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Yang Y, Li H, Ma Z, Li Z, Gu J. Lamb1-mediated Wnt/β-catenin signaling pathway drives endothelial angiogenesis for fracture healing. Gene 2025; 959:149481. [PMID: 40221061 DOI: 10.1016/j.gene.2025.149481] [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: 12/25/2024] [Revised: 03/20/2025] [Accepted: 04/06/2025] [Indexed: 04/14/2025]
Abstract
OBJECTIVES Fractures, usually caused by trauma or osteoporosis, are the most common traumatic injuries to large organs in humans. Osteogenesis and angiogenesis are two crucial parts of fracture healing that work together to promote the repair and regeneration of damaged bone. Endothelial cell migration is critical for angiogenesis. Therefore, it is well worth exploring whether endothelial cells (ECs) can enhance fracture healing. METHODS The public datasets were analyzed by scRNA-seq, and the ECs were subjected to subset analysis and pseudotime analysis. Next, ECs_Lamb1+ cells underwent GO and KEGG pathway enrichment analyses, and were subjected to GSVA. Finally, the mechanism was verified and evaluated via qRT-PCR, cellular immunofluorescence staining, and transwell assay. RESULTS After cell annotations, 9 cell types were obtained, and it was found that the proportions of ECs were significantly reduced. EC subset analysis showed that the ratio of ECs_Lamb1+ cells was significantly up-regulated in the Fracture group; pseudotime analysis showed that ECs_Lamb1- cells were gradually reduced over time, whereas ECs_Lamb1+ cells were gradually expanding along the trajectories to reach a maximum at the end of the trajectory; pathway enrichment analyses revealed that ECs_Lamb1+ cells were mainly associated with several signaling pathways regulating cell proliferation, differentiation, repair, angiogenesis, and inflammatory responses, such as PI3K-Akt signaling pathway, Wnt/β-catenin, and MAPK. The results of basic assays demonstrated that successful knockdown of Lamb1 expression via siRNA-LAMB1 was detrimental to HUVEC proliferation, migration, and tube formation, and could suppress the expression of wnt3a, GSK-3β, β-catenin, and VEGFA; whereas, HY-141873 in combination with siRNA-LAMB1 partially reversed the down-regulated wnt3a, GSK-3β, β-catenin, and VEGFA expression, and HUVEC proliferation, migration, and tube formation were partially improved. CONCLUSION Lamb1 promotes fracture repair and healing by up-regulating VEGFA expression via the activation of Wnt signaling pathway to catalyze EC growth and migration and induce endothelial angiopoiesis.
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Affiliation(s)
- Yajun Yang
- People's Hospital of Ningxia Hui Autonomous Region, Ningxia Medical University, China.
| | - Hangyu Li
- People's Hospital of Ningxia Hui Autonomous Region, Ningxia Medical University, China
| | - Zhirong Ma
- People's Hospital of Ningxia Hui Autonomous Region, Ningxia Medical University, China
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Sun MX, Zhu HC, Yu Y, Yao Y, Li HY, Feng FB, Wang QY, Liu RJ, Sun CG. Role of the Wnt signaling pathway in the complex microenvironment of breast cancer and prospects for therapeutic potential (Review). Int J Oncol 2025; 66:36. [PMID: 40145557 PMCID: PMC12068849 DOI: 10.3892/ijo.2025.5742] [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: 12/18/2024] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
The focus on breast cancer treatment has shifted from the cytotoxic effects of single drugs on tumor cells to multidimensional multi‑pathway synergistic intervention strategies targeting the tumor microenvironment (TME). The activation of the Wnt signaling pathway in the TME of breast cancer cells serves a key regulatory role in tissue homeostasis and is a key driver of the carcinogenic process. Modulating the crosstalk between the Wnt pathway and TME of breast cancer is key for understanding the biological behavior of breast cancer and advancing the development of novel antitumor drugs. The present review aimed to summarize the complex mechanisms of the Wnt signaling pathway in the breast cancer TME, interactions between the Wnt signaling pathway and components of the breast cancer TME and breast cancer‑associated genes, as well as the interactions between the Wnt signaling pathway and other signaling cascades at the molecular level. Furthermore, the present review aimed to highlight the unique advantages of the Wnt signaling pathway in the macro‑regulation of the TME and the current therapeutic strategies targeting the Wnt signaling pathway, their potential clinical value and future research directions in breast cancer treatment.
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Affiliation(s)
- Meng Xuan Sun
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Han Ci Zhu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Yang Yu
- State Key Laboratory of Quality Research in Chinese Medicine, and Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, P.R. China
| | - Yan Yao
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 261000, P.R. China
| | - Hua Yao Li
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Fu Bin Feng
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 261000, P.R. China
| | - Qing Yang Wang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Rui Juan Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 261000, P.R. China
| | - Chang Gang Sun
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 261000, P.R. China
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
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Park JM, Nam GB, Lee ES, Kim HM, Kim H, Myoung K, Lee JE, Baek HS, Ko J, Lee CS. Effects of Chlorella protothecoides-derived polydeoxyribonucleotides on skin regeneration and wound healing. Arch Dermatol Res 2025; 317:483. [PMID: 39994014 DOI: 10.1007/s00403-025-03885-w] [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: 12/02/2024] [Revised: 01/16/2025] [Accepted: 01/18/2025] [Indexed: 02/26/2025]
Abstract
The skin acts as a crucial barrier and, upon injury, initiates complex wound-healing processes involving various cell types. Polydeoxyribonucleotides (PDRNs) are well-known for their efficacy in enhancing skin regeneration and wound healing. This study sought to investigate the effectiveness of PDRNs derived from Chlorella protothecoides, a sustainable and scalable microalgal source, in promoting skin regeneration and wound healing. Keratinocytes and fibroblasts were used for assessing the impact of PDRNs on cell proliferation, migration, collagen synthesis, and angiogenesis. Gene expression and associated signaling pathways were also examined using RT-qPCR and Western blot analyses. Our findings demonstrated that PDRNs significantly enhanced the proliferation and migration of skin cells, upregulated growth arrest specific 6 (GAS6) and hepatocyte growth factor (HGF) expression, and increased collagen synthesis by modulating collagen type I alpha 1 (COLIA1) expression. Additionally, PDRNs enhanced angiogenesis by promoting vascular endothelial growth factor (VEGF) expression and activation of ERK, AKT, β-catenin and STAT3 pathways via an adenosine A2A receptor (A2AR)-dependent mechanism. These findings suggest that microalgal-derived PDRNs have significant potential as sustainable and effective agents for clinical and cosmetic applications aimed at improving skin health and wound healing.
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Affiliation(s)
- Jung Min Park
- Department of Senior Healthcare Major in Biopharmaceuticals, Eulji University, Sanseong-daero 553, Sujeong-gu, Seongnam-si, Gyeonggi-do, 13135, Republic of Korea
| | - Gi Beag Nam
- AMOREPACIFIC Research and Innovation Center, 1920, Yonggu-daero, Giheung-gu, Yongin-si, Gyeonggi-do, 17074, Republic of Korea
| | - Eun-Soo Lee
- AMOREPACIFIC Research and Innovation Center, 1920, Yonggu-daero, Giheung-gu, Yongin-si, Gyeonggi-do, 17074, Republic of Korea
| | - Hyung-Min Kim
- AMOREPACIFIC Research and Innovation Center, 1920, Yonggu-daero, Giheung-gu, Yongin-si, Gyeonggi-do, 17074, Republic of Korea
| | - Hyuk Kim
- AMOREPACIFIC Research and Innovation Center, 1920, Yonggu-daero, Giheung-gu, Yongin-si, Gyeonggi-do, 17074, Republic of Korea
| | - Kilsun Myoung
- AMOREPACIFIC Research and Innovation Center, 1920, Yonggu-daero, Giheung-gu, Yongin-si, Gyeonggi-do, 17074, Republic of Korea
| | - Ji Ean Lee
- R&D Center, Morechem Co., Ltd, 605 Heungdeok IT Valley A, 13, Heungdeok 1-ro, Giheung-gu, Yongin-si, Gyeonggi-do, 16954, Korea
| | - Heung Soo Baek
- AMOREPACIFIC Research and Innovation Center, 1920, Yonggu-daero, Giheung-gu, Yongin-si, Gyeonggi-do, 17074, Republic of Korea
| | - Jaeyoung Ko
- AMOREPACIFIC Research and Innovation Center, 1920, Yonggu-daero, Giheung-gu, Yongin-si, Gyeonggi-do, 17074, Republic of Korea.
| | - Chang Seok Lee
- Department of Senior Healthcare Major in Biopharmaceuticals, Eulji University, Sanseong-daero 553, Sujeong-gu, Seongnam-si, Gyeonggi-do, 13135, Republic of Korea.
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Yang F, Lee G, Fan Y. Navigating tumor angiogenesis: therapeutic perspectives and myeloid cell regulation mechanism. Angiogenesis 2024; 27:333-349. [PMID: 38580870 PMCID: PMC11303583 DOI: 10.1007/s10456-024-09913-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 03/04/2024] [Indexed: 04/07/2024]
Abstract
Sustained angiogenesis stands as a hallmark of cancer. The intricate vascular tumor microenvironment fuels cancer progression and metastasis, fosters therapy resistance, and facilitates immune evasion. Therapeutic strategies targeting tumor vasculature have emerged as transformative for cancer treatment, encompassing anti-angiogenesis, vessel normalization, and endothelial reprogramming. Growing evidence suggests the dynamic regulation of tumor angiogenesis by infiltrating myeloid cells, such as macrophages, myeloid-derived suppressor cells (MDSCs), and neutrophils. Understanding these regulatory mechanisms is pivotal in paving the way for successful vasculature-targeted cancer treatments. Therapeutic interventions aimed to disrupt myeloid cell-mediated tumor angiogenesis may reshape tumor microenvironment and overcome tumor resistance to radio/chemotherapy and immunotherapy.
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Affiliation(s)
- Fan Yang
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Obstetrics and Gynecology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
- Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Gloria Lee
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Yi Fan
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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Lin L, Zheng Y, Li Q, Sun Y, Huang Y, Liang L, Xu L, Zhao YE. Verteporfin regulates corneal neovascularization through inhibition of YAP protein activation. Exp Eye Res 2024; 238:109747. [PMID: 38072353 DOI: 10.1016/j.exer.2023.109747] [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: 10/20/2023] [Revised: 11/15/2023] [Accepted: 12/05/2023] [Indexed: 01/02/2024]
Abstract
Corneal neovascularization (CNV) is a vision-threatening disease that is becoming a growing public health concern. While Yes-associated protein (YAP) plays a critical role in neovascular disease and allow for the sprouting angiogenesis. Verteporfin (VP) is a classical inhibitor of the YAP-TEAD complex, which is used for clinical treatment of neovascular macular degeneration through photodynamic therapy. The purpose of this study is to explore the effect of verteporfin (VP) on the inhibition of CNV and its potential mechanism. Rat CNV model were established by suturing in the central cornea and randomly divided into three groups (control, CNV and VP group). Neovascularization was observed by slit lamp to extend along the corneal limbus to the suture line. RNA-sequencing was used to reveal the related pathways on the CNV and the results revealed the vasculature development process and genes related with angiogenesis in CNV. In CNV group, we detected the nuclear translocation of YAP and the expression of CD31 in corneal neovascular endothelial cells through immunofluorescence. After the application of VP, the proliferation, migration and the tube formation of HUVECs were significantly inhibited. Furthermore, VP showed the CNV inhibition by tail vein injection without photoactivation. Then we found that the expression of phosphorylated YAP significantly decreased, and its downstream target protein connective tissue growth factor (CTGF) increased in the CNV group, while the expression was just opposite in other groups. Besides, both the expression of vascular endothelial growth factor receptor 2 (VEGFR2) and cofilin significantly increased in CNV group, and decreased after VP treatment. Therefore, we conclude that Verteporfin could significantly inhibited the CNV without photoactivation by regulating the activation of YAP.
