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2.
Environ Sci Pollut Res Int ; 28(1): 326-335, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32812152

ABSTRACT

Although the debromination of polybrominated diphenyl ethers (PBDEs) in fish species has been studied, environmental factors, such as chemical contamination and habitat temperature, have not been well understood. This study compared debromination of BDE209 by hepatic microsomes of wild and cultured fish. PBDE concentrations in muscle tissue were lower in cultured fish than in wild fish. Debromination activity was high in wild common carp, followed by cultured common carp, moderate in cultured ayu sweetfish, and low in two cultured fish (rainbow trout and cherry salmon) and wild Japanese sea bass. Although common carps have been known as the species which have higher debromination ability, there were differences between wild and cultured common carps. First, wild common carp debrominated much more BDE209 than cultured common carp. Second was debromination of BDE209 lasted 96 h in wild carp but only 24 h in cultured carp. Wild carp were collected from warm wastewater effluent with consistently high concentrations of micropollutants. Cultured carp were collected from colder clean waters. Therefore, environmental factors in debromination include contamination or ambient temperature. To investigate the effects of habitat environment on debromination of PBDEs, we collected wild carp in summer and winter at two different locations with similar PBDE contamination levels. Carp collected from the natural river in winter had the highest BDE99 debromination activity. Although the results indicated seasonal difference of debromination of BDE209, we could not confirm whether habitat temperature or physiological cycle of carp affected to debromination ability. Thus, further investigation such as in vivo experiment is required.


Subject(s)
Carps , Water Pollutants, Chemical , Animals , Fresh Water , Halogenated Diphenyl Ethers/analysis , Microsomes, Liver/chemistry , Water Pollutants, Chemical/analysis
3.
Transplantation ; 99(8): 1598-605, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25769064

ABSTRACT

BACKGROUND: Antibody-mediated rejection is caused in part by increasing circulation/production of donor-specific antibody (DSA). Activation-induced cytidine deaminase (AID) is a key regulator of class switch recombination and somatic hypermutation of immunoglobulin in B cells, yet its role in antibody-mediated transplant rejection remains unclear. We show here that AID deficiency in mice enables suppression of allograft vasculopathy (AV) after aorta transplantation, a DSA-mediated process. METHODS: Splenocytes from C57BL/6 J (B6) AID(−/−) mice were used for determining in vitro proliferation responses, alloreactivity, cell surface marker expression, and antibody production. BALB/c mouse aortas were transplanted into B6 AID(−/−) mice with or without FK506 treatment. Blood and aorta grafts were harvested on day 30 after transplantation and were subjected to DSA, histological, and immunohistological analyses. RESULTS: The AID(−/−) splenocytes were comparable to wild type splenocytes in proliferation responses, alloreactivity, and expression of cell surface markers in vitro. However, they completely failed to produce immunoglobulin G, although they were not impaired in immunoglobulin M production relative to controls. Furthermore, BALB/c aorta grafts from B6 AID(−/−) recipient mice on day 30 after transplantation showed reduced signs of AV compared to the grafts from B6 wild type recipient mice which had severe vascular intimal hyperplasia, interstitial fibrosis, and inflammation. Treatment with FK506 produced a synergistic effect in the grafts from AID(−/−) recipients with further reduction of intimal hyperplasia and fibrosis scores. CONCLUSIONS: The AID deficiency inhibits DSA-mediated AV after aorta transplantation in mice. We propose that AID could be a novel molecular target for controlling antibody-mediated rejection in organ transplantation.


