• Title/Summary/Keyword: Drug-associated

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Role of Tumor-associated Macrophage in Tumor Microenvironment (암미세환경에서 종양관련대식세포의 역할)

  • Min, Do Sik
    • Journal of Life Science
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    • v.28 no.8
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    • pp.992-998
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    • 2018
  • Cancer cells grow in an environment composed of various components that supports tumor growth. Major cell types in the tumor microenvironment are fibroblast, endothelial cells and immune cells. All of these cells communicate with cancer cells. Among infiltrating immune cells as an abundant component of solid tumors, macrophages are a major component of the tumor microenvironment and orchestrates various aspects of immunity. The complex balance between pro-tumoral and anti-tumoral effects of immune cell infiltration can create a chronic inflammatory microenvironment essential for tumor growth and progression. Macrophages express different functional programs in response to microenvironmental signals, defined as M1 and M2 polarization. Tumor-associated macrophages (TAM) secret many cytokines, chemokines and proteases, which also promote tumor angiogenesis, growth, metastasis and immunosuppression. TAM have multifaceted roles in the development of many tumor types. TAM also interact with cancer stem cells. This interaction leads to tumorigenesis, metastasis, and drug resistance. TAM obtain various immunosuppressive functions to maintain the tumor microenvironment. TAM are characterized by their heterogeneity and plasticity, as they can be functionally reprogrammed to polarized phenotypes by exposure to cancer-related factors, stromal factors, infections, or even drug interventions. Because TAMs produce tumor-specific chemokines by the stimulation of stromal factors, chemokines might serve as biomarkers that reflect disease activity. The evidence has shown that cancer tissues with high infiltration of TAM are associated with poor patient prognosis and resistance to therapies. Targeting of TAM in tumors is considered a promising therapeutic strategy for anti-cancer treatment.

Livestock-associated methicillin-resistant Staphylococcus aureus in Korea: antimicrobial resistance and molecular characteristics of LA-MRSA strains isolated from pigs, pig farmers, and farm environment

  • Back, Seung Hyun;Eom, Hong Sik;Lee, Haeng Ho;Lee, Gi Yong;Park, Kun Taek;Yang, Soo-Jin
    • Journal of Veterinary Science
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    • v.21 no.1
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    • pp.2.1-2.14
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    • 2020
  • The emergence of livestock-associated (LA)-methicillin-resistant Staphylococcus aureus (MRSA) in livestock animal has become a significant zoonotic concern. In the present study, we investigated nationwide prevalence of LA-MRSA across pork production chain including pig farms, slaughterhouses, and retail markets. A total of 40 MRSA strains were isolated during the investigation and the overall prevalence of MRSA was 3.4% (n = 37), 0.6% (n = 2), and 0.4% (n = 1) in pig farms, slaughterhouses, and retail markets, respectively. Multilocus sequence typing analyses revealed that the 2 most significant clonal lineages in pork production chain in Korea were ST398 (n = 25) and ST541 (n = 6). All of the 40 MRSA isolates were further characterized to investigate key genotypic and phenotypic correlates associated with the emergence and spread of clonal complex 398 (CC398; ST398, and ST541) LA-MRSA. Although the prevalence of swine-associated MRSA was still relatively low and mostly restricted to pig farms, multidrug-resistant CC398 LA-MRSA isolates with new spa types (t18102 and t18103) were identified as a major clonal lineage. The CC398 LA-MRSA strains tended to exhibit increased levels of multiple drug resistance (MDR) phenotype compared with non-CC398 MRSA strains. Of note, in comparison with non-CC398 MRSA isolates, CC398 LA-MRSA isolates exhibited significantly enhanced tetracycline (TET) and zinc resistance. These findings suggested that co-selection pressure associated with MDR phenotype, especially TET resistance, and zinc resistance may have played a significant role in the emergence and persistence of CC398 LA-MRSA in pig farms in Korea.

Hepatitis C Virus Core Protein Sensitizes Cells to Apoptosis Induced by Anti-Cancer Drug

  • Kang, Mun-Il;Mong Cho;Kim, Sun-Hee;Kang, Chi-Dug;Kim, Dog-Wan
    • Journal of Microbiology
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    • v.37 no.2
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    • pp.90-96
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    • 1999
  • The core protein of the hepatitis C virus (HCV) is a multifunctional protein. The HCV core protein was reported to regulate cellular gene expression and transform primary rat embryo fibroblast cells. However, the role of the core protein in the pathogenesis of HCV-associated liver diseases is not well understood. To investigate the functional role of the core protein in cytophathogenicity, we have constructed stable expression systems of full length or truncated HCV core protein lacking the C-terminal hyderophobic domains and established HepG2 cell clones constitutively expressing the core protein. The full length core protein was localized in the cytoplasm and the C-terminal truncated core protein was localized in the nucleus. HepG2 cells expressing nuclear, truncated core protein showed elevated cell death during cultivation compared to untransfected cells and full length core-expressing cells. In the treatment with bleomycin, both cell clones expressing full length or truncated core protein appeared to be more sensitive to blemoycin than the parental HepG2 cells. These results suggest that the core protein may play a role in HCV pathogenesis promoting apoptotic cell death of infected cells.

