• The Journal of the Korea Contents Association
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• v.12 no.2
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• pp.339-348
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• 2012

Acute promyelocytic leukemia (APL) is a cancer of the blood and bone marrow. Although all-trans retionic acid (ATRA) is the agents for ALP therapy, there are various side effects. For overcome this problem, we need the development of new therapeutic agents for APL. A number of bacteria produce various virulence factors with cytotoxic effects on human cancer cells. To understand the anti-cancer effect of Listeria monocytogenes on APL, we examined alteration of the cell viability, apoptosis and cell cycle arrest of the human promyelocytic leukemia cell line, HL-60 cells. The cell supernatant (LmSup) and the extract of L. monocytogenes (LmE) inhibited the cell viability and induced apoptosis of HL-60 cells. These cytotoxic effect of LmSup and LmE mediated by modulation of cell cycle and ROS production. These results indicate that released or included bacterial molecules from L. monocytogenes have a cytotoxicity in HL-60 cells. Therefore, LmSup and LmE may be used as the potential target for the treatment of cancer induced by HL-60 cells.

• YAKHAK HOEJI
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• v.60 no.2
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• pp.92-99
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• 2016

Parkinson's disease (PD) is one of the representative neurodegenerative movement disorders with the selective loss of dopaminergic neurons in the substantia nigra. 6-Hydroxydopamine (6-OHDA) is widely used as an experimental model system to mimic PD and has been reported to cause neuronal cell death via oxidative and/or nitrosative stress. Therefore, daily intake of dietary or medicinal plants which fortifies cellular antioxidant capacity can exert neuroprotective effects in PD. In the present study, we have investigated the protective effect of Korean red ginseng (KRG) against 6-OHDA-induced nitrosative death in C6 glioma cells. Treatment of C6 cells with 6-OHDA decreased cell viability and increased expression of inducible nitric oxide synthase, production of nitric oxide as well as peroxynitrite, and formation of nitrotyrosine. 6-OHDA led to apoptotic cell death as determined by decreased Bcl-2/Bax, phosphorylation of JNK, activation of caspase-3, and cleavage of PARP. Conversely, pretreatment of C6 cells with KRG attenuated 6-ODHA-induced cytotoxicity, apoptosis, and nitrosative damages. To further elucidate the molecular mechanism of KRG protection against 6-OHDA-induced nitrosative cell death, we have focused on the cellular self-defense molecules against exogenous noxious stimuli. KRG treatment up-regulated heme oxygenase-1 (HO-1), a key antioxidant enzyme essential for cellular defense against oxidative and/or nitrosative stress via activation of Nrf2. Taken together, these findings suggest KRG may have preventive and/or therapeutic potentials for the management of PD.

• Molecules and Cells
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• v.39 no.3
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• pp.242-249
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• 2016

A balance between production and degradation of reactive oxygen species (ROS) is critical for maintaining cellular homeostasis. Increased levels of ROS during oxidative stress are associated with disease conditions. Antioxidant enzymes, such as extracellular superoxide dismutase (EC-SOD), in the extracellular matrix (ECM) neutralize the toxicity of superoxide. Recent studies have emphasized the importance of EC-SOD in protecting the brain, lungs, and other tissues from oxidative stress. Therefore, EC-SOD would be an excellent therapeutic drug for treatment of diseases caused by oxidative stress. We cloned both the full length (residues 1-240) and truncated (residues 19-240) forms of human EC-SOD (hEC-SOD) into the donor plasmid pFastBacHTb. After transposition, the bacmid was transfected into the Sf9-baculovirus expression system and the expressed hEC-SOD purified using FLAG-tag. Western blot analysis revealed that hEC-SOD is present both as a monomer (33 kDa) and a dimer (66 kDa), as detected by the FLAG antibody. A water-soluble tetrazolium (WST-1) assay showed that both full length and truncated hEC-SOD proteins were enzymatically active. We showed that a potent superoxide dismutase inhibitor, diethyldithiocarbamate (DDC), inhibits hEC-SOD activity.

