Publications by authors named "Noriko Tsuji"

58 Publications

subsp. C60 restores T Cell Population in Small Intestinal Lamina Propria in Aged Interleukin-18 Deficient Mice.

Nutrients 2020 Oct 27;12(11). Epub 2020 Oct 27.

Division of Cellular and Molecular Engineering, Department of Life Technology and Science, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 3058560, Japan.

Lactic acid bacteria (LAB), a major commensal bacterium in the small intestine, are well known beneficial bacteria which promote establishment of gut-centric immunity, such as anti-inflammation and anti-infection. In this report, we show that a LAB strain subsp. C60 possess an ability to activate antigen presenting cells, such as dendritic cells (DCs), and intestinal T cells which possibly support to maintain healthy intestinal immunological environment in aging process. We found that CD4+ T cells in the small intestine are dramatically decreased in aged Interleukin-18 knock out (IL-18KO) mice, associated with the impairment of IFN-γ production in the CD4+ T cells, especially in small intestinal lamina propria (LP). Surprisingly, heat killed-C60 (HK-C60) diet completely recovered the CD4+ T cells population and activity in SI-LP and over activated the population in Peyer's patches (PPs) of IL-18KO mice. The HK-C60 diet was effective approach not only to restore the number of cells, but also to recover IFN-γ production in the CD4+ T cell population in the small intestine of IL-18-deficient mice. As a possible cause in the age-associated impairment of CD4+ T cells activity in IL-18KO mice, we found that the immunological activity was downregulated in the IL-18-deficient DCs. The cytokines production and cellular activation markers expression were downregulated in the IL-18-deficient bone marrow derived dendritic cells (BMDCs) at the basal level, however, both activities were highly upregulated in HK-C60 stimulation as compared to those of WT cells. Antigen uptake was also attenuated in the IL-18-deficient BMDCs, and it was significantly enhanced in the cells as compared to WT cells in HK-60 stimulation. An in vitro antigen presentation assay showed that IFN-γ production in the CD4+ T cells was significantly enhanced in the culture of IL-18-deficient BMDCs compared with WT cells in the presence of HK-C60. Thus, we conclude that HK-C60 diet possesses an ability to restore T cells impairment in the small intestine of IL-18-deficient environment. In addition, the positive effect is based on the immunological modification of DCs function which directory influences into the promotion of effector CD4+ T cells generation in the small intestine.
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http://dx.doi.org/10.3390/nu12113287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693701PMC
October 2020

A nanoscale metal organic frameworks-based vaccine synergises with PD-1 blockade to potentiate anti-tumour immunity.

Nat Commun 2020 07 31;11(1):3858. Epub 2020 Jul 31.

Department of Life Science and Biotechnology, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan.

Checkpoint blockade therapy has provided noteworthy benefits in multiple cancers in recent years; however, its clinical benefits remain confined to 10-40% of patients with extremely high costs. Here, we design an ultrafast, low-temperature, and universal self-assembly route to integrate immunology-associated large molecules into metal-organic-framework (MOF)-gated mesoporous silica (MS) as cancer vaccines. Core MS nanoparticles, acting as an intrinsic immunopotentiator, provide the niche, void, and space to accommodate antigens, soluble immunopotentiators, and so on, whereas the MOF gatekeeper protects the interiors from robust and off-target release. A combination of MOF-gated MS cancer vaccines with systemic programmed cell death 1 (PD-1) blockade therapy generates synergistic effects that potentiate antitumour immunity and reduce the effective dose of an anti-PD-1 antibody to as low as 1/10 of that for PD-1 blockade monotherapy in E.G7-OVA tumour-bearing mice, with eliciting the robust adaptive OVA-specific CD8 T-cell responses, reversing the immunosuppressive pathway and inducing durable tumour suppression.
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http://dx.doi.org/10.1038/s41467-020-17637-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395732PMC
July 2020

A Double-Blind, Randomized, Placebo-Controlled Trial of Heat-Killed K15 for Prevention of Respiratory Tract Infections among Preschool Children.

Nutrients 2020 Jul 3;12(7). Epub 2020 Jul 3.

Department of Pediatrics, Chiba University Hospital, Chiba 260-8670, Japan.

Although some probiotic bacteria have been reported to prevent infections in children, there are few well-designed double-blind studies. Here we evaluated the effects of a probiotic strain of lactic acid bacteria (LAB), K15, on viral respiratory tract infections in preschool children. A four-month, randomized, double-blind, placebo-controlled study was performed in 172 healthy children aged 3 to 6 years. Subjects were administered dextrin alone or dextrin including heat-killed K15 (5 × 10 bacteria). The number of febrile days was the primary outcome. The number of absent days from preschools and the influenza incidence were secondary outcomes. Secretory IgA (sIgA) concentrations in saliva were measured as an exploratory outcome. The primary and secondary outcomes were not significantly different between both groups. Analyses in children with little intake of fermented foods including LAB showed that the duration of a fever significantly decreased by K15 intake. The salivary sIgA level in the K15 group was maintained significantly higher than it was in the placebo group. The effects of K15 on preventing viral respiratory tract infections were not observed without the restriction of fermented foods intake. However, K15 supported anti-infectious immune systems in children who took less fermented foods and the maintenance of salivary sIgA levels in all subjects.
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http://dx.doi.org/10.3390/nu12071989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400799PMC
July 2020

Biochemical properties of human full-length aryl hydrocarbon receptor (AhR).

