• Biomolecules & Therapeutics
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• v.29 no.3
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• pp.321-330
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• 2021

Oxidative stress plays a crucial role in the development of neuronal disorders including brain ischemic injury. Thioredoxin 1 (Trx1), a 12 kDa oxidoreductase, has anti-oxidant and anti-apoptotic functions in various cells. It has been highly implicated in brain ischemic injury. However, the protective mechanism of Trx1 against hippocampal neuronal cell death is not identified yet. Using a cell permeable Tat-Trx1 protein, protective mechanism of Trx1 against hydrogen peroxide-induced cell death was examined using HT-22 cells and an ischemic animal model. Transduced Tat-Trx1 markedly inhibited intracellular ROS levels, DNA fragmentation, and cell death in H2O2-treatment HT-22 cells. Tat-Trx1 also significantly inhibited phosphorylation of ASK1 and MAPKs in signaling pathways of HT-22 cells. In addition, Tat-Trx1 regulated expression levels of Akt, NF-κB, and apoptosis related proteins. In an ischemia animal model, Tat-Trx1 markedly protected hippocampal neuronal cell death and reduced astrocytes and microglia activation. These findings indicate that transduced Tat-Trx1 might be a potential therapeutic agent for treating ischemic injury.

• BMB Reports
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• v.55 no.2
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• pp.87-91
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• 2022

Aurora kinase is a family of serine/threonine kinases intimately associated with mitotic progression and the development of human cancers. Studies have shown that aurora kinases are important for the protein kinase C (PKC)-induced invasion of colon cancer cells. Recent studies have shown that aurora kinase A promotes distant metastasis by inducing epithelial-to-mesenchymal transition (EMT) in colon cancer cells. However, the role of aurora kinase A in colon cancer metastasis remains unclear. In this study, we investigated the effects of aurora kinase A on PKC-induced cell invasion, migration, and EMT in human SW480 colon cancer cells. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) changed the expression levels of EMT markers, increasing α-SMA, vimentin, and MMP-9 expression and decreasing E-cadherin expression, with changes in cell morphology. TPA treatment induced EMT in a PKC-dependent manner. Moreover, the inhibition of aurora kinase A by siRNAs and inhibitors (reversine and VX-680) suppressed TPA-induced cell invasion, migration, and EMT in SW480 human colon cells. Inhibition of aurora kinase A blocked TPA-induced vimentin and MMP-9 expression, and decreased E-cadherin expression. Furthermore, the knockdown of aurora kinase A decreased the transcriptional activity of NF-κB and AP-1 in PKC-stimulated SW480 cells. These findings indicate that aurora kinase A induces migration and invasion by inducing EMT in SW480 colon cancer cells. To the best of our knowledge, this is the first study that showed aurora kinase A is a key molecule in PKC-induced metastasis in colon cancer cells.

• The Korea Journal of Herbology
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• v.33 no.1
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• pp.47-55
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• 2018

Objectives : The current study is to evaluate the hepatoprotective effect of youngyanggak-san (YGS) on thioacetamide (TAA)-induced acute liver injury in rats. Methods : YGS is composed of Glycyrrhizae Radix, Asiasari Radix, Cimicifugae Rhizoma, Saigae Tataricae Cornu. While N-YGS (non-youngyanggak-san) doesn't include Saigae Tataricae Cornu. Two samples were administrated TAA together for 3 days. Thirty-six rats were divided into four groups. Rats except for the normal group were received TAA (200 mg/kg of body weight, I.P) were divided into three groups (n=9/group) : Group 1 (TAA only), Group 2 (TAA + 200 mg/kg YGS) and Group 3 (TAA + 200 mg/kg N-YGS). Acute liver damage confirmed using histological examination, The factors associated with oxidative stress and liver function activity measured in serum. Also, expressions of inflammation related proteins were investigated by western blot analysis. Results : Oxidative stress factors such as ROS and $ONOO^-$ in the Group 2 was manifested by a significant rise compared with Group 1. YGS markedly decreased the elevated ROS and $ONOO^-$. Furthermore, YGS significantly reduced the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) The nuclear $factor-{\kappa}B$ ($NF-{\kappa}B$) activation induced by TAA led to increase both inflammatory mediators and cytokines. While YGS administration remarkably suppressed such the overexpression. In addition, the histopathological analysis showed that the liver tissue lesions were improved obviously in YGS treatment. Conclusion : YGS provided a hepatoprotective effect on acute liver damage through the suppression of oxidative stress. Especially, this effect enhanced markedly when Saigae Tataricae Cornu is included.

