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  1. Article ; Online: Development of an SS-Cleavable pH-Activated Lipid-Like Material (ssPalm) as a Nucleic Acid Delivery Device.

    Akita, Hidetaka

    Biological & pharmaceutical bulletin

    2020  Volume 43, Issue 11, Page(s) 1617–1625

    Abstract: Gene and nucleic acid-based medication is an ultimate strategy in the field of personalized medicine. A gene or short interference RNA (siRNA) molecule needs to be delivered to the appropriate organelle (i.e., nucleus and cytoplasm, respectively). We ... ...

    Abstract Gene and nucleic acid-based medication is an ultimate strategy in the field of personalized medicine. A gene or short interference RNA (siRNA) molecule needs to be delivered to the appropriate organelle (i.e., nucleus and cytoplasm, respectively). We recently focused on improving the intrinsic activity of my original material (ssPalm) in terms of endosomal/lysosomal membrane destabilization activity by chemically modifying the tertiary amine structure. In parallel, I have been expanding the range of applications of ssPalms. The first application is a DNA or RNA vaccine. My crucial finding is that the vitamin E-scaffold ssPalm (ssPalmE) is highly immune-stimulative when combined with DNA. Thereafter, I redesigned the hydrophobic scaffold structure, and found that an oleic acid-scaffold ssPalm (ssPalmO) can confer anti-inflammatory characteristics. Based on this result, I further upgraded the ssPalmO, by inserting a newly designed linker with self-degradable properties.
    MeSH term(s) Animals ; DNA/administration & dosage ; Disease Models, Animal ; Drug Carriers/chemistry ; Drug Development ; Gene Transfer Techniques ; Genetic Therapy/methods ; Humans ; Hydrophobic and Hydrophilic Interactions ; Lipids/chemistry ; Nanoparticles ; Precision Medicine/methods ; RNA, Small Interfering/administration & dosage ; Vitamin E/chemistry
    Chemical Substances Drug Carriers ; Lipids ; RNA, Small Interfering ; Vitamin E (1406-18-4) ; DNA (9007-49-2)
    Language English
    Publishing date 2020-10-28
    Publishing country Japan
    Document type Journal Article ; Review
    ZDB-ID 1150271-x
    ISSN 1347-5215 ; 0918-6158
    ISSN (online) 1347-5215
    ISSN 0918-6158
    DOI 10.1248/bpb.b20-00534
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Toxoplasma gondii

    Hasan, Tanjila / Kawanishi, Ryo / Akita, Hidetaka / Nishikawa, Yoshifumi

    Vaccines

    2021  Volume 10, Issue 1

    Abstract: Toxoplasma ... ...

    Abstract Toxoplasma gondii
    Language English
    Publishing date 2021-12-24
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2703319-3
    ISSN 2076-393X
    ISSN 2076-393X
    DOI 10.3390/vaccines10010021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Lymphatic Endothelial Cells Produce Chemokines in Response to the Lipid Nanoparticles Used in RNA Vaccines.

    Liu, Yi / Suzuoki, Miho / Tanaka, Hiroki / Sakurai, Yu / Hatakeyama, Hiroto / Akita, Hidetaka

    Biological & pharmaceutical bulletin

    2024  Volume 47, Issue 3, Page(s) 698–707

    Abstract: RNA vaccines based on Lipid nanoparticles (LNP) were put into practical use within only one year after the global outbreak of the coronavirus disease 2019 (COVID-19). This success of RNA vaccine highlights the utility of an mRNA delivery system as a ... ...

    Abstract RNA vaccines based on Lipid nanoparticles (LNP) were put into practical use within only one year after the global outbreak of the coronavirus disease 2019 (COVID-19). This success of RNA vaccine highlights the utility of an mRNA delivery system as a vaccination strategy. Potent immunostimulatory activity of LNPs (i.e., inflammation occurring at the injection site and the production of inflammatory cytokines) have recently been reported. However, we have only limited knowledge concerning which cells are responsible for responding to the LNPs. We report herein on in vitro chemokine production from non-immune cells in response to exposure to LNPs. In this study, SM-102, an ionizable lipid that is used in the approved RNA vaccine for the clinical usage of COVID-19 mRNA vaccine, was used. Immortalized mouse lymphatic endothelial cells (mLECs) or professional antigen presenting cells (APCs) such as RAW 264.7 monocyte/macrophage cells were incubated with LNPs that contained no mRNA. As a result, chemokines involved in the recruitment of monocytes/neutrophils were produced only by the mLECs following the LNP treatment. These findings indicate that LEC appear to serve as the cell that sends out initial signals to response LNPs.
    MeSH term(s) Animals ; Humans ; Mice ; mRNA Vaccines ; COVID-19 Vaccines ; Endothelial Cells ; Chemokines ; COVID-19 ; RNA, Messenger ; Nanoparticles ; RNA, Small Interfering ; Liposomes
    Chemical Substances Lipid Nanoparticles ; mRNA Vaccines ; COVID-19 Vaccines ; Chemokines ; RNA, Messenger ; RNA, Small Interfering ; Liposomes
    Language English
    Publishing date 2024-03-27
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 1150271-x
    ISSN 1347-5215 ; 0918-6158
    ISSN (online) 1347-5215
    ISSN 0918-6158
    DOI 10.1248/bpb.b23-00689
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Cellular Binding and Internalization Assay for an Anti-FcγRIIB Antibody Using Human Liver Non-parenchymal Cells.