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Discovery of Novel DUSP4 Inhibitors through the Virtual Screening with Docking Simulations

  • Park, Hwangseo;Jeon, Tae Jin;Chien, Pham Ngoc;Park, So Ya;Oh, Sung Min;Kim, Seung Jun;Ryu, Seong Eon
    • Bulletin of the Korean Chemical Society
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    • v.35 no.9
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    • pp.2655-2659
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    • 2014
  • Dual specificity protein phosphatase 4 (DUSP4) has been considered a promising target for the development of therapeutics for various human cancers. Here, we report the first example for a successful application of the structure-based virtual screening to identify the novel small-molecule DUSP4 inhibitors. As a consequence of the virtual screening with the modified scoring function to include an effective molecular solvation free energy term, five micromolar DUSP4 inhibitors are found with the associated $IC_{50}$ values ranging from 3.5 to $10.8{\mu}M$. Because these newly identified inhibitors were also screened for having desirable physicochemical properties as a drug candidate, they may serve as a starting point of the structure-activity relationship study to optimize the medical efficacy. Structural features relevant to the stabilization of the new inhibitors in the active site of DUSP4 are discussed in detail.

Ezrin-radixin-moesin proteins are regulated by Akt-GSK3β signaling in the rat nucleus accumbens core

  • Kim, Wha Young;Cai, Wen Ting;Jang, Ju Kyong;Kim, Jeong-Hoon
    • The Korean Journal of Physiology and Pharmacology
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    • v.24 no.1
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    • pp.121-126
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    • 2020
  • The ezrin-radixin-moesin (ERM) proteins are a family of membrane-associated proteins known to play roles in cell-shape determination as well as in signaling pathways. We have previously shown that amphetamine decreases phosphorylation levels of these proteins in the nucleus accumbens (NAcc), an important neuronal substrate mediating rewarding effects of drugs of abuse. In the present study, we further examined what molecular pathways may be involved in this process. By direct microinjection of LY294002, a PI3 kinase inhibitor, or of S9 peptide, a proposed GSK3β activator, into the NAcc core, we found that phosphorylation levels of ERM as well as of GSK3β in this site are simultaneously decreased. These results indicate that ERM proteins are under the regulation of Akt-GSK3β signaling pathway in the NAcc core. The present findings have a significant implication to a novel signal pathway possibly leading to structural plasticity in relation with drug addiction.

Delayed bleeding after implant surgery in patients taking novel oral anticoagulants: a case report

  • Kim, Chihun;Dam, Chugeum;Jeong, Jieun;Kwak, Eun-Jung;Park, Wonse
    • Journal of Dental Anesthesia and Pain Medicine
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    • v.17 no.2
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    • pp.143-147
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    • 2017
  • The use of novel oral anticoagulants (NOACs) has increased in recent times in an effort to overcome the shortcomings of warfarin. They are being used primarily for the prevention of thrombosis caused by atrial fibrillation and offer the advantages of having fewer drug interactions than warfarin, no dietary restrictions, and no requirement for regular blood tests. Although there is reportedly less postoperative bleeding even if the drug is not discontinued during procedures that can cause local bleeding, such as dental procedures, no well-designed clinical studies have assessed postoperative bleeding associated with the use of these drugs. This article reports a case of a 74-year-old male patient who was taking rivaroxaban. The patient underwent a dental implant procedure after discontinuing rivaroxaban for one day and subsequently suffered delayed bleeding on postoperative day 6. Accordingly, this article also reports that the use of NOACs may also lead to delayed bleeding.

Identification and Antimicrobial Susceptibility of Microorganisms Isolated from Bovine Mastitic Milk (젖소의 유방염 원인균 분리 및 약제 감수성 검사)

