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      Anti-tumor Effect of Rhaponticum uniflorum Ethyl Acetate Extract by Regulation of Peroxiredoxin1 and Epithelial-to-Mesenchymal Transition in Oral Cancer

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          Abstract

          Objective: To explore whether Rhaponticum uniflorum ( R. uniflorum) had anti-tumor effects in oral cancer and investigate the molecular mechanisms involved in these anti-tumor effects.

          Methods: Chemical compositions of R. uniflorum ethyl acetate (RUEA) extracts were detected by ultra-performance liquid chromatography-Q/time-of-flight mass spectrometry (UPLC-Q/TOF-MS), followed by pharmacology-based network prediction analysis. The effects of RUEA extracts on proliferation, apoptosis, migration, and invasion ability of human oral squamous cell carcinoma (OSCC) cell line SCC15 were evaluated by CCK8 assay, Annexin V- fluorescein isothiocyanate/propidium iodide staining, wound healing assay, and Matrigel invasion assay, respectively. The mRNA and protein expression of peroxiredoxin1 (Prx1), the epithelial-to-mesenchymal transition (EMT) marker E-cadherin, vimentin, and Snail were determined by quantitative real-time reverse transcription polymerase chain reaction and western blotting. A mouse xenograft model of SCC15 cells was established to further evaluate the effect of RUEA extracts in vivo. Immunohistochemical assessment of Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling staining of apoptotic cells were performed on the tumor tissues to assess the effects of RUEA extracts on proliferation and apoptosis.

          Results: Fourteen compounds were identified from RUEA extracts by UPLC-Q/TOF-MS. The pharmacology-based network prediction analysis showed that Prx1 could be a potential binder of RUEA extracts. In SCC15 cells, RUEA extracts inhibited cell viability, induced apoptosis, and suppressed cell invasion and migration in a concentration-dependent manner. After treatment with RUEA extracts, the mRNA and protein expression of E-cadherin increased, whereas those of Prx1, vimentin, and Snail decreased. RUEA extracts also affected the EMT program and suppressed cell invasion and migration in Prx1 knockdown SCC15 cells. In an OSCC mouse xenograft model, RUEA extracts (25 and 250 mg/kg) significantly inhibited the growth of tumors. Compared with the control group, Ki67 expression was reduced and apoptosis rates were elevated in the transplanted tumors treated with RUEA extracts. RUEA extracts increased the expression of E-cadherin and decreased the expression of Prx1, vimentin, and Snail in vivo.

          Conclusion: RUEA extracts inhibited tumor growth and invasion by reducing Prx1 expression and suppressing the EMT process in OSCC. RUEA extracts may be a potential candidate for OSCC treatment.

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          Most cited references24

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          Living with oral cancer: epidemiology with particular reference to prevalence and life-style changes that influence survival.

          This review presents data on incidence, mortality, survival and trends on cancers of the lip, oral cavity and oropharynx using available recent data sources around the world. Oral and pharyngeal cancer, grouped together is the sixth most common cancer in the world. The review focuses primarily on prevalence of people still alive after an oral cancer diagnosis. In the world, there is close to a three quarter of a million people who previously had oral cancer and alive at 5years after diagnosis. The proportion alive at 5years is lower in less developed countries compared to earlier years. Within in Europe highest prevalence at 5years is seen in Western Europe. Our prevention strategies for this high risk group should include offering smoking cessation and other risk reduction measures. Smoking cessation in particular improves prognostic outcomes reducing the risk of secondary disease by approximately 2-3-fold. Copyright 2010 Elsevier Ltd. All rights reserved.
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            Peroxiredoxin 1 and its role in cell signaling.

