• BMB Reports
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• v.55 no.4
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• pp.198-203
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• 2022

As negative regulators of cytokine signaling pathways, suppressors of cytokine signaling (SOCS) proteins have been reported to possess both pro-tumor and anti-tumor functions. Our recent studies have demonstrated suppressive effects of SOCS1 on epithelial to mesenchymal signaling in colorectal cancer cells in response to fractionated ionizing radiation or oxidative stress. The objective of the present study was to determine the radiosensitizing action of SOCS1 as an anti-tumor mechanism in colorectal cancer cell model. In HCT116 cells exposed to ionizing radiation, SOCS1 over-expression shifted cell cycle arrest from G2/M to G1 and promoted radiation-induced apoptosis in a p53-dependent manner with down-regulation of cyclin B and up-regulation of p21. On the other hand, SOCS1 knock-down resulted in a reduced apoptosis with a decrease in G1 arrest. The regulatory action of SOCS1 on the radiation response was mediated by inhibition of radiation-induced Jak3/STAT3 and Erk activities, thereby blocking G1 to S transition. Radiation-induced early ROS signal was responsible for the activation of Jak3/Erk/STAT3 that led to cell survival response. Our data collectively indicate that SOCS1 can promote radiosensitivity of colorectal cancer cells by counteracting ROS-mediated survival signal, thereby blocking cell cycle progression from G1 to S. The resulting increase in G1 arrest with p53 activation then contributes to the promotion of apoptotic response upon radiation. Thus, induction of SOCS1 expression may increase therapeutic efficacy of radiation in tumors with low SOCS1 levels.

• Proceedings of the Plant Resources Society of Korea Conference
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• 2023.04a
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• pp.17-17
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• 2023

Chrysanthemum zawadskii (C. zawadskii) is used in traditional East Asian medicine for the treatment of various diseases, including inflammatory disease. However, it has remained unclear whether extracts of C. zawadskii inhibit inflammasome activation in macrophages. The present study assessed the inhibitory effect of an ethanol extract of C. zawadskii (CZE) on the activation of the inflammasome in macrophages and the underlying mechanism. Bone marrow[-derived macrophages (BMDMs) were obtained from wild-type C57BL/6 mice. The release of IL-1β and lactate dehydrogenase in response to nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome activators, such as ATP, nigericin and monosodium urate (MSU) crystals, was significantly decreased by CZE in lipopolysaccharide(LPS)-primed BMDMs. Western blotting revealed that CZE inhibited ATP-induced caspase-1 cleavage and IL-1β maturation. To investigate whether CZE inhibits the priming step of the NLRP3 inflammasome, we confirmed the role of CZE at the gene level using RT-qPCR. CZE also downregulated the gene expression of NLRP3 and pro-IL-1β as well as NF-κB activation in BMDMs in response to LPS. Apoptosis associated speck-like protein containing a caspase-recruitment domain (CARD) oligomerization and speck formation by NLRP3 inflammasome activators were suppressed by CZE. By contrast, CZE did not affect NLR family CARD domain containing protein 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome activation in response to Salmonella typhimurium and poly(dA:dT) in LPS-primed BMDMs, respectively. The results revealed that three key components of CZE, namely linarin, 3,5-dicaffeoylquinic acid and chlorogenic acid, decreased IL-1β secretion in response to ATP, nigericin and MSU. These findings suggest that CZE effectively inhibited activation of the NLRP3 inflammasome.

• Journal of Ginseng Research
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• v.47 no.5
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• pp.627-637
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• 2023

Background: Damage to the healthy intestinal epithelial layer and regulation of the intestinal immune system, closely interrelated, are considered pivotal parts of the curative treatment for inflammatory bowel disease (IBD). Plant-based diets and phytochemicals can support the immune microenvironment in the intestinal epithelial barrier for a balanced immune system by improving the intestinal microecological balance and may have therapeutic potential in colitis. However, there have been only a few reports on the therapeutic potential of plant-derived exosome-like nanoparticles (PENs) and the underlying mechanism in colitis. This study aimed to assess the therapeutic effect of PENs from Panax ginseng, ginseng-derived exosome-like nanoparticles (GENs), in a mouse model of IBD, with a focus on the intestinal immune microenvironment. Method: To evaluate the anti-inflammatory effect of GENs on acute colitis, we treated GENs in Caco2 and lipopolysaccharide (LPS) -induced RAW 264.7 macrophages and analyzed the gene expression of proinflammatory cytokines and anti-inflammatory cytokines such as TNF-α, IL-6, and IL-10 by real-time PCR (RT-PCR). Furthermore, we further examined bacterial DNA from feces and determined the alteration of gut microbiota composition in DSS-induced colitis mice after administration of GENs through 16S rRNA gene sequencing analysis. Result: GENs with low toxicity showed a long-lasting intestinal retention effect for 48 h, which could lead to effective suppression of pro-inflammatory cytokines such as TNF-α and IL-6 production through inhibition of NF-κB in DSS-induced colitis. As a result, it showed longer colon length and suppressed thickening of the colon wall in the mice treated with GENs. Due to the amelioration of the progression of DSS-induced colitis with GENs treatment, the prolonged survival rate was observed for 17 days compared to 9 days in the PBS-treated group. In the gut microbiota analysis, the ratio of Firmicutes/Bacteroidota was decreased, which means GENs have therapeutic effectiveness against IBD. Ingesting GENs would be expected to slow colitis progression, strengthen the gut microbiota, and maintain gut homeostasis by preventing bacterial dysbiosis. Conclusion: GENs have a therapeutic effect on colitis through modulation of the intestinal microbiota and immune microenvironment. GENs not only ameliorate the inflammation in the damaged intestine by downregulating pro-inflammatory cytokines but also help balance the microbiota on the intestinal barrier and thereby improve the digestive system.

