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Hung CY, Hsueh TY, Rethi L, Lu HT, Chuang AEY. Advancements in regenerative medicine: a comprehensive review of stem cell and growth factor therapies for osteoarthritis. J Mater Chem B 2025; 13:4494-4526. [PMID: 40042377 DOI: 10.1039/d4tb01769b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
Osteoarthritis (OA) is a widely encountered degenerative joint disorder marked by gradual cartilage deterioration, inflammation, and pain, which collectively impose considerable strain on global healthcare systems. While traditional therapies typically offer relief from symptoms, they do not tackle the core pathophysiological aspects of the disease. Regenerative medicine has recently risen as a promising field for addressing OA, capitalizing on the regenerative capabilities of stem cells and growth factors to foster tissue healing and renewal. This thorough review delves into the most recent progress in stem cell and growth factor treatments for OA, covering preclinical studies, clinical trials, and novel technological developments. We discuss the diverse origins of stem cells, such as mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and adipose-derived stem cells (ASCs), underscoring their therapeutic actions and effectiveness in both preclinical and clinical environments. Moreover, we explore contributions of growth factors like transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF) in modifying OA's pathology and enhancing tissue restoration. Additionally, this review discusses the hurdles and constraints tied to current regenerative strategies, including the standardization of cell sources, the refinement of delivery techniques, and considerations for long-term safety. By meticulously assessing the latest research outcomes and technological breakthroughs, this review aims to shed light on the potential of stem cell and growth factor therapies as forthcoming therapeutic options for OA, thereby propelling forward the domain of regenerative medicine and enhancing clinical results for individuals afflicted with this incapacitating ailment.
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Affiliation(s)
- Chen-Yuan Hung
- School of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Tai-Yuan Hsueh
- School of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Lekshmi Rethi
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, New Taipei City, Taiwan.
- International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, New Taipei City, Taiwan
| | - Hsien-Tsung Lu
- Department of Orthopedics, Taipei Medical University Hospital, Taipei City 11031, Taiwan
- Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
- International PhD Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Andrew E-Y Chuang
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, New Taipei City, Taiwan.
- International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, New Taipei City, Taiwan
- Cell Physiology and Molecular Image Research Center, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
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Zhu Z, Hu B, Zhu D, Li X, Chen D, Wu N, Rao Q, Zhang Z, Wang H, Zhu Y. Bromocriptine sensitivity in bromocriptine-induced drug-resistant prolactinomas is restored by inhibiting FGF19/FGFR4/PRL. J Endocrinol Invest 2025; 48:67-80. [PMID: 38926262 DOI: 10.1007/s40618-024-02408-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 06/03/2024] [Indexed: 06/28/2024]
Abstract
PURPOSE At present, various treatment strategies are available for pituitary adenomas, including medications, surgery and radiation. The guidelines indicate that pharmacological treatments, such as bromocriptine (BRC) and cabergoline (CAB), are important treatments for prolactinomas, but drug resistance is an urgent problem that needs to be addressed. Therefore, exploring the mechanism of drug resistance in prolactinomas is beneficial for clinical treatment. METHODS In our research, BRC-induced drug-resistant cells were established. Previous RNA sequencing data and an online database were used for preliminary screening of resistance-related genes. Cell survival was determined by Cell Counting Kit-8 (CCK-8) assay, colony formation assays and flow cytometry. Quantitative real-time polymerase chain reaction (qRT‒PCR), western blotting, immunohistochemistry, immunofluorescence and Co-immunoprecipitation (Co-IP) were used to assess the molecular changes and regulation. The therapeutic efficacy of BRC and FGFR4 inhibitor fisogatinib (FISO) combination was evaluated in drug-resistant cells and xenograft tumors in nude mice. RESULTS Consistent with the preliminary results of RNA sequencing and database screening, fibroblast growth factor 19 (FGF19) expression was elevated in drug-resistant cells and tumor samples. With FGF19 silencing, drug-resistant cells exhibited increased sensitivity to BRC and decreased intracellular phosphorylated fibroblast growth factor receptor 4 (FGFR4) levels. After confirming that FGF19 binds to FGFR4 in prolactinoma cells, we found that FGF19/FGFR4 regulated prolactin (PRL) synthesis through the ERK1/2 and JNK signaling pathways. Regarding the effect of targeting FGF19/FGFR4 on BRC efficacy, FISO and BRC synergistically inhibited the growth of tumor cells, promoted apoptosis and reduced PRL levels. CONCLUSION Overall, our study revealed FGF19/FGFR4 as a new mechanism involved in the drug resistance of prolactinomas, and combination therapy targeting the pathway could be helpful for the treatment of BRC-induced drug-resistant prolactinomas.
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MESH Headings
- Bromocriptine/pharmacology
- Bromocriptine/therapeutic use
- Prolactinoma/drug therapy
- Prolactinoma/pathology
- Prolactinoma/metabolism
- Humans
- Receptor, Fibroblast Growth Factor, Type 4/metabolism
- Receptor, Fibroblast Growth Factor, Type 4/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 4/genetics
- Pituitary Neoplasms/drug therapy
- Pituitary Neoplasms/pathology
- Pituitary Neoplasms/metabolism
- Mice
- Animals
- Drug Resistance, Neoplasm/drug effects
- Fibroblast Growth Factors/metabolism
- Fibroblast Growth Factors/genetics
- Mice, Nude
- Xenograft Model Antitumor Assays
- Prolactin/metabolism
- Female
- Cell Proliferation/drug effects
- Male
- Gene Expression Regulation, Neoplastic/drug effects
- Tumor Cells, Cultured
- Cell Line, Tumor
- Dopamine Agonists/pharmacology
- Dopamine Agonists/therapeutic use
- Apoptosis/drug effects
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Affiliation(s)
- Z Zhu
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, No.74 Zhongshan Road 2, Guangzhou, 510080, Guangdong, China
| | - B Hu
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, Guangdong, China
| | - D Zhu
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, Guangdong, China
| | - X Li
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, No.74 Zhongshan Road 2, Guangzhou, 510080, Guangdong, China
| | - D Chen
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, No.74 Zhongshan Road 2, Guangzhou, 510080, Guangdong, China
| | - N Wu
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, No.74 Zhongshan Road 2, Guangzhou, 510080, Guangdong, China
| | - Q Rao
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, No.74 Zhongshan Road 2, Guangzhou, 510080, Guangdong, China
| | - Z Zhang
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, No.74 Zhongshan Road 2, Guangzhou, 510080, Guangdong, China
| | - H Wang
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, Guangdong, China.
| | - Y Zhu
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, No.74 Zhongshan Road 2, Guangzhou, 510080, Guangdong, China.
- Department of Histology and Embryology, School of Medicine, Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
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Peng M, Deng J, Li X. Clinical advances and challenges in targeting FGF/FGFR signaling in lung cancer. Mol Cancer 2024; 23:256. [PMID: 39543657 PMCID: PMC11566285 DOI: 10.1186/s12943-024-02167-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 10/31/2024] [Indexed: 11/17/2024] Open
Abstract
Fibroblast growth factors (FGFs) and their receptors regulate numerous cellular processes, such as metabolism and signal transduction, but can also drive tumorigenesis. Specifically, in lung cancer, the overexpression of FGFs, as well as the amplification, mutation and fusion of FGFR genes, are closely linked to the initiation, progression and resistance of the disease, suggesting that targeting FGF/FGFR is an attractive therapeutic strategy for lung cancer treatment. Nintedanib, a multitarget tyrosine kinase inhibitor (TKI) used in combination with docetaxel, has shown some success as a second-line therapy for lung cancer. However, clinical trials evaluating other FGFR inhibitors have yielded mixed results, indicating substantial complexity in targeting aberrant FGF/FGFR signaling. In this review, we describe the aberrations in FGF/FGFR signaling in lung cancer and summarize the clinical efficacy of FGFR inhibitors, such as multitarget TKIs, selective FGFR-TKIs and biological agents. We also discuss various challenges associated with FGFR targeting in lung cancer, including precision patient selection, toxicity and resistance. Finally, we provide perspectives on future directions, namely, developing novel FGFR-targeting drugs, such as FGFR degraders and more specific FGFR-TKIs, adopting combination therapy and targeting FGFs.
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Affiliation(s)
- Mei Peng
- Department of Pharmacy, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, P. R. China.
| | - Jun Deng
- Department of Pharmacy, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410000, P. R. China
| | - Xiangping Li
- Department of Pharmacy, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, P. R. China.
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Ma CN, Shi SR, Zhang XY, Xin GS, Zou X, Li WL, Guo SD. Targeting PDGF/PDGFR Signaling Pathway by microRNA, lncRNA, and circRNA for Therapy of Vascular Diseases: A Narrow Review. Biomolecules 2024; 14:1446. [PMID: 39595622 PMCID: PMC11592287 DOI: 10.3390/biom14111446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Despite the significant progress in diagnostic and therapeutic strategies, vascular diseases, such as cardiovascular diseases (CVDs) and respiratory diseases, still cannot be successfully eliminated. Vascular cells play a key role in maintaining vascular homeostasis. Notably, a variety of cells produce and secrete platelet-derived growth factors (PDGFs), which promote mitosis and induce the division, proliferation, and migration of vascular cells including vascular smooth muscle cells (SMCs), aortic SMCs, endothelial cells, and airway SMCs. Therefore, PDGF/PDGR receptor signaling pathways play vital roles in regulating the homeostasis of blood vessels and the onset and development of CVDs, such as atherosclerosis, and respiratory diseases including asthma and pulmonary arterial hypertension. Recently, accumulating evidence has demonstrated that microRNA, long-chain non-coding RNA, and circular RNA are involved in the regulation of PDGF/PDGFR signaling pathways through competitive interactions with target mRNAs, contributing to the occurrence and development of the above-mentioned diseases. These novel findings are useful for laboratory research and clinical studies. The aim of this article is to conclude the recent progresses in this field, particular the mechanisms of action of these non-coding RNAs in regulating vascular remodeling, providing potential strategies for the diagnosis, prevention, and treatment of vascular-dysfunction-related diseases, particularly CVDs and respiratory diseases.
