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Polyunsaturated fatty acids block platelet-activating factor-induced phosphatidylinositol 3 kinase/Akt-mediated apoptosis in intestinal epithelial cells.

ABSTRACT: We have shown earlier that platelet-activating factor (PAF) causes apoptosis in enterocytes via a mechanism that involves Bax translocation to mitochondria, followed by caspase activation and DNA fragmentation. Herein we report that, in rat small intestinal epithelial cells (IEC-6), these downstream apoptotic effects are mediated by a PAF-induced inhibition of the phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt) signaling pathway. Treatment with PAF results in rapid dephosphorylation of Akt, phosphoinositide-dependent kinase-1, and the YXXM p85 binding motif of several proteins and redistribution of Akt-pleckstrin homology domain-green fluorescent protein, i.e., an in vivo phosphatidylinositol (3,4,5)-trisphosphate sensor, from membrane to cytosol. The proapoptotic effects of PAF were inhibited by both n-3 and n-6 polyunsaturated fatty acids but not by a saturated fatty acid palmitate. Indomethacin, an inhibitor of prostaglandin biosynthesis, did not influence the baseline or PAF-induced apoptosis, but 2-bromopalmitate, an inhibitor of protein palmitoylation, inhibited all of the proapoptotic effects of PAF. Our data strongly suggest that an inhibition of the PI 3-kinase/Akt signaling pathway is the main mechanism of PAF-induced apoptosis in enterocytes and that polyunsaturated fatty acids block this mechanism very early in the signaling cascade independently of any effect on prostaglandin synthesis, and probably directly via an effect on protein palmitoylation.

SUBMITTER: Lu J

PROVIDER: S-EPMC2692041 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Polyunsaturated fatty acids block platelet-activating factor-induced phosphatidylinositol 3 kinase/Akt-mediated apoptosis in intestinal epithelial cells.

Lu Jing J Caplan Michael S MS Li Dan D Jilling Tamas T

American journal of physiology. Gastrointestinal and liver physiology 20080320 5

We have shown earlier that platelet-activating factor (PAF) causes apoptosis in enterocytes via a mechanism that involves Bax translocation to mitochondria, followed by caspase activation and DNA fragmentation. Herein we report that, in rat small intestinal epithelial cells (IEC-6), these downstream apoptotic effects are mediated by a PAF-induced inhibition of the phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt) signaling pathway. Treatment with PAF results in rapid dephosphory ...[more]

PMID: 18356536

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Project description:Chemotherapy- or radiotherapy-related intestinal microbial dysbiosis is one of the main causes of intestinal mucositis. Cases of bacterial translocation into peripheral blood and subsequent sepsis occur as a result of dysfunction in the intestinal barrier. Evidence from recent studies depicts the characteristics of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis, which creates an imbalance between beneficial and harmful bacteria in the gut. Decreases in beneficial bacteria can lead to a weakening of the resistance of the gut to harmful bacteria, resulting in robust activation of proinflammatory signaling pathways. For example, lipopolysaccharide (LPS)-producing bacteria activate the nuclear transcription factor-κB signaling pathway through binding with Toll-like receptor 4 on stressed epithelial cells, subsequently leading to secretion of proinflammatory cytokines. Nevertheless, various studies have found that the omega-3 (n-3) polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid and eicosapentaenoic acid can reverse intestinal microbial dysbiosis by increasing beneficial bacteria species, including Lactobacillus, Bifidobacterium, and butyrate-producing bacteria, such as Roseburia and Coprococcus. In addition, the n-3 PUFAs decrease the proportions of LPS-producing and mucolytic bacteria in the gut, and they can reduce inflammation as well as oxidative stress. Importantly, the n-3 PUFAs also exert anticancer effects in colorectal cancers. In this review, we summarize the characteristics of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis and introduce the contributions of dysbiosis to the pathogenesis of intestinal mucositis. Next, we discuss how n-3 PUFAs could alleviate chemotherapy- or radiotherapy-related intestinal microbial dysbiosis. This review provides new insights into the clinical administration of n-3 PUFAs for the management of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis.

Dataset Information

Polyunsaturated fatty acids block platelet-activating factor-induced phosphatidylinositol 3 kinase/Akt-mediated apoptosis in intestinal epithelial cells.

Publications

Polyunsaturated fatty acids block platelet-activating factor-induced phosphatidylinositol 3 kinase/Akt-mediated apoptosis in intestinal epithelial cells.

Similar Datasets

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