Yun Zhu
- Center for Clinical Big Data and Analytics, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Cecilia Ka Wing Chan
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China
| | | | - Tengfei Liu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Nikki P.Y. Lee
- Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Simon Law
- Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Sai Wah Tsao
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Stephanie Ma
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.,The University of Hong Kong - Shenzhen Hospital, Shenzhen, China
| | - Annie Lai Man Cheung
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.,✉ Corresponding author: Annie L.M. Cheung, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China. Phone: 852-3917-9293; Fax: 852-2817-0857; E-mail:
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32
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Anbiyaiee A, Ramazii M, Bajestani SS, Meybodi SM, Keivan M, Khoshnam SE, Farzaneh M. The function of LncRNA-ATB in cancer. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023; 25:1-9. [PMID: 35597865 DOI: 10.1007/s12094-022-02848-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/25/2022] [Indexed: 01/07/2023]
Abstract
Cancer as a progressive and complex disease is caused by early chromosomal changes and stimulated cellular transformation. Previous studies reported that long non-coding RNAs (lncRNAs) play pivotal roles in the initiation, maintenance, and progression of cancer cells. LncRNA activated by TGF-β (ATB) has been shown to be dysregulated in different types of cancer. Aberrant expression of lncRNA-ATB plays an important role in the progression of diverse malignancies. High expression of LncRNA-ATB is associated with cancer cell growth, proliferation, metastasis, and EMT. LncRNA-ATB by targeting various signaling pathways and microRNAs (miRNAs) can trigger cancer pathogenesis. Therefore, lncRNA-ATB can be a novel target for cancer prediction and diagnosis. In this review, we will focus on the function of lncRNA-ATB in various types of human cancers.
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Affiliation(s)
- Amir Anbiyaiee
- Department of Surgery, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Ramazii
- Kerman University of Medical Sciences, University of Kerman, Kerman, Iran
| | | | | | - Mona Keivan
- Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Farzaneh
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Kartikasari AER, Cassar E, Razqan MAM, Szydzik C, Huertas CS, Mitchell A, Plebanski M. Elevation of circulating TNF receptor 2 in cancer: A systematic meta-analysis for its potential as a diagnostic cancer biomarker. Front Immunol 2022; 13:918254. [PMID: 36466914 PMCID: PMC9708892 DOI: 10.3389/fimmu.2022.918254] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 10/27/2022] [Indexed: 08/18/2023] Open
Abstract
High Tumor Necrosis Factor Receptor 2 (TNFR2) expression is characteristic of diverse malignant cells during tumorigenesis. The protein is also expressed by many immunosuppressive cells during cancer development, allowing cancer immune escape. A growing body of evidence further suggests a correlation between the circulating form of this protein and cancer development. Here we conducted a systematic meta-analysis of cancer studies published up until 1st October 2022, in which the circulating soluble TNFR2 (sTNFR2) concentrations in patients with cancers were recorded and their association with cancer risk was assessed. Of the 14,615 identified articles, 44 studies provided data on the correlation between cancer risk and the level of circulating sTNFR2. The pooled means comparison showed a consistently significant increase in the levels of sTNFR2 in diverse cancers when compared to healthy controls. These included colorectal cancer, ovarian cancer, breast cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer, hepatocarcinoma, and glioblastoma. In a random-effect meta-analysis, the cancer-specific odd ratios (OR) showed significant correlations between increased circulating sTNFR2 levels and the risk of colorectal cancer, non-Hodgkin's lymphoma, and hepatocarcinoma at 1.59 (95% CI:1.20-2.11), 1.98 (95% CI:1.49-2.64) and 4.32 (95% CI:2.25-8.31) respectively. The overall result showed an association between circulating levels of sTNFR2 and the risk of developing cancer at 1.76 (95% CI:1.53-2.02). This meta-analysis supports sTNFR2 as a potential diagnostic biomarker for cancer, albeit with different predictive strengths for different cancer types. This is consistent with a potential key role for TNFR2 involvement in cancer development.
