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Domperidone, a Dopamine Receptor D2 Antagonist, Induces Apoptosis by Inhibiting the ERK/STAT3-Mediated Pathway in Human Colon Cancer HCT116 Cells

  • So Jin Sim;Jeong-Hoon Jang;Joon-Seok Choi;Kyung-Soo Chun
    • Biomolecules & Therapeutics
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    • v.32 no.5
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    • pp.568-576
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    • 2024
  • Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is crucial. Recently, the dopamine receptor D2 (DRD2), a G protein-coupled receptor, has been reported to play multiple roles in growth of tumor cells. This study investigated the anticancer potential of domperidone, a dopamine receptor D2 antagonist, in HCT116 human CRC cells. Domperidone demonstrated concentration- and time-dependent reductions in cell viability, thereby inducing apoptosis. The molecular mechanism revealed that domperidone modulated the mitochondrial pathway, decreasing mitochondrial Bcl-2 levels, elevating cytosolic cytochrome C expression, and triggering caspase-3, -7, and -9 cleavage. Domperidone decreased in formation of β-arrestin2/MEK complex, which contributing to inhibition of ERK activation. Additionally, treatment with domperidone diminished JAK2 and STAT3 activation. Treatment of U0126, the MEK inhibitor, resulted in reduced phosphorylation of MEK, ERK, and STAT3 without alteration of JAK2 activation, indicating that domperidone targeted both MEK-ERK-STAT3 and JAK2-STAT3 signaling pathways. Immunoblot analysis revealed that domperidone also downregulated DRD2 expression. Domperidone-induced reactive oxygen species (ROS) generation and N-acetylcysteine treatment mitigated ROS levels and restored cell viability. An in vivo xenograft study verified the significant antitumor effects of domperidone. These results emphasize the multifaceted anticancer effects of domperidone, highlighting its potential as a promising therapeutic agent for human CRC.

Epidemiological characteristics on fowl typhoid outbreak in Kyongnam province and comparison of diagnostic methods for identification of salmonella gallinarum (경남지역에서 발생한 가금티푸스의 역학적 특성 및 진단방법에 대한 비교 시험)

  • 최유정;김도경;김용환
    • Korean Journal of Veterinary Service
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    • v.23 no.4
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    • pp.349-360
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    • 2000
  • An epidemiological survey was conducted to investigate fowl typhoid outbreaks in Kyungnam province of Korea. The causative agent, salmonella gallinarum was isolated from 68 chicken samples of tentatively diagnosed fowl typhoid cases occurred during the period from January 1996 to September 1999. Comparative studies were also carried out to evaluate the diagnostic methods for detection of S gallinam The results obtained were as follows; 1. Of the 68 cases of tentatively diagnosed fowl typhoid, 56 (82%) cases were determined as fowl typhoid by biochemical test and pathological findings. The other 12 (18%) cases were determined as paratyphoid. 2. Fowl typhoid outbreaks occur continuously all seasons in the year, however the incidence was remarkably increased from May to September. 3. The frequency of incidence of fowl typhoid in terms of regional distribution was relatively high in egg-laying hens facilities, and the mode of transmission is likely to be either egg-to-egg or lateral transfer by wild birds or rats. 4. All of 18 isolates from 56 cases were identified as S gallinarum by biochemical and serological test. 5. Antimicrobial drug susceptibility test against 18 isolates showed that the isolates were highly susceptible to ASH, CZ, CF and GM (above 90%), whereas those strains were 100% resistant to EM, NA and PC. 6. S gallinarum rfbS gene was targeted to be amplified by PCR for comparative detection of S gallinarum in the experimentally infected chickens. The amplified 720bp DNA fragment, which is specific in D serogroup strains of S enterica subspecies was confirmed by agarose gel electrophoresis. 7. A comparison made between fecal culture and PCR-method revealed that later-method was relatively higher in detection rate than that of former method for S gallinarum. 8. Comparison of currently applied methods, rapid serum agglutination test (RST) and microplate agglutination test (MAT), with experimentally infected chickens were made to evaluate sensitivity of detection by neutralizing antibody titration. Both methods detected neutralizing antibodies from the challenged chickens of 5 day post infection. However, positive reactions were determined after 7 and 9 days post infection by MAT and RST, respectively.

