The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Noboru Takasaki - One of the best experts on this subject based on the ideXlab platform.
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Sensitization interval and administration method alter the effect of 15-Deoxyspergualin on heart transplantation in sensitized recipient rats
Transplant International, 1996Co-Authors: Haruhiko Ueda, S. Itoh, Yusaku Iwamoto, Noboru TakasakiAbstract:We evaluated the effect of 15-Deoxyspergualin (DSG) on accelerated rejection. Brown Norway rats (BN) served as organ donors and Lewis rats (LEW) as recipients. In an accelerated rejection model, after a LEW rat was sensitized with BN skin, a BN heart was transplanted. Various intervals between sensitization and heart transplantation were examined. The heart allografts in sensitized recipients were rejected earlier than those in unmodified recipients regardless of the sensitization interval. DSG (2.5 mg/kg per day), given to the recipients during the sensitization phase, significantly prolonged graft survival compared with the untreated hosts when the sensitization interval was short. When the recipients were treated with DSG after heart transplantation, heart graft survival was significantly prolonged regardless of the sensitization interval. Flow cytometric analysis and complement-dependent cytotoxicity tests revealed that DSG suppressed antidonor antibody formation and that postoperative administration of DSG significantly decreased the proliferation of B cells when the sensitization interval was short and the proliferation of class II antigen-positive cells when the sensitization interval was long.
Haruhiko Ueda - One of the best experts on this subject based on the ideXlab platform.
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Sensitization interval and administration method alter the effect of 15-Deoxyspergualin on heart transplantation in sensitized recipient rats
Transplant International, 1996Co-Authors: Haruhiko Ueda, S. Itoh, Yusaku Iwamoto, Noboru TakasakiAbstract:We evaluated the effect of 15-Deoxyspergualin (DSG) on accelerated rejection. Brown Norway rats (BN) served as organ donors and Lewis rats (LEW) as recipients. In an accelerated rejection model, after a LEW rat was sensitized with BN skin, a BN heart was transplanted. Various intervals between sensitization and heart transplantation were examined. The heart allografts in sensitized recipients were rejected earlier than those in unmodified recipients regardless of the sensitization interval. DSG (2.5 mg/kg per day), given to the recipients during the sensitization phase, significantly prolonged graft survival compared with the untreated hosts when the sensitization interval was short. When the recipients were treated with DSG after heart transplantation, heart graft survival was significantly prolonged regardless of the sensitization interval. Flow cytometric analysis and complement-dependent cytotoxicity tests revealed that DSG suppressed antidonor antibody formation and that postoperative administration of DSG significantly decreased the proliferation of B cells when the sensitization interval was short and the proliferation of class II antigen-positive cells when the sensitization interval was long.
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Sensitization interval and administration method alter the effect of 15-Deoxyspergualin on heart transplantation in sensitized recipient rats.
Transplant international : official journal of the European Society for Organ Transplantation, 1996Co-Authors: Haruhiko Ueda, S. Itoh, Yusaku Iwamoto, Takasaki NAbstract:We evaluated the effect of 15-Deoxyspergualin (DSG) on accelerated rejection. Brown Norway rats (BN) served as organ donors and Lewis rats (LEW) as recipients. In an accelerated rejection model, after a LEW rat was sensitized with BN skin, a BN heart was transplanted. Various intervals between sensitization and heart transplantation were examined. The heart allografts in sensitized recipients were rejected earlier than those in unmodified recipients regardless of the sensitization interval. DSG (2.5 mg/kg per day), given to the recipients during the sensitization phase, significantly prolonged graft survival compared with the untreated hosts when the sensitization interval was short. When the recipients were treated with DSG after heart transplantation, heart graft survival was significantly prolonged regardless of the sensitization interval. Flow cytometric analysis and complement-dependent cytotoxicity tests revealed that DSG suppressed antidonor antibody formation and the postoperative administration of DSG significantly decreased the proliferation of B cells when the sensitization interval was short and the proliferation of class II antigen-positive cells when the sensitization interval was long.