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Affiliation(s)
- Apriliana E. R. Kartikasari
- Translational Immunology and Nanotechnology Theme, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT) University, Bundoora, VIC, Australia
| | - Emily Cassar
- Translational Immunology and Nanotechnology Theme, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT) University, Bundoora, VIC, Australia
| | - Mohammed A. M. Razqan
- Translational Immunology and Nanotechnology Theme, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT) University, Bundoora, VIC, Australia
- Integrated Photonics and Applications Centre (InPaC), School of Engineering, Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia
| | - Crispin Szydzik
- Integrated Photonics and Applications Centre (InPaC), School of Engineering, Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia
| | - Cesar S. Huertas
- Integrated Photonics and Applications Centre (InPaC), School of Engineering, Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia
| | - Arnan Mitchell
- Integrated Photonics and Applications Centre (InPaC), School of Engineering, Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia
| | - Magdalena Plebanski
- Translational Immunology and Nanotechnology Theme, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT) University, Bundoora, VIC, Australia
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34
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Nakashima N, Nakashima A, Nakashima K, Takano M. Olfactory marker protein contains a leucine-rich domain in the Ω-loop important for nuclear export. Mol Brain 2022; 15:89. [PMID: 36333725 PMCID: PMC9636679 DOI: 10.1186/s13041-022-00973-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/15/2022] [Indexed: 11/06/2022] Open
Abstract
Olfactory marker protein (OMP) is a cytosolic protein expressed in mature olfactory receptor neurons (ORNs). OMP modulates cAMP signalling and regulates olfactory sensation and axonal targeting. OMP is a small soluble protein, and passive diffusion between nucleus and cytoplasm is expected. However, OMP is mostly situated in the cytosol and is only sparsely detected in the nuclei of a subset of ORNs, hypothalamic neurons and heterologously OMP-expressing cultured cells. OMP can enter the nucleus in association with transcription factors. However, how OMP is retained in the cytosol at rest is unclear. Because OMP is proposed to affect cell differentiation, it is important to understand how OMP is distributed between cytoplasm and nucleus. To elucidate the structural profile of OMP, we applied several bioinformatics methods to a multiple sequence alignment (MSA) of OMP protein sequences and ranked the evolutionarily conserved residues. In addition to the previously reported cAMP-binding domain, we identified a leucine-rich domain in the Ω-loop of OMP. We introduced mutations into the leucine-rich region and heterologously expressed the mutant OMP in HEK293T cells. Mutations into alanine increased the nuclear distribution of OMP quantified by immunocytochemistry and western blotting. Therefore, we concluded that OMP contains a leucine-rich domain important for nuclear transport.
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Affiliation(s)
- Noriyuki Nakashima
- grid.410781.b0000 0001 0706 0776Department of Physiology, Kurume University School of Medicine, 67 Asahi-Machi, Kurume-Shi, Fukuoka 830-0011 Japan
| | - Akiko Nakashima
- grid.410781.b0000 0001 0706 0776Department of Physiology, Kurume University School of Medicine, 67 Asahi-Machi, Kurume-Shi, Fukuoka 830-0011 Japan
| | - Kie Nakashima
- grid.31432.370000 0001 1092 3077Department of Physiology and Cell Biology, Kobe University School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017 Japan
| | - Makoto Takano
- grid.410781.b0000 0001 0706 0776Department of Physiology, Kurume University School of Medicine, 67 Asahi-Machi, Kurume-Shi, Fukuoka 830-0011 Japan
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35
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Ebrahimi N, Faghihkhorasani F, Fakhr SS, Moghaddam PR, Yazdani E, Kheradmand Z, Rezaei-Tazangi F, Adelian S, Mobarak H, Hamblin MR, Aref AR. Tumor-derived exosomal non-coding RNAs as diagnostic biomarkers in cancer. Cell Mol Life Sci 2022; 79:572. [PMID: 36308630 PMCID: PMC11802992 DOI: 10.1007/s00018-022-04552-3] [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: 05/16/2022] [Revised: 09/02/2022] [Accepted: 09/04/2022] [Indexed: 12/24/2022]
Abstract
Almost all clinical oncologists agree that the discovery of reliable, accessible, and non-invasive biomarkers is necessary to decrease cancer mortality. It is possible to employ reliable biomarkers to diagnose cancer in the early stages, predict the patient prognosis, follow up the response to treatment, and estimate the risk of disease recurrence with high sensitivity and specificity. Extracellular vesicles (EVs), especially exosomes, have been the focus of translational research to develop such biomarkers over the past decade. The abundance and distribution of exosomes in bodily fluids, including serum, saliva, and urine, as well as their ability to transport various biomolecules (nucleic acids, proteins, and lipids) derived from their parent cells, make exosomes reliable, accessible, and potent biomarkers for diagnosis and follow-up of solid and hematopoietic tumors. In addition, exosomes play a vital role in various cellular processes, including tumor progression, by participating in intercellular communication. Although these advantages underline the high potential of tumor-derived exosomes as diagnostic biomarkers, the lack of standardized effective methods for their isolation, identification, and precise characterization makes their application challenging in clinical settings. We discuss the importance of non-coding RNAs (ncRNAs) in cellular processes, and the role of tumor-derived exosomes containing ncRNAs as potential biomarkers in several types of cancer. In addition, the advantages and challenges of these studies for translation into clinical applications are covered.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | | | - Siavash Seifollahy Fakhr
- Division of Biotechnology, Faculty of Applied Ecology, Agricultural Sciences and Biotechnology, Campus, Hamar, Norway
| | - Parichehr Roozbahani Moghaddam
- Department of Molecular Genetics, Faculty of Science, Tonekabon Branch, Islamic Azad University, Tehran, Mazandaran, Iran
| | - Elnaz Yazdani
- Department of Biology, Faculty of Science, University of Isfahan, Isfahan, Iran
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Zahra Kheradmand
- Department of Agriculture, Islamic Azad University Maragheh Branch, Maragheh, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Samaneh Adelian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Halimeh Mobarak
- Clinical Pathologist, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
- Translational Medicine Group, Xsphera Biosciences, 6 Tide Street, Boston, MA, 02210, USA.