  • Kang, Hee-Jung;Kim, Ik-Chun;Kim, Jin-Hoe;Son, Won-Geun;Lee, Du-Sik
    • Korean Journal of Veterinary Research
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    • v.41 no.4
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    • pp.511-521
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    • 2001
  • Microorganisms were isolated and identified from bovine 296 quarters which showed positive reaction by California Mastitis Test (CMT) in 40 farms of Jeju from September 1999 to June 2000. The organisms associated with the mastitis of bovine were 11 different bacterial species in this study. Which of them, Staphylococcus aureus was the most predominant species as 152 (51.4%) isolates. Other identified species included 49 (16.5%) coliform, 47 (15.8%) Streptococcus dysgalactiae, 15 (5.1%) Bacillus spp., 8 (2.7%) Staphylococcus epidermidis, 6 (2.1%) Streptococcus agalactiae, 5 (1.7%) Enterococcus faecalis, 5 (1.7%) Corynebacterium spp., 3 (1.0%) Streptococcus uberis, 1 (0.3%) Pseudomonas aeruginosa and 1 (0.3%) Pasteurella haemolytica. Almost of all the islolated beacterial species showed high sensitivity against kanamycin (98.6%), cephalothin (98.0%), streptomycin (94.9%), gentamicin (94.6%), ampicillin (92.2%) and polymyxin B (90.2%). On the contrary, they showed resistance against penicillin (47.0%), tetracycline (37.2%), cefazolin (26.0%), bacitracin (22.6%) and erythromycin (19.9%). Eighty-one isolates were not resistant to any antibiotics and 215 drug resistant isolates showed 89 different drug resistance patterns from single to nine multiple antibiotics resistance patterns.

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Isolation of Grb2-Shc Domain Binding Inhibition Component from Agastache rugosa (배초향으로부터 Grb2-Shc domain 결합저해 물질의 분리)

  • Lee, Eun-Sook;Ahn, Byung-Tae;Lee, Sae-Bom;Kim, Hyae-Kyeong;Bok, Song-Hae;Jeong, Tae-Sook
    • Korean Journal of Pharmacognosy
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    • v.30 no.4
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    • pp.404-408
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    • 1999
  • SH2 domains and their associated catalytic or noncatalytic proteins constitute critical signal transduction targets for drug discovery. Grb2 associates with phosphotyrosine sites of the activated receptors or Shc via their SH2 domain to link receptor tyrosine kinases to ras signalling. Blocking of the Grb2-Shc complex may be to intervene the oncogenic signal transduction pathways and to develop a new antitumor drug. In the search for blockers of Grb2 SH2-Shc interaction, Lutein, a family of carotenoids, was isolated from the extract of the leaf of Agastache rugosa O. Kuntze as SH2 domain antagonists. The $IC_{50}$ of Lutein against Grb2-Shc binding was $6.8\;{\mu}M$.

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The hypertension drug, verapamil, activates Nrf2 by promoting p62-dependent autophagic Keap1 degradation and prevents acetaminophen-induced cytotoxicity

  • Lee, Da Hyun;Park, Jeong Su;Lee, Yu Seol;Sung, Su Haeng;Lee, Yong-ho;Bae, Soo Han
    • BMB Reports
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    • v.50 no.2
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    • pp.91-96
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    • 2017
  • Nuclear factor erythroid 2-related factor 2 (Nrf2) provides a cellular defense against oxidative stress by inducing the expression of antioxidant and detoxification enzymes. The calcium antagonist, verapamil, is an FDA-approved drug prescribed for the treatment of hypertension. Here, we show that verapamil acts as a potent Nrf2 activator without causing cytotoxicity, through degradation of Kelch-like ECH-associated protein 1 (Keap1), a Nrf2 repressor. Furthermore, verapamil-induced Keap1 degradation is prominently mediated by a p62-dependent autophagic pathway. Correspondingly, verapamil protects cells from acetaminophen-induced oxidative damage through Nrf2 activation. These results demonstrated the underlying mechanisms for the protective role of verapamil against acetaminophen-induced cytotoxicity.

Cytotoxicity of Cytosine Deaminase (CD) Adenoviral Vectors(AV) with a Promoter (L-plastin) for Epithelial Cancer Cells.

  • Chung, Injae;Jung, Kihwa;Deisseroth, Albert B.
    • Proceedings of the Korean Society of Applied Pharmacology
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    • 1997.04a
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    • pp.80-80
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    • 1997
  • The object of this study was to develop a gene therapy strategy for ovarian cancer. We have previously shown that AV with a L-plastin (LP) promoter infects breast and ovarian cancer cells and expressed ${\beta}$-galactosidase cDNA in preference to normal fibroblast cells and hematopoietic cells. We now report on the cytotoxicity of Ad.LP.CD, an AV carrying a CD cDNA which converts the pro-drug, 5-Fluorocytosine (5-FC) into the toxic drug 5-Fluorouracil (5-FU). Infection of Ad.LP.CD into either 293 cells or ovarian cancer cells generated the functional CD as measured by HPLC analysis. Using a ratio of AV to OVCAR3 cell of 100 and a 5-FC concentration of 100 ${\mu}$M, we achieve an over 95 % of cell growth inhibition. We are using flow cytometry analysis for ${\beta}$ -galactosidase and ovarian cancer associated folate receptor to screen primary ascites samples for infectivity after infection with an adenoviral vector, i.e., Ad.LP.LacZ. This vector system may be of value in the treatment of microscopic disease of ovarian cancer in the peritoneal cavity.

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