• Korean Journal of Food Science and Technology
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• v.43 no.5
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• pp.633-640
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• 2011

After Ganoderma lucidum was cultured in mushroom complete medium (MCM) supplemented with ginseng extract (GE), crude polysaccharide (GL-GE-CP) was fractionated from mycelium. Among GL-GE-CP from mycelium in MCM supplemented with 5, 10, and 15% GE (v/v ratio of MCM to GE), GL-GE-15-CP (15% GE) most significantly enhanced macrophage stimulation and intestinal immune system modulating activity compared with GL-CP in MCM without GE. When GL-GE-15-CP was further fractionated on DEAE-Sepharose CL-6B, GL-GE-15-CP-II displayed more potent activity than subfractions from GL-CP on macrophage stimulation, interleukin-12 production, and intestinal immune system modulation (1.75-, 5.68-, and 1.76-fold, respectively). Anti-metastasis effect against colon 26-M3.1 carcinoma cells was also enhanced by GL-GE-15-CP-II (72.8% inhibition). In addition, GL-GE-15-CP-II contained neutral sugar (83.00%) and uronic acid (9.11%), and consisted of Ara, Man, Gal and Glc (molar ratio of 0.39:0.50:0.75:1.00). Furthermore, GE supplementation helped to enhance the immunomodulation in G. lucidum, and it is assumed that neutral polysaccharides play an important role.

• Journal of the Korean Society of Food Science and Nutrition
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• v.40 no.1
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• pp.20-28
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• 2011

Crude polysaccharide (CP) was fractionated from the submerged culture (containing both mycelia and culture broth, SC) with Phellinus linteus (PL) in mushroom complete medium (MCM) supplemented with ginseng extract ($65^{\circ}$Bx, GE) to enhance the immune activity. PL-GE-15-CP from SC cultivated in MCM supplemented with GE-15% (v/v, a ratio of MCM volume to GE) showed significantly higher macrophage stimulation (1.45 fold of the saline control at $100{\mu}g$/mL) than PL-GE-5 and 10-CP with GE-5 and 10%, or PL-CP from SC without GE. The potent intestinal immune system modulating activity through Peyer's patch was also obtained by PL-GE-15-CP (1.46 fold). When PL-GE-15-CP further fractionated on DEAE-Sepharose CL-6B (Cl- form), PL-GE-15-CP-II was the significantly higher than others from PL-GE-15-CP or PL-CP on macrophage stimulation, interleukin (IL)-12 production and intestinal immune system modulation (1.54, 3.96 and 1.56 fold, respectively). PL-GE-15-CP-II also had higher anti-metastatic activity against colon 26-M3.1 carcinoma cell (57.3% inhibition of tumor control, $200{\mu}g$/mouse) rather than PL-CP-II. This active fraction (PL-GE-15-CP-II) mainly contained neutral sugar (82.45%) and uronic acid (12.99%), and component sugar analysis showed that PL-GE-15-CP-II consisted mainly of uronic acid, Ara, Man, Gal and Glc (molar ratio of 0.52:0.97:0.63:1.00:0.54). Furthermore, the activity of GE culture was higher compared with culture without GE, indicating that GE helped to enhance the immune activity of P. linteus; also, it is assumed that the polysaccharide plays an important role in immune enhancement.

