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  • Title: Stimulation of cytosolic and mitochondrial calcium mobilization by indomethacin in Caco-2 cells: modulation by the polyphenols quercetin, resveratrol and rutin.
    Author: Carrasco-Pozo C, Pastene E, Vergara C, Zapata M, Sandoval C, Gotteland M.
    Journal: Biochim Biophys Acta; 2012 Dec; 1820(12):2052-61. PubMed ID: 23022152.
    Abstract:
    BACKGROUND: The effect of indomethacin (INDO) on Ca(2+) mobilization, cytotoxicity, apoptosis and caspase activation and the potential protective effect of quercetin (QUE), resveratrol (RES) and rutin (RUT) were determined in Caco-2 cells. METHODS: Caco-2 cells were incubated with INDO in the presence or absence of QUE, RES or RUT. The concentrations of Ca(2+) in the cytosol (Fluo-3 AM) and mitochondria (Rhod-2 AM) were determined as well as the cytotoxicity (MTT reduction and LDH leakage), apoptosis (TUNEL) and caspase-3 and 9 activities. RESULTS: INDO promoted Ca(2+) efflux from the endoplasmic reticulum (ER), resulting in an early, but transient, increment of cytosolic Ca(2+) at 3.5min, followed by a subsequent increment of intra-mitochondrial Ca(2+) at 24min. INDO also induced cytotoxicity, apoptosis, and increased caspase activities and cytochrome c release. All these alterations were prevented by the inhibitors of the IP3R and RyR receptors, 2-Aminoethoxydiphenyl borate (2-APB) and dantrolene. QUE was the most efficient polyphenol in preventing Ca(2+) mobilization induced by INDO and all of its consequences including cytotoxicity and apoptosis. CONCLUSIONS: In Caco-2 cells, INDO stimulates ER Ca(2+) mobilization, probably through the activation of IP3R and RyR receptors, and the subsequent entry of Ca(2+) into the mitochondria. Polyphenols protected the cells against the Ca(2+) mobilization induced by INDO and its consequences on cytotoxicity and apoptosis. GENERAL SIGNIFICANCE: These results confirm the possibility of using polyphenols and particularly QUE for the protection of the gastroduodenal mucosa in subjects consuming NSAIDs.
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