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Effect of 15-Deoxyspergualin on accelerated rejection in rat heart transplantation
European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes, 1994Co-Authors: Haruhiko Ueda, S. Itoh, H. Azuma, K. Isurugi, C. YutaniAbstract:The effect of 15-Deoxyspergualin (DSG) on accelerated rejection was evaluated using a rat heart transplantation model. Lewis rats (LEW, RT1l) served as the organ recipient and Brown Norway rats (BN, RT1n) as the donor. In the accelerated rejection model, the LEW recipient was sensitized with BN skin and BN heart was transplanted 7 days later; the heart graft was rejected within 2 days (n = 7). Histologically, the graft showed coagulation necrosis and hemorrhage throughout the myocardium. DSG (2.5 mg/kg/day) was administered to the recipient under the following three protocols: group 1: during the sensitization period (7 days); group 2: from 3 days after the sensitization to 2 days after grafting (7 days), and group 3: immediately after heart transplantation. The mean graft survival period in groups 1, 2, and 3 was 4.3 +/- 0.8 days (n = 7, p < 0.01 vs untreated host), 11.7 +/- 2.1 days (n = 7, p < 0.001, vs. untreated host), and 2.0 +/- 0 days (n = 6), respectively. The rejected grafts in groups 1 and 3 histologically showed coagulation necrosis and hemorrhage. By contrast, in group 2, the major histological change was interstitial lymphocyte infiltration and there were few findings such as coagulation necrosis or hemorrhage. In the complement-dependent cytotoxicity test, serum obtained at the second posttransplant day from the recipients treated in group 1 showed a high cytotoxicity level, although the cytotoxicity level of serum obtained from the recipients treated in group 2 was consistently low.(ABSTRACT TRUNCATED AT 250 WORDS)
Renaut Patrice - One of the best experts on this subject based on the ideXlab platform.
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a new efficient synthesis of the immunosuppressive agent 15 Deoxyspergualin
Tetrahedron, 2001Co-Authors: Philippe Durand, Philippe Peralba, Renaut PatriceAbstract:Abstract (±)-15-Deoxyspergualin is a new promising immunosuppressive agent, recently marketed in Japan for the control of corticoresistant acute renal graft rejection. We describe here a nine-step synthesis starting from 7-bromoheptanenitrile and N1,N4-bis(benzyloxycarbonyl)spermidine, suitable for the production of multigram quantities of this unstable highly polar compound with an 18% overall yield. Furthermore, it opens the way for the synthesis of α-hydroxyglycine analogues.
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Structure-immunosuppressive activity relationships of new analogues of 15-Deoxyspergualin. 2. Structural modifications of the spermidine moiety.
Journal of medicinal chemistry, 1999Co-Authors: Luc Lebreton, Eric Jost, Bertrand Carboni, Jocelyne Annat, Michel Vaultier, Patrick Dutartre, Renaut PatriceAbstract:A series of new analogues of 15-Deoxyspergualin (DSG), an immunosuppressive agent commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Various substitutions of the spermidine “D” region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. Various positions of methylation were first investigated leading to the discovery of the monomethylated malonic derivative 56h in which the pro-R hydrogen of the methylene α to the primary amine of the spermidine moiety has been replaced by a methyl group. Synthesis of the similarly methylated analogue of the previously reported glycolic derivative LF 08-0299 afforded 60e which demonstrated a powerful activity at a dose as low as 0.3 mg/kg in the GVHD model and was much more potent than DSG in the demanding heart allotransplantation model in rats. The improvement of in vivo activity was supposed to be related to an increase of the metabolic stability of the methylated ana...
