78 results on '"Kiyoi T"'
Search Results
2. List of contributors
- Author
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Abromova, Maria, Agarwal, Aparna, Ajaiyeoba Oriabure, Edith, Al-Awaida, Wajdy, Al-bawareed, O.A., Basu, Saikat Kumar, Behl, Shalini, Bernardo, M.A., Bharadwaj, Kshitij, Brito, J., Buttar, Harpal S., Cetzal-Ix, William, Chakravorty, Saibal, Chaudhury, Jayeeta, Chauhan, Anil K., Cheng, Qi, Chibisov, Sergey, Chintamaneni, Meena, Chupisanyarote, Kanokkarn, Cornélissen, Germaine, Dalal, Yashodhara, Darlenska, Teodora Handjiev, De, Amit Krishna, De, Minakshi, De Meester, Fabien, Dewi, Mira, Dicholkar, ParnikaDilip, Elkilany, Galal Nagib, Enríquez-Nolasco, Justo R., Fatima, Ghizal, Fedacko, Jan, Fikri, Al Mukhlas, Goyal, Ramesh K., Gupta, Om Kumari, Gvozdjáková, Anna, Hadi, Najah, Halabi, Ghazi, Handjiev, Svetslav, Hanoman, Carlin, Hardinsyah, Hardinsyah, Hashimoto, Hiroyuki, Helmyati, Siti, Hilsabeck, Kyle D., Horiuchi, Rie, Hristova, Krasimira, Hussain, Arif, Hussein, Laila A., Ifie, Josiah, Inbanathan, Asha, Isaza, Adrian, Itharat, Arunporn, Jaglan, Poonam, Jain, Ekta, Jain, Monica, Jantan, Ibrahim, Juneja, Lekh, Juneja, Lekh Raj, Kagawa, Yasuo, Karagiannis, Tom C., Kartikey, Kumar, Kaur, Ginpreet, Khan, Shairy, Kharlitskaya, Elena, Khatibi, Mojgan, Khatibi, Mozhgan, Khoshkharam, Mehdi, Kikuchi, Kota, Kiyoi, T., Kucharská, Jarmila, Kumar, Ashwani, Kumar, Maushmi S., Kumar, Mukul, Kumari, Pooja, LeBaron, Tyler W., Li, Duo, Liu, S., Magadlela, Anathi, Magaña-Magaña, Miguel A., Magomedova, Aminat, Maheshwari, Anuj, Mann, Abella, Martínez-Puc, Jesús F., Matsuo, Mana, Mauraya, Kamlesh Kumar, McCord, D. Elizabeth, Mehdi, Ammar, Mehdi, Farzana, Mesquita, M.F., Mishra, Richa, Mishra, Sanjay, Mogi, M., Mojto, Viliam, Mojtova, Maria, Moncada, M., Mulyati, Ade Heri, Nakamura, Teiji, Nash, Paul, Nayak, Bichitra N., Nwozo Onyenibe, Sarah, Omidvar, Shabnam, On-Saard, Ekasit, On-Saard, Wiriya, Otsubo, Kenichi, Park, Hyun-Ryul, Pella, Daniel, Pella, Dominic, Pella, Dominik, Pitsillou, Eleni, Priya, R Velluri, Sudha, Rai, Dinesh Chandra, Rai, Richa H., Rausová, Zuzana, Rawal, Somansh, Ray, Nancy B., Ridwan, Hardinsyah, Rupee, Khemraj, Rupee, Sunil, Saxena, Madhvi, Saxena, Prashant, Shahrajabian, Mohamad Hesam, Sharma, Asha, Sharma, Divyank, Shenoy, Avinash, Silva, M.L., Singh, Jaipaul, Singh, Mukta, Singh, Raj K., Singh, Rajesh K., Singh, Ram B., Singh, Reema, Smail, Manal M.A., Suchday, Sonia, Sulaeman, Ahmad, Sumbalová, Zuzana, Sun, Wenli, Sundaram, Madhumitha Kedhari, Takahashi, Masahito, Takahashi, Toru, Tarnava, Alex, Télessy, Istvan G., Tiwari, Poonam, Tokunaga, Miki, Tomar, Rukam S., Torshin, V.I., Tripathi, Abhishek Dutt, Tyagi, Garima, Vargova, Viola, Verma, Narsingh, Visen, Aastha, Visen, Pradeep K.S., Visen, Srishti, Watanabe, Shaw, Wichansawakun, Sanit, Wigati, Maria, Wilczynska, Agnieszka, W. Wilson, Douglas, Wongpipathpong, Wannisa, Yadav, Poonam, Yazawa, Kazuyoshi, and Zadeb, Sara Sarrafi
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- 2022
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3. 2P-0479 Interaction of CD47 with SHPS-1 negatively regulates platelet function
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Kato, H., Tomiyama, Y., Honda, S., Yoshida, H., Kashiwagi, H., Kosugi, S., Shiraga, M., Kiyoi, T., Honma, N., Kurata, Y., and Matsuzawa, Y.
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- 2003
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4. 2P-0478 Analysis of Arg-Gly-Asp-contact sites in the αv subunit of integrin αvβ3 employing single amino acid mutations
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Honda, S., Tomiyama, Y., Kashiwagi, H., Kiyoi, T., Kato, H., Kosugi, S., Shiraga, M., Kurata, Y., and Matsuzawa, Y.
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- 2003
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5. ChemInform Abstract: Palladium(0)-Catalyzed Reaction of Z-2-Butene-1,4-diyl Bis(methyl Carbonate) and Z-2-Butene-1,4-diyl Diacetate with Bifunctional Nitrogen Nucleophiles.
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TSUDA, T., KIYOI, T., and SAEGUSA, T.
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- 1990
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6. ChemInform Abstract: Optically Active Allylsilanes. Part 14. Stereochemistry and Mechanism of Asymmetric Allylation of Aldehydes with Optically Active Allylsiliconates.
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HAYASHI, T., MATSUMOTO, Y., KIYOI, T., ITO, Y., KOHRA, S., TOMINAGA, Y., and HOSOMI, A.
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- 1989
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7. ChemInform Abstract: Nickel(0)-Catalyzed Reaction of Diynes with Aldehydes.
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TSUDA, T., KIYOI, T., MIYANE, T., and SAEGUSA, T.
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- 1989
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8. ChemInform Abstract: Asymmetric Synthesis Catalyzed by Chiral Ferrocenylphosphine-Transition-Metal Complexes. Part 6. Practical Asymmetric Synthesis of 1,1′-Binaphthyls via Asymmetric Cross-Coupling with a Chiral ((Alkoxyalkyl)ferrocenyl)monophosphine/Nickel Catalyst.
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HAYASHI, T., HAYASHIZAKI, K., KIYOI, T., and ITO, Y.
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- 1989
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9. ChemInform Abstract: A Stereoselective α-Fucosylation Reaction Using 1-Hydroxy 2,3,4-Tri-O-benzyl-L-fucose Donor for the Practical Synthesis of Selectin Blocker.
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KIYOI, T. and KONDO, H.
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- 1999
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10. ChemInform Abstract: One-Pot Synthesis of Lewis X Oligosaccharide Derivatives Using 'Armed-Disarmed' Coupling Method.
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YOSHIDA, M., KIYOI, T., TSUKIDA, T., and KONDO, H.
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- 1998
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11. ChemInform Abstract: Nickel(0)-Catalyzed Reaction of Acetylenic Compounds with Carbon Dioxide and Aldehydes.
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TSUDA, T., KIYOI, T., HASEGAWA, N., and SAEGUSA, T.
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- 1990
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12. ChemInform Abstract: Nickel(0)-Catalyzed Hydroacylation of Alkynes with Aldehydes to α,β-Enones.
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TSUDA, T., KIYOI, T., and SAEGUSA, T.
