Tolrestat and epalrestat have been characterized as noncompetitive inhibitors of aldo-ketone reductase 1B1 (AKR1B1), a leading drug target for the treatment of type 2 diabetes complications.
Key findings are that (a) low doses of Nasonia venom elevate sorbitol levels in human renal mesangial cells (HRMCs) without changing glucose or fructose levels; (b) venom is a much more potent inducer of sorbitol elevation than glucose; (c) low venom doses significantly alter expression of genes involved in sterol and alcohol metabolism, transcriptional regulation, and chemical/stimulus response; (d) although venom treatment does not alter expression of the key sorbitol pathway gene aldose reductase (AR); (e) venom elevates expression of a related gene implicated in diabetes complications (AKR1C3) as well as the fructose metabolic gene (GFPT2).
To develop multifunctional aldose reductase (AKR1B1) inhibitors for anti-diabetic complications, a novel series of 2-phenoxypyrido[3,2-<i>b</i>]pyrazin-3(4<i>H</i>)-one derivatives were designed and synthesised.
Humans exhibit three members of the AKR1B subfamily: AKR1B1 (aldose reductase, participates in diabetes complications), AKR1B10 (overexpressed in several cancer types), and the recently described AKR1B15.
Aldose reductase (AR), a member of aldo-keto reductase family, is the rate-limiting enzyme in the polyol pathway, and is known to play a key role in the pathogenesis of diabetic complications.
Subtle involvement of ALR2 in invoking various pathways of diabetic complications has caused an increase in attention towards the identification of novel aldose reductase inhibitors (ARIs).
Several ALR2 inhibitors with a promising pre-clinical ability to address diabetic complications and inflammatory diseases are being developed during the observed timeframe.
Investigation of the cause of BmAR downregulation in the q-l<sup>p</sup> mutant could contribute to revealing the function of AR in insects and offers a new method of identifying AR inhibitors for the treatment of diabetic complications.
The synthetic ARIs are often associated with deleterious side effects and medicinal and edible plants, containing compounds with aldose reductase inhibitory activity, could be useful for prevention and therapy of diabetic complications.
Functional compounds with antioxidant and AR inhibitory activities have been recognized as an important strategy in the prevention and treatment of diabetic complications, and the search for tyrosinase inhibitors is important for the treatment of hyperpigmentation, development of skin-whitening agents, and use as preservatives in the food industry.
The study stands out as a systematic attempt to generate aldose reductase differential inhibitors (ARDIs) intended to target long-term diabetic complications while leaving unaltered the detoxifying role of the enzyme.
The formation of advanced glycation end-products (AGE) and aldose reductase activity have been implicated in the development of diabetic complications.
Aldose reductase (AR) inhibitors play a vital importance as a potential therapeutic and preventive medicine when it comes to hyperglycemia associated diabetic complications.
Aldose reductase (AR) is an enzyme devoted to cell detoxification and at the same time is strongly involved in the aetiology of secondary diabetic complications and the amplification of inflammatory phenomena.
The N-(aroyl)-N-(arylmethyloxy)-α-alanines are a promising starting point for the development of new ALR2 selective drugs with the aim of delaying the onset of diabetic complications.
This work represents a promising matrix for developing new potential therapeutic candidates for prevention of diabetic complications through targeting aldose reductase enzyme.[Formula: see text].