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15 Deoxyspergualin a new and efficient enantioselective synthesis which allows the definitive assignment of the absolute configuration
Journal of Organic Chemistry, 1998Co-Authors: Philippe Durand, Philippe Richard, Renaut PatriceAbstract:(±)-15-Deoxyspergualin (DSG) has recently been marketed in Japan for the control of corticoresistant acute renal graft rejection. A nine-step total synthesis of its eutomer ((−)-DSG) 2 has been developed starting from 7-bromoheptanenitrile 3 and N1,N4-bis(benzyloxycarbonyl)spermidine. The use of a chiral α-alkylbenzyl group to protect the hydroxyl of the α-hydroxyglycine moiety allowed its chromatographic resolution and afforded a practical access to 2 with a high optical purity and a 7% overall yield. Moreover, X-ray structure analysis of the key crystalline intermediate 7b definitely confirmed the previously proposed absolute configuration of 2.
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(−)-15-Deoxyspergualin: A New and Efficient Enantioselective Synthesis Which Allows the Definitive Assignment of the Absolute Configuration
The Journal of Organic Chemistry, 1998Co-Authors: Philippe Durand, Philippe Richard, Renaut PatriceAbstract:(±)-15-Deoxyspergualin (DSG) has recently been marketed in Japan for the control of corticoresistant acute renal graft rejection. A nine-step total synthesis of its eutomer ((−)-DSG) 2 has been developed starting from 7-bromoheptanenitrile 3 and N1,N4-bis(benzyloxycarbonyl)spermidine. The use of a chiral α-alkylbenzyl group to protect the hydroxyl of the α-hydroxyglycine moiety allowed its chromatographic resolution and afforded a practical access to 2 with a high optical purity and a 7% overall yield. Moreover, X-ray structure analysis of the key crystalline intermediate 7b definitely confirmed the previously proposed absolute configuration of 2.
Takashi Ohmoto - One of the best experts on this subject based on the ideXlab platform.
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Xenogeneic dopaminergic grafts reverse behavioral deficits induced by 6-OHDA in rodents : effect of 15-Deoxyspergualin treatment
Neuroscience letters, 1993Co-Authors: Jiawei Zhou, Isao Date, Kyoji Sakai, Yusuke Yoshimoto, Tomohisa Furuta, Shoji Asari, Takashi OhmotoAbstract:Foetal rat mesencephalic dopamine-containing tissue was transplanted into the lateral ventricle of mice previously subjected to a 6-OHDA lesion of dopaminergic nerve terminals in the corpus striatum. The graft recipients were immunosuppressed by subcutaneous injections of 15-Deoxyspergualin (DSG). Four weeks postgrafting, all DSG-treated mice showed partial or complete functional compensation in amphetamine-induced motor asymmetry. The immunohistochemical staining of tyrosine hydroxylase (TH) revealed large numbers of surviving dopamine neurons and abundant fibers in the grafted animals. In contrast, all grafts in non-DSG-treated animals were rejected and functional compensation was lacking. It is concluded that DSG treatment promotes xenogeneic intracerebral graft survival, recovery of function and reduce the histological sign of rejection.
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Suppression of immunorejection against rat fetal dopaminergic neurons in a mouse brain by 15-Deoxyspergualin
Brain research, 1993Co-Authors: Jiawei Zhou, Isao Date, Kyoji Sakai, Yusuke Yoshimoto, Tomohisa Furuta, Shoji Asari, Takashi OhmotoAbstract:In this study, the immunosuppressive effect of 15-Deoxyspergualin (DSG) on the survivability of rat embryonic dopaminergic neurons grafted into the lateral ventricle of adult mice was investigated. DSG was administered daily in dose of 5 mg/kg for 2 weeks postgrafting, commencing on the day of transplantation, in the immunosuppressant-treated groups. Animals were then allowed to survive for 2 to 4 weeks after transplantation. Histological analysis revealed that most of transplanted rat fetal neural tissue was destroyed and scavenged in 2 weeks after transplantation in the non-immunosuppressed group. However, a large number of tyrosine hydroxylase (TH)-positive grafted neurons survived and grew postgrafting in the brain of the host administered with DSG even if they suffered from T lymphocyte infiltrations visualized by cytotoxic T cell immunohistochemistry. The results thus indicated that DSG is an potent immunosuppressant in neural transplantation as well as in transplantation of other organs in animals. It seems to be able to block, at least in part, the ability of mature specific cytotoxic T cells to lyse their targets.