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Affiliation(s)
- Lei Lin
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yu Zheng
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Qiyuan Li
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yining Sun
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yiwen Huang
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Lili Liang
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Liming Xu
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yun-E Zhao
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
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Mankuzhy P, Dharmarajan A, Perumalsamy LR, Sharun K, Samji P, Dilley RJ. The role of Wnt signaling in mesenchymal stromal cell-driven angiogenesis. Tissue Cell 2023; 85:102240. [PMID: 37879288 DOI: 10.1016/j.tice.2023.102240] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 09/28/2023] [Accepted: 10/11/2023] [Indexed: 10/27/2023]
Abstract
Development, growth, and remodeling of blood vessels occur through an intricate process involving cell differentiation, proliferation, and rearrangement by cell migration under the direction of various signaling pathways. Recent reports highlight that resident and exogenous mesenchymal stromal cells (MSCs) have the potential to regulate the neovascularization process through paracrine secretion of proangiogenic factors. Recent research has established that the vasculogenic potential of MSCs is regulated by several signaling pathways, including the Wnt signaling pathway, and their interplay. These findings emphasize the complex nature of the vasculogenic process and underscore the importance of understanding the underlying molecular mechanisms for the development of effective cell-based therapies in regenerative medicine. This review provides an updated briefing on the canonical and non-canonical Wnt signaling pathways and summarizes the recent reports of both in vitro and in vivo studies with the involvement of MSCs of various sources in the vasculogenic process mediated by Wnt signaling pathways. Here we outline the current understanding of the plausible role of the Wnt signaling pathway, specifically in MSC-regulated angiogenesis.
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Affiliation(s)
- Pratheesh Mankuzhy
- Department of Surgery and Centre for Medical Research, Faculty of Health and Medical Sciences, The University of Western Australia, 6009 Perth, Australia; College of Veterinary and Animal Sciences - Mannuthy, Kerala Veterinary and Animal Sciences University, Pookode, Wayanad, Kerala 673576 India.
| | - Arun Dharmarajan
- Department of Biomedical Sciences, Sri Ramachandra faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai 600116, India; School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Perth, Western Australia, Australia; School of Human Sciences, Faculty of Life Sciences, University of Western Australia, 6009 Perth, Australia
| | - Lakshmi R Perumalsamy
- Department of Biomedical Sciences, Sri Ramachandra faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai 600116, India
| | - Khan Sharun
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Priyanka Samji
- Department of Biomedical Sciences, Sri Ramachandra faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai 600116, India
| | - Rodney J Dilley
- Department of Surgery and Centre for Medical Research, Faculty of Health and Medical Sciences, The University of Western Australia, 6009 Perth, Australia
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Gao HM, Chen H, Cui GY, Hu JX. Damage mechanism and therapy progress of the blood-brain barrier after ischemic stroke. Cell Biosci 2023; 13:196. [PMID: 37915036 PMCID: PMC10619327 DOI: 10.1186/s13578-023-01126-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 09/04/2023] [Indexed: 11/03/2023] Open
Abstract
The blood-brain barrier (BBB) serves as a defensive line protecting the central nervous system, while also maintaining micro-environment homeostasis and inhibiting harmful materials from the peripheral blood. However, the BBB's unique physiological functions and properties make drug delivery challenging for patients with central nervous system diseases. In this article, we briefly describe the cell structure basis and mechanism of action of the BBB, as well as related functional proteins involved. Additionally, we discuss the various mechanisms of BBB damage following the onset of an ischemic stroke, and lastly, we mention several therapeutic strategies accounting for impairment mechanisms. We hope to provide innovative ideas for drug delivery research via the BBB.
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Affiliation(s)
- Hui-Min Gao
- Institute of Stroke Research, Xuzhou Medical University, Jiangsu, China
| | - Hao Chen
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Jiangsu, China
| | - Gui-Yun Cui
- Institute of Stroke Research, Xuzhou Medical University, Jiangsu, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Jiangsu, China
| | - Jin-Xia Hu
- Institute of Stroke Research, Xuzhou Medical University, Jiangsu, China.
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Jiangsu, China.
- School of Chemical Engineering and Technology, China University of Mining and Technology, Xuzhou, 221116, China.
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Li S, Yang M, Zhao R, Peng L, Liu W, Jiang X, He Y, Dai E, Zhang L, Yang Y, Shi Y, Zhao P, Yang Z, Zhu X. Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy. Genes Dis 2023; 10:2572-2585. [PMID: 37554197 PMCID: PMC10404869 DOI: 10.1016/j.gendis.2022.10.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 09/10/2022] [Accepted: 10/01/2022] [Indexed: 11/06/2022] Open
Abstract
Endoplasmic reticulum (ER) membrane protein complex (EMC) is required for the co-translational insertion of newly synthesized multi-transmembrane proteins. Compromised EMC function in different cell types has been implicated in multiple diseases. Using inducible genetic mouse models, we revealed defects in retinal vascularization upon endothelial cell (EC) specific deletion of Emc1, the largest subunit of EMC. Loss of Emc1 in ECs led to reduced vascular progression and vascular density, diminished tip cell sprouts, and vascular leakage. We then performed an unbiased transcriptomic analysis on human retinal microvascular endothelial cells (HRECs) and revealed a pivotal role of EMC1 in the β-catenin signaling pathway. Further in-vitro and in-vivo experiments proved that loss of EMC1 led to compromised β-catenin signaling activity through reduced expression of Wnt receptor FZD4, which could be restored by lithium chloride (LiCl) treatment. Driven by these findings, we screened genomic DNA samples from familial exudative vitreoretinopathy (FEVR) patients and identified one heterozygous variant in EMC1 that co-segregated with FEVR phenotype in the family. In-vitro expression experiments revealed that this variant allele failed to facilitate the expression of FZD4 on the plasma membrane and activate the β-catenin signaling pathway, which might be a main cause of FEVR. In conclusion, our findings reveal that variants in EMC1 gene cause compromised β-catenin signaling activity, which may be associated with the pathogenesis of FEVR.
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Affiliation(s)
- Shujin Li
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China
| | - Mu Yang
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China
| | - Rulian Zhao
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China
| | - Li Peng
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Wenjing Liu
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Xiaoyan Jiang
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Yunqi He
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Erkuan Dai
- Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Lin Zhang
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Yeming Yang
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Yi Shi
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Peiquan Zhao
- Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Zhenglin Yang
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China
| | - Xianjun Zhu
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China
- Key Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining, Qinghai 810008, China
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9
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Chen B, Jin W. A comprehensive review of stroke-related signaling pathways and treatment in western medicine and traditional Chinese medicine. Front Neurosci 2023; 17:1200061. [PMID: 37351420 PMCID: PMC10282194 DOI: 10.3389/fnins.2023.1200061] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/19/2023] [Indexed: 06/24/2023] Open
Abstract
This review provides insight into the complex network of signaling pathways and mechanisms involved in stroke pathophysiology. It summarizes the historical progress of stroke-related signaling pathways, identifying potential interactions between them and emphasizing that stroke is a complex network disease. Of particular interest are the Hippo signaling pathway and ferroptosis signaling pathway, which remain understudied areas of research, and are therefore a focus of the review. The involvement of multiple signaling pathways, including Sonic Hedgehog (SHH), nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), hypoxia-inducible factor-1α (HIF-1α), PI3K/AKT, JAK/STAT, and AMPK in pathophysiological mechanisms such as oxidative stress and apoptosis, highlights the complexity of stroke. The review also delves into the details of traditional Chinese medicine (TCM) therapies such as Rehmanniae and Astragalus, providing an analysis of the recent status of western medicine in the treatment of stroke and the advantages and disadvantages of TCM and western medicine in stroke treatment. The review proposes that since stroke is a network disease, TCM has the potential and advantages of a multi-target and multi-pathway mechanism of action in the treatment of stroke. Therefore, it is suggested that future research should explore more treasures of TCM and develop new therapies from the perspective of stroke as a network disease.
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Affiliation(s)
- Binhao Chen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Weifeng Jin
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
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10
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Sadhukhan P, Seiwert TY. The role of macrophages in the tumor microenvironment and tumor metabolism. Semin Immunopathol 2023; 45:187-201. [PMID: 37002376 DOI: 10.1007/s00281-023-00988-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 03/08/2023] [Indexed: 04/03/2023]
Abstract
The complexity and plasticity of the tumor microenvironment (TME) make it difficult to fully understand the intratumoral regulation of different cell types and their activities. Macrophages play a crucial role in the signaling dynamics of the TME. Among the different subtypes of macrophages, tumor-associated macrophages (TAMs) are often associated with poor prognosis, although some subtypes of TAMs can at the same time improve treatment responsiveness and lead to favorable clinical outcomes. TAMs are key regulators of cancer cell proliferation, metastasis, angiogenesis, extracellular matrix remodeling, tumor metabolism, and importantly immunosuppression in the TME by modulating various chemokines, cytokines, and growth factors. TAMs have been identified as a key contributor to resistance to chemotherapy and cancer immunotherapy. In this review article, we aim to discuss the mechanisms by which TAMs regulate innate and adaptive immune signaling in the TME and summarize recent preclinical research on the development of therapeutics targeting TAMs and tumor metabolism.
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Affiliation(s)
- Pritam Sadhukhan
- Johns Hopkins University, Skip Viragh Outpatient Cancer Building, Baltimore, MD, 21287, USA
| | - Tanguy Y Seiwert
- Johns Hopkins University, Skip Viragh Outpatient Cancer Building, Baltimore, MD, 21287, USA.
- Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
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11
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Luo Y, Liu Y, Wang B, Tu X. CHIR99021-Treated Osteocytes with Wnt Activation in 3D-Printed Module Form an Osteogenic Microenvironment for Enhanced Osteogenesis and Vasculogenesis. Int J Mol Sci 2023; 24:ijms24066008. [PMID: 36983081 PMCID: PMC10052982 DOI: 10.3390/ijms24066008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/02/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023] Open
Abstract
Finding a bone implant that has high bioactivity that can safely drive stem cell differentiation and simulate a real in vivo microenvironment is a challenge for bone tissue engineering. Osteocytes significantly regulate bone cell fate, and Wnt-activated osteocytes can reversely regulate bone formation by regulating bone anabolism, which may improve the biological activity of bone implants. To achieve a safe application, we used the Wnt agonist CHIR99021 (C91) to treat MLO-Y4 for 24 h, in a co-culture with ST2 for 3 days after withdrawal. We found that the expression of Runx2 and Osx increased, promoted osteogenic differentiation, and inhibited adipogenic differentiation in the ST2 cells, and these effects were eliminated by the triptonide. Therefore, we hypothesized that C91-treated osteocytes form an osteogenic microenvironment (COOME). Subsequently, we constructed a bio-instructive 3D printing system to verify the function of COOME in 3D modules that mimic the in vivo environment. Within PCI3D, COOME increased the survival and proliferation rates to as high as 92% after 7 days and promoted ST2 cell differentiation and mineralization. Simultaneously, we found that the COOME-conditioned medium also had the same effects. Therefore, COOME promotes ST2 cell osteogenic differentiation both directly and indirectly. It also promotes HUVEC migration and tube formation, which can be explained by the high expression of Vegf. Altogether, these results indicate that COOME, combined with our independently developed 3D printing system, can overcome the poor cell survival and bioactivity of orthopedic implants and provide a new method for clinical bone defect repair.
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Affiliation(s)
- Yisheng Luo
- Laboratory of Skeletal Development and Regeneration, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Yangxi Liu
- Laboratory of Skeletal Development and Regeneration, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Bo Wang
- Laboratory of Skeletal Development and Regeneration, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Xiaolin Tu
- Laboratory of Skeletal Development and Regeneration, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
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12
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Abstract
Most colorectal cancers (CRC) are associated with activated Wnt signaling, making it the fourth most prevalent type of cancer globally. To function properly, the Wnt signaling pathway requires secreted glycoproteins known as Wnt ligands (Wnts). Humans have 19 Wnts, which suggest a complicated signaling and biological process, and we still know little about their functions in developing CRC. This review aims to describe the canonical Wnt signaling in CRC, particularly the Wnt3a expression pattern, and their association with the angiogenesis and progression of CRC. This review also sheds light on the inhibition of Wnt3a signaling in CRC. Despite some obstacles, a thorough understanding of Wnts is essential for effectively managing CRC.