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- 1990
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13. ChemInform Abstract: Nickel(II)-Catalyzed Synthesis of Unsymmetrical Carbodiimides Using Molecular Oxygen as an Oxidant from Isocyanides and Primary Amines.
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KIYOI, T., SEKO, N., YOSHINO, K., and ITO, Y.
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- 1994
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14. Preventative Effect of Topical Rebamipide Against Corneal Epithelium Disorders Caused by Diclofenac Sodium.
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Fukuda M, Kiyoi T, Takeda S, Sasaki Y, Masuoka T, Kubo E, and Sasaki H
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- Animals, Rabbits, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Male, Administration, Topical, Diclofenac administration & dosage, Quinolones administration & dosage, Quinolones pharmacology, Epithelium, Corneal drug effects, Epithelium, Corneal pathology, Epithelium, Corneal metabolism, Ophthalmic Solutions administration & dosage, Alanine analogs & derivatives, Alanine administration & dosage, Alanine pharmacology, Corneal Diseases prevention & control, Corneal Diseases chemically induced, Corneal Diseases pathology, Corneal Diseases drug therapy
- Abstract
Purpose: This study aimed to investigate the relationship between diclofenac sodium ophthalmic solution (DFNa) and corneal epithelial cell damage and to evaluate the preventive effect of rebamipide (RBM) on it. Methods: DFNa, DFNa/preservative-free (PF), or 0.5% chlorobutanol (CB) solution was instilled into the conjunctival sac of a normal rabbit eye, and corneal resistance measurement (using a corneal resistance device [CRD]) was performed 120 min after the end of instillation. Then, fluorescent staining (FL), corneal tissue staining (hematoxylin and eosin [H&E]), and immunostaining (zona occlusion-1) were performed (RBM-untreated group). However, RBM was instilled into the eyes of another group of normal rabbits, followed by each of the solutions; 120 min after the end of instillation, all evaluations were performed for this group (RBM treatment group). Results: Using the CRD method, in the RBM-untreated group, corneal resistance (CR; %) was found to be significantly reduced in DFNa (79.9 ± 19.4%), DFNa/PF (89.1 ± 17.3%), and 0.5% CB (83.8 ± 10.6%). In addition, DFNa and 0.5% CB solutions showed positive staining in the FL staining method. In the H&E staining method, some clear voids were observed in the outermost layer of the cornea using DFNa and 0.5% CB solutions. However, corneal epithelial damage was suppressed in the RBM treatment group. ZO-1 immunostaining in DFNa and 0.5% CB solutions revealed discontinuous localization of ZO-1 at the cell periphery. Conclusions: RBM eye drops were effective in preventing corneal epithelial damage caused by DFNa eye drops, and CB was considered to be the main causative agent of this damage.
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- 2024
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15. Corneal acetylcholine regulates sensory nerve activity via nicotinic receptors.
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Masuoka T, Kiyoi T, Zheng S, He Q, Liu L, Uwada J, and Muramatsu I
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- Animals, Guinea Pigs, Sensory Receptor Cells metabolism, Sensory Receptor Cells physiology, Blotting, Western, Cells, Cultured, Male, Trigeminal Ganglion metabolism, Immunohistochemistry, Choline O-Acetyltransferase metabolism, Vesicular Acetylcholine Transport Proteins metabolism, Acetylcholine metabolism, Acetylcholine pharmacology, Cornea innervation, Cornea metabolism, Receptors, Nicotinic metabolism
- Abstract
Purpose: Sensory nerve terminals are highly distributed in the cornea, and regulate ocular surface sensation and homeostasis in response to various endogenous and exogenous stimuli. However, little is known about mediators regulating the physiological and pathophysiological activities of corneal sensory nerves. The aim of this study was to investigate the presence of cholinergic regulation in sensory nerves in the cornea., Methods: Localization of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (vAChT) was evaluated using western blotting and immunohistochemical analysis. The synthesis and liberation of acetylcholine from the cornea were assessed using corneal segments pre-incubated with [
3 H]choline. The responsiveness of corneal neurons and nerves to cholinergic drugs was explored using calcium imaging with primary cultures of trigeminal ganglion neurons and extracellular recording from corneal preparations in guinea pigs., Results: ChAT, but not vAChT, was highly distributed in the corneal epithelium. In corneal segments, [3 H] acetylcholine was synthesized from [3 H]choline, and was also released in response to electrical stimuli. In cultured corneal neurons, the population sensitive to a transient receptor potential melastatin 8 (TRPM8) agonist exhibited high probability of responding to nicotine in a calcium imaging experiment. The firing frequency of cold-sensitive corneal nerves was increased by the application of nicotine, but diminished by an α4 nicotinic acetylcholine receptor antagonist., Conclusions: The corneal epithelium can synthesize and release acetylcholine. Corneal acetylcholine can excite sensory nerves via nicotinic receptors containing the α4 subunit. Therefore, corneal acetylcholine may be one of the important regulators of corneal nerve activity arranging ocular surface condition and sensation., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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16. Histological Analyses of Arthritic Joints in Collagen-Induced Arthritis Model Mice.
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Kiyoi T
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- Animals, Mice, Bone and Bones, Coloring Agents, Formaldehyde, Paraffin, Arthritis, Experimental chemically induced, Arthritis, Rheumatoid, Corneal Neovascularization
- Abstract
Histological analysis is a morphological technique and an effective method for understanding the pathology of rheumatoid arthritis (RA). RA is an inflammatory disease characterized by increased synovial tissue and osteoclasts, angiogenesis, infiltration of inflammatory cells, and pannus formation. These pathologies can be observed in a collagen-induced arthritis model mouse using formaldehyde-fixated paraffin-embedded (FFPE) samples. For the preparation of FFPE samples, the conditions of the fixation and decalcification process significantly affect tissue staining results. Since the lesion sites include bone tissue, a decalcification process is necessary when preparing an FFPE sample. Therefore, selecting an optimal condition for the fixating and decalcifying solution is important. In this chapter, we describe the procedures of preparing paraffin samples, including fixation, decalcification, embedding, and sectioning from the RA model mouse, as well as different staining methods (hematoxylin and eosin, tartrate-resistant acid phosphatase)., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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17. Evaluation of Skin Damage Under UV Exposure.
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Kiyoi T
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- Animals, Humans, Oxidative Stress, Ultraviolet Rays adverse effects, Dermatitis, Photosensitivity Disorders, Lupus Erythematosus, Systemic
- Abstract
Photosensitivity disorder caused by sunlight, including ultraviolet (UV) rays, often occurs in connective tissue diseases such as lupus erythematosus. In addition, UVA (320-400 nM) and UVB (280-320 nM) trigger the progression of skin inflammation in the patients. Therefore, it is crucial to evaluate skin damage under UV exposure using experimental animals to clarify the relationship between connective tissue disease and photosensitivity disorder. In this chapter, our original protocol for evaluating UVA-dependent skin damage, which is known as photoaging via oxidative stress, is described., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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18. Scanning Electron Microscopic Analysis of the Bone-Resorption Activity in Mature Osteoclasts.
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Kiyoi T
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- Humans, Osteoclasts, Electrons, Microscopy, Electron, Scanning, Osteoblasts, Bone Resorption, Arthritis, Rheumatoid
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Bone homeostasis depends on the balance between bone deposition and bone resorption, which are mediated by the activity of osteoblasts and osteoclasts, respectively. Blocking osteoclast activity can be a therapeutic strategy in rheumatoid arthritis (RA) to reduce subsequent bone erosion. Therefore, investigating the activity of osteoclasts is essential for understanding the pathology of RA. Bone-resorption pits, which are caused by activated osteoclasts, are significantly increased in RA. Scanning electron microscopic analysis of bone-resorption pits is an effective method for understanding the pathology of RA. This chapter describes the method for observing the surface microstructure of pit formation on bone slices., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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19. Intermittent environmental exposure to hydrogen prevents skin photoaging through reduction of oxidative stress.