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suppression of immunorejection against rat fetal dopaminergic neurons in a mouse brain by 15 Deoxyspergualin
Brain Research, 1993Co-Authors: Jiawei Zhou, Isao Date, Kyoji Sakai, Yusuke Yoshimoto, Tomohisa Furuta, Shoji Asari, Takashi OhmotoAbstract:Abstract In this study, the immunosuppressive effect of 15-Deoxyspergualin (DSG) on the survivability of rat embryonic dopaminergic neurons grafted into the lateral ventricle of adult mice was investigated. DSG was administered daily in dose of 5 mg/kg for 2 weeks postgrafting, commencing on the day of transplantation, in the immunosuppressant-treated groups. Animals were then allowed to survive for 2 to 4 weeks after transplantation. Histological analysis revealed that most of transplanted rat fetal tissue was destroyed and scavenged in 2 weeks after transplantation in the non-immunosuppressed group. However, a large number of tyrosine hydroxylase (TH)-positive grafted neurons survived and grew postgrafting in the brain of the host administered with DSG even if they suffered from T lymphocyte infiltrations visualized by cytotoxic T cell immunohistochemistry. The results thus indicated that DSG is an potent immunosuppressant in neural transplantation as well as in transplantation of other organs in animals. It seems to be able to block, at least in part, the ability of mature specific cytotoxic T cells to lyse their target.
Tomio Takeuchi - One of the best experts on this subject based on the ideXlab platform.
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15-Deoxyspergualin Inhibits Akt Kinase Activation and Phosphatidylcholine Synthesis
The Journal of biological chemistry, 2002Co-Authors: Manabu Kawada, Masaaki Ishizuka, Tohru Masuda, Tomio TakeuchiAbstract:15-Deoxyspergualin (DSG) strongly inhibited growth of mouse EL-4 lymphoma cells in vitro and in vivo. It significantly prolonged the survival days of EL-4-transplanted mice. In vitro study revealed that its antiproliferative effect appeared only after 2 days of treatment. At that time, protein synthesis was significantly inhibited rather than DNA and RNA syntheses. Furthermore, DSG induced apoptosis without arresting the cell cycle. p70 S6 kinase (p70S6K), a key molecule in protein synthesis, was inhibited by 2 days of treatment of DSG. Akt, an upstream kinase of p70S6K, was also deactivated by 2 days of treatment of DSG. Hsp90 is reported to bind to and stabilize Akt kinase and also to bind to DSG. Yet DSG did not inhibit the binding of Hsp90 to Akt kinase. PI3-kinase, an activator of Akt, was not affected by DSG treatment. However, when we looked into phospholipid synthesis, we found that DSG inhibited phosphatidylcholine (PC) synthesis strongly rather than phosphatidylinositol even by 1 day of treatment. Moreover, DSG failed to inhibit Akt kinase activation and PC synthesis in DSG-less sensitive human K562 leukemia cells. These results demonstrate that DSG inhibits tumor cell growth through the inhibition of protein synthesis and induction of apoptosis, which is caused by the down-regulation of Akt kinase and p70S6K. It is also indicated that the down-regulation of Akt kinase by DSG should not depend on PI3-kinase and Hsp90. There might be possible involvement of PC in Akt kinase activity.
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The long-lasting antiproliferative effect of 15-Deoxyspergualin through its spermidine moiety.
