49 results on '"Atsushi Shimoyama"'
Search Results
2. Substrate Study for Dihydroxyboryl Astatine Substitution Reaction with Fibroblast Activation Protein Inhibitor (FAPI)
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Ayaka Aso, Kazuko Kaneda-Nakashima, Hinako Nabetani, Yuichiro Kadonaga, Yoshifumi Shirakami, Tadashi Watabe, Taku Yoshiya, Masayoshi Mochizuki, Yuki Koshino, Kazuhiro Ooe, Atsuko Kawakami, Naoya Jinno, Atsushi Toyoshima, Hiromitsu Haba, Yang Wang, Jens Cardinale, Frederik L. Giesel, Atsushi Shimoyama, and Koichi Fukase
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General Chemistry - Published
- 2022
3. Development of Adjuvants Based on Parasitic and Symbiotic Bacterial Lipid A
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Atsushi Shimoyama
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Organic Chemistry ,Biochemistry - Published
- 2022
4. Chemical Synthesis and Immunomodulatory Functions of Bacterial Lipid As
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Atsushi Shimoyama and Koichi Fukase
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- 2023
5. Revisiting Glycosylations Using Glycosyl Fluoride by BF3·Et2O: Activation of Disarmed Glycosyl Fluorides with High Catalytic Turnover
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Yoshiyuki Manabe, Takuya Matsumoto, Yuka Ikinaga, Yuya Tsutsui, Shota Sasaya, Yuichiro Kadonaga, Akihito Konishi, Makoto Yasuda, Tomoya Uto, Changhao Dai, Kumpei Yano, Atsushi Shimoyama, Ayana Matsuda, and Koichi Fukase
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Organic Chemistry ,Physical and Theoretical Chemistry ,Biochemistry - Published
- 2021
6. Chemical Synthesis and Immunomodulatory Functions of Bacterial Lipid As
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Atsushi, Shimoyama and Koichi, Fukase
- Abstract
Lipopolysaccharide (LPS), a cell surface component of Gram-negative bacteria, and its active principle, lipid A, have immunostimulatory properties and thus potential to act as adjuvants. However, canonical LPS acts as an endotoxin by hyperstimulating the immune response. Therefore, it is necessary to structurally modify LPS and lipid A to minimize toxicity while maintaining adjuvant effects for use as vaccine adjuvants. Various studies have focused on the chemical synthetic method of lipid As and their structure-activity relationship, which are reviewed in this chapter.
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- 2022
7. Evaluation of Astatine-211-Labeled Fibroblast Activation Protein Inhibitor (FAPI): Comparison of Different Linkers with Polyethylene Glycol and Piperazine
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Ayaka Aso, Hinako Nabetani, Yoshifumi Matsuura, Yuichiro Kadonaga, Yoshifumi Shirakami, Tadashi Watabe, Taku Yoshiya, Masayoshi Mochizuki, Kazuhiro Ooe, Atsuko Kawakami, Naoya Jinno, Atsushi Toyoshima, Hiromitsu Haba, Yang Wang, Jens Cardinale, Frederik Lars Giesel, Atsushi Shimoyama, Kazuko Kaneda-Nakashima, and Koichi Fukase
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Inorganic Chemistry ,Organic Chemistry ,FAP alpha ,astatine-211 ,iodine-131 ,theranostics ,PEG-linker ,piperazine-linker ,cancer ,General Medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
Fibroblast activation proteins (FAP) are overexpressed in the tumor stroma and have received attention as target molecules for radionuclide therapy. The FAP inhibitor (FAPI) is used as a probe to deliver nuclides to cancer tissues. In this study, we designed and synthesized four novel 211At-FAPI(s) possessing polyethylene glycol (PEG) linkers between the FAP-targeting and 211At-attaching moieties. 211At-FAPI(s) and piperazine (PIP) linker FAPI exhibited distinct FAP selectivity and uptake in FAPII-overexpressing HEK293 cells and the lung cancer cell line A549. The complexity of the PEG linker did not significantly affect selectivity. The efficiencies of both linkers were almost the same. Comparing the two nuclides, 211At was superior to 131I in tumor accumulation. In the mouse model, the antitumor effects of the PEG and PIP linkers were almost the same. Most of the currently synthesized FAPI(s) contain PIP linkers; however, in our study, we found that PEG linkers exhibit equivalent performance. If the PIP linker is inconvenient, a PEG linker is expected to be an alternative.
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- 2023
8. α‐Emitting cancer therapy using 211 At‐AAMT targeting LAT1
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Takashi Nakano, Yoshifumi Shirakami, Takashi Yoshimura, Yoshiyuki Manabe, Kazuhiro Ooe, Atsushi Shinohara, Kazuko Kaneda-Nakashima, Zijian Zhang, Tadashi Watabe, Atsushi Shimoyama, Mitsuhiro Fukuda, Koichi Fukase, Yoshikatsu Kanai, Jun Hatazawa, Kazuya Kabayama, and Atsushi Toyoshima
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0301 basic medicine ,chemistry.chemical_classification ,Cancer Research ,Lung ,Chemistry ,Large Neutral Amino Acid-Transporter 1 ,General Medicine ,medicine.disease ,In vitro ,Metastasis ,Amino acid ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,In vivo ,030220 oncology & carcinogenesis ,Radionuclide therapy ,medicine ,Cancer research ,DNA - Abstract
α-Methyl-l-tyrosine (AMT) has a high affinity for the cancer-specific l-type amino acid transporter 1 (LAT1). Therefore, we established an anti-cancer therapy, with 211 At-labeled α-methyl-l-tyrosine (211 At-AAMT) as a carrier of 211 At into tumors. 211 At-AAMT had high affinity for LAT1, inhibited tumor cell growth, and induced DNA double-stranded breaks in vitro. We evaluated the accumulation of 211 At-AAMT in vivo and the role of LAT1. Treatment with 0.4 MBq/mouse 211 At-AAMT inhibited tumor growth in the PANC-1 tumor model and 1 MBq/mouse 211 At-AAMT inhibited metastasis in the lung of the B16F10 metastasis model. Our results suggested that 211 At would be useful for anti-cancer therapy and that LAT1 is suitable as a target for radionuclide therapy.
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- 2021
9. Endotoxin-Free Stx2B-C-CPE Vaccine and Its Optimized Adjuvant Regimen for Preventing Food Poisoning
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Jun Kunisawa, Koichi Fukase, Shinji Yamasaki, Hiroshi Kiyono, Masuo Kondoh, Mari Furuta, Yoko Tojima, Hirotaka Ebina, Takafumi Noguchi, Noritoshi Hatanaka, Atsushi Hinenoya, Atsushi Shimoyama, and Koji Hosomi
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General Immunology and Microbiology ,General Medicine ,General Biochemistry, Genetics and Molecular Biology - Published
- 2023
10. Revisiting Glycosylations Using Glycosyl Fluoride by BF
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Yoshiyuki, Manabe, Takuya, Matsumoto, Yuka, Ikinaga, Yuya, Tsutsui, Shota, Sasaya, Yuichiro, Kadonaga, Akihito, Konishi, Makoto, Yasuda, Tomoya, Uto, Changhao, Dai, Kumpei, Yano, Atsushi, Shimoyama, Ayana, Matsuda, and Koichi, Fukase
- Abstract
Catalytic glycosylations with glycosyl fluorides using BF
- Published
- 2021
11. Energetics of lipid transport by the ABC transporter MsbA is lipid dependent
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Dawei Guo, Himansha Singh, Atsushi Shimoyama, Charlotte Guffick, Yakun Tang, Sam M. Rowe, Timothy Noel, David R. Spring, Koichi Fukase, Hendrik W. van Veen, Shimoyama, Atsushi [0000-0003-1910-0450], Rowe, Sam M [0000-0003-4902-6685], Spring, David R [0000-0001-7355-2824], van Veen, Hendrik W [0000-0002-9658-8077], Apollo - University of Cambridge Repository, Rowe, Sam [0000-0003-4902-6685], and Spring, David [0000-0001-7355-2824]
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QH301-705.5 ,education ,Medicine (miscellaneous) ,Biological Transport ,Antimicrobial resistance ,Lipid Metabolism ,humanities ,Article ,General Biochemistry, Genetics and Molecular Biology ,Lactococcus lactis ,Bacterial Proteins ,Enzyme mechanisms ,Escherichia coli ,ATP-Binding Cassette Transporters ,lipids (amino acids, peptides, and proteins) ,Membrane lipids ,Biology (General) ,Energy Metabolism ,General Agricultural and Biological Sciences ,health care economics and organizations - Abstract
Funder: China Scholarship Council (CSC); doi: https://doi.org/10.13039/501100004543, Funder: Cambridge Commonwealth Trust; doi: https://doi.org/10.13039/501100003342, The ABC multidrug exporter MsbA mediates the translocation of lipopolysaccharides and phospholipids across the plasma membrane in Gram-negative bacteria. Although MsbA is structurally well characterised, the energetic requirements of lipid transport remain unknown. Here, we report that, similar to the transport of small-molecule antibiotics and cytotoxic agents, the flopping of physiologically relevant long-acyl-chain 1,2-dioleoyl (C18)-phosphatidylethanolamine in proteoliposomes requires the simultaneous input of ATP binding and hydrolysis and the chemical proton gradient as sources of metabolic energy. In contrast, the flopping of the large hexa-acylated (C12-C14) Lipid-A anchor of lipopolysaccharides is only ATP dependent. This study demonstrates that the energetics of lipid transport by MsbA is lipid dependent. As our mutational analyses indicate lipid and drug transport via the central binding chamber in MsbA, the lipid availability in the membrane can affect the drug transport activity and vice versa.