• Journal of Digestive Cancer Reports
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• v.5 no.2
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• pp.97-104
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• 2017

Background: Cachexia is a multi-factorial syndrome presenting with chronic illness, decreases in body weight, and loss of adipose tissue and skeletal muscle, mostly in patients with advanced cancer and chronic wasting disease. Even after years of intensive researches, there remains no convincing therapy to prevent cancer cachexia. Methods: In this in vivo study, we have established C26 adenocarcinoma-induced cancer cachexia model in mice to explore the underlying core changes in cytokine, signal transduction, and muscle wasting. The ultimate aim of establishing animal model is to find optimal therapeutics to mitigate cancer cachexia. Results: We have administered C26 adenocarcinoma cells onto BALB/c mice and observed 4 weeks to assess the progression of cancer cachexia. Significant loss of weight accompanied with loss of appetite was noted. As C26 adenocarcinoma xenograft progressed, mortality was started from 3 weeks, accompanied with significant sarcopenia and decreased mice movement. Surges in TNF-α and IL-6 were noted with the commencement of cancer cachexia. Conclusion: Using C26 adenocarcinoma cancer cachexia model, we can screen the optimal therapeutics to mitigate cancer cachexia, in which agents to modulate IL-6, TNF-α, and NF-κB were essential.

• Journal of Digestive Cancer Research
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• v.5 no.2
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• pp.97-104
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• 2017

Background: Cachexia is a multi-factorial syndrome presenting with chronic illness, decreases in body weight, and loss of adipose tissue and skeletal muscle, mostly in patients with advanced cancer and chronic wasting disease. Even after years of intensive researches, there remains no convincing therapy to prevent cancer cachexia. Methods: In this in vivo study, we have established C26 adenocarcinoma-induced cancer cachexia model in mice to explore the underlying core changes in cytokine, signal transduction, and muscle wasting. The ultimate aim of establishing animal model is to find optimal therapeutics to mitigate cancer cachexia. Results: We have administered C26 adenocarcinoma cells onto BALB/c mice and observed 4 weeks to assess the progression of cancer cachexia. Significant loss of weight accompanied with loss of appetite was noted. As C26 adenocarcinoma xenograft progressed, mortality was started from 3 weeks, accompanied with significant sarcopenia and decreased mice movement. Surges in TNF-α and IL-6 were noted with the commencement of cancer cachexia. Conclusion: Using C26 adenocarcinoma cancer cachexia model, we can screen the optimal therapeutics to mitigate cancer cachexia, in which agents to modulate IL-6, TNF-α, and NF-κB were essential.

• 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 Applied Biological Chemistry
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• v.66
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• pp.282-288
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• 2023

Due to the COVID-19 pandemic, the immuneenhancing health functional food market that protects our bodies from pathogens such as viruses continues to grow. In this study, we aimed to prove the Cheonggukjang, a high-nutrient food with high protein, fat, and dietary fiber content, as an immuneenhancing nutraceutical. Cheonggukjang water extract (CWE) increased the production of nitric oxide, reactive oxygen species, and cytokines such interleukin (IL)-6, IL-1β, and tumor necrosis factor-α without affecting viability in RAW 264.7 cells. Furthermore, CWE significantly upregulated the expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW 264.7 cells. CWE enhanced the phosphorylation of I kappa B kinase α/β and I kappa B (IκB)α, as well as the degradation of IκBα. CWE also induced increased phosphorylation of nuclear factor-kappa B p65 and facilitated the redistribution of p65 from the cytoplasm to the nucleus in RAW 264.7 cells. These findings suggest that CWE has potential as a health functional food material that can enhance the innate immune response.

