title: Targeting the unfolded protein response for disease intervention.
abstract: BACKGROUND
  The accumulation of misfolded proteins in the endoplasmic reticulum (ER) generates a stress condition that engages the unfolded protein response (UPR). The UPR is an adaptive reaction that aims to reestablish ER proteostasis by recovering the folding capacity of the cell. However, chronic ER stress results in apoptosis.
  
  
  METHODS
  This review focuses on discussing the emerging role of the UPR as a driver of several human pathologies including diabetes, neurodegenerative diseases and cancer. The involvement of specific UPR signaling components on different diseases is highlighted based on preclinical models and pharmacological and genetic manipulation of the pathway.
  
  
  CONCLUSIONS
  Therapeutic strategies directed to regulate the activity of different UPR signaling arms may reduce stress levels with a therapeutic gain. Recent drug discovery efforts have identified small molecules that target specific UPR components, providing protection on various disease models. However, important side effects are predicted in the chronic administration due to the fundamental role of the UPR in highly secretory organs such as liver and pancreas. To overcome these problems, we propose the use of combinatorial treatments of selected drugs with natural compounds that are known to modulate the ER proteostasis network.
authors.affiliation: University of Chile, Biomedical Neuroscience Institute, Faculty of Medicine , Santiago , Chile.
authors.forename: Alexis
authors.initials: A
authors.lastname: Rivas
authors.forename: René Luis
authors.initials: RL
authors.lastname: Vidal
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000503:physiopathology; D015195:Drug Design; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D056811:Unfolded Protein Response / Q000502:physiology*
keywords: endoplasmic reticulum stress signaling.; pharmacological modulator; protein misfolding disorders; unfolded protein response