• Biomedical Science Letters
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• v.24 no.1
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• pp.15-22
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• 2018

Pristimerin is a triterpene compound isolated from plant extracts that reportedly possesses antitumor, antioxidant, and anti-inflammatory activities. The current study was designed to evaluate the antitumor effects of pristimerin on human colon cancer cells. Treatment of the human colon cancer cells, HCT116 and SW480, with pristimerin led to a dose-dependent decrease in cell proliferation. Flow cytometry experiments showed that pristimerin increased cell apoptotic rate and decreased the mitochondrial membrane potential in HCT116 and SW480 cells. Western blot assay showed that pristimerin induced increased cleavage of caspase-3, -7, -8, and poly ADP ribose polymerase. Treatment with pristimerin also caused a marked decrease in the expression of Bcl-2 and Bcl-xL. Additionally, the levels of phosphorylated AKT and forkhead box O3a (FOXO3a) were decreased in pristimerin-treated colon cancer cells. Taken together, our study illustrated that pristimerin promoted apoptosis via the AKT/FOXO3a signaling pathway in colon cancer cells, elucidating that it might be considered as a potential agent for colon cancer therapy.

• Molecules and Cells
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• v.44 no.8
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• pp.613-622
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• 2021

In vertebrate eyes, the retinal pigment epithelium (RPE) provides structural and functional homeostasis to the retina. The RPE takes up retinol (ROL) to be dehydrogenated and isomerized to 11-cis-retinaldehyde (11-cis-RAL), which is a functional photopigment in mammalian photoreceptors. As excessive ROL is toxic, the RPE must also establish mechanisms to protect against ROL toxicity. Here, we found that the levels of retinol dehydrogenases (RDHs) are commonly decreased in phosphatase tensin homolog (Pten)-deficient mouse RPE, which degenerates due to elevated ROL and that can be rescued by feeding a ROL-free diet. We also identified that RDH gene expression is regulated by forkhead box O (FOXO) transcription factors, which are inactivated by hyperactive Akt in the Pten-deficient mouse RPE. Together, our findings suggest that a homeostatic pathway comprising PTEN, FOXO, and RDH can protect the RPE from ROL toxicity.

• Nutrition Research and Practice
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• v.11 no.5
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• pp.430-434
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• 2017

BACKGROUND/OBJECTIVE: Chronic hyperglycemia induces oxidative stress via accumulation of reactive oxygen species (ROS) and contributes to diabetic complications. Hyperglycemia induces mitochondrial superoxide anion production through the increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This study aimed to determine whether fisetin and luteolin treatments suppress the oxidative stress by modulating the expression of sirtuins (SIRTs) and forkhead box O3a (FOXO3a) under hyperglycemic conditions in human monocytes. MATERIALS/METHODS: Human monocytic cells (THP-1) were cultured under osmotic control (14.5 mmol/L mannitol), normoglycemic (NG, 5.5 mmol/L glucose), or hyperglycemic (HG, 20 mmol/L glucose) conditions, in the absence or presence of fisetin and luteolin for 48 h. To determine the effect of fisetin and luteolin treatments on high glucose-induced oxidative stress, western blotting and intracellular staining were performed. RESULTS: Hyperglycemic conditions increased the ROS production, as compared to normoglycemic condition. However, fisetin and luteolin treatments inhibited ROS production under hyperglycemia. To obtain further insight into ROS production in hyperglycemic conditions, evaluation of p47phox expression revealed that fisetin and luteolin treatments inhibited p47phox expression under hyperglycemic conditions. Conversely, the expression levels of SIRT1, SIRT3, SIRT6, and FOXO3a were decreased under high glucose conditions compared to normal glucose conditions, but exposure to fisetin and luteolin induced the expression of SIRT1, SIRT3, SIRT6, and FOXO3a. The above findings suggest that fisetin and luteolin inhibited high glucose-induced ROS production in monocytes through the activation of SIRTs and FOXO3a. CONCLUSIONS: The results of our study supports current researches that state fisetin and luteolin as potential agents for the development of novel strategies for diabetes.

