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Title: A novel nucleic acid analogue shows strong angiogenic activity

Abstract

Research highlights: {yields} A novel nucleic acid analogue (2Cl-C.OXT-A, m.w. 284) showed angiogenic potency. {yields} It stimulated the tube formation, proliferation and migration of HUVEC in vitro. {yields} 2Cl-C.OXT-A induced the activation of ERK1/2 and MEK in HUVEC. {yields} Angiogenic potency in vivo was confirmed in CAM assay and rabbit cornea assay. {yields} A synthesized small angiogenic agent would have great clinical therapeutic value. -- Abstract: A novel nucleic acid analogue (2Cl-C.OXT-A) significantly stimulated tube formation of human umbilical endothelial cells (HUVEC). Its maximum potency at 100 {mu}M was stronger than that of vascular endothelial growth factor (VEGF), a positive control. At this concentration, 2Cl-C.OXT-A moderately stimulated proliferation as well as migration of HUVEC. To gain mechanistic insights how 2Cl-C.OXT-A promotes angiogenic responses in HUVEC, we performed immunoblot analyses using phospho-specific antibodies as probes. 2Cl-C.OXT-A induced robust phosphorylation/activation of MAP kinase ERK1/2 and an upstream MAP kinase kinase MEK. Conversely, a MEK inhibitor PD98059 abolished ERK1/2 activation and tube formation both enhanced by 2Cl-C.OXT-A. In contrast, MAP kinase responses elicited by 2Cl-C.OXT-A were not inhibited by SU5416, a specific inhibitor of VEGF receptor tyrosine kinase. Collectively these results suggest that 2Cl-C.OXT-A-induces angiogenic responses in HUVEC mediated by a MAP kinasemore » cascade comprising MEK and ERK1/2, but independently of VEGF receptor tyrosine kinase. In vivo assay using chicken chorioallantoic membrane (CAM) and rabbit cornea also suggested the angiogenic potency of 2Cl-C.OXT-A.« less

Authors:
 [1]; ;  [2]; ;  [3];  [4];  [5];  [6]; ; ;  [7];  [1]
  1. Department of Pharmaco-Bio-Informatics, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan)
  2. Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193 (Japan)
  3. Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan)
  4. Department of Dermatology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan)
  5. Department of Cell Physiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan)
  6. The Tokyo Metropolitan Institute of Medical Science, 1-6 Kamikitazawa2-chome, Setagaya-ku, Tokyo 156-8506 (Japan)
  7. Teikoku Seiyaku Co., Ltd., Sanbonmatsu, Higashikagawa, Kagawa 769-2695 (Japan)
Publication Date:
OSTI Identifier:
22202765
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 399; Journal Issue: 4; Other Information: Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANGIOGENESIS; ANTIBODIES; CELL PROLIFERATION; CHICKENS; CORNEA; FETAL MEMBRANES; GROWTH FACTORS; IN VITRO; IN VIVO; NUCLEIC ACIDS; PHOSPHORYLATION; RABBITS; RECEPTORS; TYROSINE