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Kiyoi T, Liu S, Takemasa E, Hato N, and Mogi M
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- Humans, Animals, Mice, Skin metabolism, Cells, Cultured, Oxidative Stress, Collagen metabolism, Environmental Exposure, Fibroblasts metabolism, Fibroblasts radiation effects, Ultraviolet Rays adverse effects, Skin Aging, Skin Diseases
- Abstract
Aim: Molecular hydrogen is not only expected to be used as an energy-generating resource, but also to have preventive effects on a variety of clinical manifestations related to oxidative stress through scavenging radicals or regulating gene expression. In the current study, we investigated the influence of intermittent environmental exposure to hydrogen gas at a safe concentration (1.3%) on photoaging using an ultraviolet A (UVA)-irradiated murine model., Methods: To mimic the expected human daily activity cycle, UVA exposure in the daytime and hydrogen exposure in the night-time, an original design, UVA-transmission, hydrogen-exposure system was established. Mice were bred under experimental conditions of UVA irradiation and normal air for 8 h (outdoor time 09.00-17.00 hours), and UVA non-irradiation and inhalation of hydrogen gas for 16 h (indoor time 17.00-09.00 hours), and the daily cycle was continued for up to 6 weeks. The progression of photoaging, including morphological changes, collagen degradation and UVA-related DNA damage, was evaluated., Results: Intermittent administration of hydrogen gas by our system prevented UVA-induced epidermal signs, such as hyperplasia, melanogenesis and appearance of senescence cells, and UVA-induced dermal signs, such as collagen degradation. In addition, we detected attenuation of DNA damage in the hydrogen exposure group as indirect evidence that intermittent exposure to hydrogen gas reduced oxidative stress., Conclusions: Our findings support the notion that long-term, intermittent environmental exposure to hydrogen gas in daily life has a beneficial effect on UVA-induced photoaging. Geriatr Gerontol Int 2023; 23: 304-312., (© 2023 Japan Geriatrics Society.)
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- 2023
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20. Highly concentrated trehalose induces prohealing senescence-like state in fibroblasts via CDKN1A/p21.
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Muto J, Fukuda S, Watanabe K, Dai X, Tsuda T, Kiyoi T, Kameda K, Kawakami R, Mori H, Shiraishi K, Murakami M, Imamura T, Higashiyama S, Fujisawa Y, Mizukami Y, and Sayama K
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- Humans, Animals, Mice, Keratinocytes metabolism, Wound Healing physiology, Fibroblasts metabolism, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Trehalose pharmacology, Trehalose metabolism, Skin metabolism
- Abstract
Trehalose is the nonreducing disaccharide of glucose, evolutionarily conserved in invertebrates. The living skin equivalent (LSE) is an organotypic coculture containing keratinocytes cultivated on fibroblast-populated dermal substitutes. We demonstrated that human primary fibroblasts treated with highly concentrated trehalose promote significantly extensive spread of the epidermal layer of LSE without any deleterious effects. The RNA-seq analysis of trehalose-treated 2D and 3D fibroblasts at early time points revealed the involvement of the CDKN1A pathway, the knockdown of which significantly suppressed the upregulation of DPT, ANGPT2, VEGFA, EREG, and FGF2. The trehalose-treated fibroblasts were positive for senescence-associated β-galactosidase. Finally, transplantation of the dermal substitute with trehalose-treated fibroblasts accelerated wound closure and increased capillary formation significantly in the experimental mouse wounds in vivo, which was canceled by the CDKN1A knockdown. These data indicate that high-concentration trehalose can induce the senescence-like state in fibroblasts via CDKN1A/p21, which may be therapeutically useful for optimal wound repair., (© 2023. The Author(s).)
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- 2023
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21. Voluntary wheel-running activities ameliorate depressive-like behaviors in mouse dry eye models.
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Nakano K, Nakazawa H, He Q, Uwada J, Kiyoi T, Ishibashi T, and Masuoka T
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Recent clinical studies indicate that dry eye is closely associated with psychiatric disorders such as depression and anxiety. Here, we investigated whether two types of mouse dry eye models showed depressive-like behavior in forced swim and sucrose preference tests, and whether voluntary wheel-running helped ameliorate depressive states. To reproduce the dry eye models, the exorbital lacrimal glands (ELG) or exorbital and intraorbital lacrimal glands (ELG+ILG) were bilaterally excised from male C57BL/6J mice. Tear volume was persistently reduced in both models, but the ELG+ILG excision mice exhibited more severe corneal damage than the ELG excision mice. In the forced swim and sucrose preference tests, the gland excision mice showed longer immobility and shorter climbing times, and lower sucrose preference than sham-operated mice, respectively, which appeared earlier in the ELG+ILG excision mice. Wheel-running activities were significantly lower in the ELG+ILG excision mice, but not in the ELG excision mice. After short-period wheel-running, the longer immobility times and the shorter climbing times in the forced swim completely disappeared in both models. Our results suggest that dry eyes might directly cause a depressive disorder that depends on the severity and duration of the ocular surface damage, and that voluntary motor activity could help recovery from a depressive state induced by dry eye., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nakano, Nakazawa, He, Uwada, Kiyoi, Ishibashi and Masuoka.)
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- 2022
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22. Long-term impact of maternal dietary intervention on metabolic homeostasis in male offspring in mice.
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Ueno M, Liu S, Kiyoi T, Mogi M, and Sugiyama T
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- Body Weight, Diet, High-Fat adverse effects, Female, Homeostasis, Humans, Infant, Newborn, Insulin metabolism, Male, Obesity metabolism, Pregnancy, Prenatal Exposure Delayed Effects genetics
- Abstract
The long-term effect of changes in maternal dietary composition during pregnancy on the offspring's metabolic homeostasis is uncertain. We aimed to investigate the long-term effects of maternal balanced low-fat interventions on metabolic homeostasis of the offspring using a mouse model of gestational obesity induced by a high-fat diet (HFD). Male newborns in the balanced low-fat intervention group had significantly lower serum insulin and higher serum adiponectin levels than those in the HFD group. Changes in maternal dietary composition improved glucose tolerance in pups at 3 and 12 weeks of age. We also performed transcriptomic analysis of the liver in neonatal and 3-week-old pups. Genes in the peroxisome proliferator-activated receptor signaling pathway were significantly down-regulated in neonates in the balanced low-fat intervention group compared with the HFD group. A maternal balanced low-fat diet fully compensated for the detrimental effects of a maternal HFD on glucose metabolism, insulin tolerance, circulating insulin, dyslipidemia, and body weight gain in male offspring by changing the gene expression profile. These data suggest that maternal balanced low-fat intervention is critical for improving the metabolic health of future generations., (Copyright © 2022. Published by Elsevier Inc.)
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- 2022
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23. Perinatal low-fat dietary intervention affects glucose metabolism in female adult and aging offspring.
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Ueno M, Liu S, Kiyoi T, Sugiyama T, and Mogi M
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- Adult, Aging, Animals, Cholesterol, Female, Glucose metabolism, Humans, Insulin metabolism, Mice, Pregnancy, Weight Gain, Insulin Resistance
- Abstract
Aim: Diabetes confers a high risk of developing poor health in later life in women. Based on the Developmental Origins of Health and Disease theory, the present study was undertaken to investigate the efficacy of perinatal fat restriction in maternal high-fat-exposed female offspring to maintain glucose homeostasis in later life between adulthood and aging., Methods: Low-fat dietary intervention during either gestation or lactation was performed using a high-fat diet-induced maternal obesity mouse model (HFD mice). Physiological metabolic parameters, including body weight and serum levels of total cholesterol and triglycerides, were monitored. Glucose tolerance test and insulin sensitivity test were performed in 12- and 70-week-old offspring. Insulin-positive islet cells were also observed using immunohistochemical staining., Results: HFD significantly induced abnormal weight gain, hyperlipidemia and impairment of both glucose tolerance and insulin sensitivity in offspring. Standard diet intake after weaning improved weight gain, serum total cholesterol level and glucose tolerance, but not insulin sensitivity, in 70-week-old offspring. Only perinatal fat restriction during both gestation and lactation, followed by standard food intake for the rest of their life, provided adequate efficacy to restore insulin sensitivity in aging female progeny., Conclusions: Perinatal low-fat intervention may prevent deterioration of glucose metabolism. To improve the health status over a female's lifespan, appropriate nutritional intervention during the early developmental stage may reset the disease trajectory and prevent the onset and development of diabetes. Geriatr Gerontol Int 2022; 22: 441-448., (© 2022 Japan Geriatrics Society.)