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- 2021
12. Chemically Synthesized Alcaligenes Lipid A as an Adjuvant to Augment Immune Responses to Haemophilus Influenzae Type B Conjugate Vaccine
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Zilai Liu, Koji Hosomi, Atsushi Shimoyama, Ken Yoshii, Xiao Sun, Huangwenxian Lan, Yunru Wang, Haruki Yamaura, Davie Kenneth, Azusa Saika, Takahiro Nagatake, Hiroshi Kiyono, Koichi Fukase, and Jun Kunisawa
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Pharmacology ,Synthetic vaccine ,Lipopolysaccharide ,biology ,alcaligenes ,Chemistry ,medicine.medical_treatment ,Toxoid ,RM1-950 ,haemophilus influenzae type B ,biology.organism_classification ,TI antigen ,Microbiology ,Lipid A ,chemistry.chemical_compound ,adjuvant ,Antigen ,Conjugate vaccine ,medicine ,Pharmacology (medical) ,Therapeutics. Pharmacology ,Alcaligenes ,lipid A ,Adjuvant - Abstract
We previously identified Alcaligenes spp. as a commensal bacterium that resides in lymphoid tissues, including Peyer’s patches. We found that Alcaligenes-derived lipopolysaccharide acted as a weak agonist of Toll-like receptor four due to the unique structure of lipid A, which lies in the core of lipopolysaccharide. This feature allowed the use of chemically synthesized Alcaligenes lipid A as a safe synthetic vaccine adjuvant that induces Th17 polarization to enhance systemic IgG and respiratory IgA responses to T-cell–dependent antigens (e.g., ovalbumin and pneumococcal surface protein A) without excessive inflammation. Here, we examined the adjuvant activity of Alcaligenes lipid A on a Haemophilus influenzae B conjugate vaccine that contains capsular polysaccharide polyribosyl ribitol phosphate (PRP), a T-cell–independent antigen, conjugated with the T-cell–dependent tetanus toxoid (TT) antigen (i.e., PRP-TT). When mice were subcutaneously immunized with PRP alone or mixed with TT, Alcaligenes lipid A did not affect PRP-specific IgG production. In contrast, PRP-specific serum IgG responses were enhanced when mice were immunized with PRP-TT, but these responses were impaired in similarly immunized T-cell—deficient nude mice. Furthermore, TT-specific—but not PRP-specific—T-cell activation occurred in mice immunized with PRP-TT together with Alcaligenes lipid A. In addition, coculture with Alcaligenes lipid A promoted significant proliferation of and enhanced antibody production by B cells. Together, these findings suggest that Alcaligenes lipid A exerts an adjuvant activity on thymus-independent Hib polysaccharide antigen in the presence of a T-cell–dependent conjugate carrier antigen.
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- 2021
13. Limonoids with anti-inflammatory activity: A review
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Erina, Hilmayanti, Nurlelasari, Unang, Supratman, Kazuya, Kabayama, Atsushi, Shimoyama, and Koichi, Fukase
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Plant Science ,General Medicine ,Horticulture ,Molecular Biology ,Biochemistry - Abstract
The natural limonoids distributed mainly in the Meliaceae and Rutaceae plants are known for their unique and complex structure with high degree oxidation and cyclic rearrangement. However, these compounds exhibit a broad range of biological activities such as insecticidal, antibacterial, antifungal, antimalarial, antioxidant, anticancer, antiviral, and anti-inflammatory. There is still limited report about the biological activity of the anti-inflammatory effect of limonoids isolated from plants. Therefore, this study aimed to examine the effect of intact, deformed and rearranged limonoids as anti-inflammatory agents. The majority of anti-inflammatory investigations were evaluated by in vitro and in vivo assays of the isolated pure compounds and their derivatives. For the in vitro study, intact and C-ring seco limonoids showed a potent inhibitory effect against NO production. The in vivo analysis of Intact, C-seco, and AD-seco limonoids showed a potent effect based on the inhibition of pro-inflammatory cytokines expression, indicating their potency as anti-inflammatory agents.
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- 2022
14. Chemically Synthesized
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Zilai, Liu, Koji, Hosomi, Atsushi, Shimoyama, Ken, Yoshii, Xiao, Sun, Huangwenxian, Lan, Yunru, Wang, Haruki, Yamaura, Davie, Kenneth, Azusa, Saika, Takahiro, Nagatake, Hiroshi, Kiyono, Koichi, Fukase, and Jun, Kunisawa
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Pharmacology ,adjuvant ,alcaligenes ,haemophilus influenzae type B ,lipid A ,Original Research ,TI antigen - Abstract
We previously identified Alcaligenes spp. as a commensal bacterium that resides in lymphoid tissues, including Peyer’s patches. We found that Alcaligenes-derived lipopolysaccharide acted as a weak agonist of Toll-like receptor four due to the unique structure of lipid A, which lies in the core of lipopolysaccharide. This feature allowed the use of chemically synthesized Alcaligenes lipid A as a safe synthetic vaccine adjuvant that induces Th17 polarization to enhance systemic IgG and respiratory IgA responses to T-cell–dependent antigens (e.g., ovalbumin and pneumococcal surface protein A) without excessive inflammation. Here, we examined the adjuvant activity of Alcaligenes lipid A on a Haemophilus influenzae B conjugate vaccine that contains capsular polysaccharide polyribosyl ribitol phosphate (PRP), a T-cell–independent antigen, conjugated with the T-cell–dependent tetanus toxoid (TT) antigen (i.e., PRP-TT). When mice were subcutaneously immunized with PRP alone or mixed with TT, Alcaligenes lipid A did not affect PRP-specific IgG production. In contrast, PRP-specific serum IgG responses were enhanced when mice were immunized with PRP-TT, but these responses were impaired in similarly immunized T-cell—deficient nude mice. Furthermore, TT-specific—but not PRP-specific—T-cell activation occurred in mice immunized with PRP-TT together with Alcaligenes lipid A. In addition, coculture with Alcaligenes lipid A promoted significant proliferation of and enhanced antibody production by B cells. Together, these findings suggest that Alcaligenes lipid A exerts an adjuvant activity on thymus-independent Hib polysaccharide antigen in the presence of a T-cell–dependent conjugate carrier antigen.