Subject(s)
Aorta/transplantation , B-Lymphocytes/enzymology , Composite Tissue Allografts/transplantation , Cytidine Deaminase/deficiency , Graft Rejection/prevention & control , Immunoglobulin G/blood , Isoantibodies/blood , Spleen/enzymology , Animals , Aorta/drug effects , Aorta/immunology , Aorta/metabolism , Aorta/pathology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Cell Proliferation , Cells, Cultured , Composite Tissue Allografts/immunology , Composite Tissue Allografts/pathology , Cytidine Deaminase/genetics , Fibrosis , Graft Rejection/enzymology , Graft Rejection/immunology , Graft Rejection/pathology , Hyperplasia , Immunoglobulin G/immunology , Immunosuppressive Agents/pharmacology , Isoantibodies/immunology , Lymphocyte Activation , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Neointima , Signal Transduction , Spleen/immunology , Time Factors
4.
Sci Total Environ ; 449: 401-9, 2013 Apr 01.
Article in English | MEDLINE | ID: mdl-23454701

ABSTRACT

By field sampling and laboratory experiments we compared the mechanisms by which polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are biomagnified. We measured PBDEs and PCBs, together with stable carbon and nitrogen isotopes as an index of trophic level, in low-trophic-level organisms collected from a coastal area in Tokyo Bay. PBDEs were biomagnified to a lesser degree than PCBs. The more hydrophobic congeners of each were biomagnified more. However, the depletion of BDE congeners BDE99 and BDE153 from fish was suggested. To study congener-specific biotransformation of halogenated compounds, we conducted an in vitro experiment using hepatic microsomes of two species of fish and five BDE congeners (BDE47, 99, 100, 153, and 154) and five CB congeners with the same substitution positions as the PBDEs. BDE99 and 153 were partially debrominated, but BDE47 and 154 were not debrominated. This congener-specific debromination is consistent with the field results. Both in vitro and field results suggested selective debromination at the meta position. The CB congeners were not transformed in vitro. This result is also consistent with the field results, that PCBs were more biomagnified than PBDEs. We conclude that metabolizability is an important factor in the biomagnification of chemicals, but other factors must be responsible for the lower biomagnification of PBDEs in natural ecosystems.


Subject(s)
Bromine/chemistry , Polybrominated Biphenyls/chemistry , Water Pollutants, Chemical/chemistry , Animals , Chromatography, Gel , Ecosystem , Ethers/chemistry , Fishes , Mass Spectrometry , Microsomes/metabolism , Tokyo
5.
Transpl Immunol ; 27(2-3): 75-82, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22732363

ABSTRACT

Whole genome gene expression profiles were correlated with renal function and histology in a well-established animal model of chronic allograft nephropathy (CAN). Kidneys of F344 rats were transplanted into LEW recipients treated with a brief dose of FK506 (BFK). Blood and urine samples were collected weekly. Kidney grafts were harvested at an early (day 6) or late (days 30-90) phase after transplantation. BFK kidney grafts showed remarkable changes in function, histology, and gene expression profiles when compared to the isograft controls. In the early phase, renal function and histology were barely affected, yet the expression levels of 225 genes were significantly changed, reflecting both immune and non-immune pathways. In the late phase, however, 826 genes were affected in the BFK kidney grafts, including genes in the pathways of extracellular matrix and cell adhesion. Of these genes, 214 appear to be key factors for development of CAN, since they were affected at both early and late phases, including genes involved in the immune response, the inflammatory response, apoptosis, and metabolism. Kinetic studies with gene expression profiling can identify genes involved in the progressive development of chronic allograft rejection, leading to more detailed therapeutic approaches or useful biomarkers in clinical transplantation.


Subject(s)
Graft Rejection/genetics , Kidney Transplantation , Postoperative Complications/genetics , Animals , Cell Adhesion/genetics , Disease Models, Animal , Gene Expression Profiling , Graft Rejection/etiology , Graft Rejection/immunology , Graft Rejection/prevention & control , Humans , Immunity/genetics , Male , Microarray Analysis , Oligonucleotide Array Sequence Analysis , Postoperative Complications/immunology , Postoperative Complications/prevention & control , Rats , Rats, Inbred F344 , Rats, Inbred Lew , Tacrolimus/administration & dosage
6.
Transplantation ; 90(12): 1299-306, 2010 Dec 27.
Article in English | MEDLINE | ID: mdl-21076380

