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      Antiangiogenic Activity of Acer tegmentosum Maxim Water Extract in Vitro and in Vivo

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          Abstract

          Angiogenesis, the formation of new blood vessels, is critical for tumor growth and metastasis. Notably, tumors themselves can lead to angiogenesis by inducing vascular endothelial growth factor (VEGF), which is one of the most potent angiogenic factors. Inhibition of angiogenesis is currently perceived as one of the most promising strategies for the blockage of tumor growth. In this study, we investigated the effects of Acer tegmentosum maxim water extract (ATME) on angiogenesis and its underlying signal mechanism. We studied the antiangiogenic activity of ATME by using human umbilical vein endothelial cells (HUVECs). ATME strongly inhibited VEGF-induced endothelial cell proliferation, migration, invasion, and tube formation, as well as vessel sprouting in a rat aortic ring sprouting assay. Moreover, we found that the p44/42 mitogen activated protein (MAP) kinase signaling pathway is involved in the inhibition of angiogenesis by ATME. Moreover, when we performed the in vivo matrigel plug assay, VEGF-induced angiogenesis was potently reduced when compared to that for the control group. Taken together, these results suggest that ATME exhibits potent antiangiogenic activity in vivo and in vitro and that these effects are regulated by the extracellular regulated kinase (ERK) pathway.

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          Most cited references 33

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          Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo.

           G Breier,  H Weich,  W Risau (1992)
          Clinical and experimental studies suggest that angiogenesis is a prerequisite for solid tumour growth. Several growth factors with mitogenic or chemotactic activity for endothelial cells in vitro have been described, but it is not known whether these mediate tumour vascularization in vivo. Glioblastoma, the most common and most malignant brain tumour in humans, is distinguished from astrocytoma by the presence of necroses and vascular proliferations. Here we show that expression of an endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF), is induced in astrocytoma cells but is dramatically upregulated in two apparently different subsets of glioblastoma cells. The high-affinity tyrosine kinase receptor for VEGF, flt, although not expressed in normal brain endothelium, is upregulated in tumour endothelial cells in vivo. These observations strongly support the concept that tumour angiogenesis is regulated by paracrine mechanisms and identify VEGF as a potential tumour angiogenesis factor in vivo.
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            Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival.

            Mitogen-activated protein kinase (MAPK) pathways constitute a large modular network that regulates a variety of physiological processes, such as cell growth, differentiation, and apoptotic cell death. The function of the ERK pathway has been depicted as survival-promoting, in essence by opposing the proapoptotic activity of the stress-activated c-Jun NH(2)-terminal kinase (JNK)/p38 MAPK pathways. However, recently published work suggests that extracellular regulated kinase (ERK) pathway activity is suppressed by JNK/p38 kinases during apoptosis induction. In this review, we will summarize the current knowledge about JNK/p38-mediated mechanisms that negatively regulate the ERK pathway. In particular, we will focus on phosphatases (PP2A, MKPs) as inhibitors of ERK pathway activity in regulating apoptosis. A model proposed in this review places the negative regulation of the ERK pathway in a central position for the cellular decision-making process that determines whether cells will live or die in response to apoptosis-promoting signals. In addition, we will discuss the potential functional relevance of negative regulation of ERK pathway activity, for physiological and pathological conditions (e.g., cellular transformation).
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              Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells.

              Vascular endothelial growth factor (VEGF) is a regulator of vasculogenesis and angiogenesis. To investigate the role of nitric oxide (NO) in VEGF-induced proliferation and in vitro angiogenesis, human umbilical vein endothelial cells (HUVEC) were used. VEGF stimulated the growth of HUVEC in an NO-dependent manner. In addition, VEGF promoted the NO-dependent formation of network-like structures in HUVEC cultured in three dimensional (3D) collagen gels. Exposure of cells to VEGF led to a concentration-dependent increase in cGMP levels, an indicator of NO production, that was inhibited by nitro-L-arginine methyl ester. VEGF-stimulated NO production required activation of tyrosine kinases and increases in intracellular calcium, since tyrosine kinase inhibitors and calcium chelators attenuated VEGF-induced NO release. Moreover, two chemically distinct phosphoinositide 3 kinase (PI-3K) inhibitors attenuated NO release after VEGF stimulation. In addition, HUVEC incubated with VEGF for 24 h showed an increase in the amount of endothelial NO synthase (eNOS) protein and the release of NO. In summary, both short- and long-term exposure of human EC to VEGF stimulates the release of biologically active NO. While long-term exposure increases eNOS protein levels, short-term stimulation with VEGF promotes NO release through mechanisms involving tyrosine and PI-3K kinases, suggesting that NO mediates aspects of VEGF signaling required for EC proliferation and organization in vitro.
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                Author and article information

                Journal
                J Korean Med Sci
                J. Korean Med. Sci
                JKMS
                Journal of Korean Medical Science
                The Korean Academy of Medical Sciences
                1011-8934
                1598-6357
                July 2015
                10 June 2015
                : 30
                : 7
                : 979-987
                Affiliations
                [1 ]Division of Biological Science and Technology and Yonsei-Fraunhofer Medical Device Lab., College of Science and Technology, Yonsei University, Wonju, Korea.
                [2 ]Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.
                [3 ]Qingdao Endocrine & Diabetes Hospital, Qingdao, China.
                [4 ]Department of Biomedical Engineering, Institute of Medical Engineering and Yonsei-Fraunhofer Medical Device Laboratory, Yonsei University, Wonju, Korea.
                [5 ]Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea.
                [6 ]Department of Obstetrics & Gynecology, Inha University College of Medicine, Incheon, Korea.
                [7 ]Department of Clinical Pharmacology, Inha University School of Medicine, Incheon, Korea.
                Author notes
                Address for Correspondence: Moonsuk Nam, MD. Division of Endocrinology and Metabolism, Department of Internal Medicine and Department of Clinical Pharmacology, Inha University School of Medicine, 27 Inhang-ro, Jung-gu, Incheon 400-711, Korea. Tel: +82.32-890-1101, Fax: +82.32-890-2462, namms@ 123456inha.ac.kr
                Article
                10.3346/jkms.2015.30.7.979
                4479955
                3ce5ecda-4a0a-4caf-a98f-c176f19366dd
                © 2015 The Korean Academy of Medical Sciences.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funding
                Funded by: Inha University
                Funded by: Ministry of Health and Welfare
                Award ID: HI14C1062
                Categories
                Original Article
                Alternative Medicine

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