• Microbiology and Biotechnology Letters
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• v.42 no.2
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• pp.170-176
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• 2014

In this study, the anti-oxidative and anti-inflammatory activities of Euptelea pleiosperma ethanol extract (EPEE) were evaluated using in vitro assays and cell culture model systems. EPEE possessed a more potent scavenging activity against 1,1-diphenyl-2-picryl hydrazyl than the ascorbic acid used as a positive control. EPEE effectively suppressed lipopolysaccharide (LPS), in addition to hydrogen peroxide induced reactive oxygen species on RAW 264.7 cells. Furthermore, EPEE induced the expression of the anti-oxidative enzyme heme oxygenase 1 (HO-1) and its upstream transcription factor, nuclear factor-E2-related factor 2 (Nrf2), dose and time dependently. The modulation of HO-1 and Nrf2 expression might be regulated by mitogen-activated protein kinases and phosphatidyl inositol 3 kinase/Akt as their upstream signaling pathways. On the other hand, EPEE inhibited LPS induced nitric oxide (NO) formation without cytotoxicity. Suppression of NO formation was the result of the down regulation of inducible NO synthase (iNOS) by EPEE. Suppression of NO and iNOS by EPEE may be modulated by their upstream transcription factor, nuclear factor ${\kappa}B$, and AP-1 pathways. Taken together, these results provide important new insights into E. pleiosperma, namely that it possesses anti-oxidative and anti-inflammatory activities, indicating that it could be utilized as a promising material in the field of nutraceuticals.

• Tuberculosis and Respiratory Diseases
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• v.57 no.5
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• pp.449-460
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• 2004

Background : PS-341 is a novel, highly selective and potent proteasome inhibitor, which showed cytotoxicity against some tumor cells. Its anti-tumor activity has been suggested to be associated with modulation of the expression of apoptosis-associated proteins, such as p53, $p21^{WAF/CIP1}$, $p27^{KIP1}$, NF-${\kappa}B$, Bax and Bcl-2. c-Jun N-terminal kinase (JNK) and glycogen synthase kinase-$3{\beta}$ (GSK-$3{\beta}$) are important modulators of apoptosis. However, their role in PS-341-induced apoptosis is unclear. This study was undertaken to elucidate the role of JNK and GSK-$3{\beta}$ in the PS-341-induced apoptosis in lung cancer cells. Method : NCI-H157 and A549 cells were used in the experiments. The cell viability was assayed using the MTT assay and apoptosis was evaluated by proteolysis of PARP. The JNK activity was measured by an in vitro immuno complex kinase assay and by phosphorylation of endogenous c-Jun. The protein expression was evaluated by Western blot analysis. Dominant negative JNK1 (DN-JNK1) and GSK-$3{\beta}$ were overexpressed using plasmid and adenovirus vectors, respectively. Result : PS-341 reduced the cell viability via apoptosis, activated JNK and increased the c-Jun expression. Blocking of the JNK activation by overexpression of DN-JNK1, or pretreatment with SP600125, suppressed the apoptosis induced by PS-341. The activation of caspase 3 was mediated by JNK activation. Blocking of the caspase 3 activation suppressed PS-341-induced apoptosis. PS-341 activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, but its blockade enhanced the PS-341-induced cell death via apoptosis. GSK-$3{\beta}$ was inactivated by PS-341 via the PI3K/Akt pathway. Overexpression of constitutively active GSK-$3{\beta}$ enhanced PS-341-induced apoptosis; in contrast, this was suppressed by dominant negative GSK-$3{\beta}$ (DN-GSK-$3{\beta}$). Inactivation of GSK-$3{\beta}$ by pretreatment with lithium chloride or the overexpression of DN-GSK-$3{\beta}$ suppressed both the JNK activation and c-Jun up-regulation induced by PS-341. Conclusion : The JNK/caspase pathway is involved in PS-341-induced apoptosis, which is negatively regulated by the PI3K/Akt-mediated inactivation of GSK-$3{\beta}$ in lung cancer cells.

• The Journal of Korean Institute of Electromagnetic Engineering and Science
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• v.18 no.8
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• pp.880-886
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• 2007

We have proposed a new "hybrid" envelope elimination and restoration(EER) transmitter architecture using an efficiency optimized power amplifier(PA) and modified bias modulator. The efficiency of the PA at the average drain voltage is very important for the overall transmitter efficiency because the PA operates mostly at the average power region of the modulation signal. Accordingly, the efficiency of the PA has been optimized at the region. Besides, the bias modulator has been accompanied with the emitter follower for the minimization of memory effect. A saturation amplifier, class $F^{-1}$ is built using a 5-W PEP LDMOSFET for forward-link single-carrier wideband code-division multiple-access(WCDMA) at 1-GHz. For the interlock experiment, the bias modulator has been built with the efficiency of 64.16% and peak output voltage of 31.8 V. The transmitter with the proposed PA and bias modulator has been achieved an efficiency of 44.19%, an improvement of 8.11%. Besides, the output power is enhanced to 32.33 dBm due to the class F operation and the PAE is 38.28% with ACLRs of -35.9 dBc at 5-MHz offset. These results show that the proposed architecture is a very good candidate for the linear and efficient high power transmitter.

