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      Enhancement of Gastric Ulcer Healing and Angiogenesis by Cochinchina Momordica Seed Extract in Rats

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          Abstract

          Cochinchina momordica seed is the dried ripe seed of Momordica cochinchinensis, a perennial vine. The antiulcer effect of an extract from cochinchina momordica seeds (SK-MS10) was evaluated in a rat model of acetic acid-induced gastric ulcers. Gastric ulcers were produced by subserosal injection of acetic acid. SK-MS10 (200 mg/kg) or vehicle was administered orally once per day for 14 days after the acetic acid injection. The stomach was removed and the ulcer size measured at day 7 and 14 of the treatment. Expression of vascular endothelial growth factor (VEGF) was assessed by real-time RT-PCR and Western blot analysis. In addition, the microvasculature density (MVD) adjacent to the ulcer margin was examined by immunohistochemistry. The treatment with SK-MS10 for 7 and 14 days significantly accelerated ulcer healing and increased the expression of mRNA (at day 7) as well as VEGF protein (at day 14) compared to the vehicle-treated rats. The MVD for factor VIII was also higher in the SK-MS10 treatment group compared to the vehicle-treated rats; however, these differences were not statistically significant. These results suggest that SK-MS10 treatment accelerates the healing of gastric ulcers via upregulation of VEGF and angiogenesis in an acetic acid rat model.

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          Vascular endothelial growth factor is a secreted angiogenic mitogen.

          David V. Goeddel, D Leung, N Ferrara … (1989)
          Vascular endothelial growth factor (VEGF) was purified from media conditioned by bovine pituitary folliculostellate cells (FC). VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo. Complementary DNA clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, respectively. These cDNAs encode hydrophilic proteins with sequences related to those of the A and B chains of platelet-derived growth factor. DNA sequencing suggests the existence of several molecular species of VEGF. VEGFs are secreted proteins, in contrast to other endothelial cell mitogens such as acidic or basic fibroblast growth factors and platelet-derived endothelial cell growth factor. Human 293 cells transfected with an expression vector containing a bovine or human VEGF cDNA insert secrete an endothelial cell mitogen that behaves like native VEGF.
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            Cellular and molecular mechanisms of gastrointestinal ulcer healing.

            Andrzej Tarnawski (2005)
            This paper reviews cellular and molecular mechanisms of gastrointestinal ulcer healing. Ulcer healing, a genetically programmed repair process, includes inflammation, cell proliferation, re-epithelialization, formation of granulation tissue, angiogenesis, interactions between various cells and the matrix and tissue remodeling, all resulting in scar formation. All these events are controlled by the cytokines and growth factors (EGF, PDGF, KGF, HGF, TGFbeta, VEGF, angiopoietins) and transcription factors activated by tissue injury in spatially and temporally coordinated manner. These growth factors trigger mitogenic, motogenic and survival pathways utilizing Ras, MAPK, PI-3K/Akt, PLC-gamma and Rho/Rac/actin signaling. Hypoxia activates pro-angiogenic genes (e.g., VEGF, angiopoietins) via HIF, while serum response factor (SRF) is critical for VEGF-induced angiogenesis, re-epithelialization and muscle restoration. EGF, its receptor, HGF and Cox2 are important for epithelial cell proliferation, migration re-epithelializaton and reconstruction of gastric glands. VEGF, angiopoietins, nitric oxide, endothelin and metalloproteinases are important for angiogenesis, vascular remodeling and mucosal regeneration within ulcer scar. Circulating progenitor cells are also important for ulcer healing. Local gene therapy with VEGF + Ang1 and/or SRF cDNAs dramatically accelerates esophageal and gastric ulcer healing and improves quality of mucosal restoration within ulcer scar. Future directions to accelerate and improve healing include the use of stem cells and tissue engineering.
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              Squash trypsin inhibitors from Momordica cochinchinensis exhibit an atypical macrocyclic structure.

              Benjamin Heitz, J. Hernandez, Thi Nguyen … (2000)
              Three trypsin inhibitors (TIs), from the seeds of the squash Momordica cochinchinensis (MCo), have been isolated and purified using gel filtration, ion exchange chromatography, and reverse-phase HPLC. Their sequences could be determined only after proteolytic cleavages. In the case of MCoTI-I and -II, it was shown that their polypeptide backbones are cyclic, a structure that has never been described in squash TIs. They contain 34 amino acid residues with 3 disulfide bridges and measured molecular masses of 3453.0 and 3480.7, respectively. They are the largest known macrocyclic peptides containing disulfide bridges. Their sequences show strong homology to other squash TIs, suggesting a similar three-dimensional structure and an analogous mechanism of action. A model of MCoTI-II was constructed by analogy to the crystal structure of the complex between bovine trypsin and CMTI-I, indicating that the linker connecting the two termini is flexible and does not impose significant geometrical constraints. This flexibility allows an Asp-Gly peptide bond rearrangement to occur in this region, giving rise to two isoforms of MCoTI-II. Although the importance of cyclization is not clear, it might confer increased stability and resistance to proteolysis. A minor species, MCoTI-III, was also characterized as containing 30 amino acid residues with a molecular mass of 3379.6. This component possesses a linear backbone with a blocked N-terminus. MCoTIs represent interesting candidates for drug design, either by changing their specificity of inhibition or by using their structure as natural scaffolds bearing new binding activities.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Korean Med Sci
                Journal ID (publisher-id): JKMS
                Title: Journal of Korean Medical Science
                Publisher: The Korean Academy of Medical Sciences
                ISSN (Print): 1011-8934
                ISSN (Electronic): 1598-6357
                Publication date (Print): June 2010
                Publication date (Electronic): 24 May 2010
                Volume: 25
                Issue: 6
                Pages: 875-881
                Affiliations
                [1 ]Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
                [2 ]Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
                [3 ]Life Science R&D Center, SK Chemicals, Suwon, Korea.
                [4 ]Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea.
                Author notes
                Address for Correspondence: Nayoung Kim, M.D. Department of Internal Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, Korea. Tel: +82.31-787-7008, Fax: +82.31-787-4051, nayoungkim49@ 123456empal.com
                Article
                DOI: 10.3346/jkms.2010.25.6.875
                PMC ID: 2877244
                PubMed ID: 20514308
                SO-VID: 43532da4-d969-42bb-b7d4-ab04ac0e723e
                Copyright © © 2010 The Korean Academy of Medical Sciences.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 26 June 2009
                Date accepted : 12 November 2009
                Categories
                Subject: Original Article
                Subject: Gastroenterology & Hepatology

                ScienceOpen disciplines: Medicine
                Keywords: stomach ulcer,angiogenesis,acetic acid,vascular endothelial growth factor,cochinchina momordica seed extract
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: stomach ulcer, angiogenesis, acetic acid, vascular endothelial growth factor, cochinchina momordica seed extract

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