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13
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Huang K, Xu H, Han L, Xu R, Xu Z, Xie Y. Identification of therapeutic targets and prognostic biomarkers among frizzled family genes in glioma. Front Mol Biosci 2023; 9:1054614. [PMID: 36699699 PMCID: PMC9868451 DOI: 10.3389/fmolb.2022.1054614] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Background: The biological functions of the Frizzled gene family (FZDs), as the key node of wingless-type MMTV integration site family (Wnt) and mammalian target of rapamycin signaling pathways, have not been fully elucidated in glioma. This study aims to identify novel therapeutic targets and prognostic biomarkers for gliomas, which may help us understand the role of FZDs. Methods: RNA-sequence data were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects. Survival analyses, Cox regression analyses, nomograms, calibration curves, receiver operating characteristic (ROC) curves, gene function enrichment analyses, and immune cell infiltration analyses were conducted using R. Results: High expressions of FZDs were positively associated with the activation of mTOR signaling. FZD1/2/3/4/5/7/8 was significantly highly expressed in tumor tissues, and the high expression of FZD1/2/5/6/7/8 was significantly positively associated with poorer prognosis. FZD2 and FZD6 positively served as independent predictors of poor prognosis. Gene function analysis showed that FZDs were associated with mTOR signaling, immune response, cytokine-cytokine receptor interaction, extracellular matrix organization, apoptosis, and p53 signaling pathway. Conclusions: Our finding strongly indicated a crucial role of FZDs in glioma. FZD1/2/5/6/7/8 could be an unfavorable prognostic factor in glioma and FZD2 and FZD6 may be novel independent predictors of poor prognosis in glioma.
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Affiliation(s)
- Ke Huang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, China,School/Hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Huimei Xu
- Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Liang Han
- School/Hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Ruiming Xu
- The Second Hospital of Dalian Medical University, Dalian, China
| | - Zhaoqing Xu
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, China,*Correspondence: Zhaoqing Xu, ; Yi Xie,
| | - Yi Xie
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China,Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China,Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou, China,*Correspondence: Zhaoqing Xu, ; Yi Xie,
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14
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Guan X, Yu M, Wu L, Chen J, Tong J, Wu X, Yin A, Xiao T, Wang B, Zhang JV, Niu J. Elevated trophoblastic Siglec6 contributes to the impairment of vascular endothelial cell functions by downregulating Wnt6/β-catenin signaling in preeclampsia. Arch Biochem Biophys 2022; 730:109396. [PMID: 36113626 DOI: 10.1016/j.abb.2022.109396] [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: 01/16/2022] [Revised: 09/07/2022] [Accepted: 09/07/2022] [Indexed: 11/26/2022]
Abstract
Preeclampsia (PE), a systemic vascular disorder, is the leading cause of maternal and perinatal morbidity and mortality, and its pathogenesis has yet to be fully elucidated. Siglec6, a transmembrane protein, is highly expressed in human placental trophoblasts, and previous studies have shown that Siglec6 overexpression correlates with PE, but the role of Siglec6 during PE progression is unknown. Here, we demonstrated that the mRNA and protein expression levels of Siglec6 were upregulated in early-onset PE placentas compared with uncomplicated pregnancies, and Siglec6 was primarily located in syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). Moreover, our results showed that chemical reagent-induced HIF-1α accumulation promoted the mRNA and protein levels of Siglec6 in HTR8/SVneo and BeWo cells. Although Siglec6 overexpression did not affect HTR8/SVneo cell proliferation, migration, and invasion, the conditional medium derived from the Siglec6 overexpressed HTR8/SVneo cells (Siglec6-OE-CM) significantly impaired the proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs). Subsequently, the transcriptome sequencing results revealed that Siglec6 overexpression led to the downregulation of Wnt6 in HTR8/SVneo cells, which was further confirmed by qPCR and ELISA. Recombinant human Wnt6 reversed Siglec6-OE-CM-mediated suppression of HUVEC functions by reactivating the Wnt/β-catenin signaling pathway. Altogether, our study found that elevated trophoblastic Siglec6 contributed to the impairment of vascular endothelial cell functions by downregulating Wnt6/β-catenin signaling.
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Affiliation(s)
- Xiaonian Guan
- Department of Obstetrics, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, 518028, China
| | - Ming Yu
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Shenzhen Key Laboratory of Metabolic Health, Shenzhen, 518055, China
| | - Linlin Wu
- Department of Obstetrics, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, 518028, China
| | - Jie Chen
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Shenzhen Key Laboratory of Metabolic Health, Shenzhen, 518055, China
| | - Jianing Tong
- Department of Obstetrics, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, 518028, China
| | - Xiaoxia Wu
- Department of Obstetrics, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, 518028, China
| | - Aiqi Yin
- Department of Obstetrics, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, 518028, China
| | - Tianxia Xiao
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Shenzhen Key Laboratory of Metabolic Health, Shenzhen, 518055, China
| | - Baobei Wang
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Shenzhen Key Laboratory of Metabolic Health, Shenzhen, 518055, China
| | - Jian V Zhang
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Shenzhen Key Laboratory of Metabolic Health, Shenzhen, 518055, China.
| | - Jianmin Niu
- Department of Obstetrics, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, 518028, China.
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15
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Xue Z, Yuan J, Chen F, Yao Y, Xing S, Yu X, Li K, Wang C, Bao J, Qu J, Su J, Chen H. Genome-wide association meta-analysis of 88,250 individuals highlights pleiotropic mechanisms of five ocular diseases in UK Biobank. EBioMedicine 2022; 82:104161. [PMID: 35841873 PMCID: PMC9297108 DOI: 10.1016/j.ebiom.2022.104161] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Ocular diseases may exhibit common clinical symptoms and epidemiological comorbidity. However, the extent of pleiotropic mechanisms across ocular diseases remains unclear. We aim to examine shared genetic etiology in age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, retinal detachment (RD), and myopia. METHODS We analyzed genome-wide association analyses for the five ocular diseases in 43,877 cases and 44,373 controls of European ancestry from UK Biobank, estimated their genetic relationships (LDSC, GNOVA, and Genomic SEM), and identified pleiotropic loci (ASSET and METASOFT). FINDINGS The genetic correlation of common SNPs revealed a meaningful genetic structure within these diseases, identifying genetic correlations between AMD, DR, and glaucoma. Cross-trait meta-analysis identified 23 pleiotropic loci associated with at least two ocular diseases and 14 loci unique to individual disorders (non-pleiotropic). We found that the genes associated with these shared genetic loci are involved in neuron differentiation (P = 8.80 × 10-6) and eye development systems (P = 3.86 × 10-5), and single cell RNA sequencing data reveals their heightened gene expression from multipotent progenitors to other differentiated retinal cells during retina developmental process. INTERPRETATION These results highlighted the potential common genetic architectures among these ocular diseases and can deepen the understanding of the molecular mechanisms underlying the related diseases. FUNDING The National Natural Science Foundation of China (61871294), Zhejiang Provincial Natural Science Foundation of China (LR19C060001), and the Scientific Research Foundation for Talents of Wenzhou Medical University (QTJ18023).
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Affiliation(s)
- Zhengbo Xue
- Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Jian Yuan
- Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Fukun Chen
- Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Yinghao Yao
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325105, Zhejiang, China
| | - Shilai Xing
- Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Xiangyi Yu
- Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Kai Li
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325105, Zhejiang, China
| | - Chenxiao Wang
- Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Jinhua Bao
- Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Jia Qu
- Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China; Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou 325101, Zhejiang, China
| | - Jianzhong Su
- Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China; Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou 325101, Zhejiang, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325105, Zhejiang, China.
| | - Hao Chen
- Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China.
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16
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Zhang X, Meng T, Cui S, Liu D, Pang Q, Wang P. Roles of ubiquitination in the crosstalk between tumors and the tumor microenvironment (Review). Int J Oncol 2022; 61:84. [PMID: 35616129 PMCID: PMC9170352 DOI: 10.3892/ijo.2022.5374] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/27/2022] [Indexed: 11/06/2022] Open
Abstract
The interaction between a tumor and the tumor microenvironment (TME) plays a key role in tumorigenesis and tumor progression. Ubiquitination, a crucial post-translational modification for regulating protein degradation and turnover, plays a role in regulating the crosstalk between a tumor and the TME. Thus, identifying the roles of ubiquitination in the process may assist researchers to investigate the mechanisms underlying tumorigenesis and tumor progression. In the present review article, new insights into the substrates for ubiquitination that are involved in the regulation of hypoxic environments, angiogenesis, chronic inflammation-mediated tumor formation, and the function of cancer-associated fibroblasts and infiltrating immune cells (tumor-associated macrophages, T-cells, myeloid-derived suppressor cells, dendritic cells, and natural killer cells) are summarized. In addition, the potential targets of the ubiquitination proteasome system within the TME for cancer therapy and their therapeutic effects are reviewed and discussed.
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Affiliation(s)
- Xiuzhen Zhang
- Anti‑aging and Regenerative Medicine Research Institution, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, Shandong 255000, P.R. China
| | - Tong Meng
- Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, P.R. China
| | - Shuaishuai Cui
- School of Life Sciences and Medicine, Shandong University of Technology, Zibo, Shandong 255000, P.R. China
| | - Dongwu Liu
- Anti‑aging and Regenerative Medicine Research Institution, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, Shandong 255000, P.R. China
| | - Qiuxiang Pang
- Anti‑aging and Regenerative Medicine Research Institution, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, Shandong 255000, P.R. China
| | - Ping Wang
- Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, P.R. China
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17
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Sun X, Fang J, Ye F, Zhang S, Huang H, Hou J, Wang T. Diffuse Large B-Cell Lymphoma Promotes Endothelial-to-Mesenchymal Transition via WNT10A/Beta-Catenin/Snail Signaling. Front Oncol 2022; 12:871788. [PMID: 35494062 PMCID: PMC9039659 DOI: 10.3389/fonc.2022.871788] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/15/2022] [Indexed: 11/13/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is one type of highly heterogeneous lymphoid malignancy with 30%~40% of patients experiencing treatment failure. Novel risk stratification and therapeutic approaches for DLBCL are urgently needed. Endothelial-to-mesenchymal transition (EndMT), which contributes to tumor angiogenesis, metastasis, drug resistance, and cancer-associated fibroblast generation, has been detected in the microenvironment of many types of cancers. However, the existence of EndMT in the hematological malignancies microenvironment remains unknown. Here, we identified the existence of EndMT in DLBCL-associated endothelial cells and the clinical relevance of EndMT markers in DLBCL, which was associated with advanced clinical stage and poor prognosis. In vitro experiments confirmed that DLBCL cells stimulated angiogenesis and EndMT of human umbilical vein endothelial cells (HUVECs). We further unveiled the molecular mechanisms underlying this process. We demonstrated that WNT10A, a WNT family member overexpressed in DLBCL tissues and correlated with clinical features in DLBCL, promoted EndMT through glycogen synthase kinase 3β (GSK3β)/β-catenin/snail signaling. WNT10A inhibited the binding of GSK3β to β-catenin/snail, resulting in β-catenin and snail nuclear accumulation and target gene transcription. Silencing β-catenin and snail respectively attenuated WNT10A-induced angiogenesis and EndMT. The interplay between β-catenin-dependent and snail-dependent signaling was also confirmed in this study. Collectively, these findings identified that WNT10A/GSK3β/β-catenin/snail pathway performed vital roles in DLBCL-induced EndMT and indicated that EndMT markers and WNT10A may serve as novel predictors of clinical outcome.
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Affiliation(s)
- Xianting Sun
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jianchen Fang
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Fen Ye
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Shuxian Zhang
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Honghui Huang
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jian Hou
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Ting Wang
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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18
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Liang W, Huang L, Ma X, Dong L, Cheng R, Dehdarani M, Karamichos D, Ma JX. Pathogenic Role of Diabetes-Induced Overexpression of Kallistatin in Corneal Wound Healing Deficiency Through Inhibition of Canonical Wnt Signaling. Diabetes 2022; 71:747-761. [PMID: 35044447 PMCID: PMC8965664 DOI: 10.2337/db21-0740] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 12/27/2021] [Indexed: 01/21/2023]
Abstract
It was reported previously that circulation levels of kallistatin, an endogenous Wnt signaling inhibitor, are increased in patients with diabetes. The current study was conducted to determine the role of kallistatin in delayed wound healing in diabetic corneas. Immunostaining and Western blot analysis showed kallistatin levels were upregulated in corneas from humans and rodents with diabetes. In murine corneal wound healing models, the canonical Wnt signaling was activated in nondiabetic corneas and suppressed in diabetic corneas, correlating with delayed wound healing. Transgenic expression of kallistatin suppressed the activation of Wnt signaling in the cornea and delayed wound healing. Local inhibition of Wnt signaling in the cornea by kallistatin, an LRP6-blocking antibody, or the soluble VLDL receptor ectodomain (an endogenous Wnt signaling inhibitor) delayed wound healing. In contrast, ablation of the VLDL receptor resulted in overactivation of Wnt/β-catenin signaling and accelerated corneal wound healing. Activation of Wnt signaling in the cornea accelerated wound healing. Activation of Wnt signaling promoted human corneal epithelial cell migration and proliferation, which was attenuated by kallistatin. Our findings suggested that diabetes-induced overexpression of kallistatin contributes to delayed corneal wound healing by inhibiting the canonical Wnt signaling. Thus, kallistatin and Wnt/β-catenin signaling in the cornea could be potential therapeutic targets for diabetic corneal complications.