J Biochem 2020 Sep;168(3):285-294

Department of Life Science, Graduate School and Faculty of Engineering Science, Akita University, Akita 010-8502, Japan.

The aryl hydrocarbon receptor (AhR) is a very unstable protein. AhR binds to the molecular chaperone complex (HSP90-p23-XAP2) to maintain a stable structure in the cytoplasm. After binding to ligands, such as dioxin, AhR translocates from the cytoplasm to the nucleus with a molecular chaperone complex. The protein forms a heterodimer with Arnt after nuclear transfer, functions as a transcription factor by binding to a xenobiotic responsive element (XRE), and induces the cytochrome P450 1A1 (CYP1A1). Because of the unstable protein, expression of the full-length AhR in the E. coli expression system is very difficult. Many studies investigated AhR using AhR domains in vitro. We expressed and purified the human full-length AhR in E. coli expression system. Furthermore, specific antibodies were prepared. Purified full-length AhR could bind to ligand. In the presence of ligand, α-helix and random coil of AhR increased and β-sheet decreased on CD spectrum. Full-length AhR could bind to HSP90, XAP2 and p23 in the presence or absence of ligand. We now show the biochemical properties of full-length AhR.
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http://dx.doi.org/10.1093/jb/mvaa047DOI Listing
September 2020

Propolis induces Ca signaling in immune cells.

Biosci Microbiota Food Health 2019 24;38(4):141-149. Epub 2019 Aug 24.

Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Propolis possesses several immunological functions. We recently generated a conditional Ca biosensor yellow cameleon (YC3.60) transgenic mouse line and established a five-dimensional (5D) (x, y, z, time, and Ca signaling) system for intravital imaging of lymphoid tissues, including Peyer's patches (PPs). To assess the effects of propolis on immune cells, we analyzed Ca signaling and using CD11c-Cre/YC3.60 transgenic mice, in which CD11c dendritic cells (DCs) specifically express YC3.60. We found that propolis induced Ca signaling in DCs in the PPs. Intravital imaging of PPs also showed that an intraperitoneal injection of propolis augmented Ca signaling in CD11c cells, suggesting that propolis possesses immune-stimulating activity. Furthermore, CD11c cells in PPs in mice administrated propolis indicated an increase in Ca signaling. Our results indicate that propolis induces immunogenicity under physiological conditions.
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http://dx.doi.org/10.12938/bmfh.19-011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856514PMC
August 2019

Rod-Scale Design Strategies for Immune-Targeted Delivery System toward Cancer Immunotherapy.

ACS Nano 2019 07 28;13(7):7705-7715. Epub 2019 Jun 28.

School of Life Dentistry at Tokyo , The Nippon Dental University , Fujimi , Chiyoda-ku, Tokyo 102-0071 , Japan.

Strengthening the antitumor immune response to surpass the activation energy barrier associated with the immunosuppressive tumor microenvironment is an active area of cancer immunotherapy. Emerging evidence suggests that delivery of immunostimulatory molecules with the aid of a carrier system is essential for cancer immunotherapy. However, the size-dependent effect of the delivery system on immune-targeted sites and anticancer immune responses is yet to be comprehensively understood. Herein, to clarify the size-dependent effect of the delivery system on the underlying anticancer immune mechanism, rod-shaped hydroxyapatite (HA) particles with lengths from 100 nm to 10 μm are designed. HA rods stimulate anticancer immunity in a size-dependent manner. Shorter HA rods with lengths ranging from 100 to 500 nm promote antigen cellular uptake, dendritic cell (DC) maturation, and lymph node targeting antigen. In contrast, longer HA rods with lengths ranging from 500 nm to 10 μm prolong antigen retention and increase DC accumulation. Medium-sized HA rods with a length of 500 nm, taking advantage of both short and long rods, show optimized antigen release and uptake, increased DCs accumulation and maturation, highest CD4 and CD8 T cell population, and the best anticancer immunity . The present study provides a rod-scale design strategy for an immune-targeted delivery system toward cancer immunotherapy in the future.
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http://dx.doi.org/10.1021/acsnano.9b01271DOI Listing
July 2019

High TNFRSF14 and low BTLA are associated with poor prognosis in Follicular Lymphoma and in Diffuse Large B-cell Lymphoma transformation.

