title: Dextran loading protects macrophages from lipid peroxidation and induces a Keap1/Nrf2/ARE-dependent antioxidant response.
abstract: OBJECTIVE
  Linear dextrans are often proposed as drug delivery systems with milder adverse effects and lower effective drug concentrations. Linear dextrans are polysaccharides that can potentially be used to load macrophages with drugs to transport them to a site of inflammation. Recently, it was reported that dextrans may exert a protective effect vis-à-vis drug cytotoxicity and during wound healing. The aim of the current work was to evaluate molecular mechanisms of action of dextrans that may be relevant to the cytoprotective effects.
  
  
  METHODS
  We determined the effect of treatment with 40- or 70-kDa dextran on production of reactive oxygen species, lipid peroxidation, and lysosomal pH in the J774 macrophage cell line. In addition, induction of Keap1/Nrf2/ARE and autophagic activity were evaluated.
  
  
  RESULTS
  Dextrans of both molecular weights protected the cells from oxidative stress induced by cumene hydroperoxide and from lysosomal stress induced by ammonium chloride. The effect was associated with induction of the Keap1/Nrf2/ARE signaling pathway. Furthermore, dextran stimulated autophagy in a dose-dependent manner but inhibited the autophagosome-lysosome fusion in a time-dependent manner.
  
  
  CONCLUSIONS
  This study shows possible cytoprotective effects of dextran under oxidative stress, and these findings may be used for the development of novel (dextran-based) drug delivery approaches.
authors.affiliation: Research Institute of Experimental and Clinical Medicine, Novosibirsk, Russia. Electronic address: achechushkov@gmail.com.
authors.forename: Anton
authors.initials: A
authors.lastname: Chechushkov
authors.affiliation: Research Institute of Experimental and Clinical Medicine, Novosibirsk, Russia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Zaitseva
authors.affiliation: Institute of Molecular Biology and Biophysics, Novosibirsk, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Vorontsova
authors.affiliation: Research Institute of Experimental and Clinical Medicine, Novosibirsk, Russia.
authors.forename: Petr
authors.initials: P
authors.lastname: Kozhin
authors.affiliation: Research Institute of Experimental and Clinical Medicine, Novosibirsk, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Menshchikova
authors.affiliation: Research Institute of Experimental and Clinical Medicine, Novosibirsk, Russia; Novosibirsk State Medical University, Novosibirsk, Russia.
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Shkurupiy
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements; D000975:Antioxidants / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D003911:Dextrans / Q000494:pharmacology*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D003911:Dextrans; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species
keywords: Autophagy; Dextran; Lipid peroxidation; Nrf2; ROS