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Affiliation(s)
- Wentao Liang
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Li Huang
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Department of Ophthalmology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Xiang Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Lijie Dong
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Rui Cheng
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Marcus Dehdarani
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Dimitrios Karamichos
- North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX
- Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX
| | - Jian-xing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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19
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Liu Y, Ruan X, Li J, Wang B, Chen J, Wang X, Wang P, Tu X. The Osteocyte Stimulated by Wnt Agonist SKL2001 Is a Safe Osteogenic Niche Improving Bioactivities in a Polycaprolactone and Cell Integrated 3D Module. Cells 2022; 11:cells11050831. [PMID: 35269452 PMCID: PMC8909416 DOI: 10.3390/cells11050831] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/19/2022] [Accepted: 01/25/2022] [Indexed: 02/05/2023] Open
Abstract
Finding and constructing an osteogenic microenvironment similar to natural bone tissue has always been a frontier topic in orthopedics. We found that osteocytes are targeting cells controlling bone anabolism produced by PTH (JBMR 2017, PMID: 27704638), and osteocytes with activated Wnt signaling orchestrate bone formation and resorption (PNAS 2015, PMID: 25605937). However, methods for taking advantage of the leading role of osteocytes in bone regeneration remain unexplored. Herein, we found that the osteocytes with SKL2001-activated Wnt signaling could be an osteogenic microenvironment (SOOME) which upregulates the expression of bone transcription factor Runx2 and Bglap and promotes the differentiation of bone marrow stromal cell ST2 into osteoblasts. Interestingly, 60 μM SKL2001 treatment of osteocytic MLO-Y4 for 24 h maintained Wnt signaling activation for three days after removal, which was sufficient to induce osteoblast differentiation. Triptonide, a Wnt inhibitor, could eliminate this differentiation. Moreover, on day 5, the Wnt signaling naturally decreased to the level of the control group, indicating that this method of Wnt-signaling induction is safe to use. We quickly verified in vivo function of SOOME to a good proximation in 3D bioprinted modules composed of reciprocally printed polycaprolactone bundles (for support) and cell bundles (for bioactivity). In the cell bundles, SOOME stably supported the growth and development of ST2 cells, the 7-day survival rate was as high as 91.6%, and proliferation ability increased linearly. Similarly, SOOME greatly promoted ST2 differentiation and mineralization for 28 days. In addition, SOOME upregulated the expression of angiopoietin 1, promoted endothelial cell migration and angiogenesis, and increased node number and total length of tubes and branches. Finally, we found that the function of SOOME could be realized through the paracrine pathway. This study reveals that osteocytes with Wnt signaling activated by SKL2001 are a safe osteogenic microenvironment. Both SOOME itself and its cell-free culture supernatant can improve bioactivity for osteoblast differentiation, with composite scaffolds especially bearing application value.
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Affiliation(s)
| | | | | | | | | | | | | | - Xiaolin Tu
- Correspondence: ; Tel.: +86-185-2382-0685
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20
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Wnt signaling pathway in cancer immunotherapy. Cancer Lett 2022; 525:84-96. [PMID: 34740608 DOI: 10.1016/j.canlet.2021.10.034] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 10/06/2021] [Accepted: 10/20/2021] [Indexed: 12/11/2022]
Abstract
Wnt/β-catenin signaling is a highly conserved pathway that regulates cell proliferation, differentiation, apoptosis, stem cell self-renewal, tissue homeostasis, and wound healing. Dysregulation of the Wnt pathway is intricately involved in almost all stages of tumorigenesis in various cancers. Through direct and/or indirect effects on effector T cells, T-regulatory cells, T-helper cells, dendritic cells, and other cytokine-expressing immune cells, abnormal activation of Wnt/β-catenin signaling benefits immune exclusion and hinders T-cell-mediated antitumor immune responses. Activation of Wnt signaling results in increased resistance to immunotherapies. In this review, we summarize the process by which Wnt signaling affects cancer and immune surveillance, and the potential for targeting the Wnt-signaling pathway via cancer immunotherapy.
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21
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Yang B, Liu D, Ren YQ, Sun YQ, Zhang JP, Wang XG, Wu YQ, Wang SL, Guo SH, Guo G. FRAT1 promotes the angiogenic properties of human glioblastoma cells via VEGFA. Mol Med Rep 2022; 25:95. [PMID: 35059733 DOI: 10.3892/mmr.2022.12611] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/16/2021] [Indexed: 11/05/2022] Open
Abstract
Glioblastoma is a common central nervous system tumor and despite considerable advancements in treatment patient prognosis remains poor. Angiogenesis is a significant prognostic factor in glioblastoma, anti‑angiogenic treatments represent a promising therapeutic approach. Vascular endothelial growth factor A (VEGFA) is a predominant regulator of angiogenesis and mounting evidence suggests that the Wnt signaling pathway serves a significant role in tumor angiogenesis. As a positive regulator of the Wnt/β‑catenin signaling pathway, frequently rearranged in advanced T‑cell lymphomas‑1 (FRAT1) is highly expressed in human glioblastoma and is significantly associated with glioblastoma growth, invasion and migration, as well as poor patient prognosis. Bioinformatics analysis demonstrated that both VEGFA and FRAT1 were highly expressed in most tumor tissues and associated with prognosis. However, whether and how FRAT1 is involved in angiogenesis remains to be elucidated. In the present study, the relationship between FRAT1 and VEGFA in angiogenesis was investigated using the human glioblastoma U251 cell line. Small interfering RNAs (siRNAs) were used to silence FRAT1 expression in U251 cells, and the mRNA and protein expression levels of VEGFA, as well as the concentration of VEGFA in U251 cell supernatants, were determined using reverse transcription‑quantitative PCR, western blotting and ELISA. A tube formation assay was conducted to assess angiogenesis. The results demonstrated that siRNA knockdown significantly decreased the protein expression levels of FRAT1 in U251 cells and markedly decreased the mRNA and protein expression levels of VEGFA. Furthermore, the concentration of VEGFA in the cell supernatant was significantly reduced and angiogenesis was suppressed. These results suggested that FRAT1 may promote VEGFA secretion and angiogenesis in human glioblastoma cells via the Wnt/β‑catenin signaling pathway, supporting the potential use of FRAT1 as a promising therapeutic target in human glioblastoma.
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Affiliation(s)
- Biao Yang
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Dong Liu
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Ye-Qing Ren
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Yan-Qi Sun
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Jian-Ping Zhang
- Department of Neurosurgery, The Affiliated Liuzhou People's Hospital of Guangxi Medical University, Liuzhou, Guangxi Zhuang Autonomous Region 545006, P.R. China
| | - Xiao-Gang Wang
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Yong-Qiang Wu
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Shu-Le Wang
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Shi-Hao Guo
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Geng Guo
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
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22
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Rodriguez D, Watts D, Gaete D, Sormendi S, Wielockx B. Hypoxia Pathway Proteins and Their Impact on the Blood Vasculature. Int J Mol Sci 2021; 22:ijms22179191. [PMID: 34502102 PMCID: PMC8431527 DOI: 10.3390/ijms22179191] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/16/2021] [Accepted: 08/21/2021] [Indexed: 12/12/2022] Open
Abstract
Every cell in the body requires oxygen for its functioning, in virtually every animal, and a tightly regulated system that balances oxygen supply and demand is therefore fundamental. The vascular network is one of the first systems to sense oxygen, and deprived oxygen (hypoxia) conditions automatically lead to a cascade of cellular signals that serve to circumvent the negative effects of hypoxia, such as angiogenesis associated with inflammation, tumor development, or vascular disorders. This vascular signaling is driven by central transcription factors, namely the hypoxia inducible factors (HIFs), which determine the expression of a growing number of genes in endothelial cells and pericytes. HIF functions are tightly regulated by oxygen sensors known as the HIF-prolyl hydroxylase domain proteins (PHDs), which are enzymes that hydroxylate HIFs for eventual proteasomal degradation. HIFs, as well as PHDs, represent attractive therapeutic targets under various pathological settings, including those involving vascular (dys)function. We focus on the characteristics and mechanisms by which vascular cells respond to hypoxia under a variety of conditions.
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23
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Huang Z, Huang S, Song T, Yin Y, Tan C. Placental Angiogenesis in Mammals: A Review of the Regulatory Effects of Signaling Pathways and Functional Nutrients. Adv Nutr 2021; 12:2415-2434. [PMID: 34167152 PMCID: PMC8634476 DOI: 10.1093/advances/nmab070] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/05/2021] [Accepted: 05/11/2021] [Indexed: 12/13/2022] Open
Abstract
Normal placental development and proper angiogenesis are essential for fetal growth during pregnancy. Angiogenesis involves the regulatory action of many angiogenic factors and a series of signal transduction processes inside and outside the cell. The obstruction of placental angiogenesis causes fetal growth restriction and serious pregnancy complications, even leading to fetal loss and pregnancy cessation. In this review, the effects of placental angiogenesis on fetal development are described, and several signaling pathways related to placental angiogenesis and their key regulatory mediators are summarized. These factors, which include vascular endothelial growth factor (VEGF)-VEGF receptor, delta-like ligand 4 (DLL-4)-Notch, Wnt, and Hedgehog, may affect the placental angiogenesis process. Moreover, the degree of vascularization depends on cell proliferation, migration, and differentiation, which is affected by the synthesis and secretion of metabolites or intermediates and mutual coordination or inhibition in these pathways. Furthermore, we discuss recent advances regarding the role of functional nutrients (including amino acids and fatty acids) in regulating placental angiogenesis. Understanding the specific mechanism of placental angiogenesis and its influence on fetal development may facilitate the establishment of new therapeutic strategies for the treatment of preterm birth, pre-eclampsia, or intrauterine growth restriction, and provide a theoretical basis for formulating nutritional regulation strategies during pregnancy.
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Affiliation(s)
- Zihao Huang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Shuangbo Huang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Tongxing Song
- Huazhong Agricultural University, College of Animal Science and Technology, Wuhan, China
| | - Yulong Yin
- National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, China
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24
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Schofield CL, Rodrigo-Navarro A, Dalby MJ, Van Agtmael T, Salmeron-Sanchez M. Biochemical‐ and Biophysical‐Induced Barriergenesis in the Blood–Brain Barrier: A Review of Barriergenic Factors for Use in In Vitro Models. ADVANCED NANOBIOMED RESEARCH 2021. [DOI: 10.1002/anbr.202000068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
| | | | - Matthew J. Dalby
- Centre for the Cellular Microenvironment University of Glasgow Glasgow UK
| | - Tom Van Agtmael
- Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow UK
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25
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Fei Y, Zhao B, Zhu J, Fang W, Li Y. XQ-1H promotes cerebral angiogenesis via activating PI3K/Akt/GSK3β/β-catenin/VEGF signal in mice exposed to cerebral ischemic injury. Life Sci 2021; 272:119234. [PMID: 33607158 DOI: 10.1016/j.lfs.2021.119234] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/25/2021] [Accepted: 02/10/2021] [Indexed: 12/11/2022]
Abstract
Stroke still ranks as a most lethal disease worldwide. Angiogenesis during the chronic phase of ischemic stroke can alleviate ischemic injury and attenuate neurological deficit. XQ-1H is a new compound derived from the structure modification of ginkgolide B, which exerts anti-inflammation and neuroprotection against cerebral ischemic injury during the acute or subacute phase. However, whether XQ-1H facilitates angiogenesis and neural functional recovery during the chronic phase remains unclear. This research was designed to explore whether XQ-1H promotes angiogenesis after ischemic stroke and to preliminarily elucidate the mechanism. In vitro, XQ-1H was found to facilitate proliferation, migration and tube formation in bEnd.3 cells. In vivo, XQ-1H raised the CD31 positive microvessel number and increased focal cerebral blood flow in mice exposed to cerebral ischemic injury, and improved the neurological function. Mechanism studies revealed that XQ-1H exerted angiogenesis promoting effect via the PI3K/Akt/GSK3β/β-catenin/VEGF signal pathway, which was reversed by LY294002 (the specific inhibitor of PI3K/Akt). In conclusion, XQ-1H exerts angiogenetic effect both in vivo and in vitro, which is a potential agent against ischemic stroke during chronic phase.