• IMMUNE NETWORK
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• v.20 no.4
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• pp.32.1-32.15
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• 2020

Influenza virus is the major cause of seasonal and pandemic flu. Currently, oseltamivir, a potent and selective inhibitor of neuraminidase of influenza A and B viruses, is the drug of choice for treating patients with influenza virus infection. However, recent emergence of oseltamivir-resistant influenza viruses has limited its efficacy. Morin hydrate (3,5,7,2',4'-pentahydroxyflavone) is a flavonoid isolated from Morus alba L. It has antioxidant, anti-inflammatory, neuroprotective, and anticancer effects partly by the inhibition of the NF-κB signaling pathway. However, its effects on influenza virus have not been studied. We evaluated the antiviral activity of morin hydrate against influenza A/Puerto Rico/8/1934 (A/PR/8; H1N1) and oseltamivir-resistant A/PR/8 influenza viruses in vitro. To determine its mode of action, we carried out time course experiments, and time of addition, hemolysis inhibition, and hemagglutination assays. The effects of the co-administration of morin hydrate and oseltamivir were assessed using the murine model of A/PR/8 infection. We found that morin hydrate reduced hemagglutination by A/PR/8 in vitro. It alleviated the symptoms of A/PR/8-infection, and reduced the levels of pro-inflammatory cytokines and chemokines, such as TNF-α and CCL2, in infected mice. Co-administration of morin hydrate and oseltamivir phosphate reduced the virus titers and attenuated pulmonary inflammation. Our results suggest that morin hydrate exhibits antiviral activity by inhibiting the entry of the virus.

• Tuberculosis and Respiratory Diseases
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• v.46 no.5
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• pp.674-684
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• 1999

Background : It has been generally known that the incidence of lung cancer is higher in the patients with idopathic pumonary fibrosis (IPF) than those in general population. The reported incidence was variable from 4.8 to 43.2%. There were controversies on the most frequent cell type (squamous cell carcinoma vs. adenocarcinoma) and no study was done about the real concordance of cancer and the fibrotic lesion. And the pulmonary fibrosis may influence not only the development of cancer but also the treatment and prognosis of the cancer, but there was no report on that point. Method : Total 63 patients ($66.8{\pm}7.8$ year, M : F=61 : 2) were diagnosed as IPF combined with lung cancer (IFF-CA) at Asan Medical Center. A retrospective analysis was done about the risk factors of the lung cancer, pulmonary function test, the site of cancer(especially the relationship of the cancer with the fibrotic lesion), the histologic types, and the stage of cancer. The histologic types were compared with those of 2,660 patients with lung cancer who were diagnosed at the same institute for the same period. The effect of IPF on the treatment of the cancer was evaluated with the survival time after the detection of lung cancer. Results : The lung cancer was found in 63(22.9%) out of 281 patients with IPF. But in most of them(45 patients), lung cancer was detected at the same time with IPF and only in 18 patients, the cancer was diagnosed during the follow-up($25.2{\pm}17.7$ months) of IPF. So in our study, 6.7% of patients with IPF developed lung cancer during the course of the disease. The age ($66.8{\pm}7.84$ vs. $63.4{\pm}11.1$ years), percentage of smoker (88.9 vs. 67.2%), and the male gender (96.8 vs. 67.6%) were significantly higher in IPF-CA compared with lone IPF (p<0.05). The odds ratio of smoking was 4.7 compared with non smoking IPF controls. The lung cancer was located more frequently in the upper lobe and 55.5% was in the periphery of lung. The cancer was developed in the fibrotic lesion in 23 patients (35.9%), and in the majority of the patients, the cancer was separated from the fibrosis. The cell type of the lung cancer in IPF-CA was squamous cell carcinoma 34.9%, adenocarcinoma 30.2%, small cell carcinoma 19.0%, large cell undifferenciated carcinoma 6.3%, and others 9.5%. No significant difference in the distribution of histologic type of the lung cancer was found between IPF-CA and lone lung cancer. There was no significant difference in demographic features, cell types, location and the stage of the cancer between the group with concurrent IPF-CA and the group with cancer diagnosed during the follow up of IPF. There was a tendency (but statistically not significant : p=0.081) of higher incidence of adenocarcinoma among the cancers developed in the fibrotic area(43.5%) (F-CA) than in the cancers in non-fibrotic area (22.5%) (NF-CA). The prognosis of the patients with F-CA was poor (median survival : 4 months) compared with the patients with NF-CA (7 months, p=0.013), partly because the prevalence of severe IPF (the extent of fibrosis in HRCT 50%) was higher in F-CA group. Conclusion : These data suggest that the lung cancer in the patients with IPF has similar features to the ordinary lung cancer.

• 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.