Review Article | Open Access
Kenneth Maiese, "FoxO Proteins in the Nervous System", Analytical Cellular Pathology, vol. 2015, Article ID 569392, 15 pages, 2015. https://doi.org/10.1155/2015/569392
FoxO Proteins in the Nervous System
Acute as well as chronic disorders of the nervous system lead to significant morbidity and mortality for millions of individuals globally. Given the ability to govern stem cell proliferation and differentiated cell survival, mammalian forkhead transcription factors of the forkhead box class O (FoxO) are increasingly being identified as potential targets for disorders of the nervous system, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and auditory neuronal disease. FoxO proteins are present throughout the body, but they are selectively expressed in the nervous system and have diverse biological functions. The forkhead O class transcription factors interface with an array of signal transduction pathways that include protein kinase B (Akt), serum- and glucocorticoid-inducible protein kinase (SgK), IκB kinase (IKK), silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), growth factors, and Wnt signaling that can determine the activity and integrity of FoxO proteins. Ultimately, there exists a complex interplay between FoxO proteins and their signal transduction pathways that can significantly impact programmed cell death pathways of apoptosis and autophagy as well as the development of clinical strategies for the treatment of neurodegenerative disorders.
1. Clinical Significance of Nervous System Disorders
Nervous system disorders lead to disability and death in a significant proportion of the world’s population. For example, almost ten percent of the global population suffers from the sporadic form of Alzheimer’s disease (AD) while familial cases of AD account for less than 2% of all presentation [1, 2]. In the United States alone, greater than 5 million individuals have AD and another 3.5 million individuals are under treatment at an annual cost of almost 4 billion US dollars. In regards to cerebrovascular disease, stroke is presently ranked as the fourth leading cause of death and can also affect the lives of millions of individuals . A number of factors are responsible for stroke no longer being ranked higher as a cause of death. These factors include improved management of hypertension and diabetes, reduction in tobacco consumption, heightened public awareness for seeking rapid care [3, 4], treatment with recombinant tissue plasminogen activator , and novel new strategies that focus on trophic factors, improved biomarkers, and cellular pathways of oxidative stress [3, 6–10].
Yet, the availability of treatments that can prevent the initiation of acute or chronic neurodegenerative disorders or block the progression of these diseases is scarce. Therapeutic strategies that can aggressively treat AD and stroke continue to remain limited for most individuals. Furthermore, multiple other neurodegenerative disorders also greatly impact the global population with treatments that are not always optimal. By the year 2030, epilepsy is predicted to affect over 50 million people, neuropathies are estimated to afflict almost 300 million individuals, and neurological injuries may alter the lives of 243 million individuals .
2. Targeting Forkhead Transcription Factors
Given the need for novel directions that can potentially diminish or resolve the onset and progression of neurological disorders, mammalian forkhead transcription factors are surfacing as potential effective targets that can offer new developments for drug discovery. Since the documentation of the Drosophila melanogaster gene forkhead, greater than 100 forkhead genes, and 19 human subgroups that range from FOXA to FOXS is now known to exist . Prior terminology for forkhead proteins included forkhead in rhabdomyosarcoma (FKHR) (FOXO1), FKHRL1 (forkhead in rhabdomyosarcoma like protein 1) (FOXO3a), the Drosophila gene fork head (fkh), Forkhead Related Activator- (FREAC-) 1 and FREAC-2, and the acute leukemia fusion gene located in chromosome X (AFX) (FOXO4) [13, 14]. For the current nomenclature, an Arabic number is provided with the designation of “Fox,” and then a subclass or subgroup letter is provided, and finally the member number is listed within the subclasses of the Fox proteins . All letters are capitalized for human Fox proteins. For the mouse, only the initial letter is listed as uppercase and for all other chordates the initial and subclass letters are uppercased [16–19].
Mammalian FOXO proteins are assigned to the O class of the forkhead box class transcription factors and consist of FOXO1, FOXO3, FOXO4, and FOXO6 . With a butterfly-like appearance on X-ray crystallography  and nuclear magnetic resonance , the forkhead box (FOX) family of genes has a conserved forkhead domain (the “forkhead box”) described as a “winged helix.” The forkhead domain in FoxO proteins has three α-helices, three β-sheets, and two loops that compose the “wings” of the domain  which is specific for the forkhead proteins, since not all winged helix domains are considered to be Fox proteins . The α-helices and β-sheets have high sequence homology with variations in either absent β-sheets and loops or additional α-helices. As transcription factors, FoxO proteins bind DNA through the FoxO-recognized element in the C-terminal basic region of the forkhead DNA binding domain [25, 26]. Target gene expression is repressed or activated through fourteen protein-DNA contacts with the primary recognition site located at α-helix H3 . Phosphorylation or acetylation that can block FoxO activity may alter the binding of the C-terminal basic region to DNA to prevent transcriptional activity . However, multiple mechanisms may contribute to forkhead DNA binding that involve variations in the N-terminal region of the recognition helix, changes in electrostatic distribution, and nuclear translocation of FoxO proteins [28–31].
FoxO proteins are expressed in all tissues of the body (Table 1). In relation to metabolic signaling, function of FoxO proteins appears to be conserved among multiple species that include Caenorhabditis elegans, Drosophila melanogaster, and mammals. FoxO proteins are homologous to the transcription factor DAuer Formation-16 (DAF-16) in the worm Caenorhabditis elegans that can determine metabolic insulin signaling and lead to lifespan extension [32, 33]. Furthermore, individual FoxO proteins appear to have selective expression in the nervous system that may provide clues to the biology for specific FoxO proteins [26, 34]. FoxO6 may oversee memory consolidation and emotion , since it is present in several regions of the brain, such as the hippocampus, the amygdala, and the nucleus accumbens [36, 37]. FoxO1 may have a vital role in a number of functions given its broad expression that may relate to astrocyte survival , modulation of embryonic endothelial stem cell survival , regulation of ischemic brain injury , vascular disease , and motor and memory pathways in the striatum and subregions of the hippocampus . FoxO3 may have a more critical role in auditory synaptic transmission , cerebral endothelial vascular cell survival [42, 43], oxidative stress injury in mouse cerebellar granule neurons , neonatal hypoxic-ischemic encephalopathy , erythroid cell growth , and hippocampal neuronal injury [47, 48].
|Akt: protein kinase B; Aβ: beta-amyloid; EPO: erythropoietin; IKK: IκB kinase; MST1: mammalian sterile 20-like kinase-1; mHtt: mutant Huntingtin; SgK: NAD+: nicotinamide adenine dinucleotide; serum- and glucocorticoid-inducible protein kinase; SIRT1: silent mating type information regulation 2 homolog 1 (S. cerevisiae); WISP1: wnt1 inducible signaling pathway protein 1.|
3. Epigenetic and Posttranslation Modification of Forkhead Transcription Factors
Activity of FoxO proteins is controlled by epigenetic [44, 49] and posttranslation protein modifications that involve phosphorylation [28, 30, 46–48, 50–56], acetylation [44, 50, 57], and ubiquitylation [26, 58–60] of these proteins (Table 1). Phosphorylation of forkhead transcription factors can be mediated by the serine-threonine kinase protein kinase B (Akt) [2, 61–66]. In the nervous system, Akt can protect cells during ischemic preconditioning , beta-amyloid (Aβ) toxicity [68–70], oxidative stress injury in the retina , inflammatory vascular injury , cerebral ischemia , experimental subarachnoid hemorrhage , flavonoid-dependent neuroprotection , lipoic acid protection [76, 77], epidermal growth factor receptor transactivation , neuroinflammation , tau homeostasis , senile plaque memory impairment , and growth factor administration [28, 71, 82–89]. Akt phosphorylates FoxO proteins that will bind FoxOs to 14-3-3 proteins prevent nuclear translocation and block the transcription of target genes that promote apoptosis [47, 52, 90, 91]. Akt also may control FoxO proteins activity and subsequently block caspase cleavage to prevent the induction of apoptotic cell death. Akt suppresses caspase activity that ultimately leads to mitochondrial pore opening and cytochrome c release [42, 66, 92–101]. Enhanced activity of FoxO proteins such as FoxO3a also can lead to cytochrome c release and caspase-induced apoptotic death [28, 51, 57, 66, 102–104]. As a result, one mechanism by which Akt prevents apoptotic cell death is through the blockade of FoxO protein activity that would prevent caspase activation. In addition, pathways such as Akt that block caspase 3 activity appear to offer another unique regulatory mechanism. Caspase 3 cleavage of FoxO3a may result in “proapoptotic” amino-terminal (Nt) fragments that can lead to cell death . However, during caspase 3 inhibition such as that by Akt, phosphorylated FoxO3a remains intact and does not lead to apoptotic cell injury during oxidative stress [53, 106].
In addition to Akt, other pathways can lead to the phosphorylation and inactivation of FoxO proteins. The serum- and glucocorticoid-inducible protein kinase (SgK), a member of a family of kinases termed AGC (protein kinase A/protein kinase G/protein kinase C) kinases that includes Akt and phosphorylates FoxO3a and maintains this protein in the cytoplasm . Importantly, Akt and SgK can phosphorylate FoxO proteins at different sites, suggesting greater options to control FoxO protein activity. However, some protein kinases such as mammalian sterile 20-like kinase-1 (MST1) can phosphorylate FOXO proteins and disrupt the binding to 14-3-3 which then allows FOXO nuclear translocation and subsequent death in neurons , indicating that the phosphorylation site of FoxO proteins is crucial in determining the activity of forkhead transcription factors. The ability of MST1 to activate FoxO proteins may be linked to c-Jun N-terminal kinase (JNK), since MST1 can increase JNK activation  which phosphorylates 14-3-3 protein, blocks binding to FoxO, and results in the nuclear localization of FoxO proteins .
Pathways associated with ubiquitylation and acetylation also control posttranslational modification of FoxO proteins [110, 111]. For example, Akt also leads to the ubiquitination and degradation through the 26S proteasome of FoxO proteins [111, 112]. Agents that can prevent the ubiquitination and degradation of FoxO proteins may serve as important agents to induce apoptotic cell death in cancers that can be tied to silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1) [50, 113]. In a similar vein, SIRT1 activity also can lead to enhanced cell survival such as in the nervous system through inhibition of FoxO activity [57, 114–117]. Mammalian forkhead transcription factors can bind to the SIRT1 promoter region that contains a cluster of five putative core binding repeat motifs (IRS-1) and a forkhead-like consensus-binding site (FKHD-L) to affect FoxO transcription . FoxO proteins, such as FoxO1, can subsequently regulate SIRT1 transcription and increase SIRT1 expression . In some cases, SIRT1 and FoxO proteins may function synergistically to promote cell survival. In differentiated chondrocytes exposed to oxidative stress, loss of the forkhead transcription factors FoxO1 and FoxO3 in combination with decreased SIRT1 activity lead to cell death with reduced production of autophagic related proteins, indicating that SIRT1 with FoxO proteins may be necessary for cellular survival . IκB kinase (IKK) also can directly phosphorylate and block the activity of FoxO proteins that results in the proteolysis of FoxO3a via the Ub-dependent proteasome pathway . Acetylation of FoxO proteins provides another avenue for the control of these proteins. FoxO proteins are acetylated by histone acetyltransferases that include p300, the CREB-binding protein (CBP), and the CBP-associated factor. Once acetylated such as CBP, FoxO proteins translocate to the cell nucleus but have diminished activity since acetylation of lysine residues on FoxO proteins has been shown to limit the ability of FoxO proteins to bind to DNA . Furthermore, acetylation can increase phosphorylation of FoxO proteins through Akt . FoxO proteins are deacetylated by histone deacetylases, such as SIRT1 [13, 112, 123, 124]. Histone deacetylase 2 (HDAC2) also forms a physical complex with FoxO3a. This complex can influence FoxO3a-dependent gene transcription and oxidative stress-induced mouse cerebellar granule neuron cell death .
