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  • It thus appeared reasonable that AR needed to

    2023-02-01

    It thus appeared reasonable that AR needed to be inhibited and great experimental efforts began which are still on-going [6]. Indeed, hundreds of ARIs have been characterized but no significant drug development has followed. The case of Sorbinil, which did not pass clinical trials is emblematic [7] as is the withdrawal of Tolrestat-based drugs from distribution [8]. Today, to our knowledge, except for some eastern countries where Epalrestat-based drugs have been commercialized, no ARI-based drugs are used for human care in the West. There may be several reasons for such a failure, from the lack of bioavailability of the drug to the severe side effects, however they may also be somehow related to the catalytic features of the enzyme itself, as AR can reduce toxic aldehydes derived from lipid peroxidative processes [9], [10]. Thus, unlike the potential damage of increasing the polyol pathway flux, the removal of 4-hydroxy-2-nonenal (HNE), a significant product in membrane peroxidative processes, and other alkanals and alkenals, must be considered as a detoxifying function of the enzyme [11]. In addition, the ability of the AR to reduce glutathionyl-hydroxynonenal (GSHNE), the most important HNE derivative, highlights a link between AR activity and the pro-inflammatory cell response [10], [12], [13]. It is therefore not easy to predict the overall effect of the enzyme inhibition. A change in the approach to the enzyme inhibition has recently been proposed, that has moved away to a certain extent from the search for extreme inhibitory power in ARIs, but aimed at specifically intervening in the reaction that the enzyme is catalyzing in a differential manner [14]. Consequently, differential inhibitors, ARDIs, as these molecules were called, should intervene in Fosmidomycin sodium salt synthesis and or GSHNE reduction, with no or a reduced effect on HNE and other alkanal/alkenal reduction. The potential of inhibitors to act as ARDIs is linked to their inhibition model, as the targeting of the free enzyme (i.e. a competitive type of inhibition) is an important feature of these molecules. While a mixed type of differential inhibition, especially when the targeting on the free enzyme is the process preferred, is still able to differentially affect the transformation of the two agonist substrates, uncompetitive differential inhibitors cannot exert any differential inhibitory action [15]. This paper, revisiting previous observations on AR substrate specificity features, deals with the rational explanation as to why AR is an eligible target for differential inhibition. Preliminary, though important indications of edible vegetables as potential ARDIs sources are reported.
    Materials and methods
    Results and discussion
    Acknowledgments This work was supported by Regione Toscana (Italy), Progetto IDARA (DD650/2014).
    Introduction Diabetes mellitus is a metabolic disease characterized by a chronic increase in blood glucose level. This is mainly attributed to impaired insulin secretion by pancreatic β cells and insulin resistance in peripheral target tissues [1], [2]. Sulfonylureas are common in the design of oral hypoglycemic agents such as tolazamide 1 and glibenclamide 2 [3], [4]. These derivatives play a crucial role in the improvement of insulin secretion and the reduction of insulin resistance. They exert their action via several mechanisms including pancreatic ones through increasing insulin secretion from pancreatic beta-cells and the others are extra-pancreatic by improving insulin resistance in peripheral target tissues [5], [6]. Despite numerous trials to control hyperglycemia, most diabetic patients still suffer from one or more of the long-term diabetic complications including retinopathy, nephropathy, neuropathy and cataract [7], [8]. The enlarged glucose flux during the polyol pathway, which occurs in hyperglycemic conditions, is a potential factor in the onset and progression of such chronic complications (Fig. 1) [9], [10]. Aldose reductase enzyme (ALR2, E.C.1.1.1.21) is the first and key enzyme involved in the polyol pathway. The main role of ALR2 is to catalyze the NADPH-dependent reduction of glucose to sorbitol. Aldose reductase inhibitors (ARIs), therefore, could be considered as a pharmacologically direct management for diabetic complications [11].