J Clin Exp Hematop 2019 ;59(1):1-16

The microenvironment influences the behavior of follicular lymphoma (FL) but the specific roles of the immunomodulatory BTLA and TNFRSF14 (HVEM) are unknown. Therefore, we examined their immunohistochemical expression in the intrafollicular, interfollicular and total histological compartments in 106 FL cases (57M/49F; median age 57-years), and in nine relapsed-FL with transformation to DLBCL (tFL). BTLA expression pattern was of follicular T-helper cells (TFH) in the intrafollicular and of T-cells in the interfollicular compartments. The mantle zones were BTLA+ in 35.6% of the cases with similar distribution of IgD. TNFRSF14 expression pattern was of neoplastic B lymphocytes (centroblasts) and "tingible body macrophages". At diagnosis, the averages of total BTLA and TNFRSF14-positive cells were 19.2%±12.4STD (range, 0.6%-58.2%) and 46.7 cells/HPF (1-286.5), respectively. No differences were seen between low-grade vs. high-grade FL but tFL was characterized by low BTLA and high TNFRSF14 expression. High BTLA correlated with good overall survival (OS) (total-BTLA, Hazard Risk=0.479, P=0.022) and with high PD-1 and FOXP3+Tregs. High TNFRSF14 correlated with poor OS and progression-free survival (PFS) (total-TNFRSF14, HR=3.9 and 3.2, respectively, P<0.0001), with unfavorable clinical variables and higher risk of transformation (OR=5.3). Multivariate analysis including BTLA, TNFRSF14 and FLIPI showed that TNFRSF14 and FLIPI maintained prognostic value for OS and TNFRSF14 for PFS. In the GSE16131 FL series, high TNFRSF14 gene expression correlated with worse prognosis and GSEA showed that NFkB pathway was associated with the "High-TNFRSF14/dead-phenotype".In conclusion, the BTLA-TNFRSF14 immune modulation pathway seems to play a role in the pathobiology and prognosis of FL.
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http://dx.doi.org/10.3960/jslrt.19003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528140PMC
April 2019

Si-doping increases the adjuvant activity of hydroxyapatite nanorods.

Colloids Surf B Biointerfaces 2019 Feb 13;174:300-307. Epub 2018 Nov 13.

Department of Resources and Environmental Engineering, Waseda University, Shinjuku-ku, Tokyo, 169-8555, Japan.

Recombinant protein-based vaccines generally show limited immunogenicity and need adjuvants to achieve robust immune responses. Herein, to combine the excellent biocompatibility of hydroxyapatite (HA) and exciting adjuvant activity of silica, Si-doped HA nanorods with Si/P molar ratio from 0 to 0.65 were hydrothermally synthesized and evaluated as immunoadjuvants. Si-doping decreases the size and increases the BET surface area of the nanorods. Si-doping in HA nanorods increases the in vitro adjuvant activity, including CD11cCD86 expression and cytokine secretion of bone marrow derived dendritic cells (BMDCs). Moreover, Si-doping in HA increases the ex vivo adjuvant activity as shown by the increase in both Th1 and Th2 cytokines secretion. Si-doped HA nanorods are promising as a new immunoadjuvant.
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http://dx.doi.org/10.1016/j.colsurfb.2018.11.026DOI Listing
February 2019

The molecular mechanism for activating IgA production by Pediococcus acidilactici K15 and the clinical impact in a randomized trial.

Sci Rep 2018 03 22;8(1):5065. Epub 2018 Mar 22.

Biomedical Research Institute, National Institute for Advanced Industrial Science and Technology (AIST), Tsukuba, Japan.

IgA secretion at mucosal sites is important for host defence against pathogens as well as maintaining the symbiosis with microorganisms present in the small intestine that affect IgA production. In the present study, we tested the ability of 5 strains of lactic acid bacteria stimulating IgA production, being Pediococcus acidilactici K15 selected as the most effective on inducing this protective immunoglobulin. We found that this response was mainly induced via IL-10, as efficiently as IL-6, secreted by K15-stimulated dendritic cells. Furthermore, bacterial RNA was largely responsible for the induction of these cytokines; double-stranded RNA was a major causative molecule for IL-6 production whereas single-stranded RNA was critical factor for IL-10 production. In a randomized, double-blind, placebo-controlled clinical trial, ingestion of K15 significantly increased the secretory IgA (sIgA) concentration in saliva compared with the basal level observed before this intervention. These results indicate that functional lactic acid bacteria induce IL-6 and IL-10 production by dendritic cells, which contribute to upregulating the sIgA concentration at mucosal sites in humans.
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http://dx.doi.org/10.1038/s41598-018-23404-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864838PMC
March 2018

Double-Stranded RNA Derived from Lactic Acid Bacteria Augments Th1 Immunity Interferon-β from Human Dendritic Cells.

Front Immunol 2018 23;9:27. Epub 2018 Jan 23.

