&amp;#x201C;SLY AS A FOXO&amp;#x201D;: New Paths with Forkhead Signaling in the Brain

Cytokine & Growth Factor Reviews

Chong²,

Shang³

2008

Self Cite

125

Global use of erythropoietin (EPO) continues to increase as a proven agent for the treatment of anemia. Yet, EPO is no longer believed to have exclusive biological activity in the hematopoietic system and is now considered applicable for a variety of disorders such as diabetes, Alzheimer's disease, and cardiovascular disease. Treatment with EPO is considered to be robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. On the converse side, observations that EPO administration is not without risk have fueled controversy. Here we present recent advances that have elucidated a number of novel cellular pathways governed by EPO to open new therapeutic avenues for this agent and avert its potential deleterious effects. Keywordsangiogenesis; cardiac; diabetes; erythropoietin; neurodegeneration Historical Background for ErythropoietinInitially termed "hemopoietine", erythropoietin (EPO) became evident as a factor that could stimulate new red blood cell development through the pioneering studies of Carnot and Deflandre in 1906 [1]. This team of investigators demonstrated that plasma removed from rabbits following a bleeding stimulus that was later injected into control untreated rabbits would lead to the development of immature red blood cells, or reticulocytosis. A number of other investigators followed these studies that demonstrated similar findings that plasma from animals that were bled would yield a significant reticulocytosis. Interestingly, more elegant experiments later demonstrated that a rise in hemoglobin levels with reticulocytosis occurred in parabiotic rats when only one partner was exposed to hypoxia, illustrating that depressed oxygen tensions could stimulate EPO production. Eventually, human EPO protein was purified that paved the way for the cloning of the EPO gene and the development of recombinant EPO for clinical use [2,3]. *Corresponding Author: Kenneth Maiese, MD, Department of Neurology, 8C-1 UHC, Wayne State University School of Medicine, 4201 St. Antoine, Detroit,; email: aa2088@wayne.edu, kmaiese@med.wayne.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The production and secretion of the mature EPO also relies upon the integrity of the N-and O-linked chains. The EPO gene is located on chromosome 7, exists as a single copy in a 5.4 kb region of the genomic DNA, and encodes a polypeptide chain containing 193 amino acids. During the production and secretion of EPO, a 166 amino acid peptide is initially generated following the cleavage of a 27 amino acid hydrophobic secretory leader ...

Section: Pi 3-k Akt Foxo3a and Epomentioning

confidence: 99%

Raves and risks for erythropoietin

Cytokine & Growth Factor Reviews

Chong²,

Shang³

2008

Self Cite

125

“…Other studies suggest that nicotinamide also may utilize pathways of the mammalian forkhead transcription factor family that oversees processes that can involve cell metabolism, hormone modulation, and apoptosis [1,127,128]. The first member of this family was the Drosophila melanogaster gene Fork head.…”

Section: Innovative Strategies For Neurovascular Protection During Dmmentioning

confidence: 99%

“…The first member of this family was the Drosophila melanogaster gene Fork head. Since this time, greater than 100 forkhead genes and 19 human subgroups are known to exist that extend from FOXA to FOXS [128]. The forkhead box (FOX) family of genes is characterized by a conserved forkhead domain commonly noted as a "forkhead box" or a "winged helix" as a result of the butterfly-like appearance on X-ray crystallography [129] and nuclear magnetic resonance [130].…”

Section: Innovative Strategies For Neurovascular Protection During Dmmentioning

confidence: 99%

“…Of the forkhead transcription factors, FOXO3a is one member that exemplifies the ability to function as a versatile component during normal physiology as well as during disorders such as DM [128]. In relation to the designation of human Fox proteins, all letters are capitalized, otherwise only the initial letter is listed as uppercase.…”

Section: Innovative Strategies For Neurovascular Protection During Dmmentioning

confidence: 99%

See 1 more Smart Citation

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

Biomedicine & Pharmacotherapy

2008

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SummaryOxidative stress is a principal pathway for the dysfunction and ultimate destruction of cells in the neuronal and vascular systems for several disease entities, non promoting the ravages of oxidative stress to any less of a degree than diabetes mellitus. Diabetes mellitus is increasing in incidence as a result of changes in human behavior that relate to diet and daily exercise and is predicted to affect almost 400 million individuals worldwide in another two decades. Furthermore, both type 1 and type 2 diabetes mellitus can lead to significant disability in the nervous and cardiovascular systems, such as cognitive loss and cardiac insufficiency. As a result, innovative strategies that directly target oxidative stress to preserve neuronal and vascular longevity could offer viable therapeutic options to diabetic patients in addition to more conventional treatments that are designed to control serum glucose levels. Here we discuss the novel application of nicotinamide, Wnt signaling, and erythropoietin that modulate cellular oxidative stress and offer significant promise for the prevention of diabetic complications in the nervous and vascular systems. Essential to this process is the precise focus upon diverse as well as common cellular pathways governed by nicotinamide, Wnt signaling, and erythropoietin to outline not only the potential benefits, but also the challenges and possible detriments of these therapies. In this way, new avenues of investigation can hopefully bypass toxic complications, or at the very least, avoid contraindications that may limit care and offer both safe and robust clinical treatment for patients.

“…Since the initial discovery of the fly Drosophila melanogaster gene forkhead, more than 100 forkhead genes and 19 human subgroups are known to exist that range from FOXA to FOXS with a current nomenclature replacing prior terms [1,2] (Box 1). Mammalian FoxO proteins are assigned to the O class of the forkhead transcription super-family and consist of the members FoxO1, FoxO3, FoxO4 and FoxO6.…”

Section: Introductionmentioning

confidence: 99%

OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins

Trends in Molecular Medicine

Chong

Shang

2008

Self Cite

153

207

Forkhead transcription factors have a 'winged helix' domain and regulate processes that range from cell longevity to cell death. Of the mammalian forkhead family members in the O class, FoxO1, FoxO3a and FoxO4 can fill a crucial void for the treatment of disorders that include aging, cancer, diabetes, infertility, neurodegeneration and immune system dysfunction. Yet, observations that forkhead family members also can compromise clinical utility have fueled controversy and highlight the necessity to further outline the integrated cellular pathways governed by these transcription factors. Here we discuss recent advances that have elucidated the unique cellular pathways and clinical potential of targeting FoxO proteins to develop novel therapeutic strategies and avert potential pitfalls that might be closely intertwined with its benefits for patient care.