Yokohama Institute

Yokohama-shi, Japan

Yokohama Institute

Yokohama-shi, Japan
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Bourgeois-Daigneault M.-C.,University of Montréal | Pezeshki A.M.,University of Montréal | Galbas T.,University of Montréal | Houde M.,University of Montréal | And 6 more authors.
Results in Immunology | Year: 2013

In addition to their classical antigen presenting functions, MHC class II molecules potentiate the TLR-triggered production of pro-inflammatory cytokines. Here, we have addressed the effect of Tollip and MARCH1 on the regulation of MHC II trafficking and TLR signaling. Our results show that MARCH1-deficient mice splenocytes are impaired in their capacity to produce pro-inflammatory cytokines in response to poly(I:C) and that TLR3 and MHC II molecules interact in the endocytic pathway. Knocking down Tollip expression in human CIITA+ HeLa cells increased expression of HLA-DR but reduced the proportion of MHC II molecules associated with the CLIP peptide. Truncation of the HLA-DR cytoplasmic tails abrogated the effect of Tollip on MHC class II expression. While overexpression of Tollip did not affect HLA-DR levels, it antagonized the function of co-transfected MARCH1. We found that Tollip strongly reduced MARCH1 protein levels and that the two molecules appear to compete for binding to MHC II molecules. Altogether, our results demonstrate that Tollip regulates MHC class II trafficking and that MARCH1 may represent a new Tollip target. © 2013 Elsevier B.V.


Fu C.-H.,Chang Gung Memorial Hospital at Linkou | Chen W.-T.,Chang Gung University | Chang P.-Y.,Chang Gung Memorial Hospital at Linkou | Chang P.-Y.,Chang Gung University | And 4 more authors.
Biomedical Journal | Year: 2014

Background: In this study, we evaluated the performance of a point-of-care device, the CoaguChek XS Plus system, in the determination of prothrombin time and international normalized ratio (INR) based on ISO17593: 2007 criteria in Taiwanese patients. The underlying clinical and genetic factors were also investigated.Methods: Fifty patients receiving warfarin therapy were enrolled in this study. The accuracy of the CoaguChek XS Plus system was evaluated with linear regression analysis and bias plot by comparing with the data measured using Sysmex CA-1500. The clinical and genetic factors that may have caused a bias of 0.5 INR were evaluated with Fisher's exact test.Results: From the 50 patients, 93 INR values were collected by each method. Linear regression analysis indicated a high correlation with r = 0.96, a slope of 1.05, and an intercept of - 0.14. Eight patients showed an INR bias 0.5 between the two methods. Only aspartate aminotransferase (AST) >34 U/L (3/8, 37.5% vs. 3/42, 7.1%; p = 0.044) and alanine aminotransferase (ALT) >36 U/L (3/8, 37.5% vs. 3/42, 7.1%; p = 0.044) were significantly different from each other. No differences were observed for hypoalbuminemia, elevated creatinine, anemia, and the polymorphisms of VKORC1 and CYP2C9.Conclusions: The CoaguChek XS Plus system presented results that were comparable with those obtained using laboratory CA-1500 method. Both methods fell within INR in the range of 2-4.5 defined by ISO17593:2007 and the clinically recognized therapeutic INR range of 2-3.5. Elevated AST and ALT levels might have interfered with the INR results. © 2014, Biomedical Journal. All Rights Reserved.


Yasumitsu H.,Yokohama City University | Ozeki Y.,Yokohama City University | Kawsar S.M.A.,Yokohama City University | Fujii Y.,Yokohama City University | And 4 more authors.
Electrophoresis | Year: 2010

SDS-PAGE and CBB staining are two of the most popular methods used for protein analysis. Although many reports that describe such staining methods have been published, these conventional protocols require several hours or days for staining and destaining. In this study we describe a recently developed, fast and sensitive CBB staining method that utilizes the staining solution of RAMA that consists of the low-cost reagents: CBB R250, acetic acid, methanol and ammonium sulfate, and the destaining solution of water. Our method dose dependently detects 12 nanograms protein within 60 min and with a wide protein spectrum. Although the features of the dose-dependent relationship depend upon protein amounts and protein types, for most of the protein samples tested, a linear relationship was observed in the region from 12 to 330 ng. Moreover, through further washing, the detection sensitivity of protein is enhanced and reaches a maximum at 1.4 ng and then gradually decreases in the de-staining process. It has been shown recently through MS analyses that the sensitive colloidal CBB staining methods frequently result in artifactual methylations due to the strong acid and long contact during staining and the destaining processes. Such artifacts were reported to be reduced by the replacement of strong inorganic acid with acetic acid and because RAMA utilizes acetic acid and is in contact with the proteins for a short time during staining and destaining, it is expected that in vitro artifacts will be reduced. Finally, MS analyses of RAMA-stained protein bands were revealed not to have been methylated. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.