    Noguchi, Yuki / Ozeki, Kazuhisa / Akita, Hidetaka

    Biological & pharmaceutical bulletin

    2022  Volume 45, Issue 4, Page(s) 534–537

    Abstract: A cellular assay for evaluating the binding and internalization of biologics using primary human liver sinusoidal endothelial cells (LSEC) is not readily available, since human LSEC generally lose their receptor expression and internalization activity ... ...

    Abstract A cellular assay for evaluating the binding and internalization of biologics using primary human liver sinusoidal endothelial cells (LSEC) is not readily available, since human LSEC generally lose their receptor expression and internalization activity during the purifying processes and cell culturing. Here, we propose a novel cell-based assay using human liver non-parenchymal cells (NPC) as an alternative method using LSEC. To identify the LSEC population, NPC were stained with CD31 and CD45, and analyzed by flow cytometry. The expression of Fc gamma receptor IIB (FcγRIIB), one of the LSEC markers was detected in the CD31-positive and the CD45-negative fractions. The concentration-dependent binding and internalization of the anti-FcγRIIB antibody was also quantified in the LSEC fraction in human NPC. Saturated binding and internalization curves were obtained for the anti-FcγRIIB antibody. In the case of the negative control antibody, however, binding and internalization were negligible. The findings reported here indicate that cell-based assays using fresh human liver NPC will be useful for evaluating the binding and internalization of biologics as well as for determining pharmacokinetic parameters.
    MeSH term(s) Antibodies ; Cells, Cultured ; Endothelial Cells/metabolism ; Hepatocytes ; Humans ; Liver/metabolism
    Chemical Substances Antibodies
    Language English
    Publishing date 2022-04-01
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 1150271-x
    ISSN 1347-5215 ; 0918-6158
    ISSN (online) 1347-5215
    ISSN 0918-6158
    DOI 10.1248/bpb.b21-01026
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Formation of reactive metabolites of benzbromarone in humanized-liver mice.

    Cho, Naoki / Suemizu, Hiroshi / Kamimura, Hidetaka / Ohe, Tomoyuki / Ito, Fumi / Akita, Hidetaka / Kobayashi, Kaoru

    Drug metabolism and pharmacokinetics

    2022  Volume 47, Page(s) 100467

    Abstract: Benzbromarone, a uricosuric drug, has the potential to cause serious hepatotoxicity. Several studies have shown the formation of reactive metabolites of benzbromarone and their association with hepatotoxicity in mice. However, it is unknown whether those ...

    Abstract Benzbromarone, a uricosuric drug, has the potential to cause serious hepatotoxicity. Several studies have shown the formation of reactive metabolites of benzbromarone and their association with hepatotoxicity in mice. However, it is unknown whether those reactive metabolites are generated in humans in vivo. In the present study, we firstly investigated the pharmacokinetic profiles of benzbromarone in chimeric TK-NOG mice transplanted with human hepatocytes (humanized-liver mice) and then investigated whether reactive metabolites could be generated. The area under the plasma concentration-time curve ratio of benzbromarone and its major metabolites (benzbromarone: 1'-hydroxy benzbromarone: 6-hydroxy benzbromarone) in humanized-liver mice was 1: 1.2: 0.7, which was similar to that reported in humans. In addition, glutathione conjugates and their further metabolites derived from the epoxidation of the benzofuran ring and 1',6-dihydroxylation of benzbromarone were detected in the livers, urine and plasma. Furthermore, their peak intensities in mass spectrometry showed markedly higher levels compared with those of TK-NOG mice. These results suggested that the metabolic profiles of benzbromarone in humanized-liver mice were similar to those in humans and that the reactive metabolites detected in humanized-liver mice could be generated and are associated with the benzbromarone-induced hepatotoxicity in humans.
    MeSH term(s) Mice ; Humans ; Animals ; Benzbromarone/metabolism ; Liver/metabolism ; Hepatocytes/metabolism ; Microsomes, Liver/metabolism ; Chemical and Drug Induced Liver Injury/metabolism
    Chemical Substances Benzbromarone (4POG0RL69O)
    Language English
    Publishing date 2022-08-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 2095748-8
    ISSN 1880-0920 ; 1347-4367 ; 0916-1139
    ISSN (online) 1880-0920
    ISSN 1347-4367 ; 0916-1139
    DOI 10.1016/j.dmpk.2022.100467
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Toxoplasma gondii GRA15 DNA Vaccine with a Liposomal Nanocarrier Composed of an SS-Cleavable and pH-Activated Lipid-like Material Induces Protective Immunity against Toxoplasmosis in Mice