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Affiliation(s)
- Yuxiang Fei
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Bo Zhao
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Jianping Zhu
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Weirong Fang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Yunman Li
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
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26
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Vieira JR, Shah B, Ruiz de Almodovar C. Cellular and Molecular Mechanisms of Spinal Cord Vascularization. Front Physiol 2020; 11:599897. [PMID: 33424624 PMCID: PMC7793711 DOI: 10.3389/fphys.2020.599897] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/24/2020] [Indexed: 01/13/2023] Open
Abstract
During embryonic central nervous system (CNS) development, the neural and the vascular systems communicate with each other in order to give rise to a fully functional and mature CNS. The initial avascular CNS becomes vascularized by blood vessel sprouting from different vascular plexus in a highly stereotypical and controlled manner. This process is similar across different regions of the CNS. In particular for the developing spinal cord (SC), blood vessel ingression occurs from a perineural vascular plexus during embryonic development. In this review, we provide an updated and comprehensive description of the cellular and molecular mechanisms behind this stereotypical and controlled patterning of blood vessels in the developing embryonic SC, identified using different animal models. We discuss how signals derived from neural progenitors and differentiated neurons guide the SC growing vasculature. Lastly, we provide a perspective of how the molecular mechanisms identified during development could be used to better understand pathological situations.
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Affiliation(s)
- Jose Ricardo Vieira
- European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Bhavin Shah
- European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carmen Ruiz de Almodovar
- European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany
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27
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Hu K, Xie W, Ni S, Yan S, Tian G, Qi W, Duan Y. Cadmium chloride enhances cisplatin sensitivity in osteosarcoma cells by reducing FOXM1 expression. Oncol Rep 2020; 44:650-660. [PMID: 32627005 PMCID: PMC7336512 DOI: 10.3892/or.2020.7632] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 04/02/2020] [Indexed: 02/05/2023] Open
Abstract
Osteosarcoma is a highly malignant disease and is associated with a poor patient prognosis and a high mortality rate. Disease prognosis significantly correlates with chemotherapeutic responses. Cadmium is a heavy metal with specific effects on bone, but its benefits for osteosarcoma treatment have not been characterized. In the present study, cadmium chloride was used to treat MG63 osteosarcoma cells, and their gene expression profiles were assessed by GeneChip technology. We found that forkhead box protein M1 (FOXM1) was downregulated by cadmium chloride, and lentiviral‑mediated silencing of FOXM1 confirmed a role for this factor in the cisplatin resistance of MG63 cells. In nude mice, cadmium chloride enhanced the sensitivity of osteosarcoma to cisplatin, an effect mediated by FOXM1. Collectively, these data indicate that cadmium chloride can alter the sensitivity of osteosarcoma cells to cisplatin through FOXM1, highlighting it as a potential therapeutic target and prognostic factor for osteosarcoma.
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Affiliation(s)
- Konghe Hu
- Department of Spine Surgery, The Affiliated Yuebei People's Hospital of Shantou University Medical College, Shaoguan, Guangdong 512025, P.R. China
| | - Wenquan Xie
- Department of Spine Surgery, The Affiliated Yuebei People's Hospital of Shantou University Medical College, Shaoguan, Guangdong 512025, P.R. China
| | - Songjia Ni
- Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Shumin Yan
- Department of Spine Surgery, The Affiliated Yuebei People's Hospital of Shantou University Medical College, Shaoguan, Guangdong 512025, P.R. China
| | - Gaoqiang Tian
- Department of Spine Surgery, The Affiliated Yuebei People's Hospital of Shantou University Medical College, Shaoguan, Guangdong 512025, P.R. China
| | - Weizhong Qi
- Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
- Correspondence to: Dr Weizhong Qi or Dr Yang Duan, Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China, E-mail: , E-mail:
| | - Yang Duan
- Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
- Correspondence to: Dr Weizhong Qi or Dr Yang Duan, Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China, E-mail: , E-mail:
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28
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Yao MD, Jiang Q, Ma Y, Liu C, Zhu CY, Sun YN, Shan K, Ge HM, Zhang QY, Zhang HY, Yao J, Li XM, Yan B. Role of METTL3-Dependent N 6-Methyladenosine mRNA Modification in the Promotion of Angiogenesis. Mol Ther 2020; 28:2191-2202. [PMID: 32755566 DOI: 10.1016/j.ymthe.2020.07.022] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 05/28/2020] [Accepted: 07/21/2020] [Indexed: 12/28/2022] Open
Abstract
Epigenetic alterations occur in many physiological and pathological processes. N6-methyladenosine (m6A) modification is the most prevalent modification in eukaryotic mRNAs. However, the role of m6A modification in pathological angiogenesis remains elusive. In this study, we showed that the level of m6A modification was significantly upregulated in endothelial cells and mouse retinas following hypoxic stress, which was caused by increased METTL3 levels. METTL3 silencing or METTL3 overexpression altered endothelial cell viability, proliferation, migration, and tube formation in vitro. METTL3 knockout in vivo decreased avascular area and pathological neovascular tufts in an oxygen-induced retinopathy model and inhibited alkali burn-induced corneal neovascularization. Mechanistically, METTL3 exerted its angiogenic role by regulating Wnt signaling through the m6A modification of target genes (e.g., LRP6 and dishevelled 1 [DVL1]). METTL3 enhanced the translation of LRP6 and DVL1 in an YTH m6A RNA-binding protein 1 (YTHDF1)-dependent manner. Collectively, this study suggests that METTL3-mediated m6A modification is an important hypoxic stress-response mechanism. The targeting of m6A through its writer enzyme METTL3 is a promising strategy for the treatment of angiogenic diseases.
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Affiliation(s)
- Mu-Di Yao
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Qin Jiang
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Yan Ma
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Chang Liu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Chuan-Yan Zhu
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Ya-Nan Sun
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Kun Shan
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Hui-Min Ge
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Qiu-Yang Zhang
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Hui-Ying Zhang
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Jin Yao
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Xiu-Miao Li
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Biao Yan
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China.
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29
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Caputo T, Tran VDT, Bararpour N, Winkler C, Aguileta G, Trang KB, Giordano Attianese GMP, Wilson A, Thomas A, Pagni M, Guex N, Desvergne B, Gilardi F. Anti-adipogenic signals at the onset of obesity-related inflammation in white adipose tissue. Cell Mol Life Sci 2020; 78:227-247. [PMID: 32157317 PMCID: PMC7867564 DOI: 10.1007/s00018-020-03485-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 02/07/2020] [Accepted: 02/17/2020] [Indexed: 12/17/2022]
Abstract
Chronic inflammation that affects primarily metabolic organs, such as white adipose tissue (WAT), is considered as a major cause of human obesity-associated co-morbidities. However, the molecular mechanisms initiating this inflammation in WAT are poorly understood. By combining transcriptomics, ChIP-seq and modeling approaches, we studied the global early and late responses to a high-fat diet (HFD) in visceral (vWAT) and subcutaneous (scWAT) AT, the first being more prone to obesity-induced inflammation. HFD rapidly triggers proliferation of adipocyte precursors within vWAT. However, concomitant antiadipogenic signals limit vWAT hyperplastic expansion by interfering with the differentiation of proliferating adipocyte precursors. Conversely, in scWAT, residing beige adipocytes lose their oxidizing properties and allow storage of excessive fatty acids. This phase is followed by tissue hyperplastic growth and increased angiogenic signals, which further enable scWAT expansion without generating inflammation. Our data indicate that scWAT and vWAT differential ability to modulate adipocyte number and differentiation in response to obesogenic stimuli has a crucial impact on the different susceptibility to obesity-related inflammation of these adipose tissue depots.
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Affiliation(s)
- Tiziana Caputo
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Van Du T Tran
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Nasim Bararpour
- Unit of Forensic Toxicology and Chemistry, CURML, Lausanne University Hospital, Geneva University Hospitals, Lausanne, Switzerland.,Faculty Unit of Toxicology, Faculty of Biology and Medicine, CURML, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Carine Winkler
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Gabriela Aguileta
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Khanh Bao Trang
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | | | - Anne Wilson
- Department of Oncology, University of Lausanne, Epalinges, Switzerland
| | - Aurelien Thomas
- Unit of Forensic Toxicology and Chemistry, CURML, Lausanne University Hospital, Geneva University Hospitals, Lausanne, Switzerland.,Faculty Unit of Toxicology, Faculty of Biology and Medicine, CURML, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Marco Pagni
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Nicolas Guex
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.,Bioinformatics Competence Center, University of Lausanne, Lausanne, Switzerland
| | - Béatrice Desvergne
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
| | - Federica Gilardi
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. .,Unit of Forensic Toxicology and Chemistry, CURML, Lausanne University Hospital, Geneva University Hospitals, Lausanne, Switzerland. .,Faculty Unit of Toxicology, Faculty of Biology and Medicine, CURML, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
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30
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Wu Y, Liu X, Zheng H, Zhu H, Mai W, Huang X, Huang Y. Multiple Roles of sFRP2 in Cardiac Development and Cardiovascular Disease. Int J Biol Sci 2020; 16:730-738. [PMID: 32071544 PMCID: PMC7019133 DOI: 10.7150/ijbs.40923] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 12/14/2019] [Indexed: 12/13/2022] Open
Abstract
The Wnt signaling pathway plays important roles in organ development and disease processes. Secreted frizzled-related protein 2 (sFRP2), a vital molecule of Wnt signaling, can regulate cardiac development and cardiovascular disease. Recent studies have suggested that sFRP2 is not only an antagonist of the canonical Wnt signaling pathway, but also has a more complex relationship in myocardial fibrosis, angiogenesis, cardiac hypertrophy and cardiac regeneration. Here, we review the role of sFRP2 and Wnt signaling in cardiac development and cardiovascular disease.
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Affiliation(s)
- Yu Wu
- Department of Cardiology, Shunde hospital, Southern Medical University, Jiazi Road 1 Lunjiao Town, Shunde District, Foshan, Guangdong, 528308, China
| | - Xinyue Liu
- Department of Cardiology, Shunde hospital, Southern Medical University, Jiazi Road 1 Lunjiao Town, Shunde District, Foshan, Guangdong, 528308, China
| | - Haoxiao Zheng
- Department of Cardiology, Shunde hospital, Southern Medical University, Jiazi Road 1 Lunjiao Town, Shunde District, Foshan, Guangdong, 528308, China
| | - Hailan Zhu
- Department of Cardiology, Shunde hospital, Southern Medical University, Jiazi Road 1 Lunjiao Town, Shunde District, Foshan, Guangdong, 528308, China
| | - Weiyi Mai
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou
| | - Xiaohui Huang
- Department of Cardiology, Shunde hospital, Southern Medical University, Jiazi Road 1 Lunjiao Town, Shunde District, Foshan, Guangdong, 528308, China
| | - Yuli Huang
- Department of Cardiology, Shunde hospital, Southern Medical University, Jiazi Road 1 Lunjiao Town, Shunde District, Foshan, Guangdong, 528308, China
- The George Institute for Global Health, NSW 2042 Australia
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31
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He Z, Du X, Wu Y, Hua L, Wan L, Yan N. Simvastatin promotes endothelial dysfunction by activating the Wnt/β‑catenin pathway under oxidative stress. Int J Mol Med 2019; 44:1289-1298. [PMID: 31432100 PMCID: PMC6713427 DOI: 10.3892/ijmm.2019.4310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 07/11/2019] [Indexed: 12/15/2022] Open
Abstract
Atherosclerosis is a major pathogenic factor in patients with cardiovascular diseases, and endothelial dysfunction (ED) plays a primary role in its occurrence and development. Simvastatin is a lipid‑lowering drug, which is commonly used to prevent or treat risk factors of cardiovascular diseases with a significant anti‑atherogenic effect. However, its impact on endothelial cells under conditions of oxidative stress and broader mechanisms of action remain unclear. The present study evaluated the effect of simvastatin on human umbilical vein endothelial cells (HUVECs) under oxidative stress with H2O2, and the associated mechanisms. At a high dose (1 µM), simvastatin exacerbated H2O2‑induced endothelial cell dysfunction. Moreover, inhibition of the Wnt/β‑catenin pathway by salinomycin significantly suppressed the simvastatin‑associated HUVEC dysfunction. Western blot analysis further demonstrated that simvastatin promoted the phosphorylation of low‑density lipoprotein receptor‑related protein 6 (LRP6) and activated the Wnt/β‑catenin pathway. Simvastatin also activated endoplasmic reticulum (ER) stress, which was reversed by salinomycin treatment. Based on these results, it was hypothesized that simvastatin may promote ER stress by facilitating LRP6 phosphorylation and the subsequent activation of the Wnt/β‑catenin pathway, thereby enhancing H2O2‑induced ED. Therefore, high‑dose simvastatin treatment could have potential toxic side effects, indicating the need for close clinical management, monitoring and patient selection.