4. Forkhead Transcription Factors, Oxidative Stress, Apoptosis, and Autophagy
FoxO proteins are important components in the control of cell survival and neurodegenerative disorders determined by apoptosis and autophagy in the presence of oxidative stress [7, 125–128]. During oxidative stress, reactive oxygen species (ROS) are generated that include nitric oxide, peroxynitrite, superoxide free radicals, hydrogen peroxide, and singlet oxygen [97, 129–135]. These ROS can lead to cellular organelle injury, protein misfolding, DNA destruction, and neuronal synaptic dysfunction [48, 132, 136–138]. Endogenous systems exist in the body to prevent cellular injury during oxidative stress, but these systems can become overwhelmed such as glutathione peroxidase [139, 140], superoxide dismutase [120, 132, 138, 141–148], and vitamins B, C, D, and K [59, 140, 149–151]. FoxO proteins have been linked to disease progression and oxidative stress such as that with vitiligo  (Table 1). In patients with polymorphism of the FOXO3A gene, FOXO3A levels and catalase enzyme activity in vitiligo patients were decreased compared with control groups, suggesting in this case that FoxO proteins may confer protection. In other systems such as the maternal decidua, FoxO proteins may function independently in regards to oxidative stress with FOXO1 preventing oxidative stress damage and FOXO3a promoting oxidative cell death . In addition, oxidative stress can serve as an epigenetic modifier of FoxO interactions with other proteins that can influence neuronal cell survival .
Autophagy is a process that recycles cytoplasmic components while removing dysfunctional organelles for tissue remodeling [7, 153–156]. Macroautophagy is the most prevalent type of autophagy that sequesters cytoplasmic proteins and organelles into autophagosomes [6, 157–160] and plays a role with FoxO proteins [2, 49, 127]. Autophagosomes, once produced, combine with lysosomes for degradation and are recycled for future cellular processes [125, 159, 161–163]. Under conditions of oxidative stress, FoxO proteins can lead to the induction of autophagy and promote cell survival (Table 1). During exposure with the oxidant tert-butyl hydroperoxide, constitutive active form of FoxO3 increases human articular chondrocyte cell viability and the expression of autophagy related proteins . SIRT1-mediated deacetylation of FoxO1 also appears to mediate starvation-induced increases in autophagic flux that can maintain left ventricular function during periods of starvation . Cardiac expression of constitutively active FoxO3 results in reversible heart atrophy through the activation of autophagic pathways . In experimental models of full-length mutant Huntingtin (mHtt) transgenic mice, ectopic expression of FoxO1 enhances autophagy and toxic mHtt protein clearance in neuronal cell cultures . However, under some conditions, a reduction in autophagy has been reported in the presence of increased FoxO expression, suggesting that FoxO cytoprotection may not always be directly tied to the induction of autophagy. Upregulation of FoxO3 and SIRT1 with a reduction in autophagy occurs in human bronchial epithelial cells exposed to cigarette smoke condensates in the presence of Amurensis H (Vam3), a dimeric derivative of resveratrol that can reduce oxidative stress .
In regards to the programmed cell death pathway of apoptosis, a later phase that leads to genomic DNA degradation is preceded by an early phase with the loss of plasma membrane lipid phosphatidylserine (PS) asymmetry [156, 167, 168]. The later phase of apoptosis results in DNA destruction [8, 19, 169–171], but the early phase of apoptosis represents an important target to save injured cells. Prevention or reversal of membrane PS externalization [68, 172–177] can result in the salvage of neurons and prevent inflammatory cells such as microglia from removing otherwise functional neurons [174, 178, 179]. During oxidative stress, FoxO proteins can lead to initial membrane PS externalization and subsequent DNA degradation (Table 1). In the presence of high glucose exposure, the development of endothelial cell dysfunction occurs with a reduction in SIRT1 expression and an increase in FoxO1 expression . It has been suggested that FoxO proteins, such as FoxO1 and FoxO3a, must be present for oxidative stress to result in apoptosis . This observation is supported by cell culture and animal studies demonstrating that inhibition or gene knockdown of FoxO1 or FoxO3a results in stroke reduction by estradiol , protects against microglial cell demise during oxidative stress  and Aβ exposure , promotes the protective effects of metabotropic glutamate receptors , increases neuronal cell survival through nicotinamide adenine dinucleotide (NAD+) precursors , and provides trophic factor protection with erythropoietin (EPO) [28, 42, 46, 52] and neurotrophins [183–185]. However, under some scenarios that may impact other cellular signal transduction pathways, the activation of FoxO proteins may prevent apoptotic cell injury during oxidative stress such as chondrocytes . Other studies show that in some cellular populations such as mouse hematopoietic stem cells, the conditional deletion of FoxO1, FoxO3a, and FoxO4 can lead to an increase in ROS , suggesting that FoxO proteins may be beneficial in regulation ROS in some cellular environments.
FoxO proteins such as FoxO3a can lead to the induction of “proapoptotic genes” and disrupt proliferative pathways of Wnt signaling . A converse relationship exists between Wnt signaling and FoxO proteins. For example, FoxO3a can block prostate cell malignant phenotypes through the downregulation of Wnt signaling and β-catenin . Wnt signaling includes the family member Wnt1 that can oversee neuronal development, angiogenesis, immunity, tumorigenesis, and stem cell proliferation [188–192]. Wnt1 expression is increased during injury of endothelial cells , metabolic disturbance , nonneuronal cell activation [69, 104, 193–195], spinal cord injury , stroke , and oxidative stress [104, 179, 197]. This increased expression of Wnt1 appears to be protective since loss of Wnt1 translates into progressive spinal cord injury , impaired neurogenesis , and apoptosis [156, 193, 200]. Wnt1 signaling pathways can prevent cellular injury during experimental diabetes [28, 201], ischemic brain injury [197, 202], dopaminergic neuronal cell injury [179, 189, 195, 203], toxic environments for microglia and other inflammatory cells [69, 104, 191, 193], and neuronal synaptic dysfunction . Wnt signaling can afford cellular protection against apoptotic cell death through the inactivation of FoxO proteins. Phosphorylation and inhibition of FoxO3a activity by β-catenin during oxidative stress can protect hepatocytes from apoptotic cell death . Osteoblastic differentiation can be preserved in the presence of oxidative stress through the increased expression of Wnt signaling pathways and the inhibition of FoxO3a . In microglial cells of the central nervous system, Wnt1 prevents apoptosis through the posttranslational phosphorylation and maintenance of FoxO3a in the cytoplasm to prevent the loss of mitochondrial membrane permeability, cytochrome c release, Bad phosphorylation, and activation of caspases . Neuroprotective trophic factors and cytokines, such as EPO [83, 87, 206, 207], also use Wnt signaling to offer cellular protection through the inhibition of FoxO proteins. EPO protects cerebral endothelial cells during oxygen-glucose deprivation by phosphorylating FoxO3a and preventing its subcellular trafficking to the nucleus [42, 208]. During elevated glucose exposure, EPO relies upon Wnt1 to block FoxO3a activity and maintain cerebral endothelial survival . Wnt1 inducible signaling pathway protein 1 (WISP1), also known as CCN4, is a target of Wnt1 and affects programmed cell death, cancer cell growth, extracellular matrix production, cellular migration, and mitosis [159, 209–213]. WISP1 also protects neurons through the posttranslational phosphorylation of FoxO3a, by sequestering FoxO3a in the cytoplasm with protein 14-3-3, and by limiting deacetylation of FoxO3a . Overexpression of FoxO3a during oxidative stress results in caspase 1 and caspase 3 [58, 214]. Through an autoregulatory loop, WISP1 has been shown to increase neuronal survival by limiting FoxO3a deacytelation, blocking caspases 1 and 3 activation, and fostering SIRT1 nuclear trafficking . It should be noted that, under some conditions, Wnt signaling through β-catenin may increase FoxO transcriptional activity and competitively limit β-catenin interaction with members of the lymphoid enhancer factor/T cell factor family .
5. Forkhead Transcription Factors, Development, Stem Cell Proliferation, and Neurodegeneration
FoxO proteins have a prominent role not only in new cell development and differentiation, but also in determining the survival of mature cells in the nervous system (Table 1). Each of forkhead transcription factors may have different biological effects during development. For example, Foxo3a and Foxo4 mice can develop without incidence and have similar weight gain . Yet, mice singly deficient in Foxo1 die by embryonic day eleven and lack development of the vascular system . Overexpression of FoxO1, such as in skeletal muscle in mice, can lead to weight loss, reduced skeletal muscle mass, and impaired glycemic control . On further analysis, FoxO3a null animals experience a number of developmental abnormalities that were not present in mice singly deficient for FoxO4. Foxo3a mice are known to become infertile with ovarian follicles that are depleted of oocytes . FoxO3a overexpression retards oocyte growth and follicular development and leads to anovulation and luteinization of unruptured follicles , indicating a specific function for FoxO3a in the development and maintenance of the reproductive system. This work may suggest a role for FoxO3a in relation to oocyte and follicular development . Mutations in FOXO3a and FOXO1a have been reported in a small percentage of women who suffer from premature ovarian failure . Deletion of Foxo1, Foxo3a, and Foxo4 or a single deletion of Foxo3a also blocks the repopulation of hematopoietic stem cells in murine models [186, 222], illustrating the need for FoxO proteins to maintain hematopoietic stem cells. Other work suggests that FoxO3a alone may play a role in maintaining hematopoietic stem cells, since hematopoietic stem cells are decreased in aged FoxO3 mice compared to the littermate controls . FoxO3 in combination with type 2 deiodinase (D2) and circulation thyroid hormone also is necessary for normal mouse myogenesis and muscle regeneration . Nuclear translocation of FoxO1 in cooperation with SMAD3/4 and Sp1 by transforming growth factor β (TGFβ) is required for oligodendrocyte progenitor development and myelination in the central nervous system .
In contrast, other studies suggest that inhibition of FoxO protein activity or prevention of Wnt pathway disruption may be necessary for stem cell survival. FoxO1 may negatively affect pancreatic beta cell survival . Work that examines osteoblastogenesis demonstrates that FoxO proteins during oxidative stress and aging may antagonize Wnt signaling pathways and block the proliferation of osteoblast precursors . SIRT1 deficiency in mouse embryonic stem cells has been shown to enhance the acetylation and phosphorylation FoxO1, block nuclear localization of FoxO1, and prevent apoptotic cell death that would otherwise ensue with FoxO1 activity . SIRT1 is also necessary to promote cortical bone formation with osteoblast progenitors by deacetylating FoxOs and preventing FoxO protein binding to β-catenin and inhibiting Wnt signaling .
In the nervous system, FoxO proteins similarly determine the fate of neuronal precursors and the maintenance of neurons [137, 229]. Studies that employ genetic deletions of Foxa1 and Foxa2 in mice result in the decline of striatal dopamine metabolites, reduction in dopaminergic cells, and locomotor deficits . Stem cell maintenance may also be governed by the interactions between WISP1 and FoxO proteins. WISP1 is upregulated during stem cell migration  and WISP1 may be one of several components that affect induced pluripotent stem cell reprogramming [232, 233]. WISP1 requires β-catenin for the differentiation of marrow derived mesenchymal stem cells . During oxidative stress, FoxO may bind to β-catenin and prevent stem cell development similar to the previously described pathways with Wnt signaling [212, 235]. Cellular mechanisms that utilize Wnt signaling such as EPO also control FoxO protein activity for stem cell growth [236–241]. EPO promotes erythroid progenitor cell development that requires the modulation of FoxO3a activity [46, 172, 242, 243]. Other trophic factors, such as glial cell line-derived neurotrophic factor, require the inhibition of FoxO1 and FoxO3a to promote rat enteric nervous system precursor development .