ABSTRACT

BACKGROUND: Monocarboxylate transporter (MCT)-1, a member of a family of molecules, transports monocarboxylates such as lactate. Inhibiting MCT-1 leads to long-term graft survival in rodent heart transplantation and induces tolerance. We evaluated an MCT-1 inhibitor, AS2495674, in a rat heart transplant model and analyzed its underlying mechanism. METHODS: AS2495674 was tested on rat lymphocytes to determine its effect on lactate accumulation, proliferation, and immunoglobulin production. The effect of AS2495674 on graft survival was tested on the Brown Norway to Lewis rat strain combination with a second heart transplantation to test donor-specific suppression. Histology and ex vivo analyses were done to examine the AS2495674 effects on the immune response. RESULTS: In vitro, AS2495674 resulted in lactate accumulation, inhibited lymphocyte proliferation, and prevented immunoglobulin production. AS2495674 induced long-term allograft survival with little evidence of chronic rejection and induced donor-specific suppression. Evaluation of the allograft and peripheral T lymphocytes from the AS2495674 group compared with that of vehicle showed (1) decreased donor-specific T lymphocyte response, (2) more forkhead box P3+ (Foxp3+) and CD45RA+ cells in the allograft, (3) higher gene expression of chemokines and chemokine receptors in the allograft, and (4) preferential inhibition of Foxp3(-) cells with little or no effect on Foxp3+ cells. CONCLUSIONS: AS2495674 prevents acute rejection, reduces features of chronic rejection, and induces tolerance. Our data suggest that the mechanism of AS2495674 involves generating a tolerogenic graft environment by preferentially targeting T effector cells while sparing the generation of T regulatory cells.


Subject(s)
B-Lymphocytes/immunology , Graft Survival/immunology , Heart Transplantation/immunology , Monocarboxylic Acid Transporters/antagonists & inhibitors , Symporters/antagonists & inhibitors , T-Lymphocytes/immunology , Animals , Graft Survival/drug effects , Heart Transplantation/pathology , Immunoglobulins/biosynthesis , Interferon-gamma/metabolism , Lactates/blood , Lymphocyte Activation , Male , Rats , Rats, Inbred BN , Rats, Inbred Lew , Transplantation, Homologous/immunology
7.
J Antibiot (Tokyo) ; 63(11): 643-7, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20924384

ABSTRACT

We screened actinomycetes capable of converting AS1387392 to AS1429716 and identified those strains capable of hydroxylation. Amycolatopsis azurea JCM 3275 was found to be a particularly efficient strain, capable of converting AS1387392 to AS1429716, with a yield of 44% after 9 h. This strain can metabolize not only the hydroxylation of phenylalanine at the meta and para positions but also the reduction of hydroxyketones, as shown by the isolation of bioconversion products. Examination of more suitable conversion conditions showed that pH 7.8 and 25 °C were the optimum pH and temperature for bioconversion, respectively. We also demonstrated the effect of carbon and nitrogen sources in the culture media on hydroxylation. Using this strain, we were able to efficiently produce AS1429716 as a chemical template. Further derivatization studies may provide more effective, safer immunosuppressants than those that are currently on-market.


Subject(s)
Actinomycetales/metabolism , Immunosuppressive Agents/metabolism , Peptides, Cyclic/metabolism , Carbon/chemistry , Culture Media/chemistry , Hydrogen-Ion Concentration , Hydroxylation , Nitrogen/chemistry , Temperature
8.
J Antibiot (Tokyo) ; 63(11): 633-6, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20588300

ABSTRACT

The novel immunosuppressant AS1387392 has been isolated from Acremonium sp. No. 27082. This compound showed a strong inhibitory effect against mammalian histone deacetylase and T-cell proliferation. Further, AS1387392 showed a good oral absorption, and its plasma concentration was higher than that of FR235222, an analog of AS1387392 that inhibited histone deacetylase previously reported. Given these findings, AS1387392 may represent an important new lead in developing immunosuppressant.


