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  1. Article ; Online: Selenium and Glutathione-Depleted Rats as a Sensitive Animal Model to Predict Drug-Induced Liver Injury in Humans.

    Goda, Keisuke / Muta, Kyotaka / Yasui, Yuzo / Oshida, Shin-Ichi / Kitatani, Kanae / Takekoshi, Susumu

    International journal of molecular sciences

    2019  Volume 20, Issue 13

    Abstract: Drug-induced liver injury (DILI) is one of the most serious and frequent drug-related adverse events in humans. Selenium (Se) and glutathione (GSH) have a crucial role for the hepatoprotective effect against reactive metabolites or oxidative damage ... ...

    Abstract Drug-induced liver injury (DILI) is one of the most serious and frequent drug-related adverse events in humans. Selenium (Se) and glutathione (GSH) have a crucial role for the hepatoprotective effect against reactive metabolites or oxidative damage leading to DILI. The hepatoprotective capacity related to Se and GSH in rodents is considered to be superior compared to the capacity in humans. Therefore, we hypothesize that Se/GSH-depleted rats could be a sensitive animal model to predict DILI in humans. In this study, Se-deficiency is induced by feeding a Se-deficient diet and GSH-deficiency is induced by l-buthionine-
    MeSH term(s) Animals ; Chemical and Drug Induced Liver Injury/etiology ; Chemical and Drug Induced Liver Injury/metabolism ; Chemical and Drug Induced Liver Injury/pathology ; Disease Models, Animal ; Flutamide/toxicity ; Glutathione/deficiency ; Glutathione/metabolism ; Male ; Oxidative Stress ; Rats ; Selenium/deficiency ; Selenium/metabolism
    Chemical Substances Flutamide (76W6J0943E) ; Glutathione (GAN16C9B8O) ; Selenium (H6241UJ22B)
    Language English
    Publishing date 2019-06-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms20133141
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A pharmacologic increase in activity of plasma transaminase derived from small intestine in animals receiving an acyl CoA: diacylglycerol transferase (DGAT) 1 inhibitor.

    Yokoyama, Hideaki / Kobayashi, Akio / Kondo, Kazuma / Oshida, Shin-Ichi / Takahashi, Tadakazu / Masuyama, Taku / Shoda, Toshiyuki / Sugai, Shoichiro

    The Journal of toxicological sciences

    2018  Volume 43, Issue 2, Page(s) 135–157

    Abstract: Acyl CoA: diacylglycerol acyltransferase (DGAT) 1 is an enzyme that catalyzes the re-synthesis of triglycerides (TG) from free fatty acids and diacylglycerol. JTT-553 is a DGAT1 inhibitor and exhibits its pharmacological action (inhibition of re- ... ...

    Abstract Acyl CoA: diacylglycerol acyltransferase (DGAT) 1 is an enzyme that catalyzes the re-synthesis of triglycerides (TG) from free fatty acids and diacylglycerol. JTT-553 is a DGAT1 inhibitor and exhibits its pharmacological action (inhibition of re-synthesis of TG) in the enterocytes of the small intestine leading to suppression of a postprandial elevation of plasma lipids. After repeated oral dosing JTT-553 in rats and monkeys, plasma transaminase levels were increased but there were neither changes in other hepatic function parameters nor histopathological findings suggestive of hepatotoxicity. Based on the results of exploratory studies for investigation of the mechanism of the increase in transaminase levels, plasma transaminase levels were increased after dosing JTT-553 only when animals were fed after dosing and a main factor in the diet contributing to the increase in plasma transaminase levels was lipids. After dosing JTT-553, transaminase levels were increased in the small intestine but not in the liver, indicating that the origin of transaminase increased in the plasma was not the liver but the small intestine where JTT-553 exhibits its pharmacological action. The increase in small intestinal transaminase levels was due to increased enzyme protein synthesis and was suppressed by inhibiting fatty acid-transport to the enterocytes. In conclusion, the JTT-553-related increase in plasma transaminase levels is considered not to be due to release of the enzymes from injured cells into the circulation but to be phenomena resulting from enhancement of enzyme protein synthesis in the small intestine due to the pharmacological action of JTT-553 in this organ.
    MeSH term(s) Administration, Oral ; Animals ; Diacylglycerol O-Acyltransferase/antagonists & inhibitors ; Diacylglycerol O-Acyltransferase/metabolism ; Dogs ; Enterocytes/enzymology ; Fatty Acids/metabolism ; Intestine, Small/cytology ; Intestine, Small/enzymology ; Intestine, Small/metabolism ; Macaca fascicularis ; Oxazines/administration & dosage ; Oxazines/pharmacology ; Rats, Inbred F344 ; Spiro Compounds/administration & dosage ; Spiro Compounds/pharmacology ; Time Factors ; Transaminases/blood
    Chemical Substances (5'-(4-amino-7,7-dimethyl-2-trifluoromethyl-7H-pyrimido(4,5-b)(1,4)oxazin-6-yl)-2',3'-dihydrospiro(cyclohexane-1,1'-inden)-4-yl)acetic acid ; Fatty Acids ; Oxazines ; Spiro Compounds ; Diacylglycerol O-Acyltransferase (EC 2.3.1.20) ; Transaminases (EC 2.6.1.-)
    Language English
    Publishing date 2018
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 770623-6
    ISSN 1880-3989 ; 0388-1350
    ISSN (online) 1880-3989
    ISSN 0388-1350
    DOI 10.2131/jts.43.135
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1682: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

