| KMUP-1 inhibits H441 lung epithelial cell growth, migration and proinflammation via increased NO/CGMP and inhibited RHO kinase/VEGF signaling pathways. | |
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MedLine Citation:
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PMID: 22230399 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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This study investigates whether KMUP-1 protects soluble guanylate cyclase (sGC) and inhibits vascular endothelial growth factor (VEGF) expression in lung epithelial cells in hypoxia, therapeutically targeting epithelial proinflammation. H441 cells were used as a representative epithelial cell line to examine the role of sGC and VEGF in hypoxia and the anti-proinflammatory activity of KMUP-1 in normoxia. Human H441 cells were grown in hypoxia for 24-72 h. KMUP-1 (1, 10, 100 microM) arrested cells at the G0/G1 phase of the cell cycle, reduced cell survival and migration, increased p21/p27, restored eNOS, increased soluble guanylate cyclase (sGC) and PKG and inhibited Rho kinase II (ROCK-II). KMUP-1 (0.001-0.1 microM) concentration dependently increased eNOS in normoxia and did not inhibit phosphodiesterase-5A (PDE-5A) in hypoxic cells. Hypoxia-induced factor-1alpha (HIF-1alpha) and VEGF were suppressed by KMUP-1 but not by L-NAME (100 microM). The PKG inhibitor Rp-8-CPT-cGMPS (10 microM) blunted the inhibition of ROCK-II by KMUP-1. KMUP-1 inhibited thromboxane A2-mimetic agonist U46619-induced PDE-5A, TNF-alpha (100 ng/ml)-induced iNOS, and ROCK-II and associated phospho-p38 MAPK, suggesting multiple anti-proinflammatory activities. In addition, increased p21/p27 by KMUP-1 at higher concentrations might contribute to an increased Bax/Bcl-2 and active caspase-3/procaspase-3 ratio, concomitantly causing apoptosis. KMUP-1 inhibited ROCK-II/VEGF in hypoxia, indicating its anti-neoplastic and anti-inflammatory properties. KMUP-1 inhibited TNF-alpha-induced iNOS and U46619-induced PDE-5A and phospho-p38 MAPK in normoxia, confirming its anti-proinflammatory action. KMUP-1 could be used as an anti-proinflammatory to reduce epithelial inflammation. |
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Authors:
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B N Wu; H Y Chen; C P Liu; L Y Hsu; I J Chen |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: International journal of immunopathology and pharmacology Volume: 24 ISSN: 0394-6320 ISO Abbreviation: Int J Immunopathol Pharmacol Publication Date: 2011 Oct-Dec |
Date Detail:
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Created Date: 2012-01-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8911335 Medline TA: Int J Immunopathol Pharmacol Country: Italy |
Other Details:
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Languages: eng Pagination: 925-40 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. |
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