Subject(s)
Acremonium/chemistry , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/drug effects , Immunosuppressive Agents/pharmacology , Peptides, Cyclic/pharmacology , Animals , Cell Proliferation/drug effects , Female , Fermentation , Histone Deacetylase Inhibitors/isolation & purification , Histone Deacetylase Inhibitors/pharmacokinetics , Histone Deacetylases/metabolism , Humans , Immunosuppressive Agents/isolation & purification , Male , Mice , Mice, Inbred BALB C , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/pharmacokinetics , Rats , Rats, Inbred Lew , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism
9.
Biol Pharm Bull ; 31(9): 1723-6, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18758066

ABSTRACT

Histone deacetylase (HDAC) is a known modulator of gene transcription, and the immunosuppressive activity of HDAC inhibitors has been demonstrated in recent several reports. In this study, the HDAC inhibitor FR276457, a hydroxamic derivative, was found to have a similar inhibitory effect on all mammalian HDACs tested, but no isozyme selectivity. Both FR276457 and tacrolimus exerted an immunosuppressive effect on in vitro rat splenocyte proliferation stimulated with Concanavalin A. Next, the effect of FR276457 on allograft rejection when administered either as a monotherapy or in combination with tacrolimus was investigated in a rat heterotopic cardiac transplant model. Orally administered FR276457 prolonged the median survival times (MST) of the transplanted grafts in the vehicle group from 6 d to 17 or 21 d at doses of 20 or 40 mg/kg, respectively. Histopathological analysis showed the structures of the myocardium were not affected, but interstitial cellular infiltration could not be suppressed completely. Tacrolimus (0.032 mg/kg) prolonged allograft MST to 16 d. FR276457, when combined with tacrolimus, prevented allograft rejection at a dose lower than that of the monotherapy. The combination dose prolonged the MST in the groups treated with 10 and 20 mg/kg to >28 d, and cellular infiltration was suppressed completely. In conclusion, this study demonstrated that the oral administration of HDAC inhibitor FR276457 can prevent allograft rejection as a monotherapy, and has additive or synergistic effects when combined with tacrolimus.


Subject(s)
Heart Transplantation/immunology , Histone Deacetylase Inhibitors , Hydroxamic Acids/pharmacology , Immunosuppressive Agents/pharmacology , Animals , Cell Proliferation/drug effects , Female , Graft Rejection/pathology , Graft Rejection/prevention & control , Graft Survival/drug effects , Histone Deacetylases/genetics , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics , Myocardium/pathology , Rats , Rats, Inbred Lew , T-Lymphocytes/drug effects , Tacrolimus/pharmacology
10.
Biol Pharm Bull ; 31(2): 305-8, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18239292

ABSTRACT

Histone deacetylase (HDAC) inhibitors repress interleukin-2 (IL-2) gene expression in T cells and possess immunosuppressive activity in vivo. In addition to its immunosuppressive activity, HDAC inhibitors block GATA binding protein-1 (GATA-1) gene expression in megakaryocytes and elicit thrombocytopenia. In this report we state that for a given immunosuppressive dose of HDAC inhibitor, the ratio of GATA-1 reporter gene activity relative to IL-2 reporter gene assay (G/I ratio of measured IC(50)) can be predictive of a HDAC inhibitor's thrombocytopenic effect. This study utilized nine HDAC inhibitors at a minimal effective dose in a rat heterotopic cardiac transplantation model and the resultant G/I ratios and platelet depletion rates were highly correlated (r=0.933). These results indicate that calculation of G/I ratio can be a novel method for selecting immunosuppressive HDAC inhibitor having minimal thrombocytopenic effect which will benefit the search for new immunosuppressants of greater safety and efficacy.