    Tanjila Hasan / Ryo Kawanishi / Hidetaka Akita / Yoshifumi Nishikawa

    Vaccines, Vol 10, Iss 21, p

    2022  Volume 21

    Abstract: Toxoplasma gondii affects the health of humans and livestock and causes severe illness in the fetus and immunocompromised individuals. Because of the high incidence and severe consequences of T. gondii infection, a safe and suitable vaccine is needed. We ...

    Abstract Toxoplasma gondii affects the health of humans and livestock and causes severe illness in the fetus and immunocompromised individuals. Because of the high incidence and severe consequences of T. gondii infection, a safe and suitable vaccine is needed. We found that lipid nanoparticles (LNPs) consisting of a series of functional materials prepared with vitamin E, such as SS-cleavable and pH-activated lipid-like materials (ssPalmE), were a safe and efficient way to develop next-generation DNA vaccines. In this study, we prepared ssPalmE-LNP to encapsulate pCpG-free- T. gondii dense granule protein 15 DNA (ssPalmE-LNP TgGRA15 ). Following a challenge infection with avirulent PLK strain of T. gondii , the mice immunized with ssPalmE-LNP TgGRA15 had a significantly higher survival rate and lower clinical scores compared with unimmunized and ssPalmE-LNP non-coding -immunized mice. Immunization of mice with the ssPalmE-LNP TgGRA15 led to a significantly higher production of specific IgG1 and IG2c antibodies compared with unimmunized and ssPalmE-LNP non-coding -immunized mice, while there was no statistically significant difference in the concentration of serum interferon-gamma at the acute stage of the infection. These findings indicate that ssPalmE-LNP is an effective cargo for the transportation of DNA vaccines for protozoan infections. To explore the mechanism of protective immunity induced by ssPalmE-LNP TgGRA15 , further immunological study is needed in the future.
    Keywords DNA vaccine ; lipid nanoparticle ; TgGRA15 ; Medicine ; R
    Subject code 572
    Language English
    Publishing date 2022-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: A Lipid Nanoparticle-Based Method for the Generation of Liver-Specific Knockout Mice.

    Morita, Sumiyo / Horii, Takuro / Kimura, Mika / Kobayashi, Ryosuke / Tanaka, Hiroki / Akita, Hidetaka / Hatada, Izuho

    International journal of molecular sciences

    2023  Volume 24, Issue 18

    Abstract: Knockout mice are useful tools that can provide information about the normal function of genes, including their biochemical, developmental, and physiological roles. One problem associated with the generation of knockout mice is that the loss of some ... ...

    Abstract Knockout mice are useful tools that can provide information about the normal function of genes, including their biochemical, developmental, and physiological roles. One problem associated with the generation of knockout mice is that the loss of some genes of interest produces a lethal phenotype. Therefore, the use of conditioned knockout mice, in which genes are disrupted in specific organs, is essential for the elucidation of disease pathogenesis and the verification of drug targets. In general, conditional knockout mice are produced using the Cre/loxP system; however, the production of the large numbers of Cre/flox knockout and control mice required for analysis requires substantial time and effort. Here, we describe the generation of liver-specific conditional knockout mice via the introduction of lipid nanoparticles encapsulating
    Language English
    Publishing date 2023-09-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms241814299
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Reactivation of Anticancer Immunity by Resetting Interorgan Crosstalk in Immune-Suppressive Cells with a Nanoparticulated Anti-Inflammatory Drug.

    Doi, Mizuki / Tanaka, Hiroki / Ohoto, Takara / Miura, Naoya / Sakurai, Yu / Hatakeyama, Hiroto / Akita, Hidetaka

    Small (Weinheim an der Bergstrasse, Germany)

    2023  Volume 19, Issue 16, Page(s) e2205131

    Abstract: The reactivation of anticancer immunity is a fundamental principle in cancer immunotherapy as evidenced by the use of immune checkpoint inhibitors (ICIs). While treatment with the ICIs is shown to have remarkable and durable therapeutic effects in the ... ...

