title: The isolation and characterization of β-glucogallin as a novel aldose reductase inhibitor from Emblica officinalis.
abstract: Diabetes mellitus is recognized as a leading cause of new cases of blindness. The prevalence of diabetic eye disease is expected to continue to increase worldwide as a result of the dramatic increase in the number of people with diabetes. At present, there is no medical treatment to delay or prevent the onset and progression of cataract or retinopathy, the most common causes of vision loss in diabetics. The plant Emblica officinalis (gooseberry) has been used for thousands of years as a traditional Indian Ayurvedic preparation for the treatment of diabetes in humans. Extracts from this plant have been shown to be efficacious against the progression of cataract in a diabetic rat model. Aldose reductase (ALR2) is implicated in the development of secondary complications of diabetes including cataract and, therefore, has been a major drug target for the development of therapies to treat diabetic disease. Herein, we present the bioassay-guided isolation and structure elucidation of 1-O-galloyl-β-D-glucose (β-glucogallin), a major component from the fruit of the gooseberry that displays selective as well as relatively potent inhibition (IC(50) = 17 µM) of AKR1B1 in vitro. Molecular modeling demonstrates that this inhibitor is able to favorably bind in the active site. Further, we show that β-glucogallin effectively inhibits sorbitol accumulation by 73% at 30 µM under hyperglycemic conditions in an ex-vivo organ culture model of lenses excised from transgenic mice overexpressing human ALR2 in the lens. This study supports the continued development of natural products such as β-glucogallin as therapeutic leads in the development of novel therapies to treat diabetic complications such as cataract.
authors.affiliation: Department of Biochemistry, National Institute of Nutrition, Hyderabad, India.
authors.forename: Muthenna
authors.initials: M
authors.lastname: Puppala
authors.forename: Jessica
authors.initials: J
authors.lastname: Ponder
authors.forename: Palla
authors.initials: P
authors.lastname: Suryanarayana
authors.forename: Geereddy Bhanuprakash
authors.initials: GB
authors.lastname: Reddy
authors.forename: J Mark
authors.initials: JM
authors.lastname: Petrash
authors.forename: Daniel V
authors.initials: DV
authors.lastname: LaBarbera
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D020134:Catalytic Domain; D003198:Computer Simulation; D005638:Fruit / Q000737:chemistry*; D006801:Humans; D018054:Hydrobromic Acid; D047348:Hydrolyzable Tannins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D007908:Lens, Crystalline / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D010084:Oxidation-Reduction; D029842:Phyllanthus emblica / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D011485:Protein Binding; D013012:Sorbitol / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D047348:Hydrolyzable Tannins; D010936:Plant Extracts; D018054:Hydrobromic Acid; D013012:Sorbitol; C060474:glucogallin; D000449:Aldehyde Reductase