Biomedical Research Institute, National Institute for Advanced Industrial Science and Technology (AIST), Tsukuba, Japan.

Lactic acid bacteria (LAB) are one of the major commensal species in the small intestine and known for contributing to maintenance of protective immunity and immune homeostasis. However, currently there has been no evidence regarding the cellular mechanisms involved in the probiotic effects of LAB on human immune cells. Here, we demonstrated that LAB double-stranded RNA (dsRNA) triggered interferon-β (IFN-β) production by human dendritic cells (DCs), which activated IFN-γ-producing T cells. Interleukin-12 (IL-12) secretion from human DCs in response to LAB was abrogated by depletion of bacterial dsRNA, and was attenuated by neutralizing IFN-β, indicating LAB dsRNA primarily activated the IFN-β/IL-12 pathway. Moreover, the induction of IL-12 secretion from DCs by LAB was abolished by the inhibition of endosomal acidification, confirming the critical role of the endosomal digestion of LAB. In a coculture of human naïve CD4 T cells and BDCA1 DCs, DCs stimulated with LAB containing dsRNA induced IFN-γ-producing T cells. These results indicate that human DCs activated by LAB enhance Th1 immunity depending on IFN-β secretion in response to bacterial dsRNA.
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http://dx.doi.org/10.3389/fimmu.2018.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787129PMC
February 2019

Synergistic effects of stellated fibrous mesoporous silica and synthetic dsRNA analogues for cancer immunotherapy.

Chem Commun (Camb) 2018 Jan;54(9):1057-1060

Health Research Institute, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.

Stellated fibrous mesoporous silica nanospheres significantly improve the cellular uptake of cancer antigen and the maturation of bone marrow derived dendritic cells in vitro. Moreover, the combination of poly(I:C) with stellated fibrous MS nanospheres markedly decreases the necessary dose of poly(I:C) for anti-tumor immunity, and thus opens new opportunities for the future clinical application of poly(I:C) in cancer immunotherapy.
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http://dx.doi.org/10.1039/c7cc08222cDOI Listing
January 2018

Biodegradable Metal Ion-Doped Mesoporous Silica Nanospheres Stimulate Anticancer Th1 Immune Response in Vivo.

ACS Appl Mater Interfaces 2017 Dec 11;9(50):43538-43544. Epub 2017 Dec 11.

School of Life Dentistry at Tokyo, The Nippon Dental University , Fujimi, Chiyoda-ku, Tokyo 102-0071, Japan.

Modern vaccines usually require accompanying adjuvants to increase the immune response to antigens. Aluminum (alum) compounds are the most commonly used adjuvants in human vaccinations for infection diseases. However, alum adjuvants are nondegradable, cause side effects due to the persistence of alum at injection sites, and are rather ineffective for cancer immunotherapy, which requires the Th1 immune response. Recently, we have shown that a plain mesoporous silica (MS) adjuvant can stimulate Th1 anticancer immunity for cancer vaccines. Herein, MS nanospheres doped with Ca, Mg, and Zn (MS-Ca, MS-Mg, and MS-Zn) showed significantly higher degradation rates than pure MS. Moreover, MS-Ca, MS-Mg, and MS-Zn nanospheres  stimulated anticancer immune response and increased the CD4 and CD8 T cell populations in spleen. The MS-Ca, MS-Mg, and MS-Zn nanospheres with improved biodegradability and excellent ability to induce Th1 anticancer immunity show potential for clinical applications as cancer immunoadjuvants.
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http://dx.doi.org/10.1021/acsami.7b16118DOI Listing
December 2017

The regulation mechanisms of AhR by molecular chaperone complex.

J Biochem 2018 Mar;163(3):223-232

Department of Life Science, Graduate School and Faculty of Engineering Science, Akita University, 1-1 Tegata Gakuen Town, Akita 010-8502, Japan.

The AhR, so called the dioxin receptor, is a member of the nuclear receptor superfamily. The ligand-free AhR forms a cytosolic protein complex with the molecular chaperone HSP90, co-chaperone p23, and XAP2 in the cytoplasm. Following ligand binding like 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), the AhR translocates into the nucleus. Although it has been reported that HSP90 regulates the translocation of the AhR to the nucleus, the precise activation mechanisms of the AhR have not yet been fully understood. AhR consists of the N-terminal bHLH domain containing NLS and NES, the middle PAS domain and the C-terminal transactivation domain. The PAS domain is familiar as a ligand and HSP90 binding domain. In this study, we focused on the bHLH domain that was thought to be a HSP90 binding domain. We investigated the binding properties of bHLH to HSP90. We analyzed the direct interaction of bHLH with HSP90, p23 and XAP2 using purified proteins. We found that not only the PAS domain but also the bHLH domain bound to HSP90. The bHLH domain forms complex with HSP90, p23 and XAP2. We also determined the bHLH binding domain was HSP90 N-domain. The bHLH domain makes a complex with HSP90, p23 and XAP2 via the HSP90 N-domain. Although the NLS is closed in the absence of a ligand, the structure of AhR will be changed in the presence of a ligand, which leads to NLS open, result in the nuclear translocation of AhR.
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http://dx.doi.org/10.1093/jb/mvx074DOI Listing
March 2018

In vitro and in vivo pharmacological characterization of ASP8477: A novel highly selective fatty acid amide hydrolase inhibitor.

