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Hokkaido University Collection of Scholarly and Academic Papers (135.711 recursos)

HUSCAP (Hokkaido University Collection of Scholarly and Academic Papers) contains peer-reviewed journal articles, proceedings, educational resources and any kind of scholarly works of Hokkaido University.

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Mostrando recursos 1 - 20 de 307

  1. STAP-2 interacts with Pyk2 and enhances Pyk2 activity in T-cells

    Saitoh, Kodai; Tsuchiya, Takuya; Kashiwakura, Jun-ichi; Muromoto, Ryuta; Kitai, Yuichi; Sekine, Yuichi; Oritani, Kenji; Matsuda, Tadashi
    STAP-2 is an adaptor molecule regulating several signaling pathways, including TLRs and cytokine/chemokine receptors in immune cells. We previously reported that STAP-2 enhances SDF-1 a-induced Vavl/Racl-mediated T-cell chemotaxis. However, the detailed mechanisms of STAP-2 involvement in enhancing T-cell chemotaxis remain unknown. In the present study, we demonstrate that STAP-2 directly interacts with Pyk2, which is a key molecule in the regulation of SDF-la/CXCR4-mediated T-cell chemotaxis, and increases phosphorylation of Pyk2. Pyk2 itself can induce STAP-2 Y250 phosphorylation, and this phosphorylation is critical for maximal interactions between STAP-2 and Pyk2. Finally, SDF-1 a induced T-cell chemotaxis is inhibited by treatment with...

  2. Stereoselective Synthesis of Tetrasubstituted Alkenes via a Cp*Co-III-Catalyzed C-H Alkenylation/Directing Group Migration Sequence

    Ikemoto, Hideya; Tanaka, Ryo; Sakata, Ken; Kanai, Motomu; Yoshino, Tatsuhiko; Matsunaga, Shigeki
    A highly atom economical and stereoselective synthesis of tetrasubstituted alpha,beta-unsaturated amides was achieved by a Cp*Co-III-catalyzed C-H alkenylation/directing group migration sequence. A carbamoyl directing group, which is typically removed after C-H functionalization, worked as an internal acylating agent and migrated onto the alkene moiety of the product. The directing group migration was realized with the Cp*Co-III catalyst, while a related Cp*Rh-III catalyst did not promote the migration process. The product was further converted into two types of tricyclic compounds, one of which had fluorescent properties.

  3. Cp*Co-III-catalyzed directed C-H trifluoromethylthiolation of 2-phenylpyridines and 6-arylpurines

    Yoshida, Misaki; Kawai, Kentaro; Tanaka, Ryo; Yoshino, Tatsuhiko; Matsunaga, Shigeki
    Cp*Co-III-catalyzed directed C-H trifluoromethylthiolation using N-trifluoromethylthiodibenzenesulfonimide as an electrophilic SCF3 source is described. 6-Arylpurines, an important structural motif in medicinal chemistry, and 2-phenylpyridines selectively afforded mono-trifluoromethylthiolated products in moderate to good yields using an inexpnsive first-row transition metal catalyst.

  4. Inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h between alpha-tocopherol and ezetimibe

    Nashimoto, Shunsuke; Sato, Yuki; Takekuma, Yoh; Sugawara, Mitsuru
    Tocopherol is used not only as an ethical drug but also as a supplement. In 2008, it was reported that alpha-tocopherol is partly transported via an intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1). Ezetimibe, a selective inhibitor of NPC1L1, is administered for a long time to inhibit cholesterol absorption and there is a possibility that the absorption of alpha-tocopherol is also inhibited by ezetimibe. This study investigated the influence of ezetimibe on the absorption of alpha-tocopherol with single administration and long-term administration. An approach to avoid its undesirable consequence was also examined. alpha-Tocopherol (10 mg/kg) and ezetimibe (0.1 mg/kg) were...

  5. Modality of tumor endothelial VEGFR2 silencing-mediated improvement in intratumoral distribution of lipid nanoparticles

    Yamamoto, Shoshiro; Kato, Akari; Sakurai, Yu; Hada, Tomoya; Harashima, Hideyoshi
    The vascular endothelial growth factor (VEGF)-mediated enhancement in vascular permeability is considered to be a major factor in tumor-targeting delivery via the enhanced permeability and retention (EPR) effect. We previously reported that the silencing of the endothelial VEGF receptor (VEGFR2) by a liposomal siRNA system (RGD-MEND) resulted in an enhanced intratumoral distribution of polyethylene glycol (PEG)-modified liposomes (LPs) in a renal cell carcinoma, a type of hypervascularized cancer, although the inhibition of VEGF signaling would be expected to decrease the permeability of the tumor vasculature. We herein report that the enhancement in the intratumoral distribution of LPs by VEGFR2 inhibition...