Okada Y.,Yokohama Institute | Okada Y.,University of Tokyo | Yamazaki K.,RIKEN | Umeno J.,RIKEN | And 14 more authors.
Gastroenterology | Year: 2011

Background & Aims: There are many genetic factors that are associated with both ulcerative colitis (UC) and Crohn's disease (CD). However, genetic factors that have distinct effects on UC and CD have not been examined. Methods: We performed a comparative genome-wide association study (GWAS) and a replication study using data from 748 patients with UC and 979 with CD, selected from a Japanese population. We conducted high-resolution (4-digit) genotyping of human leukocyte antigen (HLA) alleles in patients with UC and CD and additional 905 healthy individuals (controls). We performed haplotype-based analysis using data from the GWAS and HLA alleles to associate them with UC or CD. Results: The comparative GWAS and the replication study identified significant associations in the major histocompatibility complex region at 6p21 with UC and CD (rs9271366, P = 1.6 × 1070; odds ratio [OR] = 4.44). Haplotype-based analysis in the major histocompatibility complex region showed that HLA-Cw (*)1202-B (*)5201-DRB1 (*)1502 haplotype was significantly associated with increased risk of UC compared with CD (P = 1.1 × 10-33; OR = 6.58), accounting for most of the associations observed in the GWAS. Compared with the controls, this HLA haplotype significantly increases susceptibility to UC (P = 4.0 × 10-21; OR = 2.65), but reduces risk for CD (P = 1.1 × 10-7; OR = 0.40). Distinct effects of this HLA haplotype on UC and CD were independent of other HLA alleles and haplotypes (P = 2.0 × 10-19 and P = 7.2 × 10-5, respectively). Conclusions: The HLA-Cw (*)1202-B (*)5201-DRB1 (*)1502 haplotype increases susceptibility to UC but reduces risk for CD, based on a GWAS of a Japanese population. © 2011 AGA Institute.


Umeno J.,RIKEN | Umeno J.,Kyushu University | Asano K.,RIKEN | Asano K.,Kyushu University | And 9 more authors.
Inflammatory Bowel Diseases | Year: 2011

Background: Both ulcerative colitis (UC) and Crohn's disease (CD) have a complex etiology involving multiple genetic and environmental factors. Many genome-wide association studies (GWAS) and subsequent replication studies revealed that both diseases share some of the susceptibility loci; however, common genetic factors for both diseases are not fully elucidated. This study is aimed to identify the common genetic factors for CD and UC by a meta-analysis of published studies. Methods: We first reviewed the 10 GWAS for CD to select candidate single nucleotide polymorphisms (SNPs). Next, we performed a PubMed literature search up to June 30, 2010 and carried out a systemic review of published studies that examined the association of CD susceptibility loci in UC patients. Meta-analysis was carried out using the inverse variance-weighted method or the DerSimonian-Laird method after estimating the heterogeneity among the studies. The data for highly linked SNPs were combined. Finally, we performed a meta-analysis of 43 published studies in 45 SNPs located at 33 loci by using a total of 4852 to 31,125 subjects. Results: We confirmed the association of 17 reported common susceptibility loci. Moreover, we found associations at eight additional loci: GCKR, ATG16L1, CDKAL1, ZNF365, LRRK2-MUC19, C13orf31, PTPN2, and SBNO2. The genetic risk of each locus was modest (odds ratios ranged from 1.05-1.22) except IL23R. Conclusions: These results indicate that CD and UC share many susceptibility loci with small genetic effect. Our data provide further understanding of the common pathogenesis between CD and UC. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.


Shiozaki M.,RIKEN | Tashiro T.,RIKEN | Koshino H.,RIKEN | Nakagawa R.,Yokohama Institute | And 5 more authors.
Carbohydrate Research | Year: 2010

These three ester analogues showed activity for IFNγ, and IL-4 production of iNKT cells. α-Galactosylceramide (αGalCer, KRN7000) has been identified as a modulator of immunological processes through its capacity to bind iNKT cells mediated by CD1d molecules. Some analogues in while the amide group in αGalCer is replaced with ester or ether groups were synthesized from d-arabinitol or l-ribose to evaluate their ability to activate iNKT cells. Ester analogues 30a, 31a, and 61 showed activity for IFNγ and IL-4 production of iNKT cells, while ether (31b) and 4-methoxy ester (76) analogues of α-galactosylceramide were not active for iNKT cells. © 2010 Elsevier Ltd. All rights reserved.


