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      Ginsenoside Rg3 inhibits angiogenesis in a rat model of endometriosis through the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway

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          Abstract

          Objective

          This study aimed to investigate the link between the inhibitory effect of ginsenoside Rg3 on the ectopic endometrium growth and the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway, a mechanism known to inhibit angiogenesis and induce ectopic endometrial cell apoptosis.

          Materials and methods

          A model of endometriosis was established by allotransplantation in rats. The rats were randomly divided into 5 groups: the ginsenoside Rg3 low-dose group (group A,5mg/kgBW/d of ginsenoside Rg3), the ginsenoside Rg3 high-dose group (group B, 10mg/kgBW/d of ginsenoside Rg3), the gestrinone group (group C, 0.5mg/kgBW/d of gestrinone), the control group (groupD, 10ml/kg BW/d of 0.5%CMC-Na) and the ovariectomized group (group E, 10ml/kgBW/d of 0.5%CMC-Na). Rats were executed after 21 days of continuous administration. The ectopic endometrium volume was measured and the inhibitory rate was calculated. The levels of serum estradiol (E 2) and progesterone (P) were detected by Electro-Chemiluminescence Immunoassay (ECLI). The protein expressionof VEGF, VEGFR-2, p-Akt, and p-mTOR inthe ectopic endometrium wastested by immunohistochemistry(IHC) and Western Blotting. The mRNA expression levels of VEGF, VEGFR-2, Akt, and mTOR were tested by Real-Time Polymerase Chain Reaction (PCR). The apoptosis rate of the ectopic endometrial cells was detected by Terminal Deoxynucleotidyl Transferase-mediated Digoxigenin-dUTP Nick-End Labeling Assay(TUNEL).

          Main results

          Tissue measurements revealed a dose-dependent inhibition effect of ginsenoside Rg3 on the growth of the ectopic endometrium in treated rats compared to controls. Immunohistochemical and Western Blotting assays confirmed that the expression of VEGF, p-Akt, and p-mTOR was down-regulated in ginsenoside Rg3 -treated lesions. Real-time PCR results also showed that the mRNA expression levels of VEGF, Akt, and mTOR in the ectopic endometrium were reduced.

          Conclusions

          The present study demonstrates, for the first time, that ginsenoside Rg3 suppresses angiogenesis in developing endometrial lesions. The ginsenoside Rg3 inhibitory effect on the growth of the ectopic endometrium in EMs rats might occur through the blocking of the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway, thus halting angiogenesis and promoting the apoptosis of ectopic endometrial cells.

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          Most cited references25

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          Recurrence of endometriosis and its control.

          S.-W. Guo (2009)
          BACKGROUND Although surgery is currently the treatment of choice for managing endometriosis, recurrence poses a formidable challenge. To delay or to eliminate the recurrence is presently an unmet medical need in the management of endometriosis. To this end, proposals to investigate patterns of recurrence, to develop biomarkers for recurrence and to carry out biomarker-based intervention have been made. METHODS Publications pertaining to the recurrence of endometriosis and its related yet unaddressed issues were identified through MEDLINE. The reported recurrence rates, risk factors for recurrence, the effects of post-operative medication and causes of recurrence were reviewed and synthesized. In addition, several poorly explored issues such as time hazard function and mechanisms of recurrence were reviewed. Approaches to the development of biomarkers for recurrence and future intervention are discussed. RESULTS The reported recurrence rate was high, estimated as 21.5% at 2 years and 40-50% at 5 years. Few risk factors for recurrence have been consistently identified, and the evidence on the efficacy of the post-operative use of medication was scanty. The investigation on the patterns of recurrence may provide us with new insight into the possible mechanisms of recurrence and its control. The attempt to identify biomarkers for recurrence has started only very recently. CONCLUSIONS Much research is needed to better understand the patterns of recurrence and risk factors, and to develop biomarkers. One top priority is to develop biomarkers for recurrence, which may provide much needed clues to the possible mechanisms underlying recurrence and would allow the identification of patients with high recurrence risk, and permit for targeted intervention.
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            Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications.