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Davitt E, Davitt C, Mazer MB, Areti SS, Hotchkiss RS, Remy KE. COVID-19 disease and immune dysregulation. Best Pract Res Clin Haematol 2022; 35:101401. [PMID: 36494149 PMCID: PMC9568269 DOI: 10.1016/j.beha.2022.101401] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/11/2022] [Indexed: 12/15/2022]
Abstract
The SARS-CoV-2 virus has complex and divergent immune alterations in differing hosts and over disease evolution. Much of the nuanced COVID-19 disease immune dysregulation was originally dominated by innate cytokine changes, which has since been replaced with a more complex picture of innate and adaptive changes characterized by simultaneous hyperinflammatory and immunosuppressive phenomena in effector cells. These intricacies are summarized in this review as well as potential relevance from acute infection to a multisystem inflammatory syndrome commonly seen in children. Additional consideration is made for the influence of variant to variant host cellular changes and the impact of potential vaccination upon these phenotypes. Finally, therapeutic benefit for immune alterations are discussed.
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Affiliation(s)
- Ethan Davitt
- School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Colin Davitt
- Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Monty B. Mazer
- Department of Pediatrics, University Hospitals of Cleveland, Cleveland, OH, USA,School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Sathya S. Areti
- Department of Internal Medicine, University Hospitals of Cleveland, Cleveland, OH, USA
| | - Richard S. Hotchkiss
- School of Medicine, Washington University in St. Louis, St. Louis, MO, USA,Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Kenneth E. Remy
- Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA,Department of Pediatrics, University Hospitals of Cleveland, Cleveland, OH, USA,Department of Internal Medicine, University Hospitals of Cleveland, Cleveland, OH, USA,School of Medicine, Case Western Reserve University, Cleveland, OH, USA,Corresponding author.Department of Internal Medicine, Case Western Reserve University, School of Medicine, University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH, USA
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Guo F, Ren Z, Liu D, Wang L, Hou X, Chen W. The Inhibitory Effect of Regulatory T Cells on the Intimal Hyperplasia of Tissue-Engineered Blood Vessels in Diabetic Pigs. Front Bioeng Biotechnol 2022; 10:929867. [PMID: 35957644 PMCID: PMC9360552 DOI: 10.3389/fbioe.2022.929867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/17/2022] [Indexed: 11/13/2022] Open
Abstract
Severe inflammatory response and functional impairment of endothelial progenitor cells (EPCs) often lead to the implantation failure of EPC-captured tissue-engineered blood vessels (TEBVs) in diabetes. Regulatory T cells (Treg cells) are the most important inhibitory immune cells, but their effects in angiogenesis remain undefined, and the differences in the microenvironment may be an important reason. Here, we constructed a TEBV coated with an anti-CD34 antibody-functionalized heparin-collagen multilayer (anti-CD34 antibody-modified TEBV) using layer-by-layer self-assembly. Then, TEBVs were implanted into diabetic pigs. All TEBVs remained unobstructed 60 days after implantation, although varying degrees of intimal hyperplasia were detectable. Severe intimal hyperplasia was observed in the control group and peripheral injection of Treg cells group. Intravenous injection of Treg cells significantly inhibited intimal hyperplasia, inflammation, and cell apoptosis. Moreover, intravenous injection increased the proportion of circulating EPCs, while peripheral injection did not have these effects and reduced microvessel density around the TEBV. Interestingly, many Nestin+ cells could be detected in TEBVs, most of which were fusiform, showing the characteristics of smooth-muscle cells. Treg cell intravenous transplantation markedly reduced the number of Nestin+ cells in the TEBV. In conclusion, Treg cells inhibited the intimal hyperplasia of TEBVs in diabetic pigs by promoting EPC mobilization, anti-inflammatory action, and cellular protection.
