Aldose reductase [ALR2; EC 1.1.1.21], a key enzyme of polyol pathway, catalyzes NADPH-dependent reduction of glucose to sorbitol (Sorbitol pathway), and an excessive accumulation of intracellular sorbitol found in various tissues of diabetic animals and in cells cultured under high glucose conditions has been proposed to be an important factor for the pathogenesis of diabetic complications. The only strategy shown to be consistently beneficial in the treatment of diabetic complications is meticulous control of blood glucose. However, aldose reductase (AR) enzyme inhibition is becoming one of the therapeutic strategies that have been proposed to prevent or ameliorate long-term diabetic complications. Therefore, AR inhibitors (ARIs) hold promise for reducing metabolic nerve injury, but further study is needed. On the other hand, there is strong evidence to show that diabetes is associated with increased oxidative stress. However, the source of this oxidative stress remains unclear. This relationship between diabetic complications and free radical production was also under investigation. The studies suggest that hydroxyl radical is indirectly inhibited by ARIs resulting from decreasing polyol levels and hydroxyl radical formation is related to the early stages of diabetic complications, possibly via the Fenton reaction involving H(2)O(2) produced from the activated polyol pathway. Therefore, it is proposed that hydroxyl radical may accelerate damage to the cell membranes resulting from polyol accumulation. The search for specific inhibitors of AR enzyme has still become a major pharmaceutic challenge, though a number of AR inhibitors have so far been assessed for diabetic complications.
The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.
During the last decade there has been growing interest in physical-chemical oxidation processes and the behavior of free radicals in living systems. Radicals are known as intermediate species in a variety of biochemical reactions. Numerous techniques, assays and biomarkers have been used to measure reactive oxygen and nitrogen species (ROS and RNS), and to examine oxidative stress. However, many of these assays are not entirely satisfactory or are used inappropriately. The purpose of this chapter is to review current EPR (Electron Paramagnetic Resonance) spectroscopy methods for measuring ROS, RNS, and their secondary products, and to discuss the strengths and limitations of specific methodological approaches.
The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective responses through the induction of a complex transcriptional program that ultimately renders cancer cells resistant to oxidative, metabolic and therapeutic stress. Interestingly, accumulating evidence in recent years has indicated that metabolic reprogramming is closely interrelated with the regulation of redox homeostasis, suggesting that the disruption of NRF2 signaling might represent a valid therapeutic strategy against a variety of solid and hematologic cancers. These aspects will be the focus of the present review.
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