• Title/Summary/Keyword: Development of New Drug

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Differential Sensitivities of Human Multidrug-resistant Cancer Cells to BIIB021 and Modulation of Hsp90 Inhibitors by NSAIDs and Niclosamide (항암제 다제내성(MDR) 암세포의 Hsp90 저해제 BIIB021에 대한 감수성의 차이 및 NSAIDs 및 Niclosamide에 의한 Hsp90 저해제의 활성 변화)

  • Moon, Hyun-Jung;Lee, Su-Hoon;Kim, Sun-Hee;Kang, Chi-Dug
    • Journal of Life Science
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    • v.28 no.10
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    • pp.1212-1219
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    • 2018
  • The critical role of heat shock protein 90 (Hsp90) in tumorigenesis led to the development of several first- and second-generation Hsp90 inhibitors, which have demonstrated promising responses in cancers. In this study, we found second-generation Hsp90 inhibitor BIIB021-resistant multidrug-resistant (MDR) human cancer cells, although BIIB021 was shown to be active in first-generation Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)-resistant MDR cells. MCF7-MDR and HeyA8- MDR cells were more resistant to BIIB021 than their parental counterparts, indicating that BIIB021 cannot be applicable to all cancer cells expressing MDR proteins. We revealed that dimethyl-celecoxib (DMC), one of the non-steroidal anti-inflammatory drugs (NSAIDs), potentiated cytotoxicity of BIIB021 against both BIIB021-resistant and BIIB021-sensitive MDR cells. The effectiveness of NSAIDs involving celecoxib and DMC in combination with BIIB021 led to the autophagic degradation/down-regulation of mutant p53 (mutp53) that overexpressed MDR cells and the suppression of Hsp70 induction. This resulted in sensitization of MDR cells to BIIB021. Moreover, autophagy induction by sulindac sulfide, another type of NSAID, and niclosamide, an FDA-approved anthelmintic drug, potentiated 17-AAG-mediated autophagic degradation/down-regulation of mutp53 and c-Myc, client proteins of Hsp90. Therefore, our results suggest that NSAIDs and niclosamide positively enhance the anticancer activity of Hsp90 inhibitors through an autophagic pathway. They may also be new candidates for sensitizing MDR cells to Hsp90 inhibitors.

Development of Seed Culture Using Soybean for Mass Production of Lovastatin with Aspergillus terreus ATCC 20542 Mutant (대두를 이용한 Lovastatin 대량생산용 Seed Culture의 제조기술)

  • Kim, Soo-Jung;Ko, Hee-Sun;Kim, Hyun-Soo
    • Journal of the Korean Society of Food Science and Nutrition
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    • v.37 no.5
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    • pp.666-670
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    • 2008
  • Lovastatin (Mevinolin, Monacolin K) is a well-known drug for the therapy of hypercholesterolemia. It is an important fungal secondary metabolite as it inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, EC 1.1.1.34) which catalyzes a major rate-limiting step in the biosynthesis of cholesterol. Both soybeans and black soybeans with Aspergillus terreus ATCC 20542 mutant were used as the seed culture for the mass production of lovastatin. The production of lovastatin in soybean seed culture of Asp. terreus was twofold compared to that of black soybean seed culture. The effect of two different vessels (petri dish and Erlenmeyer flask) on lovastatin production was also studied. The production of lovastatin on petri dish was tenfold to that of Erlenmeyer flask. Furthermore, the most lovastatin production on rice bran was achieved when the soybean seed culture was treated by heat shock at $30^{\circ}C$ for 1 hour, representing 82% of HMG-CoA reductase inhibition in the koji extract. We estimated that the heat treated soybean seed culture could be a new method for the mass production of lovastatin.

