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      Silibinin Inhibits Platelet-Derived Growth Factor-Driven Cell Proliferation via Downregulation of N-Glycosylation in Human Tenon's Fibroblasts in a Proteasome-Dependent Manner

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          Abstract

          The objective of this study was to evaluate the effects of silibinin on cell proliferation in platelet-derived growth factor (PDGF)-treated human Tenon's fibroblasts (HTFs). The effect of silibinin on cell proliferation in PDGF-treated HTFs was determined by examining the expression of proliferating cell nuclear antigen (PCNA) and performing WST-1 assays. Cell cycle progression was evaluated using flow cytometry. The related cyclins and cyclin-dependent kinases (CDKs) were also analyzed using western blot. A modified rat trabeculectomy model was established to evaluate the effect of silibinin on cell proliferation in vivo. Western blot analysis was carried out to determine the effect of silibinin on the expression of PDGF receptor and on the downstream signaling pathways regulated by PDGF receptor. PDGF elevated the expression of PCNA in HTFs, and this elevation was inhibited by silibinin. The inhibitory effect of silibinin on cell proliferation was also confirmed via WST-1 assay. PDGF-stimulated cell cycle in HTFs was delayed by silibinin, and the related cyclin D1 and CDK4 were also suppressed by silibinin. In the rat model of trabeculectomy, silibinin reduced the expression of PCNA at the site of blebs in vivo. The effects of silibinin on PDGF-stimulated HTFs were mediated via the downregulation of PDGF receptor-regulated signaling pathways, such as ERKs and STATs, which may be partially caused by the downregulation of N-glycosylation of PDGF receptor beta (PDGFRβ). The effect of silibinin on modulation of N-glycosylation of PDGFRβ was mediated in a proteasome-dependent manner. Silibinin inhibited cell proliferation and delayed cell cycle progression in PDGF-treated HTFs in vitro. PDGF also modulated the process of N-glycosylation of the PDGFRβ in a proteasome-dependent manner. Our findings suggest that silibinin has potential therapeutic applications in glaucoma filtering surgery.

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          Most cited references40

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          PCNA, the maestro of the replication fork.

          Inheritance requires genome duplication, reproduction of chromatin and its epigenetic information, mechanisms to ensure genome integrity, and faithful transmission of the information to progeny. Proliferating cell nuclear antigen (PCNA)-a cofactor of DNA polymerases that encircles DNA-orchestrates several of these functions by recruiting crucial players to the replication fork. Remarkably, many factors that are involved in replication-linked processes interact with a particular face of PCNA and through the same interaction domain, indicating that these interactions do not occur simultaneously during replication. Switching of PCNA partners may be triggered by affinity-driven competition, phosphorylation, proteolysis, and modification of PCNA by ubiquitin and SUMO.
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            Global data on blindness.

            Globally, it is estimated that there are 38 million persons who are blind. Moreover, a further 110 million people have low vision and are at great risk of becoming blind. The main causes of blindness and low vision are cataract, trachoma, glaucoma, onchocerciasis, and xerophthalmia; however, insufficient data on blindness from causes such as diabetic retinopathy and age-related macular degeneration preclude specific estimations of their global prevalence. The age-specific prevalences of the major causes of blindness that are related to age indicate that the trend will be for an increase in such blindness over the decades to come, unless energetic efforts are made to tackle these problems. More data collected through standardized methodologies, using internationally accepted (ICD-10) definitions, are needed. Data on the incidence of blindness due to common causes would be useful for calculating future trends more precisely.
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              Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle.

              Erich Nigg (1995)
              Passage through the cell cycle requires the successive activation of different cyclin-dependent protein kinases (CDKs). These enzymes are controlled by transient associations with cyclin regulatory subunits, binding of inhibitory polypeptides and reversible phosphorylation reactions. To promote progression towards DNA replication, CDK/cyclin complexes phosphorylate proteins required for the activation of genes involved in DNA synthesis, as well as components of the DNA replication machinery. Subsequently, a different set of CDK/cyclin complexes triggers the phosphorylation of numerous proteins to promote the profound structural reorganizations that accompany the entry of cells into mitosis. At present, much research is focused on elucidating the links between CDK/cyclin complexes and signal transduction pathways controlling cell growth, differentiation and death. In future, a better understanding of the cell cycle machinery and its deregulation during oncogenesis may provide novel opportunities for the diagnostic and therapeutic management of cancer and other proliferation-related diseases.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                28 December 2016
                2016
                : 11
                : 12
                : e0168765
                Affiliations
                [1 ]Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
                [2 ]Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
                Centre de Recherche en Cancerologie de Lyon, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: YHC JTC.

                • Data curation: YHC CLC CML.

                • Formal analysis: YHC CLC MCT.

                • Funding acquisition: YHC JTC DWL.

                • Investigation: YHC CLC DWL.

                • Methodology: CLC CML YHC.

                • Project administration: YHC JTC DWL.

                • Resources: YHC CLC CML.

                • Software: CLC YHC MCT.

                • Supervision: YHC JTC DWL.

                • Validation: CML JTC MCT.

                • Visualization: YHC JTC DWL.

                • Writing – original draft: YHC DWL.

                • Writing – review & editing: YHC JTC CLC.

                Article
                PONE-D-16-37504
                10.1371/journal.pone.0168765
                5193421
                28030611
                a1e21154-4dd4-415d-bc11-8f60f9c12700
                © 2016 Chen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 26 September 2016
                : 6 December 2016
                Page count
                Figures: 7, Tables: 0, Pages: 18
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001868, National Science Council;
                Award ID: NSC 102-2314-B-016-046-MY3
                Award Recipient :
                Funded by: Tri-Service General Hospital, Taiwan
                Award ID: TSGH-C105-099
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: MOST 104-2314-B-016-035
                Award Recipient :
                Funded by: Tri-Service General Hospital, Taiwan
                Award ID: TSGH-C105-098
                Award Recipient :
                Yi-Hao Chen was supported by Tri-Service General Hospital, Taiwan—TSGH-C105-099, Da-Wen Lu by Tri-Service General Hospital, Taiwan—TSGH-C105-098, Jiann-Torng Chen by National Science Council, Taiwan—NSC 102-2314-B-016-046-MY3, and Yi-Hao Chen by the Ministry of Science and Technology, Taiwan—MOST 104-2314-B-016-035.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Cyclins
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Proliferation
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Connective Tissue Cells
                Fibroblasts
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Connective Tissue Cells
                Fibroblasts
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Connective Tissue Cells
                Fibroblasts
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Ophthalmic Procedures
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Musculoskeletal System Procedures
                Trabeculectomy
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                STAT signaling
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Cell Cycle Inhibitors
                Custom metadata
                All relevant data are within the paper.

                Uncategorized
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