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Affiliation(s)
- Fengjie Guo
- Outpatient Department, The 8th Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhipeng Ren
- Department of Thoracic Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Dongxu Liu
- Department of Pathology, The 8th Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Linghui Wang
- Department of Thoracic Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiaobin Hou
- Department of Thoracic Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- *Correspondence: Wen Chen, ; Xiaobin Hou,
| | - Wen Chen
- Department of Pathology, The 8th Medical Center, Chinese PLA General Hospital, Beijing, China
- *Correspondence: Wen Chen, ; Xiaobin Hou,
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Kraus X, van de Flierdt E, Renzelmann J, Thoms S, Witt M, Scheper T, Blume C. Peripheral blood derived endothelial colony forming cells as suitable cell source for pre-endothelialization of arterial vascular grafts under dynamic flow conditions. Microvasc Res 2022; 143:104402. [PMID: 35753506 DOI: 10.1016/j.mvr.2022.104402] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/11/2022] [Accepted: 06/14/2022] [Indexed: 11/26/2022]
Abstract
In regenerative medicine, autologous peripheral blood derived endothelial colony forming cells (PB-derived ECFC) represent a promising source of endothelial cells (EC) for pre-endothelialization of arterial tissue engineered vascular grafts (TEVG) since they are readily attainable, can easily be isolated and possess a high proliferation potential. The aim of this study was to compare the phenotype of PB-derived ECFC with arterial and venous model cells such as human aortic endothelial cells (HAEC) and human umbilical vein endothelial cells (HUVEC) under dynamic cell culture conditions to find a suitable cell source of EC for pre-endothelialization. In this study PB-derived ECFC were cultivated over 24 h under a high pulsatile shear stress (20 dyn/cm2, 1 Hz) and subsequently analyzed. ECFC oriented and elongated in the direction of flow and expressed similar anti-thrombotic and endothelial differentiation markers compared to HAEC. There were significant differences observable in gene expression levels of CD31, CD34 and NOTCH4 between ECFC and HUVEC. These results therefore suggest an arterial phenotype for PB-derived ECFC both under static and flow conditions, and this was supported by NOTCH4 protein expression profiles. ECFC also significantly up-regulated gene expression levels of anti-thrombotic genes such as krueppel-like factor 2, endothelial nitric oxide synthase 3 and thrombomodulin under shear stress cultivation as compared to static conditions. Dynamically cultured PB-derived ECFC therefore may be a promising cell source for pre-endothelialization of arterial TEVGs.
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Affiliation(s)
- Xenia Kraus
- Leibniz University Hannover, Institute of Technical Chemistry, Callinstr. 5, D-30167 Hannover, Germany; Lower Saxony Centre for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany.
| | - Edda van de Flierdt
- Leibniz University Hannover, Institute of Technical Chemistry, Callinstr. 5, D-30167 Hannover, Germany; Lower Saxony Centre for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany
| | - Jannis Renzelmann
- Leibniz University Hannover, Institute of Technical Chemistry, Callinstr. 5, D-30167 Hannover, Germany; Lower Saxony Centre for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany
| | - Stefanie Thoms
- Leibniz University Hannover, Institute of Technical Chemistry, Callinstr. 5, D-30167 Hannover, Germany; Lower Saxony Centre for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany
| | - Martin Witt
- Leibniz University Hannover, Institute of Technical Chemistry, Callinstr. 5, D-30167 Hannover, Germany; Lower Saxony Centre for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany
| | - Thomas Scheper
- Leibniz University Hannover, Institute of Technical Chemistry, Callinstr. 5, D-30167 Hannover, Germany; Lower Saxony Centre for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany
| | - Cornelia Blume
- Leibniz University Hannover, Institute of Technical Chemistry, Callinstr. 5, D-30167 Hannover, Germany; Lower Saxony Centre for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany
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Signaling pathway(s) of TNFR2 required for the immunoregulatory effect of CD4 +Foxp3 + regulatory T cells. Int Immunopharmacol 2022; 108:108823. [PMID: 35623290 DOI: 10.1016/j.intimp.2022.108823] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/26/2022] [Accepted: 04/29/2022] [Indexed: 11/23/2022]
Abstract
CD4+Foxp3+ regulatory T cells (Tregs), a subpopulation of CD4+ T cells, are engaged in maintaining the periphery tolerance and preventing autoimmunity. Recent studies showed that tumor necrosis factor receptor 2 (TNFR2) is preferentially expressed by Tregs and the expression of this receptor identifies the maximally suppressive Tregs. That is, TNFR2 is a liable phenotypic and functional surface marker of Tregs. Moreover, TNF activates and expands Tregs through TNFR2. However, it is very interesting which signaling pathway(s) of TNFR2 is required for the inhibitory effect of Tregs. Compelling evidence shows three TNFR2 signaling pathways in Tregs, including NF-κB, MAPK and PI3K-Akt pathways. Here, we summarize and discuss the latest progress in the studies on the downstream signaling pathways of TNF-TNFR2 for controlling Treg homeostasis, differentiation and proliferation.
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Cortesi M, Giordano E. Non-destructive monitoring of 3D cell cultures: new technologies and applications. PeerJ 2022; 10:e13338. [PMID: 35582620 PMCID: PMC9107788 DOI: 10.7717/peerj.13338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/05/2022] [Indexed: 01/13/2023] Open
Abstract
3D cell cultures are becoming the new standard for cell-based in vitro research, due to their higher transferrability toward in vivo biology. The lack of established techniques for the non-destructive quantification of relevant variables, however, constitutes a major barrier to the adoption of these technologies, as it increases the resources needed for the experimentation and reduces its accuracy. In this review, we aim at addressing this limitation by providing an overview of different non-destructive approaches for the evaluation of biological features commonly quantified in a number of studies and applications. In this regard, we will cover cell viability, gene expression, population distribution, cell morphology and interactions between the cells and the environment. This analysis is expected to promote the use of the showcased technologies, together with the further development of these and other monitoring methods for 3D cell cultures. Overall, an extensive technology shift is required, in order for monolayer cultures to be superseded, but the potential benefit derived from an increased accuracy of in vitro studies, justifies the effort and the investment.