            Angiogenesis, or formation of new blood vessels from pre-existing ones, is essential for normal development and wound healing/reproductive functions in adults. Abnormal regulation of angiogenesis has been implicated in the pathogenesis of several disorders, including cancer. Vascular endothelial growth factor (VEGF)-A is a pivotal stimulator of angiogenesis because its binding to VEGF receptors has been shown to promote endothelial cell migration and proliferation, two key features required for the development of new blood vessels. In addition, VEGF-A increases vascular permeability, which may also contribute to angiogenesis and tumor growth. Recognition of the central role of VEGF-A in angiogenesis has led to the hypothesis that its inhibition may represent a novel and effective approach to the treatment of cancer and other conditions characterized by pathologic angiogenesis. Several lines of evidence support this idea, and early clinical experience with the humanized anti-VEGF-A monoclonal antibody bevacizumab (Avastin, rhuMAb-VEGF; Genentech, South San Francisco, CA) has been encouraging. Clinical efficacy of antiangiogenic therapy with bevacizumab is being evaluated in several phase 3 trials in various types of cancer, as well as in patients with age-related macular degeneration. Copyright 2002, Elsevier Science (USA). All rights reserved.
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              BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin.

              Recent data suggest that vascular endothelial growth factor (VEGF), a cytokine involved in autocrine growth of tumor cells and tumor angiogenesis, is up-regulated and plays a potential role in myelogenous leukemias. In chronic myelogenous leukemia (CML), VEGF is expressed at high levels in the bone marrow and peripheral blood. We show here that the CML-associated oncogene BCR/ABL induces VEGF gene expression in growth factor-dependent Ba/F3 cells. Whereas starved cells were found to contain only baseline levels of VEGF mRNA, Ba/F3 cells induced to express BCR/ABL exhibited substantial amounts of VEGF mRNA. BCR/ABL also induced VEGF promoter activity and increased VEGF protein levels in Ba/F3 cells. Moreover, BCR/ABL was found to promote the expression of functionally active hypoxia-inducible factor-1 (HIF-1), a major transcriptional regulator of VEGF gene expression. BCR/ABL-induced VEGF gene expression was counteracted by the phosphoinositide 3-kinase (PI3-kinase) inhibitor LY294002 and rapamycin, an antagonist of mammalian target of rapamycin (mTOR), but not by inhibition of the mitogen-activated protein kinase pathway. Similarly, BCR/ABL-dependent HIF-1alpha expression was inhibited by the addition of LY294002 and rapamycin. Together, our data show that BCR/ABL induces VEGF- and HIF-1alpha gene expression through a pathway involving PI3-kinase and mTOR. BCR/ABL-induced VEGF expression may contribute to the pathogenesis and increased angiogenesis in CML.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Project administrationRole: SupervisionRole: Writing – original draft
                Role: InvestigationRole: Validation
                Role: Data curation
                Role: Formal analysisRole: Investigation
                Role: Investigation
                Role: Investigation
                Role: Data curation
                Role: ConceptualizationRole: Supervision
                Role: ConceptualizationRole: Supervision
                Role: Conceptualization
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 November 2017
                2017
                : 12
                : 11
                : e0186520
                Affiliations
                [1 ] Department of Gynecology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
                [2 ] Department of Neurology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
                [3 ] Department of Reproductive Pharmacology, NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, China
                [4 ] Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
                Rutgers University, UNITED STATES
                Author notes

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

                Author information
                http://orcid.org/0000-0002-1919-1471
                Article
                PONE-D-17-12962
                10.1371/journal.pone.0186520
                5687597
                29140979
                abd40d85-8c34-47d9-aa7d-7b41e1f1b0f5
                © 2017 Cao 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 April 2017
                : 3 October 2017
                Page count
                Figures: 8, Tables: 0, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81302996
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100008410, Shanghai Municipal Population and Family Planning Commission;
                Award ID: ZY3-CCCX-3-3019
                Award Recipient : Ting-ting Zhang
                This project was supported by the National Natural Science Foundation of China (No. 81302996) and Shanghai Municipal population and Family Planning commission (No.ZY3-CCCX-3-3019). The funders provide only financial aid, and there was no individuals employed or contracted by the funders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Physiology
                Cardiovascular Physiology
                Angiogenesis
                Medicine and Health Sciences
                Physiology
                Cardiovascular Physiology
                Angiogenesis
                Biology and Life Sciences
                Developmental Biology
                Angiogenesis
                Biology and Life Sciences
                Anatomy
                Reproductive System
                Uterus
                Endometrium
                Medicine and Health Sciences
                Anatomy
                Reproductive System
                Uterus
                Endometrium
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
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                Ovariectomy
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