In relation to neurodegenerative disorders and neuronal cell survival, activation of FoxO proteins under most conditions leads to cell death [13, 245]. Manganese toxicity that may be a factor in neurodegenerative disorders such as Parkinson’s disease has been associated with the cell death of astrocytes through increased expression and activation of FoxO proteins . Iron-induced oxidative stress that results in apoptotic death of hippocampal neurons can lead to a protective response that activates Akt and blocks FoxO protein translocation to the nucleus . Protection of primary hippocampal neurons by group I metabotropic receptors during exposure to ROS requires the phosphorylation and inactivation of FoxO3a as well as the prevention of caspase cleavage of FoxO3a  to block the generation of potentially “proapoptotic” amino-terminal (Nt) fragments . Antioxidant administration to protect cortical neurons and hippocampal neuronal cell lines during excitotoxicity  and in experimental models of AD with Aβ toxicity  employs FoxO3 inactivation and blocked translocation to the cell nucleus . Independent of Wnt signaling, EPO has been shown to offer neuronal and vascular cell protection through pathways that inactivate FoxO proteins, such as FoxO3a [46, 52]. During cerebral ischemia, FoxO3a expression increases in the hippocampus  and FoxO3a interaction with cell cycle induction proteins may play a role in neuronal apoptotic cell death . Toxin exposure in cortical neurons that fosters FoxO3a activation and p27 (kip1) transcription leads to apoptosis . In microglial cells of the nervous system as well as neurons, knockdown of FoxO3a and prevention of nuclear shuttling lead to the increased survival during oxidative stress [47, 104]. During periods of elevated glucose, cortical neurons  and vascular cells [28, 42, 53, 58] are protected through inhibitory phosphorylation of FoxO3a and the nuclear export of this protein.
However, it is important to recognize the antiproliferative and anticancer effects of FoxO proteins that make these transcription factors attractive targets for the inhibition of tumor growth [14, 50]. Increased activity of FoxO3a with cyclin-dependent kinase inhibitor p27 in isolated human breast cancer cells can suppress breast cancer progression . Colorectal cancer progression may be checked by the activation of FoxO1  and angiogenesis that is necessary for tumor growth can be blocked by the activation of FoxO3a . Through the disruption of proliferative pathways such as Wnt signaling, a number of cancers that include breast cancer, gastric cancer, central nervous system tumors, and lung carcinoma [190, 209, 212, 254–257] can be inhibited through FoxO protein activity  while loss of FoxO activity may signal an increased risk for cancer development . As a result, pathways that inactivate FoxO proteins may have some potential risk for latent tumor growth.
In some experimental scenarios, FoxO protein activation may be required for neuronal protection. Blockade of neurodegenerative disease and adverse behavioral deficits during selenium exposure that may be linked to the development of amyotrophic lateral sclerosis occurs during increased FoxO protein expression . FoxO3a also may be necessary for cochlear auditory activity and the maintenance of synaptic function . In Drosophila models of Aβ toxicity, loss of FoxO results in decreased survival and locomotive activity . FoxO proteins such as FoxO3 may also be important for the control of autophagic flux in Parkinson’s disease . In dopaminergic neurons, overexpressing human α-synuclein, inhibition of FoxO3 is protective. However, a small degree of FoxO3 activity prevents nigral neuron cell death in the presence of human α-synuclein accumulation by reducing the amount of α-synuclein and fostering the accumulation of autophagic vacuoles containing lipofuscin . Interestingly, a controlled upregulation of FoxO3a and SIRT1 expression in cardiac tissue may be important during exercise . Levels of SIRT1 that are less than 7.5-fold are associated with catalase expression that is also controlled by FoxO1a to possibly reduce cell injury during oxidative stress. Conversely, elevated levels of SIRT1 at 12.5-fold can result in cardiomyocyte apoptosis and decreased cardiac function . Activation of FoxO proteins may also be protective during aging. Loss of FoxO3a activity leads to decreased manganese-superoxide dismutase and enhanced cell injury with aging . This extension of cellular lifespan that may be provided by FoxO proteins can be dependent on the negative regulation of Akt to allow for the activation of FoxO3a .
Neurodegenerative disorders result in significant death and disability for millions of individuals throughout the world but remain for the most part with limited treatment options and palliative therapies. Forkhead transcription factors and especially those of the FoxO subgroup are increasingly being identified as potential targets for disorders of the nervous system. FoxO proteins are expressed throughout the body, but their varied expression in the nervous system suggests that specific FoxO proteins may be vital for selective cellular and biological function and may be applicable for Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and auditory neuronal disease. For example, FoxO3 may be important for auditory synaptic transmission, cerebral endothelial vascular cell survival, and erythroid cell growth. In contrast, FoxO6 may be critical for memory consolidation and emotion. FoxOs are regulated by epigenetic and posttranslational modifications that involve phosphorylation, ubiquitylation, and acetylation by cellular pathways that involve Akt, SgK, MST1, IKK, SIRT1, and Wnt signaling to control the activity and integrity of these proteins. The ability of FoxO proteins to ultimately determine cell development and survival in the nervous system during oxidative stress resides with FoxO control of the programmed cell death pathways of apoptosis and autophagy. During oxidative stress cell injury, activation of FoxO proteins often leads to apoptotic cell death that initially fosters membrane PS residue externalization and subsequent DNA degradation. FoxO activity also can disrupt proliferative pathways of Wnt signaling involving β-catenin to result in apoptotic cell death. Conversely, Wnt signaling that includes WISP1 can phosphorylate, limit deacetylation, and sequester FoxO proteins in the cytoplasm to block apoptotic pathways that include caspase activation. FoxO proteins can promote autophagy to preserve cell survival during oxidative stress and clear toxic proteins from the cell. Yet, under some conditions, FoxO proteins may be tied to enhanced cell survival that is independent of autophagy. These observations do not always provide crisp conclusions and suggest the presence of a complex interplay between FoxO proteins and multiple signal transduction pathways in the cell. Furthermore, the degree of FoxO activity as well as companion pathways that involve SIRT1 can significantly impact cell development and survival. Elevated FoxO or SIRT1 activity can be detrimental to cells, but a minimal level of activity that can shepherd autophagic accumulation of toxic proteins may be beneficial. Importantly, these considerations provide further insight for the targeting of FoxO in the nervous system that may involve Wnt signaling, SIRT1, and trophic factors such as EPO to block cellular injury during oxidative stress. In addition, one should be cognizant of the nonproliferative role FoxO proteins play in tumorigenesis. Inactivation of FoxO proteins could yield unexpected cell growth not only in the nervous system but also in other regions of the body. Focusing upon FoxO proteins for the consideration of new therapeutic strategies against neurodegenerative disorders that oversee early cell development as well as differentiated cellular function can offer potentially high returns for new drug development.
Conflict of Interests
The author declares no conflict of interests regarding the publication of this paper.
This research was supported by the following grants to Kenneth Maiese: American Diabetes Association, American Heart Association, NIH NIEHS, NIH NIA, NIH NINDS, and NIH ARRA.
- C. M. Filley, Y. D. Rollins, C. Alan Anderson et al., “The genetics of very early onset Alzheimer disease,” Cognitive and Behavioral Neurology, vol. 20, no. 3, pp. 149–156, 2007.
- K. Maiese, “Taking aim at Alzheimer's disease through the mammalian target of rapamycin,” Annals of Medicine, vol. 46, no. 8, pp. 587–596, 2014.
- K. Maiese, “Cutting through the complexities of mTOR for the treatment of stroke,” Current Neurovascular Research, vol. 11, no. 2, pp. 177–186, 2014.
- P. E. Pergola, C. L. White, J. M. Szychowski et al., “Achieved blood pressures in the secondary prevention of small subcortical strokes (SPS3) study: challenges and lessons learned,” American Journal of Hypertension, vol. 27, no. 8, pp. 1052–1060, 2014.
- D. Pineda, C. Ampurdanés, M. G. Medina et al., “Tissue plasminogen activator induces microglial inflammation via a noncatalytic molecular mechanism involving activation of mitogen-activated protein kinases and Akt signaling pathways and AnnexinA2 and Galectin-1 receptors,” Glia, vol. 60, no. 4, pp. 526–540, 2012.
- K. Maiese, “Driving neural regeneration through the mammalian target of rapamycin,” Neural Regeneration Research, vol. 9, no. 15, pp. 1413–1417, 2014.
- V. P. Nakka, P. Prakash-babu, and R. Vemuganti, “Crosstalk between endoplasmic reticulum stress, oxidative stress, and autophagy: potential therapeutic targets for acute CNS injuries,” Molecular Neurobiology, 2014.
- A. Q. Nguyen, B. H. Cherry, G. F. Scott, M. Ryou, and R. T. Mallet, “Erythropoietin: powerful protection of ischemic and post-ischemic brain,” Experimental Biology and Medicine, vol. 239, no. 11, pp. 1461–1475, 2014.
- A. Selvamani, M. H. Williams, R. C. Miranda, and F. Sohrabji, “Circulating miRNA profiles provide a biomarker for severity of stroke outcomes associated with age and sex in a rat model,” Clinical Science, vol. 127, no. 2, pp. 77–89, 2014.
- X. Xiong, R. Xie, H. Zhang et al., “PRAS40 plays a pivotal role in protecting against stroke by linking the Akt and mTOR pathways,” Neurobiology of Disease, vol. 66, pp. 43–52, 2014.
- World Health Organization, Neurological Disorders: Public Health Challenges, WHO Library Cataloguing-in-Publication Data, 2006.
- D. Weigel, G. Jürgens, F. Küttner, E. Seifert, and H. Jäckle, “The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo,” Cell, vol. 57, no. 4, pp. 645–658, 1989.
- K. Maiese, Z. C. Zhao, and C. S. Yan, “‘Sly as a FOXO’: new paths with forkhead signaling in the brain,” Current Neurovascular Research, vol. 4, no. 4, pp. 295–302, 2007.
- K. Maiese, Z. Z. Chong, Y. C. Shang, and J. Hou, “Clever cancer strategies with FoxO transcription factors,” Cell Cycle, vol. 7, no. 24, pp. 3829–3839, 2008.
- K. Maiese, J. Hou, Z. Z. Chong, and Y. C. Shang, “A fork in the path: developing therapeutic inroads with foxO proteins,” Oxidative Medicine and Cellular Longevity, vol. 2, no. 3, pp. 119–129, 2009.
- Z. Cheng and M. F. White, “Targeting forkhead Box O1 from the concept to metabolic diseases: Lessons from mouse models,” Antioxidants and Redox Signaling, vol. 14, no. 4, pp. 649–661, 2011.
- K. H. Kaestner, W. Knöchel, and D. E. Martínez, “Unified nomenclature for the winged helix/forkhead transcription factors,” Genes and Development, vol. 14, no. 2, pp. 142–146, 2000.
- K. Maiese, Z. Z. Chong, Y. C. Shang, and J. Hou, “FoxO proteins: cunning concepts and considerations for the cardiovascular system,” Clinical Science, vol. 116, no. 3, pp. 191–203, 2009.
- S. Shao, Y. Yang, G. Yuan, M. Zhang, and X. Yu, “Signaling molecules involved in lipid-induced pancreatic beta-cell dysfunction,” DNA and Cell Biology, vol. 32, no. 2, pp. 41–49, 2013.
- K. Maiese, Forkhead Transcription Factors: Vital Elements in Biology and Medicine, vol. 665 of Advances in Experimental Medicine and Biology, Springer Science+Business Media, 2010.
- K. L. Clark, E. D. Halay, E. Lai, and S. K. Burley, “Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5,” Nature, vol. 364, no. 6436, pp. 412–420, 1993.
- C. Jin, I. Marsden, X. Chen, and X. Liao, “Sequence specific collective motions in a winged helix DNA binding domain detected by 15N relaxation NMR,” Biochemistry, vol. 37, no. 17, pp. 6179–6187, 1998.
- K. Maiese, Z. Z. Chong, and Y. C. Shang, “OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins,” Trends in Molecular Medicine, vol. 14, no. 5, pp. 219–227, 2008.
- E. T. Larson, B. Eilers, S. Menon et al., “A winged-helix protein from sulfolobus turreted icosahedral virus points toward stabilizing disulfide bonds in the intracellular proteins of a hyperthermophilic virus,” Virology, vol. 368, no. 2, pp. 249–261, 2007.
- W. H. Biggs III, W. K. Cavenee, and K. C. Arden, “Identification and characterization of members of the FKHR (FOX O) subclass of winged-helix transcription factors in the mouse,” Mammalian Genome, vol. 12, no. 6, pp. 416–425, 2001.
- H. Huang and D. J. Tindall, “Dynamic FoxO transcription factors,” Journal of Cell Science, vol. 120, no. 15, pp. 2479–2487, 2007.