A preliminary study to determine the order of the latent fingerprint deposition on thermal paper - A short term study - (감열지상 잠재지문의 남겨진 순서결정에 대한 예비적 연구 - 단기연구 -)

  • Lim, Dong-A;Ok, Yun-Seok;Heo, Bo-Reum;Choi, Sung-Woon
    • Analytical Science and Technology
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    • v.30 no.5
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    • pp.279-286
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    • 2017
  • Determination of the order of latent fingerprints deposition on the surface of thermal paper, often found in crime scenes, is related to the study of time course and aging of fingerprints and can provide additional information in criminal investigations. A preliminary study was performed to determine the deposition order of fingerprints left with two different conditions of deposition pressure and time (in seconds) after 1 day intervals for 7 days on thermal paper (receipt and fax thermal paper) using an iodine fuming method. The resultant images of the visualized fingerprints were analyzed with densitometric image analysis to measure the changes in the areas of the ridges, which can be correlated to the deposition order. No significant variation was found with the different types of thermal paper. The average areas of the friction ridges increased gradually or were similar to the values from day 1 for 3 days, and then a continual decrease was shown from day 4 through day 7. The area values from day 6 and day 7 were less than half of those from day 1. Furthermore, the test with overlapped fingerprints showed the possibility of differentiation between fingerprints that are 1-3 and 6-7 days old based on the clarity visible to the naked eye. Additional experiments with the deposition conditions can prove that the current method is valuable for the determining the order of fingerprint deposition on thermal paper.

Screening of Natural Product Libraries for the Extension of Cell Life-span through Immune System (면역시스템을 통한 세포수명연장 천연물질 스크린)

  • Yoo, Bo-Kyung;Kwon, Kisang;Ko, Young Hwa;Kim, Hong Geun;Lee, Seokhyun;Park, Kwan-Ho;Choi, Ji-Young;Kwon, O-Yu
    • Journal of Life Science
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    • v.26 no.3
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    • pp.359-363
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    • 2016
  • We have screened four natural products against 640 single compounds, which shows more two folds gene expression for both endoplasmic reticulum aminopeptidase 1 (ERAP1) and FOXO-family transcription factor (FOXO1). The results were as follows. (±)-Car-3-ene-2,5-dione from Asarum sieboldii Miq. is C10H12O2 molecular formula and the 164 kDa molecular weight. Cinobufagin from Bufonis Venennum is C26H34O6 molecular formula and 442 kDa molecular weight. So far reported main biological function is Na+/K+-ATPase inhibition. Corilagin from Euphorbia pekinensis is C27H22O18 molecular formula and 634 kDa molecular weight. Carbonic anhydrase inhibition is well known its biological function. Corydaline from Corydalis turtschaninovii is C22H27NO4 molecular formula and 369 kDa molecular weight. The main biological function is acetylcholinesterase inhibition. In the short future, four types of natural products will be used in longevity experiments with insects. The results may give one of the clues for studying new drug development candidates of the longevity.

Inhibitory Effect of Jeungaektang Water Extract on Nitric Oxide and Cytokine Production in Lipopolysaccharide - activated RAW 264.7 Cells (증액탕(增液湯) 물추출물이 LPS로 유도된 RAW 264.7 cell에서의 Nitric Oxide 및 Cytokine에 미치는 영향)

  • Ahn, Sun-June;Lee, Jong-Rok;Kim, Sang-Chan;Jee, Seon-Young
    • Herbal Formula Science
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    • v.15 no.1
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    • pp.163-173
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    • 2007
  • Jeungaektang (JAT) is the herbal formula, has the effect of moistening the dryness by activating lung Qi and by nourishing Yin, has being used for dryness syndromes. Generally the herbal formulae for moistening dryness are used for exogenous or endogenous dryness syndromes. JAT has been clinically used for the treatment of endogenous dryness syndromes. It is composed of Scrophulariae Radix. Rehmanniae Radix and Liriopis Tuber. Recent studies showed that JAT has a protective effect against $CCl_{4}-induced$ hepatotoxicity and anti-inflammatory effects against ear swelling of mouse induced by Crotonis Fructus. However, the effect of JAT on the immunological activity was rarely studied. Therefore, this study evaluated the effects of JAT the regulatory mechanism of nitric oxide (NO) and cytokines in the lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. After the treatment of JAT water extract, cell viability was measured by MTT assay, NO production was monitored by measuring the nitrite content in culture medium. Cyclooxygenase-2 (COX -2) and inducible nitric oxide synthase (iNOS) were determined by immunoblot analysis, and levels of cytokine were analyzed by sandwich immunoassays. Results provided evidence that JAT inhibited the production of nitrite and nitrate ($0.1{\sim}1.0$ mg/ml), iNOS ($0.1{\sim}1.0$ mg/ml), $interleukin-1{\beta}$ ( $0.1{\sim}1.0$ mg/ml) and tumor necrosis $factor-{\alpha}$ ($0.1{\sim}1.0$ mg/ml) in RAW 264.7 cells activated with LPS. Furthermore, JAT inhibited the expression of COX-2 expression and production of prostagladin E2 ($0.1{\sim}1.0$ mg/ml). These findings suggest that JAT can produce anti-inflammatory effect, which may play a role in adjunctive therapy in Gram-negative bacterial infections.