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Performance of Magnesia Cement Using MgCO3 and Serpentine

  • Lee, Jong-Kyu;Soh, Jung-Sub
    • Journal of the Korean Ceramic Society
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    • v.53 no.1
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    • pp.116-121
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    • 2016
  • The amount of carbon dioxide ($CO_2$) released while producing building materials is substantial and has been targeted as a leading contributor to global climate change. One of the most typical methods of reducing $CO_2$ in building materials is the addition of slag and fly ash, like pozzolan material another method is to reduce $CO_2$ production by developing carbon negative cement. MgO-based cement from the low-temperature calcination of magnesite required less energy and emitted less $CO_2$ than the manufacturing of Portland cements. It is also believed that adding reactive MgO to Portland-pozzolan cements can improve their performance and also increase their capacity to absorb atmospheric $CO_2$. In this study, basic research on magnesia cement using $MgCO_3$ and magnesium silicate ore (serpentine) as the main starting materials, as well as blast furnace slag for the mineral admixture, was carried out for industrial waste material recycling. In order to increase the overall hydration activity, $MgCl_2$ was also added. In the case of the addition of $MgCl_2$as accelerating admixture, there was a promoting effect on the compressive strength. This was found to be due to the production of needle-like dense Mg-Cl hydrates. Mgnesia cement has a high viscosity due to its high specific surface area therefore, when the PC-based dispersing agent was added at a level of more than 1.0%, it had the effect of improving fluidity. In particular, the addition of $MgCl_2$ in magnesia cement using $MgCO_3$and magnesium silicate ore (serpentine) as main starting materials led to a lower expansion ratio and an increase in the freeze-thaw resistance finally, the addition of $MgCl_2$ as accelerating admixture led to good overall durability.

Cytotoxic T Lymphocytes Elicited by Dendritic Cell-Targeted Delivery of Human Papillomavirus Type-16 E6/E7 Fusion Gene Exert Lethal Effects on CaSki Cells

  • Wu, Xiang-Mei;Liu, Xing;Jiao, Qing-Fang;Fu, Shao-Yue;Bu, You-Quan;Song, Fang-Zhou;Yi, Fa-Ping
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.6
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    • pp.2447-2451
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    • 2014
  • Human papillomavirus (HPV) is the primary etiologic agent of cervical cancer. Consideration of safety and non human leukocyte antigen restriction, protein vaccine has become the most likely form of HPV therapeutic vaccine, although none have so far been reported as effective. Since tumor cells consistently express the two proteins E6 and E7, most therapeutic vaccines target one or both of them. In this study, we fabricated DC vaccines by transducing replication-defective recombinant adenoviruses expressing E6/E7 fusion gene of HPV-16, to investigate the lethal effects of specific cytotoxic T lymphocytes (CTL) against CaSki cells in vitro. Mouse immature dendritic cells (DC) were generated from bone marrow, and transfected with pAd-E6/E7 to prepare a DC vaccine and to induce specific CTL. The surface expression of CD40, CD68, MHC II and CD11c was assessed by flow cytometry (FCM), and the lethal effects of CTL against CaSki cells were determined by DAPI, FCM and CCK-8 methods. Immature mouse DC was successfully transfected by pAd-E6/E7 in vitro, and the transfecting efficiency was 40%-50%. A DC vaccine was successfully prepared and was used to induce specific CTL. Experimental results showed that the percentage of apoptosis and killing rate of CaSki cells were significantly increased by coculturing with the specific CTL (p <0.05). These results illustrated that a DC vaccine modified by HPV-16 E6/E7 gene can induce apoptosis of CaSki cells by inducing CTL, which may be used as a new strategy for biological treatment of cervical cancer.