• Proceedings of the Plant Resources Society of Korea Conference
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• 2018.04a
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• pp.91-91
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• 2018

Poncirus Fructus (PF) is obtained by drying the trifoliate orange fruit belonging to the Rutaceae family. In our country of medicine, PF has been used as a treatment of indigestion, allergy and inflammation. But Mechanism and medical data for PF is insignificant. Recently, the effect of the study PF of biological activity was reported, such as anti- thrombosis, anti-bacteria, anti-virus, anti- allergic. We investigated that the effect of PF on anti-inflammatory in murine macrophage-like cell line Raw264.7 cells. Our results show that the expression level of Nitric Oxide (NO) and Matrix-metallopeptidase-9 (MMP-9) significantly decreased. Moreover, to determine the expression level of pro-inflammatory cytokines such as Tumor Necrosis Factor ($TNF-{\alpha}$) and Interleukin-6 (IL-6) and the phosphorylation pattern of signaling molecules of mitogen-activated protein kinase (MAPK) family, we performed ELISA and westren blot in Raw264.7 cells. In addition, nuclear factor-kappa B ($NF-{\kappa}B$) pathway was confirmed. PF extract inhibited the production of $TNF-{\alpha}$ and IL-6. The extract suppressed the phosphorylation of ERK1/2, JNK, and p38 MAPK, and the nuclear translocation of $NF-{\kappa}B$ p65 in activated cells. Our results suggest that PF can be used as a potential therapeutic agent or functional food to relieve inflammation.

• Journal of Integrative Natural Science
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• v.5 no.2
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• pp.107-119
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• 2012

Polymerization of monomeric amyloid-${\beta}$ peptides ($A{\beta}$) into soluble oligomers and insoluble fibrils is one of the major pathways triggering the pathogenesis of Alzheimer's disease (AD). Using small molecules to prevent the polymerization of $A{\beta}$ peptides can, therefore, be an effective therapeutic strategy for AD. In this study, we investigated the effects of mono- and bi-flavonoids on $A{\beta}42$ toxicity and fibrillogenesis and found that the bi-flavonoid, taiwaniaflavone (TF) effectively and specifically inhibits $A{\beta}$ toxicity and fibrillogenesis. Compared to TF, the mono-flavonoid apigenin (AP) is less effective and less specific. Our data showed that differential effects of the mono- and bi-flavonoids on $A{\beta}$ fibrillogenesis correlate with their varying cytoprotective efficacies. We also found that other bi-flavonoids, namely 2',8"-biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit $A{\beta}$ toxicity and fibrillogenesis, implying that the participation of two mono-flavonoids in a single bi-flavonoid molecule enhanced their activity. Bi-flavonoids, while strongly inhibited $A{\beta}$ fibrillogenesis, accumulated nontoxic $A{\beta}$ oligomeric structures, suggesting that these are off-pathway-oligomers. Moreover, TF abrogated the toxicity of preformed $A{\beta}$ oligomers and fibrils, indicating that TF and other bi-flavonoids may also reduce the toxicity of toxic $A{\beta}$ species. Altogether, our data clearly show that bi-flavonoids, possibly due to the possession of two $A{\beta}$ binders separated by an appropriate size linker, are likely to be promising therapeutics to suppress $A{\beta}$ toxicity.

• IMMUNE NETWORK
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• v.11 no.1
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• pp.11-41
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• 2011

The discovery of microRNA (miRNA) is one of the major scientific breakthroughs in recent years and has revolutionized current cell biology and medical science. miRNAs are small (19~25nt) noncoding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3' untranslated region (3'UTR) of specific messenger RNAs (mRNAs) for degradation of translation repression. Genetic ablation of the miRNA machinery, as well as loss or degradation of certain individual miRNAs, severely compromises immune development and response, and can lead to immune disorders. Several sophisticated regulatory mechanisms are used to maintain immune homeostasis. Regulatory T (Treg) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. Recent publications have provided compelling evidence that miRNAs are highly expressed in Treg cells, that the expression of Foxp3 is controlled by miRNAs and that a range of miRNAs are involved in the regulation of immunity. A large number of studies have reported links between alterations of miRNA homeostasis and pathological conditions such as cancer, cardiovascular disease and diabetes, as well as psychiatric and neurological diseases. Although it is still unclear how miRNA controls Treg cell development and function, recent studies certainly indicate that this topic will be the subject of further research. The specific circulating miRNA species may also be useful for the diagnosis, classification, prognosis of diseases and prediction of the therapeutic response. An explosive literature has focussed on the role of miRNA. In this review, I briefly summarize the current studies about the role of miRNAs in Treg cells and in the regulation of the innate and adaptive immune response. I also review the explosive current studies about clinical application of miRNA.

