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dc.contributor.authorZhang, Liang
dc.contributor.authorZhao, Huiping
dc.contributor.authorBlagg, Brian S. J.
dc.contributor.authorDobrowsky, Rick T.
dc.date.accessioned2017-05-05T16:39:20Z
dc.date.available2017-05-05T16:39:20Z
dc.date.issued2012-04-06
dc.identifier.citationZhang, L., Zhao, H., Blagg, B. S. J., & Dobrowsky, R. T. (2012). A C-Terminal Heat Shock Protein 90 Inhibitor Decreases Hyperglycemia-induced Oxidative Stress and Improves Mitochondrial Bioenergetics in Sensory Neurons. Journal of Proteome Research, 11(4), 2581–2593. http://doi.org/10.1021/pr300056men_US
dc.identifier.urihttp://hdl.handle.net/1808/23905
dc.description.abstractDiabetic peripheral neuropathy (DPN) is a common complication of diabetes in which hyperglycemia-induced mitochondrial dysfunction and enhanced oxidative stress contribute to sensory neuron pathology. KU-32 is a novobiocin-based, C-terminal inhibitor of the molecular chaperone, heat shock protein 90 (Hsp90). KU-32 ameliorates multiple sensory deficits associated with the progression of DPN and protects unmyelinated sensory neurons from glucose-induced toxicity. Mechanistically, KU-32 increased the expression of Hsp70 and this protein was critical for drug efficacy in reversing DPN. However, it remained unclear if KU-32 had a broader effect on chaperone induction and if its efficacy was linked to improving mitochondrial dysfunction. Using cultures of hyperglycemically stressed primary sensory neurons, the present study investigated whether KU-32 had an effect on the translational induction of other chaperones and improved mitochondrial oxidative stress and bioenergetics. A variation of stable isotope labeling with amino acids in cell culture called pulse SILAC (pSILAC) was used to unbiasedly assess changes in protein translation. Hyperglycemia decreased the translation of numerous mitochondrial proteins that affect superoxide levels and respiratory activity. Importantly, this correlated with a decrease in mitochondrial oxygen consumption and an increase in superoxide levels. KU-32 increased the translation of Mn superoxide dismutase and several cytosolic and mitochondrial chaperones. Consistent with these changes, KU-32 decreased mitochondrial superoxide levels and significantly enhanced respiratory activity. These data indicate that efficacy of modulating molecular chaperones in DPN may be due in part to improved neuronal mitochondrial bioenergetics and decreased oxidative stress.en_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Proteome Research, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/pr300056m.en_US
dc.subjectDiabetesen_US
dc.subjectHyperglycemiaen_US
dc.subjectSILACen_US
dc.subjectChaperonesen_US
dc.subjectSensory neuronsen_US
dc.subjectMitochondriaen_US
dc.subjectSuperoxide dismutaseen_US
dc.subjectOxidative stressen_US
dc.titleA C-Terminal Heat Shock Protein 90 Inhibitor Decreases Hyperglycemia-induced Oxidative Stress and Improves Mitochondrial Bioenergetics in Sensory Neuronsen_US
dc.typeArticleen_US
kusw.kuauthorZhang, Liang
kusw.kuauthorZhao, Huiping
kusw.kuauthorBlagg, Brian S. J.
kusw.kuauthorDobrowsky, Rick T.
kusw.kudepartmentMedicinal Chemistryen_US
kusw.kudepartmentPharmacology and Toxicologyen_US
dc.identifier.doi10.1021/pr300056men_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC3329766en_US
dc.rights.accessrightsopenAccess


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