- Published
- 2021
15. Intratumoral administration of astatine-211-labeled gold nanoparticle for alpha therapy
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Yuichiro Kadonaga, Atsushi Toyoshima, Xuhao Huang, Koichi Fukase, Jun Hatazawa, Kazuhiro Ooe, Kazuya Kabayama, Hiroki Kato, Daisuke Katayama, Atsushi Shinohara, and Atsushi Shimoyama
- Subjects
Male ,Biodistribution ,Cancer therapy ,Biomedical Engineering ,Mice, Nude ,Pharmaceutical Science ,Medicine (miscellaneous) ,Bioengineering ,Scintigraphy ,Applied Microbiology and Biotechnology ,Polyethylene Glycols ,030218 nuclear medicine & medical imaging ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Astatine-211 ,Medical technology ,medicine ,Animals ,Gold nanoparticles ,Cytotoxic T cell ,Tissue Distribution ,Particle Size ,R855-855.5 ,Radionuclide Imaging ,Cytotoxicity ,Mice, Inbred BALB C ,Staining and Labeling ,medicine.diagnostic_test ,Research ,Glioma ,Molecular medicine ,Rats ,chemistry ,Colloidal gold ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Nanoparticles ,Molecular Medicine ,Gold ,Astatine ,Ethylene glycol ,TP248.13-248.65 ,Alpha emitters ,Radiolabeling ,Biotechnology - Abstract
Background 211At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of 211At-labeled gold nanoparticles (211At-AuNP) administered intratumorally. Results AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with 211At (211At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. 211At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, 211At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of 211At. Tumor growth was strongly suppressed for both C6 and PANC-1 by 211At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with 211At-AuNP-S-mPEG with a diameter of 5 nm. Conclusions The intratumoral single administration of a simple nanoparticle, 211At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide. Graphic Abstract
- Published
- 2021
16. Kinetically Controlled Fischer Glycosidation under Flow Conditions: A New Method for Preparing Furanosides
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Seiji Masui, Kohtaro Hirao, Takahide Fukuyama, Yoshiyuki Manabe, Atsushi Shimoyama, Ilhyong Ryu, and Koichi Fukase
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chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Flow chemistry ,Sulfonic acid ,010402 general chemistry ,Residence time (fluid dynamics) ,01 natural sciences ,0104 chemical sciences ,Catalysis ,symbols.namesake ,Reaction temperature ,Flow conditions ,symbols ,Organic chemistry ,Fischer glycosidation - Abstract
Kinetically controlled Fischer glycosidation was achieved under flow conditions. β-Hydroxy-substituted sulfonic acid functionalized silica (HO-SAS) was used as an acid catalyst. This reaction directly converted aldohexoses into kinetically favored furanosides to enable the practical synthesis of furanosides. After optimization of the reaction temperature and residence time, glucofuranosides, galactofuranosides, and mannofuranosides were synthesized in good yields.
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- 2019
17. Chemically Synthesized TLR4 Ligands, Their Immunological Functions, and Potential as Vaccine Adjuvant
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Atsushi Shimoyama and Koichi Fukase
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Innate immune system ,Lipopolysaccharide ,medicine.medical_treatment ,Lipid A ,chemistry.chemical_compound ,Immune system ,chemistry ,Biochemistry ,Adjuvanticity ,TLR4 ,medicine ,lipids (amino acids, peptides, and proteins) ,Bacterial outer membrane ,Adjuvant - Abstract
Lipopolysaccharide (LPS), the major glycoconjugates in the outer membrane of Gram-negative bacteria, and its active center glycolipid, lipid A, are recognized by an innate immune system receptor, Toll-like receptor (TLR) 4, and trigger immunostimulatory effects and thus have the potential to act as vaccine adjuvants. Although canonical Escherichia coli LPS induces strong inflammation and acts as an endotoxin due to the ability that hyperstimulates the immune system, recent studies revealed that inflammatory activity of lipid A can be attenuated by the structural modification. Here, we discuss the structure–activity relationship of lipid A and the potential as a vaccine adjuvant, and introduce currently used vaccines that contain LPS and lipid A. We also introduce the strategy of safe lipid A adjuvant development based on human symbiotic bacterial lipid As. Finally, we present studies on lipid A–based self-adjuvant strategy and how structural modifications and conjugations can help regulate the adjuvanticity of lipid A.
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- 2020
18. α-Emitting cancer therapy using
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Kazuko, Kaneda-Nakashima, ZiJian, Zhang, Yoshiyuki, Manabe, Atsushi, Shimoyama, Kazuya, Kabayama, Tadashi, Watabe, Yoshikatsu, Kanai, Kazuhiro, Ooe, Atsushi, Toyoshima, Yoshifumi, Shirakami, Takashi, Yoshimura, Mitsuhiro, Fukuda, Jun, Hatazawa, Takashi, Nakano, Koichi, Fukase, and Atsushi, Shinohara
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Male ,Drug Carriers ,Original Articles ,Alpha Particles ,anti‐cancer drug ,Xenograft Model Antitumor Assays ,Large Neutral Amino Acid-Transporter 1 ,Disease Models, Animal ,Mice ,HEK293 Cells ,alpha-Methyltyrosine ,Drug Discovery and Delivery ,astatine‐211 ,Cell Line, Tumor ,Neoplasms ,Animals ,Feasibility Studies ,Humans ,DNA Breaks, Double-Stranded ,Female ,Original Article ,large neutral amino acid transporter 1 ,nuclear medicine ,Astatine ,amino acid - Abstract
α‐Methyl‐l‐tyrosine (AMT) has a high affinity for the cancer‐specific l‐type amino acid transporter 1 (LAT1). Therefore, we established an anti‐cancer therapy, with 211At‐labeled α‐methyl‐l‐tyrosine (211At‐AAMT) as a carrier of 211At into tumors. 211At‐AAMT had high affinity for LAT1, inhibited tumor cell growth, and induced DNA double‐stranded breaks in vitro. We evaluated the accumulation of 211At‐AAMT in vivo and the role of LAT1. Treatment with 0.4 MBq/mouse 211At‐AAMT inhibited tumor growth in the PANC‐1 tumor model and 1 MBq/mouse 211At‐AAMT inhibited metastasis in the lung of the B16F10 metastasis model. Our results suggested that 211At would be useful for anti‐cancer therapy and that LAT1 is suitable as a target for radionuclide therapy., α‐Methyl‐l‐tyrosine (AMT) has a high affinity for the cancer‐specific l‐type amino acid transporter 1 (LAT1). Therefore, we establish an anti‐cancer therapy using 211At‐labeled α‐methyl‐l‐tyrosine (211At‐AAMT) as a carrier of 211At into tumors. 211At is useful for anti‐cancer therapy and LAT1 was suitable as a target for nuclear medicine.
- Published
- 2020
19. Lymphoid Tissue–Resident Alcaligenes Establish an Intracellular Symbiotic Environment by Creating a Unique Energy Shift in Dendritic Cells
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Koji Hosomi, Naoko Shibata, Atsushi Shimoyama, Tomoya Uto, Takahiro Nagatake, Yoko Tojima, Tomomi Nishino, Haruko Takeyama, Koichi Fukase, Hiroshi Kiyono, and Jun Kunisawa
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Microbiology (medical) ,Lipopolysaccharide ,lipopolysaccharid ,lcsh:QR1-502 ,chemical and pharmacologic phenomena ,Biology ,lymphoid-tissue-resident commensal bacteria ,medicine.disease_cause ,Microbiology ,lcsh:Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,Immune system ,mitochondrial respiration ,medicine ,dendritic cells ,inducible nitric oxide synmase ,Escherichia coli ,030304 developmental biology ,0303 health sciences ,Alcaligenes faecalis ,030306 microbiology ,apoptosis ,hemic and immune systems ,biology.organism_classification ,Cell biology ,Lymphatic system ,chemistry ,Apoptosis ,Alcaligenes ,Intracellular - Abstract
Lymphoid-tissue–resident commensal bacteria (LRCs), including Alcaligenes faecalis, are present in intestinal lymphoid tissue including the Peyer’s patches (PPs) of mammals and modulate the host immune system. Although LRCs can colonize within dendritic cells (DCs), the mechanisms through which LRCs persist in DCs and the symbiotic relationships between LRCs and DCs remain to be investigated. Here, we show an intracellular symbiotic system in which the LRC Alcaligenes creates a unique energy shift in DCs. Whereas DCs showed low mitochondrial respiration when they were co-cultured with Escherichia coli, DCs carrying A. faecalis maintained increased mitochondrial respiration. Furthermore, E. coli induced apoptosis of DCs but A. faecalis did not. Regarding an underlying mechanism, A. faecalis—unlike E. coli—did not induce intracellular nitric oxide (NO) production in DCs due to the low activity of its lipopolysaccharide (LPS). Therefore, A. faecalis, an example of LRCs, may persist within intestinal lymphoid tissue because they elicit little NO production in DCs. In addition, the symbiotic DCs exhibit characteristic physiologic changes, including a low rate of apoptosis and increased mitochondrial respiration.