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Affiliation(s)
- Chao-Nan Ma
- Institute of Lipid Metabolism and Atherosclerosis, School of Pharmacy, Shandong Second Medical University, Weifang 261053, China; (C.-N.M.); (S.-R.S.); (X.-Y.Z.)
| | - Shan-Rui Shi
- Institute of Lipid Metabolism and Atherosclerosis, School of Pharmacy, Shandong Second Medical University, Weifang 261053, China; (C.-N.M.); (S.-R.S.); (X.-Y.Z.)
| | - Xue-Ying Zhang
- Institute of Lipid Metabolism and Atherosclerosis, School of Pharmacy, Shandong Second Medical University, Weifang 261053, China; (C.-N.M.); (S.-R.S.); (X.-Y.Z.)
| | - Guo-Song Xin
- School of Pharmacy, Engineering Research Center for Medicine, Harbin University of Commerce, Harbin 150076, China; (G.-S.X.); (X.Z.)
| | - Xiang Zou
- School of Pharmacy, Engineering Research Center for Medicine, Harbin University of Commerce, Harbin 150076, China; (G.-S.X.); (X.Z.)
| | - Wen-Lan Li
- School of Pharmacy, Engineering Research Center for Medicine, Harbin University of Commerce, Harbin 150076, China; (G.-S.X.); (X.Z.)
| | - Shou-Dong Guo
- Institute of Lipid Metabolism and Atherosclerosis, School of Pharmacy, Shandong Second Medical University, Weifang 261053, China; (C.-N.M.); (S.-R.S.); (X.-Y.Z.)
- School of Pharmacy, Engineering Research Center for Medicine, Harbin University of Commerce, Harbin 150076, China; (G.-S.X.); (X.Z.)
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Umur E, Bulut SB, Yiğit P, Bayrak E, Arkan Y, Arslan F, Baysoy E, Kaleli-Can G, Ayan B. Exploring the Role of Hormones and Cytokines in Osteoporosis Development. Biomedicines 2024; 12:1830. [PMID: 39200293 PMCID: PMC11351445 DOI: 10.3390/biomedicines12081830] [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: 06/04/2024] [Revised: 08/07/2024] [Accepted: 08/09/2024] [Indexed: 09/02/2024] Open
Abstract
The disease of osteoporosis is characterized by impaired bone structure and an increased risk of fractures. There is a significant impact of cytokines and hormones on bone homeostasis and the diagnosis of osteoporosis. As defined by the World Health Organization (WHO), osteoporosis is defined as having a bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average for young and healthy women (T score < -2.5 SD). Cytokines and hormones, particularly in the remodeling of bone between osteoclasts and osteoblasts, control the differentiation and activation of bone cells through cytokine networks and signaling pathways like the nuclear factor kappa-B ligand (RANKL)/the receptor of RANKL (RANK)/osteoprotegerin (OPG) axis, while estrogen, parathyroid hormones, testosterone, and calcitonin influence bone density and play significant roles in the treatment of osteoporosis. This review aims to examine the roles of cytokines and hormones in the pathophysiology of osteoporosis, evaluating current diagnostic methods, and highlighting new technologies that could help for early detection and treatment of osteoporosis.
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Affiliation(s)
- Egemen Umur
- Department of Biomedical Engineering, İzmir Democracy University, İzmir 35140, Türkiye
| | - Safiye Betül Bulut
- Department of Biomedical Engineering, İzmir Democracy University, İzmir 35140, Türkiye
| | - Pelin Yiğit
- Department of Biomedical Engineering, İzmir Democracy University, İzmir 35140, Türkiye
| | - Emirhan Bayrak
- Department of Biomedical Engineering, İzmir Democracy University, İzmir 35140, Türkiye
| | - Yaren Arkan
- Department of Biomedical Engineering, İzmir Democracy University, İzmir 35140, Türkiye
| | - Fahriye Arslan
- Department of Biomedical Engineering, İzmir Democracy University, İzmir 35140, Türkiye
| | - Engin Baysoy
- Department of Biomedical Engineering, Bahçeşehir University, İstanbul 34353, Türkiye
| | - Gizem Kaleli-Can
- Department of Biomedical Engineering, İzmir Democracy University, İzmir 35140, Türkiye
| | - Bugra Ayan
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA
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Li HZ, Zhang JL, Yuan DL, Xie WQ, Ladel CH, Mobasheri A, Li YS. Role of signaling pathways in age-related orthopedic diseases: focus on the fibroblast growth factor family. Mil Med Res 2024; 11:40. [PMID: 38902808 PMCID: PMC11191355 DOI: 10.1186/s40779-024-00544-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 06/12/2024] [Indexed: 06/22/2024] Open
Abstract
Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.
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Affiliation(s)
- Heng-Zhen Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jing-Lve Zhang
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- Xiangya School of Medicine Central, South University, Changsha, 410083, China
| | - Dong-Liang Yuan
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Xiangya School of Medicine Central, South University, Changsha, 410083, China
| | - Wen-Qing Xie
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | | | - Ali Mobasheri
- Faculty of Medicine, Research Unit of Health Sciences and Technology, University of Oulu, 90014, Oulu, Finland.
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, 08406, Vilnius, Lithuania.
- Department of Rheumatology and Clinical Immunology, Universitair Medisch Centrum Utrecht, Utrecht, 3508, GA, the Netherlands.
- Department of Joint Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
- World Health Organization Collaborating Centre for Public Health Aspects of Musculoskeletal Health and Aging, Université de Liège, B-4000, Liège, Belgium.
| | - Yu-Sheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Jain NK, Tailang M, Thangavel N, Makeen HA, Albratty M, Najmi A, Alhazmi HA, Zoghebi K, Alagusundaram M, Jain HK, Chandrasekaran B. A comprehensive overview of selective and novel fibroblast growth factor receptor inhibitors as a potential anticancer modality. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2024; 74:1-36. [PMID: 38554385 DOI: 10.2478/acph-2024-0005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/09/2023] [Indexed: 04/01/2024]
Abstract
The arrival of comprehensive genome sequencing has accelerated the understanding of genetically aberrant advanced cancers and target identification for possible cancer treatment. Fibroblast growth factor receptor (FGFR) gene alterations are frequent findings in various rare and advanced cancers refractive to mainstay chemo-therapy or surgical interventions. Several FGFR inhibitors have been developed for addressing these genetically altered FGFR-harboring malignancies, and some have performed well in clinical trials. In contrast, others are still being investigated in different phases of clinical trials. FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. These include cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid malignancies. Pemigatinib is the only FGFR inhibitor globally approved (USA, EU, and Japan) and available as a targeted therapy for two types of cancer, including FGFR2 fusion or other rearrangements harboring cholangiocarcinoma and relapsed/refractory myeloid/lymphoid neoplasms with FGFR1 rearrangements. Myeloid/lymphoid neoplasm is the latest area of application added to the therapeutic armamentarium of FGFR inhibitors. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.
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Affiliation(s)
- Nem Kumar Jain
- School of Pharmacy, ITM University Gwalior 474001, Madhya Pradesh, India
- School of Studies in Pharmaceutical Sciences, Jiwaji University Gwalior 474001, Madhya Pradesh, India
| | - Mukul Tailang
- School of Studies in Pharmaceutical Sciences, Jiwaji University Gwalior 474001, Madhya Pradesh, India
| | - Neelaveni Thangavel
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 82912, Saudi Arabia
| | - Hafiz A Makeen
- Pharmacy Practice Research Unit Department of Clinical Pharmacy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 82912, Saudi Arabia
| | - Mohammed Albratty
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 82912, Saudi Arabia
| | - Asim Najmi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 82912, Saudi Arabia
| | - Hassan Ahmad Alhazmi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 82912, Saudi Arabia
| | - Khalid Zoghebi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 82912, Saudi Arabia
| | | | - Hemant Kumar Jain
- Department of General Medicine Government Medical College Datia 475661, Madhya Pradesh, India
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Li J, Nie J, Zhou Z, Guo M, Yang Q, Yuan D, Huang J, Li R, Li Q. Changes of FGF23 and hearing in chronic renal failure and their correlation analysis. Cytokine 2024; 174:156478. [PMID: 38134554 DOI: 10.1016/j.cyto.2023.156478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 12/01/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023]
Abstract
BACKGROUND To explore the association between fibroblast growth factor 23 (FGF23) and hearing in chronic renal failure (CRF). METHODS Pure tone audiometry was used to detect the hearing of patients with CRF; the level of serum FGF23, creatinine, blood urea nitrogen (BUN), parathyroid hormone (PTH), and mean binaural hearing threshold were compared to the control group (people without kidney disease). The rat model of renal failure was established by 5/6 nephrectomy, and the auditory brainstem response (ABR) of rats after modeling was detected by the Tucker Davis Technologies (TDT) system; the expression level of FGF23 in the peripheral blood, renal and cochlear tissue was also detected. RESULTS The incidence of hearing loss (HL) and serum FGF23 were higher in CRF patients than the control group; the sFGF23 was positively correlated with the mean binaural hearing threshold. Animal studies showed that the ABR threshold, creatinine, FGF23, BUN, and PTH increased after modeling; although, an increase in FGF23 was observed earlier than other indicators. The HL of rats with renal failure was significantly correlated with BUN, phosphate, PTH, sFGF23, kFGF23/β-actin, eFGF23/β-actin, weight, and modeling cycle. CONCLUSIONS Both CRF patients and rat models showed high-frequency HL. FGF23 was highly expressed in the serum of HL renal failure patients and rats, as well as in the renal tissue and cochlea of renal failure rats. Therefore, FGF23 may be involved in the occurrence and development of HL caused by CRF.