Benefits of Metformin Use for Cholangiocarcinoma

  • Kaewpitoon, Soraya J;Loyd, Ryan A;Rujirakul, Ratana;Panpimanmas, Sukij;Matrakool, Likit;Tongtawee, Taweesak;Kootanavanichpong, Nusorn;Kompor, Ponthip;Chavengkun, Wasugree;Kujapun, Jirawoot;Norkaew, Jun;Ponphimai, Sukanya;Padchasuwan, Natnapa;Pholsripradit, Poowadol;Eksanti, Thawatchai;Phatisena, Tanida;Kaewpitoon, Natthawut
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.18
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    • pp.8079-8083
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    • 2016
  • Metformin is an oral anti-hyperglycemic agent, which is the most commonly prescribed medication in the treatment of type-2 diabetes mellitus. It is purportedly associated with a reduced risk for various cancers, mainly exerting anti-proliferation effects on various human cancer cell types, such as pancreas, prostate, breast, stomach and liver. This mini-review highlights the risk and benefit of metformin used for cholangiocarcinoma (CCA) prevention and therapy. The results indicated metformin might be a quite promising strategy CCA prevention and treatment, one mechanism being inhibition of CCA tumor growth by cell cycle arrest in both in vitro and in vivo. The AMPK/mTORC1 pathway in intrahepatic CCA cells is targeted by metformin. Furthermore, metformin inhibited CCA tumor growth via the regulation of Drosha-mediated expression of multiple carcinogenic miRNAs. The use of metformin seems to be safe in patients with cirrhosis, and provides a survival benefit. Once hepatic malignancies are already established, metformin does not offer any therapeutic potential. Clinical trials and epidemiological studies of the benefit of metformin use for CCA should be conducted. To date, whether metformin as a prospective chemotherapeutic for CCA is still questionable and waits further atttention.

The Utility Evaluation of Reconstructed 3-D Images by Maximum Intensity Projection in Magnetic Resonance Mammography and Cholangiopancreatography

  • Cho, Jae-Hwan;Lee, Hae-Kag;Park, Cheol-Soo;Kim, Ham-Gyum;Baek, Jong-Geun;Kim, Eng-Chan
    • Journal of Magnetics
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    • v.19 no.4
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    • pp.365-371
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    • 2014
  • The aim of this study was to evaluate the utility of 3-D images by comparing and analyzing reconstructed 3-D images from fast spin echo images of MRI cholangiopancreatography (MRCP) images using maximum intensity projection (MIP) with the subtraction images derived from dynamic tests of magnetic resonance mammography. The study targeted 20 patients histologically diagnosed with pancreaticobiliary duct disease and 20 patients showing pancreaticobiliary duct diseases, where dynamic breast MR (magnetic resonance) images, fast spin echo imaged of pancreaticobiliary duct, and 3-D reconstitution images using a 1.5T MR scanner and 3.0T MR scanner were taken. As a result of the study, the signal-to-noise ratio in the subtracted breast image before and after administering the contrast agent and in the reconstructed 3-D breast image showed a high ratio in the reconstructed image of lesional tissue, relevant tissue, and fat tissue. However, no statistically meaningful differences were found in the contrast-to-noise ratio of the two images. In the case of the MRCP image, no differences were found in the ratios of the fast spin echo image and reconstructed 3-D image.

Screening of Photosensitizer for Photodynamic Therapy (광역동 항암치료를 위한 광과민제 스크리닝 연구)

  • Kim, So-Young;Yoo, Gui-Jae;Park, Keun-Hyoung;Lim, Byung-Lak;Kim, Shi-Surk;Yom, Heng-Cherl;Chae, Hee-Jeong
    • KSBB Journal
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    • v.22 no.5
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    • pp.318-321
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    • 2007
  • Photodynamic therapy (PDT) is a targeted-tumor treatment system using a photosensitizer, light and oxygen to treat malignant tumor. We have investigated the cytotoxicity of 4 types of phthalocyanine derivative (silver phthalocyanine, iron (III) phthalocyanine, copper (II) phthalocyanine, nickel (II) phthalocyanine) against lung and breast cancers based on photodynamic therapy. As a result, phthalocyanine derivatives indicated a higher anticancer activity on a breast cancer cell line. Among the tested phthalocyanines, silver phthalocyanine (AgPc) showed a lower cytotoxicity against a normal cell line. In addition AgPc gave a good color characteristic when it is solubilized in water. Finally AgPc was selected as a potential antitumor agent for breast cancer.

