Aldose reductase (AR) is widely expressed aldehyde-metabolizing enzyme. The reduction of glucose by the AR-catalyzed polyol pathway has been linked to the development of secondary diabetic complications. Although treatment with AR inhibitors has been shown to prevent tissue injury in animal models of diabetes, the clinical efficacy of these drugs remains to be established. Recent studies suggest that glucose may be an incidental substrate of AR, which appears to be more adept in catalyzing the reduction of a wide range of aldehydes generated from lipid peroxidation. Moreover, inhibition of the enzyme has been shown to increase inflammation-induced vascular oxidative stress and prevent myocardial protection associated with the late phase of ischemic preconditioning. On the basis of these studies, several investigators have ascribed an important antioxidant role to the enzyme. Additionally, ongoing work indicates that AR is a critical component of intracellular signaling, and inhibition of the enzyme prevents high glucose-, cytokine-, or growth factor-induced activation of protein kinase C and nuclear factor-κ-binding protein. Thus, treatment with AR inhibitors prevents vascular smooth muscle cell growth and endothelial cell apoptosis in culture and inflammation and restenosis in vivo. Additional studies indicate that the antioxidant and signaling roles of AR are interlinked and that AR regulates protein kinase C and nuclear factor-κB via redox-sensitive mechanisms. These data underscore the need for reevaluating anti-AR interventions for the treatment of diabetic complications. Potentially, the development of newer drugs that selectively inhibit ARmediated glucose metabolism and signaling, without affecting aldehyde detoxification, may be useful in preventing inflammation associated with the development of diabetic complications, particularly micro- and macrovascular diseases.

Metastable aldehydes produced by lipid peroxidation act as 'toxic second messengers' that extend the injurious potential of free radicals. 4-hydroxy 2-nonenal (HNE), a highly toxic and most abundant stable end product of lipid peroxidation, has been implicated in the tissue damage, dysfunction, injury associated with aging and other pathological states such as cancer, Alzheimer, diabetes, cardiovascular and inflammatory complications. Further, HNE has been considered as a oxidative stress marker and it act as a secondary signaling molecule to regulates a number of cell signaling pathways. Biological activity of HNE depends on its intracellular concentration, which can differentially modulate cell death, growth and differentiation. Therefore, the mechanisms responsible for maintaining the intracellular levels of HNE are most important, not only in the defense against oxidative stress but also in the pathophysiology of a number of disease processes. In this review, we discussed the significance of HNE in mediating various disease processes and how regulation of its metabolism could be therapeutically effective.

In the past years aldose reductase (AKR1B1; AR) is thought to be involved in the pathogenesis of secondary diabetic complications such as retinopathy, neuropathy, nephropathy and cataractogenesis. Subsequently, several AR inhibitors have been developed and tested for diabetic complications. Although these inhibitors have found to be safe for human use, they have not been successful in clinical studies because of limited efficacy. Recently, the potential physiological role of AR has been reassessed from a different point of view. Diverse groups suggested that AR, in addition to reducing glucose, also efficiently reduces oxidative stress-generated lipid peroxidation-derived aldehydes and their glutathione conjugates. Because lipid aldehydes alter cellular signals by regulating the activation of transcription factors such as NF-κB and AP1, inhibition of AR could inhibit such events. Indeed, a wide array of recent experimental evidence indicates that the inhibition of AR prevents oxidative stress-induced activation of NF-κB and AP1 signals that lead to cell death or growth. Furthermore, AR inhibitors have been shown to prevent inflammatory complications such as sepsis, asthma, colon cancer and uveitis in rodent animal models. The new experimental in vitro and in vivo data has provided a basis for investigating the clinical efficacy of AR inhibitors in preventing other inflammatory complications than diabetes. This review describes how recent studies have identified novel plethoric physiological and pathophysiological significance of AR in mediating inflammatory complications, and how the discovery of such new insights for this old enzyme could have considerable importance in envisioning potential new therapeutic strategies for the prevention or treatment of inflammatory diseases.

Oxidative stress plays a critical role in the pathophysiology of a wide range of diseases including cancer. This view has broadened significantly with the recent discoveries that reactive oxygen species initiated lipid peroxidation leads to the formation of potentially toxic lipid aldehyde species such as 4-hydroxy-trans-2-nonenal (HNE), acrolein, and malondialdehyde which activate various signaling intermediates that regulate cellular activity and dysfunction via a process called redox signaling. The lipid aldehyde species formed during synchronized enzymatic pathways result in the posttranslational modification of proteins and DNA leading to cytotoxicity and genotoxicty. Among the lipid aldehyde species, HNE has been widely accepted as a most toxic and abundant lipid aldehyde generated during lipid peroxidation. HNE and its glutathione conjugates have been shown to regulate redox-sensitive transcription factors such as NF-B and AP-1 via signaling through various protein kinase cascades. Activation of redox-sensitive transcription factors and their nuclear localization leads to transcriptional induction of several genes responsible for cell survival, differentiation, and death. In this review, we describe the mechanisms by which the lipid aldehydes transduce activation of NF-B signaling pathways that may help to develop therapeutic strategies for the prevention of a number of inflammatory diseases.