• Title/Summary/Keyword: Heterogeneous Agents

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Antitumor profiles and cardiac electrophysiological effects of aurora kinase inhibitor ZM447439

  • Lee, Hyang-Ae;Kwon, Miso;Kim, Hyeon-A;Kim, Ki-Suk
    • The Korean Journal of Physiology and Pharmacology
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    • v.23 no.5
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    • pp.393-402
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    • 2019
  • Aurora kinases inhibitors, including ZM447439 (ZM), which suppress cell division, have attracted a great deal of attention as potential novel anti-cancer drugs. Several recent studies have confirmed the anti-cancer effects of ZM in various cancer cell lines. However, there have been no studies regarding the cardiac safety of this agent. We performed several cytotoxicity, invasion and migration assays to examine the anti-cancer effects of ZM. To evaluate the potential effects of ZM on cardiac repolarisation, whole-cell patch-clamp experiments were performed with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cells with heterogeneous cardiac ion channel expression. We also conducted a contractility assay with rat ventricular myocytes to determine the effects of ZM on myocardial contraction and/or relaxation. In tests to determine in vitro efficacy, ZM inhibited the proliferation of A549, H1299 (lung cancer), MCF-7 (breast cancer) and HepG2 (hepatoma) cell lines with $IC_{50}$ in the submicromolar range, and attenuated the invasive and metastatic capacity of A549 cells. In cardiac toxicity testing, ZM did not significantly affect $I_{Na}$, $I_{Ks}$ or $I_{K1}$, but decreased $I_{hERG}$ in a dose-dependent manner ($IC_{50}$: $6.53{\mu}M$). In action potential (AP) assay using hiPSC-CMs, ZM did not induce any changes in AP parameters up to $3{\mu}M$, but it at $10{\mu}M$ induced prolongation of AP duration. In summary, ZM showed potent broad-spectrum anti-tumor activity, but relatively low levels of cardiac side effects compared to the effective doses to tumor. Therefore, ZM has a potential to be a candidate as an anti-cancer with low cardiac toxicity.

Lessons From the Success and Failure of Targeted Drugs for Rheumatoid Arthritis: Perspectives for Effective Basic and Translational Research

  • Mingyo Kim;Yong-ho Choe;Sang-il Lee
    • IMMUNE NETWORK
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    • v.22 no.1
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    • pp.8.1-8.20
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    • 2022
  • Rheumatoid arthritis (RA) is a representative autoimmune disease that is primarily characterized by persistent inflammation and progressive destruction of synovial joints. RA has a complex and heterogeneous pathophysiology, involving interactions among various immune and joint stromal cells and a diverse network of cytokines and intracellular signaling pathways. With improved understanding of RA, over the past decades, therapeutic strategies have become considerably advanced and now included targeted molecular therapies, such as tumor necrosis factor inhibitors, IL-6 blockers, B-cell depletion agents, as well as inhibitors of T-cell co-stimulation and Janus kinases. However, a considerable proportion of RA patients experience refractory disease and interrupted treatment owing to the associated risk of developing serious infections and cancers. In contrast, although IL-1β, IL-17A, and p38α play significant roles in RA pathogenesis, several drugs targeting these factors have not been approved because of their low efficacy and severe adverse effects. In this review, we provide an overview of the working mechanism, advantages, and limitations of the currently available targeted drugs for RA. Additionally, we suggest potential mechanistic causes for clinically approved and failed drugs. Thus, this review provides perspectives on approaches for basic and translational studies that hold promise for identifying future next-generation therapeutics for RA.