    Maeba, Takaki / Hirata, Kazuyuki / Kotoku, Masayuki / Seki, Noriyoshi / Maeda, Katsuya / Hirashima, Shintaro / Yamanaka, Hiroshi / Sakai, Takayuki / Obika, Shingo / Hori, Akimi / Hara, Yoshinori / Noji, Satoru / Suwa, Yoshihiro / Yokota, Masahiro / Fujioka, Shingo / Yamaguchi, Takayuki / Katsuda, Yoshiaki / Hata, Takahiro / Miyagawa, Naoki /
    Arita, Kojo / Nomura, Yukihiro / Taniguchi, Toshio / Asahina, Kota / Aratsu, Yusuke / Naka, Yuichi / Adachi, Tsuyoshi / Nomura, Akihiro / Akai, Shota / Oshida, Shin-Ichi / Pai, Sudhakar / Crowe, Paul / Bradley, Erin / Steensma, Ruo / Tao, Haiyan / Fenn, Morgan / Babine, Robert / Li, Xiaolin / Thacher, Scott / Soeta, Takahiro / Ukaji, Yutaka / Shiozaki, Makoto

    Journal of medicinal chemistry

    2024  Volume 67, Issue 2, Page(s) 952–970

    Abstract: A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future ... ...

    Abstract A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.
    Language English
    Publishing date 2024-01-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.3c01933
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 151: Show issues Location:
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    Zs.MB 1: Show issues

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  4. Article ; Online: Relationships between plasma and tissue transaminase activities in rats maintained under different feeding conditions.

    Kobayashi, Akio / Oshida, Shin-ichi / Yamazaki, Yuji / Maekawa, Tatsuya / Kuno, Hideyuki / Sugai, Shoichiro / Sakakibara, Hiroyuki / Shimoi, Kayoko

    The Journal of toxicological sciences

    2010  Volume 35, Issue 5, Page(s) 639–652

    Abstract: In order to verify the nutritional aspect of alterations of the plasma and tissue transaminase activities, rats were fed 4 hr per day for 35 days (the spaced-fed (SF) rats) and the time course of the alterations in plasma and tissue transaminase activity ...

    Abstract In order to verify the nutritional aspect of alterations of the plasma and tissue transaminase activities, rats were fed 4 hr per day for 35 days (the spaced-fed (SF) rats) and the time course of the alterations in plasma and tissue transaminase activity was compared with those in the ad libitum fed (ALF) rats. Plasma transaminase activities were stable throughout the experiment period in the ALF rats. In the SF rats there were alterations in the plasma alanine aminotransferase (ALT) activities, the direction of which was different between the early phase and late phase of the experiment period; plasma ALT activities decreased in the early phase and gradually increased in the late phase. Plasma aspartate aminotransferase (AST) activities were stable in the SF rats throughout the experiment period as well as the ALF rats. The decreases in plasma ALT activities in the early phase were considered to be related to decreases in ALT activities in the small intestinal mucosa (SI mucosa). On the other hand, the increases in plasma ALT activities in the late phase were considered to be related to increases in ALT activities in the liver. Multiple regression analyses (MRAs) revealed that plasma ALT activities in the SF rats could be estimated by the ALT activities in the SI mucosa and liver. From these results, the alterations of the plasma ALT activities in the SF rats could be explained by those in the SI mucosa and liver under the conditions in our study.
    MeSH term(s) Animals ; Body Weight ; Eating ; Feeding Behavior ; Intestinal Mucosa/enzymology ; Intestine, Small/enzymology ; Liver/enzymology ; Male ; Multivariate Analysis ; Organ Specificity ; Rats ; Rats, Sprague-Dawley ; Regression Analysis ; Transaminases/blood ; Transaminases/metabolism
    Chemical Substances Transaminases (EC 2.6.1.-)
    Language English
    Publishing date 2010-10-07
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 770623-6
    ISSN 1880-3989 ; 0388-1350
    ISSN (online) 1880-3989
    ISSN 0388-1350
    DOI 10.2131/jts.35.639
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1682: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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