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A Case Report of Tuberculous Brain Abscess and Tuberculous Peritonitis Developing Due to Paradoxical Reactions (역설적 반응에 의하여 동시에 결핵성 뇌농양 및 결핵성 복막염이 발생한 증례 1예)

  • Ahn, Tae Hong;Park, Min Bum;Lee, Key Jo;Jung, Eun Ho;Kim, Jin Woo;Suh, Sang Yeol;Kang, Seok Woo;Kim, Eun Na;Han, Yoon Ju;Cho, Sam Kwon
    • Tuberculosis and Respiratory Diseases
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    • v.66 no.6
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    • pp.457-462
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    • 2009
  • While receiving appropriate treatment, patients with tuberculosis occasionally have unusual, paradoxical reactions, with transient worsening of lesions or the development of new lesions. This report is a case of tuberculosis brain abscess and tuberculosis peritonitis with intra-abdominal abscess that developed during appropriate anti-tuberculosis chemotherapy. A 45-year-old male patient had been diagnosed as with all-drug susceptible pulmonary tuberculosis with pleurisy. Subsequently, the patient underwent standard treatment with anti-tuberculosis therapy; the pulmonary lesions improved. Three months after initial treatment, the patient developed brain abscesses and peritonitis. With the addition of corticosteroid treatment, the patient's neurologic symptoms were relieved. Exploratory laparotomy with surgical drainage was performed and a diagnosis of tuberculosis peritonitis was confirmed on biopsy. Anti-tuberculosis therapy was continued for 19 months, the patient improved eventually without further complications, although the therapeutic regimen had not been altered. In this case, the paradoxical response to treatment may have been involved in the pathogenesis of disease.

Anti-mycobacterial Effects of the Extract of Humulus japonicus (환삼덩굴(Humulus japonicus) 추출물의 항결핵 효과)

  • Hong, Min-Sun;Son, Eun-Soon;Lee, Sung-Joong;Lee, Sun-Kyoung;Lee, Ye-Jin;Song, Sun-Dae;Cho, Sang-Nae;Barry, Clifton E. III;Eum, Seok-Yong
    • Korean Journal of Food Science and Technology
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    • v.46 no.1
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    • pp.94-99
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    • 2014
  • The present study aimed to evaluate the in vitro antimycobacterial effects of hop plant, Humulus japonicus. Methanol extract of H. japonicus (MeOH extract) showed strong direct bactericidal effects against Mycobacterium tuberculosis in vitro. Furthermore, the MeOH extract significantly inhibited M. tuberculosis growth in human macrophages. When five fractions obtained from MeOH extract were examined using the same methods, the hexane and ethyl acetate fractions showed bactericidal effects against M. tuberculosis in vitro, whereas the butanol and water fractions inhibited M. tuberculosis growth in macrophages. Because H. japonicus extract exhibited antimycobacterial activity against both free M. tuberculosis in culture medium and intracellular M. tuberculosis in human macrophages, this plant might be a good candidate for development of a new anti-tuberculosis drug.

Anti-proliferation Effect of Coscinoderma sp. Extract on Human Colon Cancer Cells (Coscinoderma sp.의 대장암세포 증식 억제 효과)