            Peroxiredoxins (Prdxs) are a family of small (22-27 kDa) nonseleno peroxidases currently known to possess six mammalian isoforms. Although their individual roles in cellular redox regulation and antioxidant protection are quite distinct, they all catalyze peroxide reduction of H(2)O(2), organic hydroperoxides and peroxynitrite. They are found to be expressed ubiquitously and in high levels, suggesting that they are both an ancient and important enzyme family. Prdxs can be divided into three major subclasses: typical 2-cysteine (2-Cys) Prdxs (Prdx1-4), atypical 2-Cys Prdx (Prdx 5) and 1-Cys Prdx (Prdx 6). Recent evidence suggests that 2-Cys peroxiredoxins are more than "just simple peroxidases". This hypothesis has been discussed elegantly in recent review articles, considering "over"-oxidation of the protonated thiolate peroxidatic cysteine and post-translational modification of Prdxs as processes initiating a mechanistic switch from peroxidase to chaperon function. The process of over-oxidation of the peroxidatic cysteine (C(P)) occurs during catalysis in the presence of thioredoxin (Trx), thus rendering the sulfenic moiety to sulfinic acid, which can be reduced by sulfiredoxin (Srx). However, further oxidation to sulfonic acid is believed to promote Prdx degradation or, as recently shown, the formation of oligomeric peroxidase-inactive chaperones with questionable H(2)O(2)-scavenging capacity. In the light of this and given that Prdx1 has recently been shown by us and by others to interact directly with signaling molecules, we will explore the possibility that H(2)O(2) regulates signaling in the cell in a temporal and spatial fashion via oxidizing Prdx1. Therefore, this review will focus on H(2)O(2) modulating cell signaling via Prdxs by discussing: (1) the activity of Prdxs towards H(2)O(2); (2) sub cellular localization and availability of other peroxidases, such as catalase or glutathione peroxidases; (3) the availability of Prdxs reducing systems, such as thioredoxin and sulfiredoxin and lastly, (4) Prdx1 interacting signaling molecules.
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              systemsDock: a web server for network pharmacology-based prediction and analysis

              We present systemsDock, a web server for network pharmacology-based prediction and analysis, which permits docking simulation and molecular pathway map for comprehensive characterization of ligand selectivity and interpretation of ligand action on a complex molecular network. It incorporates an elaborately designed scoring function for molecular docking to assess protein–ligand binding potential. For large-scale screening and ease of investigation, systemsDock has a user-friendly GUI interface for molecule preparation, parameter specification and result inspection. Ligand binding potentials against individual proteins can be directly displayed on an uploaded molecular interaction map, allowing users to systemically investigate network-dependent effects of a drug or drug candidate. A case study is given to demonstrate how systemsDock can be used to discover a test compound's multi-target activity. systemsDock is freely accessible at http://systemsdock.unit.oist.jp/.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                23 November 2017
                2017
                : 8
                : 870
                Affiliations
                [1] 1Division of Oral Pathology, Beijing Institute of Dental Research, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University , Beijing, China
                [2] 2Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College , Beijing, China
                Author notes

                Edited by: Pierre Sonveaux, Université catholique de Louvain, Belgium

                Reviewed by: Weicheng Liang, The Chinese University of Hong Kong, Hong Kong; Christian Stock, University of Münster, Germany

                *Correspondence: Linfang Huang, lfhuang@ 123456implad.ac.cn Xiaofei Tang, xftang10@ 123456ccmu.edu.cn

                This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2017.00870
                5703707
                29218012
                19d8cdbc-616a-438b-917e-10a9d4b1ea68
                Copyright © 2017 Chen, Wang, Qi, Ge, Tian, Li, Zhang, Wang, Huang and Tang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 August 2017
                : 10 November 2017
                Page count
                Figures: 7, Tables: 2, Equations: 0, References: 31, Pages: 10, Words: 0
                Funding
                Funded by: Beijing Municipal Natural Science Foundation 10.13039/501100005089
                Award ID: 7152066
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                rhaponticum uniflorum,oral squamous cell carcinoma,peroxiredoxin1,epithelial-to-mesenchymal transition,traditional chinese medicine

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