Shiozaki M.,RIKEN | Tashiro T.,RIKEN | Koshino H.,RIKEN | Shigeura T.,Yokohama Institute | And 3 more authors.
Tetrahedron | Year: 2013

RCAI-80 is one of the ester analogs of KRN7000 (α-galactosylceramide) . This compound released mainly T helper 2 (Th2) cytokines, such as IL-4 rather than T helper 1 (Th1) cytokines, such as IFNγ from the invariant natural killer T (iNKT) cells. In addition, it has been known that some of the hydroxylated derivatives of KRN7000 make the cytokine secretion bias to Th2 by decreasing the IFNγ production to almost zero. This time, the three compounds having these two characteristic properties, namely an ester group and also some extra hydroxy groups existing on the ester side chain and/or on the 2-acyloxy-3,4-dihydroxyoctadecyl main chain of RCAI-80, were synthesized to examine the biological activities. As a result, it was found that these compounds made the cytokine secretion skew to Th2. Therefore, their effectiveness for experimental autoimmune encephalomyelitis (EAE) was examined. It was recognized that one of them showed moderate suppression of EAE symptom. © 2013 Elsevier Ltd. All rights reserved.


Shiozaki M.,RIKEN | Tashiro T.,RIKEN | Koshino H.,RIKEN | Shigeura T.,Yokohama Institute | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

RCAI-147 is one of the hydroxylated analogues of KRN7000 which is known as a ligand for the activation of CD1d mediated invariant natural killer T cells (iNKT cells) and releases both T helper 1 (Th1) cytokines such as IFN-γ and T helper 2 (Th2) cytokines such as IL-4. KRN7000 has been anticipated as an antitumor drug or an adjuvant for viral infection such as influenza, because of its strong secretion of IFN-γ. In an interesting twist, it has been obvious in our previous paper that RCAI-147 induces much more Th2 cytokines (IL-4) than Th1 cytokines (IFN-γ) from iNKT cells compared to KRN7000, and shows fairly good result in the experimental autoimmune encephalomyelitis (EAE) test. Therefore, synthesis of RCAI-172 (C6-OH epimer of RCAI-147) was attempted to examine the biological activity. As a result, RCAI-172 was synthesized and its biological activity biased to Th2 response largely compared to that of KRN7000. However, this level decreased to approximately 61% compared to that of RCAI-147. And the clinical score of RCAI-172 for EAE suppression was disappointing. There exist seven chiral centers in the aglycon part of RCAI-172, and even though the change of configuration is just one position (C6-OH), the effect on both Th1/Th2 response and EAE test is fairly large. © 2013 Elsevier Ltd. All rights reserved.


Oshima K.,Yokohama Institute | Yamazaki K.,Shinshu University | Nakajima Y.,Toyokawa City Hospital | Kobayashi A.,Toyokawa City Hospital | And 4 more authors.
Modern Rheumatology | Year: 2010

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent and self-limited fever attacks and serositis/arthritis. The M694V, M694I, M680I, V726A, and E148Q mutations in MEFV, the gene responsible for FMF, account for most FMF cases in Mediterranean populations. In Japan, M694I and E148Q are most frequently detected; M694V, M680I, and V726A have not been identified so far. We report the first case of FMF associated with M680I in Japan. © Japan College of Rheumatology 2009.


Galbas T.,University of Montréal | Steimle V.,Université de Sherbrooke | Lapointe R.,University of Montréal | Ishido S.,Yokohama Institute | Thibodeau J.,University of Montréal
Cytokine | Year: 2012

IL-10 is vastly studied for its anti-inflammatory properties on most immune cells. However, it has been reported that IL-10 activates B cells, up-regulates their MHC class II molecules and prevents apoptosis. As MARCH1 was shown to be responsible for the intracellular sequestration of MHC class II molecules in dendritic cells and monocytes in response to IL-10, we set out to clarify the role of this ubiquitin ligase in B cells. Here, we demonstrate in mice that splenic follicular B cells represent the major cell population that up-regulate MHC II molecules in the presence of IL-10. Activation of these cells through TLR4, CD40 or the IL-10 receptor caused the down-regulation of MARCH1 mRNA. Accordingly, B cells from MARCH1-deficient mice do not up-regulate I-A b in response to IL-10. In all, our results demonstrate that IL-10 can have opposite effects on MARCH1 regulation in different cell types. © 2012 Elsevier Ltd.

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