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- 2022
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24. PSMA-positive membranes secreted from prostate cancer cells have potency to transform vascular endothelial cells into an angiogenic state.
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Watanabe R, Maekawa M, Kiyoi T, Kurata M, Miura N, Kikugawa T, Higashiyama S, and Saika T
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- Aged, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Culture Media, Conditioned, Gene Expression Profiling methods, Human Umbilical Vein Endothelial Cells, Humans, Immunohistochemistry, Male, Neoplasm Grading, Prostate, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant surgery, Tumor Cells, Cultured, Antigens, Surface metabolism, Endothelial Cells pathology, Glutamate Carboxypeptidase II metabolism, Neovascularization, Pathologic metabolism, Prostatic Neoplasms, Castration-Resistant metabolism
- Abstract
Background: Prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration-resistant prostate cancers. Recently, 68Ga-PSMA positron emission tomography/computed tomography has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear., Methods: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected by robotic surgery in 2019 at Ehime University from patients with prostate cancer. In vitro, we prepared conditioned medium (CM) derived from a PSMA-positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the CM. We assessed angiogenic activities by treatment of HUVECs with LNCaP-derived CM using a tube formation assay that mimics angiogenesis., Results: Immunohistochemistry of PSMA and CD31, a marker of endothelial cells, and PSMA-expressing tumor endothelial cells were observed in 4 of 33 prostate cancer patients (12.1%). We also found that the 10,000g pellet fraction of the LNCaP-derived CM containing PSMA-positive membranes, such as microvesicles transformed HUVECs "PSMA-negative" into "PSMA-positive." Furthermore, treatment of HUVECs with the 10,000g pellet fraction of the LNCaP-derived CM significantly promoted tube formation, mimicking angiogenesis in a PSMA-dependent manner., Conclusions: Our findings revealed the existence of PSMA-positive tumor endothelial cells in human prostate tumors, which enhances tumor angiogenesis in prostate cancer tissues., (© 2021 The Authors. The Prostate published by Wiley Periodicals LLC.)
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- 2021
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25. Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase.
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Kawahata W, Asami T, Kiyoi T, Irie T, Kashimoto S, Furuichi H, and Sawa M
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- Administration, Oral, Agammaglobulinaemia Tyrosine Kinase metabolism, Dose-Response Relationship, Drug, Humans, Molecular Structure, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Drug Discovery, Protein Kinase Inhibitors pharmacology
- Abstract
Although Bruton's tyrosine kinase (BTK) has been recognized as a validated drug target for the treatment of B-cell malignances, the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious concern. As a part of our effort to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines was identified as noncovalent inhibitors of both the wild-type and C481S mutant BTKs. Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor 13f (AS-1763) as a next-generation noncovalent BTK inhibitor. With significant efficacies in vivo tumor xenograft models, AS-1763 has advanced to phase 1 clinical trials.
- Published
- 2021
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26. Possible Therapeutic Strategy Involving the Purine Synthesis Pathway Regulated by ITK in Tongue Squamous Cell Carcinoma.
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Onidani K, Miura N, Sugiura Y, Abe Y, Watabe Y, Kakuya T, Mori T, Yoshimoto S, Adachi J, Kiyoi T, Kabe Y, Suematsu M, Tomonaga T, Shibahara T, and Honda K
- Abstract
The epidermal growth factor receptor is the only available tyrosine kinase molecular target for treating oral cancer. To improve the prognosis of tongue squamous cell carcinoma (TSCC) patients, a novel molecular target for tyrosine kinases is thus needed. We examined the expression of interleukin-2-inducible T-cell kinase (ITK) using immunohistochemistry, and the biological function of ITK was investigated using biochemical, phosphoproteomic, and metabolomic analyses. We found that ITK is overexpressed in TSCC patients with poor outcomes. The proliferation of oral cancer cell lines expressing ITK via transfection exhibited significant increases in three-dimensional culture assays and murine inoculation models with athymic male nude mice as compared with mock control cells. Suppressing the kinase activity using chemical inhibitors significantly reduced the increase in cell growth induced by ITK expression. Phosphoproteomic analyses revealed that ITK expression triggered phosphorylation of a novel tyrosine residue in trifunctional purine biosynthetic protein adenosine-3, an enzyme in the purine biosynthesis pathway. A significant increase in de novo biosynthesis of purines was observed in cells expressing ITK, which was abolished by the ITK inhibitor. ITK thus represents a potentially useful target for treating TSCC through modulation of purine biosynthesis.
- Published
- 2021
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27. CNKSR1 serves as a scaffold to activate an EGFR phosphatase via exclusive interaction with RhoB-GTP.
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Nishiyama K, Maekawa M, Nakagita T, Nakayama J, Kiyoi T, Chosei M, Murakami A, Kamei Y, Takeda H, Takada Y, and Higashiyama S
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms etiology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carrier Proteins, Cell Line, Tumor, Cullin Proteins metabolism, ErbB Receptors agonists, ErbB Receptors genetics, ErbB Receptors metabolism, Female, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins genetics, Middle Aged, Models, Biological, Phosphorylation, Potassium Channels, Voltage-Gated metabolism, Prognosis, Protein Array Analysis, Protein Binding, Proteolysis, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 3 metabolism, Intracellular Signaling Peptides and Proteins metabolism, rhoB GTP-Binding Protein metabolism
- Abstract
Epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) phosphorylation drives HER2-positive breast cancer cell proliferation. Enforced activation of phosphatases for those receptors could be a therapeutic option for HER2-positive breast cancers. Here, we report that degradation of an endosomal small GTPase, RhoB, by the ubiquitin ligase complex cullin-3 (CUL3)/KCTD10 is essential for both EGFR and HER2 phosphorylation in HER2-positive breast cancer cells. Using human protein arrays produced in a wheat cell-free protein synthesis system, RhoB-GTP, and protein tyrosine phosphatase receptor type H (PTPRH) were identified as interacting proteins of connector enhancer of kinase suppressor of Ras1 (CNKSR1). Mechanistically, constitutive degradation of RhoB, which is mediated by the CUL3/KCTD10 E3 complex, enabled CNKSR1 to interact with PTPRH at the plasma membrane resulting in inactivation of EGFR phosphatase activity. Depletion of CUL3 or KCTD10 led to the accumulation of RhoB-GTP at the plasma membrane followed by its interaction with CNKSR1, which released activated PTPRH from CNKSR1. This study suggests a mechanism of PTPRH activation through the exclusive binding of RhoB-GTP to CNKSR1., (© 2021 Nishiyama et al.)
- Published
- 2021
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28. Inhibition of Histamine Release from RBL-2H3 Cells by Zoledronate Did Not Affect Rab27a/Doc2a Interaction.