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Affiliation(s)
- Marilisa Cortesi
- Department of Electrical, Electronic and Information Engineering ”G.Marconi”, University of Bologna, Bologna, Italy
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, Australia
| | - Emanuele Giordano
- Department of Electrical, Electronic and Information Engineering ”G.Marconi”, University of Bologna, Bologna, Italy
- BioEngLab, Health Science and Technology, Interdepartmental Center for Industrial Research (HST-CIRI), University of Bologna, Ozzano Emilia, Italy
- Advanced Research Center on Electronic Systems (ARCES), University of Bologna, Bologna, Italy
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Baghban N, Khoradmehr A, Nabipour I, Tamadon A, Ullah M. The potential of marine-based gold nanomaterials in cancer therapy: a mini-review. GOLD BULLETIN 2022; 55:53-63. [DOI: 10.1007/s13404-021-00304-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/07/2021] [Indexed: 01/21/2025]
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Bai J, Ding B, Li H. Targeting TNFR2 in Cancer: All Roads Lead to Rome. Front Immunol 2022; 13:844931. [PMID: 35251045 PMCID: PMC8891135 DOI: 10.3389/fimmu.2022.844931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 01/25/2022] [Indexed: 12/14/2022] Open
Abstract
TNF receptor 2 (TNFR2) has become one of the best potential immune checkpoints that might be targeted, mainly because of its vital role in tumor microenvironments (TMEs). Overexpression of TNFR2 in some tumor cells and essential function in immunosuppressive cells, especially regulatory T cells (Tregs), makes blocking TNFR2 an excellent strategy in cancer treatment; however, there is evidence showing that activating TNFR2 can also inhibit tumor progression in vivo. In this review, we will discuss drugs that block and activate TNFR2 under clinical trials or preclinical developments up till now. Meanwhile, we summarize and explore the possible mechanisms related to them.
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Affiliation(s)
- Jingchao Bai
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Bowen Ding
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Hui Li
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
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Effect of Photo-Mediated Ultrasound Therapy on Nitric Oxide and Prostacyclin from Endothelial Cells. APPLIED SCIENCES-BASEL 2022; 12. [PMID: 35983461 PMCID: PMC9384428 DOI: 10.3390/app12052617] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Several studies have investigated the effect of photo-mediated ultrasound therapy (PUT) on the treatment of neovascularization. This study explores the impact of PUT on the release of the vasoactive agents nitric oxide (NO) and prostacyclin (PGI2) from the endothelial cells in an in vitro blood vessel model. In this study, an in vitro vessel model containing RF/6A chorioretinal endothelial cells was used. The vessels were treated with ultrasound-only (0.5, 1.0, 1.5 and 2.0 MPa peak negative pressure at 0.5 MHz with 10% duty cycle), laser-only (5, 10, 15 and 20 mJ/cm2 at 532 nm with a pulse width of 5 ns), and synchronized laser and ultrasound (PUT) treatments. Passive cavitation detection was used to determine the cavitation activities during treatment. The levels of NO and PGI2 generally increased when the applied ultrasound pressure and laser fluence were low. The increases in NO and PGI2 levels were significantly reduced by 37.2% and 42.7%, respectively, from 0.5 to 1.5 MPa when only ultrasound was applied. The increase in NO was significantly reduced by 89.5% from 5 to 20 mJ/cm2, when only the laser was used. In the PUT group, for 10 mJ/cm2 laser fluence, the release of NO decreased by 76.8% from 0.1 to 1 MPa ultrasound pressure. For 0.5 MPa ultrasound pressure in the PUT group, the release of PGI2 started to decrease by 144% from 15 to 20 mJ/cm2 laser fluence. The decreases in NO and PGI2 levels coincided with the increased cavitation activities in each group. In conclusion, PUT can induce a significant reduction in the release of NO and PGI2 in comparison with ultrasound-only and laser-only treatments.
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Mestrallet G, Carosella ED, Martin MT, Rouas-Freiss N, Fortunel NO, LeMaoult J. Immunosuppressive Properties of Epidermal Keratinocytes Differ According to Their Immaturity Status. Front Immunol 2022; 13:786859. [PMID: 35222373 PMCID: PMC8878806 DOI: 10.3389/fimmu.2022.786859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 01/14/2022] [Indexed: 12/04/2022] Open
Abstract
Preservation of a functional keratinocyte stem cell pool is essential to ensure the long-term maintenance of epidermis integrity, through continuous physiological renewal and regeneration in case of injury. Protecting stem cells from inflammation and immune reactions is thus a critical issue that needs to be explored. Here, we show that the immature CD49fhigh precursor cell fraction from interfollicular epidermis keratinocytes, comprising stem cells and progenitors, is able to inhibit CD4+ T-cell proliferation. Of note, both the stem cell-enriched CD49fhigh/EGFRlow subpopulation and the less immature CD49fhigh/EGFRhigh progenitors ensure this effect. Moreover, we show that HLA-G and PD-L1 immune checkpoints are overexpressed in CD49fhigh precursors, as compared to CD49flow differentiated keratinocytes. This potency may limit immune reactions against immature precursors including stem cells, and protect them from exacerbated inflammation. Further exploring this correlation between immuno-modulation and immaturity may open perspectives in allogenic cell therapies.
