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      Inhibition of MMP-2 and MMP-9 Activities by Limonium tetragonum Extract

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          Abstract

          Matrix metalloproteinases (MMPs) are crucial extracellular matrices degrading enzymes that take important roles in metastasis of cancer progression as well as other significant conditions such as oxidative stress and hepatic fibrosis. Natural products are on the rise for their potential to provide remarkable health benefits. In this context, halophytes have been of interest in the nutraceutical field with reported instances of isolation of bioactive compounds. In this study, Limonium tetragonum, an edible halophyte, was studied for its ability to inhibit MMP-2 and -9 using HT1080 fibrosarcoma cells. Results showed that L. tetragonum extract was able to inhibit the enzymatic activity and mRNA expression of MMP-2 and -9 according to gelatin zymography and RT-PCR assays, respectively, but it was not able to significantly change the MMP pathway related factors such as tissue inhibitors of metalloproteinases. Also, Mitogen-activated protein kinases pathway-related protein levels and their phosphorylation were assayed. While the phosphorylated p38 levels were decreased, extracellular signal-regulated kinase and c-Jun N-terminal kinase were not affected by L. tetragonum treatment. In conclusion, it was suggested that L. tetragonum contains substances acting as MMP inhibitors on enzymatic activity rather than intracellular pathway intervention, which could be useful for further utilization of L. tetragonum as a source for anti-MMP agents.

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          Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion.

          Cells adhere to one another and/or to matrices that surround them. Regulation of cell-cell (intercellular) and cell-matrix adhesion is tightly controlled in normal cells, however, defects in cell adhesion are common in the majority of human cancers. Multilateral communication among tumor cells with the extracellular matrix (ECM) and neighbor cells is accomplished through adhesion molecules, ECM components, proteolytic enzymes and their endogenous inhibitors. There is sufficient evidence to suggest that reduced adherence is a tumor cell property engaged during tumor progression. Tumor cells acquire the ability to change shape, detach and easily move through spaces disorganizing the normal tissue architecture. This property is due to changes in expression levels of adhesion molecules and/or due to elevated levels of secreted proteolytic enzymes, including matrix metalloproteinases (MMPs). Among other roles, MMPs degrade the ECM and, therefore, prepare the path for tumor cells to migrate, invade and spread to distant secondary areas, where they form metastasis. Tissue inhibitors of metalloproteinases or TIMPs control MMP activities and, therefore, minimize matrix degradation. Both MMPs and TIMPs are involved in tissue remodeling and decisively regulate tumor cell progression including tumor angiogenesis. In this review, we describe and discuss data that support the important role of MMPs and TIMPs in cancer cell adhesion and tumor progression. Published by Elsevier Ltd.
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            Natural products in anticancer therapy.

            Many pharmaceutical agents have been discovered by screening natural products from plants, animals, marine organisms and microorganisms. Vincristine, irinotecan, etoposide and paclitaxel are examples of plant-derived compounds that are being employed in cancer treatment, and dactinomycin, bleomycin and doxorubicin are anticancer agents derived from microbial sources. Citarabine is an example of an anticancer agent originating from a marine source. Other agents originating from marine sources are bryostatin-1, aplidine, dolastatin 10 and ET-743, which have recently entered phase I and II clinical trials.
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              Expressions of MMP-2, MMP-9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma.

              Gastric carcinoma is still a major leading cause of cancer death in East Asia. Since angiogenesis is a necessary condition for invasion and metastasis, its regulation is of essential significance. Expressions of MMP-2, MMP-9 and VEGF were examined with microarray of gastric carcinoma tissue samples (n = 249) by immunostaining. In addition, microvessel density (MVD) was assessed after labelling with the anti-CD34 antibody. Data were cross-compared with clinicopathological parameters of tumors, including PTEN expression. Expressions of MMP-2, MMP-9 and VEGF were positively correlated with tumour size, depth of invasion, lymphatic and venous invasion, lymph node metastasis, UICC staging and MVD of gastric carcinomas (p < 0.05).VEGF expression was positively linked with levels of MMP-2 and MMP-9 (p < 0.05), but negatively with PTEN (p < 0.05). The latter was also inversely associated with the MVD in gastric carcinomas (p < 0.05). MMP-2, MMP-9 and VEGF largely contribute to the angiogenesis and progression of gastric carcinomas. PTEN might inhibit the processes by down-regulating VEGF expression. These parameters should be regarded as good markers to indicate pathobiological behaviours of gastric carcinomas.
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                Author and article information

                Journal
                Prev Nutr Food Sci
                Prev Nutr Food Sci
                Preventive Nutrition and Food Science
                The Korean Society of Food Science and Nutrition
                2287-1098
                2287-8602
                March 2016
                31 March 2016
                : 21
                : 1
                : 38-43
                Affiliations
                [1 ]Department of Food and Nutrition, College of Medical and Life Sciences, Silla University, Busan 46958, Korea
                [2 ]Marine Biotechnology Center for Pharmaceuticals and Foods, Silla University, Busan 46958, Korea
                [3 ]Department of Convergence Study on the Ocean Science and Technology, Ocean Science and Technology School, Korea Maritime and Ocean University, Busan 49112, Korea
                [4 ]Division of Marine Bioscience, College of Ocean Science and Technology, Korea Maritime and Ocean University, Busan 49112, Korea
                Author notes
                Correspondence to Chang-Suk Kong, Tel: +82-51-999-5429, E-mail: cskong@ 123456silla.ac.kr
                Article
                pnfs-21-038
                10.3746/pnf.2016.21.1.38
                4827633
                27069904
                3bece10a-234e-4b23-b90c-036d0b838ec6
                Copyright © 2016 by The Korean Society of Food Science and Nutrition

                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.

                History
                : 04 January 2016
                : 17 February 2016
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                ht1080,limonium tetragonum,mmp,timp,mapk
                ht1080, limonium tetragonum, mmp, timp, mapk

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