  • Choi, Ki Heon;Jung, Joohee
    • Journal of Food Hygiene and Safety
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    • v.31 no.4
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    • pp.294-298
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    • 2016
  • Natural products are attractive as the source of new drug development. Especially, numerous unknown marine bioresources are an object of attention because the ocean occupies three fourth of the earth. Survival of marine bioresources in extreme environment may induce the production of biological active compounds. As previous study, we examined over 40 specimens of marine sponges collected from Micronesia and screened their anti-proliferative activities in various cancer cell lines. Among them, we investigated Coscinoderma sp.'s activity and mechanism in human colon carcinoma HCT116 and RKO cells. Furthermore, we also used the p53-knockout of HCT116 cells and the p53 loss of RKO cells for elucidating the role of p53. Coscinoderma sp. inhibited cellular viability independently of the p53 status. Therefore, we compared the expression level of cell death-related proteins by Coscinoderma sp. in HCT16 and in HCT116 p53KO cells. Coscinoderma sp. increased p53 level and NOXA levels and induced apoptosis under the condition of p53 existence. On the other hand, Coscinoderma sp. increased p21 and mTOR levels in HCT116 p53KO cells. These results suggest that Coscinoderma sp. induced anti-proliferation effect through different pathway depending on p53 status.

Development of a Recombinant Streptomyces griseus with sprA and sprB Genes for Proteolytic Enzyme Production (Streptomyces griseus IFO13350 유래 sprA 및 sprB 유전자를 이용한 Pretense 생산균주 개발)

  • Hwang Ji-Hwan;Lee Chang-Kwon;Lee Kang-Mu;Jo Byoung-Kee;Park Hae-Ryong;Hwang Yong-Il
    • Korean Journal of Microbiology
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    • v.41 no.1
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    • pp.87-92
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    • 2005
  • Pronase, a protease produced for commercial purpose by Streptomyces griseus, was composed of serine protease, alkaline protease, aminopeptidase and carboxypeptidase complex, and it has been widely used as anti-inflammatory drugs for human therapy. In this study, we developed a new integration vector, pHJ101 derived from pSET152, containing strong promoter, ermE, to overexpress a certain protease gene. Specific PCR primers for cloning of sprA (a gene for S. griseus protease A) and sprB (a gene for S. griseus protease B) genes were designed from the basis of nucleotide sequence in databases and amplified by PCR. Plasmid pHJ201 and pHJ202 were constructed by inserting of amplified each gene in a vector pHJ101. S. griseus HA and S. griseus HB were respectively obtained by conjugal process of a parent strain, S. griseus IFO 13350 with the recombinant Escherichia coli harboring plasmid pHJ201 or pHJ202. When protease activity was measured in flask cultivation, produced protease levels of S. griseus HA and S. griseus HB increased about 5.3 times and 5 times, respectively, more than that of parent strain. And, the constructed integrating plasmid pHJ101 was applicable for overexpression of a certain gene in Streptomyces sp.

A Meta-Analysis on the Effect of Entrepreneurship on the Entrepreneurial Intention: Mediating Effect of Entrepreneur Education (기업가정신이 창업의지에 미치는 영향에 관한 메타분석: 창업교육의 매개효과)

  • Yoon, Byeong seon;Kim, Chun Kyu
    • Asia-Pacific Journal of Business Venturing and Entrepreneurship
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    • v.15 no.3
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    • pp.207-221
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    • 2020
  • This study conducted a meta-analysis on the effects of innovation, risk-taking, and enterprising on entrepreneurship. From 2013 to 2020, 392 papers, which were judged as quantitative research from doctoral and master thesis, and academic journals published in Korea were selected as research subjects. 28 duplicates of thesis and thesis are excluded. A total of 52 papers were finally selected, excluding 312 papers that were insufficient to be used as research data because there were no statistical values such as correlation coefficients. For the 52 selected papers, the homogeneity of the variables was first verified. As a result of the homogeneity test, the innovativeness, risk-taking, initiative, and entrepreneurship education all showed great effects on heterogeneity, and the average effect size was analyzed by random effect model. The average effect size analyzed was 0.38 ~ 0.49, and all four variables showed moderate average effect size. As a result of analyzing the average effect size by forest plot, all showed proper results. From the results of funnel plot analysis of entrepreneurship education, published errors were confirmed asymmetric. Research data on entrepreneurship education shows that it cannot represent the whole. It is a structural equation model with entrepreneurship and entrepreneurial intention as a parameter. Iinnovation and risk-taking have an impact on entrepreneurship by taking entrepreneurship education as a parameter. Initiative had an effect on the entrepreneurial intention a business, regardless of entrepreneurship education. In a number of studies, university entrepreneurship education has had an impact on the entrepreneurial intention. It should be changed to entrepreneurship education that combines theory and practice. Entrepreneurship education should be transformed into continuous and field-oriented education.