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Affiliation(s)
- Guillaume Mestrallet
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Evry, France
- Université Paris-Saclay, Saint-Aubin, France
| | - Edgardo D. Carosella
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, Paris, France
- U976 HIPI Unit, IRSL, Université Paris, Paris, France
| | - Michele T. Martin
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Evry, France
- Université Paris-Saclay, Saint-Aubin, France
| | - Nathalie Rouas-Freiss
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, Paris, France
- U976 HIPI Unit, IRSL, Université Paris, Paris, France
| | - Nicolas O. Fortunel
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Evry, France
- Université Paris-Saclay, Saint-Aubin, France
- *Correspondence: Joel LeMaoult, ; Nicolas O. Fortunel,
| | - Joel LeMaoult
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, Paris, France
- U976 HIPI Unit, IRSL, Université Paris, Paris, France
- *Correspondence: Joel LeMaoult, ; Nicolas O. Fortunel,
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Kang X, Jiao T, Wang H, Pernow J, Wirdefeldt K. Mendelian randomization study on the causal effects of tumor necrosis factor inhibition on coronary artery disease and ischemic stroke among the general population. EBioMedicine 2022; 76:103824. [PMID: 35074627 PMCID: PMC8792065 DOI: 10.1016/j.ebiom.2022.103824] [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: 11/15/2021] [Revised: 01/07/2022] [Accepted: 01/07/2022] [Indexed: 12/12/2022] Open
Abstract
Background Tumor necrosis factor (TNF) is a potent inflammatory cytokine that has been causally associated with coronary artery disease (CAD) and ischemic stroke (IS), implying opportunities for disease prevention by anti-TNF therapeutics. Methods Leveraging summary statistics of several genome-wide association studies (GWAS), we assessed the repurposing potential of TNF inhibitors for CAD and IS using drug-target Mendelian randomization (MR) design. Pharmacologic blockade of the pro-inflammatory TNF signalling mediated by TNF receptor 1 (TNFR1) was instrumented by four validated variants. Causal effects of TNF/TNFR1 blockade on CAD (Ncase/control upto 122,733/424,528) and IS (Ncase/control upto 60,341/454,450) were then estimated via various MR estimators using circulating C-reactive protein (CRP; NGWAS=204,402) as downstream biomarker to reflect treatment effect. Associations of a functional variant, rs1800693, with CRP, CAD and IS were also examined. Findings No protective effect of TNF/TNFR1 inhibition on CAD or IS was observed. For every 10% decrease of circulating CRP achieved by TNF/TNFR1 blockade, odds ratio was 0.98 (95% confidence interval [CI]: 0.60-1.60) for CAD and 0.77 (95% CI: 0.36-1.63) for IS. Findings remained null in all supplement analyses. Interpretation Our findings do not support TNFR1 as a promising target for CAD or IS prevention among the general population. Future research is warranted to investigate whether the detrimental effect of circulating TNF on CAD and IS might be counteracted by modulating other relevant drug targets. Funding No.
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Affiliation(s)
- Xiaoying Kang
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
| | - Tong Jiao
- Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Haiyang Wang
- Department of Vascular Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - John Pernow
- Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
| | - Karin Wirdefeldt
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
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Zhang Q, Wan XX, Hu XM, Zhao WJ, Ban XX, Huang YX, Yan WT, Xiong K. Targeting Programmed Cell Death to Improve Stem Cell Therapy: Implications for Treating Diabetes and Diabetes-Related Diseases. Front Cell Dev Biol 2021; 9:809656. [PMID: 34977045 PMCID: PMC8717932 DOI: 10.3389/fcell.2021.809656] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/06/2021] [Indexed: 12/14/2022] Open
Abstract
Stem cell therapies have shown promising therapeutic effects in restoring damaged tissue and promoting functional repair in a wide range of human diseases. Generations of insulin-producing cells and pancreatic progenitors from stem cells are potential therapeutic methods for treating diabetes and diabetes-related diseases. However, accumulated evidence has demonstrated that multiple types of programmed cell death (PCD) existed in stem cells post-transplantation and compromise their therapeutic efficiency, including apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Understanding the molecular mechanisms in PCD during stem cell transplantation and targeting cell death signaling pathways are vital to successful stem cell therapies. In this review, we highlight the research advances in PCD mechanisms that guide the development of multiple strategies to prevent the loss of stem cells and discuss promising implications for improving stem cell therapy in diabetes and diabetes-related diseases.
