Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

Kovacikova, Lucia; Prnová, Marta Šoltésová; Májeková, Magdaléna; Boháč, Andrej; Karasu, Çi̇men; Štefek, Milan

doi:10.3390/molecules26102867

Cited by 11 publications

(7 citation statements)

References 90 publications

(164 reference statements)

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“…У нормі цей ензим відіграє важливу роль у передачі сигналів ядерних рецепторів, запальних реакціях, осморегуляції, детоксикації ендо-та ксенобіотиків, синтезі гормонів, клітинному метаболізмі [16] За умов гіперглікемії, з одного боку, альдегідредуктаза забезпечує ефективний каталіз середньо-та довголанцюгових альдегідів, які є продуктами ПОЛ, регулюючи таким чином сигнали оксидативного стресу. З іншого боку, альдегідредуктаза задіяна у активації поліольного шляху, що розглядають як одну з причин ушкодження клітин за гіперглікемії [8,26]. Також встановлено зв'язок між поліморфізмом гену альдегідредуктази та формуванням ускладнень за цукрового діабету.…”

Section: результати й обговоренняunclassified

Activity of the cytosolic enzymes of endogenous aldehydes catabolism under the conditions of different nutrients content in a diet

Voloshchuk¹,

Luchyk²

2022

Bìol. Tvarin

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The research was conducted to study the activity of aldehyde dehydrogenase (EC 1.2.1.3) and aldehyde reductase (EC 1.1.1.21), the levels of TBA reactive substances and protein carbonyl derivates in the cytosolic fraction of rat liver under the conditions of different dietary sucrose and protein content. The animals were distributed into the 4 experimental groups: group I — animals receiving full-value semi-synthetic feed (control group); group II — animals on a low-protein diet (LPD); III group — animals on a high-sucrose diet (HS); IV group — animals on a low-protein and high-sucrose diet (LPD/HS). It was found that in animals under conditions of dietary protein deficiency, there was a two-fold increase in the levels of TBA reactive substances and protein carbonyl derivates in the liver cytosolic fraction against the absence of changes in the aldehyde reductase and aldehyde dehydrogenase activity. At the same time, in animals on a high-sucrose diet, there was a significant accumulation of the TBA reactive substances and carbonyl derivatives in the liver cytosolic fraction along with a 2–2.5-fold increase in both aldehyde reductase and aldehyde dehydrogenase activity. The maximum accumulation of the products of oxidative damage to proteins and lipids along with the insufficient activation of the enzymes ensuring their catabolism can be considered as one of the possible mechanisms of liver cell damage under conditions of the low-protein/high-sucrose diet. The obtained results open new prospects for future studies of the mechanisms of endogenous aldehydes detoxification and further development of a strategy for the correction of metabolic liver disorders under the conditions of nutrient imbalance.

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Section: результати й обговоренняunclassified

Activity of the cytosolic enzymes of endogenous aldehydes catabolism under the conditions of different nutrients content in a diet

Voloshchuk¹,

Luchyk²

2022

Bìol. Tvarin

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“…15,16 In this respect, the beneficial effects of some redox modulatory compounds [16][17][18] and natural 19,20 or synthetic derivatives 21 of AR inhibitors (ARIs) on the diabetic eye has been reported. Cemtirestat (CMTI; 3-mercapto-5H-1,2,4-triazino [5,6-b]indole-5-acetic acid), a highly selective and efficient ARI compound endowed with antioxidant (AO) activity has been synthesized by the Slovak Academy of Sciences, 22,23 and demonstrated to exhibit neuroprotection in cell culture models for glycolipotoxicity [24][25][26] and various models for experimentally DM. 27,28 In the present study, the effects of ARI/AO agent CMTI on the markers for ocular glycotoxicity and inflammation were compared with the effects of stobadine (STB), 17,23,29 a synthetic pyridoindole AO, as well as epalrestat (EPA), an ARI drug, 30 in rats induced by high dietary fructose (F) and fructose plus streptozotocin (STZ) (D; type-2 DM model).…”

Section: Introductionmentioning

confidence: 99%

“…Cemtirestat (CMTI; 3‐mercapto‐5H‐1,2,4‐triazino[5,6‐b]indole‐5‐acetic acid), a highly selective and efficient ARI compound endowed with antioxidant (AO) activity has been synthesized by the Slovak Academy of Sciences, 22,23 and demonstrated to exhibit neuroprotection in cell culture models for glycolipotoxicity 24–26 and various models for experimentally DM 27,28 …”

Section: Introductionmentioning

confidence: 99%

Cemtirestat, an aldose reductase inhibitor and antioxidant compound, induces ocular defense against oxidative and inflammatory stress in rat models for glycotoxicity

