Aldose reductase enzyme (ALR2) of the polyol metabolic pathway, apart from its role as detoxifying enzyme towards toxic aldehydes, osmoregulator in the kidney and regulator of sperm maturation, was first found to be implicated in the etiology of the long term diabetic complications. However, to date, emerging reports have suggested that under normal glucose concentration, ALR2 may be up-regulated by factors other than hyperglycemia and therefore be involved also in other pathological processes that have become major threats to human health in the 21(st) century. Such pathologies are a number of cardiac disorders, inflammation, mood disorders, renal insufficiency and ovarian abnormalities. In addition, ALR2 was found to be over-expressed in different human cancers such as liver, breast, ovarian, cervical and rectal cancers. Although several aldose reductase inhibitors (ARIs) have progressed to the clinical level, only one is currently on the market. Thus, attention is currently targeted to discover ARIs of distinct chemical structures, being neither hydantoin nor carboxylic acid derivatives. The present review focuses on the molecular mechanisms by which ALR2 is implicated in a number of pathologies, on various aspects concerning its catalytic mechanism and its active site, and on the main classes of ARIs that have been developed to date, as well as on reported (quantitive) structure-activity relationships. The presented data aim to support the notion that ARIs are of pharmacotherapeutic interest for the pharmaceutical community and highlight essential aspects for the development of efficient and potent ARIs.

Receptor for advanced glycation end products (RAGE) is expressed in a range of cell types such as endothelial cells, smooth muscle cells, mesangial cells, mononuclear phagocytes and certain neurons. It is a multi-ligand receptor and a member of the immunoglobulin superfamily of cell surface molecules. Its repertoire of ligands includes advanced glycation end products (AGEs), amyloid fibrils, amphoterin and S100/calgranulins. This variety of ligands allows RAGE to be implicated in a wide spectrum of pathological conditions such as diabetes and its complications, Alzheimer's disease, cancer and inflammation. Additionally, genetic polymorphisms in the RAGE gene may have impact on the functional activity of the receptor. It becomes obvious that RAGE pathway is a complicated one and the question of whether blockade of RAGE is a feasible and safe strategy for the prevention/treatment of chronic diseases is gradually gaining the attention of the pharmaceutical community. In this review the biology of RAGE and the triggered signaling cascades involved in health and disease will be presented. Additionally, its potential as an attractive pharmacotherapeutic target will be explored by pointing out the pharmacotherapeutic agents that have been developed for RAGE blockade.

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It is important that future efforts focus on delineating all the steps of the molecular mechanism that implicates ALR2 in inflammatory pathologies. At the same time, utilizing the previous efforts in the field of ARIs, several candidates that have been proven safe in the clinic may be evaluated for their clinical significance as anti-inflammatory medication. Finally, structurally novel ARIs, designed to target specifically the proinflammatory subpocket of ALR2, should be pursued.

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