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Affiliation(s)
- Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Xin-xing Wan
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Xi-min Hu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Wen-juan Zhao
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Xiao-xia Ban
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Yan-xia Huang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Wei-tao Yan
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
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Lachaux J, Hwang G, Arouche N, Naserian S, Harouri A, Lotito V, Casari C, Lok T, Menager JB, Issard J, Guihaire J, Denis CV, Lenting PJ, Barakat AI, Uzan G, Mercier O, Haghiri-Gosnet AM. A compact integrated microfluidic oxygenator with high gas exchange efficiency and compatibility for long-lasting endothelialization. LAB ON A CHIP 2021; 21:4791-4804. [PMID: 34309615 DOI: 10.1039/d1lc00356a] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
We have developed and tested a novel microfluidic device for blood oxygenation, which exhibits a large surface area of gas exchange and can support long-term sustainable endothelialization of blood microcapillaries, enhancing its hemocompatibility for clinical applications. The architecture of the parallel stacking of the trilayers is based on a central injection for blood and a lateral injection/output for gas which allows significant reduction in shear stress, promoting sustainable endothelialization since cells can be maintained viable for up to 2 weeks after initial seeding in the blood microchannel network. The circular design of curved blood capillaries allows covering a maximal surface area at 4 inch wafer scale, producing high oxygen uptake and carbon dioxide release in each single unit. Since the conventional bonding process based on oxygen plasma cannot be used for surface areas larger than several cm2, a new "wet bonding" process based on soft microprinting has been developed and patented. Using this new protocol, each 4 inch trilayer unit can be sealed without a collapsed membrane even at reduced 15 μm thickness and can support a high blood flow rate. The height of the blood channels has been optimized to reduce pressure drop and enhance gas exchange at a high volumetric blood flow rate up to 15 ml min-1. The simplicity of connecting different units in the stacked architecture is demonstrated for 3- or 5-unit stacked devices that exhibit remarkable performance with low primary volume, high oxygen uptake and carbon dioxide release and high flow rate of up to 80 ml min-1.
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Affiliation(s)
- Julie Lachaux
- Université Paris-Saclay, CNRS, Centre de Nanosciences et Nanotechnologies C2N, UMR9001, Palaiseau 91120, France.
| | - Gilgueng Hwang
- Université Paris-Saclay, CNRS, Centre de Nanosciences et Nanotechnologies C2N, UMR9001, Palaiseau 91120, France.
| | - Nassim Arouche
- Université Paris-Saclay, INSERM, UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
| | - Sina Naserian
- Université Paris-Saclay, INSERM, UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
| | - Abdelmounaim Harouri
- Université Paris-Saclay, CNRS, Centre de Nanosciences et Nanotechnologies C2N, UMR9001, Palaiseau 91120, France.
| | - Valeria Lotito
- Université Paris-Saclay, CNRS, Centre de Nanosciences et Nanotechnologies C2N, UMR9001, Palaiseau 91120, France.
| | - Caterina Casari
- Université Paris-Saclay, INSERM, UMR S1176, Le Kremin-Bicêtre, France
| | - Thevy Lok
- LadHyX, CNRS, Ecole polytechnique, Institut polytechnique de Paris, Palaiseau 91120, France
| | - Jean Baptiste Menager
- Université Paris-Saclay, INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | - Justin Issard
- Université Paris-Saclay, INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | - Julien Guihaire
- Université Paris-Saclay, INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | - Cécile V Denis
- Université Paris-Saclay, INSERM, UMR S1176, Le Kremin-Bicêtre, France
| | - Peter J Lenting
- Université Paris-Saclay, INSERM, UMR S1176, Le Kremin-Bicêtre, France
| | - Abdul I Barakat
- LadHyX, CNRS, Ecole polytechnique, Institut polytechnique de Paris, Palaiseau 91120, France
| | - Georges Uzan
- Université Paris-Saclay, INSERM, UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
| | - Olaf Mercier
- Université Paris-Saclay, INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | - Anne-Marie Haghiri-Gosnet
- Université Paris-Saclay, CNRS, Centre de Nanosciences et Nanotechnologies C2N, UMR9001, Palaiseau 91120, France.
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Combination of human endothelial colony-forming cells and mesenchymal stromal cells exert neuroprotective effects in the growth-restricted newborn. NPJ Regen Med 2021; 6:75. [PMID: 34795316 PMCID: PMC8602245 DOI: 10.1038/s41536-021-00185-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 10/19/2021] [Indexed: 11/09/2022] Open
Abstract
The foetal brain is particularly vulnerable to the detrimental effects of foetal growth restriction (FGR) with subsequent abnormal neurodevelopment being common. There are no current treatments to protect the FGR newborn from lifelong neurological disorders. This study examines whether pure foetal mesenchymal stromal cells (MSC) and endothelial colony-forming cells (ECFC) from the human term placenta are neuroprotective through modulating neuroinflammation and supporting the brain vasculature. We determined that one dose of combined MSC-ECFCs (cECFC; 106 ECFC 106 MSC) on the first day of life to the newborn FGR piglet improved damaged vasculature, restored the neurovascular unit, reduced brain inflammation and improved adverse neuronal and white matter changes present in the FGR newborn piglet brain. These findings could not be reproduced using MSCs alone. These results demonstrate cECFC treatment exerts beneficial effects on multiple cellular components in the FGR brain and may act as a neuroprotectant.
