Non-steroidal anti-inflammatory drugs inhibit calpain activity and membrane localization of calpain 2 protease |
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| Authors: | Kristopher Silver Ludovic Leloup Lisa C. Freeman Alan Wells James D. Lillich |
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| Affiliation: | 1. Laboratory Experimental Cardiology, Research Institute for Cardiology, Siberian Branch of the Russian Academy of Medical Sciences, Tomsk 634012, Russia;2. Department of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague 14220, Czech Republic;3. Department of Physiology, Hebei Medical University, Shijiazhuang 050017, China;4. Department of Pharmacology, Liaoning Medical College, Jinzhou City 121001, Liaoning Province, China;1. Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;2. Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan;3. Institute of Biomedical Informatics, National Yang-Ming University, Taipei 112, Taiwan;4. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan;5. Center of Infectious Disease and Signaling Research Center, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;6. School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan;1. Department of Animal Science, National Chiayi University, Chiayi City, Taiwan;2. Department of Animal Science, Iowa State University, Ames, IA, USA |
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| Abstract: | Non-steroidal anti-inflammatory drugs (NSAIDs) are used frequently worldwide for the alleviation of pain despite their capacity to cause adverse gastrointestinal (GI) side effects. GI toxicity, once thought to be the result of non-specific inhibition of cyclooxegenase (COX) enzymes, is now hypothesized to have multiple other causes that are COX independent. In particular, NSAIDs inhibit intestinal epithelial restitution, the process by which barrier function in intestinal mucosa is restored at sites of epithelial wounds within hours through cell spreading and migration. Accordingly, recent evidence indicates that the expression of calpain proteases, which play a key role in cell migration, is decreased by NSAIDs that inhibit cell migration in intestinal epithelial cells (IEC). Here, we examine the effect of NSAIDs on calpain activity and membrane expression in IEC-6 cells. Indomethacin, NS-398, and SC-560 inhibited calpain activity and decreased expression of calpain 2 in total membrane fractions and in plasma membranes involved in cell attachment to the substrate. Additionally, we demonstrated that inhibition of calpain activity by NSAIDs or ALLM, a calpain inhibitor, limits cell migration and in vitro wound healing of IEC-6 cells. Our results indicate that NSAIDs may inhibit cell migration by decreasing calpain activity and membrane-associated expression of calpain 2. Our results provide valuable insight into the mechanisms behind NSAID-induced GI toxicity and provide a potential pathway through which these negative side effects can be avoided in future members of the NSAID class. |
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