  6. Modifying Antigen-Encapsulating Liposomes with KALA Facilitates MHC Class I Antigen Presentation and Enhances Anti-tumor Effects

    Miura, Naoya; Akita, Hidetaka; Tateshita, Naho; Nakamura, Takashi; Harashima, Hideyoshi
    For a successful anti-cancer vaccine, antigen presentation on the major histocompatibility complex (MHC) class I is a requirement. To accomplish this, an antigen must be delivered to the cytoplasm by overcoming the endosome/lysosome. We previously reported that a lipid nanoparticle modified with a KALA peptide (WEAKLAKALAKALAKHLAKALAICALICA), an alpha-helical cationic peptide, permits the encapsulated pDNA to be efficiently delivered to the cytoplasm in bone marrow derived dendritic cells (BMDCs). Herein, we report on the use of KALA-modified liposomes as an antigen carrier, in an attempt to induce potent antigen-specific cellular immunity. The subcutaneous injection of KALA-modified ovalbumin (OVA)-encapsulating liposomes (KALA-OVA-LPs) elicited...

  7. Decreases in 15-lipoxygenase metabolites in Olmsted syndrome model rats

    Wakabayashi, Masato; Yoshioka, Takeshi; Higashino, Kenichi; Numata, Yoshito; Igarashi, Yasuyuki; Kihara, Akio
    Background: Olmsted syndrome (OS) is a congenital dermatosis characterized by palmoplantar keratoderma and periorificial keratotic plaque. TRPV3 (transient receptor potential vanilloid subtype 3) encodes a thermosensitive Ca2+ channel and is the causative gene of OS. However, the molecular mechanism that causes the pathological development of OS is unclear. Objective: We aimed to investigate the molecular mechanisms underlying OS pathology from the perspective of lipid metabolism. Methods: Comprehensive lipidomics and microarray analyses were conducted on tissue samples from a non-lesional skin area of OS model rats (Ht rats) and from wild type (WT) rats as the control. Results: Infiltration of leukocytes...

  8. Fructose suppresses uric acid excretion to the intestinal lumen as a result of the induction of oxidative stress by NADPH oxidase activation

    Kaneko, Chihiro; Ogura, Jiro; Sasaki, Shunichi; Okamoto, Keisuke; Kobayashi, Masaki; Kuwayama, Kaori; Narumi, Katsuya; Iseki, Ken
    Background: A high intake of fructose increases the risk for hyperuricemia. It has been reported that long-term fructose consumption suppressed renal uric acid excretion and increased serum uric acid level. However, the effect of single administration of fructose on excretion of uric acid has not been clarified. Methods: We used male Wistar rats, which were orally administered fructose (5 g/kg). Those rats were used in each experiment at 12 h after administration. Results: Single administration of fructose suppressed the function of ileal uric acid excretion and had no effect on the function of renal uric acid excretion. Breast cancer resistance...

  9. Loop 5 region is important for the activity of the long-chain base transporter Rsb1

    Makuta, Hiroshi; Obara, Keisuke; Kihara, Akio
    Intracellular lipid amounts are regulated not only by metabolism but also by efflux. Yeast Rsb1 is the only known transporter/floppase of the sphingolipid components long-chain bases (LCBs). However, even fundamental knowledge about Rsb1, such as important amino acid residues for activity and substrate recognition, still remains unclear. Rsb1 belongs to the Rtal-like family. To date, it has not been determined whether all family members share a common ability to export LCBs. Here, we revealed that within the Rtal-like family, only Rsb1 suppressed the hypersensitivity of the mutant cells lacking LCB 1-phoshate-degrading enzymes, suggesting that LCB-exporting activity is specific to Rsb1....

  10. Cell Type-Specific Survey of Epigenetic Modifications by Tandem Chromatin Immunoprecipitation Sequencing

    Mito, Mari; Kadota, Mitsutaka; Tanaka, Kaori; Furuta, Yasuhide; Abe, Kuniya; Iwasaki, Shintaro; Nakagawa, Shinichi
    The nervous system of higher eukaryotes is composed of numerous types of neurons and glia that together orchestrate complex neuronal responses. However, this complex pool of cells typically poses analytical challenges in investigating gene expression profiles and their epigenetic basis for specific cell types. Here, we developed a novel method that enables cell type-specific analyses of epigenetic modifications using tandem chromatin immunoprecipitation sequencing (tChIP-Seq). FLAG-tagged histone H2B, a constitutive chromatin component, was first expressed in Camk2a-positive pyramidal cortical neurons and used to purify chromatin in a cell type-specific manner. Subsequent chromatin immunoprecipitation using antibodies against H3K4me3-a chromatin modification mainly associated...