- K. L. Tsai, Y. J. Sun, C. Y. Huang, J. Y. Yang, M. C. Hung, and C. D. Hsiao, “Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification,” Nucleic Acids Research, vol. 35, no. 20, pp. 6984–6994, 2007.
- Z. Z. Chong, J. Hou, Y. C. Shang, S. Wang, and K. Maiese, “EPO relies upon novel signaling of Wnt1 that requires Akt1, FoxO3a, GSK-3beta, and beta-catenin to foster vascular integrity during experimental diabetes,” Current Neurovascular Research, vol. 8, no. 2, pp. 103–120, 2011.
- M. K. Lehtinen, Z. Yuan, P. R. Boag et al., “A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span,” Cell, vol. 125, no. 5, pp. 987–1001, 2006.
- P. Scodelaro Bilbao and R. Boland, “Extracellular ATP regulates FoxO family of transcription factors and cell cycle progression through PI3K/Akt in MCF-7 cells,” Biochimica et Biophysica Acta, vol. 1830, no. 10, pp. 4456–4469, 2013.
- L. P. Van Der Heide, M. F. M. Hoekman, and M. P. Smidt, “The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation,” Biochemical Journal, vol. 380, no. 2, pp. 297–309, 2004.
- K. Lin, J. B. Dorman, A. Rodan, and C. Kenyon, “daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans,” Science, vol. 278, no. 5341, pp. 1319–1322, 1997.
- S. Ogg, S. Paradis, S. Gottlieb et al., “The fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans,” Nature, vol. 389, no. 6654, pp. 994–999, 1997.
- K. Maiese, Z. Z. Chong, J. Hall, and Y. C. Shang, “The ‘O’ class: crafting clinical care with FoxO transcription factors,” Advances in Experimental Medicine and Biology, vol. 665, pp. 242–260, 2009.
- D. A. M. Salih, A. J. Rashid, D. Colas et al., “FoxO6 regulates memory consolidation and synaptic function,” Genes and Development, vol. 26, no. 24, pp. 2780–2801, 2012.
- M. F. M. Hoekman, F. M. J. Jacobs, M. P. Smidt, and J. P. H. Burbach, “Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain,” Gene Expression Patterns, vol. 6, no. 2, pp. 134–140, 2006.
- L. P. van der Heide, F. M. J. Jacobs, J. P. H. Burbach, M. F. M. Hoekman, and M. P. Smidt, “FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling,” Biochemical Journal, vol. 391, no. 3, pp. 623–629, 2005.
- S.-J. Lee, B.-R. Seo, E.-J. Choi, and J.-Y. Koh, “The role of reciprocal activation of cAbl and Mst1 in the Oxidative death of cultured astrocytes,” Glia, vol. 62, no. 4, pp. 639–648, 2014.
- B. Merkely, E. Gara, Z. Lendvai et al., “Signaling via PI3K/FOXO1A pathway modulates formation and survival of human embryonic stem cell-derived endothelial cells,” Stem Cells and Development, vol. 24, no. 7, pp. 869–878, 2015.
- Y. Zhao, Y. Yu, X. Tian et al., “Association study to evaluate FoxO1 and FoxO3 gene in CHD in Han Chinese,” PLoS ONE, vol. 9, no. 1, Article ID e86252, 2014.
- F. Gilels, S. T. Paquette, J. Zhang, I. Rahman, and P. M. White, “Mutation of foxo3 causes adult onset auditory neuropathy and alters cochlear synapse architecture in mice,” Journal of Neuroscience, vol. 33, no. 47, pp. 18409–18424, 2013.
- J. Hou, S. Wang, Y. C. Shang, Z. Z. Chong, and K. Maiese, “Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress,” Current Neurovascular Research, vol. 8, no. 3, pp. 220–235, 2011.
- K. Maiese, F. Li, and Z. Z. Chong, “Erythropoietin in the brain: can the promise to protect be fulfilled?” Trends in Pharmacological Sciences, vol. 25, no. 11, pp. 577–583, 2004.
- S. Peng, S. Zhao, F. Yan et al., “HDAC2 selectively regulates foxo3a-mediated gene transcription during oxidative stress-induced neuronal cell death,” Journal of Neuroscience, vol. 35, no. 3, pp. 1250–1259, 2015.
- Z. Rong, R. Pan, Y. Xu, C. Zhang, Y. Cao, and D. Liu, “Hesperidin pretreatment protects hypoxia-ischemic brain injury in neonatal rat,” Neuroscience, vol. 255, pp. 292–299, 2013.
- M. E. Chamorro, S. D. Wenker, D. M. Vota, D. C. Vittori, and A. B. Nesse, “Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative,” Biochimica et Biophysica Acta, vol. 1833, no. 8, pp. 1960–1968, 2013.
- S. Wang, Z. Z. Chong, Y. C. Shang, and K. Maiese, “WISP1 neuroprotection requires FoxO3a post-translational modulation with autoregulatory control of SIRT1,” Current Neurovascular Research, vol. 10, no. 1, pp. 54–69, 2013.
- E. Zeldich, C. Chen, T. A. Colvin et al., “The neuroprotective effect of Klotho is mediated via regulation of members of the redox system,” The Journal of Biological Chemistry, vol. 289, no. 35, pp. 24700–24715, 2014.
- A. Jenwitheesuk, C. Nopparat, S. Mukda, P. Wongchitrat, and P. Govitrapong, “Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways,” International Journal of Molecular Sciences, vol. 15, no. 9, pp. 16848–16884, 2014.
- S. Carbajo-Pescador, J. L. Mauriz, A. García-Palomo, and J. González-Gallego, “FoxO proteins: regulation and molecular targets in liver cancer,” Current Medicinal Chemistry, vol. 21, no. 10, pp. 1231–1246, 2014.
- Z. Z. Chong, S.-H. Lin, and K. Maiese, “The NAD+ precursor nicotinamide governs neuronal survival during oxidative stress through protein kinase B coupled to FOXO3a and mitochondrial membrane potential,” Journal of Cerebral Blood Flow and Metabolism, vol. 24, no. 7, pp. 728–743, 2004.
- Z. Z. Chong and K. Maiese, “Erythropoietin involves the phosphatidylinositol 3-kinase pathway, 14-3-3 protein and FOXO3a nuclear trafficking to preserve endothelial cell integrity,” British Journal of Pharmacology, vol. 150, no. 7, pp. 839–850, 2007.
- J. Hou, Z. Z. Chong, Y. C. Shang, and K. Maiese, “Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead trafficking, bad, and mitochondrial caspase activation,” Current Neurovascular Research, vol. 7, no. 2, pp. 95–112, 2010.
- G.-Z. Tao, N. Lehwald, K. Y. Jang et al., “Wnt/-catenin signaling protects mouse liver against oxidative stress-induced apoptosis through the inhibition of forkhead transcription factor FoxO3,” Journal of Biological Chemistry, vol. 288, no. 24, pp. 17214–17224, 2013.
- R. M. Uranga, S. Katz, and G. A. Salvador, “Enhanced phosphatidylinositol 3-kinase (PI3K)/Akt signaling has pleiotropic targets in hippocampal neurons exposed to iron-induced oxidative stress,” Journal of Biological Chemistry, vol. 288, no. 27, pp. 19773–19784, 2013.
- C. P. Wong, T. Kaneda, A. H. A. Hadi, and H. Morita, “Ceramicine B, a limonoid with anti-lipid droplets accumulation activity from Chisocheton ceramicus,” Journal of Natural Medicines, vol. 68, no. 1, pp. 22–30, 2014.
- W. Wang, C. Yan, J. Zhang et al., “SIRT1 inhibits TNF-alpha-induced apoptosis of vascular adventitial fibroblasts partly through the deacetylation of FoxO1,” Apoptosis, vol. 18, no. 6, pp. 689–701, 2013.
- J. Hou, Z. Z. Chong, Y. C. Shang, and K. Maiese, “FOXO3a governs early and late apoptotic endothelial programs during elevated glucose through mitochondrial and caspase signaling,” Molecular and Cellular Endocrinology, vol. 321, no. 2, pp. 194–206, 2010.
- K. Maiese, Z. Z. Chong, J. Hou, and Y. C. Shang, “The vitamin nicotinamide: translating nutrition into clinical care,” Molecules, vol. 14, no. 9, pp. 3446–3485, 2009.
- T. Tanaka and M. Iino, “Knockdown of Sec8 promotes cell-cycle arrest at G1/S phase by inducing p21 via control of FOXO proteins,” The FEBS Journal, vol. 281, no. 4, pp. 1068–1084, 2014.
- Z. Z. Chog, F. Li, and K. Maiese, “Activating Akt and the brain's resources to drive cellular survival and prevent inflammatory injury,” Histology and Histopathology, vol. 20, no. 1, pp. 299–315, 2005.
- C.-Y. Huang, C.-Y. Chan, I.-T. Chou, C.-H. Lien, H.-C. Hung, and M.-F. Lee, “Quercetin induces growth arrest through activation of FOXO1 transcription factor in EGFR-overexpressing oral cancer cells,” Journal of Nutritional Biochemistry, vol. 24, no. 9, pp. 1596–1603, 2013.
- K. Maiese, Z. Z. Chong, and Y. C. Shang, “Mechanistic insights into diabetes mellitus and oxidative stress,” Current Medicinal Chemistry, vol. 14, no. 16, pp. 1729–1738, 2007.
- J. Park, Y. S. Ko, J. Yoon et al., “The forkhead transcription factor FOXO1 mediates cisplatin resistance in gastric cancer cells by activating phosphoinositide 3-kinase/Akt pathway,” Gastric Cancer, vol. 17, no. 3, pp. 423–430, 2014.
- P. Puthanveetil, A. Wan, and B. Rodrigues, “FoxO1 is crucial for sustaining cardiomyocyte metabolism and cell survival,” Cardiovascular Research, vol. 97, no. 3, pp. 393–403, 2013.
- X.-F. Qi, Y.-J. Li, Z.-Y. Chen, S.-K. Kim, K.-J. Lee, and D.-Q. Cai, “Involvement of the FoxO3a pathway in the ischemia/reperfusion injury of cardiac microvascular endothelial cells,” Experimental and Molecular Pathology, vol. 95, no. 2, pp. 242–247, 2013.
- W. Balduini, S. Carloni, and G. Buonocore, “Autophagy in hypoxia-ischemia induced brain injury,” Journal of Maternal-Fetal and Neonatal Medicine, vol. 25, supplement 1, pp. 30–34, 2012.
- L. Bing, J. Wu, J. Zhang, Y. Chen, Z. Hong, and H. Zu, “DHT inhibits the A25-35-induced apoptosis by regulation of seladin-1, survivin, XIAP, bax, and bcl-xl expression through a rapid PI3-K/Akt signaling in C6 glial cell lines,” Neurochemical Research, vol. 40, no. 1, pp. 41–48, 2015.
- Y. C. Shang, Z. Z. Chong, S. Wang, and K. Maiese, “Prevention of beta-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL,” Aging, vol. 4, no. 3, pp. 187–201, 2012.
- Y. C. Shang, Z. Z. Chong, S. Wang, and K. Maiese, “Tuberous sclerosis protein 2 (TSC2) modulates CCN4 cytoprotection during apoptotic amyloid toxicity in microglia,” Current Neurovascular Research, vol. 10, no. 1, pp. 29–38, 2013.
- Z.-Y. Chang, M.-K. Yeh, C.-H. Chiang, Y.-H. Chen, and D.-W. Lu, “Erythropoietin protects adult retinal ganglion cells against NMDA-, trophic factor withdrawal-, and TNF-alpha-induced damage,” PLoS ONE, vol. 8, no. 1, Article ID e55291, 2013.
- Z. Z. Chong, J. Q. Kang, and K. Maiese, “AKT1 drives endothelial cell membrane asymmetry and microglial activation through Bcl-xL and caspase 1, 3, and 9,” Experimental Cell Research, vol. 296, no. 2, pp. 196–207, 2004.
