Accumulation of intracellular sorbitol due to increased aldose reductase (ALR2) activity has been implicated in the development of various secondary complications of diabetes. Thus, ALR2 inhibition could be an effective strategy in the prevention or delay of certain diabetic complications. Gentiana lutea grows naturally in the central and southern areas of Europe. Its roots are commonly consumed as a beverage in some European countries and are also known to have medicinal properties. The water, ethanol, methanol, and ether extracts of the roots of G. lutea were subjected to in vitro bioassay to evaluate their inhibitory activity on the ALR2. While the ether and methanol extracts showed greater inhibitory activities against both rat lens and human ALR2, the water and ethanol extracts showed moderate inhibitory activities. Moreover, the ether and methanol extracts of G. lutea roots significantly and dose-dependently inhibited sorbitol accumulation in human erythrocytes under high glucose conditions. Molecular docking studies with the constituents commonly present in the roots of G. lutea indicate that a secoiridoid glycoside, amarogentin, may be a potential inhibitor of ALR2. This is the first paper that shows G. lutea extracts exhibit inhibitory activity towards ALR2 and these results suggest that Gentiana or its constituents might be useful to prevent or treat diabetic complications. 1. Introduction According to the latest WHO estimates, currently approximately 200 million people all over the world are suffering from diabetes. This may increase to at least 350 million by the year 2025, which could have a severe impact on human health . Prolonged exposure to chronic hyperglycemia in diabetes can lead to various complications affecting the cardiovascular, renal, neurological, and visual systems . Although mechanisms leading to diabetic complications are not completely understood, many biochemical pathways associated with hyperglycemia have been implicated . Among these, the polyol pathway has been extensively studied . Aldose reductase (ALR2; EC: 220.127.116.11) belongs to aldo-keto reductases (AKR) super family. It is the first and rate-limiting enzyme in the polyol pathway where it reduces glucose to sorbitol utilizing NADPH as a cofactor. Subsequently, sorbitol dehydrogenase catalyzes the conversion of sorbitol to fructose, thus constituting the polyol pathway . Accumulation of sorbitol leads to osmotic swelling, changes in membrane permeability, and also oxidative stress culminating in tissue injury . Experimental animal models suggest
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