  11. Phosphorylation of KLC1 modifies interaction with JIP1 and abolishes the enhanced fast velocity of APP transport by kinesin-1.

    Chiba, Kyoko; Chien, Ko-Yi; Sobu, Yuriko; Hata, Saori; Kato, Shun; Nakaya, Tadashi; Okada, Yasushi; Nairn, Angus C; Kinjo, Masataka; Taru, Hidenori; Wang, Rong; Suzuki, Toshiharu
    In neurons, amyloid β-protein precursor (APP) is transported by binding to kinesin-1, mediated by JNK-interacting protein 1b (JIP1b), which generates the enhanced fast velocity (EFV) and efficient high frequency (EHF) of APP anterograde transport. Previously, we showed that EFV requires conventional interaction between the JIP1b C-terminal region and the kinesin light chain 1 (KLC1) tetratricopeptide repeat, whereas EHF requires a novel interaction between the central region of JIP1b and the coiled-coil domain of KLC1. We found that phosphorylatable Thr466 of KLC1 regulates the conventional interaction with JIP1b. Substitution of Glu for Thr466 abolished this interaction and EFV, but did not...

  12. Phosphorylation of multiple sites within an acidic region of Alcadein α is required for kinesin-1 association and Golgi exit of Alcadein α cargo.

    Sobu, Yuriko; Furukori, Keiko; Chiba, Kyoko; Nairn, Angus C; Kinjo, Masataka; Hata, Saori; Suzuki, Toshiharu
    Alcadein α (Alcα) is a major cargo of kinesin-1 that is subjected to anterograde transport in neuronal axons. Two tryptophan- and aspartic acid-containing (WD) motifs located in its cytoplasmic domain directly bind the tetratricopeptide repeat (TPR) motifs of the kinesin light chain (KLC), which activate kinesin-1 and recruit kinesin-1 to Alcα cargo. We found that phosphorylation of three serine residues in the acidic region located between the two WD motifs is required for interaction with KLC. Phosphorylation of these serine residues may alter the disordered structure of the acidic region to induce direct association with KLC. Replacement of these serines with...

  13. Solid-Phase Modular Synthesis of Park Nucleotide and Lipids I and II Analogues

    Katsuyama, Akira; Sato, Kousuke; Yakushiji, Fumika; Matsumaru, Takanori; Ichikawa, Satoshi
    A solid-phase synthesis of Park nucleotide as well as lipids I and II analogues, which is applicable to the synthesis of a range of analogues, is described in this work. This technique allows highly functionalized macromolecules to be modularly labeled. Multiple steps are used in a short time (4d) with a single purification step to synthesize the molecules by solid-phase synthesis.

  14. Synthesis of Fluorine-Containing 6-Arylpurine Derivatives Cp*Co(III)-Catalyzed C-H Bond Activation

    Murakami, Nanami; Yoshida, Misaki; Yoshino, Tatsuhiko; Matsunaga, Shigeki
    Cp*Co(III)-catalyzed (Cp*=pentamethylcyclopentadienyl) C-H bond functionalization of 6-arylpurines using gem-difluoroalkenes and allyl fluorides is described. The reaction with gem-difluoroalkenes afforded monofluoroalkenes with high (Z)-selectivity, while the reaction with allyl fluorides led to C-H allylation in moderate (Z)-selectivity. Both reactions proceeded using a user-friendly single-component catalyst [Cp*Co(CH3CN)(3)](SbF6)(2) in fluorinated alcohol solvents without any additives. Robustness was also demonstrated by a preparative-scale reaction under air.

  15. Scalable preparation of poly(ethyleneglycol)-grafted siRNA-loaded lipid nanoparticles using a commercially available fluidic device and tangential flow filtration

    Sakurai, Yu; Hada, Tomoya; Harashima, Hideyoshi
    While a number of siRNA delivery systems have been developed, the methods used in their preparation are not suitable for large-scale production. We herein report on methodology for the large-scale preparation of liposomal siRNA using a fluidic device and tangential flow filtration (TFF). A number of studies have appeared on the use of fluidic devices for preparing and purifying liposomes, but no systematic information regarding appropriate membrane type of commercially available apparatus is available. The findings reported herein indicate that, under optimized conditions, a microfluidic device and TFF can be used to produce siRNA lipid nanoparticles with the same characteristics...