- Author
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Sahid MNA, Liu S, Kiyoi T, Maeyama K, and Mogi M
- Subjects
- Animals, Calcium metabolism, Calcium Ionophores pharmacology, Cell Line, Tumor, Exocytosis, Histamine, Ionomycin pharmacology, Proteins, Bone Density Conservation Agents pharmacology, Calcium-Binding Proteins metabolism, Histamine Release drug effects, Mast Cells metabolism, Nerve Tissue Proteins metabolism, Zoledronic Acid pharmacology, rab27 GTP-Binding Proteins metabolism
- Abstract
Mast cell (MC) exocytosis is organized by prenylated protein, including Rab families. Among Rab proteins, Rab3a, Rab27a, and Rab11 are responsible for exocytosis arrangement. Rab3a and Rab27a are contributed to exocytosis by interacting with other exocytosis proteins. Zoledronate administration disrupted the Rab prenylation process that affected its interaction with other proteins, and finally, its function. The present study has investigated the effect of zoledronate on the histamine release (HR) from RBL-2H3 cells. The main focus is to answer the question of whether zoledronate affects Rab27a/Doc2a interaction. Histamine release on RBL-2H3 cells after zoledronate or clodronate administration was measured using HPLC-fluorometry. Dinitrophenylated bovine serum albumin (DNP-BSA) (20 ng/mL) or ionomycin (1 µM) are used as secretagogues. Calcium (Ca
2+ ) influx observation was performed using Fura-2A/M. In situ proximity ligation assay (PLA) is used to investigate Rab27a/Doc2a interaction after bisphosphonates (BPs) treatment. Histamine concentration measurement with HPLC-fluorometry showed that zoledronate (30, 100 µM) inhibited HR from antigen-activated RBL-2H3 cells. Zoledronate showed less inhibition in cells activated with ionomycin. Intracellular Ca2+ concentration and Ca2+ flux rate from the extracellular compartment was not changed by zoledronate administration. No changes in Rab27a/Doc2a interaction after zoledronate treatment. Histamine release inhibition by zoledronate in DNP-BSA-activated RBL-2H3 cells is not related to the disruption of Rab27a/Doc2a interaction and is not involve the change in Ca2+ influx.- Published
- 2021
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29. Dihydroxystilbenes prevent azoxymethane/dextran sulfate sodium-induced colon cancer by inhibiting colon cytokines, a chemokine, and programmed cell death-1 in C57BL/6J mice.
- Author
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Kimura Y, Sumiyoshi M, Kiyoi T, and Baba K
- Subjects
- Animals, Azoxymethane, Carcinogens antagonists & inhibitors, Chemokine CCL2 drug effects, Colonic Neoplasms metabolism, Cyclooxygenase 2 Inhibitors pharmacology, Dextran Sulfate, Dihydrostilbenoids chemical synthesis, Dihydrostilbenoids chemistry, Humans, Macrophages drug effects, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Tumor Microenvironment drug effects, Apoptosis drug effects, Chemokines antagonists & inhibitors, Colonic Neoplasms chemically induced, Colonic Neoplasms prevention & control, Cytokines antagonists & inhibitors, Dihydrostilbenoids therapeutic use
- Abstract
The incidence of colon cancer increased worldwide in 2019 and its treatment is urgent from a quality of life perspective. A relationship has been reported between elevated numbers of tumor-associated macrophages (TAMs) in the tumor microenvironment and a poor prognosis in cancer patients, and M2 TAMs have been shown to promote tumor growth by immunosuppression through the stimulation of programmed death-1 (PD-1, an immune check point receptor), interleukin (IL)-1β, and monocyte chemoattractant protein (MCP)-1. We herein examined the effects of three synthetic dihydroxystilbenes (2,3-, 3,4-, and 4,4'-dihydroxystilbenes) on colon carcinogenesis, colon tumor growth, and colon cytokines (IL-1β, IL-6, and tumor necrosis factor (TNF)-α), a chemokine (MCP-1), vascular endothelial growth factor (VEGF), and PD-1 levels in azoxymethane (AOM) plus dextran sulfate sodium (DSS)-treated C57BL/6J mice. The three dihydroxystilbenes inhibited colon carcinogenesis and tumor growth as well as increases in colon IL-1β, IL-6, MCP-1, and PD-1 levels in AOM/DDS-treated mice (in vivo). The three dihydroxystilbenes also suppressed COX-2 expression in colon tumors (in vivo). The results obtained also revealed that the three dihydroxystilbenes inhibited PD-1 elevations in M2-THP-1 macrophages (in vitro). Therefore, the inhibition of AOM/DSS-induced colon carcinogenesis and colon tumor growth by 2,3-, 3,4-, and 4,4'-dihydroxystilbenes appears to be due to the suppression of M2 TAM differentiation and activation and PD-1 expression (immunosuppression) via reductions in COX-2 expression levels in the colon tumor microenvironment., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2020
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30. Evaluation of the structure of the otoconial layer using micro-computed tomography.
- Author
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Nishihara E, Okada M, Kiyoi T, Shudou M, Imai Y, and Hato N
- Subjects
- Animals, Bone Density, Female, Mice, Mice, Inbred C57BL, Models, Animal, Otolithic Membrane diagnostic imaging, Uterus anatomy & histology, Otolithic Membrane anatomy & histology, Ovariectomy, X-Ray Microtomography
- Abstract
Objective: Estrogen deficiency caused by bilateral ovariectomy (OVX) has been reported to lead to morphological changes in otoconia. Thus, we examined the morphological changes in the otoconial layer after OVX. We also investigated whether micro-computed tomography (µCT) is useful for the detection of morphological changes in the otoconial layer., Methods: The otic capsules of C57BL/6 J mice were removed and evaluated using histological techniques and µCT at 2, 4, and 8 weeks after OVX or sham surgery. The volume of the utricle otoconial layer was measured and compared between the OVX and sham groups. The µCT scan and histological study results were also compared., Results: The volume of the utricle otoconial layer was significantly increased 4 weeks after OVX compared to the sham group in both histological and µCT studies (p < 0.05). The volume of the otoconial layer measured using µCT was significantly correlated with the histological study results (p < 0.05)., Conclusion: The volume of the utricle otoconial layer increased after OVX. These morphological changes could be detected by µCT., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020. Published by Elsevier B.V.)
- Published
- 2020
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31. Mast cell activation markers for in vitro study.
- Author
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Sahid MNA and Kiyoi T
- Subjects
- Animals, Histamine analysis, Histamine metabolism, Humans, Mast Cells cytology, beta-N-Acetylhexosaminidases analysis, beta-N-Acetylhexosaminidases metabolism, Biomarkers analysis, Biomarkers metabolism, Mast Cells immunology, Mast Cells metabolism
- Abstract
Mast cells (MCs) are well known for their role in allergic conditions. This cell can be activated by various types of secretagogues, ranging from a small chemical to a huge protein. Mast cell activation by secretagogues triggers the increase in intracellular calcium (iCa
2+ ) concentration, granule trafficking, and exocytosis. Activated mast cells release their intra-granular pre-stored mediator or the newly synthesized mediator in the exocytosis process, in the form of degranulation or secretion. There are at least three types of exocytosis in mast cells, which are suggested to contribute to the release of different mediators, i.e.,, piecemeal, kiss-and-run, and compound exocytosis. The status of mast cells, i.e., activated or resting, is often determined by measuring the concentration of the released mediator such as histamine or β-hexosaminidase. This review summarizes several mast cell components that have been and are generally used as mast cell activation indicator, from the classical histamine and β-hexosaminidase measurement, to eicosanoid and granule trafficking observation. Basic principle of the component determination is also explained with their specified research application and purpose. The information will help to predict the experiment results with a certain study design.- Published
- 2020
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32. Assessment and Comparison of the Efficacy of Methotrexate, Prednisolone, Adalimumab, and Tocilizumab on Multipotency of Mesenchymal Stem Cells.