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Salvia miltiorrhiza Protects Endothelial Dysfunction against Mitochondrial Oxidative Stress. Life (Basel) 2021; 11:life11111257. [PMID: 34833133 PMCID: PMC8622679 DOI: 10.3390/life11111257] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/05/2021] [Accepted: 11/16/2021] [Indexed: 11/23/2022] Open
Abstract
Salvia miltiorrhiza (SM) is a common traditional Chinese medicine used in the treatment of cardiovascular and cerebrovascular diseases. Endothelial dysfunction plays an important role in the pathology of cardiovascular diseases. Endothelial dysfunction may induce inflammation and change vascular tone and permeability. The main pathological mechanism of endothelial dysfunction is the formation of reactive oxygen species (ROS). Mitochondria are the main source of energy and can also produce large amounts of ROS. Recent studies have shown that extracts of SM have antioxidative, anti-inflammatory, and antithrombus properties. In this review, we discuss the mechanism of oxidative stress in the mitochondria, endothelial dysfunction, and the role of SM in these oxidative events.
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Catar R, Moll G, Kamhieh-Milz J, Luecht C, Chen L, Zhao H, Ernst L, Willy K, Girndt M, Fiedler R, Witowski J, Morawietz H, Ringdén O, Dragun D, Eckardt KU, Schindler R, Zickler D. Expanded Hemodialysis Therapy Ameliorates Uremia-Induced Systemic Microinflammation and Endothelial Dysfunction by Modulating VEGF, TNF-α and AP-1 Signaling. Front Immunol 2021; 12:774052. [PMID: 34858433 PMCID: PMC8632537 DOI: 10.3389/fimmu.2021.774052] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 10/20/2021] [Indexed: 12/15/2022] Open
Abstract
Abstract Systemic chronic microinflammation and altered cytokine signaling, with adjunct cardiovascular disease (CVD), endothelial maladaptation and dysfunction is common in dialysis patients suffering from end-stage renal disease and associated with increased morbidity and mortality. New hemodialysis filters might offer improvements. We here studied the impact of novel improved molecular cut-off hemodialysis filters on systemic microinflammation, uremia and endothelial dysfunction. Human endothelial cells (ECs) were incubated with uremic serum obtained from patients treated with two different hemodialysis regimens in the Permeability Enhancement to Reduce Chronic Inflammation (PERCI-II) crossover clinical trial, comparing High-Flux (HF) and Medium Cut-Off (MCO) membranes, and then assessed for their vascular endothelial growth factor (VEGF) production and angiogenesis. Compared to HF membranes, dialysis with MCO membranes lead to a reduction in proinflammatory mediators and reduced endothelial VEGF production and angiogenesis. Cytokine multiplex screening identified tumor necrosis factor (TNF) superfamily members as promising targets. The influence of TNF-α and its soluble receptors (sTNF-R1 and sTNF-R2) on endothelial VEGF promoter activation, protein release, and the involved signaling pathways was analyzed, revealing that this detrimental signaling was indeed induced by TNF-α and mediated by AP-1/c-FOS signaling. In conclusion, uremic toxins, in particular TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel MCO membranes. Translational Perspective and Graphical Abstract Systemic microinflammation, altered cytokine signaling, cardiovascular disease, and endothelial maladaptation/dysfunction are common clinical complications in dialysis patients suffering from end-stage renal disease. We studied the impact of novel improved medium-cut-off hemodialysis filters on uremia and endothelial dysfunction. We can show that uremic toxins, especially TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel improved medium-cut-off membranes.
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Affiliation(s)
- Rusan Catar
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Guido Moll
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Julian Kamhieh-Milz
- Institute of Transfusion Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Christian Luecht
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Lei Chen
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Hongfan Zhao
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Lucas Ernst
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Kevin Willy
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- Department of Cardiology, University Hospital Münster, Münster, Germany
| | - Matthias Girndt
- Department of Internal Medicine II, Martin-Luther-University Halle, Halle, Germany
| | - Roman Fiedler
- Department of Internal Medicine II, Martin-Luther-University Halle, Halle, Germany
| | - Janusz Witowski
- Department of Pathophysiology, Poznan University of Medical Sciences, Poznan, Poland
| | - Henning Morawietz
- Division of Vascular Endothelium and Microcirculation, Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Olle Ringdén
- Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden
| | - Duska Dragun
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Ralf Schindler
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Daniel Zickler
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
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