The Journal of antibiotics, 2000Co-Authors: Manabu Kawada, Masaaki Ishizuka, Tetsuya Someno, Hironobu Iinuma, Tohru Masuda, Tomio TakeuchiAbstract:15-Deoxyspergualin (DSG) inhibited growth of mouse EL-4 lymphoma cells with an IC50 0.02 μg/ml. Even though the cells were treated with DSG for only 4 hours and then washed, the antiproliferative effect lasted long with an IC50 0.4μg/ml. DSG has spermidine and guanidine moieties in its structure. One decomposed element containing guanidine moiety inhibited the growth at higher doses than DSG, but the effect did not last long unlike DSG. While another element containing spermidine moiety did not affect the growth, it diminished the long-lasting antiproliferative effect of DSG by pretreatment of the cells. Pretreatment with polyamines such as putrescine, spermidine, and spermine also diminished the effect of DSG. Furthermore, N-alkylation of spermidine moiety in DSG abolished the antiproliferative effect. These results suggested that DSG binds to the cells through its spermidine moiety and exerts its long-lasting antiproliferative effect.
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inhibition of nitric oxide synthase induction by 15 Deoxyspergualin in a cultured macrophage cell line j744a 1 activated with ifn γ and lps
The Journal of Antibiotics, 1999Co-Authors: Chisato Nosaka, Setsuko Kunimoto, Sonoko Atsumi, Tomio TakeuchiAbstract:Immunosuppressant 15-Deoxyspergualin (DSG) inhibited induction of inducible nitric oxide synthase (iNOS) following stimulation with IFN-γ and LPS in a cultured macrophage cell line, J744A.1. By DSG treatment NQ2- accumulation in the medium was blocked, and cellular iNOS protein level decreased as shown by Western blotting. DSG didn't have any direct effect on iNOS activity. DSG was not used as a substrate of NOS in in vitro enzyme systems, and it was too weak an inhibitor of iNOS and cNOS to cause the inhibition of accumulation of NO2-. DSG did not scavenge NO spontaneously generated from NOR. Structure-activity relationships of analogs and decomposed elements showed that there is correlation between the inhibition of iNOS induction and immunosuppressive activity.
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The decrease of cytochrome c oxidase activity by 15-Deoxyspergualin results in enhancement of XTT reduction in cultured cells.
The Journal of antibiotics, 1999Co-Authors: Chisato Nosaka, Setsuko Kunimoto, Tomio TakeuchiAbstract:Exposure to immunosuppressant, 15-Deoxyspergualin (DSG) induced enhanced formazan producing activity from XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carb oxanilide, sodium salt) in cultured cells, but not from MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Formazan generation from XTT is known to be stimulated by cytochrome c oxidase (COX) inhibitors such as KCN and NaN3, whereas MTT reduction is not affected by them. So, the effect of DSG on COX was examined. DSG did not directly inhibit the enzyme, but the cellular enzyme activity was decreased by exposure to DSG. It was thought that stimulation of XTT reduction by DSG resulted from the decrease of cellular cytochrome c oxidase activity.
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Inhibition of Nitric Oxide Synthase Induction by 15-Deoxyspergualin in a Cultured Macrophage Cell Line, J744A.1 Activated with IFN-γ and LPS
The Journal of antibiotics, 1999Co-Authors: Chisato Nosaka, Setsuko Kunimoto, Sonoko Atsumi, Tomio TakeuchiAbstract:Immunosuppressant 15-Deoxyspergualin (DSG) inhibited induction of inducible nitric oxide synthase (iNOS) following stimulation with IFN-gamma and LPS in a cultured macrophage cell line, J774A.1 [corrected]. By DSG treatment NO2- accumulation in the medium was blocked, and cellular iNOS protein level decreased as shown by Western blotting. DSG didn't have any direct effect on iNOS activity. DSG was not used as a substrate of NOS in in vitro enzyme systems, and it was too weak an inhibitor of iNOS and cNOS to cause the inhibition of accumulation of NO2-. DSG did not scavenge NO spontaneously generated from NOR. Structure-activity relationships of analogs and decomposed elements showed that there is correlation between the inhibition of iNOS induction and immunosuppressive activity.