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Affiliation(s)
- Zhiqiang He
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xinyue Du
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yifan Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Lingyue Hua
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Linxi Wan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Nianlong Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Machlowska J, Pucułek M, Sitarz M, Terlecki P, Maciejewski R, Sitarz R. State of the art for gastric signet ring cell carcinoma: from classification, prognosis, and genomic characteristics to specified treatments. Cancer Manag Res 2019; 11:2151-2161. [PMID: 30936747 PMCID: PMC6421895 DOI: 10.2147/cmar.s188622] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is responsible for 9% of cancer deaths worldwide. Over 950,000 new cases are diagnosed each year, and about 90% of them are in advanced stage, requiring chemotherapy. In Europe there has been research based on pre- and postoperative chemotherapy treatment, using 5-fluorouracil, epirubicin, cisplatin, capecitabine, and docetaxel. Chemotherapy significantly impairs the quality of life of patients; however, the final effects are not always satisfactory. There is scientific evidence that gastric mucus tumors and signet ring cell carcinomas have a pattern of specific signatures, that distinguish them from other gastric cancer subtypes, and may be associated with a poor response to systematic treatment. Signet ring cell carcinoma is less chemosensitive than others, and the increase in the percentage of signet ring cells correlates with resistance to chemotherapy. Perioperative chemotherapy in advanced signet ring cell carcinomas is an independent factor of poor prognosis and survival, which is explained by the toxicity of neoadjuvant treatment. Therefore, curative surgical resection enhanced by standardized lymphadenectomy remains the recommended gold standard in GC therapy. According to presented studies, early detection and aggressive treatments for this subtype of GC is a reasonable approach. This review paper is mostly addressed to physicians who are interested in updating to the state of the art concerning different subtypes of gastric carcinoma.
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Affiliation(s)
- Julita Machlowska
- Department of Human Anatomy, Medical University of Lublin, Lublin, Poland,
| | - Małgorzata Pucułek
- Department of Human Anatomy, Medical University of Lublin, Lublin, Poland,
| | - Monika Sitarz
- Department of Conservative Dentistry and Endodontics, Medical University of Lublin, Lublin, Poland
| | - Paweł Terlecki
- Department of Surgery, St. John's Cancer Center, Lublin, Poland,
| | | | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, Lublin, Poland,
- Department of Surgery, St. John's Cancer Center, Lublin, Poland,
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Wang Z, Liu CH, Huang S, Chen J. Wnt Signaling in vascular eye diseases. Prog Retin Eye Res 2018; 70:110-133. [PMID: 30513356 DOI: 10.1016/j.preteyeres.2018.11.008] [Citation(s) in RCA: 135] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 11/21/2018] [Accepted: 11/28/2018] [Indexed: 12/16/2022]
Abstract
The Wnt signaling pathway plays a pivotal role in vascular morphogenesis in various organs including the eye. Wnt ligands and receptors are key regulators of ocular angiogenesis both during the eye development and in vascular eye diseases. Wnt signaling participates in regulating multiple vascular beds in the eye including regression of the hyaloid vessels, and development of structured layers of vasculature in the retina. Loss-of-function mutations in Wnt signaling components cause rare genetic eye diseases in humans such as Norrie disease, and familial exudative vitreoretinopathy (FEVR) with defective ocular vasculature. On the other hand, experimental studies in more prevalent vascular eye diseases, such as wet age-related macular degeneration (AMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), and corneal neovascularization, suggest that aberrantly increased Wnt signaling is one of the causations for pathological ocular neovascularization, indicating the potential of modulating Wnt signaling to ameliorate pathological angiogenesis in eye diseases. This review recapitulates the key roles of the Wnt signaling pathway during ocular vascular development and in vascular eye diseases, and pharmaceutical approaches targeting the Wnt signaling as potential treatment options.
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Affiliation(s)
- Zhongxiao Wang
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, United States
| | - Chi-Hsiu Liu
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, United States
| | - Shuo Huang
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, United States
| | - Jing Chen
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, United States.
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Characterization of canonical Wnt signalling changes after induced disruption of Müller cell in murine retina. Exp Eye Res 2018; 175:173-180. [PMID: 29913166 DOI: 10.1016/j.exer.2018.06.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 06/06/2018] [Accepted: 06/14/2018] [Indexed: 02/05/2023]
Abstract
Müller cells are the primary glia in the retina, playing a critical role in retinal homeostasis and retinal pathology. This study evaluated the canonical Wnt signalling pathway and its downstream effects on retinal degeneration in a transgenic mouse model of inducible Müller cell disruption. Increased expression of the LacZ reporter gene in the retina suggested Wnt signalling had been activated after induced Müller cell disruption. Activation was validated by observing nuclear translocation of β-Catenin. The mRNA expression of 80 Wnt related genes were assessed using real-time PCR. The Wnt signalling inhibitors Dkk1, Dkk3 and sFRP3 were significantly downregulated. Furthermore, the ubiquitin-mediated β-Catenin proteolysis genes β-TrCP and SHFM3, were also significantly downregulated. The downstream target genes of the Wnt signalling, including Fra1, CyclinD2 and C-Myc were upregulated. The changes of these genes at the protein level were validated by Western blot. Their distributions in the retina were evaluated by immunofluorescent staining. Our findings indicate that Müller cells are involved in retinal Wnt signalling. Activation of Wnt signalling and its downstream target genes may play important roles in photoreceptor degeneration and neovascularization occurring in the retina after induced disruption of Müller cells.
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Planar Cell Polarity Signaling in Mammalian Cardiac Morphogenesis. Pediatr Cardiol 2018; 39:1052-1062. [PMID: 29564519 PMCID: PMC5959767 DOI: 10.1007/s00246-018-1860-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 03/06/2018] [Indexed: 01/16/2023]
Abstract
The mammalian heart is the first organ to form and is critical for embryonic survival and development. With an occurrence of 1%, congenital heart defects (CHDs) are also the most common birth defects in humans, and major cause of childhood morbidity and mortality (Hoffman and Kaplan in J Am Coll Cardiol 39(12):1890-1900, 2002; Samanek in Cardiol Young 10(3):179-185, 2000). Understanding how the heart forms will not only help to determine the etiology and to design diagnostic and therapeutic approaches for CHDs, but may also provide insight into regenerative medicine to repair injured adult hearts. Mammalian heart development requires precise orchestration of growth, differentiation, and morphogenesis to remodel a simple linear heart tube into an intricate, four-chambered heart with properly connected pulmonary artery and aorta, a structural basis for establishing the pulmonary and systemic circulation. Here we will review the recent advance in our understanding of how the planar cell polarity pathway, a highly conserved morphogenetic engine in vertebrates, regulates polarized morphogenetic processes to contribute to both the arterial and venous poles development of the heart.
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Padwal M, Cheng G, Liu L, Boivin F, Gangji AS, Brimble KS, Bridgewater D, Margetts PJ. WNT signaling is required for peritoneal membrane angiogenesis. Am J Physiol Renal Physiol 2018; 314:F1036-F1045. [DOI: 10.1152/ajprenal.00497.2017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The wingless-type mouse mammary tumor virus integration site family (WNT) signaling pathway is involved in wound healing and fibrosis. We evaluated the WNT signaling pathway in peritoneal membrane injury. We assessed WNT1 protein expression in the peritoneal effluents of 54 stable peritoneal dialysis (PD) patients and WNT-related gene expression in ex vivo mesothelial cell cultures from 21 PD patients. In a transforming growth factor-β (TGF-β)-mediated animal model of peritoneal fibrosis, we evaluated regulation of the WNT pathway and the effect of WNT inhibition on peritoneal fibrosis and angiogenesis. WNT1 and WNT2 gene expression were positively correlated with peritoneal membrane solute transport in PD patients. In the mouse peritoneum, TGF-β-induced peritoneal fibrosis was associated with increased expression of WNT2 and WNT4. Peritoneal β-catenin protein was significantly upregulated after infection with adenovirus expressing TGF-β (AdTGF-β) along with elements of the WNT signaling pathway. Treatment with a β-catenin inhibitor (ICG-001) in mice with AdTGF-β-induced peritoneal fibrosis resulted in attenuation of peritoneal angiogenesis and reduced vascular endothelial growth factor. Similar results were also observed with the WNT antagonist Dickkopf-related protein (DKK)-1. In addition to this, DKK-1 blocked epithelial-mesenchymal transition and increased levels of the cell adhesion protein E-cadherin. We provide evidence that WNT signaling is active in the setting of experimental peritoneal fibrosis and WNT1 correlates with patient peritoneal membrane solute transport in PD patients. Intervention in this pathway is a possible therapy for peritoneal membrane injury.
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Affiliation(s)
- Manreet Padwal
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Genyang Cheng
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Limin Liu
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Felix Boivin
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Azim S. Gangji
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | | | | | - Peter J. Margetts
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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Qiu F, Shin Y, Chen D, Cheng R, Chen Q, Zhou K, Larrick JW, Mendelson AR, Ma JX. Anti-angiogenic effect of a humanized antibody blocking the Wnt/β-catenin signaling pathway. Microvasc Res 2018; 119:29-37. [PMID: 29630973 DOI: 10.1016/j.mvr.2018.03.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 01/14/2018] [Accepted: 03/24/2018] [Indexed: 10/17/2022]
Abstract
PURPOSE Our previous study demonstrated that Mab2F1, a murine monoclonal antibody blocking the Wnt/β-catenin signaling pathway, has beneficial effects on experimental diabetic retinopathy and choroidal neovascularization (NV). The aforementioned antibody has been humanized. This study evaluated effects of the humanized antibody, H1L1, on NV. METHODS H1L1 was evaluated in the alkali burn-induced corneal NV rat model. Rats with corneal NV were injected subconjunctivally with Mab2F1 or H1L1 using non-specific mouse or human IgG as controls. Corneal NV and opacity were evaluated using corneal NV area and inflammatory index. Expression of angiogenic and inflammatory factors and components of the Wnt/β-catenin pathway in both the corneas of the animal model and human corneal epithelial (HCE) cells exposed to Wnt3a conditioned medium (WCM) were determined by Western blotting and a luciferase-based promoter assay. Cytotoxicities of these antibodies were evaluated by MTT assay. RESULTS H1L1 reduced the area of corneal NV and opacity, similar to Mab2F1. Both Mab2F1 and H1L1 down-regulated the overexpression of angiogenic and inflammatory factors including VEGF, TNF-α and ICAM-1, and blocked the aberrant activation of the Wnt/β-catenin pathway as shown by down-regulation of phosphorylated LRP6, total LRP6 and non-phosphorylated β-catenin in the cornea of the NV model and cultured HCE cells exposed to WCM. Both antibodies also inhibited the transcriptional activity of β-catenin induced by WCM in HCE cells. No toxic effects of the antibodies were observed in cultured HCE cells. CONCLUSIONS H1L1 exhibits anti-angiogenic activities through blocking the Wnt/β-catenin pathway.
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Affiliation(s)
- Fangfang Qiu
- Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Younghwa Shin
- Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | | | - Rui Cheng
- Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Qian Chen
- Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Kelu Zhou
- Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | | | | | - Jian-Xing Ma
- Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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Foulquier S, Daskalopoulos EP, Lluri G, Hermans KCM, Deb A, Blankesteijn WM. WNT Signaling in Cardiac and Vascular Disease. Pharmacol Rev 2018; 70:68-141. [PMID: 29247129 PMCID: PMC6040091 DOI: 10.1124/pr.117.013896] [Citation(s) in RCA: 258] [Impact Index Per Article: 36.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
WNT signaling is an elaborate and complex collection of signal transduction pathways mediated by multiple signaling molecules. WNT signaling is critically important for developmental processes, including cell proliferation, differentiation and tissue patterning. Little WNT signaling activity is present in the cardiovascular system of healthy adults, but reactivation of the pathway is observed in many pathologies of heart and blood vessels. The high prevalence of these pathologies and their significant contribution to human disease burden has raised interest in WNT signaling as a potential target for therapeutic intervention. In this review, we first will focus on the constituents of the pathway and their regulation and the different signaling routes. Subsequently, the role of WNT signaling in cardiovascular development is addressed, followed by a detailed discussion of its involvement in vascular and cardiac disease. After highlighting the crosstalk between WNT, transforming growth factor-β and angiotensin II signaling, and the emerging role of WNT signaling in the regulation of stem cells, we provide an overview of drugs targeting the pathway at different levels. From the combined studies we conclude that, despite the sometimes conflicting experimental data, a general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology. The rapidly increasing collection of drugs interfering at different levels of WNT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future, translating the outcomes of the many preclinical studies into a clinically relevant context.