- Author
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Liu S, Kiyoi T, Ishida M, and Mogi M
- Abstract
Mesenchymal stem cell (MSC)-based articular regeneration might be beneficial for both protecting and rebuilding cartilaginous tissues in the management of rheumatoid arthritis. However, it is unclear how current immunosuppressive strategies influence the multipotency of MSCs. The present study was undertaken to profile the direct effectiveness of major antirheumatic drugs including methotrexate, prednisolone, adalimumab, and tocilizumab on the multipotency of MSCs, with a special focus on chondrogenesis. The inhibitory effects of methotrexate on adipogenesis, osteogenesis, and chondrogenesis were observed to occur in a dose-dependent manner in an in vitro differentiation system. Prednisolone enhanced adipogenesis, but reduced alkaline phosphatase activity in osteoprogenitors and suppressed the formation of chondrospheroids. Adalimumab suppressed alkaline phosphatase activity, while tocilizumab diminished osteogenesis and chondrogenesis of MSCs in vitro . Chondrogenesis of antirheumatic drug-treated MSCs was also evaluated in viv o using a scaffolded spheroid-engrafted murine model. The biologics examined appeared to be relatively safe for cartilaginous formation, but methotrexate and prednisolone exhibited opposing influences on chondrogenesis. Taken together, these results reveal the direct efficacy of major antirheumatic agents on the multipotency of MSCs. Therefore, our findings suggest that optimization of medication protocols is further required for therapeutic approaches involving cartilaginous tissue engineering., (Copyright © 2020 Liu, Kiyoi, Ishida and Mogi.)
- Published
- 2020
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33. Constitutive hydrogen inhalation prevents vascular remodeling via reduction of oxidative stress.
- Author
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Kiyoi T, Liu S, Takemasa E, Nakaoka H, Hato N, and Mogi M
- Subjects
- Administration, Inhalation, Animals, DNA Damage drug effects, Disease Models, Animal, Down-Regulation drug effects, Gases administration & dosage, Gases chemistry, Humans, Hydroxyl Radical metabolism, Male, Mice, Mice, Inbred C57BL, Myocardial Ischemia pathology, NADPH Oxidase 1 metabolism, Neointima etiology, Neointima pathology, Nitrogen administration & dosage, Oxidative Stress drug effects, Oxygen administration & dosage, Peroxynitrous Acid metabolism, Hydrogen administration & dosage, Myocardial Ischemia prevention & control, Neointima prevention & control, Vascular Remodeling drug effects, Vascular System Injuries complications
- Abstract
Molecular hydrogen is thought to have an inhibitory effect on oxidative stress, thereby attenuating the onset and progression of various diseases including cardiovascular disease; however, few reports have assessed the preventive effect of constitutive inhalation of hydrogen gas on of vascular remodeling. Here, we investigated the effect of constitutive inhalation of hydrogen gas on vascular neointima formation using a cuff-induced vascular injury mouse model. After constitutive inhalation of compressed hydrogen gas (O2 21%, N2 77.7%, hydrogen 1.3%) or compressed air only (O2 21%, N2 79%) by C57BL/6 mice for 2 weeks from 8 weeks of age in a closed chamber, inflammatory cuff injury was induced by polyethylene cuff placement around the femoral artery under anesthesia, and hydrogen gas administration was continued until sampling of the femoral artery. Neointima formation, accompanied by an increase in cell proliferation, was significantly attenuated in the hydrogen group compared with the control group. NADPH oxidase NOX1 downregulation in response to cuff injury was shown in the hydrogen group, but the expression levels of NADPH oxidase subunits, p40phox and p47phox, did not differ significantly between the hydrogen and control groups. Although the increase in superoxide anion production did not significantly differ between the hydrogen and control groups, DNA damage was decreased as a result of reduction of reactive oxygen species such as hydroxyl radical (⋅OH) and peroxynitrite (ONOO-) in the hydrogen group. These results demonstrate that constitutive inhalation of hydrogen gas attenuates vascular remodeling partly via reduction of oxidative stress, suggesting that constitutive inhalation of hydrogen gas at a safe concentration in the living environment could be an effective strategy for prevention of vascular diseases such as atherosclerosis., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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34. SNX9 determines the surface levels of integrin β1 in vascular endothelial cells: Implication in poor prognosis of human colorectal cancers overexpressing SNX9.
- Author
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Tanigawa K, Maekawa M, Kiyoi T, Nakayama J, Kitazawa R, Kitazawa S, Semba K, Taguchi T, Akita S, Yoshida M, Ishimaru K, Watanabe Y, and Higashiyama S
- Subjects
- Angiogenesis Inducing Agents metabolism, Cell Membrane metabolism, Cell Movement physiology, Cell Proliferation physiology, Human Umbilical Vein Endothelial Cells metabolism, Humans, Integrins metabolism, Neovascularization, Pathologic genetics, Protein Transport physiology, Colorectal Neoplasms metabolism, Integrin beta1 metabolism, Neovascularization, Pathologic metabolism, Sorting Nexins metabolism
- Abstract
Angiogenesis, the formation of new blood vessels, is involved in a variety of diseases including the tumor growth. In response to various angiogenic stimulations, a number of proteins on the surface of vascular endothelial cells are activated to coordinate cell proliferation, migration, and spreading processes to form new blood vessels. Plasma membrane localization of these angiogenic proteins, which include vascular endothelial growth factor receptors and integrins, are warranted by intracellular membrane trafficking. Here, by using a siRNA library, we screened for the sorting nexin family that regulates intracellular trafficking and identified sorting nexin 9 (SNX9) as a novel angiogenic factor in human umbilical vein endothelial cells (HUVECs). SNX9 was essential for cell spreading on the Matrigel, and tube formation that mimics in vivo angiogenesis in HUVECs. SNX9 depletion significantly delayed the recycling of integrin β1, an essential adhesion molecule for angiogenesis, and reduced the surface levels of integrin β1 in HUVECs. Clinically, we showed that SNX9 protein was highly expressed in tumor endothelial cells of human colorectal cancer tissues. High-level expression of SNX9 messenger RNA significantly correlated with poor prognosis of the patients with colorectal cancer. These results suggest that SNX9 is an angiogenic factor and provide a novel target for the development of new antiangiogenic drugs., (© 2019 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.)
- Published
- 2019
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35. Morphological and functional analysis of beige (Chèdiak-Higashi syndrome) mouse mast cells with giant granules.
- Author
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Kiyoi T, Liu S, Sahid MNA, Shudou M, Ogasawara M, Mogi M, and Maeyama K
- Subjects
- Animals, Cell Degranulation, Cells, Cultured, Chediak-Higashi Syndrome genetics, Disease Models, Animal, Histamine metabolism, Homozygote, Humans, Intracellular Signaling Peptides and Proteins, Mast Cells pathology, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mutation genetics, Proteins genetics, Vesicular Transport Proteins, Chediak-Higashi Syndrome immunology, Cytoplasmic Granules pathology, Killer Cells, Natural immunology, Lysosomes pathology, Mast Cells physiology, Neutrophils immunology
- Abstract
Chèdiak-Higashi syndrome is a rare autosomal recessive disease that causes hypopigmentation, recurrent infections, mild coagulation defects and neurological problems. Beige mice carry a mutation in the lysosome trafficking regulator (LYST) gene and display some of the key characteristics of human Chèdiak-Higashi syndrome, in particular, a high susceptibility to infection due to aberrant natural killer (NK) cell and polymorphonuclear leucocyte function. Morphological analysis of beige mice reveals the presence of enlarged lysosomes in a variety of cell types, including leucocytes, hepatocytes, fibroblasts and renal tubule cells. To examine the process of granule maturation and degranulation in beige mice mast cells, morphological studies have been conducted using a combination of electrophysiological techniques; however, few functional studies have been conducted with mast cells, such as mediator release. The aim of the present study was to determine the morphological and functional characteristics of skin and peritoneal mast cells and bone marrow-derived mast cells of homozygous (bg/bg) and heterozygous (bg/+) beige mice and wild-type (+/+) mice. The histamine concentration was lower in the peritoneal and bone marrow-derived mast cells of bg/bg mice compared with those of bg/+ and +/+ mice, but the histamine release response was potentiated. In vivo studies of passive cutaneous anaphylaxis showed no differences between bg/bg mice and either bg/+ or +/+ mice. Although bg/bg mast cells with enlarged granules display specific exocytotic processes in vitro, the consequences of mast cell activation in beige mice were similar to those of wild-type mice in vivo., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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36. Genetic Manipulation of Calcium Release-Activated Calcium Channel 1 Modulates the Multipotency of Human Cartilage-Derived Mesenchymal Stem Cells.
