title: Natural osmolytes alleviate GRP78 and ATF-4 levels: Corroboration for potential modulators of unfolded protein response.
abstract: OBJECTIVE
  Osmolytes are small organic molecules which play a significant role in maintaining functional homeostasis of proteins under extreme hostile stresses. Any imbalance to cell homeostasis leads to Endoplasmic Reticulum stress (ER-stress) to which a set of cellular responses both at transcriptional and translational level are initialed for restoration of cellular homeostasis called Unfolded Protein Response (UPR). In the present study we evaluated the role of Sarcosine, Betaine, Hydroxyectoine and Ectoine as potential modulators of UPR. ER-stress was induced by Tunicamycin, a prototypic experimental ER-stress inducer.
  
  
  METHODS
  The endogenous cellular levels of UPR markers Glucose-Regulated Protein 78 (GRP78) and Activating Transcription Factor-4 (ATF-4) were evaluated in presence and absence of these osmolytes after inducing UPR with tunicamycin. As a prelude to this, IC50 values of these osmolytes were determined by using cell viability assays like MTT and Trypan Blue exclusion assay.
  
  
  RESULTS
  We found that these osmolytes in a dose-dependent manner increased the rate of restoration of homeostasis as was evident by the decreased endogenous levels of GRP78 and ATF-4.
  
  
  CONCLUSIONS
  These natural osmolytes can thus be useful in therapeutic intervention to mitigate the pathophysiological state resulting from ER-stress.
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar 190006, Jammu and Kashmir, India.
authors.forename: Younis Mohammad
authors.initials: YM
authors.lastname: Hazari
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar 190006, Jammu and Kashmir, India.
authors.forename: Mudasir
authors.initials: M
authors.lastname: Habib
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar 190006, Jammu and Kashmir, India.
authors.forename: Samirul
authors.initials: S
authors.lastname: Bashir
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar 190006, Jammu and Kashmir, India.
authors.forename: Arif
authors.initials: A
authors.lastname: Bashir
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar 190006, Jammu and Kashmir, India.
authors.forename: Nazia
authors.initials: N
authors.lastname: Hilal
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar 190006, Jammu and Kashmir, India.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Irfan
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar 190006, Jammu and Kashmir, India.
authors.forename: Ehtisham
authors.initials: E
authors.lastname: Ul Haq
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar 190006, Jammu and Kashmir, India. Electronic address: fazili@kashmiruniversity.ac.in.
authors.forename: Khalid Majid
authors.initials: KM
authors.lastname: Fazili
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000599:Amino Acids, Diamino / Q000494:pharmacology; D001622:Betaine / Q000494:pharmacology; D015415:Biomarkers; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D012521:Sarcosine / Q000494:pharmacology; D014415:Tunicamycin / Q000633:toxicity; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: C497109:ATF4 protein, human; D000599:Amino Acids, Diamino; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C121557:hydroxyectoine; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D001622:Betaine; C045628:ectoine; D012521:Sarcosine
keywords: ATF-4; ER stress; GRP 78; IRE1; Osmolytes; PERK; UPR; XBP1