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Affiliation(s)
- Sébastien Foulquier
- Department of Pharmacology and Toxicology, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands (S.F., K.C.M.H., W.M.B.); Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium (E.P.D.); Department of Medicine, Division of Cardiology, David Geffen School of Medicine (G.L., A.D.); and Department of Molecular Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California (A.D.)
| | - Evangelos P Daskalopoulos
- Department of Pharmacology and Toxicology, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands (S.F., K.C.M.H., W.M.B.); Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium (E.P.D.); Department of Medicine, Division of Cardiology, David Geffen School of Medicine (G.L., A.D.); and Department of Molecular Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California (A.D.)
| | - Gentian Lluri
- Department of Pharmacology and Toxicology, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands (S.F., K.C.M.H., W.M.B.); Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium (E.P.D.); Department of Medicine, Division of Cardiology, David Geffen School of Medicine (G.L., A.D.); and Department of Molecular Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California (A.D.)
| | - Kevin C M Hermans
- Department of Pharmacology and Toxicology, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands (S.F., K.C.M.H., W.M.B.); Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium (E.P.D.); Department of Medicine, Division of Cardiology, David Geffen School of Medicine (G.L., A.D.); and Department of Molecular Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California (A.D.)
| | - Arjun Deb
- Department of Pharmacology and Toxicology, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands (S.F., K.C.M.H., W.M.B.); Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium (E.P.D.); Department of Medicine, Division of Cardiology, David Geffen School of Medicine (G.L., A.D.); and Department of Molecular Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California (A.D.)
| | - W Matthijs Blankesteijn
- Department of Pharmacology and Toxicology, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands (S.F., K.C.M.H., W.M.B.); Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium (E.P.D.); Department of Medicine, Division of Cardiology, David Geffen School of Medicine (G.L., A.D.); and Department of Molecular Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California (A.D.)
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Zhang YK, Li JM, Qin L. Suppression of corneal neovascularization by curcumin via inhibition of Wnt/β-catenin pathway activation. Int J Ophthalmol 2017; 10:1791-1797. [PMID: 29259894 DOI: 10.18240/ijo.2017.12.01] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 11/09/2016] [Indexed: 12/22/2022] Open
Abstract
AIM To investigate whether curcumin suppressed corneal neovascularization (CNV) formation via inhibiting activation of Wnt/β-catenin pathway. METHODS Suture-induced CNV was established on Sprague-Dawley (SD) rats. Curcumin were daily administrated by subconjunctival injection. Phosphorylation of low-density lipoprotein receptor-related protein 6 (LRP6) and nuclear accumulation of β-catenin, two indicators of activated Wnt/β-catenin pathway, were determined by Western-blot analysis in subconfluent/proliferating human microvascular endothelial cells (HMEC) and neovascularized corneas. Wnt3a conditioned medium (WCM) were harvested from Wnt3a expressing cells. WCM-induced cell proliferation and endothelial tubular formation capacity was measured by MTT assay and Matrigel assay, respectively. RESULTS Phosphorylation of LRP6 and nuclear accumulation of β-catenin was significantly increased in subconfluent/proliferating endothelial cells. Activation of Wnt/β-catenin pathway by WCM markedly promotes HMEC proliferation and tubular formation. Curcumin inhibited LRP6 phosphorylation and nuclear accumulation of β-catenin. In addition, curcumin attenuated WCM-induced HMEC proliferation and disrupted tubular structure of endothelial cells on Matrigel. Meanwhile curcumin suppressed suture-induced CNV and inhibited LRP6 phosphorylation as well as β-catenin accumulation in SD rats. CONCLUSION Taken together, activation of Wnt/β-catenin pathway could be involved in endothelial proliferation during suture-induced CNV formation and curcumin attenuated CNV formation via inhibition of Wnt/β-catenin pathway activation.
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Affiliation(s)
- Yong-Kang Zhang
- Department of Ophthalmology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.,Department of Ophthalmology, Shaanxi Kangfu Hospital, Xi'an 710065, Shaanxi Province, China
| | - Jing-Ming Li
- Department of Ophthalmology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
| | - Li Qin
- Department of Ophthalmology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
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Siddique A, Yu B, Khan K, Buyting R, Al-Kindi H, Alaws H, Rhéaume E, Tardif JC, Cecere R, Schwertani A. Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves. Can J Physiol Pharmacol 2017; 96:208-214. [PMID: 29244962 DOI: 10.1139/cjpp-2017-0577] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The cellular mechanisms that induce calcific aortic stenosis are yet to be unraveled. Wnt signaling is increasingly being considered as a major player in the disease process. However, the presence of Wnt Frizzled (Fzd) receptors and co-receptors LRP5 and 6 in normal and diseased human aortic valves remains to be elucidated. Immunohistochemistry and quantitative polymerase chain reaction were used to determine Fzd receptor expression in normal and calcified human aortic valve tissue, as well as human aortic valve interstitial cells (HAVICs) isolated from calcified and normal human aortic valves. There was significantly higher mRNA expression of 4 out of the 10 Fzd receptors in calcified aortic valve tissues and 8 out of the 10 in HAVICs, and both LRP5/6 co-receptors in calcified aortic valves (P < 0.05). These results were confirmed by immunohistochemistry, which revealed abundant increase in immunoreactivity for Fzd3, 7, and 8, mainly in areas of lipid core and calcified nodules of diseased aortic valves. The findings of abundant expression of Fzd and LRP5/6 receptors in diseased aortic valves suggests a potential role for both canonical and noncanonical Wnt signaling in the pathogenesis of human aortic valve calcification. Future investigations aimed at targeting these molecules may provide potential therapies for aortic valve stenosis.
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Affiliation(s)
- Ateeque Siddique
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Bin Yu
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Kashif Khan
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Ryan Buyting
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Hamood Al-Kindi
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Hossny Alaws
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Eric Rhéaume
- b Montreal Heart Institute, Montreal, QC H1T 1C8, Canada
| | | | - Renzo Cecere
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Adel Schwertani
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
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Campos MM, Abu-Asab MS. Loss of endothelial planar cell polarity and cellular clearance mechanisms in age-related macular degeneration. Ultrastruct Pathol 2017; 41:312-319. [PMID: 28796562 DOI: 10.1080/01913123.2017.1348418] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Apoptosis, autophagosomes, and lysosomes are lacking in the retinal pigment epithelium (RPE) of age-related macular degeneration (AMD) eyes. Necrosis, not apoptosis, appeared to be the prominent type of cell death in RPE, which led to the accumulation of cell debris within and on both sides of Bruch's membrane. The endothelium of the choriocapillaris had an altered planar cell polarity which encompassed the disappearance of fenestrations, the thickening of cytoplasm, and anterior nuclear dislocation. There were no significant differences in RPE and choroidal aberrations between macular and temporal regions. Loss of endothelial polarity could be at the crux of AMD initiation and progression.
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Affiliation(s)
- Maria Mercedes Campos
- a Section of Histopathology , National Eye Institute, NIH , Bethesda , Maryland , USA
| | - Mones S Abu-Asab
- a Section of Histopathology , National Eye Institute, NIH , Bethesda , Maryland , USA
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Trigiani LJ, Hamel E. An endothelial link between the benefits of physical exercise in dementia. J Cereb Blood Flow Metab 2017; 37:2649-2664. [PMID: 28617071 PMCID: PMC5536816 DOI: 10.1177/0271678x17714655] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 04/25/2017] [Accepted: 05/19/2017] [Indexed: 12/29/2022]
Abstract
The current absence of a disease-modifying treatment for Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) highlights the necessity for investigating the benefits of non-pharmacological approaches such as physical exercise (PE). Although evidence exists to support an association between regular PE and higher scores on cognitive function tests, and a slower rate of cognitive decline, there is no clear consensus on the underlying molecular mechanisms of the advantages of PE. This review seeks to summarize the positive effects of PE in human and animal studies while highlighting the vascular link between these benefits. Lifestyle factors such as cardiovascular diseases, metabolic syndrome, and sleep apnea will be addressed in relation to the risk they pose in developing AD and VCID, as will molecular factors known to have an impact on either the initiation or the progression of AD and/or VCID. This will include amyloid-beta clearance, oxidative stress, inflammatory responses, neurogenesis, angiogenesis, glucose metabolism, and white matter integrity. Particularly, this review will address how engaging in PE can counter factors that contribute to disease pathogenesis, and how these alterations are linked to endothelial cell function.
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Affiliation(s)
- Lianne J Trigiani
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Canada
| | - Edith Hamel
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Canada
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Asslaber M, Schauer S, Gogg-Kamerer M, Bernhart E, Quehenberger F, Haybaeck J. Native Oligodendrocytes in Astrocytomas Might Inhibit Tumor Proliferation by WIF1 Expression. J Neuropathol Exp Neurol 2017; 76:16-26. [PMID: 28040794 DOI: 10.1093/jnen/nlw098] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Malignant astrocytoma remains incurable and rapidly fatal despite multimodal therapy. In particular, accelerated tumor cell heterogeneity often overcomes therapeutic effects of molecular protein targeting. This study aimed at identifying a gene with therapeutic potential that was consistently downregulated with astrocytoma progression. Analysis of the "Rembrandt" gene expression data revealed Wnt inhibitory factor 1 (WIF1) gene as the most promising candidate with tumor suppressor function. Consequently, 288 randomly selected tissue regions of astrocytoma specimens were investigated immunohistochemically with the aid of image analysis. This in situ approach identified tumor areas with numerous single cells strongly expressing Wif-1. In diffuse and anaplastic astrocytoma, the proliferation index was independent of the generally weak Wif-1 expression in tumor cells but was significantly correlated with the density of Wif-1-expressing single cells, subsequently characterized as native and non-neoplastic oligodendrocytes. Because these cells may contribute to inhibition of tumor cell proliferation by paracrine signaling, the endogenous protein Wif-1 may represent a promising therapeutic agent with expected minimal side effects. Moreover, we suggest that immunohistochemistry for Wif might be useful for discriminating between astrocytic tumors and reactive changes.
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Affiliation(s)
- Martin Asslaber
- Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Silvia Schauer
- Department of Pathology, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Margit Gogg-Kamerer
- Department of Pathology, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Eva Bernhart
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Franz Quehenberger
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Johannes Haybaeck
- Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria
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Mu J, Hui T, Shao B, Li L, Du Z, Lu L, Ye L, Li S, Li Q, Xiao Q, Qiu Z, Zhang Y, Fan J, Ren G, Tao Q, Xiang T. Dickkopf-related protein 2 induces G0/G1 arrest and apoptosis through suppressing Wnt/β-catenin signaling and is frequently methylated in breast cancer. Oncotarget 2017; 8:39443-39459. [PMID: 28467796 PMCID: PMC5503624 DOI: 10.18632/oncotarget.17055] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 03/20/2017] [Indexed: 12/05/2022] Open
Abstract
Dickkopf-related protein 2 (DKK2) is one of the antagonists of Wnt/β-catenin signaling, with its downregulation reported in multiple cancers. However, how DKK2 contributes to breast tumorigenesis remains unclear. We examined its expression and promoter methylation in 10 breast tumor cell lines, 98 primary tumors, and 21 normal breast tissues. Compared with normal tissues, DKK2 was frequently silenced in breast cell lines (7/8). DKK2 promoter methylation was detected in 77.8% of cell lines and 86.7% of breast tumors; while rarely detected in normal breast tissues (19%), indicating common DKK2 methylation in breast cancer. Ectopic expression of DKK2 changed breast tumor cell morphology, inhibited cell proliferation and colony formation by inducing G0/G1 cell cycle arrest and apoptosis, and suppressed tumor cell migration by reversing epithelial-mesenchymal transition (EMT) and downregulating stem cell markers. Moreover, restored expression of DKK2 in MCF7 cells disrupted the microtube formation of human umbilical vein endothelial cells on Matrigel®. In vivo, the growth of MDA-MB-231 cells in nude mice was markedly decreased after stable expression of DKK2. DKK2 suppressed canonical Wnt/β-catenin signaling by inhibiting β-catenin activity with decreased active β-catenin protein. Thus, our findings demonstrate that DKK2 functions as a tumor suppressor through inhibiting cell proliferation and inducing apoptosis via regulating Wnt signaling during breast tumorigenesis.