- Author
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Liu S, Takahashi M, Kiyoi T, Toyama K, and Mogi M
- Subjects
- Adipogenesis, Cell Differentiation, Cell Lineage, Cell Proliferation, Cells, Cultured, Chondrogenesis, Genetic Engineering, Humans, ORAI1 Protein genetics, Osteogenesis, Primary Cell Culture, Signal Transduction, Calcium metabolism, Cartilage pathology, Mesenchymal Stem Cells pathology, ORAI1 Protein metabolism
- Abstract
Calcium is a ubiquitous intracellular messenger that has a crucial role in determining the proliferation, differentiation, and functions of multipotent mesenchymal stem cells (MSCs). Our study is aimed at elucidating the influence of genetically manipulating Ca
2+ release-activated Ca2+ (CRAC) channel-mediated intercellular Ca2+ signaling on the multipotency of MSCs. The abilities of genetically engineered MSCs, including CRAC-overexpressing and CRAC-knockout MSCs, to differentiate into multiple mesenchymal lineages, including adipogenic, osteogenic, and chondrogenic lineages, were evaluated. CRAC channel-mediated Ca2+ influx into these cells was regulated, and the differentiation fate of MSCs was modified. Upregulation of intracellular Ca2+ signals attenuated the adipogenic differentiation ability and slightly increased the osteogenic differentiation potency of MSCs, whereas downregulation of CRACM1 expression promoted chondrogenic differentiation potency. The findings demonstrated the effects of genetically manipulating MSCs by targeting CRACM1. CRAC-modified MSCs had distinct differentiation fates to adipocytes, osteoblasts, and chondrocytes. To aid in the clinical implementation of tissue engineering strategies for joint regeneration, these data may allow us to identify prospective factors for effective treatments and could maximize the therapeutic potential of MSC-based transplantation.- Published
- 2019
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37. Design and Synthesis of Novel Amino-triazine Analogues as Selective Bruton's Tyrosine Kinase Inhibitors for Treatment of Rheumatoid Arthritis.
- Author
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Kawahata W, Asami T, Kiyoi T, Irie T, Taniguchi H, Asamitsu Y, Inoue T, Miyake T, and Sawa M
- Subjects
- Animals, Antitubercular Agents chemical synthesis, Antitubercular Agents pharmacology, Arthritis, Experimental chemically induced, Arthritis, Experimental microbiology, Arthritis, Rheumatoid microbiology, Arthritis, Rheumatoid prevention & control, Male, Mice, Mice, Inbred DBA, Molecular Structure, Tuberculosis complications, Tuberculosis microbiology, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Arthritis, Experimental prevention & control, Drug Design, Mycobacterium tuberculosis drug effects, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology
- Abstract
Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of multiple diseases, such as B-cell malignances, asthma, and rheumatoid arthritis. A series of novel aminotriazines were identified as highly selective inhibitors of BTK by a scaffold-hopping approach. Subsequent SAR studies of this series using two conformationally different BTK proteins, an activated form of BTK and an unactivated form of BTK, led to the discovery of a highly selective BTK inhibitor, 4b. With significant efficacy in models in vivo and good ADME and safety profiles, 4b was advanced into preclinical studies.
- Published
- 2018
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38. High-throughput screening system for dynamic monitoring of exocytotic vesicle trafficking in mast cells.
- Author
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Kiyoi T, Liu S, Sahid MNA, Shudou M, Maeyama K, and Mogi M
- Subjects
- Animals, Cell Line, Tumor, Drug Evaluation, Preclinical methods, Female, Fluorescent Dyes chemistry, Fluorescent Dyes metabolism, Male, Mice, Mice, Inbred C57BL, Primary Cell Culture, Rats, Vesicular Monoamine Transport Proteins metabolism, Bone Marrow Cells metabolism, Exocytosis, High-Throughput Screening Assays methods, Mast Cells metabolism, Secretory Vesicles metabolism
- Abstract
Mast cells, in addition to endocrine cells and neurons, are typical secretory cells. Their function in allergic inflammation is to secrete inflammatory mediators from secretory vesicles. Intracellular synthesized inflammatory mediators are transported by vesicular monoamine transporters (VMATs) to vesicles where they are stored. After stimulation, the contents of the secretory vesicles are released via exocytosis. This study established a high throughput imaging screening system to monitor the functions of secretory vesicles in mast cells, including molecular uptake via VMAT2 and the exocytotic process, by using a novel fluorescent probe, FFN206, which was developed as a VMAT2 substrate. After loading with FFN206, the rapid uptake of FFN206 was observed and secretory vesicles in mouse bone marrow derived mast cells and a cultured mast cell line were clearly visualized. FFN206 uptake by secretory vesicles was time-dependent and was blocked by reserpine. Furthermore, exocytotic trafficking was monitored dynamically by real-time high-throughput fluorescence quantitation. In the present study, we verified the application of FFN206 for the monitoring of functional vesicles. This high-throughput screening system may benefit instinctive drug evaluation., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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39. Efficacy of constant long-term delivery of YM-58483 for the treatment of rheumatoid arthritis.
- Author
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Miyoshi M, Liu S, Morizane A, Takemasa E, Suzuki Y, Kiyoi T, Maeyama K, and Mogi M
- Subjects
- Anilides therapeutic use, Animals, Anti-Inflammatory Agents therapeutic use, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid metabolism, Autoantibodies biosynthesis, Cytokines metabolism, Inflammation Mediators metabolism, Injections, Subcutaneous, Male, Mice, Safety, Spleen immunology, Synovial Fluid immunology, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Thiadiazoles therapeutic use, Anilides administration & dosage, Anilides pharmacology, Anti-Inflammatory Agents pharmacology, Arthritis, Rheumatoid drug therapy, Thiadiazoles administration & dosage, Thiadiazoles pharmacology
- Abstract
The aim of this study was to investigate the efficacy and safety of YM-58483, a small molecular antagonist of Ca
2+ release-activated Ca2+ (CRAC) channels, for the treatment of rheumatoid arthritis (RA), in vivo and ex vivo. YM-58483 was continuously injected subcutaneously in a collagen-induced arthritis (CIA) mouS.E.M.odel using an implanted osmotic pump. The severity of CIA was evaluated using the following parameters: body weight, hind paw volume, clinical score, histological analysis, cytokine levels, Ca2+ influx, and specific IgG production. The efficacy of long-term application of YM-58483 was also verified ex vivo in RA patient-derived peripheral blood monocytes. Assessment of the clinical severity of CIA, cytokine profile in serum and joint protein extracts, and specific IgG production showed that continuous application of YM-58483 suppressed synovial inflammation by inhibiting immune cell activity. Chemical screening and hepatography indicated that long-term subcutaneous delivery of YM-58483 was safer than oral administration for systemic application. Moreover, constant preincubation with YM-58483 at an IC50 of 0.1-1 nM altered proinflammatory cytokine production ex vivo in peripheral T cells derived from RA patients. Our findings suggest that continuous long-term application of appropriate CRAC inhibitors such as YM-58483 is a potential therapeutic strategy for global immunosuppression in RA., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2018
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40. Bone Resorption Activity in Mature Osteoclasts.