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- 2020
20. Chemically Synthesized
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Ken, Yoshii, Koji, Hosomi, Atsushi, Shimoyama, Yunru, Wang, Haruki, Yamaura, Takahiro, Nagatake, Hidehiko, Suzuki, Huangwenxian, Lan, Hiroshi, Kiyono, Koichi, Fukase, and Jun, Kunisawa
- Subjects
IgA antibody ,Th17 response ,pneumococcal surface protein A (PspA), Streptococcus pneumoniae ,neutrophil ,Alcaligenes lipid A ,Article - Abstract
Effective and safe vaccine adjuvants are needed to appropriately augment mucosal vaccine effects. Our previous study demonstrated that lipopolysaccharide (LPS) from Peyer’s patch resident Alcaligenes stimulated dendritic cells to promote the production of mucosal immunity-enhancing cytokines (e.g., IL-6 and BAFF), thus enhancing antigen-specific immune responses (including IgA production and Th17 responses) without excessive inflammation. Here, we chemically synthesized Alcaligenes lipid A, the biologically active part of LPS, and examined its efficacy as a nasal vaccine adjuvant for the induction of protectively immunity against Streptococcus pneumoniae infection. Mice were nasally immunized with pneumococcal surface protein A (PspA) as a vaccine antigen for S. pneumoniae, together with Alcaligenes lipid A. Alcaligenes lipid A supported the generation of high levels of PspA-specific IgA and IgG responses through the augmentation of germinal center formation in the nasopharynx-associated lymphoid tissue and cervical lymph nodes (CLNs). Moreover, Alcaligenes lipid A promoted PspA-specific CD4+ Th17 responses in the CLNs and spleen. Furthermore, neutrophils were recruited to infection sites upon nasal infection and synchronized with the antigen-specific T and B cell responses, resulting in the protection against S. pneumoniae infection. Taken together, Alcaligenes lipid A could be applied to the prospective adjuvant to enhance nasal vaccine efficacy by means of augmenting both the innate and acquired arms of mucosal immunity against respiratory bacterial infection.
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- 2020
21. Lymphoid Tissue-Resident
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Koji, Hosomi, Naoko, Shibata, Atsushi, Shimoyama, Tomoya, Uto, Takahiro, Nagatake, Yoko, Tojima, Tomomi, Nishino, Haruko, Takeyama, Koichi, Fukase, Hiroshi, Kiyono, and Jun, Kunisawa
- Subjects
lipopolysaccharid ,mitochondrial respiration ,apoptosis ,chemical and pharmacologic phenomena ,hemic and immune systems ,dendritic cells ,lymphoid-tissue-resident commensal bacteria ,Microbiology ,inducible nitric oxide synmase ,Original Research - Abstract
Lymphoid-tissue–resident commensal bacteria (LRCs), including Alcaligenes faecalis, are present in intestinal lymphoid tissue including the Peyer’s patches (PPs) of mammals and modulate the host immune system. Although LRCs can colonize within dendritic cells (DCs), the mechanisms through which LRCs persist in DCs and the symbiotic relationships between LRCs and DCs remain to be investigated. Here, we show an intracellular symbiotic system in which the LRC Alcaligenes creates a unique energy shift in DCs. Whereas DCs showed low mitochondrial respiration when they were co-cultured with Escherichia coli, DCs carrying A. faecalis maintained increased mitochondrial respiration. Furthermore, E. coli induced apoptosis of DCs but A. faecalis did not. Regarding an underlying mechanism, A. faecalis—unlike E. coli—did not induce intracellular nitric oxide (NO) production in DCs due to the low activity of its lipopolysaccharide (LPS). Therefore, A. faecalis, an example of LRCs, may persist within intestinal lymphoid tissue because they elicit little NO production in DCs. In addition, the symbiotic DCs exhibit characteristic physiologic changes, including a low rate of apoptosis and increased mitochondrial respiration.
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- 2020
22. Homeostatic and pathogenic roles of <scp>GM</scp> 3 ganglioside molecular species in <scp>TLR</scp> 4 signaling in obesity
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Umeharu Ohto, Shinji Go, Mika Nagasaki, Kei-ichiro Inamori, Hiromune Ando, Marilena Letizia, Makoto Kiso, Maria Grazia Ciampa, Hideharu Ishida, Kazuya Kabayama, Toshiyuki Shimizu, Jin-ichi Inokuchi, Anna Giulia Cattaneo, Atsushi Shimoyama, Naoko Komura, Sorama Aoki, Hirotaka Kanoh, Mayu Fujii, Hiroki Shindo, Yoshihiro Natori, Taku Watanabe, Yuichi Yoshimura, Koichi Fukase, Wataru Nihei, Akemi Suzuki, Asia Zonca, Lucas Veillon, Laura Mauri, Takahiro Nitta, Yutaka Yatomi, Alessandro Prinetti, Sandro Sonnino, and Kenichi Sato
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chronic inflammation ,obesity ,endocrine system ,medicine.medical_specialty ,Immunology ,Adipose tissue ,Inflammation ,HMGB1 ,inflammation amplification loop ,Article ,Monocytes ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,medicine ,Animals ,G(M3) Ganglioside ,Humans ,TLR4 ,ganglioside GM3 ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Innate immune system ,General Immunology and Microbiology ,biology ,General Neuroscience ,Articles ,medicine.disease ,Mice, Mutant Strains ,Toll-Like Receptor 4 ,carbohydrates (lipids) ,HEK293 Cells ,Endocrinology ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Protein Multimerization ,medicine.symptom ,030217 neurology & neurosurgery ,Homeostasis ,Signal Transduction - Abstract
Innate immune signaling via TLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear. GM3 ganglioside in human serum is composed of a variety of fatty acids, including long‐chain (LCFA) and very‐long‐chain (VLCFA). Analysis of circulating levels of human serum GM3 species from patients at different stages of insulin resistance and chronic inflammation reveals that levels of VLCFA‐GM3 increase significantly in metabolic disorders, while LCFA‐GM3 serum levels decrease. Specific GM3 species also correlates with disease symptoms. VLCFA‐GM3 levels increase in the adipose tissue of obese mice, and this is blocked in TLR4‐mutant mice. In cultured monocytes, GM3 by itself has no effect on TLR4 activation; however, VLCFA‐GM3 synergistically and selectively enhances TLR4 activation by LPS/HMGB1, while LCFA‐GM3 and unsaturated VLCFA‐GM3 suppresses TLR4 activation. GM3 interacts with the extracellular region of TLR4/MD2 complex to modulate dimerization/oligomerization. Ligand‐molecular docking analysis supports that VLCFA‐GM3 and LCFA‐GM3 act as agonist and antagonist of TLR4 activity, respectively, by differentially binding to the hydrophobic pocket of MD2. Our findings suggest that VLCFA‐GM3 is a risk factor for TLR4‐mediated disease progression., Analysis of GM3 ganglioside composition in human serum under chronic inflammation conditions reveals that the fatty acid chain length of GM3 ganglioside impacts the inflammatory activation of macrophages via direct modulation of TLR4 signaling.
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- 2020
23. Lymphoid tissue-resident Alcaligenes LPS induces IgA production without excessive inflammatory responses via weak TLR4 agonist activity
- Author
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Ken Ishii, Koji Hosomi, Natsuko Kishishita, Shintaro Sato, Naohiro Kitayama, Jun Kunisawa, Atsushi Shimoyama, Naoko Shibata, Koichi Fukase, Keisuke Mizote, Yukari Fujimoto, Hiroshi Kiyono, and Hitomi Mimuro
- Subjects
Lipopolysaccharides ,0301 basic medicine ,Agonist ,Lipopolysaccharide ,medicine.drug_class ,Immunology ,Mice, Transgenic ,Inflammation ,Microbiology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Immune system ,Adjuvants, Immunologic ,medicine ,Animals ,Homeostasis ,Immunology and Allergy ,Alcaligenes ,Receptor ,Cells, Cultured ,Mice, Knockout ,Mice, Inbred BALB C ,biology ,Interleukin-6 ,Dendritic Cells ,biology.organism_classification ,In vitro ,Immunoglobulin A ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,030104 developmental biology ,chemistry ,Antibody Formation ,TLR4 ,medicine.symptom ,Gram-Negative Bacterial Infections - Abstract
Alcaligenes are opportunistic commensal bacteria that reside in gut-associated lymphoid tissues such as Peyer's patches (PPs); however, how they create and maintain their homeostatic environment, without inducing an excessive inflammatory response remained unclear. We show here that Alcaligenes-derived lipopolysaccharide (Alcaligenes LPS) acts as a weak agonist of toll-like receptor 4 and promotes IL-6 production from dendritic cells, which consequently enhances IgA production. The inflammatory activity of Alcaligenes LPS was weaker than that of Escherichia coli-derived LPS and therefore no excessive inflammation was induced by Alcaligenes LPS in vitro or in vivo. Alcaligenes LPS also showed adjuvanticity, inducing antigen-specific immune responses without excessive inflammation. These findings reveal the presence of commensal bacteria-mediated homeostatic inflammatory conditions within PPs that produce optimal IgA induction without causing pathogenic inflammation and suggest that Alcaligenes LPS could be a safe and potent adjuvant.