Eur J Pharmacol 2017 Nov 7;815:42-48. Epub 2017 Oct 7.

Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.

Although exogenous agonists for cannabinoid (CB) receptors are clinically effective for treating chronic pain, global activation of brain CB receptors causes frequent central nervous system (CNS) side-effects. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide (AEA), an endogenous CB. Recently, we discovered a novel FAAH inhibitor, 3-pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477). In vitro studies demonstrated that ASP8477 inhibited human FAAH-1, FAAH-1 (P129T) and FAAH-2 activity with IC values of 3.99, 1.65 and 57.3nM, respectively. ASP8477 at 10µM had no appreciable interactions with 65 different kinds of receptors, ion channels, transporters and enzymes, including CB and CB receptors and monoacylglycerol lipase. In adolescent rats, orally administered ASP8477 (0.3-10mg/kg) elevated AEA concentrations in both plasma and brain. In a capsaicin-induced secondary hyperalgesia model, a pretreatment with ASP8477 significantly improved mechanical allodynia and thermal hyperalgesia at 0.3-3mg/kg p.o. ASP8477 also significantly improved mechanical allodynia in an L5/L6 spinal nerve ligation neuropathic pain model, with an ED value of 0.63mg/kg, and in a streptozotocin-induced diabetic neuropathy model at 3 and 10mg/kg p.o. Furthermore, ASP8477 significantly attenuated the reduction in rearing events at 1 and 3mg/kg p.o. in a monoiodoacetic acid-induced osteoarthritis model. Importantly, ASP8477 had no significant effect on motor coordination up to 30mg/kg p.o. These results indicate that ASP8477 is a potent, selective, and oral active FAAH inhibitor with activity in the CNS, with the potential to be a new analgesic agent with a wide safety margin.
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http://dx.doi.org/10.1016/j.ejphar.2017.10.007DOI Listing
November 2017

Hollow ZnO Nanospheres Enhance Anticancer Immunity by Promoting CD4 and CD8 T Cell Populations In Vivo.

Small 2017 10 21;13(38). Epub 2017 Aug 21.

Biomedical Research Institute, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan.

Appropriate adjuvant aiding in generating robust anticancer immunity is crucial for cancer immunotherapy. Herein, hollow ZnO (HZnO) nanospheres are synthesized by a facile method using carbon nanospheres as the template. The HZnO nanospheres significantly promote the cellular uptake of a model antigen, and cytokine secretion by antigen-presenting cells in vitro. HZnO loaded with ovalbumin and polyinosinic-polycytidylic acid (poly(I:C)) inhibits cancer growth and metastasis to inguinal lymph node in a cancer cell challenge model. Moreover, HZnO loaded with autologous cancer antigens inhibits cancer cell growth in a cancer cell re-challenge model. HZnO nanospheres significantly improve the CD4 and/or CD8 T cell population in splenocytes of mice in both cancer cell challenge model and re-challenge model. The HZnO nanospheres can be used for cancer immunotherapy as adjuvant.
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http://dx.doi.org/10.1002/smll.201701816DOI Listing
October 2017

An optimistic protein assembly from sequence reads salvaged an uncharacterized segment of mouse picobirnavirus.

Sci Rep 2017 01 10;7:40447. Epub 2017 Jan 10.

Bioinformatics Division, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.

Advances in Next Generation Sequencing technologies have enabled the generation of millions of sequences from microorganisms. However, distinguishing the sequence of a novel species from sequencing errors remains a technical challenge when the novel species is highly divergent from the closest known species. To solve such a problem, we developed a new method called Optimistic Protein Assembly from Reads (OPAR). This method is based on the assumption that protein sequences could be more conserved than the nucleotide sequences encoding them. By taking advantage of metagenomics, bioinformatics and conventional Sanger sequencing, our method successfully identified all coding regions of the mouse picobirnavirus for the first time. The salvaged sequences indicated that segment 1 of this virus was more divergent from its homologues in other Picobirnaviridae species than segment 2. For this reason, only segment 2 of mouse picobirnavirus has been detected in previous studies. OPAR web tool is available at http://bioinformatics.czc.hokudai.ac.jp/opar/.
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http://dx.doi.org/10.1038/srep40447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223137PMC
January 2017

Improvement of Intestinal Immune Cell Function by Lactic Acid Bacteria for Dairy Products.

Microorganisms 2016 Dec 23;5(1). Epub 2016 Dec 23.

Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan.

Lactic acid bacteria (LAB) form a major component of gut microbiota and are often used as probiotics for fermented foods, such as yoghurt. In this study, we aimed to evaluate immunomodulatory activity of LAB, especially that of ME-552 (ME552) and ME-553 (ME553). In vivo/in vitro assay was performed in order to investigate their effects on T cell function. After oral administration of ME553 to C57BL/6 mice, the amount of both interferon γ (IFN-γ) and interleukin 17 (IL-17) produced by cluster of differentiation (CD) 4⁺ T cells from Peyer's patches (PPs) were significantly enhanced. On the other hand, ME552 only up-regulated the production of IL-17 from PP cells. The extent of induction for IFN-γ production differed between ME552 and ME553. These results suggest that LAB modulate T cell effector functions and mucosal immunity.
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http://dx.doi.org/10.3390/microorganisms5010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374378PMC
December 2016

Visualization of Probiotic-Mediated Ca Signaling in Intestinal Epithelial Cells .

Front Immunol 2016 16;7:601. Epub 2016 Dec 16.

Biomedical Research Institute, National Institute for Advanced Industrial Science and Technology (AIST) , Tsukuba , Japan.

Probiotics, such as lactic acid bacteria (LAB) and var. , have been shown to modulate immune responses. It is important to understand how probiotic bacteria impact intestinal epithelial cells (IECs), because IECs are the first line of defense at the mucosal surface barrier and their activities substantially affect the gut microenvironment and immunity. However, to date, their precise mechanism remains unknown due to a lack of analytical systems available for live animal models. Recently, we generated a conditional Ca biosensor Yellow Cameleon (YC3.60) transgenic mouse line and established 5D (, time, and Ca) intravital imaging systems of lymphoid tissues including those in Peyer's patches and bone marrow. In the present study, we further advance our intravital imaging system for intestinal tracts to visualize IEC responses against orally administrated food compounds in real time. Using this system, heat-killed , a probiotic TTCC012 strain, is shown to directly induce Ca signaling in IECs in mice housed under specific pathogen-free conditions. In contrast, this activation is not observed in the strain C60; however, when we generate germ-free YC3.60 mice and observe the LAB stimulation of IECs in the absence of gut microbiota, C60 is capable of inducing Ca signaling. This is the first study to successfully visualize the direct effect of probiotics on IECs in live animals. These data strongly suggest that probiotic strains stimulate IECs under physiological conditions and that their activity is affected by the microenvironment of the small intestine, such as commensal bacteria.
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http://dx.doi.org/10.3389/fimmu.2016.00601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159486PMC
December 2016

Cancer Immunotherapy: Comprehensive Mechanism Analysis of Mesoporous-Silica-Nanoparticle-Induced Cancer Immunotherapy (Adv. Healthcare Mater. 10/2016).

Adv Healthc Mater 2016 May;5(10):1246

Health Research Institute, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan.

A plain mesoporous silica (MS) nanoparticle without any immunomodulatory molecules enhances anti-cancer immunity in vivo. On page 1169, X.P. Wang, N. M. Tsuji, A. Ito and co-workers show that a plain MS nanoparticle promotes both Th1 and Th2 immune responses, and enhances the effector memory of CD4(+) and CD8(+) T cell populations in the three most important immune organs (bone marrow, lymph node and spleen) of mice.
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http://dx.doi.org/10.1002/adhm.201670051DOI Listing
May 2016

Hollow Structure Improved Anti-Cancer Immunity of Mesoporous Silica Nanospheres In Vivo.

Small 2016 Jul 18;12(26):3510-5. Epub 2016 May 18.

Biomedical Research Institute, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan.

Hollow and non-hollow mesoporous silica nanospheres are synthesized and used for cancer vaccine adjuvants. The hollow structure of mesoporous silica nanospheres significantly promote cellular uptake of a model cancer antigen by macrophage-like cells in vitro, improve anti-cancer immunity, CD4(+) and CD8(+) T cell populations in splenocytes of mice in vivo.
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http://dx.doi.org/10.1002/smll.201600677DOI Listing
July 2016

Rod-shaped and fluorine-substituted hydroxyapatite free of molecular immunopotentiators stimulates anti-cancer immunity in vivo.

Chem Commun (Camb) 2016 Jun 28;52(44):7078-81. Epub 2016 Apr 28.

Health Research Institute, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.

Herein, rod-shaped and fluorine-substituted hydroxyapatite nanoparticles (FHA) were synthesized using a facile hydrothermal method. The rod-shaped FHA significantly increased the cellular uptake of a model antigen by bone marrow dentritic cells in vitro, improved antigen presentation in vivo, stimulated immune-related cytokine secretion in vitro and ex vivo, and enhanced the anti-cancer immunity in vivo.
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http://dx.doi.org/10.1039/c6cc02848aDOI Listing
June 2016

Comprehensive Mechanism Analysis of Mesoporous-Silica-Nanoparticle-Induced Cancer Immunotherapy.