- C. Gubern, S. Camós, O. Hurtado et al., “Characterization of Gcf2/Lrrfip1 in experimental cerebral ischemia and its role as a modulator of Akt, mTOR and β-catenin signaling pathways,” Neuroscience, vol. 268, pp. 48–65, 2014.
- Y. Hong, A. Shao, J. Wang et al., “Neuroprotective effect of hydrogen-rich saline against neurologic damage and apoptosis in early brain injury following subarachnoid hemorrhage: possible role of the Akt/GSK3β signaling pathway,” PLoS ONE, vol. 9, no. 4, Article ID e96212, 2014.
- A. Jalsrai, T. Numakawa, Y. Ooshima, N. Adachi, and H. Kunugi, “Phosphatase-mediated intracellular signaling contributes to neuroprotection by flavonoids of Iris tenuifolia,” The American Journal of Chinese Medicine, vol. 42, no. 1, pp. 119–130, 2014.
- M. N. A. Kamarudin, N. A. M. Raflee, S. S. S. Hussein, J. Y. Lo, H. Supriady, and H. Abdul Kadir, “(R)-(+)-α-Lipoic acid protected NG108-15 cells against H2O2-induced cell death through PI3K-Akt/GSK-3β pathway and suppression of NF-κβ-cytokines,” Drug Design Development and Therapy, vol. 8, pp. 1765–1780, 2014.
- S. Zara, M. de Colli, M. Rapino et al., “Ibuprofen and lipoic acid conjugate neuroprotective activity is mediated by Ngb/Akt intracellular signaling pathway in alzheimer's disease rat model,” Gerontology, vol. 59, no. 3, pp. 250–260, 2013.
- R. Kimura, M. Okouchi, T. Kato et al., “Epidermal growth factor receptor transactivation is necessary for glucagon-like peptide-1 to protect PC12 cells from apoptosis,” Neuroendocrinology, vol. 97, no. 4, pp. 300–308, 2013.
- E. Russo, F. Andreozzi, R. Iuliano et al., “Early molecular and behavioral response to lipopolysaccharide in the WAG/Rij rat model of absence epilepsy and depressive-like behavior, involves interplay between AMPK, AKT/mTOR pathways and neuroinflammatory cytokine release,” Brain, Behavior, and Immunity, vol. 42, pp. 157–168, 2014.
- Z. Tang, E. Bereczki, H. Zhang et al., “Mammalian target of rapamycin (mTor) mediates tau protein dyshomeostasis: implication for Alzheimer disease,” Journal of Biological Chemistry, vol. 288, no. 22, pp. 15556–15570, 2013.
- Z. Zhu, J. Yan, W. Jiang et al., “Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance,” Journal of Neuroscience, vol. 33, no. 32, pp. 13138–13149, 2013.
- S. Busch, A. Kannt, M. Kolibabka et al., “Systemic treatment with erythropoietin protects the neurovascular unit in a rat model of retinal neurodegeneration,” PLoS ONE, vol. 9, no. 7, Article ID e102013, 2014.
- Z. Z. Chong, J. Q. Kang, and K. Maiese, “Erythropoietin is a novel vascular protectant through activation of AKt1 and mitochondrial modulation of cysteine proteases,” Circulation, vol. 106, no. 23, pp. 2973–2979, 2002.
- Z. Z. Chong, Y. C. Shang, S. Wang, and K. Maiese, “PRAS40 is an integral regulatory component of erythropoietin mTOR signaling and cytoprotection,” PLoS ONE, vol. 7, no. 9, Article ID e45456, 2012.
- M.-S. Kwon, M.-H. Kim, S.-H. Kim et al., “Erythropoietin exerts cell protective effect by activating PI3k/Akt and MAPK pathways in c6 cells,” Neurological Research, vol. 36, no. 3, pp. 215–223, 2014.
- K. Maiese, Z. Z. Chong, Y. C. Shang, and S. Wang, “Erythropoietin: new directions for the nervous system,” International Journal of Molecular Sciences, vol. 13, no. 9, pp. 11102–11129, 2012.
- K. Maiese, F. Li, and Z. Z. Chong, “New avenues of exploration for erythropoietin,” Journal of the American Medical Association, vol. 293, no. 1, pp. 90–95, 2005.
- T. Maurice, M.-H. Mustafa, C. Desrumaux et al., “Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the Aβ25–35 non-transgenic mouse model of Alzheimer's disease,” Journal of Psychopharmacology, vol. 27, no. 11, pp. 1044–1057, 2013.
- G.-B. Wang, Y.-L. Ni, X.-P. Zhou, and W.-F. Zhang, “The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis,” Molecular and Cellular Biochemistry, vol. 385, no. 1-2, pp. 125–132, 2014.
- E. Arimoto-Ishida, M. Ohmichi, S. Mabuchi et al., “Inhibition of phosphorylation of a Forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin,” Endocrinology, vol. 145, no. 4, pp. 2014–2022, 2004.
- C. K. Won, H. H. Ji, and P. O. Koh, “Estradiol prevents the focal cerebral ischemic injury-induced decrease of forkhead transcription factors phosphorylation,” Neuroscience Letters, vol. 398, no. 1-2, pp. 39–43, 2006.
- C. Chen, Y. Xu, and Y. Song, “IGF-1 gene-modified muscle-derived stem cells are resistant to oxidative stress via enhanced activation of IGF-1R/PI3K/AKT signaling and secretion of VEGF,” Molecular and Cellular Biochemistry, vol. 386, no. 1-2, pp. 167–175, 2014.
- Z. Z. Chong, J.-Q. Kang, and K. Maiese, “Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways,” British Journal of Pharmacology, vol. 138, no. 6, pp. 1107–1118, 2003.
- Z. Z. Chong, S.-H. Lin, J.-Q. Kang, and K. Maiese, “Erythropoietin prevents early and late neuronal demise through modulation of akt1 and induction of caspase 1, 3, and 8,” Journal of Neuroscience Research, vol. 71, no. 5, pp. 659–669, 2003.
- L. Dong, S. Zhou, X. Yang, Q. Chen, Y. He, and W. Huang, “Magnolol protects against oxidative stress-mediated neural cell damage by modulating mitochondrial dysfunction and PI3K/Akt signaling,” Journal of Molecular Neuroscience, vol. 50, no. 3, pp. 469–481, 2013.
- Y. Jiang, L. Li, B. Liu et al., “Vagus nerve stimulation attenuates cerebral ischemia and reperfusion injury via endogenous cholinergic pathway in rat,” PLoS ONE, vol. 9, no. 7, Article ID e102342, 2014.
- S. H. Kwon, S. I. Hong, S. X. Ma, S. Y. Lee, and C. G. Jang, “3′,4′,7-trihydroxyflavone prevents apoptotic cell death in neuronal cells from hydrogen peroxide-induced oxidative stress,” Food and Chemical Toxicology, vol. 80, pp. 41–51, 2015.
- Y. Li, M. Zeng, W. Chen et al., “Dexmedetomidine reduces isoflurane-induced neuroapoptosis partly by preserving PI3K/Akt pathway in the hippocampus of neonatal rats,” PLoS ONE, vol. 9, no. 4, Article ID e93639, 2014.
- Y. Nakazawa, T. Nishino, Y. Obata et al., “Recombinant human erythropoietin attenuates renal tubulointerstitial injury in murine adriamycin-induced nephropathy,” Journal of Nephrology, vol. 26, no. 3, pp. 527–533, 2013.
- L.-L. Pan, X.-H. Liu, Y.-L. Jia et al., “A novel compound derived from danshensu inhibits apoptosis via upregulation of heme oxygenase-1 expression in SH-SY5Y cells,” Biochimica et Biophysica Acta, vol. 1830, no. 4, pp. 2861–2871, 2013.
- Y. Zhu, G. Wu, G. Zhu, C. Ma, and H. Zhao, “Chronic sleep restriction induces changes in the mandibular condylar cartilage of rats: roles of Akt, Bad and Caspase-3,” International Journal of Clinical and Experimental Medicine, vol. 7, no. 9, pp. 2585–2592, 2014.
- Z. Z. Chong, F. Li, and K. Maiese, “Group I metabotropic receptor neuroprotection requires Akt and its substrates that govern FOXO3a, bim, and β-catenin during oxidative stress,” Current Neurovascular Research, vol. 3, no. 2, pp. 107–117, 2006.
- P. Obexer, K. Geiger, P. F. Ambros, B. Meister, and M. J. Ausserlechner, “FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cells,” Cell Death and Differentiation, vol. 14, no. 3, pp. 534–547, 2007.
- Y. C. Shang, Z. Z. Chong, J. Hou, and K. Maiese, “Wnt1, FoxO3a, and NF-kappaB oversee microglial integrity and activation during oxidant stress,” Cellular Signalling, vol. 22, no. 9, pp. 1317–1329, 2010.
- C. Charvet, I. Alberti, F. Luciano et al., “Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases,” Oncogene, vol. 22, no. 29, pp. 4557–4568, 2003.
- C. S. Yan, Z. C. Zhao, H. Jinling, and K. Maiese, “FoxO3a governs early microglial proliferation and employs mitochondrial depolarization with caspase 3, 8, and 9 cleavage during oxidant induced apoptosis,” Current Neurovascular Research, vol. 6, no. 4, pp. 223–238, 2009.
- M. L. L. Leong, A. C. Maiyar, B. Kim, B. A. O'Keeffe, and G. L. Firestone, “Expression of the serum- and glucocorticoid-inducible protein kinase, Sgk, is a cell survival response to multiple types of environmental stress stimuli in mammary epithelial cells,” The Journal of Biological Chemistry, vol. 278, no. 8, pp. 5871–5882, 2003.
- J. J. Song and Y. J. Lee, “Differential cleavage of Mst1 by caspase-7/-3 is responsible for TRAIL-induced activation of the MAPK superfamily,” Cellular Signalling, vol. 20, no. 5, pp. 892–906, 2008.
- J. Sunayama, F. Tsuruta, N. Masuyama, and Y. Gotoh, “JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3,” Journal of Cell Biology, vol. 170, no. 2, pp. 295–304, 2005.
- H. Matsuzaki, H. Daitoku, M. Hatta, K. Tanaka, and A. Fukamizu, “Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 20, pp. 11285–11290, 2003.
- D. R. Plas and C. B. Thompson, “Akt activation promotes degradation of tuberin and FOXO3a via the proteasome,” Journal of Biological Chemistry, vol. 278, no. 14, pp. 12361–12366, 2003.
- Z. Jagani, A. Singh, and R. Khosravi-Far, “FoxO tumor suppressors and BCR-ABL-induced leukemia: a matter of evasion of apoptosis,” Biochimica et Biophysica Acta—Reviews on Cancer, vol. 1785, no. 1, pp. 63–84, 2008.
- F. Wang, C.-H. Chan, K. Chen, X. Guan, H.-K. Lin, and Q. Tong, “Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation,” Oncogene, vol. 31, no. 12, pp. 1546–1557, 2012.
- Z. Z. Chong, Y. C. Shang, S. Wang, and K. Maiese, “SIRT1: new avenues of discovery for disorders of oxidative stress,” Expert Opinion on Therapeutic Targets, vol. 16, no. 2, pp. 167–178, 2012.
- Z. Z. Chong, S. Wang, Y. C. Shang, and K. Maiese, “Targeting cardiovascular disease with novel SIRT1 pathways,” Future Cardiology, vol. 8, no. 1, pp. 89–100, 2012.
- K. Maiese, Z. Z. Chong, Y. C. Shang, and S. Wang, “Translating cell survival and cell longevity into treatment strategies with SIRT1,” Romanian Journal of Morphology and Embryology, vol. 52, no. 4, pp. 1173–1185, 2011.
- A. F. Paraíso, K. L. Mendes, and S. H. S. Santos, “Brain activation of SIRT1: role in neuropathology,” Molecular Neurobiology, vol. 48, no. 3, pp. 681–689, 2013.
- Y. Kobayashi, Y. Furukawa-Hibi, C. Chen et al., “SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress,” International Journal of Molecular Medicine, vol. 16, no. 2, pp. 237–243, 2005.
- S. Xiong, G. Salazar, N. Patrushev, and R. W. Alexander, “FoxO1 mediates an autofeedback loop regulating SIRT1 expression,” The Journal of Biological Chemistry, vol. 286, no. 7, pp. 5289–5299, 2011.
