Aldose Reductase: a cause and a potential target for the treatment of diabetic complications

Thakur, Sapna; Gupta, Sonu Kumar; Ali, Villayat; Singh, Priyanka; Verma, Malkhey

doi:10.1007/s12272-021-01343-5

Cited by 93 publications

(73 citation statements)

References 80 publications

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“…Therefore, for the first time, we investigated the way in which PE interacts with PTP1B, also clarifying the role of the phosphate group in stabilising the enzyme-inhibitor complex. Concerning AR, it is worth noting the effort in the last decades in synthetising AR inhibitors (ARI), with the aim to treat secondary complications related to diabetes [38]. Despite the proved clinical efficacy of some of these, the main limitation to their use in clinic is the severe side effects they induce [20].…”

Section: Discussionmentioning

confidence: 99%

Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes

et al. 2021

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An in-depth study on the inhibitory mechanism on protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) enzymes, including analysis of the insulin signalling pathway, of phosphoeleganin, a marine-derived phosphorylated polyketide, was achieved. Phosphoeleganin was demonstrated to inhibit both enzymes, acting respectively as a pure non-competitive inhibitor of PTP1B and a mixed-type inhibitor of AR. In addition, in silico docking analyses to evaluate the interaction mode of phosphoeleganin with both enzymes were performed. Interestingly, this study showed that phosphoeleganin is the first example of a dual inhibitor polyketide extracted from a marine invertebrate, and it could be used as a versatile scaffold structure for the synthesis of new designed multiple ligands.

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Section: Discussionmentioning

confidence: 99%

Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes

et al. 2021

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“…The present study deals with aldose reductase (E.C. 1.1.1.21; AKR1B1), a NADPH-dependent reductase that, since its ability to transform glucose within the polyol pathway, is involved in the onset of a number of pathological states linked to hyperglycaemic conditions 2 . Thus, this enzyme is subjected to an intense investigation aiming to inhibit its activity.…”

Section: Introductionmentioning

confidence: 99%

Models of enzyme inhibition and apparent dissociation constants from kinetic analysis to study the differential inhibition of aldose reductase

Balestri

Cappiello

Moschini

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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In order to explain the negative slope of versus inhibitor concentration observed in the study of epigallocatechin gallate acting as an inhibitor of aldose reductase, a kinetic analysis was performed to rationalise the phenomenon. Classical and non-classical models of complete and incomplete enzyme inhibition were devised and analysed to obtain rate equations suitable for the interpretation of experimental data. The results obtained from the different approaches were discussed in terms of the meaning of the emerging kinetic constants. A decrease of versus the inhibitor concentration was revealed to be a valuable indication of the occurrence of an incomplete inhibition. This indication, which is univocal in the case of an uncompetitive inhibition, may be especially useful when the residual activity resulting from inhibition is rather low.

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“…In addition, NADPH is a cofactor for glutathione reductase, which converts oxidized glutathione (GSSG) to the critical cellular reductant, reduced glutathione (GSH). Furthermore, NADPH is required for many anabolic pathways such as nitric oxide and fatty acid synthesis, however, NADPH consumption in the aldose reductase pathway under diabetic conditions causes a harmful effect on the biosynthesis process of these molecules in the retina (Thakur et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Many studies have proved that sorbitol is increased in the retina of diabetic animals and diabetic patients (Dagher et al, 2004 ; Lorenzi, 2007 ; Ola et al, 2012 ). The increased levels of sorbitol through the polyol pathway can alter the osmotic pressure of the membrane and cause osmotic stress, which causes electrolyte imbalance, hydration and membrane damage (D'Andrea et al, 2020 ; Thakur et al, 2021 ). Additionally, polyol pathway activation in the retina of diabetic rats shows increased lipid peroxidation products and depletion of antioxidant enzymes, suggesting that retinal cells and more specifically neuronal cells might be more prone to oxidative stress induced by the polyol pathway early in diabetes (Ola et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Implications of Diabetes-Induced Altered Metabolites on Retinal Neurodegeneration

et al. 2022

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Diabetic retinopathy (DR) is one of the major complications of diabetic eye diseases, causing vision loss and blindness worldwide. The concept of diabetic retinopathy has evolved from microvascular disease into more complex neurovascular disorders. Early in the disease progression of diabetes, the neuronal and glial cells are compromised before any microvascular abnormalities clinically detected by the ophthalmoscopic examination. This implies understanding the pathophysiological mechanisms at the early stage of disease progression especially due to diabetes-induced metabolic alterations to damage the neural retina so that early intervention and treatments options can be identified to prevent and inhibit the progression of DR. Hyperglycemia has been widely considered the major contributor to the progression of the retinal damage, even though tight control of glucose does not seem to have a bigger effect on the incidence or progression of retinal damage that leads to DR. Emerging evidence suggests that besides diabetes-induced hyperglycemia, dyslipidemia and amino acid defects might be a major contributor to the progression of early neurovascular retinal damage. In this review, we have discussed recent advances in the alterations of key metabolites of carbohydrate, lipid, and amino acids and their implications for neurovascular damage in DR.

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Aldose Reductase: a cause and a potential target for the treatment of diabetic complications

Cited by 93 publications

References 80 publications

Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes

Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes

Models of enzyme inhibition and apparent dissociation constants from kinetic analysis to study the differential inhibition of aldose reductase

Implications of Diabetes-Induced Altered Metabolites on Retinal Neurodegeneration

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