title: Characterization of Emodin as a Therapeutic Agent for Diabetic Cataract.
abstract: Aldose reductase (AR) in the lens plays an important role in the pathogenesis of diabetic cataract (DC) by contributing to osmotic and oxidative stress associated with accelerated glucose metabolism through the polyol pathway. Therefore, inhibition of AR in the lens may hold the key to prevent DC formation. Emodin, a bioactive compound isolated from plants, has been implicated as a therapy for diabetes. However, its inhibitory activity against AR remains unclear. Our results showed that emodin has good selectively inhibitory activity against AR (IC50 = 2.69 ± 0.90 μM) but not other aldo-keto reductases and is stable at 37 °C for at least 7 days. Enzyme kinetic studies demonstrated an uncompetitive inhibition against AR with a corresponding inhibition constant of 2.113 ± 0.095 μM. In in vivo studies, oral administration of emodin reduced the incidence and severity of morphological markers of cataract in lenses of AR transgenic mice. Computational modeling of the AR-NADP(+)-emodin ternary complex indicated that the 3-hydroxy group of emodin plays an essential role by interacting with Ser302 through hydrogen bonding in the specificity pocket of AR. All the findings above provide encouraging evidence for emodin as a potential therapeutic agent to prevent cataract in diabetic patients.
authors.affiliation: Department of Ophthalmology, School of Medicine, and ‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: Kun-Che
authors.initials: KC
authors.lastname: Chang
authors.affiliation: Department of Ophthalmology, School of Medicine, and ‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, School of Medicine, and ‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Sanborn
authors.affiliation: Department of Ophthalmology, School of Medicine, and ‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: Biehuoy
authors.initials: B
authors.lastname: Shieh
authors.affiliation: Department of Ophthalmology, School of Medicine, and ‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lenhart
authors.affiliation: Department of Ophthalmology, School of Medicine, and ‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: David
authors.initials: D
authors.lastname: Ammar
authors.affiliation: Department of Ophthalmology, School of Medicine, and ‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: LaBarbera
authors.affiliation: Department of Ophthalmology, School of Medicine, and ‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Petrash
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074408:Aldo-Keto Reductases; D000818:Animals; D002386:Cataract / Q000188:drug therapy* / Q000517:prevention & control; D048909:Diabetes Complications / Q000188:drug therapy*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004642:Emodin / Q000494:pharmacology*; D006801:Humans; D007908:Lens, Crystalline / Q000201:enzymology; D008822:Mice, Transgenic; D015394:Molecular Structure; D018384:Oxidative Stress; D013329:Structure-Activity Relationship
chemical_list: D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; C000614209:AKR7A5 protein, mouse; D004642:Emodin