• BMB Reports
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• v.41 no.10
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• pp.728-732
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• 2008

FoxO3a is a member of the forkhead box class O (FoxO) transcription factor family and an important regulator of apoptosis. This work aimed to elucidate the involvement of FoxO3a in transforming growth factor-${\beta}1$(TGF-${\beta}1$)-induced apoptosis in FaO rat hepatoma cells. TGF-${\beta}1$ caused a time-dependent activation of FoxO3a and a subsequent increase in FoxO response-element-containing luciferase reporter activity, which was Akt-sensitive. The FaO cells stably transfected with a wild type FoxO3a were more susceptible to the formation of apoptotic bodies, populations of sub-G1 apoptotic cells, and collapse of the mitochondrial-membrane potential triggered by TGF-${\beta}1$. In contrast, transfection with small-interfering RNA (siRNA) oligonucleotide specific for FoxO3a significantly inhibited caspase activation in FaO cells treated with TGF-${\beta}1$. It thus appears that FoxO3a plays a crucial mediatory role in the TGF-${\beta}1$ signaling pathway leading to apoptosis.

• Journal of Life Science
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• v.25 no.3
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• pp.293-298
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• 2015

Muscle atrophy, known as a sarcopenia, is defined as a loss of muscle mass resulting from a reduction in the muscle fiber area or density due to a decrease in muscle protein synthesis and an increase in protein breakdown. Schisandrae fructus (SF) extract of the fruits of Schisandra chinensis (Turcz) Baillon has been used as a tonic in traditional medicine for thousands of years. Although a great deal of work has been carried out on the therapeutic potential of SF, its pharmacological mechanisms of action in muscle diseases actions remain unclear. In the present study, we investigated the inhibitory effects of SF ethanol extracts on the production of muscle atrophy factors in C2C12 myotubes stimulated with 5-aminoimidazole-4-carboxamide-ribonucleotide (AICAR), an AMP-activated kinase (AMPK) activator, and sought to determine the underlying mechanisms of action. AICAR upregulated atrophy-related ubiquitin ligase muscle RING finger-1 (MuRF-1) and stimulated the levels of the forkhead box O3a (FoxO3a) transcription factor in the C2C12 myotubes. SF supplementation effectively and concentration- dependently counteracted AICAR-induced muscle cell atrophy and reversed the increased expression of MuRF-1 and FoxO3a. Our study demonstrates that SF can reverse the muscle cell atrophy caused by AICAR through regulation of the AMPK and FoxO3a signaling pathways, followed by inhibition of MuRF-1.

• Clinical and Experimental Reproductive Medicine
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• v.39 no.1
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• pp.10-14
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• 2012

The ovarian follicles develop initially from primordial follicles. The majority of ovarian primordial follicles are maintained quiescently as a reserve for the reproductive life span. Only a few of them are activated and develop to an advanced follicular stage. The maintenance of dormancy and activation of primordial follicles are controlled by coordinated actions of a suppressor/activator with close communications with somatic cells and intra-oocyte signaling pathways. Many growth factors and signaling pathways have been identified and the transforming growth factor-beta superfamily plays important roles in early folliculogenesis. However, the mechanism of maintaining the dormancy and survival of primordial follicles has remained unknown for decades. Recently, since the first finding that all primordial follicles are activated prematurely in mice deficient forkhead box O3a, phosphatidylinositol 3 kinase/phosphatase and tensin homolog (PTEN) signaling pathway was reported to be important in the regulation of dormancy and initial follicular activation. With these informations on early folliculogenesis, clinical application can be expected such as in vitro maturation of immature oocytes or in vitro activation of follicles by PTEN inhibitor in cryopreserved ovarian cortical tissues for fertility preservation.

• Journal of Ginseng Research
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• v.41 no.3
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• pp.247-256
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• 2017