- Published
- 2018
24. Time-lapse monitoring of TLR2 ligand internalization with newly developed fluorescent probes
- Author
-
Yohei Arai, Shinsuke Inuki, Yukari Fujimoto, Yuki Kawahara, Kazuya Kabayama, Kouhei Yokoyama, Ippei Ohta, Qi Feng, Koichi Fukase, and Atsushi Shimoyama
- Subjects
0301 basic medicine ,Ligand ,Chemistry ,CD14 ,media_common.quotation_subject ,Organic Chemistry ,Colocalization ,Biochemistry ,Fluorescence ,03 medical and health sciences ,TLR2 ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Biophysics ,Physical and Theoretical Chemistry ,Receptor ,Internalization ,030215 immunology ,media_common - Abstract
As a mammalian toll-like receptor family member protein, TLR2 recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. We have developed fluorescence-labeled TLR2 ligands with either hydrophilic or hydrophobic fluorescence groups. The labeled ligands maintained the inflammatory IL-6 induction activity and enabled us to observe the internalization and colocalization of the TLR2 ligands using live-cell imaging. The time-lapse monitoring in the live-cell imaging of the fluorescence-labeled TLR2 ligand showed that TLR2/CD14 expression in the host cells enhanced the internalization of TLR2 ligand molecules.
- Published
- 2018
25. Development of Chemically Synthesized Self-Adjuvanting Vaccines
- Author
-
Atsushi Shimoyama
- Subjects
Tumor-Associated Carbohydrate Antigens ,Vaccine adjuvant ,business.industry ,Immunology ,Organic Chemistry ,Medicine ,business ,Biochemistry - Published
- 2018
26. Chemically Synthesized Alcaligenes Lipid A Shows a Potent and Safe Nasal Vaccine Adjuvant Activity for the Induction of Streptococcus pneumoniae-Specific IgA and Th17 Mediated Protective Immunity
- Author
-
Atsushi Shimoyama, Jun Kunisawa, Ken Yoshii, Koji Hosomi, Hidehiko Suzuki, Hiroshi Kiyono, Takahiro Nagatake, Huangwenxian Lan, Yunru Wang, Haruki Yamaura, and Koichi Fukase
- Subjects
0301 basic medicine ,Microbiology (medical) ,Lipopolysaccharide ,Th17 response ,medicine.medical_treatment ,medicine.disease_cause ,Microbiology ,Lipid A ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,IgA antibody ,Immunity ,Virology ,Streptococcus pneumoniae ,Alcaligenes lipid A ,Medicine ,pneumococcal surface protein A (PspA), Streptococcus pneumoniae ,lcsh:QH301-705.5 ,biology ,business.industry ,neutrophil ,Vaccine efficacy ,biology.organism_classification ,030104 developmental biology ,lcsh:Biology (General) ,chemistry ,Alcaligenes ,business ,Adjuvant ,030215 immunology - Abstract
Effective and safe vaccine adjuvants are needed to appropriately augment mucosal vaccine effects. Our previous study demonstrated that lipopolysaccharide (LPS) from Peyer&rsquo, s patch resident Alcaligenes stimulated dendritic cells to promote the production of mucosal immunity-enhancing cytokines (e.g., IL-6 and BAFF), thus enhancing antigen-specific immune responses (including IgA production and Th17 responses) without excessive inflammation. Here, we chemically synthesized Alcaligenes lipid A, the biologically active part of LPS, and examined its efficacy as a nasal vaccine adjuvant for the induction of protectively immunity against Streptococcus pneumoniae infection. Mice were nasally immunized with pneumococcal surface protein A (PspA) as a vaccine antigen for S. pneumoniae, together with Alcaligenes lipid A. Alcaligenes lipid A supported the generation of high levels of PspA-specific IgA and IgG responses through the augmentation of germinal center formation in the nasopharynx-associated lymphoid tissue and cervical lymph nodes (CLNs). Moreover, Alcaligenes lipid A promoted PspA-specific CD4+ Th17 responses in the CLNs and spleen. Furthermore, neutrophils were recruited to infection sites upon nasal infection and synchronized with the antigen-specific T and B cell responses, resulting in the protection against S. pneumoniae infection. Taken together, Alcaligenes lipid A could be applied to the prospective adjuvant to enhance nasal vaccine efficacy by means of augmenting both the innate and acquired arms of mucosal immunity against respiratory bacterial infection.
- Published
- 2020
27. Adjuvant Activity of Synthetic Lipid A of Alcaligenes, a Gut-Associated Lymphoid Tissue-Resident Commensal Bacterium, to Augment Antigen-Specific IgG and Th17 Responses in Systemic Vaccine
- Author
-
Ken Yoshii, Hiroshi Kiyono, Tomomi Nishino, Atsushi Shimoyama, Koichi Fukase, Koji Hosomi, Takahiro Nagatake, Haruki Yamaura, Yunru Wang, and Jun Kunisawa
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Gut-associated lymphoid tissue ,education ,Immunology ,lcsh:Medicine ,Spleen ,Article ,Microbiology ,Lipid A ,03 medical and health sciences ,0302 clinical medicine ,parasitic diseases ,Drug Discovery ,medicine ,Pharmacology (medical) ,lipid A ,Pharmacology ,MHC class II ,Alcaligenes faecalis ,CD40 ,biology ,Chemistry ,lcsh:R ,hemic and immune systems ,biology.organism_classification ,humanities ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,biology.protein ,Th17 ,Alcaligenes ,tissues ,Adjuvant ,030215 immunology - Abstract
Alcaligenes spp. are identified as commensal bacteria and have been found to inhabit Peyer&rsquo, s patches in the gut. We previously reported that Alcaligenes-derived lipopolysaccharides (LPS) exerted adjuvant activity in systemic vaccination, without excessive inflammation. Lipid A is one of the components responsible for the biological effect of LPS and has previously been applied as an adjuvant. Here, we examined the adjuvant activity and safety of chemically synthesized Alcaligenes lipid A. We found that levels of OVA-specific serum IgG antibodies increased in mice that were subcutaneously immunized with ovalbumin (OVA) plus Alcaligenes lipid A relative to those that were immunized with OVA alone. In addition, Alcaligenes lipid A promoted antigen-specific T helper 17 (Th17) responses in the spleen, upregulated the expression of MHC class II, CD40, CD80, and CD86 on bone marrow-derived dendritic cells (BMDCs), enhanced the production of Th17-inducing cytokines IL-6 and IL-23 from BMDCs. Stimulation with Alcaligenes lipid A also induced the production of IL-6 and IL-1&beta, in human peripheral blood mononuclear cells. Moreover, Alcaligenes lipid A caused minor side effects, such as lymphopenia and thrombocytopenia. These findings suggest that Alcaligenes lipid A is a safe and effective Th17-type adjuvant by directly stimulating dendritic cells in systemic vaccination.