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Affiliation(s)
- Jiaqing Li
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jingwen Nie
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhu Zhou
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Min Guo
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qing Yang
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Dunlu Yuan
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jingjing Huang
- Department of Medical Record, The Third People's Hospital of Kunming, Kunming, China
| | - Ruomei Li
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qing Li
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
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Boutin L, Roger E, Gayat E, Depret F, Blot-Chabaud M, Chadjichristos CE. The role of CD146 in renal disease: from experimental nephropathy to clinics. J Mol Med (Berl) 2024; 102:11-21. [PMID: 37993561 DOI: 10.1007/s00109-023-02392-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 10/10/2023] [Accepted: 10/24/2023] [Indexed: 11/24/2023]
Abstract
Vascular endothelial dysfunction is a major risk factor in the development of renal diseases. Recent studies pointed out a major interest for the inter-endothelial junction protein CD146, as its expression is modulated during renal injury. Indeed, some complex mechanisms involving this adhesion molecule and its multiple ligands are observed in a large number of renal diseases in fundamental or clinical research. The purpose of this review is to summarize the most recent literature on the role of CD146 in renal pathophysiology, from experimental nephropathy to clinical trials.
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Affiliation(s)
- Louis Boutin
- FHU PROMICE AP-HP, Saint Louis and DMU Parabol, Critical Care Medicine and Burn Unit, AP-HP, Department of Anesthesiology, University Paris Cité, 75010, Paris, France
- INSERM, UMR-942, MASCOT, Cardiovascular Markers in Stress Condition, University Paris Cité, 75010, Paris, France
- INSERM, UMR-S1155, Bâtiment Recherche, Tenon Hospital, 4 rue de la Chine, 75020, Paris, France
| | - Elena Roger
- INSERM, UMR-S1155, Bâtiment Recherche, Tenon Hospital, 4 rue de la Chine, 75020, Paris, France
- Faculty of Medicine, Sorbonne University, 75013, Paris, France
| | - Etienne Gayat
- FHU PROMICE AP-HP, Saint Louis and DMU Parabol, Critical Care Medicine and Burn Unit, AP-HP, Department of Anesthesiology, University Paris Cité, 75010, Paris, France
- INSERM, UMR-942, MASCOT, Cardiovascular Markers in Stress Condition, University Paris Cité, 75010, Paris, France
| | - François Depret
- FHU PROMICE AP-HP, Saint Louis and DMU Parabol, Critical Care Medicine and Burn Unit, AP-HP, Department of Anesthesiology, University Paris Cité, 75010, Paris, France
- INSERM, UMR-942, MASCOT, Cardiovascular Markers in Stress Condition, University Paris Cité, 75010, Paris, France
| | | | - Christos E Chadjichristos
- INSERM, UMR-S1155, Bâtiment Recherche, Tenon Hospital, 4 rue de la Chine, 75020, Paris, France.
- Faculty of Medicine, Sorbonne University, 75013, Paris, France.
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Lyu Z, Li H, Li X, Wang H, Jiao H, Wang X, Zhao J, Lin H. Fibroblast growth factor 23 inhibits osteogenic differentiation and mineralization of chicken bone marrow mesenchymal stem cells. Poult Sci 2022; 102:102287. [PMID: 36442309 PMCID: PMC9706642 DOI: 10.1016/j.psj.2022.102287] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 10/20/2022] [Accepted: 10/20/2022] [Indexed: 11/05/2022] Open
Abstract
Fibroblast growth factor 23 (FGF23), a bone-derived hormone, is involved in the reabsorption of phosphate (P) and the production of vitamin D hormones in the kidney. However, whether and how FGF23 regulates chicken bone metabolism remains largely unknown. In the present study, we investigated the effect of FGF23 on osteogenic differentiation and mineralization of chicken bone marrow mesenchymal stem cells (BMSCs). First, we found that the transcription of FGF23 was inhibited by β-glycerophosphate sodium (GPS, 5 mM, 10 mM, 20 mM) and 10-9 M 1, 25-dihydroxyvitamin D3 (1, 25(OH)2D3), but was stimulated by 10-7 M 1, 25(OH)2D3 and parathyroid hormone (PTH, 10-9 M, 10-8 M, 10-7 M). Second, overexpression of FGF23 by the FGF23 adenovirus (Adv-FGF23) suppressed the formation of mineralized nodules (P < 0.001) and alkaline phosphatase (ALP) activity (P < 0.05) in both differentiated and mineralized osteoblasts. Administration of FGF receptor 3 (FGFR3) inhibitor (50 nM) was sufficient to restore the FGF23-decreased ALP activity (P < 0.05), but not for the formation of mineralized nodules. In addition, the phosphorylation of ERK increased considerably with Adv-FGF23 overexpression (P < 0.05). Administration of an ERK-specific inhibitor (10 μM) could down-regulate the phosphorylation of ERK (P-ERK) (P < 0.05) and slightly restored the Adv-FGF23-reduction of ALP activity (P = 0.08). In summary, our data suggest that GPS, 1, 25(OH)2D3, and PTH could regulate FGF23 mRNA expression in vitro. FGF23 is a negative regulator of bone remodeling. FGF23 not only inhibits BMSCs osteogenesis through the FGFR3-ERK signaling pathway but also suppresses the mineralization of mature osteoblasts.
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Affiliation(s)
- Zhengtian Lyu
- Department of Animal Science, Shandong Agricultural University, Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Key Lab for Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, 271018, China
| | - Haifang Li
- Department of Life Science, Shandong Agricultural University, Taian City, Shandong Province, 271018, China
| | - Xin Li
- Department of Animal Science, Shandong Agricultural University, Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Key Lab for Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, 271018, China
| | - Hui Wang
- Department of Animal Science, Shandong Agricultural University, Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Key Lab for Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, 271018, China
| | - Hongchao Jiao
- Department of Animal Science, Shandong Agricultural University, Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Key Lab for Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, 271018, China
| | - Xiaojuan Wang
- Department of Animal Science, Shandong Agricultural University, Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Key Lab for Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, 271018, China
| | - Jingpeng Zhao
- Department of Animal Science, Shandong Agricultural University, Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Key Lab for Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, 271018, China
| | - Hai Lin
- Department of Animal Science, Shandong Agricultural University, Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Key Lab for Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, 271018, China.
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11
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Activation of cAMP Signaling in Response to α-Phellandrene Promotes Vascular Endothelial Growth Factor Levels and Proliferation in Human Dermal Papilla Cells. Int J Mol Sci 2022; 23:ijms23168959. [PMID: 36012223 PMCID: PMC9409021 DOI: 10.3390/ijms23168959] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 11/17/2022] Open
Abstract
Dermal papilla cells (DPCs) are growth factor reservoirs that are specialized for hair morphogenesis and regeneration. Due to their essential role in hair growth, DPCs are commonly used as an in vitro model to investigate the effects of hair growth-regulating compounds and their molecular mechanisms of action. Cyclic adenosine monophosphate (cAMP), an intracellular second messenger, is currently employed as a growth-promoting target molecule. In a pilot test, we found that α-phellandrene, a naturally occurring phytochemical, increased cAMP levels in DPCs. Therefore, we sought to determine whether α-phellandrene increases growth factors and proliferation in human DPCs and to identify the underlying mechanisms. We demonstrated that α-phellandrene promotes cell proliferation concentration-dependently. In addition, it increases the cAMP downstream effectors, such as protein kinase A catalytic subunit (PKA Cα) and phosphorylated cAMP-responsive element-binding protein (CREB). Also, among the CREB-dependent growth factor candidates, we identified that α-phellandrene selectively upregulated vascular endothelial growth factor (VEGF) mRNA expression in DPCs. Notably, the beneficial effects of α-phellandrene were nullified by a cAMP inhibitor. This study demonstrated the cAMP-mediated growth effects in DPCs and the therapeutic potential of α-phellandrene for preventing hair loss.
