title: α-Lipoic acid prevents the intestinal epithelial monolayer damage under heat stress conditions: model experiments in Caco-2 cells.
abstract: OBJECTIVE
  Under conditions of high ambient temperatures and/or strenuous exercise, humans and animals experience considerable heat stress (HS) leading among others to intestinal epithelial damage through induction of cellular oxidative stress. The aim of this study was to characterize the effects of α-Lipoic Acid (ALA) on HS-induced intestinal epithelial injury using an in vitro Caco-2 cell model.
  
  
  METHODS
  A confluent monolayer of Caco-2 cells was pre-incubated with ALA (24 h) prior to control (37 °C) or HS conditions (42 °C) for 6 or 24 h and the expression of heat shock protein 70 (HSP70), heat shock factor-1 (HSF1), and the antioxidant Nrf2 were investigated. Intestinal integrity was determined by measuring transepithelial resistance, paracellular permeability, junctional complex reassembly, and E-cadherin expression and localization. Furthermore, cell proliferation was measured in an epithelial wound healing assay and the expression of the inflammatory markers cyclooxygenase-2 (COX-2) and transforming growth Factor-β (TGF-β) was evaluated.
  
  
  RESULTS
  ALA pretreatment increased the HSP70 mRNA and protein expression under HS conditions, but did not significantly modulate the HS-induced activation of HSF1. The HS-induced increase in Nrf2 gene expression as well as the Nrf2 nuclear translocation was impeded by ALA. Moreover, ALA prevented the HS-induced impairment of intestinal integrity. Cell proliferation under HS conditions was improved by ALA supplementation as demonstrated in an epithelial wound healing assay and ALA was able to affect the HS-induced inflammatory response by decreasing the COX-2 and TGF-β mRNA expression.
  
  
  CONCLUSIONS
  ALA supplementation could prevent the disruption of intestinal epithelial integrity by enhancing epithelial cell proliferation, and reducing the inflammatory response under HS conditions in an in vitro Caco-2 cell model.
authors.affiliation: Division of Veterinary Pharmacology, Pharmacotherapy and Toxicology, Institute for Risk Assessment Sciences, Utrecht University, 3584 CM, Utrecht, The Netherlands. s.braber@uu.nl.|Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. s.braber@uu.nl.
authors.forename: Soheil
authors.initials: S
authors.lastname: Varasteh
authors.affiliation: Division of Veterinary Pharmacology, Pharmacotherapy and Toxicology, Institute for Risk Assessment Sciences, Utrecht University, 3584 CM, Utrecht, The Netherlands.
authors.forename: Johanna
authors.initials: J
authors.lastname: Fink-Gremmels
authors.affiliation: Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.|Nutricia Research, 3584 CT, Utrecht, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Garssen
authors.affiliation: Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Braber
mesh_terms: D000818:Animals; D000975:Antioxidants; D018938:Caco-2 Cells; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa; D007422:Intestines / Q000166:cytology* / Q000473:pathology; D018384:Oxidative Stress; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D008063:Thioctic Acid
keywords: Heat stress; Inflammatory response; Intestinal integrity; Oxidative stress; α-Lipoic acid