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Plantago ovata (Isabgol) and Rauvolfia serpentina (Indian Snakeroot)
Published in Azamal Husen, Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Ankur Anavkar, Nimisha Patel, Ahmad Ali, Hina Alim
Aldose reductase is a possible target for treatment of diabetes because of being associated with secondary complications in diabetes. Using the SerpentinaDB database 2, plant-derived molecule (PDM) leads, i.e., indobine and indobinine were identified as potential inhibitors of aldose reductase. Further, through structural analogs, 16 leads were determined from the ZINC database. All the leads thus could help in the design of potential drugs that would act as aldose reductase inhibitors with minimal side effects (Pathania et al., 2013).
Recent Advancements of Curcumin Analogs and Curcumin Formulations in Context to Modern Pharmacotherapeutics Perspectives
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Animeshchandra G. M. Haldar, Kanhaiya M. Dadure, Debarshi Kar Mahapatra
Kondhare et al.55 have developed novel aldose reductase inhibitors (ARIs) of therapeutic significance. The nanodispersion of curcumin THERACURMIN tested for better ARI activity and evaluated the product for aldose reductase inhibition. Aldose Reductase, the key enzyme involved in the first and rate-limiting step of polyol pathway has been implicated in the development of late microvascular complications such as nerve-damaging due to diabetic, cataract, nephropathy, etc. As a consequence, the inhibition of this enzyme is of therapeutic significance to reduce the seriousness of chronic diabetic complications. It is evident from studies that THERACURMIN as expected exhibited excellent ARI activity in 20–30 μM range with IC50 of 3 μM. This is remarkable as the product contains only 15% curcuminoids in the total dispersion and curcumin itself displays potent aldose reductase inhibition activity.
Diabetes and the Microcirculation
Published in John H. Barker, Gary L. Anderson, Michael D. Menger, Clinically Applied Microcirculation Research, 2019
Several agents show promise for the future treatment of diabetic microvascular complications. The aldose reductase inhibitors, which inhibit polyol pathway activity, have shown marked benefits in experimental diabetes. In contrast, studies in human subjects have so far been disappointing and there have been problems with toxic side effects; however, most studies to date have looked at aldose reductase inhibitors in established microvascular disease and it may be that they are more effective in prevention. In neuropathy, regeneration and repair of myelinated fibers have been observed in sural nerve biopsy specimens from patients treated with sorbinil,66 and decreased glomerular hyperfiltration has been seen with ponalrestat.67 Another treatment that has shown great promise in experimental diabetes is inhibition of the advanced stages of protein glycation using aminoguanidine; however, no clinical trials have yet been reported using this agent.
Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Abdelrahman Hamdi, Muhammad Yaseen, Wafaa A. Ewes, Mashooq Ahmad Bhat, Noha I. Ziedan, Hamed W. El-Shafey, Ahmed A. B. Mohamed, Mohamed R. Elnagar, Abdullah Haikal, Dina I. A. Othman, Abdullah A. Elgazar, Ahmed H. A. Abusabaa, Kamal S. Abdelrahman, Osama M. Soltan, Mostafa M. Elbadawi
Under hyperglycaemic state, higher than 30% of the BG is bio-transformed into sorbitol by aldose reductase (AR) enzyme resulting in the major diabetic secondary complications7–11. Subsequently, sorbitol dehydrogenase converts sorbitol to fructose through polyol pathway, which is a necessary mechanism for regulation of glucose metabolism in mammalian cells. AR is a key enzyme that belongs to aldo-keto reductase super-family involved in the polyol pathway for glucose reduction to sorbitol (Figure 1). It is believed that activation of this metabolic pathway is associated with the chronic diabetic complications like retinopathy, diabetic cataract, neuropathy, and nephropathy. Therefore, aldose reductase inhibitors (ARIs) emerged as a fruitful therapeutic tool to prevent the development of these metabolic complications via inhibition of the first step of polyol pathway1,7,8. ARIs have been found to supress and prevent sorbitol accumulation in specific tissues such as peripheral nerves, lens, and kidney. Accordingly, the decreased sorbitol flux by ARIs could be exploited as emerging approach for the management of major diabetes complications. Furthermore, the pathogenesis of sorbitol-induced diabetic complications may be result from interruption in cellular redox, sorbitol-osmotic effects, free radical defence, in addition to elevated oxidative and glycation stress1.
Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies
Published in Expert Opinion on Therapeutic Targets, 2019
Annabelle M. Warren, Søren T. Knudsen, Mark E. Cooper
Aldose reductase inhibitors (ARI) have demonstrated renoprotection in animal models of diabetic kidney disease for many decades [106]. A number of ARIs have been trialed in humans, with varying success. Clinical trials of the ARI tolrestat showed improvements in urinary albumin excretion and indeed it was approved for clinical use; however, it was later withdrawn due to severe hepatic toxicity [109,110]. An alternative ARI epalrestat has been shown to attenuate increases in urinary albumin excretion in diabetic patients without significant toxicity [111]. Epalrestat remains approved for use in some jurisdictions, but its modest impact has limited its uptake worldwide.
Novel 2-phenoxypyrido[3,2-b]pyrazin-3(4H)-one derivatives as potent and selective aldose reductase inhibitors with antioxidant activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Xin Hao, Gang Qi, Hongxing Ma, Changjin Zhu, Zhongfei Han
Diabetes mellitus (DM) is a metabolic disorder resulting from defects in insulin secretion, insulin action, or both1. People suffering from DM are vulnerable to chronic diabetic complications, including neuropathy, retinopathy, nephropathy, and cataracts, which are the major menace to diabetic patients2,3. Increasing clinical research indicated that the abnormal polyol pathway flux of blood glucose is obviously related to pathogenesis of diabetes complications4. Normally, the blood glucose is predominantly converted to glucose-6-phosphate by hexokinase and then enters the glycolytic pathway. However, at high glucose concentration, specifically in diabetics, the combining capacity of aldose reductase (AKR1B1) to glucose is motivated and about one-third of the total glucose is metabolised through the polyol pathway in tissues such as lens, kidney, retina, and peripheral nerves5–7. In polyol pathway (Figure 1), AKR1B1 is the first enzyme and catalyses the reduction of glucose by NADPH to sorbitol, which can, in turn, be oxidised by the enzyme sorbitol dehydrogenase with concomitant reduction of NAD+. In the tissues implicated in these pathologies, the increased polyol pathway flux would directly cause the accumulation of sorbitol, which is hard to penetrate through cellular membranes, resulting in osmotic imbalance, cell swelling, and membrane permeability changes. All these AKR1B1-mediated biochemical alterations contribute to the pathogenesis of diabetic complications8–10. Therefore, design and synthesis aldose reductase inhibitors (ARIs) to inhibit the activity of AKR1B1 and further regulate the polyol pathway of glucose are likely to be a promising therapy to prevent the development of diabetic complications.