RESUMEN
A common feature of different types of diabetes is the high blood glucose levels, which are known to induce a series of metabolic alterations, leading to damaging events in different tissues. Among these alterations, both increased polyol pathway flux and oxidative stress are considered to play relevant roles in the response of different cells. In this work, the effect on a human lens epithelial cell line of stress conditions, consisting of exposure to either high glucose levels or to the lipid peroxidation product 4-hydroxy-2-nonenal, is reported. The occurrence of osmotic imbalance, alterations of glutathione levels, and expression of inflammatory markers was monitored. A common feature of the two stress conditions was the expression of COX-2, which, only in the case of hyperglycemic stress, occurred through NF-κB activation. In our cell model, aldose reductase activity, which is confirmed as the only activity responsible for the osmotic imbalance occurring in hyperglycemic conditions, seemed to have no role in controlling the onset of the inflammatory phenomena. However, it played a relevant role in cellular detoxification against lipid peroxidation products. These results, in confirming the multifactorial nature of the inflammatory phenomena, highlight the dual role of aldose reductase as having both damaging but also protecting activity, depending on stress conditions.
RESUMEN
Type 2 diabetes mellitus (T2DM) is a serious chronic disease with an alarmingly growing worldwide prevalence. Current treatment of T2DM mainly relies on drug combinations in order to control blood glucose levels and consequently prevent the onset of hyperglycaemia-related complications. The development of multiple-targeted drugs recently emerged as an attractive alternative to drug combinations for the treatment of complex diseases with multifactorial pathogenesis, such as T2DM. Protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AKR1B1) are two enzymes crucially involved in the development of T2DM and its chronic complications and, therefore, dual inhibitors targeted to both these enzymes could provide novel agents for the treatment of this complex pathological condition. In continuing our search for dual-targeted PTP1B/AKR1B1 inhibitors, we designed new (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic acids. Among them, 3-(4-phenylbutoxy)benzylidene derivatives 6f and 7f, endowed with interesting inhibitory activity against both targets, proved to control specific cellular pathways implicated in the development of T2DM and related complications.