The Effect of Laminaria japonica Diet on the Pharmacokinetics of Glipizide in Rats (다시마 식이가 흰쥐에서 글리피지드의 체내동태에 미치는 영향)

  • Choi, Han-Gon;Jang, Bo-Hyun;Rhee, Jong-Dal;Yu, Bong-Kyu;Yong, Chul-Soon
    • Journal of Pharmaceutical Investigation
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    • v.33 no.2
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    • pp.113-120
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    • 2003
  • Drug interactions with food, on occasion, lead to serious nutritional and functional changes in the body as well as alternations of pharmacological effect. It, therefore, should be necessary to take drug interactions with food into consideration for effective and safe therapeutics. Diabetes mellitus is a heterogeneous group of disorders characterized by abnormal glucose homeostasis, resulting in hyperglycemia, and is associated with increased risk of micovascular, macrovascular, and neuropathic complications. However, the precise mechanism of diabetes mellitus remains unclear. Three basic objectives in the care of diabetic patients are maintaining optimal nutrition, avoiding hypo- or hyperglycemia and preventing complications. The purpose of this study was to investigate thε effect of Laminaria japonica diet on the absorption, distribution, metabolism and excretion of glipizide which are frequently used in the treatment of diabetes. Diabetic rats induced by streptozotocin were employed in this study. Blood concentrations of oral hypoglycemic agents were measured by HPLC and resultant pharmacokinetic parameters were calculated by RSTRIP. The mechanisms of drug interaction with food were evaluated on the basis of pharmacokinetic parameters such as $k_{a},\;t_{1/2},\;C_{max},\;t_{max}$ and AUC. Administration of glipizide in normal rats treated with Laminaria japonica diet showed significant increase in AUC, $k_{a},\;t_{1/2},\;t_{max}$ and decrease in $C_{max}$, compared to those without Laminaria japonica diet. This might result from adsorption of glipizide on components of Laminaria japonica, causing delayed absorption. Administration of glipizide in diabetic rats treated with Laminaria japonica diet showed significant increase in $t_{1/2}\;and\;t_{max}$, and decrease in $C_{max}$, compared to those without Laminaria japonica diet. This might also result from adsorption of glipizide on components of Laminaria japonica, causing delayed absorption and flattened blood concentration of glipizide. The oral glucose test showed that Laminaria japonica diet could lower blood glucose level probably through either inhibiting the activity of disaccharidases, intestinal digestive enzymes, or delaying the absorption of glucose. More studies should be followed to fully understand pharmacokinetic changes of glipizide caused by long-term Laminaria japonica diet.

Trends of Semantic Web Services and Technologies : Focusing on the Business Support (비즈니스를 지원하는 시멘틱 웹서비스와 기술의 동향)

  • Kim, Jin-Sung;Kwon, Soon-Jae
    • Journal of Intelligence and Information Systems
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    • v.16 no.4
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    • pp.113-130
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    • 2010
  • During the decades, considerable human interventions to comprehend the web information were increased continually. The successful expansion of the web services made it more complex and required more contributions of the users. Many researchers have tried to improve the comprehension ability of computers in supporting an intelligent web service. One reasonable approach is enriching the information with machine understandable semantics. They applied ontology design, intelligent reasoning and other logical representation schemes to design an infrastructure of the semantic web. For the features, the semantic web is considered as an intelligent access to understanding, transforming, storing, retrieving, and processing the information gathered from heterogeneous, distributed web resources. The goal of this study is firstly to explore the problems that restrict the applications of web services and the basic concepts, languages, and tools of the semantic web. Then we highlight some of the researches, solutions, and projects that have attempted to combine the semantic web and business support, and find out the pros and cons of the approaches. Through the study, we were able to know that the semantic web technology is trying to offer a new and higher level of web service to the online users. The services are overcoming the limitations of traditional web technologies/services. In traditional web services, too much human interventions were needed to seek and interpret the information. The semantic web service, however, is based on machine-understandable semantics and knowledge representation. Therefore, most of information processing activities will be executed by computers. The main elements required to develop a semantic web-based business support are business logics, ontologies, ontology languages, intelligent agents, applications, and etc. In using/managing the infrastructure of the semantic web services, software developers, service consumers, and service providers are the main representatives. Some researchers integrated those technologies, languages, tools, mechanisms, and applications into a semantic web services framework. Therefore, future directions of the semantic web-based business support should be start over from the infrastructure.