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Affiliation(s)
- Junhao Mu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tianli Hui
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bianfei Shao
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lili Li
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong
| | - Zhenfang Du
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong
| | - Li Lu
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong
| | - Lin Ye
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shuman Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qianqian Li
- Chinese Medicine Hospital of Linyi City, Shandong, China
| | - Qian Xiao
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhu Qiu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Zhang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiangxia Fan
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guosheng Ren
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qian Tao
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong
| | - Tingxiu Xiang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Mu J, Zhu D, Shen Z, Ning S, Liu Y, Chen J, Li Y, Li Z. The repressive effect of miR-148a on Wnt/β-catenin signaling involved in Glabridin-induced anti-angiogenesis in human breast cancer cells. BMC Cancer 2017; 17:307. [PMID: 28464803 PMCID: PMC5414299 DOI: 10.1186/s12885-017-3298-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 04/24/2017] [Indexed: 03/04/2023] Open
Abstract
BACKGROUND Glabridin (GLA), a major component extracted from licorice root, has anti-inflammatory and antioxidant activities, but few studies report its mechanism of inhibition of angiogenesis. This study was an extension of our previous work, which demonstrated that GLA suppressed angiogenesis in human breast cancer (MDA-MB-231 and Hs-578T) cells. Breast cancer is one of the most common malignant diseases in females worldwide, and the major cause of mortality is metastasis that is primarily attributed to angiogenesis. Thus, anti-angiogenesis has become a strategy for the treatment of breast cancer. METHODS Cell viability of different concentration treatment groups were detected by Cell Counting Kit-8 assay. The expression of several related genes in the Wnt1 signaling pathway in MDA-MB-231 and Hs-578T cells treated with GLA were measured at both the transcription and translation levels using quantitative real-time PCR analyses and western blotting. Immunofluorescence assay analyzed the nuclear translocation of β-catenin. The microRNA-inhibitor was used to knockdown microRNA-148a (miR-148a) expression. Angiogenic potentials of breast cancer cells were analyzed by enzyme-linked immunosorbent assay (ELISA) and tube formation in vitro. RESULTS GLA attenuated angiogenesis by the suppression of miR-148a-mediated Wnt/β-catenin signaling pathway in two human breast cancer cell lines (MDA-MB-231 and Hs-578T). GLA also upregulated the expression of miR-148a in a dose-dependent manner, miR-148a, which could directly target Wnt-3'-untranslated regions (UTRs), and decreased the expression of Wnt1, leading to β-catenin accumulation in the membranes from the cytoplasm and nucleus. Downregulation of miR-148a contributed to the reduction of GLA-induced suppression of the Wnt/β-catenin signaling pathway, the angiogenesis and vascular endothelial grow factor (VEGF) secretion. CONCLUSIONS Our study identified a molecular mechanism of the GLA inhibition of angiogenesis through the Wnt/β-catenin signaling pathway via miR-148a, suggesting that GLA could serve as an adjuvant chemotherapeutic agent for breast cancer.
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Affiliation(s)
- Juan Mu
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211100 China
| | - Dongmei Zhu
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211100 China
| | - Zhaoxia Shen
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211100 China
| | - Shilong Ning
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211100 China
| | - Yun Liu
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211100 China
| | - Juan Chen
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211100 China
| | - Yuan Li
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211100 China
| | - Zhong Li
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211100 China
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Chen D, Tang J, Wan Q, Zhang J, Wang K, Shen Y, Yu Y. E-Prostanoid 3 Receptor Mediates Sprouting Angiogenesis Through Suppression of the Protein Kinase A/β-Catenin/Notch Pathway. Arterioscler Thromb Vasc Biol 2017; 37:856-866. [DOI: 10.1161/atvbaha.116.308587] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 02/16/2017] [Indexed: 01/14/2023]
Abstract
Objective—
Angiogenesis is a hallmark of embryonic development and various ischemic and inflammatory diseases. Prostaglandin E2 receptor subtype 3 (EP3) plays an important role in pathophysiologic angiogenesis; however, the precise mechanisms remain unknown. Here, we investigated the role of EP3 in zebra fish embryo and mouse retina angiogenesis and evaluated the underlying mechanisms.
Approach and Results—
The EP3 receptor was highly expressed in the vasculature in both zebra fish embryos and murine fetal retinas. Pharmacological inhibition or genetic deletion of EP3 significantly reduced vasculature formation in zebra fish embryos and mouse retinas. Further characterization revealed reduced filopodia extension of tip cells in embryonic retinas in EP3-deficient mice. EP3 deletion activated Notch activity by upregulation of delta-like ligand 4 expression in endothelial cells (ECs). Inhibition of Notch signaling rescued the angiogenic defects in EP3-deficient mouse retinas. Moreover, EP3 deficiency led to a significant increase in β-catenin phosphorylation at Ser675 and nuclear accumulation of β-catenin in ECs. Knockdown or inhibition of β-catenin restored the impaired sprouting angiogenesis resulting from EP3 deficiency in ECs. The EP3 receptor depressed protein kinase A activity in ECs by coupling to Gαi. Inhibition of protein kinase A activity significantly reduced Ser675 phosphorylation and nuclear translocation of β-catenin, abolished the increased delta-like ligand 4 expression, and subsequently restored the impaired angiogenic capacity of EP3-deficient ECs both in vitro and in vivo.
Conclusions—
Activation of the EP3 receptor facilitates sprouting angiogenesis through protein kinase A–dependent Notch signaling, suggesting that EP3 and its downstream pathways maybe potential therapeutic targets in the treatment of ischemic diseases.
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Affiliation(s)
- Di Chen
- From the Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (D.C., J.Z., Y.S., Y.Y.); and Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China (D.C., J.T., Q.W., K.W., Y.Y.)
| | - Juan Tang
- From the Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (D.C., J.Z., Y.S., Y.Y.); and Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China (D.C., J.T., Q.W., K.W., Y.Y.)
| | - Qiangyou Wan
- From the Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (D.C., J.Z., Y.S., Y.Y.); and Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China (D.C., J.T., Q.W., K.W., Y.Y.)
| | - Jian Zhang
- From the Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (D.C., J.Z., Y.S., Y.Y.); and Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China (D.C., J.T., Q.W., K.W., Y.Y.)
| | - Kai Wang
- From the Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (D.C., J.Z., Y.S., Y.Y.); and Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China (D.C., J.T., Q.W., K.W., Y.Y.)
| | - Yujun Shen
- From the Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (D.C., J.Z., Y.S., Y.Y.); and Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China (D.C., J.T., Q.W., K.W., Y.Y.)
| | - Ying Yu
- From the Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (D.C., J.Z., Y.S., Y.Y.); and Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China (D.C., J.T., Q.W., K.W., Y.Y.)
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The Transcription Factor Bach1 Suppresses the Developmental Angiogenesis of Zebrafish. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:2143875. [PMID: 28392885 PMCID: PMC5368388 DOI: 10.1155/2017/2143875] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 02/23/2017] [Indexed: 12/29/2022]
Abstract
Bach1 disrupts Wnt/β-catenin signaling, reduces the proliferation, migration, and tube formation activity of endothelial cells (ECs), and suppresses angiogenesis in mice with surgically induced hind-limb ischemia (HLI). However, the function of Bach1 during developmental angiogenesis in zebrafish remains unclear. Here, we found that zebrafish Bach1 was expressed ubiquitously during early embryonic development in zebrafish. Bach1b mRNA injection of Tg(fli1:gfp) fish disrupted intersegmental vessels (ISV) and dorsal longitudinal anastomotic vessels (DLAV) and suppressed endogenous Wnt/β-catenin signaling and Wnt8a stimulated vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) gene expression at early embryonic stages of zebrafish. Furthermore, chromatin immunoprecipitation experiments confirmed that Bach1 occupied the TCF/LEF-binding site of the VEGF promoter in human umbilical vein endothelial cells (HUVECs). Bach1 inhibited VEGF transcription by recruiting histone deacetylase 1 (HDAC1) to the VEGF promoter in HUVECs. Exogenous administration of VEGF or IL-8 partially rescued Bach1-driven antiangiogenic functions in HUVECs. Taken together, these observations indicate that Bach1 suppresses the developmental angiogenesis of zebrafish and that this function is associated with declines in Wnt/β-catenin signaling and VEGF and IL-8 expression.
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Markovič R, Peltan J, Gosak M, Horvat D, Žalik B, Seguy B, Chauvel R, Malandain G, Couffinhal T, Duplàa C, Marhl M, Roux E. Planar cell polarity genes frizzled4 and frizzled6 exert patterning influence on arterial vessel morphogenesis. PLoS One 2017; 12:e0171033. [PMID: 28253274 PMCID: PMC5333836 DOI: 10.1371/journal.pone.0171033] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 01/14/2017] [Indexed: 11/19/2022] Open
Abstract
Quantitative analysis of the vascular network anatomy is critical for the understanding of the vasculature structure and function. In this study, we have combined microcomputed tomography (microCT) and computational analysis to provide quantitative three-dimensional geometrical and topological characterization of the normal kidney vasculature, and to investigate how 2 core genes of the Wnt/planar cell polarity, Frizzled4 and Frizzled6, affect vascular network morphogenesis. Experiments were performed on frizzled4 (Fzd4-/-) and frizzled6 (Fzd6-/-) deleted mice and littermate controls (WT) perfused with a contrast medium after euthanasia and exsanguination. The kidneys were scanned with a high-resolution (16 μm) microCT imaging system, followed by 3D reconstruction of the arterial vasculature. Computational treatment includes decomposition of 3D networks based on Diameter-Defined Strahler Order (DDSO). We have calculated quantitative (i) Global scale parameters, such as the volume of the vasculature and its fractal dimension (ii) Structural parameters depending on the DDSO hierarchical levels such as hierarchical ordering, diameter, length and branching angles of the vessel segments, and (iii) Functional parameters such as estimated resistance to blood flow alongside the vascular tree and average density of terminal arterioles. In normal kidneys, fractal dimension was 2.07±0.11 (n = 7), and was significantly lower in Fzd4-/- (1.71±0.04; n = 4), and Fzd6-/- (1.54±0.09; n = 3) kidneys. The DDSO number was 5 in WT and Fzd4-/-, and only 4 in Fzd6-/-. Scaling characteristics such as diameter and length of vessel segments were altered in mutants, whereas bifurcation angles were not different from WT. Fzd4 and Fzd6 deletion increased vessel resistance, calculated using the Hagen-Poiseuille equation, for each DDSO, and decreased the density and the homogeneity of the distal vessel segments. Our results show that our methodology is suitable for 3D quantitative characterization of vascular networks, and that Fzd4 and Fzd6 genes have a deep patterning effect on arterial vessel morphogenesis that may determine its functional efficiency.
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Affiliation(s)
- Rene Markovič
- Department of Physics, Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
- Faculty of Education, University of Maribor, Maribor, Slovenia
| | - Julien Peltan
- INSERM, Biology of Cardiovascular Diseases U1034, Pessac, France
- Université de Bordeaux, Biology of Cardiovascular Diseases U1034, Pessac, France
- Service des Maladies Cardiaques et Vasculaires, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Marko Gosak
- Department of Physics, Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Denis Horvat
- Faculty of Electrical Engineering and Computer Science, University of Maribor, Maribor, Slovenia
| | - Borut Žalik
- Faculty of Electrical Engineering and Computer Science, University of Maribor, Maribor, Slovenia
| | - Benjamin Seguy
- INSERM, Biology of Cardiovascular Diseases U1034, Pessac, France
- Service des Maladies Cardiaques et Vasculaires, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Remi Chauvel
- INSERM, Biology of Cardiovascular Diseases U1034, Pessac, France
- Université de Bordeaux, Biology of Cardiovascular Diseases U1034, Pessac, France
- Service des Maladies Cardiaques et Vasculaires, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | | | - Thierry Couffinhal
- INSERM, Biology of Cardiovascular Diseases U1034, Pessac, France
- Université de Bordeaux, Biology of Cardiovascular Diseases U1034, Pessac, France
- Service des Maladies Cardiaques et Vasculaires, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Cécile Duplàa
- INSERM, Biology of Cardiovascular Diseases U1034, Pessac, France
| | - Marko Marhl
- Department of Physics, Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
- Faculty of Education, University of Maribor, Maribor, Slovenia
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Etienne Roux
- INSERM, Biology of Cardiovascular Diseases U1034, Pessac, France
- Université de Bordeaux, Biology of Cardiovascular Diseases U1034, Pessac, France
- * E-mail:
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Khalili S, Rasaee MJ, Bamdad T. 3D structure of DKK1 indicates its involvement in both canonical and non-canonical Wnt pathways. Mol Biol 2017. [DOI: 10.1134/s0026893317010095] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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