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  • In conclusion our study would seem to indicate

    2023-11-29

    In conclusion, our study would seem to indicate that a hydrophilic microenvironment, which is suitable to accommodate highly hydrophilic molecules with steric hindrance such as aldose hemiacetals, allows the enzyme modulation by one of its most important physiopathological substrates. It is difficult at the moment to envisage the physical placement of the hemiacetal on the enzyme. Nevertheless the flexibility and adaptability of the induced cavity region at the inhibitory site of AR [55], [56] may contribute to the hemiacetal binding. While providing a plausible interpretation of the apparent negative cooperative behavior of the reduction of Tianeptine sodium synthesis and, in more general terms, of long chain aldoses by AR, the effect reported here of the hemiacetal ring on the enzyme activity strengthens the particular interaction of AR with aldoses compared to other non-sugar substrates. This increases the possibility of intervening on the enzyme by a differential inhibitory action, aimed at targeting the enzyme while working on glucose without, or only partially, affecting the reduction of hydrophobic cytotoxic aldehydes such as alkenals or alkanals [15]. In any event, although modest in terms of absolute values, the partial inhibitory action of aldose hemiacetals is worth considering when planning kinetic studies of AR in which the enzyme is targeted for inhibition to develop drugs against the onset of diabetic complications. In fact the presence of an additional species (i.e., the hemiacetal), trafficking in or near by the AR active site, must be taken in consideration when performing in vitro studies for ARIs or ARDIs selection.
    Transparency document
    Acknowledgments This work was supported in part by Regione Toscana, Progetto IDARA (DD650/2014) and in part by Pisa University. We are indebted to Dr. G. Pasqualetti and Dr. R. Di Sacco (veterinary staff of Consorzio Macelli S. Miniato, Pisa) for their valuable co-operation in collecting the bovine lenses.
    Introduction Posterior capsular opacification (PCO) is the most common complication of cataract surgery and occurs in up to approximately 25–30% of patients [1]. Surgical removal of the cataractous lens mass usually results in some quantity of lens epithelial cells (LEC) left behind due to their adherence to the inner lining of the capsular bag. Following surgery, these LEC are exposed to transforming growth factor beta (TGF-β) that becomes elevated in the eye as part of the surgical wound response [2]. Engagement of the TGF-β receptor expressed on the cell surface of LECs induces them to undergo epithelial-to-mesenchymal transition (EMT), a process that leads to migration of LECs to the posterior aspect of the lens capsular bag. During the EMT process, LECs begin to secrete extracellular matrix proteins and induce fibrosis and wrinkling of the capsular bag. These changes reduce the transparency of the postsurgical capsular bag, which results in a severe degradation of visual acuity due to scattering of light that should be focused on the retina. To recreate the visual axis in lenses with PCO, treatment with a Nd:YAG is used to produce a capsulotomy. However, this procedure adds additional costs to cataract care as well as increased risk for subsequent complications such as retinal detachment and retinal edema [3]. Therefore, an alternative strategy is needed for alleviating the onset and/or progression of PCO. Initiation of the postsurgical EMT response in the lens is thought to be stimulated primarily by TGF-β2 [4]. EMT markers such as α-smooth muscle actin (αSMA) and fibronectin are upregulated by TGF-β in the progression of PCO [4], [5]. In addition, TGF-β-induced EMT increases matrix proteins such as secreted protein acidic rich in cysteine (SPARC) [6] and matrix metalloproteinase (MMP) [7], [8], which are known to be involved in cell migration. In previous studies we showed that aldose reductase (AR) can play a role in the TGF-β-mediated EMT response through interactions the Smad protein family of signaling proteins [9]. In a similar manner, Nahomi and colleagues showed that αB-crystallin plays an essential role for the TGF-β2-mediated EMT of LECs [10].