Integration Process of Federation Object Model for Interoperation of Federations (페더레이션 연동을 위한 객체 모델 통합 프로세스)

  • Kwon, Se Jung;Yu, Minwook;Kim, Tag Gon
    • Journal of the Korea Society for Simulation
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    • v.26 no.2
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    • pp.1-8
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    • 2017
  • High Level Architecture(HLA) is a specification for interoperation among heterogeneous simulators which are executed in a distributed environment. HLA originally allows many federates to join in a federation using a single RTI(Run-Time Infrastructure). As the target systems become more complex, the need for the interoperation of federations, performed in a RTI-RTI interoperation environment, has been growing. It can be performed by the confederation interface with the agents, which subrogate the API calls and callbacks of each federation. The existing studies have assumed that the object models of each federation are based on same HLA standard and their object descriptions are equal. Because the existing federations are usually not under this assumption, this paper proposes the integration process of object models for the federation interoperation environment. To integrate the object models for the interoperation of federations, this process resolves the differences of HLA standards, provides conversion process between objects with different descriptions and excludes the security objects. We expect that this process enhances the reusability and effectiveness of interoperation of federations in various domains.

The role of the middle term in the integration of the two premises in linear syllogistic reasoning (선형 삼단 논법의 두 전제 통합 과정에서 중간 항목의 역할)

  • 정혜선;조명한
    • Korean Journal of Cognitive Science
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    • v.12 no.3
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    • pp.29-46
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    • 2001
  • This study attempted to demonstrate that the integration of the two premises in linear syllogism is mediated by the middle term the term that is repeated in the two premises. In Experiment 1. we examined whether representing the middle term is more important than representing the end terms. We asked a question to each premise. Depending on the order of the questions either the two end terms or the middle term became the answer in both premises. Participants solved the problems better when the middle term became the answer suggesting that it is more important to represent the middle term than the end terms. In Experiment 2 we examined whether additional processing is needed for the integration beyond establishing co-referential link through the middle term. We pronominalized the middle term in the second premise and provided two kinds of information to disambiguate the pronoun. In the direct information condition we provided information about who the pronoun is whereas in the indirect information condition we provided information about the relative location of the pronoun. Participants solved the problems more quickly in the indirect information condition than in the direct information condition indicating that mere co-referential link was not enough and that the relative location of the middle term needs to be computed for the integration of the two premises.

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Identification of Matrix Mineralization-Related Genes in Human Periodontal Ligament Cells Using cDNA Microarray (cDNA microarray에 의한 치주인대세포의 광물화 결절형성에 관여하는 유전자들의 분석)

  • Shin, Jae-Hee;Park, Jin-Woo;Yeo, Shin-Il;Noh, Woo-Chang;Kim, Moon-Kyu;Kim, Jung-Chul;Suh, Jo-Young
    • Journal of Periodontal and Implant Science
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    • v.37 no.sup2
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    • pp.447-463
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    • 2007
  • Periodontal ligament (PDL) cells have been known as multipotential cells, and as playing an important rolesin periodontal regeneration. The PDL cells are composed of heterogeneous cell populations which have the capacity to differentiate into either cementoblasts or osteoblasts, depending on needs and conditions. Therefore, PDL cells have the capacity to produce mineralized nodules in vitro in mineralization medium which include ascorbic acid, ${\beta}$-glycerophosphate and dexamethasone. In spite of these well-known osteoblast like properties of PDL cells, very little is known about the molecules involved in the formation of the mineralized nodules in the PDL cells. In the present study, we analysed gene-expression profiles during the mineralization process of cultured PDL cells by means of a cDNA microarray consisting of 3063 genes. Nodules of mineralized matrix were strongly stained with alizarin red S on the PDL cells cultured in the media with mineralization supplements. Among 3,063 genes analyzed, 35 were up-regulated more than two-fold at one or more time points in cells that developed matrix mineralization nodules, and 38 were down-regulated to less than half their normal level of expression. In accord with the morphological change we observed, several genes related to calcium-related or mineral metabolism were induced in PDL cells during osteogenesis, such as IGF-II and IGFBP-2. Proteogycan 1, fibulin-5, keratin 5, ,${\beta}$-actin, ${\alpha}$-smooth muscle actin and capping protein, and cytoskeleton and extracellular matrix proteins were up-regulated during mineralization. Several genes encoding proteins related to apoptosis weredifferentially expressed in PDL cells cultured in the medium containing mineralization supplements. Dkk-I and Nip3, which are apoptosis-inducing agents, were up-regulated, and Btf and TAXlBP1, which have an anti-apoptosis activity, were down-regulated during mineralization. Also periostin and S100 calciumbinding protein A4 were down-regulated during mineralization.