Citation Formats

Tsukamoto, Ikuko, E-mail: tukamoto@med.kagawa-u.ac.jp, Sakakibara, Norikazu, Maruyama, Tokumi, Igarashi, Junsuke, Kosaka, Hiroaki, Kubota, Yasuo, Tokuda, Masaaki, Ashino, Hiromi, Hattori, Kenichi, Tanaka, Shinji, Kawata, Mitsuhiro, and Konishi, Ryoji. A novel nucleic acid analogue shows strong angiogenic activity. United States: N. p., 2010. Web. doi:10.1016/J.BBRC.2010.08.003.
Tsukamoto, Ikuko, E-mail: tukamoto@med.kagawa-u.ac.jp, Sakakibara, Norikazu, Maruyama, Tokumi, Igarashi, Junsuke, Kosaka, Hiroaki, Kubota, Yasuo, Tokuda, Masaaki, Ashino, Hiromi, Hattori, Kenichi, Tanaka, Shinji, Kawata, Mitsuhiro, & Konishi, Ryoji. A novel nucleic acid analogue shows strong angiogenic activity. United States. doi:10.1016/J.BBRC.2010.08.003.
Tsukamoto, Ikuko, E-mail: tukamoto@med.kagawa-u.ac.jp, Sakakibara, Norikazu, Maruyama, Tokumi, Igarashi, Junsuke, Kosaka, Hiroaki, Kubota, Yasuo, Tokuda, Masaaki, Ashino, Hiromi, Hattori, Kenichi, Tanaka, Shinji, Kawata, Mitsuhiro, and Konishi, Ryoji. 2010. "A novel nucleic acid analogue shows strong angiogenic activity". United States. doi:10.1016/J.BBRC.2010.08.003.
@article{osti_22202765,
title = {A novel nucleic acid analogue shows strong angiogenic activity},
author = {Tsukamoto, Ikuko, E-mail: tukamoto@med.kagawa-u.ac.jp and Sakakibara, Norikazu and Maruyama, Tokumi and Igarashi, Junsuke and Kosaka, Hiroaki and Kubota, Yasuo and Tokuda, Masaaki and Ashino, Hiromi and Hattori, Kenichi and Tanaka, Shinji and Kawata, Mitsuhiro and Konishi, Ryoji},
abstractNote = {Research highlights: {yields} A novel nucleic acid analogue (2Cl-C.OXT-A, m.w. 284) showed angiogenic potency. {yields} It stimulated the tube formation, proliferation and migration of HUVEC in vitro. {yields} 2Cl-C.OXT-A induced the activation of ERK1/2 and MEK in HUVEC. {yields} Angiogenic potency in vivo was confirmed in CAM assay and rabbit cornea assay. {yields} A synthesized small angiogenic agent would have great clinical therapeutic value. -- Abstract: A novel nucleic acid analogue (2Cl-C.OXT-A) significantly stimulated tube formation of human umbilical endothelial cells (HUVEC). Its maximum potency at 100 {mu}M was stronger than that of vascular endothelial growth factor (VEGF), a positive control. At this concentration, 2Cl-C.OXT-A moderately stimulated proliferation as well as migration of HUVEC. To gain mechanistic insights how 2Cl-C.OXT-A promotes angiogenic responses in HUVEC, we performed immunoblot analyses using phospho-specific antibodies as probes. 2Cl-C.OXT-A induced robust phosphorylation/activation of MAP kinase ERK1/2 and an upstream MAP kinase kinase MEK. Conversely, a MEK inhibitor PD98059 abolished ERK1/2 activation and tube formation both enhanced by 2Cl-C.OXT-A. In contrast, MAP kinase responses elicited by 2Cl-C.OXT-A were not inhibited by SU5416, a specific inhibitor of VEGF receptor tyrosine kinase. Collectively these results suggest that 2Cl-C.OXT-A-induces angiogenic responses in HUVEC mediated by a MAP kinase cascade comprising MEK and ERK1/2, but independently of VEGF receptor tyrosine kinase. In vivo assay using chicken chorioallantoic membrane (CAM) and rabbit cornea also suggested the angiogenic potency of 2Cl-C.OXT-A.},
doi = {10.1016/J.BBRC.2010.08.003},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 399,
place = {United States},
year = 2010,
month = 9
}
  • This paper is a compilation of all the pipeline development and construction activity going on in the world. It breaks the world into the various geographic regions and reviews all of the major pipeline construction projects being developed or completed. It includes information on the types of products to be transported, the size of the pipe, and the length of the pipeline. Papers also discuss capacity of both on and offshore service pipelines.
  • Background: Alleviating the oxidant stress associated with myocardial ischemia reperfusion has been demonstrated as a potential therapeutic approach to limit ischemia reperfusion (I/R)-induced cardiac damage. Curcumin, a natural compound with anti-oxidative activity, exerts beneficial effect against cardiac I/R injury, but poor chemical and metabolic stability. Previously, we have designed and synthesized a series of mono-carbonyl analogues of curcumin (MACs) with high stability. This study aims to find new anti-oxidant MACs and to demonstrate their effects and mechanisms against I/R-induced heart injury. Methods: H9c2 cells challenged with H{sub 2}O{sub 2} or TBHP were used for in vitro bio-screening and mechanistic studies.more » The MDA, H{sub 2}O{sub 2} and SOD levels in H9C2 cells were determined, and the cell viability was assessed by MTT assay. Myocardial I/R mouse models administrated with or without the compound were used for in vivo studies. Results: The in vitro cell-based screening showed that curcumin analogues 8d and 14p exhibited strong anti-oxidative effects. Pre-treatment of H9c2 cells with 14p activated Nrf2 signaling pathway, attenuated H{sub 2}O{sub 2}-increased MDA and SOD level, followed by the inhibition of TBHP-induced cell death and Bax/Bcl-2–caspase-3 pathway activation. Silencing Nrf2 significantly reversed the protective effects of 14p. In in vivo animal model of myocardial I/R, administration of low dose 14p (10 mg/kg) reduced infarct size and myocardial apoptosis to the same extent as the high dose curcumin (100 mg/kg). Conclusion: These data support the novel curcumin analogue 14p as a promising antioxidant to decrease oxidative stress and limit myocardial ischemia reperfusion injury via activating Nrf2. - Highlights: • Mono-carbonyl analogue of curcumin, 14p, exhibited better chemical stability. • Compound 14p inhibited TBHP-induced apoptosis through activating Nrf2 in vitro. • Compound 14p limited myocardial ischemia/reperfusion (I/R) injury in vivo. • Compound 14p functioned through both antioxidant and anti-apoptotic pathways. • Compound 14p limited myocardial I/R injury as a promising antioxidant.« less