- Y. Akasaki, O. Alvarez-Garcia, M. Saito, B. Caramés, Y. Iwamoto, and M. K. Lotz, “FOXO transcription factors support oxidative stress resistance in human chondrocytes,” Arthritis & Rheumatology, vol. 66, no. 12, pp. 3349–3358, 2014.
- M. C.-T. Hu, D.-F. Lee, W. Xia et al., “IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a,” Cell, vol. 117, no. 2, pp. 225–237, 2004.
- H. Matsuzaki, H. Daitoku, M. Hatta, H. Aoyama, K. Yoshimochi, and A. Fukamizu, “Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 32, pp. 11278–11283, 2005.
- S. S. Myatt and E. W.-F. Lam, “The emerging roles of forkhead box (Fox) proteins in cancer,” Nature Reviews Cancer, vol. 7, no. 11, pp. 847–859, 2007.
- A. van der Horst and B. M. T. Burgering, “Stressing the role of FoxO proteins in lifespan and disease,” Nature Reviews Molecular Cell Biology, vol. 8, no. 6, pp. 440–450, 2007.
- K. A. Kim, Y. J. Shin, M. Akram et al., “High glucose condition induces autophagy in endothelial progenitor cells contributing to angiogenic impairment,” Biological and Pharmaceutical Bulletin, vol. 37, no. 7, pp. 1248–1252, 2014.
- Y. Liu, S. Shi, Z. Gu et al., “Impaired autophagic function in rat islets with aging,” Age, vol. 35, no. 5, pp. 1531–1544, 2013.
- K. Maiese, Z. Z. Chong, Y. C. Shang, and S. Wang, “Novel directions for diabetes mellitus drug discovery,” Expert Opinion on Drug Discovery, vol. 8, no. 1, pp. 35–48, 2013.
- H. Zhang, C. Duan, and H. Yang, “Defective autophagy in Parkinson's disease: lessons from genetics,” Molecular Neurobiology, vol. 51, no. 1, pp. 89–104, 2015.
- Z. C. Zhao, F. Li, and K. Maiese, “Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease,” Brain Research Reviews, vol. 49, no. 1, pp. 1–21, 2005.
- Y. Liu, R. Palanivel, E. Rai et al., “Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high fat diet feeding in mice,” Diabetes, vol. 64, no. 1, pp. 36–48, 2014.
- K. Maiese, “mTOR: driving apoptosis and autophagy for neurocardiac complications of diabetes mellitus,” World Journal of Diabetes, vol. 6, no. 2, pp. 217–224, 2015.
- K. Maiese, Z. Z. Chong, S. Wang, and Y. C. Shang, “Oxidant stress and signal transduction in the nervous system with the PI 3-K, Akt, and mTOR cascade,” International Journal of Molecular Sciences, vol. 13, no. 11, pp. 13830–13866, 2012.
- E. Mhillaj, M. Morgese, and L. Trabace, “Early life and oxidative stress in psychiatric disorders: what can we learn from animal models?” Current Pharmaceutical Design, vol. 21, no. 11, pp. 1396–1403, 2015.
- U. Ozel Turkcu, N. Solak Tekin, T. Gokdogan Edgunlu, S. Karakas Celik, and S. Oner, “The association of FOXO3A gene polymorphisms with serum FOXO3A levels and oxidative stress markers in vitiligo patients,” Gene, vol. 536, no. 1, pp. 129–134, 2014.
- P. Zolotukhin, Y. Kozlova, A. Dovzhik et al., “Oxidative status interactome map: towards novel approaches in experiment planning, data analysis, diagnostics and therapy,” Molecular BioSystems, vol. 9, no. 8, pp. 2085–2096, 2013.
- G. Harish, A. Mahadevan, N. Pruthi et al., “Characterization of traumatic brain injury in human brains reveals distinct cellular and molecular changes in contusion and pericontusion,” Journal of Neurochemistry, 2015.
- K. Maiese, “SIRT1 and stem cells: in the forefront with cardiovascular disease, neurodegeneration and cancer,” World Journal of Stem Cells, vol. 7, no. 2, pp. 235–242, 2015.
- H. E. Palma, P. Wolkmer, M. Gallio et al., “Oxidative stress parameters in blood, liver, and kidney of diabetic rats treated with curcumin and/or insulin,” Molecular and Cellular Biochemistry, vol. 386, no. 1-2, pp. 199–210, 2014.
- K. Rjiba-Touati, I. Ayed-Boussema, Y. Guedri, A. Achour, H. Bacha, and S. Abid-Essefi, “Effect of recombinant human erythropoietin on mitomycin C-induced oxidative stress and genotoxicity in rat kidney and heart tissues,” Human & Experimental Toxicology, 2015.
- J. M. Yousef and A. M. Mohamed, “Prophylactic role of B vitamins against bulk and zinc oxide nano-particles toxicity induced oxidative DNA damage and apoptosis in rat livers,” Pakistan Journal of Pharmaceutical Sciences, vol. 28, no. 1, pp. 175–184, 2015.
- S. Gezginci-Oktayoglu, O. Sacan, S. Bolkent et al., “Chard (Beta vulgaris L. var. cicla) extract ameliorates hyperglycemia by increasing GLUT2 through Akt2 and antioxidant defense in the liver of rats,” Acta Histochemica, vol. 116, no. 1, pp. 32–39, 2014.
- R.-P. Li, Z.-Z. Wang, M.-X. Sun et al., “Polydatin protects learning and memory impairments in a rat model of vascular dementia,” Phytomedicine, vol. 19, no. 8-9, pp. 677–681, 2012.
- X.-Y. Mao, D.-F. Cao, X. Li et al., “Huperzine A ameliorates cognitive deficits in streptozotocin-induced diabetic rats,” International Journal of Molecular Sciences, vol. 15, no. 5, pp. 7667–7683, 2014.
- M. Moghaddasi, S. H. Javanmard, P. Reisi, M. Tajadini, and M. Taati, “The effect of regular exercise on antioxidant enzyme activities and lipid peroxidation levels in both hippocampi after occluding one carotid in rat,” The Journal of Physiological Sciences, vol. 64, no. 5, pp. 325–332, 2014.
- M. M. Muley, V. N. Thakare, R. R. Patil, A. D. Kshirsagar, and S. R. Naik, “Silymarin improves the behavioural, biochemical and histoarchitecture alterations in focal ischemic rats: a comparative evaluation with piracetam and protocatachuic acid,” Pharmacology Biochemistry and Behavior, vol. 102, no. 2, pp. 286–293, 2012.
- A. Srivastava and T. Shivanandappa, “Prevention of hexachlorocyclohexane-induced neuronal oxidative stress by natural antioxidants,” Nutritional Neuroscience, vol. 17, no. 4, pp. 164–171, 2014.
- D. K. Vishwas, A. Mukherjee, C. Haldar, D. Dash, and M. K. Nayak, “Improvement of oxidative stress and immunity by melatonin: an age dependent study in golden hamster,” Experimental Gerontology, vol. 48, no. 2, pp. 168–182, 2013.
- Q. Zhou, C. Liu, W. Liu et al., “Rotenone induction of hydrogen peroxide inhibits mTOR-mediated S6K and 4E-BP1/eIF4E pathways, leading to neuronal apoptosis,” Toxicological Sciences, vol. 143, no. 1, pp. 81–96, 2014.
- C. Bowes Rickman, S. Farsiu, C. A. Toth, and M. Klingeborn, “Dry age-related macular degeneration: mechanisms, therapeutic targets, and imaging,” Investigative Ophthalmology and Visual Science, vol. 54, no. 14, pp. ORSF68–ORSF80, 2013.
- J. A. Miret and S. Munné-Bosch, “Plant amino acid-derived vitamins: biosynthesis and function,” Amino Acids, vol. 46, no. 4, pp. 809–824, 2014.
- Y.-J. Xu, P. S. Tappia, N. S. Neki, and N. S. Dhalla, “Prevention of diabetes-induced cardiovascular complications upon treatment with antioxidants,” Heart Failure Reviews, vol. 19, no. 1, pp. 113–121, 2014.
- T. Kajihara, M. Jones, L. Fusi et al., “Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization,” Molecular Endocrinology, vol. 20, no. 10, pp. 2444–2455, 2006.
- Z. Cai and L. J. Yan, “Rapamycin, autophagy, and Alzheimer's disease,” Journal of Biochemical and Pharmacological Research, vol. 1, no. 2, pp. 84–90, 2013.
- W. Chen, Y. Sun, K. Liu, and X. Sun, “Autophagy: a double-edged sword for neuronal survival after cerebral ischemia,” Neural Regeneration Research, vol. 9, no. 12, pp. 1210–1216, 2014.
- Y. Chen, X. Liu, Y. Yin et al., “Unravelling the multifaceted roles of Atg proteins to improve cancer therapy,” Cell Proliferation, vol. 47, no. 2, pp. 105–112, 2014.
- K. Maiese, Z. Z. Chong, Y. C. Shang, and S. Wang, “Targeting disease through novel pathways of apoptosis and autophagy,” Expert Opinion on Therapeutic Targets, vol. 16, no. 12, pp. 1203–1214, 2012.
- J. H. Fox, T. Connor, V. Chopra et al., “The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease,” Molecular Neurodegeneration, vol. 5, no. 1, article 26, 2010.
- K. Maiese, “Novel applications of trophic factors, Wnt and WISP for neuronal repair and regeneration in metabolic disease,” Neural Regeneration Research, vol. 10, no. 4, pp. 518–528, 2015.
- K. Maiese, “Programming apoptosis and autophagy with novel approaches for diabetes mellitus,” Current Neurovascular Research, vol. 12, no. 2, pp. 173–188, 2015.
- R. L. Vidal, A. Figueroa, F. A. Court et al., “Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy,” Human Molecular Genetics, vol. 21, no. 10, pp. 2245–2262, 2012.
- C. He, H. Zhu, H. Li, M.-H. Zou, and Z. Xie, “Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes,” Diabetes, vol. 62, no. 4, pp. 1270–1281, 2013.
- Y. M. Lim, H. Lim, K. Y. Hur et al., “Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes,” Nature Communications, vol. 5, article 4934, 2014.
- H. Vakifahmetoglu-Norberg, H. Xia, and J. Yuan, “Pharmacologic agents targeting autophagy,” Journal of Clinical Investigation, vol. 125, no. 1, pp. 5–13, 2015.
- N. Hariharan, Y. Maejima, J. Nakae, J. Paik, R. A. Depinho, and J. Sadoshima, “Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes,” Circulation Research, vol. 107, no. 12, pp. 1470–1482, 2010.
- T. G. Schips, A. Wietelmann, K. Höhn et al., “FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model,” Cardiovascular Research, vol. 91, no. 4, pp. 587–597, 2011.
- J. Shi, N. Yin, L. L. Xuan, C. S. Yao, A. M. Meng, and Q. Hou, “Vam3, a derivative of resveratrol, attenuates cigarette smoke-induced autophagy,” Acta Pharmacologica Sinica, vol. 33, no. 7, pp. 888–896, 2012.
- Y. Fong, Y. Lin, C. Wu et al., “The antiproliferative and apoptotic effects of sirtinol, a sirtuin inhibitor on human lung cancer cells by modulating Akt/-catenin-Foxo3a axis,” The Scientific World Journal, vol. 2014, Article ID 937051, 8 pages, 2014.
- X. Guo, Y. Chen, Q. Liu et al., “Ac-cel, a novel antioxidant, protects against hydrogen peroxide-induced injury in PC12 cells via attenuation of mitochondrial dysfunction,” Journal of Molecular Neuroscience, vol. 50, no. 3, pp. 453–461, 2013.
- Z. C. Zhao, F. Li, and K. Maiese, “Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease,” Progress in Neurobiology, vol. 75, no. 3, pp. 207–246, 2005.
- B. Favaloro, N. Allocati, V. Graziano, C. di Ilio, and V. de Laurenzi, “Role of apoptosis in disease,” Aging, vol. 4, no. 5, pp. 330–349, 2012.