• IMMUNE NETWORK
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• v.13 no.6
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• pp.283-288
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• 2013

The pro-inflammatory cytokines tumor necrosis factor-${\alpha}$ (TNF${\alpha}$) and interleukin (IL)-$1{\beta}$ are crucial mediators involved in chronic inflammatory diseases. Inflammatory signal pathways regulate inflammatory cytokine expression-mediated by p38 mitogen activated protein kinase (p38MAPK). Therefore, considerable attention has been given to p38MAPK as a target molecule for the development of a novel anti-inflammatory therapeutics. BIRB 796, one of p38MAPK inhibitor, is a candidate of therapeutic drug for chronic inflammatory diseases. In this study, we investigated the effect of BIRB 796 on inflammatory cytokine productions by lipopolysaccharide (LPS) in different immune cell types. BIRB 796 reduced LPS-mediated IL-8 production in THP-1 cells but not in Raw 264.7 cells. Further analysis of signal molecules by western blot revealed that BIRB 796 sufficiently suppressed LPS-mediated phosphorylation of p38MAPK in both cell types whereas it failed to block inhibitor of kappa B (I-${\kappa}B$) degradation in Raw 264.7 cells. Taken together, these results suggest that the anti-inflammatory function of BIRB 796 depends on cell types.

• YAKHAK HOEJI
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• v.56 no.5
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• pp.293-298
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• 2012

The present study tested the effect of Schizandra chinensis lignan compounds, Gomisin A and Schizandrin, on the aggregation and dissociation of beta-amyloid $(A{\beta})_{1-42}$ to explore a possible therapeutic target for Alzheimer's disease. Gomisin A significantly inhibited the $A{\beta}_{1-42}$ aggregation in a dose dependent manner, but did not induced the dissociation of aggregated $A{\beta}_{1-42}$. On the other hand, Schizandrin significantly suppressed the aggregation and dissociation of $A{\beta}_{1-42}$. These results suggest that Gomisin A and Schizandrin, which are known as biologically active ingredients from Schizandra chinensis, may be potentially useful target molecules to develop a drug for the prevention or treatment of Alzheimer's disease.

• IMMUNE NETWORK
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• v.14 no.3
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• pp.138-148
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• 2014

MicroRNAs (miRNAs) are endogenous small RNA molecules best known for their function in post-transcriptional gene regulation. Immunologically, miRNA regulates the differentiation and function of immune cells and its malfunction contributes to the development of various autoimmune diseases including systemic lupus erythematosus (SLE). Over the last decade, accumulating researches provide evidence for the connection between dysregulated miRNA network and autoimmunity. Interruption of miRNA biogenesis machinery contributes to the abnormal T and B cell development and particularly a reduced suppressive function of regulatory T cells, leading to systemic autoimmune diseases. Additionally, multiple factors under autoimmune conditions interfere with miRNA generation via key miRNA processing enzymes, thus further skewing the miRNA expression profile. Indeed, several independent miRNA profiling studies reported significant differences between SLE patients and healthy controls. Despite the lack of a consistent expression pattern on individual dysregulated miRNAs in SLE among these studies, the aberrant expression of distinct groups of miRNAs causes overlapping functional outcomes including perturbed type I interferon signalling cascade, DNA hypomethylation and hyperactivation of T and B cells. The impact of specific miRNA-mediated regulation on function of major immune cells in lupus is also discussed. Although research on the clinical application of miRNAs is still immature, through an integrated approach with advances in next generation sequencing, novel tools in bioinformatics database analysis and new in vitro and in vivo models for functional evaluation, the diagnostic and therapeutic potentials of miRNAs may bring to fruition in the future.

• Molecules and Cells
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• v.38 no.10
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• pp.843-850
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• 2015

The1hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose.