Aldose reductase (AKR1B1) is an enzyme involved in the etiology of secondary diabetic complications and inflammation and it has at the same time a central role in cell detoxification. In this work different approaches were applied in order to find novel inhibitors of AKR1B1 from natural sources. To reach this purpose, two different strategies have been used. The first method is aimed to limit the massive convertion of glucose to sorbitol, typical of hyperglicemic condition, leaving the detoxifying role of the enzyme unaffected (intra-site inhibition of aldose reductase). The role of the DMSO, the most commonly used solvent to solubilize the tested molecules, was investigated. In fact, DMSO acts itself as an inhibitor of AKR1B1 with different mechanisms of action on the basis of the reduced substrate. In this work a kinetic model was developed to perform a characterization of new potential inhibitors, independently from the used solvent. Furthermore a preliminary investigation of fractions deriving from chromatographic separation of basil, celery, myrtle berries and myrtle leaves led to the identification of differently AKR1B1 inhibiting compounds. The second approach is based on the knowledge that currently present ARIs have shown many undesirable side effects in their clinic application, because of their ability to inhibit more aldo-keto reductases in the meantime, especially the ubiquitous AKR1A1, the most studied cross-inhibition target and AKR1B10, an enzyme sharing a high similarity with AKR1B1 (71%). In this context, selectively inhibiting one enzyme, leaving the others unaffected is a main goal of current research, because it would limit side effects due to an unspecific action of the drug on two or more homologue enzymes during clinic application. The three investigated molecules xanthohumol, isoxanthohumol and 8-prenylnaringenin revealed to act as tight binding inhibitors of AKR1B1 and AKR1B10, leaving the activity of AKR1A1 unaffected.
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|Titolo:||STRATEGIES IN ALDOSE REDUCTASE INHIBITION|
|Appare nelle tipologie:||8.1 Tesi Dottorato|