Mammalian forkhead transcription factors of the O class (FoxO) are exciting targets under consideration for the
development of new clinical entities to treat metabolic disorders and diabetes mellitus (DM). DM, a disorder that currently
affects greater than 350 million individuals globally, can become a devastating disease that leads to cellular injury through
oxidative stress pathways and affects multiple systems of the body. FoxO proteins can regulate insulin signaling, gluconeogenesis,
insulin resistance, immune cell migration, and cell senescence. FoxO proteins also control cell fate through
oxidative stress and pathways of autophagy and apoptosis that either lead to tissue regeneration or cell demise. Furthermore,
FoxO signaling can be dependent upon signal transduction pathways that include silent mating type information
regulation 2 homolog 1 (S. cerevisiae) (SIRT1), Wnt, and Wnt1 inducible signaling pathway protein 1 (WISP1). Cellular
metabolic pathways driven by FoxO proteins are complex, can lead to variable clinical outcomes, and require in-depth
analysis of the epigenetic and post-translation protein modifications that drive FoxO protein activation and degradation.
Keywords: Akt, Apoptosis, Autophagy, β-catenin, Caspase, CCN, Diabetes mellitus, Epigenetic, Erythropoietin, Forkhead,
FoxO, Metabolism, Nicotinamide, Oxidative stress, Sirtuins, SgK, SIRT1, Stem cells, WISP, Wnt.
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