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12
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Identification of key sex-specific pathways and genes in the subcutaneous adipose tissue from pigs using WGCNA method. BMC Genom Data 2022; 23:35. [PMID: 35538407 PMCID: PMC9086418 DOI: 10.1186/s12863-022-01054-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 05/04/2022] [Indexed: 02/08/2023] Open
Abstract
Background Adipose tissues (ATs), including visceral ATs (VATs) and subcutaneous ATs (SATs), are crucial for maintaining energy and metabolic homeostasis. SATs have been found to be closely related to obesity and obesity-induced metabolic disease. Some studies have shown a significant association between subcutaneous fat metabolism and sexes. However, the molecular mechanisms for this association are still unclear. Here, using the pig as a model, we investigated the systematic association between the subcutaneous fat metabolism and sexes, and identified some key sex-specific pathways and genes in the SATs from pigs. Results The results revealed that 134 differentially expressed genes (DEGs) were identified in female and male pigs from the obese group. A total of 17 coexpression modules were detected, of which six modules were significantly correlated with the sexes (P < 0.01). Among the significant modules, the greenyellow module (cor = 0.68, P < 9e-06) and green module (cor = 0.49, P < 0.003) were most significantly positively correlated with the male and female, respectively. Functional analysis showed that one GO term and four KEGG pathways were significantly enriched in the greenyellow module while six GO terms and six KEGG pathways were significantly enriched in the green module. Furthermore, a total of five and two key sex-specific genes were identified in the two modules, respectively. Two key sex-specific pathways (Ras-MAPK signaling pathway and type I interferon response) play an important role in the SATs of males and females, respectively. Conclusions The present study identified some key sex-specific pathways and genes in the SATs from pigs, which provided some new insights into the molecular mechanism of being involved in fat formation and immunoregulation between pigs of different sexes. These findings may be beneficial to breeding in the pig industry and obesity treatment in medicine. Supplementary Information The online version contains supplementary material available at 10.1186/s12863-022-01054-w.
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Zheng J, Zhang W, Li L, He Y, Wei Y, Dang Y, Nie S, Guo Z. Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review. Front Chem 2022; 10:860985. [PMID: 35494629 PMCID: PMC9046545 DOI: 10.3389/fchem.2022.860985] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/28/2022] [Indexed: 12/23/2022] Open
Abstract
Targeted therapy is a groundbreaking innovation for cancer treatment. Among the receptor tyrosine kinases, the fibroblast growth factor receptors (FGFRs) garnered substantial attention as promising therapeutic targets due to their fundamental biological functions and frequently observed abnormality in tumors. In the past 2 decades, several generations of FGFR kinase inhibitors have been developed. This review starts by introducing the biological basis of FGF/FGFR signaling. It then gives a detailed description of different types of small-molecule FGFR inhibitors according to modes of action, followed by a systematic overview of small-molecule-based therapies of different modalities. It ends with our perspectives for the development of novel FGFR inhibitors.
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Affiliation(s)
| | | | | | | | | | | | - Shenyou Nie
- Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Zufeng Guo
- Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
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14
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Chen K, Rao Z, Dong S, Chen Y, Wang X, Luo Y, Gong F, Li X. Roles of the fibroblast growth factor signal transduction system in tissue injury repair. BURNS & TRAUMA 2022; 10:tkac005. [PMID: 35350443 PMCID: PMC8946634 DOI: 10.1093/burnst/tkac005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 12/13/2021] [Indexed: 12/13/2022]
Abstract
Following injury, tissue autonomously initiates a complex repair process, resulting in either partial recovery or regeneration of tissue architecture and function in most organisms. Both the repair and regeneration processes are highly coordinated by a hierarchy of interplay among signal transduction pathways initiated by different growth factors, cytokines and other signaling molecules under normal conditions. However, under chronic traumatic or pathological conditions, the reparative or regenerative process of most tissues in different organs can lose control to different extents, leading to random, incomplete or even flawed cell and tissue reconstitution and thus often partial restoration of the original structure and function, accompanied by the development of fibrosis, scarring or even pathogenesis that could cause organ failure and death of the organism. Ample evidence suggests that the various combinatorial fibroblast growth factor (FGF) and receptor signal transduction systems play prominent roles in injury repair and the remodeling of adult tissues in addition to embryonic development and regulation of metabolic homeostasis. In this review, we attempt to provide a brief update on our current understanding of the roles, the underlying mechanisms and clinical application of FGFs in tissue injury repair.
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Affiliation(s)
| | | | - Siyang Dong
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Department of breast surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yajing Chen
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Xulan Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yongde Luo
- Correspondence. Xiaokun Li, ; Fanghua Gong, ; Yongde Luo,
| | - Fanghua Gong
- Correspondence. Xiaokun Li, ; Fanghua Gong, ; Yongde Luo,
| | - Xiaokun Li
- Correspondence. Xiaokun Li, ; Fanghua Gong, ; Yongde Luo,
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15
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Zhou X, Zhang Y, Wang N. Regulation and Potential Biological Role of Fibroblast Growth Factor 21 in Chronic Kidney Disease. Front Physiol 2021; 12:764503. [PMID: 34675822 PMCID: PMC8525706 DOI: 10.3389/fphys.2021.764503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/15/2021] [Indexed: 12/23/2022] Open
Abstract
Chronic kidney disease (CKD) is an incurable progressive disease with the progressive impairment of kidney function, which can accelerate the progression of cardiovascular disease, increase the risk of infection, and lead to related complications such as anemia and bone disease. CKD is to a great extent preventable and treatable, and it is particularly important to improve the early diagnosis, strengthen the research underlying the mechanism of disease occurrence and development, and innovate new intervention measures. Fibroblast growth factor 21 (FGF21) belongs to one of members of endocrine FGF subfamily with evolutionarily conserved functions and performs a vital role in the regulation of energy balance and adipose metabolism. FGF21 needs to rely on β-Klotho protein to specifically bind to FGF receptor (FGFR), which activates the FGF21 signaling exerting the biological function. FGF21 is deemed as an important regulatory factor extensively modulating many cellular functions under physiologic and pathologic conditions. Although the metabolic effect of FGF21 has been extensively studied, its potential biological role in the kidney has not been generally investigated. In this review, we summarize the biological characteristics, regulation and biological function of FGF21 based on the current studies, and briefly discuss the potential relationship with chronic kidney disease.
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Affiliation(s)
- Xue Zhou
- Department of Nephrology, Tianjin Haihe Hospital, Tianjin, China
| | - Yuefeng Zhang
- Department of Nephrology, Tianjin Haihe Hospital, Tianjin, China
| | - Ning Wang
- Tianjin Third Central Hospital, Tianjin, China
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Repetto M, Crimini E, Giugliano F, Morganti S, Belli C, Curigliano G. Selective FGFR/FGF pathway inhibitors: inhibition strategies, clinical activities, resistance mutations, and future directions. Expert Rev Clin Pharmacol 2021; 14:1233-1252. [PMID: 34591728 DOI: 10.1080/17512433.2021.1947246] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: Fibroblast growth factor receptor (FGFR)/fibroblast growth factor (FGF) is a pathway characterized by recurring alterations in cancer. Its dysregulations enhance cancer cell proliferation, survival, migration and invasion, as well as angiogenesis and immune evasion.Areas covered: FGFR/FGF selective inhibitors belong to a broad class of drugs with some being approved for specific indications and others under investigation in ongoing phase I and II clinical trials. In this review, all available clinical data from trials on selective FGFR/FGF inhibitors as well as described resistance mutations and mechanisms are presented. FGFR/FGF pathway inhibitors are classified according to the mechanism they employ to dampen/suppress signaling and to the preferred FGFR binding mode when X-ray crystal structure is available.Expert opinion: Data presented suggests the general actionability of FGFR1,2,3 mutations and fusions across histologies, whereas FGFR1,2,3 amplifications alone are poor predictors of response to tyrosine kinase inhibitors. Overexpression on immunohistochemistry (IHC) of FGF19, the stimulatory ligand of FGFR4, can predict response to FGFR selective inhibitors in hepatocellular carcinoma. Whereas IHC overexpression of FGFR1,2,3 is not sufficient to predict benefit from FGFR inhibitors across solid tumors. FGFR1,2,3 mRNA overexpression can predict response even in absence of structural alteration. Data on resistance mutations suggests the need for new inhibitors to overcome gatekeeper mutations.
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Affiliation(s)
- Matteo Repetto
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Edoardo Crimini
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Federica Giugliano
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Stefania Morganti
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Carmen Belli
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - Giuseppe Curigliano
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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Abstract
Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or β-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure–function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs.
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Trivedi N, Kumar D. Fibroblast growth factor and kidney disease: Updates for emerging novel therapeutics. J Cell Physiol 2021; 236:7909-7925. [PMID: 34196395 DOI: 10.1002/jcp.30497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/04/2021] [Accepted: 05/28/2021] [Indexed: 01/01/2023]
Abstract
The discovery of fibroblast growth factors (FGFs) and fibroblast growth factor receptors (FGFRs) provided a profound new insight into physiological and metabolic functions. FGF has a large family by having divergent structural elements and enable functional divergence and specification. FGF and FGFRs are highly expressed during kidney development. Signals from the ureteric bud regulate morphogenesis, nephrogenesis, and nephron progenitor survival. Thus, FGF signaling plays an important role in kidney progenitor cell aggregation at the sites of new nephron formation. This review will summarize the current knowledge about functions of FGF signaling in kidney development and their ability to promote regeneration in injured kidneys and its use as a biomarker and therapeutic target in kidney diseases. Further studies are essential to determine the predictive significance of the various FGF/FGFR deviations and to integrate them into clinical algorithms.