- Published
- 2020
28. Activities of the Consortium for Medicine, Chemistry, and Physics at Osaka University
- Author
-
Tadashi Watabe, Atsushi Toyoshima, Takashi Yoshimura, Yoshifumi Shirakami, Kazuko Kaneda, Koichi Fukase, Yoshiyuki Manabe, Zijian Zhang, Atsushi Shinohara, Atsushi Shimoyama, and Kazuya Kabayama
- Subjects
Radiological and Ultrasound Technology ,Chemistry ,Library science ,Radiology, Nuclear Medicine and imaging ,Chemistry (relationship) - Published
- 2019
29. Gut Microbial Lipopolysaccharide Interacts with Host Immune System
- Author
-
Atsushi Shimoyama
- Subjects
Autoimmune disease ,Innate immune system ,Lipopolysaccharide ,biology ,Host (biology) ,Organic Chemistry ,Immune regulation ,Gut flora ,biology.organism_classification ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,Immune system ,chemistry ,Immunology ,medicine - Published
- 2019
30. Effective Synthesis of Oligosaccharide under Microfluidic Conditions
- Author
-
Atsushi Shimoyama, Koichi Fukase, and Yoshiyuki Manabe
- Subjects
chemistry.chemical_classification ,Chemistry ,Organic Chemistry ,Microfluidics ,Nanotechnology ,Oligosaccharide - Published
- 2015
31. Establishment of novel targeted alpha-radionuclide medicine
- Author
-
Zijian Zhang, Takashi Nakano, Takashi Yoshimura, Tadashi Watabe, Atsushi Shimoyama, Atsushi Shinohara, Mitsuhiro Fukuda, Norifumi Shirakami, Yoshiyuki Manabey, Kazuko Kaneda, Atsushi Toyoshima, Koichi Fukase, Kazuya Kabayama, Yoshikatsu Kanai, and Jun Hatazawaj
- Subjects
Thesaurus (information retrieval) ,Information retrieval ,Computer science ,Applied Mathematics ,General Mathematics ,Alpha (navigation) - Published
- 2019
32. Access to a novel near-infrared photodynamic therapy through the combined use of 5-aminolevulinic acid and lanthanide nanoparticles
- Author
-
Kiwamu Takahashi, Hideya Yuasa, Katsushi Inoue, Yasutoshi Murayama, Atsushi Shimoyama, Hiroya Watase, Eigo Otsuji, Tohru Tanaka, Shun-ichiro Ogura, Yuichiro Hagiya, Yu Liu, and Akihiro Ohkubo
- Subjects
Infrared Rays ,medicine.medical_treatment ,Biophysics ,Photodynamic therapy ,Dermatology ,Photochemistry ,Lanthanoid Series Elements ,chemistry.chemical_compound ,Stomach Neoplasms ,Cell Line, Tumor ,medicine ,Humans ,Pharmacology (medical) ,MTT assay ,Viability assay ,Irradiation ,Cytotoxicity ,Photosensitizing Agents ,Protoporphyrin IX ,Chemistry ,Singlet oxygen ,Aminolevulinic Acid ,Treatment Outcome ,Photochemotherapy ,Oncology ,Cancer cell ,Nanoparticles ,Drug Therapy, Combination - Abstract
Summary Background There have been considerable efforts to develop photodynamic therapy (PDT) for cancer, in which photoirradiation of a sensitizer delivered near cancer cells results in the conversion of oxygen into active species, causing cell destruction. Aiming at the best cancer selectivity, one PDT method employed protoporphyrin IX (PPIX), which selectively accumulated in cancer cells after oral administration of 5-aminolevulinic acid (ALA). The drawback, however, is that blue incident lights are required to excite PPIX, resulting in low tissue penetrability, and therefore limiting its application to surface cancers. Methods To overcome the low penetrability of the incident light, we employed a light energy upconverter, lanthanide nanoparticle (LNP), which, upon irradiation with highly penetrative near-infrared (NIR) radiation, emits visible light within the Q-band region of PPIX absorbance allowing its sensitization. To discover the optimum conditions for the LNP-assisted PDT, the cytotoxicity and PPIX-sensitizability of LNPs were first studied. Then, the LNP-assisted PDT was validated using the MKN45 cell line: cells were pretreated with ALA and LNP, irradiated with a 975-nm diode laser, and subjected to MTT assay to measure cell viability. Results The singlet oxygen generation on NIR-irradiation of the PPIX-LNP mixture was proved, indicating that the emission from LNP could excite the PPIX sensitizer. An intermittent NIR-irradiation for 32 min of MKN45, pretreated with LNP (1 mg/mL) and ALA (2 mM), caused 87% cell destruction. Conclusions The potential applicability of the NIR-irradiation PDT with ALA- and LNP-pretreated cancer cells was demonstrated.
- Published
- 2013
33. SUGAR SYNTHESIS BY MICROFLUIDIC TECHNIQUES
- Author
-
Atsushi Shimoyama, Katsunori Tanaka, Koichi Fukase, Yukari Fujimoto, and Yoshiyuki Manabe
- Subjects
N-linked glycosylation ,Biochemistry ,Chemistry ,Microfluidics ,Asparagine ,Sugar ,Oligosaccharide synthesis - Published
- 2016
34. Synthesis of Bacterial Glycoconjugates and Their Bio-functional Studies in Innate Immunity
- Author
-
Yukari Fujimoto, Katsunori Tanaka, Atsushi Shimoyama, and Koichi Fukase
- Subjects
chemistry.chemical_classification ,Innate immune system ,Lipopolysaccharide ,Glycoconjugate ,Organic Chemistry ,body regions ,Lipid A ,chemistry.chemical_compound ,chemistry ,Biochemistry ,NOD1 ,TLR4 ,Peptidoglycan ,Receptor - Abstract
Immunostimulating glycoconjugates from bacteria were synthesized for elucidation of the recognition with innate immune receptors. Synthesis of partial structures and analogues of lipopolysaccharide and its bioactive principle ‘lipid A’ contributed the elucidation of mode of action, i.e., interaction of lipopolysaccharide with its receptor ‘TLR4/MD-2 complex’. Immunomodulation by parasitic bacteria ‘Helicobacter pylori’ was elucidated by using synthetic lipopolysaccharide partial structures. Intracellular peptidoglycan receptors, ‘Nod1’ and ‘Nod2’, and their ligand structures were identified by using synthetic peptidoglycan partial structures. New Nod1 ligands were identified from the bacterial supernatant. In vivo function of Nod1 was studied by using synthetic ligands found from small library of Nod1 ligands.
- Published
- 2012
35. Chemical Synthesis of Helicobacter pylori Lipopolysaccharide Partial Structures and their Selective Proinflammatory Responses
- Author
-
Atsushi Shimoyama, Kensuke Miyake, Yasuo Suda, Koichi Fukase, Yukari Fujimoto, Natsuko Tanimura, Hiroko Tsutsui, and Akinori Saeki
- Subjects
Lipopolysaccharides ,Glycosylation ,Lipopolysaccharide ,medicine.medical_treatment ,Chronic gastritis ,Inflammation ,Catalysis ,Proinflammatory cytokine ,Microbiology ,Lipid A ,Structure-Activity Relationship ,chemistry.chemical_compound ,Escherichia coli ,medicine ,Humans ,Helicobacter pylori ,biology ,Interleukin-6 ,Chemistry ,Interleukin-8 ,Organic Chemistry ,NF-kappa B ,General Chemistry ,medicine.disease ,biology.organism_classification ,Interleukin-12 ,Cytokine ,Biochemistry ,Ethanolamines ,Gastritis ,Cytokines ,lipids (amino acids, peptides, and proteins) ,medicine.symptom - Abstract
Helicobacter pylori is a common cause of gastroduodenal inflammatory diseases such as chronic gastritis and peptic ulcers and also an important factor in gastric carcinogenesis. Recent reports have demonstrated that bacterial inflammatory processes, such as stimulation with H. pylori lipopolysaccharide (LPS), initiate atherosclerosis. To establish the structures responsible for the inflammatory response of H. pylori LPS, we synthesized various kinds of lipid A structures (i.e., triacylated lipid A and Kdo-lipid A compounds), with or without the ethanolamine group at the 1-phosphate moiety, by a new divergent synthetic route. Stereoselective α-glycosylation of Kdo N-phenyltrifluoroacetimidate was achieved by use of microfluidic methods. None of the lipid A and Kdo-lipid A compounds were a strong inducer of IL-1β, IL-6, or IL-8, suggesting that H. pylori LPS is unable to induce acute inflammation. In fact, the lipid A and Kdo-lipid A compounds showed antagonistic activity against cytokine induction by E. coli LPS, except for the lipid A compound with the ethanolamine group, which showed very weak agonistic activity. On the other hand, these H. pylori LPS partial structures showed potent IL-18- and IL-12-inducing activities. IL-18 has been shown to correlate with chronic inflammation, so H. pylori LPS might be implicated in the chronic inflammatory responses induced by H. pylori. These results also indicated that H. pylori LPS can modulate the immune response: NF-κB activation through hTLR4/MD-2 was suppressed, whereas production of IL-18 and IL-12 was promoted.
- Published
- 2011
36. Stereoselective Glycosylation of 3-Deoxy-d-manno-2-octulosonic Acid with Batch and Microfluidic Methods
- Author
-
Atsushi Shimoyama, Koichi Fukase, and Yukari Fujimoto
- Subjects
chemistry.chemical_compound ,Glycosylation ,Stereochemistry ,Chemistry ,Organic Chemistry ,Organic chemistry ,Stereoselectivity ,Carbocation ,2-Octulosonic acid - Published
- 2011
37. Synthesis of immunoregulatory Helicobacter pylori lipopolysaccharide partial structures
- Author
-
Yukari Fujimoto, Koichi Fukase, Shoichi Kusumoto, Atsushi Shimoyama, Noriko Imakita, Masato Iwata, and Yasuo Suda
- Subjects
chemistry.chemical_classification ,Lipopolysaccharide ,biology ,Glycoconjugate ,Organic Chemistry ,Helicobacter pylori ,biology.organism_classification ,Biochemistry ,Microbiology ,chemistry.chemical_compound ,Immune system ,chemistry ,Drug Discovery ,lipids (amino acids, peptides, and proteins) - Abstract
The synthesis of immunoregulatory glycoconjugates, namely the active entity of lipopolysaccharide (LPS) from Helicobacter pylori was achieved. The results of biological activities of the LPS partial structures provide the structural basis for the immunobiological activity, especially for the immune inhibitory activity of H. pylori LPS.
