Isoscutellarein from Bixa orellana leaves uncompetitively inhibits recombinant human aldose reductase and prevents sorbitol accumulation and lens opacity

Q4 Pharmacology, Toxicology and Pharmaceutics

Current Enzyme Inhibition Pub Date : 2023-05-17 DOI:10.2174/1573408019666230517142826

Sreedhar Bodiga, Mohan Krishna Durgam, V. Bodiga, P. Vemuri

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Abstract

Enhanced aldose reductase activity results in increased accumulation of sorbitol. Therefore, inhibition of aldose reductase is an effective strategy to prevent or delay certain diabetic complications. Various extracts of the leaves of B. orellana were tested for their inhibitory activity on the aldose reductase. Ethyl acetate extract that showed maximum inhibition was further fractionated and the inhibitor was identified as isoscutellarein by spectroscopic methods. IC50 of recombinant human aldose reductase by isoscutellarein was found to be 14 M and the mode of inhibition was uncompetitive with a decrease in both Km and Vmax. Isoscutellarein was bound to the active site of aldose reductase (3RX3), namely to Ala-299, Leu-300, Leu-301, His-110 and Tyr-48. Docking results exhibited a binding energy of -9.15 kJ/mol. The incubation of red blood cells with high glucose concentrations mimicking hyperglycemic conditions promoted sorbitol accumulation, which was effectively inhibited by isoscutellarein. Further, xylose-induced opacity of the lens was effectively inhibited by isoscutellarein.

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Bixa orellana叶中的异黄芩苷抑制重组人醛糖还原酶，防止山梨醇积累和晶状体混浊

醛糖还原酶活性增强导致山梨醇积累增加。因此，抑制醛糖还原酶是预防或延缓某些糖尿病并发症的有效策略。对不同叶提取物对醛糖还原酶的抑制活性进行了研究。对抑菌效果最好的乙酸乙酯提取物进行进一步分馏，通过波谱法鉴定其为异花蓟甙。异花糖苷对重组人醛糖还原酶的IC50为14M，抑制模式为非竞争性，Km和Vmax均降低。异花糖苷结合到醛糖还原酶(3RX3)的活性位点，即Ala-299、Leu-300、Leu-301、His-110和Tyr-48。对接结果显示结合能为-9.15 kJ/mol。模拟高血糖状态的高葡萄糖浓度红细胞孵育促进山梨糖醇积累，而异花糖甙可有效抑制山梨糖醇积累。此外，木糖诱导的晶状体混浊可被异花糖甙有效抑制。

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来源期刊

Current Enzyme Inhibition Pharmacology, Toxicology and Pharmaceutics-Drug Discovery

CiteScore

1.30

自引率

0.00%

发文量

期刊介绍： Current Enzyme Inhibition aims to publish all the latest and outstanding developments in enzyme inhibition studies with regards to the mechanisms of inhibitory processes of enzymes, recognition of active sites, and the discovery of agonists and antagonists, leading to the design and development of new drugs of significant therapeutic value. Each issue contains a series of timely, in-depth reviews written by leaders in the field, covering a range of enzymes that can be exploited for drug development. Current Enzyme Inhibition is an essential journal for every pharmaceutical and medicinal chemist who wishes to have up-to-date knowledge about each and every development in the study of enzyme inhibition.