Durability Assessment for Crushed Sand Wet-mix Shotcrete Mixed with Mineral Admixtures (부순모래를 사용한 습식 숏크리트의 광물성 혼화재료 혼입에 따른 내구성 평가)

  • Lee, Kyeo-Re;Han, Seung-Yeon;Nam Gung, Kyeong;Yun, Kyong-Ku
    • Journal of the Korea Concrete Institute
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    • v.26 no.5
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    • pp.607-614
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    • 2014
  • The purpose of this dissertation was to investigate the effect of mineral admixtures, such as fly ash, blast furnace slag powder, meta kaolin and silica fume, on the basic properties and durability of crushed sand shotcrete, selecting a series of shotcrete mixtures with a variable admixture. Compressive strength increased as the content of mineral admixtures increased, specially it was the most effective when using meta kaolin both at sample specimen and core after shotcreting. Rapid chloride ion permeability test and sulfuric acid resistance test showed that both durability increased as the substitute rate of mineral admixture increased. In air void analysis with image analysis, the targeted the spacing factor and specific surface were not satisfied because air-entrained agent was not used.

Senescence Effects of Angelica sinensis Polysaccharides on Human Acute Myelogenous Leukemia Stem and Progenitor Cells

  • Liu, Jun;Xu, Chun-Yan;Cai, Shi-Zhong;Zhou, Yue;Li, Jing;Jiang, Rong;Wang, Ya-Ping
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.11
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    • pp.6549-6556
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    • 2013
  • Leukemia stem cells (LSCs) play important roles in leukemia initiation, progression and relapse, and thus represent a critical target for therapeutic intervention. Hence, it is extremely urgent to explore new therapeutic strategies directly targeting LSCs for acute myelogenous leukemia (AML) therapy. We show here that Angelica sinensis polysaccharide (ASP), a major active component in Dong quai (Chinese Angelica sinensis), effectively inhibited human AML $CD34^+CD38^-$ cell proliferation in vitro culture in a dose-dependent manner while sparing normal hematopoietic stem and progenitor cells at physiologically achievable concentrations. Furthermore, ASP exerted cytotoxic effects on AML K562 cells, especially LSC-enriched $CD34^+CD38^-$ cells. Colony formation assays further showed that ASP significantly suppressed the formation of colonies derived from AML $CD34^+CD38^-$ cells but not those from normal $CD34^+CD38^-$ cells. Examination of the underlying mechanisms revealed that ASP induced $CD34^+CD38^-$ cell senescence, which was strongly associated with a series of characteristic events, including up-regulation of p53, p16, p21, and Rb genes and changes of related cell cycle regulation proteins P16, P21, cyclin E and CDK4, telomere end attrition as well as repression of telomerase activity. On the basis of these findings, we propose that ASP represents a potentially important agent for leukemia stem cell-targeted therapy.

Anticancer Effect of COX-2 Inhibitor DuP-697 Alone and in Combination with Tyrosine Kinase Inhibitor (E7080) on Colon Cancer Cell Lines

  • Altun, Ahmet;Turgut, Nergiz Hacer;Kaya, Tijen Temiz
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.7
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    • pp.3113-3121
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    • 2014
  • Colorectal cancer remains one of the most common types of cancer and a leading cause of cancer death worldwide. In this study, we aimed to investigate effects of DuP-697, an irreversible selective inhibitor of COX-2 on colorectal cancer cells alone and in combination with a promising new multi-targeted kinase inhibitor E7080. The HT29 colorectal cancer cell line was used. Real time cell analysis (xCELLigence system) was conducted to determine effects on colorectal cell proliferation, angiogenesis was assessed with a chorioallantoic membrane model and apoptosis was determined with annexin V staining. We found that DuP-697 alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. For the antiproliferative effect the half maximum inhibition concentration ($IC_{50}$) was $4.28{\times}10^{-8}mol/L$. Antiangiogenic scores were 1.2, 0.8 and 0.5 for 100, 10 and 1 nmol/L DuP-697 concentrations, respectively. We detected apoptosis in 52% of HT29 colorectal cancer cells after administration of 100 nmol/L DuP-697. Also in combination with the thyrosine kinase inhibitor E7080 strong antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells were observed. This study indicates that DuP-697 may be a promising agent in the treatment of colorectal cancer. Additionally the increased effects observed in the combination with thyrosine kinase inhibitor give the possibility to use lower doses of DuP-697 and E7080 which can avoid and/or minimize side effects.