- Published
- 2007
38. IEIIS Meeting minireview: Chemical synthesis of peptidoglycan fragments for elucidation of the immunostimulating mechanism
- Author
-
Seiichi Inamura, Zenyu Shiokawa, Shoichi Kusumoto, Atsushi Shimoyama, Koichi Fukase, Yukari Fujimoto, Takashi Hashimoto, and Akiko Kawasaki
- Subjects
0301 basic medicine ,030106 microbiology ,Immunology ,Biological activity ,Cell Biology ,Transfection ,Biology ,Microbiology ,Chemical synthesis ,carbohydrates (lipids) ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Infectious Diseases ,chemistry ,Biochemistry ,Cell culture ,NOD1 ,Moiety ,Molecule ,Peptidoglycan ,Molecular Biology ,030215 immunology - Abstract
Partial structures of peptidoglycan were chemically synthesized for elucidation of their precise biological activities. By using an efficient synthetic strategy, mono-, di-, tetra- and octasaccharide fragments of peptidoglycan were synthesized in good yields. The biological activity of synthetic fragments of peptidoglycan was evaluated by induction of TNF-α from human monocytes, and TLR2 and NOD2 dependencies by using transfected HEK293 cells, respectively. We revealed that TLR2 was not stimulated by the series of synthetic peptidoglycan partial structures, whereas NOD2 recognizes the partial structures containing the MDP moiety. We also synthesized potent NOD1 agonists, which showed several hundred-fold stronger activity than γ-D-glutamyl- meso-diaminopimelic acid (iE-DAP). Interaction of PGRPs with synthetic peptidoglycan fragments is also described.
- Published
- 2007
39. A symmetrical and biodegradable cationic lipid. Synthesis and application for efficient gene transfection
- Author
-
Takeshi Uneda, Kazuyuki Miyashita, Takefumi Doi, Atsushi Shimoyama, Wei Yu, Satoshi Obika, and Takeshi Imanishi
- Subjects
Phosphatidylethanolamine ,Liposome ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Phospholipid ,Cationic polymerization ,Pharmaceutical Science ,Lipid metabolism ,Transfection ,Biochemistry ,Combinatorial chemistry ,chemistry.chemical_compound ,Drug Discovery ,Molecular Medicine ,Organic chemistry ,lipids (amino acids, peptides, and proteins) ,Cationic liposome ,Cytotoxicity ,Molecular Biology - Abstract
A novel cationic lipid with a symmetrical and biodegradable structure was synthesized, and the transfection efficiency and the cytotoxicity of the cationic liposomes composed of the cationic lipid and dioleoylphosphatidylethanolamine (DOPE) were studied.
- Published
- 1997
40. Innate immunomodulation by lipophilic termini of lipopolysaccharide; synthesis of lipid As from Porphyromonas gingivalis and other bacteria and their immunomodulative responses
- Author
-
Naohiro Kitayama, Akinori Saeki, Chika Kasamatsu, Hiroko Tsutsui, Atsushi Shimoyama, Koichi Fukase, and Yukari Fujimoto
- Subjects
Lipopolysaccharides ,medicine.medical_treatment ,Inflammation ,Enzyme-Linked Immunosorbent Assay ,Chemistry Techniques, Synthetic ,Microbiology ,Helicobacter Infections ,Lipid A ,Immunomodulation ,Immune system ,Immunity ,medicine ,Bacteroidaceae Infections ,Humans ,Molecular Biology ,Porphyromonas gingivalis ,biology ,Helicobacter pylori ,Molecular Structure ,Interleukin-6 ,Interleukin-8 ,biology.organism_classification ,Immunity, Innate ,Cytokine ,Biochemistry ,Models, Chemical ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Bacteria ,Biotechnology - Abstract
Synthetic studies of lipid A and LPS partial structures have been performed to investigate the relationship between structures and functions of LPS. Recent studies have suggested several pathological implications of LPS from parasitic bacteria due to its influence on the host immune responses. To address this issue, we established an efficient synthetic strategy that is widely applicable to the synthesis of various lipid As by using a key disaccharide intermediate with selectively cleavable protecting groups. Porphyromonas gingivalis and Helicobacter pylori lipid As were synthesized and their biological activities were evaluated. All synthetic lipid As did not induce strong inflammatory responses: some are very weak cytokine inducers and others are antagonistic in IL-6 and IL-8 induction with E. coli LPS. On the other hand, P. gingivalis lipid As showed potent IL-18 inducing activity. Since IL-18 has been shown to correlate with chronic inflammation, P. gingivalis LPS may be implicated in the chronic inflammatory responses.
- Published
- 2013
41. Sugar-attached upconversion lanthanide nanoparticles: a novel tool for high-throughput lectin assay
- Author
-
Tatsumi Tanaka, Izumi Sotokawa, Shun-ichiro Ogura, Yasutoshi Murayama, Takuya Kobayashi, Yu Liu, Eigo Otsuji, Atsushi Shimoyama, Hideya Yuasa, and Masayuki Iizuka
- Subjects
Lanthanide ,Clinical Biochemistry ,Pharmaceutical Science ,Nanoparticle ,Biochemistry ,Lanthanoid Series Elements ,chemistry.chemical_compound ,Mice ,Microscopy, Electron, Transmission ,Lectins ,Drug Discovery ,Animals ,Sugar ,Molecular Biology ,Cell Aggregation ,Spectroscopy, Near-Infrared ,biology ,Macrophages ,Organic Chemistry ,Lectin ,Galactose ,Combinatorial chemistry ,Photon upconversion ,High-Throughput Screening Assays ,chemistry ,Luminescent Measurements ,Luminophore ,biology.protein ,Molecular Medicine ,Nanoparticles ,Luminescence ,Mannose - Abstract
To create a novel high-throughput lectin assay (HTPLA) method based on the emission of a luminophore by highly penetrable near-infrared excitation, sugar-attached upconversion lanthanide nanoparticles (LNPs) were synthesized as a tool to highlight the aggregates caused by the sugar-mediated specific bridging between LNP and lectin. The emissions from a mannose-coated LNP in the aggregates with a mannose-binding lectin were much stronger than those from the non-aggregated samples, being sensitive enough for HTPLA. A galactose-coated LNP was also applicable to a macrophage aggregation assay for the sugar specificity of its surface lectin.
- Published
- 2013
42. ChemInform Abstract: Synthesis and Immunomodulatory Activities of Helicobacter Pylori Lipophilic Terminus of Lipopolysaccharide Including Lipid A
- Author
-
Atsushi Shimoyama, Yasuo Suda, Yukari Fujimoto, and Koichi Fukase
- Subjects
biology ,Lipopolysaccharide ,Chemistry ,medicine.medical_treatment ,Chronic gastritis ,General Medicine ,Helicobacter pylori ,biology.organism_classification ,medicine.disease ,Chemical synthesis ,Microbiology ,Lipid A ,chemistry.chemical_compound ,Cytokine ,Immune system ,medicine ,lipids (amino acids, peptides, and proteins) ,Bacteria - Abstract
Helicobacter pylori, a Gram-negative bacterium, causes gastroduodenal inflammatory diseases such as chronic gastritis and peptic ulcers, and is also a risk factor for gastric carcinogenesis. In this article, we review recent developments and findings in the chemical synthesis and immunomodulatory activities of H. pylori lipid A and 3-deoxy-D-manno-2-octulosonic acid (Kdo)-lipid A, to clarify the structural basis for the inflammatory response to H. pylori LPS. The synthetic methods include a new divergent synthetic approach with a widely applicable key intermediate for other types of lipid A structures, as well as a selective α-glycosylation reaction between Kdo and lipid A. Cytokine induction assays of the chemically synthesized lipid A structures showed selective cytokine induction depending on the patterns of acyl groups and phosphate groups. The results of cytokine induction assay suggested that H. pylori LPS can modulate the immune response during infection, and also plays a role in chronic inflammatory responses.
