Citrus Peels Phenolic Derivatives Alleviate Benzo[α]pyrene-Induced Inflammatory Injury of Human Intestinal Epithelial Cells Through NLRP3 and AhR Signaling Pathways

Abstract Benzo[α]pyrene (BaP) is ubiquitous in foods, and possesses a fatal cytotoxicity. In current study, ten Citrus peels (Chenpi) phenolic derivatives (CPDs) were isolated in a cell model of human intestinal epithelial (Caco-2) cells under BaP-exposure by a bio-assay guided method. Among them, methyl (3,4,5-trimethoxybenzoyl) valylphenylalaninate (Citrus peels phenolic derivative-2, CPD-2) performed the most protective activity by promoting the antiinflammatory potential on BaP-induced Caco-2 cells. CPD-2 inhibited BaP-induced intracellular ROS over-production and inflammatory epithelial cytokine, IL-4, IL-8, TNF-α, IL-1β and IL-18 over-expression, but not IL-6. CPD-2 also inhibited BaP-induced NLRP3 inflammasome and AhR signaling pathway activation. Overall, CPD-2 attenuates BaP-induced apoptotic death via promoting the antiinflammatory potentials by inhibiting the NLRP3 and AhR signaling pathways activation of Caco-2 cells. Finally, the Citrus peels phenolic derivatives was observed for the first time against BaP-induced inflammation and oxidative stress in human intestinal epithelial cells.

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Iron Chelator Triggers Inflammatory Signals in Human Intestinal Epithelial Cells: Involvement of p38 and Extracellular Signal-Regulated Kinase Signaling Pathways

The Journal of Immunology ◽

10.4049/jimmunol.172.11.7069 ◽

2004 ◽

Vol 172 (11) ◽

pp. 7069-7077 ◽

Cited By ~ 41

Author(s):

Eun-Young Choi ◽

Eun-Cheol Kim ◽

Hyun-Mee Oh ◽

Soonhag Kim ◽

Hyun-Ju Lee ◽

...

Keyword(s):

Epithelial Cells ◽

Signaling Pathways ◽

Intestinal Epithelial Cells ◽

Iron Chelator ◽

Intestinal Epithelial ◽

Kinase Signaling ◽

Extracellular Signal Regulated Kinase ◽

Inflammatory Signals ◽

Human Intestinal Epithelial Cells ◽

Extracellular Signal

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Glucose-dependent insulinotropic polypeptide-mediated signaling pathways enhance apical PepT1 expression in intestinal epithelial cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00168.2014 ◽

2015 ◽

Vol 308 (1) ◽

pp. G56-G62 ◽

Cited By ~ 9

Author(s):

Steven D. Coon ◽

Vazhaikkurichi M. Rajendran ◽

John H. Schwartz ◽

Satish K. Singh

Keyword(s):

Epithelial Cells ◽

Signaling Pathways ◽

Intestinal Epithelial Cells ◽

Cell Model ◽

Intestinal Epithelial ◽

Akt Inhibitor ◽

Membrane Expression ◽

Intracellular Ca ◽

Glucagon Like Peptide 1 ◽

Apical Membranes

We have shown recently that glucose-dependent insulinotropic polypeptide (GIP), but not glucagon-like peptide 1 (GLP-1) augments H+ peptide cotransporter (PepT1)-mediated peptide absorption in murine jejunum. While we observed that inhibiting cAMP production decreased this augmentation of PepT1 activity by GIP, it was unclear whether PKA and/or other regulators of cAMP signaling pathway(s) were involved. This study utilized tritiated glycyl-sarcosine [3H-glycyl-sarcosine (Gly-Sar), a relatively nonhydrolyzable dipeptide] uptake to measure PepT1 activity in CDX2-transfected IEC-6 (IEC-6/CDX2) cells, an absorptive intestinal epithelial cell model. Similar to our earlier observations with mouse jejunum, GIP but not GLP-1 augmented Gly-Sar uptake (control vs. +GIP: 154 ± 22 vs. 454 ± 39 pmol/mg protein; P < 0.001) in IEC-6/CDX2 cells. Rp-cAMP (a PKA inhibitor) and wortmannin [phosophoinositide-3-kinase (PI3K) inhibitor] pretreatment completely blocked, whereas neither calphostin C (a potent PKC inhibitor) nor BAPTA (an intracellular Ca2+ chelator) pretreatment affected the GIP-augmented Gly-Sar uptake in IEC-6/CDX2 cells. The downstream metabolites Epac (control vs. Epac agonist: 287 ± 22 vs. 711 ± 80 pmol/mg protein) and AKT (control vs. AKT inhibitor: 720 ± 50 vs. 75 ± 19 pmol/mg protein) were shown to be involved in GIP-augmented PepT1 activity as well. Western blot analyses revealed that both GIP and Epac agonist pretreatment enhance the PepT1 expression on the apical membranes, which is completely blocked by wortmannin in IEC-6/CDX2 cells. These observations demonstrate that both cAMP and PI3K signaling pathways augment GIP-induced peptide uptake through Epac and AKT-mediated pathways in intestinal epithelial cells, respectively. In addition, these observations also indicate that both Epac and AKT-mediated signaling pathways increase apical membrane expression of PepT1 in intestinal absorptive epithelial cells.

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