- J. Folch, F. Junyent, E. Verdaguer et al., “Role of cell cycle re-entry in neurons: a common apoptotic mechanism of neuronal cell death,” Neurotoxicity Research, vol. 22, no. 3, pp. 195–207, 2012.
- K. Maiese, Z. Z. Chong, J. Hou, and Y. C. Shang, “Oxidative stress: biomarkers and novel therapeutic pathways,” Experimental Gerontology, vol. 45, no. 3, pp. 217–234, 2010.
- K. Maiese, Z. Z. Chong, Y. C. Shang, and J. Hou, “Novel avenues of drug discovery and biomarkers for diabetes mellitus,” Journal of Clinical Pharmacology, vol. 51, no. 2, pp. 128–152, 2011.
- K. Schutters and C. Reutelingsperger, “Phosphatidylserine targeting for diagnosis and treatment of human diseases,” Apoptosis, vol. 15, no. 9, pp. 1072–1082, 2010.
- Z. Tang, A. T. Baykal, H. Gao et al., “MTor is a signaling hub in cell survival: a mass-spectrometry-based proteomics investigation,” Journal of Proteome Research, vol. 13, no. 5, pp. 2433–2444, 2014.
- T. Wang, H. Cui, N. Ma, and Y. Jiang, “Nicotinamide-mediated inhibition of SIRT1 deacetylase is associated with the viability of cancer cells exposed to antitumor agents and apoptosis,” Oncology Letters, vol. 6, no. 2, pp. 600–604, 2013.
- Y. Yang, H. Li, S. Hou, B. Hu, J. Liu, and J. Wang, “The noncoding RNA expression profile and the effect of lncRNA AK126698 on cisplatin resistance in non-small-cell lung cancer cell,” PLoS ONE, vol. 8, no. 5, Article ID e65309, 2013.
- K. Maiese, “New insights for oxidative stress and diabetes mellitus,” Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 875961, 17 pages, 2015.
- L. Wei, C. Sun, M. Lei et al., “Activation of Wnt/β-catenin pathway by exogenous Wnt1 protects SH-SY5Y cells against 6-hydroxydopamine toxicity,” Journal of Molecular Neuroscience, vol. 49, no. 1, pp. 105–115, 2013.
- G. Arunachalam, S. M. Samuel, I. Marei, H. Ding, and C. R. Triggle, “Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1,” British Journal of Pharmacology, vol. 171, no. 2, pp. 523–535, 2014.
- T. Nakamura and K. Sakamoto, “Forkhead transcription factor FOXO subfamily is essential for reactive oxygen species-induced apoptosis,” Molecular and Cellular Endocrinology, vol. 281, no. 1-2, pp. 47–55, 2008.
- C. S. Yan, Z. C. Zhao, J. Hou, and K. Maiese, “The forkhead transcription factor FOXO3a controls microglial inflammatory activation and eventual apoptotic injury through caspase 3,” Current Neurovascular Research, vol. 6, no. 1, pp. 20–31, 2009.
- M. Anitha, C. Gondha, R. Sutliff et al., “GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway,” The Journal of Clinical Investigation, vol. 116, no. 2, pp. 344–356, 2006.
- W.-H. Zheng, S. Kar, and R. Quirion, “FKHRL1 and its homologs are new targets of nerve growth factor Trk receptor signaling,” Journal of Neurochemistry, vol. 80, no. 6, pp. 1049–1061, 2002.
- W. Zhu, G. N. Bijur, N. A. Styles, and X. Li, “Regulation of FOXO3a by brain-derived neurotrophic factor in differentiated human SH-SY5Y neuroblastoma cells,” Molecular Brain Research, vol. 126, no. 1, pp. 45–56, 2004.
- Z. Tothova, R. Kollipara, B. J. Huntly et al., “FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress,” Cell, vol. 128, no. 2, pp. 325–339, 2007.
- H. Liu, J. Yin, H. Wang et al., “FOXO3a modulates WNT/β-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate cancer cells,” Cellular Signalling, vol. 27, no. 3, pp. 510–518, 2015.
- S. Bayod, I. Menella, S. Sanchez-Roige et al., “Wnt pathway regulation by long-term moderate exercise in rat hippocampus,” Brain Research, vol. 1543, pp. 38–48, 2014.
- D. C. Berwick and K. Harvey, “The regulation and deregulation of Wnt signaling by PARK genes in health and disease,” Journal of Molecular Cell Biology, vol. 6, no. 1, pp. 3–12, 2014.
- K. Maiese, F. Li, Z. Z. Chong, and Y. C. Shang, “The Wnt signaling pathway: aging gracefully as a protectionist?” Pharmacology and Therapeutics, vol. 118, no. 1, pp. 58–81, 2008.
- B. Marchetti and S. Pluchino, “Wnt your brain be inflamed? Yes, it Wnt!,” Trends in Molecular Medicine, vol. 19, no. 3, pp. 144–156, 2013.
- T. J. Sun, R. Tao, Y. Q. Han, G. Xu, J. Liu, and Y. F. Han, “Therapeutic potential of umbilical cord mesenchymal stem cells with Wnt/beta-catenin signaling pathway pre-activated for the treatment of diabetic wounds,” European Review for Medical and Pharmacological Sciences, vol. 18, no. 17, pp. 2460–2464, 2014.
- Z. Z. Chong, F. Li, and K. Maiese, “Cellular demise and inflammatory microglial activation during -amyloid toxicity are governed by Wnt1 and canonical signaling pathways,” Cellular Signalling, vol. 19, no. 6, pp. 1150–1162, 2007.
- F. L'Episcopo, C. Tirolo, N. Testa et al., “Reactive astrocytes and Wnt/beta-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease,” Neurobiology of Disease, vol. 41, no. 2, pp. 508–527, 2011.
- B. Marchetti, F. L'Episcopo, M. C. Morale et al., “Uncovering novel actors in astrocyte-neuron crosstalk in Parkinson's disease: the Wnt/β-catenin signaling cascade as the common final pathway for neuroprotection and self-repair,” European Journal of Neuroscience, vol. 37, no. 10, pp. 1550–1563, 2013.
- C. González-Fernández, C. M. Fernández-Martos, S. D. Shields, E. Arenas, and F. J. Rodríguez, “Wnts are expressed in the spinal cord of adult mice and are differentially induced after injury,” Journal of Neurotrauma, vol. 31, no. 6, pp. 565–581, 2014.
- Z. Z. Chong, Y. C. Shang, J. Hou, and K. Maiese, “Wnt1 neuroprotection translates into improved neurological function during oxidant stress and cerebral ischemia through AKT1 and mitochondrial apoptotic pathways,” Oxidative Medicine and Cellular Longevity, vol. 3, no. 2, pp. 153–165, 2010.
- D. Xu, W. Zhao, G. Pan et al., “Expression of nemo-like kinase after spinal cord injury in rats,” Journal of Molecular Neuroscience, vol. 52, no. 3, pp. 410–418, 2014.
- F. L'Episcopo, C. Tirolo, N. Testa et al., “Plasticity of subventricular zone neuroprogenitors in MPTP (1-Methyl-4-Phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease involves cross talk between inflammatory and Wnt/β-catenin signaling pathways: functional consequences for neuroprotection and repair,” Journal of Neuroscience, vol. 32, no. 6, pp. 2062–2085, 2012.
- B. He, N. Reguart, L. You et al., “Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations,” Oncogene, vol. 24, no. 18, pp. 3054–3058, 2005.
- S. Pandey, “Targeting Wnt-Frizzled signaling in cardiovascular diseases,” Molecular Biology Reports, vol. 40, no. 10, pp. 6011–6018, 2013.
- Y. Xing, X. Zhang, K. Zhao et al., “Beneficial effects of sulindac in focal cerebral ischemia: a positive role in Wnt/β-catenin pathway,” Brain Research, vol. 1482, pp. 71–80, 2012.
- F. L'Episcopo, M. F. Serapide, C. Tirolo et al., “A Wnt1 regulated Frizzled-1/-catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: therapeutical relevance for neuron survival and neuroprotection,” Molecular Neurodegeneration, vol. 6, no. 1, article 49, 2011.
- L. P. Sowers, L. Loo, Y. Wu et al., “Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction,” Molecular Psychiatry, vol. 18, no. 10, pp. 1077–1089, 2013.
- Y. Yang, Y. Su, D. Wang et al., “Tanshinol attenuates the deleterious effects of oxidative stress on osteoblastic differentiation via wnt/FoxO3a signaling,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 351895, 18 pages, 2013.
- P. Esmaeili Tazangi, S. M. Moosavi, M. Shabani, and M. Haghani, “Erythropoietin improves synaptic plasticity and memory deficits by decrease of the neurotransmitter release probability in the rat model of Alzheimer's disease,” Pharmacology Biochemistry and Behavior, vol. 130, pp. 15–21, 2015.
- T. Yu, L. Li, T. Chen, Z. Liu, H. Liu, and Z. Li, “Erythropoietin attenuates advanced glycation endproducts-induced toxicity of schwann cells in vitro,” Neurochemical Research, vol. 40, no. 4, pp. 698–712, 2015.
- K. Maiese, J. Hou, Z. Z. Chong, and Y. C. Shang, “Erythropoietin, forkhead proteins, and oxidative injury: biomarkers and biology,” The Scientific World Journal, vol. 9, pp. 1072–1104, 2009.
- D. J. Klinke II, “Induction of Wnt-inducible signaling protein-1 correlates with invasive breast cancer oncogenesis and reduced type 1 cell-mediated cytotoxic immunity: a retrospective study,” PLoS Computational Biology, vol. 10, no. 1, Article ID e1003409, 2014.
- K. Knoblich, H. X. Wang, C. Sharma, A. L. Fletcher, S. J. Turley, and M. E. Hemler, “Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits beta-catenin degradation,” Cellular and Molecular Life Sciences, vol. 71, no. 7, pp. 1305–1314, 2014.
- A. Maeda, M. Ono, K. Holmbeck et al., “WNT1 induced secreted protein-1 (WISP1) : a novel regulator of bone turnover and Wnt signaling,” The Journal of Biological Chemistry, vol. 290, no. 22, pp. 14004–14018, 2015.
- K. Maiese, “WISP1: clinical insights for a proliferative and restorative member of the CCN family,” Current Neurovascular Research, vol. 11, no. 4, pp. 378–389, 2014.
- V. Murahovschi, O. Pivovarova, I. Ilkavets et al., “WISP1 is a novel adipokine linked to inflammation in obesity,” Diabetes, vol. 64, no. 3, pp. 856–866, 2015.
- K. R. Kelly, S. T. Nawrocki, C. M. Espitia et al., “Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO-dependent mechanism,” International Journal of Cancer, vol. 131, no. 11, pp. 2693–2703, 2012.
- D. Hoogeboom, M. A. G. Essers, P. E. Polderman, E. Voets, L. M. M. Smits, and B. M. T. Burgering, “Interaction of FOXO with beta-catenin inhibits beta-catenin/T cell factor activity,” The Journal of Biological Chemistry, vol. 283, no. 14, pp. 9224–9230, 2008.
- T. Hosaka, W. H. Biggs III, D. Tieu et al., “Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 9, pp. 2975–2980, 2004.
- Y. Kamei, S. Miura, M. Suzuki et al., “Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated type I (slow twitch/red muscle) fiber genes, and impaired glycemic control,” The Journal of Biological Chemistry, vol. 279, no. 39, pp. 41114–41123, 2004.
- D. H. Castrillon, L. Miao, R. Kollipara, J. W. Horner, and R. A. DePinho, “Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a,” Science, vol. 301, no. 5630, pp. 215–218, 2003.
- L. Liu, S. Rajareddy, P. Reddy et al., “Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a,” Development, vol. 134, no. 1, pp. 199–209, 2007.
- N. H. Uhlenhaut and M. Treier, “Forkhead transcription factors in ovarian function,” Reproduction, vol. 142, no. 4, pp. 489–495, 2011.
- W. J. Watkins, A. J. Umbers, K. J. Woad et al., “Mutational screening of FOXO3A and FOXO1A in women with premature ovarian failure,” Fertility and Sterility, vol. 86, no. 5, pp. 1518–1521, 2006.