Adv Healthc Mater 2016 05 14;5(10):1169-76. Epub 2016 Mar 14.

Health Research Institute, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan.

A plain mesoporous silica nanoparticle without any immunomodulatory molecules significantly enhances anticancer immunity in vivo. Comprehensive mechanism of mesoporous-silica-nanoparticle-induced cancer immunotherapy is analyzed in this paper. The mesoporous silica nanoparticle promotes both Th1 and Th2 immune responses, as it accelerates lymphocytes proliferation, stimulates IFN-γ, IL-2, IL-4, and IL-10 cytokine secretion by lymphocytes ex vivo, and increases IgG, IgG1, IgG2a, IgM, and IgA antibody titers in mice serum compared with those of alum and adjuvant-free groups. Moreover, the mesoporous silica nanoparticle enhances effector memory CD4(+) and CD8(+) T cell populations in three most important immune organs (bone marrow, lymph node, and spleen) of mice compared with those of alum and adjuvant-free groups three months after adjuvant injection. The present study paves the way for the application of mesoporous silica nanoparticle as immunoadjuvant for cancer immunotherapy.
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http://dx.doi.org/10.1002/adhm.201501013DOI Listing
May 2016

Rod-shaped and substituted hydroxyapatite nanoparticles stimulating type 1 and 2 cytokine secretion.

Colloids Surf B Biointerfaces 2016 Mar 3;139:10-6. Epub 2015 Dec 3.

Biomedical Research Institute, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1Higashi, Tsukuba, Ibaraki 305-8566, Japan.

A Th1 immune response is required for modern vaccines as the most commonly used alum adjuvant has weak capacity for inducing Th1 immune response. Herein, rod-shaped hydroxyapatite (HA), magnesium-substituted HA (MgHA) and zinc-substituted HA (ZnHA) nanoparticles with irregular nanopores were synthesized and used as immunoadjuvants. Magnesium and zinc substitution in HA showed no influence on morphology, particle size, zeta potential and surface area of the nanoparticles. The rod-shaped MgHA and ZnHA nanoparticles promoted the cellular uptake of a molecular immunopotentiator, stimulated both type 1 and 2 cytokine secretion in vitro that relate to Th1 and Th2 immunity of bone marrow dentritic cells, respectively. The MgHA and ZnHA nanoparticles may be useful as immunoadjuvants for human.
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http://dx.doi.org/10.1016/j.colsurfb.2015.12.004DOI Listing
March 2016

CRTAM determines the CD4+ cytotoxic T lymphocyte lineage.

J Exp Med 2016 Jan 22;213(1):123-38. Epub 2015 Dec 22.

Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan

Naive T cells differentiate into various effector T cells, including CD4(+) helper T cell subsets and CD8(+) cytotoxic T cells (CTL). Although cytotoxic CD4(+) T cells (CD4 +: CTL) also develop from naive T cells, the mechanism of development is elusive. We found that a small fraction of CD4(+) T cells that express class I-restricted T cell-associated molecule (CRTAM) upon activation possesses the characteristics of both CD4(+) and CD8(+) T cells. CRTAM(+) CD4(+) T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM(+) T cells are the precursor of CD4(+)CTL. Indeed, ectopic expression of CRTAM in T cells induced the production of IFN-γ, expression of CTL-related genes, and cytotoxic activity. The induction of CD4(+)CTL and IFN-γ production requires CRTAM-mediated intracellular signaling. CRTAM(+) T cells traffic to mucosal tissues and inflammatory sites and developed into CD4(+)CTL, which are involved in mediating protection against infection as well as inducing inflammatory response, depending on the circumstances, through IFN-γ secretion and cytotoxic activity. These results reveal that CRTAM is critical to instruct the differentiation of CD4(+)CTL through the induction of Eomes and CTL-related gene.
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http://dx.doi.org/10.1084/jem.20150519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710199PMC
January 2016

Stimulation of In Vivo Antitumor Immunity with Hollow Mesoporous Silica Nanospheres.

Angew Chem Int Ed Engl 2016 Jan 25;55(5):1899-903. Epub 2015 Sep 25.

School of Life Dentistry at Tokyo, The Nippon Dental University, Fujimi, Chiyoda-ku Tokyo, 102-0071, Japan.

The use of appropriate adjuvants that support the generation of robust and long-lasting antitumor immune responses is crucial for tumor immunotherapy owing to the immunosuppressive environment of the growing tumor. However, the most commonly used adjuvant, aluminum hydroxide, is ineffective for generating such immune responses and therefore not suitable for cancer immunotherapy. It is now shown that plain hollow mesoporous silica nanospheres markedly improve the antitumor immunity, the Th1 and Th2 immunity, and the CD4(+) and CD8(+) effector memory T cell population in bone marrow in vivo and may thus be used as immunoadjuvants to treat cancer in humans.
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http://dx.doi.org/10.1002/anie.201506179DOI Listing
January 2016

Targeting C-Type Lectin Receptors for Cancer Immunity.

