(-)-Epicatechin and NADPH oxidase inhibitors prevent bile acid-induced Caco-2 monolayer permeabilization through ERK1/2 modulation
| Autor: | Michael Müller, Patricia I. Oteiza, Ziwei Wang, M. Corina Litterio, David Vauzour |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male High fat Clinical Biochemistry Deoxycholic acid Medical Biochemistry and Metabolomics Occludin Biochemistry Catechin Oral and gastrointestinal chemistry.chemical_compound Mice 0302 clinical medicine ERK extracellular signal-regulated kinase MLC myosin light chain MLCK MLC kinase Intestinal Mucosa Enzyme Inhibitors lcsh:QH301-705.5 Epicatechin lcsh:R5-920 Benzoxazoles EC (-)-epicatechin NADPH oxidase biology Bile acid Pharmacology and Pharmaceutical Sciences GI gastrointestinal NOX NADPH oxidase Cell biology MMP matrix metalloproteinase TJ tight junction EGFR EGF receptor lcsh:Medicine (General) Research Paper Myosin light-chain kinase medicine.drug_class MAP Kinase Signaling System DCFDA 5-(and-6)-carboxy-2′7′-dichlorodihydrofluorescein diacetate Phosphatase Intestinal permeability Diet High-Fat Permeability MEM minimum essential medium Bile Acids and Salts 03 medical and health sciences ROS reactive oxygen species medicine Animals Humans Nutrition EGF epidermal growth factor Prevention Organic Chemistry Acetophenones NADPH Oxidases Triazoles Bile acids Diet High-Fat 030104 developmental biology DCA deoxycholic acid lcsh:Biology (General) chemistry Caco-2 Apocynin biology.protein Biochemistry and Cell Biology Caco-2 Cells Digestive Diseases DHE dihydroethidium 030217 neurology & neurosurgery |
| Zdroj: | Redox Biology, Vol 28, Iss, Pp-(2020) Redox Biology |
| Popis: | Secondary bile acids promote gastrointestinal (GI) tract permeabilization both in vivo and in vitro. Consumption of high fat diets increases bile acid levels in the GI tract which can contribute to intestinal permeabilization and consequent local and systemic inflammation. This work investigated the mechanisms involved in bile acid (deoxycholic acid (DCA))-induced intestinal epithelial cell monolayer permeabilization and the preventive capacity of (-)-epicatechin (EC). While EC prevented high fat diet-induced intestinal permeabilization in mice, it did not mitigate the associated increase in fecal/cecal total and individual bile acids. In vitro, using differentiated Caco-2 cells as a model of epithelial barrier, EC and other NADPH oxidase inhibitors (VAS-2870 and apocynin) mitigated DCA-induced Caco-2 monolayer permeabilization. While EC inhibited DCA-mediated increase in cell oxidants, it did not prevent DCA-induced mitochondrial oxidant production. Prevention of DCA-induced ERK1/2 activation with EC, VAS-2870, apocynin and the MEK inhibitor U0126, also prevented monolayer permeabilization, stressing the key involvement of ERK1/2 in this process and its redox regulation. Downstream, DCA promoted myosin light chain (MLC) phosphorylation which was related to MLC phosphatase (MLCP) inhibition by ERK1/2. DCA also decreased the levels of the tight junction proteins ZO-1 and occludin, which can be related to MMP-2 activation and consequent ZO-1 and occludin degradation. Both events were prevented by EC, NADPH oxidase and ERK1/2 inhibitors. Thus, DCA-induced Caco-2 monolayer permeabilization occurs mainly secondary to a redox-regulated ERK1/2 activation and downstream disruption of TJ structure and dynamic. EC's capacity to mitigate in vivo the gastrointestinal permeabilization caused by consumption of high-fat diets can be in part related to its capacity to inhibit bile-induced NADPH oxidase and ERK1/2 activation. Graphical abstract Image 1 |
| Databáze: | OpenAIRE |
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