- Published
- 2012
43. Bioorthogonal Reactions for Biomolecular Functionalization and Imaging
- Author
-
Atsushi Shimoyama
- Subjects
Chemistry ,Organic Chemistry ,Surface modification ,Nanotechnology ,Bioorthogonal chemistry - Published
- 2014
44. Self and nonself recognition with bacterial and animal glycans, surveys by synthetic chemistry
- Author
-
Yukari, Fujimoto, Katsunori, Tanaka, Atsushi, Shimoyama, and Koichi, Fukase
- Subjects
Lipopolysaccharides ,Toll-Like Receptor 4 ,Bacteria ,Carbohydrate Sequence ,Polysaccharides ,Gram-Negative Bacteria ,Host-Pathogen Interactions ,Molecular Sequence Data ,Animals ,Humans ,Peptidoglycan ,Immunity, Innate - Abstract
In this chapter, we describe synthetic studies on partial structures of lipopolysaccharide (LPS) and peptidoglycan (PGN), which work as tags for nonself recognition in innate immune system. Our previous studies demonstrated that lipid A is the endotoxic principle of LPS. The synthetic homogeneous preparations have enabled not only precise structure-activity relationships, but also recognition mechanisms of LPS with innate immune receptor complexes, including the TLR4/MD-2 complex, to be studied. Synthetic studies of lipid A and Kdo-lipid A from parasitic Helicobacter pylori revealed their low inflammatory activities, suggesting the molecular evolution to escape from the host immune system. A synthetic study of the partial structures of PGN has also contributed to the understanding of the innate immune mechanism. The biological activities of the synthetic fragments have revealed that the intracellular receptor Nod2 recognizes partial structures containing the muramyl dipeptide (MDP) moiety. The PGN of Gram-negative bacteria and some Gram-positive bacteria contain meso-diaminopimelic acid (meso-DAP), and recent studies have revealed that the intracellular receptor Nod1 recognizes DAP-containing peptides. We have synthesized DAP-containing PGN fragments, including the first chemical synthesis of tracheal cytotoxin (TCT). The ability of these fragments to stimulate human Nod1 as well as differences in Nod1 recognition for various synthesized ligand structures was elucidated. Cell-surface glycans such as N-glycans and O-glycans on glycoproteins and glycoconjugates work as signaling molecules for self-recognition and control immune system. Our new strategy using glycan-imaging in whole-body system is expected to unveil the dynamics of glycans in the body. Positron emission tomography (PET) is a noninvasive method that visualizes the locations and levels of radiotracer accumulation. We developed the facile labeling of peptides and proteins for PET imaging. The labeled glycoproteins and glycoclusters were then subjected to PET imaging in order to examine their in vivo dynamics, visualizing the differences in the circulatory residence of glycoproteins and glycoclusters in the presence or absence of sialic acid residues.
- Published
- 2010
45. ChemInform Abstract: A Symmetrical and Biodegradable Cationic Lipid. Synthesis and Application for Efficient Gene Transfection
- Author
-
Takeshi Uneda, Kazuyuki Miyashita, Takeshi Imanishi, Atsushi Shimoyama, Takefumi Doi, Wei Yu, and Satoshi Obika
- Subjects
Chemistry ,Cationic polymerization ,lipids (amino acids, peptides, and proteins) ,Cationic liposome ,Lipid metabolism ,General Medicine ,Transfection ,Cytotoxicity ,Combinatorial chemistry - Abstract
A novel cationic lipid with a symmetrical and biodegradable structure was synthesized, and the transfection efficiency and the cytotoxicity of the cationic liposomes composed of the cationic lipid and dioleoylphosphatidylethanolamine (DOPE) were studied.
- Published
- 2010
46. Self and Nonself Recognition with Bacterial and Animal Glycans, Surveys by Synthetic Chemistry
- Author
-
Katsunori Tanaka, Koichi Fukase, Yukari Fujimoto, and Atsushi Shimoyama
- Subjects
Lipid A ,chemistry.chemical_compound ,Gram-negative bacteria ,Innate immune system ,biology ,chemistry ,Biochemistry ,NOD2 ,Tracheal cytotoxin ,NOD1 ,biology.organism_classification ,Muramyl dipeptide ,Sialic acid - Abstract
In this chapter, we describe synthetic studies on partial structures of lipopolysaccharide (LPS) and peptidoglycan (PGN), which work as tags for nonself recognition in innate immune system. Our previous studies demonstrated that lipid A is the endotoxic principle of LPS. The synthetic homogeneous preparations have enabled not only precise structure-activity relationships, but also recognition mechanisms of LPS with innate immune receptor complexes, including the TLR4/MD-2 complex, to be studied. Synthetic studies of lipid A and Kdo-lipid A from parasitic Helicobacter pylori revealed their low inflammatory activities, suggesting the molecular evolution to escape from the host immune system. A synthetic study of the partial structures of PGN has also contributed to the understanding of the innate immune mechanism. The biological activities of the synthetic fragments have revealed that the intracellular receptor Nod2 recognizes partial structures containing the muramyl dipeptide (MDP) moiety. The PGN of Gram-negative bacteria and some Gram-positive bacteria contain meso-diaminopimelic acid (meso-DAP), and recent studies have revealed that the intracellular receptor Nod1 recognizes DAP-containing peptides. We have synthesized DAP-containing PGN fragments, including the first chemical synthesis of tracheal cytotoxin (TCT). The ability of these fragments to stimulate human Nod1 as well as differences in Nod1 recognition for various synthesized ligand structures was elucidated. Cell-surface glycans such as N-glycans and O-glycans on glycoproteins and glycoconjugates work as signaling molecules for self-recognition and control immune system. Our new strategy using glycan-imaging in whole-body system is expected to unveil the dynamics of glycans in the body. Positron emission tomography (PET) is a noninvasive method that visualizes the locations and levels of radiotracer accumulation. We developed the facile labeling of peptides and proteins for PET imaging. The labeled glycoproteins and glycoclusters were then subjected to PET imaging in order to examine their in vivo dynamics, visualizing the differences in the circulatory residence of glycoproteins and glycoclusters in the presence or absence of sialic acid residues.
- Published
- 2010
47. ChemInform Abstract: Chemical Synthesis of Peptidoglycan Fragments for Elucidation of the Immunostimulating Mechanism
- Author
-
Yukari Fujimoto, Akiko Kawasaki, Takashi Hashimoto, Atsushi Shimoyama, Seiichi Inamura, Shoichi Kusumoto, Zenyu Shiokawa, and Koichi Fukase
- Subjects
carbohydrates (lipids) ,TLR2 ,chemistry.chemical_compound ,Chemistry ,Stereochemistry ,HEK 293 cells ,NOD1 ,Moiety ,Biological activity ,General Medicine ,Transfection ,Peptidoglycan ,Chemical synthesis - Abstract
Partial structures of peptidoglycan were chemically synthesized for elucidation of their precise biological activities. By using an efficient synthetic strategy, mono-, di-, tetra- and octasaccharide fragments of peptidoglycan were synthesized in good yields. The biological activity of synthetic fragments of peptidoglycan was evaluated by induction of TNF-alpha from human monocytes, and TLR2 and NOD2 dependencies by using transfected HEK293 cells, respectively. We revealed that TLR2 was not stimulated by the series of synthetic peptidoglycan partial structures, whereas NOD2 recognizes the partial structures containing the MDP moiety. We also synthesized potent NOD1 agonists, which showed several hundred-fold stronger activity than gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP). Interaction of PGRPs with synthetic peptidoglycan fragments is also described.
- Published
- 2008
48. Chemical synthesis of peptidoglycan fragments for elucidation of the immunostimulating mechanism
- Author
-
Yukari, Fujimoto, Seiichi, Inamura, Akiko, Kawasaki, Zenyu, Shiokawa, Atsushi, Shimoyama, Takashi, Hashimoto, Shoichi, Kusumoto, and Koichi, Fukase
- Subjects
Toll-Like Receptor 4 ,Molecular Structure ,Tumor Necrosis Factor-alpha ,Nod1 Signaling Adaptor Protein ,Nod2 Signaling Adaptor Protein ,Humans ,Peptidoglycan ,Transfection ,Monocytes ,Peptide Fragments ,Toll-Like Receptor 2 ,Cell Line - Abstract
Partial structures of peptidoglycan were chemically synthesized for elucidation of their precise biological activities. By using an efficient synthetic strategy, mono-, di-, tetra- and octasaccharide fragments of peptidoglycan were synthesized in good yields. The biological activity of synthetic fragments of peptidoglycan was evaluated by induction of TNF-alpha from human monocytes, and TLR2 and NOD2 dependencies by using transfected HEK293 cells, respectively. We revealed that TLR2 was not stimulated by the series of synthetic peptidoglycan partial structures, whereas NOD2 recognizes the partial structures containing the MDP moiety. We also synthesized potent NOD1 agonists, which showed several hundred-fold stronger activity than gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP). Interaction of PGRPs with synthetic peptidoglycan fragments is also described.
- Published
- 2007
49. Clinical and follow-up study of cenesthopathic patients
- Author
-
Atsushi Shimoyama
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Follow up studies ,Medicine ,business - Published
- 1978
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