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Affiliation(s)
- Neerja Trivedi
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Devendra Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA
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Li C, Deng C, Zhou T, Hu J, Dai B, Yi F, Tian N, Jiang L, Dong X, Zhu Q, Zhang S, Cui H, Cao L, Shang Y. MicroRNA-370 carried by M2 macrophage-derived exosomes alleviates asthma progression through inhibiting the FGF1/MAPK/STAT1 axis. Int J Biol Sci 2021; 17:1795-1807. [PMID: 33994863 PMCID: PMC8120458 DOI: 10.7150/ijbs.59715] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/12/2021] [Indexed: 12/22/2022] Open
Abstract
Emerging evidence has suggested the functions of exosomes in allergic diseases including asthma. By using a mouse model with asthma induced by ovalbumin (OVA), we explored the roles of M2 macrophage-derived exosomes (M2Φ-Exos) in asthma progression. M2Φ-Exos significantly alleviated OVA-induced fibrosis and inflammatory responses in mouse lung tissues, as well as inhibited abnormal proliferation, invasion, and fibrosis-related protein production in platelet derived growth factor (PDGF-BB) treated primary mouse airway smooth muscle cells (ASMCs). The OVA administration in mice or the PDGF-BB treatment in ASMCs reduced the expression of miR-370, which was detected in M2Φ-Exos by miRNA sequencing. However, treating the mice or ASMCs with M2Φ-Exos reversed the inhibitory effect of OVA or PDGF-BB on miR-370 expression. We identified that the target of miR-370 was fibroblast growth factor 1 (FGF1). Downregulation of miR-370 by Lv-miR-370 inhibitor or overexpression of FGF1 by Lv-FGF1 blocked the protective roles of M2Φ-Exos in asthma-like mouse and cell models. M2Φ-Exos were found to inactivate the MAPK signaling pathway, which was recovered by miR-370 inhibition or FGF1 overexpression. Collectively, we conclude that M2Φ-Exos carry miR-370 to alleviate asthma progression through downregulating FGF1 expression and the MAPK/STAT1 signaling pathway. Our study may offer a novel insight into asthma treatment.
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Affiliation(s)
- Chunlu Li
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Chengsi Deng
- College of Basic Medicine Science, China Medical University, Shenyang 110122, China
| | - Tingting Zhou
- College of Basic Medicine Science, China Medical University, Shenyang 110122, China
| | - Jiapeng Hu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Bing Dai
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Fei Yi
- College of Basic Medicine Science, China Medical University, Shenyang 110122, China
| | - Na Tian
- Jilin Tuohua Biotechnology Co., Ltd. Changchun, Jilin 13000, China
| | - Lijun Jiang
- Jilin Tuohua Biotechnology Co., Ltd. Changchun, Jilin 13000, China
| | - Xiang Dong
- College of Basic Medicine Science, China Medical University, Shenyang 110122, China
| | - Qingfeng Zhu
- College of Basic Medicine Science, China Medical University, Shenyang 110122, China
| | - Siyi Zhang
- College of Basic Medicine Science, China Medical University, Shenyang 110122, China
| | - Hongyan Cui
- College of Basic Medicine Science, China Medical University, Shenyang 110122, China
| | - Liu Cao
- College of Basic Medicine Science, China Medical University, Shenyang 110122, China
| | - Yunxiao Shang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
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Sasaki N, Gomi F, Yoshimura H, Yamamoto M, Matsuda Y, Michishita M, Hatakeyama H, Kawano Y, Toyoda M, Korc M, Ishiwata T. FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12102976. [PMID: 33066597 PMCID: PMC7602396 DOI: 10.3390/cancers12102976] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 10/06/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that is projected to become the leading cause of cancer death by 2050. Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane receptor that is overexpressed in half of PDACs. We determined that its expression in PDAC positively correlated with larger tumor size and more advanced tumor stage, and that BLU9931, a selective FGFR4 inhibitor, reduced PDAC cell proliferation and invasion while promoting their senescence. Quercetin, a senolytic drug, induced cell death in BLU9931-treated cells. We propose that targeting FGFR4 in combination with senolysis could provide a novel therapeutic strategy in patients whose PDAC expresses high FGFR4 levels. Abstract Fibroblast growth factor receptor 4 (FGFR4), one of four tyrosine kinase receptors for FGFs, is involved in diverse cellular processes. Activation of FGF19/FGFR4 signaling is closely associated with cancer development and progression. In this study, we examined the expression and roles of FGF19/FGFR4 signaling in human pancreatic ductal adenocarcinoma (PDAC). In human PDAC cases, FGFR4 expression positively correlated with larger primary tumors and more advanced stages. Among eight PDAC cell lines, FGFR4 was expressed at the highest levels in PK-1 cells, in which single-nucleotide polymorphism G388R in FGFR4 was detected. For inhibition of autocrine/paracrine FGF19/FGFR4 signaling, we used BLU9931, a highly selective FGFR4 inhibitor. Inhibition of signal transduction through ERK, AKT, and STAT3 pathways by BLU9931 reduced proliferation in FGF19/FGFR4 signaling-activated PDAC cells. By contrast, BLU9931 did not alter stemness features, including stemness marker expression, anticancer drug resistance, and sphere-forming ability. However, BLU9931 inhibited cell invasion, in part, by downregulating membrane-type matrix metalloproteinase-1 in FGF19/FGFR4 signaling-activated PDAC cells. Furthermore, downregulation of SIRT1 and SIRT6 by BLU9931 contributed to senescence induction, priming these cells for quercetin-induced death, a process termed senolysis. Thus, we propose that BLU9931 is a promising therapeutic agent in FGFR4-positive PDAC, especially when combined with senolysis (195/200).
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Affiliation(s)
- Norihiko Sasaki
- Research team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Sakae-cho 35-2, Itabashi-ku, Tokyo 173-0015, Japan; (N.S.); (M.T.)
| | - Fujiya Gomi
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan;
| | - Hisashi Yoshimura
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan; (H.Y.); (M.Y.)
| | - Masami Yamamoto
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan; (H.Y.); (M.Y.)
| | - Yoko Matsuda
- Oncology Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa 761-0793, Japan;
| | - Masaki Michishita
- Department of Veterinary Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan;
| | - Hitoshi Hatakeyama
- Department of Comprehensive Education in Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan;
| | - Yoichi Kawano
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo 113-8603, Japan;
| | - Masashi Toyoda
- Research team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Sakae-cho 35-2, Itabashi-ku, Tokyo 173-0015, Japan; (N.S.); (M.T.)
| | - Murray Korc
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, CA 92697, USA;
| | - Toshiyuki Ishiwata
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan;
- Correspondence: ; Tel.: +81-3-3964-1141 (ext. 4414)
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Li C, Dai B, Hu J, Shang Y. WITHDRAWN: M2 macrophage-derived exosomes carry microRNA-370 to alleviate asthma progression through inhibiting the FGF1/MAPK/STAT1 axis. Exp Cell Res 2020:112285. [PMID: 32941809 DOI: 10.1016/j.yexcr.2020.112285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 01/16/2023]
Abstract
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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Affiliation(s)
- Chunlu Li
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, P.R. China
| | - Bing Dai
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, P.R. China
| | - Jiapeng Hu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, P.R. China
| | - Yunxiao Shang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, P.R. China
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22
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Wang Z, Xu Q, Zhang N, Du X, Xu G, Yan X. CD146, from a melanoma cell adhesion molecule to a signaling receptor. Signal Transduct Target Ther 2020; 5:148. [PMID: 32782280 PMCID: PMC7421905 DOI: 10.1038/s41392-020-00259-8] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 06/14/2020] [Accepted: 06/18/2020] [Indexed: 12/11/2022] Open
Abstract
CD146 was originally identified as a melanoma cell adhesion molecule (MCAM) and highly expressed in many tumors and endothelial cells. However, the evidence that CD146 acts as an adhesion molecule to mediate a homophilic adhesion through the direct interactions between CD146 and itself is still lacking. Recent evidence revealed that CD146 is not merely an adhesion molecule, but also a cellular surface receptor of miscellaneous ligands, including some growth factors and extracellular matrixes. Through the bidirectional interactions with its ligands, CD146 is actively involved in numerous physiological and pathological processes of cells. Overexpression of CD146 can be observed in most of malignancies and is implicated in nearly every step of the development and progression of cancers, especially vascular and lymphatic metastasis. Thus, immunotherapy against CD146 would provide a promising strategy to inhibit metastasis, which accounts for the majority of cancer-associated deaths. Therefore, to deepen the understanding of CD146, we review the reports describing the newly identified ligands of CD146 and discuss the implications of these findings in establishing novel strategies for cancer therapy.
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Affiliation(s)
- Zhaoqing Wang
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
| | - Qingji Xu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
- College of Life Science, University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Nengwei Zhang
- Department of Gastrointestinal Hepatobiliary Tumor Surgery, Beijing Shijitan Hospital, Capital Medical University, 100038, Beijing, China
| | - Xuemei Du
- Departments of Pathology, Beijing Shijitan Hospital, Capital Medical University, 100038, Beijing, China
| | - Guangzhong Xu
- Department of Gastrointestinal Hepatobiliary Tumor Surgery, Beijing Shijitan Hospital, Capital Medical University, 100038, Beijing, China
| | - Xiyun Yan
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
- College of Life Science, University of Chinese Academy of Sciences, 100049, Beijing, China.
- Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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Marchelek-Mysliwiec M, Dziedziejko V, Dolegowka K, Pawlik A, Safranow K, Stepniewska J, Wisniewska M, Malyszko J, Ciechanowski K. Association of FGF19, FGF21 and FGF23 with carbohydrate metabolism parameters and insulin resistance in patients with chronic kidney disease. J Appl Biomed 2020; 18:61-69. [PMID: 34907727 DOI: 10.32725/jab.2020.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 02/11/2020] [Indexed: 11/05/2022] Open
Abstract
Insulin resistance (IR) is characterised by increased gluconeogenesis in the liver and the resistance of peripheral receptors to insulin. Several factors, including IR, type 2 diabetes, new-onset diabetes after transplant (NODAT) and secondary parathyroidism, are related to chronic kidney disease (CKD). These factors are associated with higher mortality due to the increased risk of cardiovascular complications. Many factors have been identified as potential markers of IR in CKD. These factors include fibroblast growth factors (FGFs), a subfamily of endocrine polypeptides. In this study, we examined the association of FGF19, FGF21 and FGF23 with selected parameters related to carbohydrate metabolism and insulin resistance in non diabetic patients with predialysis CKD and in non diabetic patients after renal transplantation. The study included 108 non diabetic subjects: 40 patients with predialysis CKD, 45 patients with CKD who had undergone renal transplantation, and 23 healthy subjects (control group). In patients who had undergone renal transplantation, concentrations of FGF23 were increased compared to the control group and patients with predialysis CKD. The highest and lowest FGF19 concentrations were observed in CKD patients and in patients who had undergone kidney transplantation, respectively. This difference was statistically significant. Leptin concentrations were higher in CKD patients compared to the control group and patients who had undergone kidney transplantation. There were no statistically significant differences in adiponectin concentrations, lean body mass or fat tissue mass between the studied groups. HOMA-IR and insulin levels were significantly increased in CKD patients and in patients who had undergone renal transplantation in comparison to the control group. The results of the study suggest the involvement of FGF in carbohydrate metabolism and insulin resistance in patients with predialysis CKD, as well as a correlation with kidney function.
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Affiliation(s)
- Malgorzata Marchelek-Mysliwiec
- Pomeranian Medical University, Clinical Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland
| | - Violetta Dziedziejko
- Pomeranian Medical University, Department of Biochemistry and Medical Chemistry, Szczecin, Poland
| | - Katarzyna Dolegowka
- Pomeranian Medical University, Clinical Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland
| | - Andrzej Pawlik
- Pomeranian Medical University, Department of Physiology, Szczecin, Poland
| | - Krzysztof Safranow
- Pomeranian Medical University, Department of Biochemistry and Medical Chemistry, Szczecin, Poland
| | - Joanna Stepniewska
- Pomeranian Medical University, Clinical Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland
| | - Magda Wisniewska
- Pomeranian Medical University, Clinical Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland
| | - Jolanta Malyszko
- Warsaw Medical University, Department of Nephrology, Dialysis and Internal Medicine, Warsaw, Poland
| | - Kazimierz Ciechanowski
- Pomeranian Medical University, Clinical Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland
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24
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Effects of fasting on the expression pattern of FGFs in different skeletal muscle fibre types and sexes in mice. Biol Sex Differ 2020; 11:9. [PMID: 32156311 PMCID: PMC7063800 DOI: 10.1186/s13293-020-00287-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 03/02/2020] [Indexed: 02/07/2023] Open
Abstract
Fibroblast growth factors (FGFs) belong to a large family comprising 22 FGF polypeptides that are widely expressed in tissues. Most of the FGFs can be secreted and involved in the regulation of skeletal muscle function and structure. However, the role of fasting on FGF expression pattern in skeletal muscles remains unknown. In this study, we combined bioinformatics analysis and in vivo studies to explore the effect of 24-h fasting on the expression of Fgfs in slow-twitch soleus and fast-twitch tibialis anterior (TA) muscle from male and female C57BL/6 mice. We found that fasting significantly affected the expression of many Fgfs in mouse skeletal muscle. Furthermore, skeletal muscle fibre type and sex also influenced Fgf expression and response to fasting. We observed that in both male and female mice fasting reduced Fgf6 and Fgf11 in the TA muscle rather than the soleus. Moreover, fasting reduced Fgf8 expression in the soleus and TA muscles in female mice rather than in male mice. Fasting also increased Fgf21 expression in female soleus muscle and female and male plasma. Fasting reduced Fgf2 and Fgf18 expression levels without fibre-type and sex-dependent effects in mice. We further found that fasting decreased the expression of an FGF activation marker gene-Flrt2 in the TA muscle but not in the soleus muscle in both male and female mice. This study revealed the expression profile of Fgfs in different skeletal muscle fibre types and different sexes and provides clues to the interaction between the skeletal muscle and other organs, which deserves future investigations.
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25
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Ocker M. Fibroblast growth factor signaling in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: Paving the way to hepatocellular carcinoma. World J Gastroenterol 2020; 26:279-290. [PMID: 31988589 PMCID: PMC6969880 DOI: 10.3748/wjg.v26.i3.279] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/17/2019] [Accepted: 01/01/2020] [Indexed: 02/06/2023] Open
Abstract
Metabolic disorders are increasingly leading to non-alcoholic fatty liver disease, subsequent steatohepatitis, cirrhosis and hepatocellular carcinoma. Fibroblast growth factors and their receptors play an important role in maintaining metabolic homeostasis also in the liver and disorders in signaling have been identified to contribute to those pathophysiologic conditions leading to hepatic lipid accumulation and chronic inflammation. While specific and well tolerated inhibitors of fibroblast growth factor receptor activity are currently developed for (non-liver) cancer therapy, treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis is still limited. Fibroblast growth factor-mimicking or restoring approaches have recently evolved as a novel therapeutic option and the impact of such interactions with the fibroblast growth factor receptor signaling network during non-alcoholic fatty liver disease/non-alcoholic steatohepatitis development is reviewed here.
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Affiliation(s)
- Matthias Ocker
- Department of Gastroenterology (CBF), Charité University Medicine Berlin, Berlin 10117, Germany
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26
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Xu Q, Lin S, Li Q, Lin Y, Xiong Y, Zhu J, Wang Y. Fibroblast growth factor 21 regulates lipid accumulation and adipogenesis in goat intramuscular adipocyte. Anim Biotechnol 2019; 32:318-326. [PMID: 31880478 DOI: 10.1080/10495398.2019.1691010] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Fibroblast growth factor 21 (FGF21) plays a critical role in the regulation of lipid metabolism; however, its function in goat intramuscular fat (IMF) deposition remains unknown. To explore the role of FGF21 for goat IMF deposition, we performed gain and loss function of FGF21 in intramuscular adipocyte. Our results showed that overexpression of FGF21 mediated by adenovirus inhibits lipid accumulation of goat intramuscular adipocyte, accompanied by down-regulating the mRNA levels of peroxisome proliferator activated receptor γ (PPARγ), adipocyte fatty acid-binding protein 2 (aP2) and sterol regulatory element-binding protein 1 (SREBP1), but up-regulating counterpart of preadipocyte factor1 (Pref1). Conversely, siRNAs knocking down FGF21 promotes the expression of PPARγ and CCAAT/enhancer binding protein-α (C/EBPα) but suppressed that of lipoprotein lipase (LPL) and Pref1. Meanwhile, we found that FGF21 regulates the expression of many KLFs transcription factors, such as KLF3, 7, 9, 11, 14, and 16. These findings demonstrate a key role of FGF21 as a negative factor in the regulation of adipogenic differentiation in goat intramuscular preadipocyte.
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Affiliation(s)
- Qing Xu
- School of Life Science and Technology, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Sen Lin
- School of Life Science and Technology, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Qian Li
- School of Life Science and Technology, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Yaqiu Lin
- School of Life Science and Technology, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Yan Xiong
- School of Life Science and Technology, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Jiangjiang Zhu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Chengdu, China
| | - Yong Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Chengdu, China
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27
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Xu X, Guo C, Liang X, Li R, Chen J. Potential biomarker of fibroblast growth factor 21 in valproic acid-treated livers. Biofactors 2019; 45:740-749. [PMID: 31120577 DOI: 10.1002/biof.1519] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 05/08/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Valproic acid (VPA) is a clinical medicine primarily prescribed to control epileptic symptoms. VPA has potential side-effects, such as hepatotoxicity. Fibroblast growth factor 21 (FGF21) is a functional cytokine for metabolic regulation. In this article, we aimed to evaluate the possible clinical application of FGF21 in VPA-treated livers in early undetected liver injury (EULI). METHODS Methodologically, plasma samples of VPA-treated epileptic patients were isolated for biochemical and high-performance liquid chromatography tests. In addition, VPA-dosed mice were subjected to determinations of serological parameters, key regulatory effectors and FGF21 expressions through biochemical analyses, enzyme-linked immunosorbent assay, immunohistochemistry stain, immunofluorescence stain, and reverse transcription-polymerase chain reaction (RT-PCR) test, respectively. RESULTS The serological data suggested that VPA-treated epileptic patients showed visibly elevated FGF21 contents in plasma samples. However, other diagnostic parameters showed inconspicuous changes. As revealed in animal study, VPA-dosed mice exhibited undetected morphological alterations and hormonal changes in the liver, pancreas, and kidneys. Furthermore, serological parameters and key regulatory proteins in VPA-dosed livers and controls showed inconspicuous changes. Interestingly, endogenous FGF21 expressions in VPA-dosed mice were increased in sera. In further experiments, the findings showed that intracellular expressions of FGF21 mRNA and protein were upregulated in VPA-dosed livers as revealed in RT-PCR and immunoassay. CONCLUSIONS Taken together, these preliminary data reveal that functional FGF21 cytokine may serve as a potent predictor in VPA-related EULI.