Front Immunol 2015 24;6:408. Epub 2015 Aug 24.

Immune Homeostasis Laboratory, Biomedical Research Institute, National Institute for Advanced Industrial Science and Technology (AIST) , Tsukuba , Japan.

C-type lectin receptors (CLRs) are a large family of soluble and trans-membrane pattern recognition receptors that are widely and primarily expressed on myeloid cells. CLRs are important for cell-cell communication and host defense against pathogens through the recognition of specific carbohydrate structures. Similar to a family of Toll-like receptors, CLRs signaling are involved in the various steps for initiation of innate immune responses and promote secretion of soluble factors such as cytokines and interferons. Moreover, CLRs contribute to endocytosis and antigen presentation, thereby fine-tune adaptive immune responses. In addition, there may also be a direct activation of acquired immunity. On the other hand, glycans, such as mannose structures, Lewis-type antigens, or GalNAc are components of tumor antigens and ligate CLRs, leading to immunoregulation. Therefore, agonists or antagonists of CLRs signaling are potential therapeutic reagents for cancer immunotherapy. We aim to overview the current knowledge of CLRs signaling and the application of their ligands on tumor-associating immune response.
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http://dx.doi.org/10.3389/fimmu.2015.00408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547497PMC
September 2015

Gut to systemic immune-homeostasis mediated by innate signals.

Nihon Rinsho Meneki Gakkai Kaishi 2015 ;38(6):448-56

Immune Homeostasis Lab., Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST).

To accommodate the vast antigenic exposure from both food components and commensal bacteria, the gut has evolved a naturally anti-inflammatory environment. We have recently shown that lactic acid bacteria (LAB), a major population of small intestinal microbiota and often found in fermented foods, contain a large amount of double-stranded RNA and capable of inducing interferon-β (IFN-β) production from dendritic cells (DCs) via the Toll-like receptor 3 (TLR3) pathway. It is a significant feature of LAB and was not observed in other bacteria tested. Moreover, IFN-β secreted in response to LAB prevented experimental colitis. These results identify TLR3 as a sensor to small intestinal commensal bacteria and contribute to anti-inflammatory mechanism. We also show that oral administration of β-glucan enhance intestinal and systemic immune response in dectin-1-dependent manner. Thus elucidation of "gut to systemic immune-homeostasis" mediated by innate signals will be valued for the development of gut-biology and science-based food immunology, with a focus on innovation in the health and medical industries.
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http://dx.doi.org/10.2177/jsci.38.448DOI Listing
March 2017

The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90.

FEBS Open Bio 2014 16;4:796-803. Epub 2014 Sep 16.

Department of Life Science, Graduate School and Faculty of Engineering Science, Akita University, Akita 010-8502, Japan.

The aryl hydrocarbon receptor is a member of the nuclear receptor superfamily that associates with the molecular chaperone HSP90 in the cytoplasm. The activation mechanism of the AhR is not yet fully understood. It has been proposed that after binding of ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3methylcholanthrene (3-MC), or β-naphthoflavone (β-NF), the AhR dissociates from HSP90 and translocates to the nucleus. It has also been hypothesized that the AhR translocates to the nucleus and forms a complex with HSP90 and other co-chaperones. There are a few reports about the direct association or dissociation of AhR and HSP90 due to difficulties in purifying AhR. We constructed and purified the PAS domain from AhR. Binding of the AhR-PAS domain to β-NF affinity resin suggested that it possesses ligand-binding affinity. We demonstrated that the AhR-PAS domain binds to HSP90 and the association is not affected by ligand binding. The ligand 17-DMAG inhibited binding of HSP90 to GST-PAS. In an immunoprecipitation assay, HSP90 was co-immunoprecipitated with AhR both in the presence or absence of ligand. Endogenous AhR decreased in the cytoplasm and increased in the nucleus of HeLa cells 15 min after treatment with ligand. These results suggested that the ligand-bound AhR is translocated to nucleus while in complex with HSP90. We used an in situ proximity ligation assay to confirm whether AhR was translocated to the nucleus alone or together with HSP90. HSP90 was co-localized with AhR after the nuclear translocation. It has been suggested that the ligand-bound AhR was translocated to the nucleus with HSP90. Activated AhR acts as a transcription factor, as shown by the transcription induction of the gene CYP1A1 8 h after treatment with β-NF.
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http://dx.doi.org/10.1016/j.fob.2014.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208086PMC
October 2014

Difficulties in care management felt by care managers.

Nihon Ronen Igakkai Zasshi 2014 ;51(2):192

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http://dx.doi.org/10.3143/geriatrics.51.192DOI Listing
January 2016