Background: KG-135, a standardized formulation enriched with Rk1, Rg3, and Rg5 ginsenosides, has been shown to inhibit various types of cancer cells; however, the underlying mechanisms are not fully understood. In this study, we explored its effects in A549 human lung cancer cells to investigate the induction of Forkhead Class box O3a (FOXO3a) and autophagy. Methods: Cell viability was determined by sulforhodamine B staining. Apoptosis and cell cycle distribution were analyzed using flow cytometry. The changes of protein levels were determined using Western blot analysis. Autophagy induction was monitored by the formation of acidic vesicular organelles stained with acridine orange. Results: KG-135 effectively arrested the cells in G1 phase with limited apoptosis. Accordingly, a decrease of cyclin-dependent kinase-4, cyclin-dependent kinase-6, cyclin D1, and phospho-retinoblastoma protein, and an increase of p27 and p18 proteins were observed. Intriguingly, KG-135 increased the tumor suppressor FOXO3a and induced the accumulation of autophagy hallmark LC3-II and acidic vesicular organelles without an increase of the upstream marker Beclin-1. Unconventionally, the autophagy adaptor protein p62 (sequestosome 1) was increased rather than decreased. Blockade of autophagy by hydroxychloroquine dramatically potentiated KG-135-induced FOXO3a and its downstream (FasL) ligand accompanied by the cleavage of caspase-8. Meanwhile, the decrease of Bcl-2 and survivin, as well as the cleavage of caspase-9, were also drastically enhanced, resulting in massive apoptosis. Conclusion: Besides arresting the cells in G1 phase, KG-135 increased FOXO3a and induced an unconventional autophagy in A549 cells. Both the KG-135-activated extrinsic FOXO3a/FasL/caspase-8 and intrinsic caspase-9 apoptotic pathways were potentiated by blockade of autophagy. Combination of KG-135 and autophagy inhibitor may be a novel strategy as an integrative treatment for cancers.

• Biomedical Science Letters
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• v.26 no.1
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• pp.42-46
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• 2020

Tuberculosis (TB) remains a major health problem worldwide. TB depends not only on the characteristics of the Mycobacterium tuberculosis (MTB) but also on the genetic susceptibility of infected patients. Recent studies have suggested that FOXO3 play an important role in the human immune associated disorder, such as TB. It was previously reported that FOXO3 genetic variants associated with a risk of TB in Chinese population. In this study, we confirm whether the genetic polymorphism of the FOXO3 gene, which was previously in Chinese, is reproduced in Korean population. Of the 154 SNPs were extracted from the FOXO3 gene, reproducibility analysis of the four SNPs performed in the previous study showed that there was a statistically significant correlation in the three SNPs (rs4946935, rs1536057, rs3800228). This study suggests that polymorphism of the FOXO3 gene in Koreans may affect the onset of tuberculosis and could be used to treat and prevent tuberculosis.

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.2
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• pp.149-156
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• 2020

Sodium 2-mercaptoethanesulfonate (mesna) is a protective agent that is widely used in medicine because of its antioxidant effects. Recently, reactive oxygen species (ROS) were shown to increase pigmentation. Thus, ROS scavengers and inhibitors of ROS production may suppress melanogenesis. Forkhead box-O3a (FoxO3a) is an antimelanogenic factor that mediates ROS-induced skin pigmentation. In this study, we aimed to investigate the whitening effect of mesna and the signaling mechanism mediating this effect. Human melanoma (MNT-1) cells were used in this study. mRNA and protein expression were measured by real-time quantitative PCR and Western blotting analysis to track changes in FoxO3a-related signals induced by mesna. An immunofluorescence assay was performed to determine the nuclear translocation of FoxO3a. When MNT-1 melanoma cells were treated with mesna, melanin production and secretion decreased. These effects were accompanied by increases in FoxO3a activation and nuclear translocation, resulting in downregulation of four master genes of melanogenesis: MITF, TYR, TRP1, and TRP2. We found that mesna, an antioxidant and radical scavenger, suppresses melanin production and may therefore be a useful agent for the clinical treatment of hyperpigmentation disorders.

• Clinical and Experimental Reproductive Medicine
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• v.46 no.2
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• pp.43-49
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• 2019

Primordial follicle activation is a process in which individual primordial follicles leave their dormant state and enter a growth phase. While existing hormone stimulation strategies targeted the growing follicles, the remaining dormant primordial follicles were ruled out from clinical use. Recently, in vitro activation (IVA), which is a method for controlling primordial follicle activation, has provided an innovative technology for primary ovarian insufficiency (POI) patients. IVA was developed based on Hippo signaling and phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/forkhead box O3 (FOXO3) signaling modulation. With this method, dormant primordial follicles are activated to enter growth phase and developed into competent oocytes. IVA has been successfully applied in POI patients who only have a few remaining remnant primordial follicles in the ovary, and healthy pregnancies and deliveries have been reported. IVA may also provide a promising option for fertility preservation in cancer patients and prepubertal girls whose fertility preservation choices are limited to tissue cryopreservation. Here, we review the basic mechanisms, translational studies, and current clinical results for IVA. Limitations and further study requirements that could potentially optimize IVA for future use will also be discussed.