    Abstract The reactivation of anticancer immunity is a fundamental principle in cancer immunotherapy as evidenced by the use of immune checkpoint inhibitors (ICIs). While treatment with the ICIs is shown to have remarkable and durable therapeutic effects in the responders, the low objective response rate (<40%) continues to be a major problem. Since myeloid-derived suppressor cells (MDSCs), heterogenous cells with strong immunosuppressive activity that originate in the hematopoietic system, suppress the anticancer immunity via parallel immune checkpoint-dependent and independent pathways, these cells are potential targets for improving the efficacy of cancer immunotherapy. In this study, it is demonstrated that MDSCs can be depleted by delivering synthetic glucocorticoid dexamethasone to phagocytic cells in the spleen using a lipid nanoparticle. Since the interaction of nanoparticles with T cells is intrinsically poor, this strategy also enables the "detargeting" from T cells, thus avoiding the nonspecific suppression of cytotoxic immune responses against cancer cells. In addition to the direct anticancer effect of the nanoparticulated dexamethasone, their synergistic anticancer effect with ICIs is also reported.
    MeSH term(s) Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Myeloid-Derived Suppressor Cells/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Immunotherapy ; Tumor Microenvironment ; Dexamethasone/pharmacology
    Chemical Substances Anti-Inflammatory Agents ; Antineoplastic Agents ; Dexamethasone (7S5I7G3JQL)
    Language English
    Publishing date 2023-01-26
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2168935-0
    ISSN 1613-6829 ; 1613-6810
    ISSN (online) 1613-6829
    ISSN 1613-6810
    DOI 10.1002/smll.202205131
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: A cell based assay for evaluating binding and uptake of an antibody using hepatic nonparenchymal cells.

    Noguchi, Yuki / Ozeki, Kazuhisa / Takesue, Hiroaki / Akita, Hidetaka

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 8383

    Abstract: Evaluation of the binding and uptake of an antibody in liver non-parenchymal cells (NPC), including liver sinusoidal endothelial cells, is important for revealing its pharmacokinetic (PK) behavior, since NPC has important roles in eliminating an antibody ...

    Abstract Evaluation of the binding and uptake of an antibody in liver non-parenchymal cells (NPC), including liver sinusoidal endothelial cells, is important for revealing its pharmacokinetic (PK) behavior, since NPC has important roles in eliminating an antibody from the blood via the Fc fragment of IgG receptor IIB (FcγRIIB). However, there is currently no in vitro quantitative assay using NPC. This study reports on the development of a cell-based assay for evaluating the binding and uptake of such an antibody using liver NPC of mice and monkeys. In mice, the FcγRIIB-expressing cells were identified in the CD146-positive and CD45-negative fraction by flow cytometry. A titration assay was performed to determine the PK parameters, and the obtained parameter was comparable to that determined by the fitting of the in vivo PK. This approach was also extended to NPC from monkeys. The concentration-dependent binding and uptake was measured to determine the PK parameters using monkey NPC, the FcγRIIB-expressing fraction of which was identified by CD31 and CD45. The findings presented herein demonstrate that the in vitro liver NPC assay using flow cytometry is a useful tool to determine the binding and uptake of biologics and to predict the PK.
    MeSH term(s) Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/metabolism ; Endothelial Cells/immunology ; Endothelial Cells/metabolism ; Haplorhini ; Hepatocytes/immunology ; Hepatocytes/metabolism ; Immunoglobulin Fc Fragments/immunology ; Immunoglobulin Fc Fragments/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Receptors, IgG/immunology ; Receptors, IgG/physiology
    Chemical Substances Antibodies, Monoclonal ; Fcgr2b protein, mouse ; Immunoglobulin Fc Fragments ; Receptors, IgG
    Language English
    Publishing date 2021-04-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-87912-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Retiform hemangioendothelioma of the breast in a man with

    Ogura, Kaoru / Shibasaki, Yoko / Honda, Satoshi / Akita, Hidetaka / Aoki, Nobuhiko / Chong, Ja-Mun / Motoi, Toru

    Surgical case reports

    2023  Volume 9, Issue 1, Page(s) 53

    Abstract: Background: Retiform hemangioendothelioma (RH) is a rare, intermediate-grade vascular tumor that often arises in the trunk and extremities. The clinical and radiological features of RH remain largely unknown.: Case presentation: A male patient in his ...

    Abstract Background: Retiform hemangioendothelioma (RH) is a rare, intermediate-grade vascular tumor that often arises in the trunk and extremities. The clinical and radiological features of RH remain largely unknown.
    Case presentation: A male patient in his 70s presented with shortness of breath on exertion, and computed tomography incidentally revealed a tumor in his right breast. Positron emission tomography (PET) revealed moderate
    Conclusions: RH was found in the male breast and was accompanied by FDG uptake on PET. PET may be useful in diagnosing RH. Although metastasis is rare in RH, local recurrence may occur, and careful follow-up is required.
    Language English
    Publishing date 2023-04-07
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2809613-7
    ISSN 2198-7793
    ISSN 2198-7793
    DOI 10.1186/s40792-023-01633-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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