Investigation of synergistic mechanism and identification of interaction site of aldose reductase with the combination of gigantol and syringic acid for prevention of diabetic cataract

Abstract

BackgroundGigantol and syringic acid (SA) have been shown to synergistically prevent formation of diabetic cataract (DC). However, the exact mechanism of this effect is unknown. Here, we investigate the effect of these compounds on the activity of aldose reductase (AR) and cataract formation.MethodsWe examined the synergistic anti-cataract efficacy of gigantol and SA in the high glucose- and streptozotocin -induced DC rat model; synergism was evaluated using Jin’s formula. We investigated possible mechanisms of action by measuring AR expression and activity and levels of sorbitol using enzyme kinetics, Western blot, and RT-PCR. Finally, we examined binding interaction between AR and both compounds using a combination of site-directed mutagenesis, recombinant expression of wild-type and mutant proteins, and enzyme kinetics.ResultsCombination treatment of gigantol and SA synergistically protected both HLECs(human lens epithelial cells) grown in vitro and DC formation in STZ-induced rats in vivo. Synergism was attributed to inhibition of AR activity, downregulation of AR expression via impaired transcription, and decreased sorbitol levels. Enzyme kinetics studies showed that the activity of an AR Asn160Ala mutant protein was significantly decreased compared to wild-type AR, confirming that Asn160 is a key residue for interaction between AR and both compounds.ConclusionCombined administration of gigantol and SA synergize to enhance anti-cataract efficacy. The synergistic effect is mainly attributed to disruption of the polyol pathway and inhibition of AR activity.

Protective effects of sulforaphane on diabetic retinopathy: activation of the Nrf2 pathway and inhibition of NLRP3 inflammasome formation

“…The number of people with diabetes worldwide has exploded in the past several years and is expected to sustain rapid growth. Long-term and uncontrollable high blood glucose generates various diabetic complications, including DR [34]. A global epidemiological analysis showed that 35% of people with diabetes have some form of DR [36], which is characterized by a progressive alteration in retinal microvasculature, leading to capillary closure [24].…”

Phytochemicals: Target-Based Therapeutic Strategies for Diabetic Retinopathy

“…Further studies on its bioactive constituents demonstrated that gigantol ( Figure 2 ), an important bioactive constituent, has a synergistic effect with syringic acid ( Figure 2 ), and plays an important role in preventing diabetic cataracts by inhibiting aldose reductase activity through downregulation of its expression via reduced transcription, and by controlling sorbitol levels. The synergistic effect is thus mainly due to disruption of AR activity and the polyol pathway [ 36 ].…”

“…Many plants exhibit potential pharmacological activities and antidiabetic effects, but thus far no standardization and toxicological experiments have been carried out using the active ingredient as a biomarker. For example, while C. religiosum is commonly employed to treat jaundice, syphilis, and gonorrhea, and is a source of two bioactive constituents, namely isorhamnetin and myricetin (Stefek [ 28 ]), and D. chrysotoxum is a rich source potential agents such as gigantol and syringic acid, having antihyperglycemic, antioxidant, immunomodulatory, and anti-tumor effects [ 36 ], no standardization study aimed at reliably getting high-quality extracts from these plants has been performed to date. Fruit pericarp L. Chinensis , usually wasted after eating the fruit, is a rich source of polyphenols and tannins, having potential ethnopharmacological anti-tussive, antipyretic, analgesic, and diuretic properties, could be utilized as a source of antidiabetic agents in different pharmaceutical industries [ 43 ].…”

<p>Identification Of Natural Compound Derivative For Inhibition Of XLF And Overcoming Chemoresistance In Colorectal Cancer Cells</p>

“…It has been reported that gigantol, which is a natural compound extracted from Dendrobium draconis , has a variety of bioactivities as well as antitumor effects in liver and lung cancers 25,26,29,36,37. To our knowledge, it has not been used in anti-CRC therapy by itself or as a sensitizer for existing anticancer drugs.…”