  16. Packaging of the Coenzyme Q(10) into a Liposome for Mitochondrial Delivery and the Intracellular Observation in Patient Derived Mitochondrial Disease Cells

    Yamada, Yuma; Burger, Laila; Kawamura, Eriko; Harashima, Hideyoshi
    While Coenzyme Q(10) (CoQ(10)) is thought to be effective for the treatment of a variety of diseases, it limits its cellular uptake. Because of the hydrophobic nature of CoQ(10), it is reasonable to assume that it could be encapsulated within a liposomal carrier. Several reports regarding the packaging of CoQ(10) in liposomes have appeared, but detailed investigations of the preparation of CoQ(10) encapsulated liposomes have not been reported. As a result, information regarding the optimal method of packaging CoQ(10) in liposomes is not available. In this study, several types of liposomes were prepared using different methods and their characteristics were...

  17. The Rim101 pathway contributes to ER stress adaptation through sensing the state of plasma membrane

    Obara, Keisuke; Kihara, Akio
    Yeast cells sense alterations in the plasma membrane (PM) lipid asymmetry and external alkalization by the sensor protein Rim21, which functions in the Rim101 pathway. Rim101 signaling is initiated at the PM by the recruitment of the Rim101 signaling complex. The PM physically associates with the cortical endoplasmic reticulum (ER) to form ER-PM contact sites, where several signaling events, lipid exchange, and ion transport take place. In the present study, we investigated the spatial relationship between ER-PM contact sites and the sites of Rim101 signaling. Rim101 signaling mostly proceeds outside ER-PM contact sites in the PM and did not require...

  18. The Rim101 pathway contributes to ER stress adaptation through sensing the state of plasma membrane

    Obara, Keisuke; Kihara, Akio
    Yeast cells sense alterations in the plasma membrane (PM) lipid asymmetry and external alkalization by the sensor protein Rim21, which functions in the Rim101 pathway. Rim101 signaling is initiated at the PM by the recruitment of the Rim101 signaling complex. The PM physically associates with the cortical endoplasmic reticulum (ER) to form ER-PM contact sites, where several signaling events, lipid exchange, and ion transport take place. In the present study, we investigated the spatial relationship between ER-PM contact sites and the sites of Rim101 signaling. Rim101 signaling mostly proceeds outside ER-PM contact sites in the PM and did not require...

  19. Psychological stress in aged female mice causes acute hypophagia independent of central serotonin 2C receptor activation

    Matsumoto, Chinami; Yamada, Chihiro; Sadakane, Chiharu; Nahata, Miwa; Hattori, Tomohisa; Takeda, Hiroshi
    Sex differences exist in the activation of the hypothalamic-pituitary-adrenal axis following exposure to stress, and the stress response is further affected by aging. This study was conducted to elucidate the mechanism of hypophagia in aged female mice exposed to stress. Immediately after a stress load, aged female mice exhibited acute hypophagia and a rise in plasma corticosterone levels. The administration of a serotonin 2C receptor (5-T2CR) antagonist suppressed plasma corticosterone but did not affect the reduction in food intake. In contrast, an endogenous ghrelin enhancer, rikkunshito (RKT), significantly inhibited the reduction in food intake. An increase in peripheral acylated ghrelin...

  20. Remodeling of the Extracellular Matrix by Endothelial Cell-Targeting siRNA Improves the EPR-Based Delivery of 100 nm Particles

    Sakurai, Yu; Hada, Tomoya; Yamamoto, Shoshiro; Kato, Akari; Mizumura, Wataru; Harashima, Hideyoshi
    A number of nano drug delivery systems have recently been developed for cancer treatment, most of which are based on the enhanced permeability and retention effect. The advantages of the enhanced permeability and retention effect can be attributed to immature vasculature. Herein we evaluated the intratumoral distribution of lipid nanoparticles when the VEGF receptor 2 on tumor endothelial cells was inhibited by liposomal siRNA. VEGF receptor 2 inhibition resulted in an increase in intratumoral distribution and therapeutic efficacy despite the maturation of the tumor vasculature. A small molecule inhibitor against matrix metalloproteinase and macrophage depletion cancelled the improvement in the...

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