• Radiation Oncology Journal
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• v.25 no.4
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• pp.233-241
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• 2007

Purpose: We examined the effect of the dual EGFR/HER2 tyrosine kinase inhibitor, GW572016, on EGFR/HER2 receptor phosphorylation, inhibition of downstream signaling and radiosensitization in either an EGFR or HER2 overexpressing human breast cancer xenograft. Materials and Methods: We established SCID mice xenografts from 4 human breast cancer cell line that overexpressed EGFR or HER 2 (SUM 102, SUM 149, SUM 185, SUM 225). Two series of xenografts were established. One series was established for determining inhibition of the EGFR/HER2 receptor and downstream signaling activities by GW572016. The other series was established for determining the radiosensitization effect of GW572016. Inhibition of the receptor and downstream signaling proteins were measured by the use of immunoprecipitation and Western blotting. For determining the in vivo radiosensitization effect of GW572016, we compared tumor growth delay curves in the following four treatment arms: a) control; b) GW572016 alone; c) radiotherapy (RT) alone; d) GW572016 and RT. Results: GW572016 inhibited EGFR, HER2 receptor phosphorylation in SUM 149 and SUM 185 xenografts. In addition, the p44/42 MAPK (ERK 1/2) downstream signaling pathway was inactivated by GW572016 in the SUM 185 xenograft. In the SUM 225 xenograft, we could not observe inhibition of HER2 receptor phosphorylation by GW572016; both p44/42 MAPK (Erk1/2) and Akt downstream signal protein phosphorylation were inhibited by GW572016. GW572016 inhibited growth of the tumor xenograft of SUM 149 and SUM 185. The combination of GW572016 and RT enhanced growth inhibition greater than that with GW572016 alone or with RT alone in the SUM 149 xenograft. GW572016 appears to act as an in vivo radiosensitizer. Conclusion: GW572016 inhibited EGFR/HER2 receptor phosphorylation and downstream signaling pathway proteins. GW572016 modestly inhibited the growth of tumor in the SUM 185 xenograft and showed radiosensitization in the SUM 149 xenograft. Our results suggest that a better predictor of radiation response would be inhibition of a crucial signaling pathway than inhibition of a receptor.

• Korean Journal of Food Science and Technology
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• v.40 no.1
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• pp.82-87
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• 2008

Atopic dermatitis (AD) is characterized by chronic relapsing inflammation and is associated with hyper-production of immunoglobulin E (IgE). Recent studies have suggested that one of the treatments to alleviate symptoms of AD could be a supplementation of probiotics, Lactobacillus, Rhamnosus, Bifidus, etc. The purpose of this study was to evaluate the effects of probiotics on immune parameters in NC/Nga mice treated with 1-chloro-2,4-dinitro-benzene (DNCB). To induce atopic dermatitis, DNCB was treated to the back of mice for 2 weeks. Then, NC/Nga mice were divided into the four experimental groups randomly. Probiotics fragment, probiotics with other complex (Lactobacillus rhamnosus GG, Bifidobacterium lactis Bb-12LbL, L. plantarum K8, L. plantarum K8 fragment, ${\gamma}$-linolenic acid), antihistamine, and distilled water were administrated orally to the NC/Nga mouse for 4 weeks of experimental period. The groups were probiotics fragment group (DPF), probiotics with other complex group (DPOC), antihistamine group (DAH) and distilled water group (DDW) as a control group. The levels of serum IgE, interlukin-4 (IL-4), interlukin-5 (IL-5), interferon-gamma (IFN-${\gamma}$) and spleenocyte IgE were measured. The levels of serum IgE were significantly different among the four experimental groups. Before the treatment, there was no differences among the groups. However, from the first through the third week of the treatments, the levels of serum IgE in the probiotics (DPF, DPOC) and antihistamine (DAH) groups were lower than those of control group (p < 0.05). The levels of serum IL-4 of DPOC group was significantly lower than that of control group (p < 0.05) and serum IL-5 levels of DPF, DPOC, and DAH groups were significantly lower than that of control group. The levels of serum IFN-${\gamma}$ were not different among the four experimental groups. The levels of serum IgE in supernatant of spleen lymphocytes were not significantly different among the groups. These results suggest that probiotics supplementation showed partial effectiveness in the DNCB treated NC/Nga mice via modulation of IgE level and IL-4, IL-5 production. Based on these findings, probiotics exhibited the inhibitory effect via IL-4 production thereby inhibited the production of IgE in atopic animal model NC/Nga mice.