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Affiliation(s)
- Xiaoxiao Xu
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
- Department of Pathophysiology, School of Basic Medical Sciences, Guilin Medical University, Guilin, China
| | - Chao Guo
- Department of Pharmacy, Guigang City People's Hospital, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, China
| | - Xiaoliu Liang
- College of Pharmacy, Guangxi Medical University, Nanning, China
| | - Rong Li
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
| | - Jian Chen
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
- Department of Pathophysiology, School of Basic Medical Sciences, Guilin Medical University, Guilin, China
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28
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Zamani M, Yaghoubi Y, Movassaghpour A, Shakouri K, Mehdizadeh A, Pishgahi A, Yousefi M. Novel therapeutic approaches in utilizing platelet lysate in regenerative medicine: Are we ready for clinical use? J Cell Physiol 2019; 234:17172-17186. [PMID: 30912141 DOI: 10.1002/jcp.28496] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 02/18/2019] [Accepted: 02/20/2019] [Indexed: 12/13/2022]
Abstract
Hemoderivative materials are used to treat different diseases. These derivatives include platelet-rich plasma, serum, platelet gel, and platelet lysate (PL). Among them, PL contains more growth factors than the others and its production is inexpensive and easy. PL is one of the proper sources of platelet release factors. It is used in cells growth and proliferation and is a good alternative to fetal bovine serum. In recent years, the clinical use of PL has gained more appeal by scientists. PL is a solution saturated by growth factors, proteins, cytokines, and chemokines and is administered to treat different diseases such as wound healing, bone regeneration, alopecia, oral mucositis, radicular pain, osteoarthritis, and ocular diseases. In addition, it can be used in cell culture for cell therapy and tissue transplantation purposes. Platelet-derived growth factor, fibroblast growth factor, insulin-like growth factor, transforming growth factor β, and vascular endothelial growth factor are key PL growth factors playing a major role in cell proliferation, wound healing, and angiogenesis. In this paper, we scrutinized recent advances in using PL and PL-derived growth factors to treat diseases and in regenerative medicine, and the ability to replace PL with other hemoderivative materials.
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Affiliation(s)
- Majid Zamani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yoda Yaghoubi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aliakbar Movassaghpour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Hematology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kazem Shakouri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Pishgahi
- Department of Hematology, Tabriz University of Medical Sciences, Tabriz, Iran.,Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
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29
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Hui Q, Jin Z, Li X, Liu C, Wang X. FGF Family: From Drug Development to Clinical Application. Int J Mol Sci 2018; 19:ijms19071875. [PMID: 29949887 PMCID: PMC6073187 DOI: 10.3390/ijms19071875] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 06/17/2018] [Accepted: 06/21/2018] [Indexed: 01/13/2023] Open
Abstract
Fibroblast growth factor (FGF) belongs to a large family of growth factors. FGFs use paracrine or endocrine signaling to mediate a myriad of biological and pathophysiological process, including angiogenesis, wound healing, embryonic development, and metabolism regulation. FGF drugs for the treatment of burn and ulcer wounds are now available. The recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in maintaining homeostasis of bile acid, glucose, and phosphate further extended the activity profile of this family. Here, the applications of recombinant FGFs for the treatment of wounds, diabetes, hypophosphatemia, the development of FGF receptor inhibitors as anti-neoplastic drugs, and the achievements of basic research and applications of FGFs in China are reviewed.
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Affiliation(s)
- Qi Hui
- School of Pharmacy, Wenzhou Medical University, Chashan University Park, Wenzhou 325035, China.
| | - Zi Jin
- School of Pharmacy, Wenzhou Medical University, Chashan University Park, Wenzhou 325035, China.
| | - Xiaokun Li
- School of Pharmacy, Wenzhou Medical University, Chashan University Park, Wenzhou 325035, China.
- Key Laboratory Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Chashan University Park, Wenzhou 325035, China.
| | - Changxiao Liu
- School of Pharmacy, Wenzhou Medical University, Chashan University Park, Wenzhou 325035, China.
- State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, 308 Anshan West Road, Tianjin 300193, China.
| | - Xiaojie Wang
- School of Pharmacy, Wenzhou Medical University, Chashan University Park, Wenzhou 325035, China.
- Key Laboratory Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Chashan University Park, Wenzhou 325035, China.
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30
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Wang Y, Terrell AM, Riggio BA, Anand D, Lachke SA, Duncan MK. β1-Integrin Deletion From the Lens Activates Cellular Stress Responses Leading to Apoptosis and Fibrosis. Invest Ophthalmol Vis Sci 2017; 58:3896-3922. [PMID: 28763805 PMCID: PMC5539801 DOI: 10.1167/iovs.17-21721] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 05/30/2017] [Indexed: 12/18/2022] Open
Abstract
Purpose Previous research showed that the absence of β1-integrin from the mouse lens after embryonic day (E) 13.5 (β1MLR10) leads to the perinatal apoptosis of lens epithelial cells (LECs) resulting in severe microphthalmia. This study focuses on elucidating the molecular connections between β1-integrin deletion and this phenotype. Methods RNA sequencing was performed to identify differentially regulated genes (DRGs) in β1MLR10 lenses at E15.5. By using bioinformatics analysis and literature searching, Egr1 (early growth response 1) was selected for further study. The activation status of certain signaling pathways (focal adhesion kinase [FAK]/Erk, TGF-β, and Akt signaling) was studied via Western blot and immunohistochemistry. Mice lacking both β1-integrin and Egr1 genes from the lenses were created (β1MLR10/Egr1-/-) to study their relationship. Results RNA sequencing identified 120 DRGs that include candidates involved in the cellular stress response, fibrosis, and/or apoptosis. Egr1 was investigated in detail, as it mediates cellular stress responses in various cell types, and is recognized as an upstream regulator of numerous other β1MLR10 lens DRGs. In β1MLR10 mice, Egr1 levels are elevated shortly after β1-integrin loss from the lens. Further, pErk1/2 and pAkt are elevated in β1MLR10 LECs, thus providing the potential signaling mechanism that causes Egr1 upregulation in the mutant. Indeed, deletion of Egr1 from β1MLR10 lenses partially rescues the microphthalmia phenotype. Conclusions β1-integrin regulates the appropriate levels of Erk1/2 and Akt phosphorylation in LECs, whereas its deficiency results in the overexpression of Egr1, culminating in reduced cell survival. These findings provide insight into the molecular mechanism underlying the microphthalmia observed in β1MLR10 mice.
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Affiliation(s)
- Yichen Wang
- Department of Biological Sciences, University of Delaware, Newark, Delaware, United States
| | - Anne M. Terrell
- Department of Biological Sciences, University of Delaware, Newark, Delaware, United States
| | - Brittany A. Riggio
- Department of Biological Sciences, University of Delaware, Newark, Delaware, United States
| | - Deepti Anand
- Department of Biological Sciences, University of Delaware, Newark, Delaware, United States
| | - Salil A. Lachke
- Department of Biological Sciences, University of Delaware, Newark, Delaware, United States
| | - Melinda K. Duncan
- Department of Biological Sciences, University of Delaware, Newark, Delaware, United States
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31
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Abstract
Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate numerous cellular processes. Deregulation of FGFR signalling is observed in a subset of many cancers, making activated FGFRs a highly promising potential therapeutic target supported by multiple preclinical studies. However, early-phase clinical trials have produced mixed results with FGFR-targeted cancer therapies, revealing substantial complexity to targeting aberrant FGFR signalling. In this Review, we discuss the increasing understanding of the differences between diverse mechanisms of oncogenic activation of FGFR, and the factors that determine response and resistance to FGFR targeting.
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Affiliation(s)
- Irina S Babina
- Breast Cancer Now Research Centre, Institute of Cancer Research, London SW3 6JB, UK
| | - Nicholas C Turner
- Breast Cancer Now Research Centre, Institute of Cancer Research, London SW3 6JB, UK
- Breast Unit, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK
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32
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Nakayama Y, Masuda Y, Ohta H, Tanaka T, Washida M, Nabeshima YI, Miyake A, Itoh N, Konishi M. Fgf21 regulates T-cell development in the neonatal and juvenile thymus. Sci Rep 2017; 7:330. [PMID: 28336912 PMCID: PMC5428243 DOI: 10.1038/s41598-017-00349-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 02/22/2017] [Indexed: 11/09/2022] Open
Abstract
We have previously shown that Fibroblast growth factor 21 (Fgf21) is expressed in the thymus as well as in the liver. In line with this expression profile, Fgf21 was recently reported to protect against ageing-related thymic senescence by improving the function of thymic epithelial cells (TECs). However, the function of Fgf21 in the juvenile thymus remained to be elucidated. We investigated the physiological roles of Fgf21 in the juvenile thymus and found that young Fgf21 knockout mice, but not β-Klotho knockout mice nor adult Fgf21 knockout mice, showed a significant reduction in the percentage of single-positive CD4+ and CD8+ thymocytes without obvious alteration in TECs. Furthermore, treatment with recombinant FGF21 protein rescued the impairment in fetal thymus organ culture (FTOC) of Fgf21 knockout mice. Annexin V staining revealed FGF21 protein enhanced apoptosis of immature thymocytes undergoing selection process in FTOC, suggesting that FGF21 may facilitate the selection of developing T cells. Endocrine Fgf21 from the liver induced by metabolic stimulation did not affect juvenile thymocyte development. Our data suggest that Fgf21 acts as one of intrathymic cytokines in the neonatal and juvenile thymus, involving thymocyte development in a β-Klotho-independent manner.
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Affiliation(s)
- Yoshiaki Nakayama
- Department of Microbial Chemistry, Kobe Pharmaceutical University, Kobe, Japan
| | - Yuki Masuda
- Department of Microbial Chemistry, Kobe Pharmaceutical University, Kobe, Japan
| | - Hiroya Ohta
- Department of Microbial Chemistry, Kobe Pharmaceutical University, Kobe, Japan
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Tomohiro Tanaka
- Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Laboratory of Molecular Life Science, Foundation for Biomedical Research and Innovation, Kobe, Hyogo, Japan
| | - Miwa Washida
- Laboratory of Molecular Life Science, Foundation for Biomedical Research and Innovation, Kobe, Hyogo, Japan
| | - Yo-Ichi Nabeshima
- Laboratory of Molecular Life Science, Foundation for Biomedical Research and Innovation, Kobe, Hyogo, Japan
| | - Ayumi Miyake
- Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo, Kyoto, Japan
| | - Nobuyuki Itoh
- Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo, Kyoto, Japan
| | - Morichika Konishi
- Department of Microbial Chemistry, Kobe Pharmaceutical University, Kobe, Japan.
- Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo, Kyoto, Japan.
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Guo DD, Guan WZ, Sun YW, Chen J, Jiang XY, Zou SM. Comparative expression and regulation of duplicated fibroblast growth factor 1 genes in grass carp (Ctenopharyngodon idella). Gen Comp Endocrinol 2017; 240:61-68. [PMID: 27677452 DOI: 10.1016/j.ygcen.2016.09.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 09/18/2016] [Accepted: 09/23/2016] [Indexed: 10/21/2022]
Abstract
Fibroblast growth factor 1 (Fgf1) is known as a mitogenic factor involved in the regulation of cell growth, proliferation, and differentiation in vertebrates. Here, we report the isolation and characterization of two fgf1 genes in grass carp (Ctenopharyngodon idella). Grass carp fgf1a and fgf1b cDNAs are highly divergent, sharing a relatively low amino acid sequence identity of 50%, probably due to fish-specific gene duplication. fgf1a and fgf1b mRNAs were detected in the zygote and expressed throughout embryogenesis. Both fgf1a and fgf1b mRNAs were primarily detectable in the notochord at 12 hpf. At 24 hpf, fgf1a mRNA was mainly expressed in the gut and somites, while fgf1b transcript persisted in the notochord and was detected in the tailbud. At 36 hpf, both fgf1a and fgf1b transcripts were detected in the brain, somites, and tailbud. In addition, the fgf1a mRNA was detected at the base of the yolk sac, whereas the fgf1b mRNA was expressed in the pectoral fin. In adult fish, duplicated fgf1a and fgf1b mRNAs were distributed in most tissues. After 2-6days of starvation, both fgf1a and fgf1b mRNAs were upregulated in the muscle and liver. In the brain, fgf1a mRNA was upregulated, while fgf1b mRNA was significantly downregulated at 6days. Furthermore, both fgf1a and fgf1b mRNA levels were significantly decreased in the brain and muscle after administration of 10 or 50μg of the human growth hormone (hGH),while their mRNA levels were no significant difference in the liver. These results suggest that duplicated fgf1s may play important but divergent roles in the grass carp development.
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Affiliation(s)
- Dan-Dan Guo
- Key Laboratory of Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Huchenghuan Road 999, Shanghai 201306, China
| | - Wen-Zhi Guan
- Key Laboratory of Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Huchenghuan Road 999, Shanghai 201306, China
| | - Yi-Wen Sun
- Key Laboratory of Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Huchenghuan Road 999, Shanghai 201306, China
| | - Jie Chen
- Key Laboratory of Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Huchenghuan Road 999, Shanghai 201306, China
| | - Xia-Yun Jiang
- Key Laboratory of Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Huchenghuan Road 999, Shanghai 201306, China.
| | - Shu-Ming Zou
- Key Laboratory of Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Huchenghuan Road 999, Shanghai 201306, China.
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Song G, Shao XX, Wu QP, Xu ZG, Liu YL, Guo ZY. Novel Bioluminescent Binding Assays for Ligand-Receptor Interaction Studies of the Fibroblast Growth Factor Family. PLoS One 2016; 11:e0159263. [PMID: 27414797 PMCID: PMC4944982 DOI: 10.1371/journal.pone.0159263] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 06/29/2016] [Indexed: 12/22/2022] Open
Abstract
We recently developed novel bioluminescent binding assays for several protein/peptide hormones to study their interactions with receptors using the so far brightest NanoLuc reporter. To validate the novel bioluminescent binding assay using a variety of protein/peptide hormones, in the present work we applied it to the fibroblast growth factor (FGF) family using the prototype member FGF2 as an example. A fully active recombinant FGF2 retaining a unique exposed cysteine (Cys) residue was chemically conjugated with an engineered NanoLuc carrying a unique exposed Cys residue at the C-terminus via formation of an intermolecular disulfide linkage. The NanoLuc-conjugated FGF2 (FGF2-Luc) retained high binding affinity to the overexpressed FGFR1 and the endogenous FGF receptor with the calculated dissociation constants of 161 ± 21 pM (n = 3) and 25 ± 4 pM (n = 3), respectively. In competition binding assays using FGF2-Luc as a tracer, receptor-binding potencies of wild-type or mutant FGF2s were accurately quantified. Thus, FGF2-Luc represents a novel non-radioactive tracer for the quantitative measurement of ligand–receptor interactions in the FGF family. These data suggest that the novel bioluminescent binding assay can be applied to a variety of protein/peptide hormones for ligand–receptor interaction studies.
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Affiliation(s)
- Ge Song
- Research Center for Translational Medicine at East Hospital, College of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xiao-Xia Shao
- Research Center for Translational Medicine at East Hospital, College of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Qing-Ping Wu
- Research Center for Translational Medicine at East Hospital, College of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Zeng-Guang Xu
- Research Center for Translational Medicine at East Hospital, College of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Ya-Li Liu
- Research Center for Translational Medicine at East Hospital, College of Life Sciences and Technology, Tongji University, Shanghai, China
- * E-mail: (ZYG); (YLL)
| | - Zhan-Yun Guo
- Research Center for Translational Medicine at East Hospital, College of Life Sciences and Technology, Tongji University, Shanghai, China
- * E-mail: (ZYG); (YLL)
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Li HY, Lin HA, Nien FJ, Wu VC, Jiang YD, Chang TJ, Kao HL, Lin MS, Wei JN, Lin CH, Shih SR, Hung CS, Chuang LM. Serum Vascular Adhesion Protein-1 Predicts End-Stage Renal Disease in Patients with Type 2 Diabetes. PLoS One 2016; 11:e0147981. [PMID: 26845338 PMCID: PMC4742057 DOI: 10.1371/journal.pone.0147981] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 01/10/2016] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Diabetes is the leading cause of end-stage renal disease (ESRD) worldwide. Vascular adhesion protein-1 (VAP-1) participates in inflammation and catalyzes the deamination of primary amines into aldehydes, hydrogen peroxide, and ammonia, both of which are involved in the pathogenesis of diabetic complications. We have shown that serum VAP-1 is higher in patients with diabetes and in patients with chronic kidney disease (CKD), and can predict cardiovascular mortality in subjects with diabetes. In this study, we investigated if serum VAP-1 can predict ESRD in diabetic subjects. METHODS In this prospective cohort study, a total of 604 type 2 diabetic subjects were enrolled between 1996 to 2003 at National Taiwan University Hospital, Taiwan, and were followed for a median of 12.36 years. The development of ESRD was ascertained by linking our database with the nationally comprehensive Taiwan Society Nephrology registry. Serum VAP-1 concentrations at enrollment were measured by time-resolved immunofluorometric assay. RESULTS Subjects with serum VAP-1 in the highest tertile had the highest incidence of ESRD (p<0.001). Every 1-SD increase in serum VAP-1 was associated with a hazard ratio of 1.55 (95%CI 1.12-2.14, p<0.01) for the risk of ESRD, adjusted for smoking, history of cardiovascular disease, body mass index, hypertension, HbA1c, duration of diabetes, total cholesterol, use of statins, ankle-brachial index, estimated GFR, and proteinuria. We developed a risk score comprising serum VAP-1, HbA1c, estimated GFR, and proteinuria, which could predict ESRD with good performance (area under the ROC curve = 0.9406, 95%CI 0.8871-0.9941, sensitivity = 77.3%, and specificity = 92.8%). We also developed an algorithm based on the stage of CKD and a risk score including serum VAP-1, which can stratify these subjects into 3 categories with an ESRD risk of 0.101%/year, 0.131%/year, and 2.427%/year, respectively. CONCLUSIONS In conclusion, serum VAP-1 can predict ESRD and is a useful biomarker to improve risk stratification in type 2 diabetic subjects.
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Affiliation(s)
- Hung-Yuan Li
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-An Lin
- Lo-Sheng Sanatorium and Hospital, Ministry of Health and Welfare, Taipei, Taiwan
| | - Feng-Jung Nien
- Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan
| | - Vin-Cent Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Der Jiang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tien-Jyun Chang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsien-Li Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Mao-Shin Lin
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, Medical College, National Taiwan University, Taipei, Taiwan
| | - Jung-Nan Wei
- Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Cheng-Hsin Lin
- Division of Cardiovascular Surgery, Department of Surgery, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
| | - Shyang-Rong Shih
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Sheng Hung
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Lee-Ming Chuang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, Medical College, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Preventive Medicine, National Taiwan University School of Public Health, Taipei, Taiwan
- * E-mail:
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