Subject(s)
Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Immunosuppressive Agents/pharmacology , Thrombocytopenia/chemically induced , Animals , Cell Survival/drug effects , Drug Evaluation, Preclinical , Enzyme Inhibitors/adverse effects , GATA1 Transcription Factor/genetics , Genes, Reporter/drug effects , Heart Transplantation/immunology , Humans , Immunosuppressive Agents/adverse effects , Interleukin-2/genetics , Jurkat Cells , Male , Plasmids/genetics , Rats , Rats, Inbred Lew , Reverse Transcriptase Polymerase Chain Reaction , Structure-Activity Relationship , Tetrazolium Salts , Thiazoles , Thrombocytopenia/blood , Transplantation, Heterotopic/immunology
11.
Genes Genet Syst ; 80(2): 135-9, 2005 Apr.
Article in English | MEDLINE | ID: mdl-16172526

ABSTRACT

Members of the NAC gene family encode plant-specific transcription factors and are widely distributed in plant species. The OsNAC6 gene is one of many NAC genes in rice and has high similarity to genes in the ATAF subfamily. Here we show that OsNAC6 is induced by cold, salt, drought and abscisic acid (ABA). We found that OsNAC6 is also induced by wounding. The response of OsNAC6 to wounding is very rapid and strong. OsNAC6 was also induced by jasmonic acid (JA), a plant hormone that activates defense responses against herbivores and pathogens. Our results imply that OsNAC6, besides having a role in plant adaptation to abiotic stresses, also integrates signals derived from both abiotic and biotic stresses.


Subject(s)
Adaptation, Physiological/genetics , Gene Expression Regulation, Plant , Oryza/genetics , Oryza/physiology , Plant Proteins/genetics , Plant Proteins/physiology , Abscisic Acid/pharmacology , Cold Temperature , Cyclopentanes/pharmacology , Disasters , Oxylipins , Plant Proteins/biosynthesis , Signal Transduction , Sodium Chloride/pharmacology
12.
Mutat Res ; 504(1-2): 101-18, 2002 Jul 25.
Article in English | MEDLINE | ID: mdl-12106651

ABSTRACT

Radioadaptive response is a biological defense mechanism in which low-dose ionizing irradiation elicits cellular resistance to the genotoxic effects of subsequent irradiation. However, its molecular mechanism remains largely unknown. We previously demonstrated that the dose recognition and adaptive response could be mediated by a feedback signaling pathway involving protein kinase C (PKC), p38 mitogen activated protein kinase (p38MAPK) and phospholipase C (PLC). Further, to elucidate the downstream effector pathway, we studied the X-ray-induced adaptive response in cultured mouse and human cells with different genetic background relevant to the DNA damage response pathway, such as deficiencies in TP53, DNA-PKcs, ATM and FANCA genes. The results showed that p53 protein played a key role in the adaptive response while DNA-PKcs, ATM and FANCA were not responsible. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), mimicked the priming irradiation in that the inhibitor alone rendered the cells resistant against the induction of chromosome aberrations and apoptosis by the subsequent X-ray irradiation. The adaptive response, whether it was afforded by low-dose X-rays or wortmannin, occurred in parallel with the reduction of apoptotic cell death by challenging doses. The inhibitor of p38MAPK which blocks the adaptive response did not suppress apoptosis. These observations indicate that the adaptive response and apoptotic cell death constitute a complementary defense system via life-or-death decisions. The p53 has a pivotal role in channeling the radiation-induced DNA double-strand breaks (DSBs) into an adaptive legitimate repair pathway, where the signals are integrated into p53 by a circuitous PKC-p38MAPK-PLC damage sensing pathway, and hence turning off the signals to an alternative pathway to illegitimate repair and apoptosis. A possible molecular mechanism of adaptive response to low-dose ionizing irradiation has been discussed in relation to the repair of DSBs and implicated to the current controversial observations on the expression of adaptive response.


Subject(s)
Adaptation, Physiological/radiation effects , DNA Damage , DNA-Binding Proteins , Adaptation, Physiological/genetics , Animals , Apoptosis/genetics , Apoptosis/radiation effects , Ataxia Telangiectasia Mutated Proteins , Cell Cycle Proteins , Cell Line , Cells, Cultured , DNA/genetics , DNA/metabolism , DNA/radiation effects , Dose-Response Relationship, Radiation , Fanconi Anemia Complementation Group A Protein , Humans , In Situ Nick-End Labeling , Mice , Mice, Knockout , Mice, SCID , Models, Biological , Mutation , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/physiology , Proteins/genetics , Proteins/physiology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/physiology , Tumor Suppressor Proteins
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