Reihanifar,

Şahin,

Stefek

et al. 2023

Cell Biochemistry & Function

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Fructose, endogenously produced as a consequence of activation of the polyol pathway under hyperglycemic conditions, contribute to formation of advanced glycoxidation end products (AGEs) and carbonyl stress. Oxidative stress is increased in diabetes (DM) due to AGEs formation and the utilization of NADPH by aldo‐keto reductase, AKR1B1(AR), the first enzyme in polyol pathway. Since inhibition of AR is an attractive approach for the management of diabetic eye diseases, we aimed to compare the effects of a novel AR inhibitor (ARI)/antioxidant (AO) compound cemtirestat on eye tissues with the effects of ARI drug epalrestat and AO agent stobadine in rat model for glycotoxicity. One group of rats was fed high fructose (10% drinking water; 14 weeks), while type‐2 DM was induced in the other group of rats with fructose plus streptozotocin (40 mg/kg‐bw/day). Diabetic (D) and nondiabetic fructose‐fed rats (F) were either untreated or treated with two different doses of cemtirestat (2.5 and 7.5 mg/kg‐bw/day), epalrestat (25 and 50 mg/kg‐bw/day), or stobadine (25 and 50 mg/kg‐bw/day) for 14 weeks. Cemtirestat, epalrestat, and stobadine elaviate the increase in TNF‐α, IL‐1β, NF‐ƙB, and caspase‐3 in retina, lens, cornea, and sclera of F and D rats. Both glycotoxicity models resulted in a decrease in GSH to GSSG ratio and a change in glutathione S‐transferase activity in eye tissues, but these alterations were improved especially with cemtirestat and stobadine. Lens D‐sorbitol of D rats increased more than that of F rats, this increase was only attenuated by cemtirestat and epalrestat. Epalrestat was more effective than cemtirestat and stobadine in inhibiting the increase of vascular endothelial growth factor (VEGF) in the retina of F and D rats. Cemtirestat and stobadine but not epalrestat decreased high level of Nε‐(carboxymethyl)lysine in the lens and retina of F and D rats. Cemtirestat is a potential therapeutic in protecting the rat eye against glycotoxicity insults.

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“…1.1.1.21; AKR1B1) is a NADPH-dependent oxidoreductase, belonging to the aldo-keto reductase superfamily [ 1 ]. The involvement of AKR1B1 in the aetiology and progression of pathological states related to diabetes (the so-called “diabetic complications”) is well documented [ 2 , 3 ] and represents the rational basis for the strong experimental effort, ongoing since decades, in attempting to inhibit the enzyme [ 4 , 5 , 6 , 7 , 8 ]. The enzyme is metabolically located in the polyol pathway in which it catalyzes the first step, i.e., the conversion of glucose to sorbitol.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the Activity of Catechins as Incomplete Aldose Reductase Differential Inhibitors through Kinetic and Computational Approaches

Balestri

Poli

Piazza

et al. 2022

Biology

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The inhibition of aldose reductase is considered as a strategy to counteract the onset of both diabetic complications, upon the block of glucose conversion in the polyol pathway, and inflammation, upon the block of 3-glutathionyl-4-hydroxynonenal reduction. To ameliorate the outcome of aldose reductase inhibition, minimizing the interference with the detoxifying role of the enzyme when acting on toxic aldehydes, “differential inhibitors”, i.e., molecules able to inhibit the enzyme depending on the substrate the enzyme is working on, has been proposed. Here we report the characterization of different catechin derivatives as aldose reductase differential inhibitors. The study, conducted through both a kinetic and a computational approach, highlights structural constraints of catechin derivatives relevant in order to affect aldose reductase activity. Gallocatechin gallate and catechin gallate emerged as differential inhibitors of aldose reductase able to preferentially affect aldoses and 3-glutathionyl-4-hydroxynonenal reduction with respect to 4-hydroxynonenal reduction. Moreover, the results highlight how, in the case of aldose reductase, a substrate may affect not only the model of action of an inhibitor, but also the degree of incompleteness of the inhibitory action, thus contributing to differential inhibitory phenomena.

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Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

Cited by 11 publications

References 90 publications

Activity of the cytosolic enzymes of endogenous aldehydes catabolism under the conditions of different nutrients content in a diet

Activity of the cytosolic enzymes of endogenous aldehydes catabolism under the conditions of different nutrients content in a diet

Cemtirestat, an aldose reductase inhibitor and antioxidant compound, induces ocular defense against oxidative and inflammatory stress in rat models for glycotoxicity

Dissecting the Activity of Catechins as Incomplete Aldose Reductase Differential Inhibitors through Kinetic and Computational Approaches

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