Detection of Campylobacter jejuni in food and poultry visors using immunomagnetic separation and microtitre hybridization

  • Simard, Ronald-E.
    • Proceedings of the Korean Society of Fisheries Technology Conference
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    • 2000.05a
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    • pp.71-73
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    • 2000
  • Campylobacter jejuni is most frequently identified cause of cause of acute diarrhoeal infections in developeed countries, exceeding rates of illness caused by both salmonella and shigilla(Skirrow, 1990 ; Lior 1994). Previous studies on campylobacter jejuni contamination of commercial broiler carcasses in u.s.(Stern, 1992). Most cases of the disease result from indirect transmission of Campylobactor from animals via milk, water and meat. In addition to Campylobactor jejuni. the closely relates species Campylobactor coli and Campylobactor lari have also been implicated as agents of gastroenteritis in humans. Campylobactor coli represented only approximately 3% of the Campylobactor isolates from patients with Campylobactor enteritis(Griffiths and Park, 1990) whereas Campylobactor coli is mainly isolated from pork(Lmmerding et al., 1988). Campylobactor jejuni has also been isolated from cases of bacteremia, appendicitis and, recently, has been associated with Guillai-Barre syndrome(Allos and Blaser, 1994; von Wulffen et al., 1994; Phillips, 1995). Studies in volunteers indicated that the infectious dose for Campylobactor jejuni is low(about 500 organisms)(Robinson, 1981). The methods traditionally used to detect Campylobactor ssp. in food require at least two days of incubation in an enrichment broth followed by plating and two days of incubation on complex culture media containing many antibiotics(Goossens and Butzler, 1992). Finnaly, several biochemical tests must be done to confirm the indentification at the species level. Therfore, sensitive and specific methods for the detection of small numbers of Campylobactor cells in food are needed. Polymerase chain reaction(PCR) assays targeting specific DNA sequences have been developed for the detection of Campylobactor(Giesendorf and Quint, 1995; Hemandex et al., 1995; Winter and Slavidk, 1995). In most cases, a short enrichment step is needed to enhance the sensitivity of the assay prior to detection by PCR as the number of bacteria in the food products is low in comparison with those found in dinical samples, and because the complex composition of food matrices can hinder the PCR and lower its sensitivity. However, these PCR systems are technically demanding to carry out and cumbersome when processing a large number of samples simutaneously. In this paper, an immunomagnetic method to concentrate Campylobactor cells present in food or clinical samples after an enrichment step is described. To detect specifically the thermophilic Campylobactor. a monoclonal antibody was adsorbed on the surface of the magnetic beads which react against a major porin of 45kDa present on the surface of the cells(Huyer et al., 1986). After this partial purification and concentration step, detection of bound cells was achieved using a simple, inexpensive microtitre plate-based hybridization system. We examined two alternative detection systems, one specific for thermophilic Campylobactor based on the detection of 23S rRNA using an immobilized DNA probe. The second system is less specific but more sensitive because of the high copy number of the rRNA present in bacterial cell($10^3-10^4$). By using specific immunomagnetic beads against thermophilic Campylobactor, it was possible to concentrate these cells from a heterogeneous media and obtain highly specific hybridization reactions with good sensitivity. There are several advantages in using microtitre plates instead of filter membranes or other matrices for hybridization techniques. Microtitre plates are much easier to handle than filter membranes during the adsorption, washing, hybridization and detection steps, and their use faciilitates the simultanuous analysis of multiple sample. Here we report on the use of a very simple detection procedure based on a monoclonal anti-RNA-DNA hybrid antibody(Fliss et al., 1999) for detection of the RNA-DNA hybrids formed in the wells.

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