- K. Miyamoto, K. Y. Araki, K. Naka et al., “Foxo3a is essential for maintenance of the hematopoietic stem cell pool,” Cell Stem Cell, vol. 1, no. 1, pp. 101–112, 2007.
- M. Dentice, A. Marsili, R. Ambrosio et al., “The FoxO3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration,” Journal of Clinical Investigation, vol. 120, no. 11, pp. 4021–4030, 2010.
- J. Palazuelos, M. Klingener, and A. Aguirre, “TGFβ signaling regulates the timing of CNS myelination by modulating oligodendrocyte progenitor cell cycle exit through SMAD3/4/FoxO1/Sp1,” The Journal of Neuroscience, vol. 34, no. 23, pp. 7917–7930, 2014.
- C. Kibbe, J. Chen, G. Xu, G. Jing, and A. Shalev, “FOXO1 competes with carbohydrate response element-binding protein (ChREBP) and inhibits thioredoxin-interacting protein (TXNIP) transcription in pancreatic beta cells,” Journal of Biological Chemistry, vol. 288, no. 32, pp. 23194–23202, 2013.
- M. Almeida, L. Han, M. Martin-Millan, C. A. O'Brien, and S. C. Manolagas, “Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting β-catenin from T cell factor- to forkhead box O-mediated transcription,” The Journal of Biological Chemistry, vol. 282, no. 37, pp. 27298–27305, 2007.
- H.-D. Chae and H. E. Broxmeyer, “SIRT1 deficiency downregulates PTEN/JNK/FOXO1 pathway to block reactive oxygen species-induced apoptosis in mouse embryonic stem cells,” Stem Cells and Development, vol. 20, no. 7, pp. 1277–1285, 2011.
- S. Iyer, L. Han, S. M. Bartell et al., “Sirtuin1 (Sirt1) promotes cortical bone formation by preventing beta-catenin sequestration by FoxO transcription factors in osteoblast progenitors,” The Journal of Biological Chemistry, vol. 289, no. 35, pp. 24069–24078, 2014.
- E. C. Genin, N. Caron, R. Vandenbosch, L. Nguyen, and B. Malgrange, “Concise review: forkhead pathway in the control of adult neurogenesis,” Stem Cells, vol. 32, no. 6, pp. 1398–1407, 2014.
- A. Domanskyi, H. Alter, M. A. Vogt, P. Gass, and I. A. Vinnikov, “Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance,” Frontiers in Cellular Neuroscience, vol. 8, article 275, 2014.
- D. Lough, H. Dai, M. Yang et al., “Stimulation of the follicular bulge lgr5+ and lgr6+ stem cells with the gut-derived human alpha defensin 5 results in decreased bacterial presence, enhanced wound healing, and hair growth from tissues devoid of adnexal structures,” Plastic and Reconstructive Surgery, vol. 132, no. 5, pp. 1159–1171, 2013.
- D.-W. Jung, W.-H. Kim, and D. R. Williams, “Reprogram or reboot: small molecule approaches for the production of induced pluripotent stem cells and direct cell reprogramming,” ACS Chemical Biology, vol. 9, no. 1, pp. 80–95, 2014.
- C.-S. Yang, C. G. Lopez, and T. M. Rana, “Discovery of nonsteroidal anti-inflammatory drug and anticancer drug enhancing reprogramming and induced pluripotent stem cell generation,” Stem Cells, vol. 29, no. 10, pp. 1528–1536, 2011.
- N. Case, Z. Xie, B. Sen et al., “Mechanical activation of β-catenin regulates phenotype in adult murine marrow-derived mesenchymal stem cells,” Journal of Orthopaedic Research, vol. 28, no. 11, pp. 1531–1538, 2010.
- J. Heo, E.-K. Ahn, H.-G. Jeong et al., “Transcriptional characterization of Wnt pathway during sequential hepatic differentiation of human embryonic stem cells and adipose tissue-derived stem cells,” Biochemical and Biophysical Research Communications, vol. 434, no. 2, pp. 235–240, 2013.
- R. Castaneda-Arellano, C. Beas-Zarate, A. I. Feria-Velasco, E. W. Bitar-Alatorre, and M. C. Rivera-Cervantes, “From neurogenesis to neuroprotection in the epilepsy: signalling by erythropoietin,” Frontiers in Bioscience, vol. 19, pp. 1445–1455, 2014.
- K. Maiese, Z. Z. Chong, F. Li, and Y. C. Shang, “Erythropoietin: elucidating new cellular targets that broaden therapeutic strategies,” Progress in Neurobiology, vol. 85, no. 2, pp. 194–213, 2008.
- K. Maiese, Z. Z. Chong, and Y. C. Shang, “Raves and risks for erythropoietin,” Cytokine and Growth Factor Reviews, vol. 19, no. 2, pp. 145–155, 2008.
- A. M. Messier and R. K. Ohls, “Neuroprotective effects of erythropoiesis-stimulating agents in term and preterm neonates,” Current Opinion in Pediatrics, vol. 26, no. 2, pp. 139–145, 2014.
- A. Palazzuoli, G. Ruocco, M. Pellegrini et al., “The role of erythropoietin stimulating agents in anemic patients with heart failure: solved and unresolved questions,” Therapeutics and Clinical Risk Management, vol. 10, pp. 641–650, 2014.
- L. Wang, L. Di, and C. T. Noguchi, “Erythropoietin, a novel versatile player regulating energy metabolism beyond the erythroid system,” International Journal of Biological Sciences, vol. 10, no. 8, pp. 921–939, 2014.
- W. J. Bakker, T. B. van Dijk, M. P.-V. Amelsvoort et al., “Differential regulation of Foxo3a target genes in erythropoiesis,” Molecular and Cellular Biology, vol. 27, no. 10, pp. 3839–3854, 2007.
- N. Kaushal, S. Hegde, J. Lumadue, R. F. Paulson, and K. S. Prabhu, “The regulation of erythropoiesis by selenium in mice,” Antioxidants and Redox Signaling, vol. 14, no. 8, pp. 1403–1412, 2011.
- S. Srinivasan, M. Anitha, S. Mwangi, and R. O. Heuckeroth, “Enteric neuroblasts require the phosphatidylinositol 3-kinase/Akt/Forkhead pathway for GDNF-stimulated survival,” Molecular and Cellular Neuroscience, vol. 29, no. 1, pp. 107–119, 2005.
- K. Maiese, Z. Z. Chong, Y. C. Shang, and H. Jinling, “Rogue proliferation versus restorative protection: where do we draw the line for Wnt and Forkhead signaling?” Expert Opinion on Therapeutic Targets, vol. 12, no. 7, pp. 905–916, 2008.
- V. Exil, L. Ping, Y. Yu et al., “Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures,” PLoS ONE, vol. 9, no. 5, Article ID e94753, 2014.
- P. K. Bahia, V. Pugh, K. Hoyland, V. Hensley, M. Rattray, and R. J. Williams, “Neuroprotective effects of phenolic antioxidant tBHQ associate with inhibition of FoxO3a nuclear translocation and activity,” Journal of Neurochemistry, vol. 123, no. 1, pp. 182–191, 2012.
- K. Y. Yoo, S. H. Kwon, C. H. Lee et al., “FoxO3a changes in pyramidal neurons and expresses in non-pyramidal neurons and astrocytes in the gerbil hippocampal CA1 region after transient cerebral ischemia,” Neurochemical Research, vol. 37, no. 3, pp. 588–595, 2012.
- G. Xu, J. Liu, K. Yoshimoto et al., “2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces expression of p27kip1 and FoxO3a in female rat cerebral cortex and PC12 cells,” Toxicology Letters, vol. 226, no. 3, pp. 294–302, 2014.
- A. Wilk, K. Urbanska, S. Yang et al., “Insulin-like growth factor-I-forkhead box O transcription factor 3a counteracts high glucose/tumor necrosis factor-α-mediated neuronal damage: implications for human immunodeficiency virus encephalitis,” Journal of Neuroscience Research, vol. 89, no. 2, pp. 183–198, 2011.
- S. F. Eddy, S. E. Kane, and G. E. Sonenshein, “Trastuzumab-resistant HER2-driven breast cancer cells are sensitive to epigallocatechin-3 gallate,” Cancer Research, vol. 67, no. 19, pp. 9018–9023, 2007.
- F. Gao and W. Wang, “MicroRNA-96 promotes the proliferation of colorectal cancer cells and targets tumor protein p53 inducible nuclear protein 1, forkhead box protein O1 (FOXO1) and FOXO3a,” Molecular Medicine Reports, vol. 11, no. 2, pp. 1200–1206, 2015.
- J. Wang, X. Zheng, G. Zeng, Y. Zhou, and H. Yuan, “Purified vitexin compound 1 inhibits growth and angiogenesis through activation of FOXO3a by inactivation of Akt in hepatocellular carcinoma,” International Journal of Molecular Medicine, vol. 33, no. 2, pp. 441–448, 2014.
- A. Kafka, S. Bašić-Kinda, and N. Pećina-Šlaus, “The cellular story of dishevelleds,” Croatian Medical Journal, vol. 55, no. 5, pp. 459–46667, 2014.
- F. Li, Z. Z. Chong, and K. Maiese, “Winding through the WNT pathway during cellular development and demise,” Histology and Histopathology, vol. 21, no. 1–3, pp. 103–124, 2006.
- H. Y. Park, K. Toume, M. A. Arai, S. K. Sadhu, F. Ahmed, and M. Ishibashi, “Calotropin: a cardenolide from calotropis gigantea that inhibits Wnt signaling by increasing casein kinase 1alpha in colon cancer cells,” ChemBioChem, vol. 15, no. 6, pp. 872–878, 2014.
- Z.-H. Yang, R. Zheng, Y. Gao, Q. Zhang, and H. Zhang, “Abnormal gene expression and gene fusion in lung adenocarcinoma with high-throughput RNA sequencing,” Cancer Gene Therapy, vol. 21, no. 2, pp. 74–82, 2014.
- C. Tan, S. Liu, S. Tan et al., “Polymorphisms in MicroRNA target sites of forkhead box O genes are associated with hepatocellular carcinoma,” PLOS ONE, vol. 10, no. 3, Article ID e0119210, 2015.
- A. O. Estevez, K. L. Morgan, N. J. Szewczyk, D. Gems, and M. Estevez, “The neurodegenerative effects of selenium are inhibited by FOXO and PINK1/PTEN regulation of insulin/insulin-like growth factor signaling in Caenorhabditis elegans,” NeuroToxicology, vol. 41, pp. 28–43, 2014.
- Y. K. Hong, S. Lee, S. H. Park et al., “Inhibition of JNK/dFOXO pathway and caspases rescues neurological impairments in Drosophila Alzheimer's disease model,” Biochemical and Biophysical Research Communications, vol. 419, no. 1, pp. 49–53, 2012.
- E. Pino, R. Amamoto, L. Zheng et al., “FOXO3 determines the accumulation of α-synuclein and controls the fate of dopaminergic neurons in the substantia nigra,” Human Molecular Genetics, vol. 23, no. 6, pp. 1435–1452, 2014.
- N. Ferrara, B. Rinaldi, G. Corbi et al., “Exercise training promotes SIRT1 activity in aged rats,” Rejuvenation Research, vol. 11, no. 1, pp. 139–150, 2008.
- R. R. Alcendor, S. Gao, P. Zhai et al., “Sirt1 regulates aging and resistance to oxidative stress in the heart,” Circulation Research, vol. 100, no. 10, pp. 1512–1521, 2007.
- M. Li, J.-F. Chiu, B. T. Mossman, and N. K. Fukagawa, “Down-regulation of manganese-superoxide dismutase through phosphorylation of FOXO3a by Akt in explanted vascular smooth muscle cells from old rats,” Journal of Biological Chemistry, vol. 281, no. 52, pp. 40429–40439, 2006.
- H. Miyauchi, T. Minamino, K. Tateno, T. Kunieda, H. Toko, and I. Komuro, “Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway,” EMBO Journal, vol. 23, no. 1, pp. 212–220, 2004.
Copyright © 2015 Kenneth Maiese. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.