- Author
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Kiyoi T
- Subjects
- Animals, Collagen, Mice, Osteoclasts ultrastructure, Bone Resorption pathology, Cell Differentiation, Osteoclasts pathology
- Abstract
Bone homeostasis depends on balanced bone deposition and bone resorption, which are mediated by osteoblasts and osteoclasts, respectively. As one therapeutic strategy, the blockage of osteoclast activity reduces subsequent bone erosion. Morphological analysis of bone resorption pits formed by osteoclasts by using scanning electron microscope is an effective method for understanding rheumatoid arthritis. Here we describe methods for observing surface microstructure of pits formed by osteoclasts on hard tissue sections.
- Published
- 2018
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41. Histological Analysis of Arthritic Joints.
- Author
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Kiyoi T
- Subjects
- Animals, Calcium Channels metabolism, Disease Models, Animal, Mice, Paraffin Embedding, Staining and Labeling, Tartrate-Resistant Acid Phosphatase, Tissue Fixation, Arthritis, Rheumatoid pathology, Immunohistochemistry methods, Joints pathology
- Abstract
Histological analysis is a morphological technique and an effective method for understanding the pathology of rheumatoid arthritis (RA). Here, we describe the processes of paraffin samples, including fixation, decalcifying, embedding, sectioning, and staining (hematoxylin and eosin, tartrate-resistant acid phosphatase, and immunohistochemistry) for an RA model mouse.
- Published
- 2018
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42. Inhibition of the mevalonate pathway by simvastatin interferes with mast cell degranulation by disrupting the interaction between Rab27a and double C2 alpha proteins.
- Author
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Sahid MNA, Liu S, Kiyoi T, and Maeyama K
- Subjects
- Animals, Calcium metabolism, Cell Line, Tumor, Exocytosis drug effects, Gene Expression Regulation drug effects, Histamine Release drug effects, Prenylation drug effects, Protein Binding drug effects, Rats, Calcium-Binding Proteins metabolism, Cell Degranulation drug effects, Mast Cells cytology, Mast Cells drug effects, Mevalonic Acid metabolism, Nerve Tissue Proteins metabolism, Simvastatin pharmacology, rab27 GTP-Binding Proteins metabolism
- Abstract
Statins are well-known inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which block the mevalonate pathway. The activity of statins not only decreases cholesterol levels but also ameliorates inflammation and modulates the immune system. In this study, we investigated the effects of simvastatin on histamine release using rat basophilic leukaemia (RBL-2H3) cells, and examined its interaction with proteins involved in the exocytosis process. Treatment with simvastatin for 24h inhibited histamine release in RBL-2H3 cells in a concentration-dependent manner after stimulation with dinitrophenylated bovine serum albumin (DNP-BSA, as an antigen), ionomycin (a calcium ion [Ca
2+ ] ionophore), and thapsigargin (an inhibitor of Ca2+ -ATPase in the endoplasmic reticulum). Simvastatin-induced inhibition was counteracted by co-administration of mevalonolactone or geranylgeraniol, but not farnesol. Indeed, several exocytotic proteins were post-translationally modified by isoprenylation, which is required for proper localization in the lipid membrane. RBL-2H3 cells express proteins involved in the fusion of granules and the plasma membrane, such as Ras-like protein in the brain 27a (Rab27a), synaptosome-associated protein 23 (SNAP23), and vesicle-associated membrane protein 7 (VAMP7), as well as Ca2+ binding proteins, such as double C2 alpha (Doc2a), synaptotagmin2, and mammalian uncoordinated13-4 (munc13-4). The interaction of Rab27a and Doc2a proteins was detected using proximity ligation assays. Antigen stimulation caused these proteins to interact, and this interaction could be disrupted by co-administration of simvastatin. In conclusion, simvastatin inhibited the mevalonate pathway, which suppressed the geranylgeranylation of Rab27a by depleting geranylgeranyl pyrophosphate and interfering with the Rab27a-Doc2a interaction. This activity resulted in the inhibition of exocytosis in RBL-2H3 cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)- Published
- 2017
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43. Efficiency and Safety of CRAC Inhibitors in Human Rheumatoid Arthritis Xenograft Models.
- Author
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Liu S, Hasegawa H, Takemasa E, Suzuki Y, Oka K, Kiyoi T, Takeda H, Ogasawara T, Sawasaki T, Yasukawa M, and Maeyama K
- Subjects
- Anilides adverse effects, Animals, Antibodies, Neutralizing adverse effects, Arthritis, Rheumatoid immunology, B-Lymphocytes immunology, Cells, Cultured, Disease Models, Animal, Heterografts, Humans, Hyperglycemia etiology, Immunosuppression Therapy, Mice, Mice, SCID, T-Lymphocytes immunology, Thiadiazoles adverse effects, Anilides therapeutic use, Anti-Inflammatory Agents therapeutic use, Antibodies, Neutralizing therapeutic use, Arthritis, Rheumatoid therapy, B-Lymphocytes drug effects, Calcium Release Activated Calcium Channels antagonists & inhibitors, Immunotherapy methods, T-Lymphocytes drug effects, Thiadiazoles therapeutic use
- Abstract
Store-operated Ca
2+ release-activated Ca2+ (CRAC) channels are involved in the pathogenesis of rheumatoid arthritis (RA) and have been studied as therapeutic targets in the management of RA. We investigated the efficacy and safety of CRAC inhibitors, including a neutralizing Ab (hCRACM1-IgG) and YM-58483, in the treatment of RA. Patient-derived T cell and B cell activity was suppressed by hCRACM1-IgG as well as YM-58483. Systemically constant, s.c. infused CRAC inhibitors showed anti-inflammatory activity in a human-NOD/SCID xenograft RA model as well as protective effects against the destruction of cartilage and bone. hCRACM1-IgG appeared to be safe for systemic application, whereas YM-58483 showed hepatic and renal toxicity in xenograft mice. Treatment with both CRAC inhibitors also caused hyperglycemia in xenograft mice. These results indicate the potential of hCRACM1-IgG and YM-58483 as anti-immunological agents for the treatment of RA. However, some safety issues should be addressed and application methods should be optimized prior to their clinical use., (Copyright © 2017 by The American Association of Immunologists, Inc.)- Published
- 2017
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44. Intra-articular lentivirus-mediated gene therapy targeting CRACM1 for the treatment of collagen-induced arthritis.
- Author
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Liu S, Kiyoi T, Takemasa E, and Maeyama K
- Subjects
- Animals, Arthritis, Experimental blood, Arthritis, Experimental immunology, Arthritis, Experimental pathology, Arthritis, Rheumatoid blood, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid pathology, Cytokines blood, Cytokines immunology, Gene Silencing, Joints immunology, Joints pathology, Lentivirus genetics, Lymph Nodes, Male, Mice, Inbred DBA, RANK Ligand blood, RANK Ligand immunology, RNA, Small Interfering genetics, Spleen cytology, Synovial Membrane cytology, Arthritis, Experimental therapy, Arthritis, Rheumatoid therapy, Genetic Therapy, ORAI1 Protein genetics
- Abstract
Abnormal store-operated calcium uptake has been observed in peripheral T lymphocytes of rheumatoid arthritis (RA) patients, and sustained intracellular calcium signalling is known to mediate the functions of many types of immune cells. Thus, it is hypothesized that regulating calcium entry through CRACM1 (the pore-forming subunit of calcium release-activated calcium (CRAC) channels; also known as ORAI1) may be beneficial for the management of RA. Localized CRACM1 knockdown in the joints and draining lymph nodes (DLNs) of mice with collagen-induced arthritis (CIA) was achieved via lentiviral-based delivery of shRNA targeting mouse CRACM1. Consistent with CRACM1 knockdown, calcium influx in synovial cells and the histopathological features of CIA were reduced. These effects were also associated with reduced levels of several notable inflammatory cytokines, such as IL-6, IL-17A, and IFN-γ, in the joints. Additionally, CRACM1-shRNA reduced the number of bone marrow-derived osteoclasts in vitro as well as osteoclasts in CIA joints, which was associated with reduced RANKL levels in the serum and joints. In summary, inhibiting calcium entry by CRACM1 knockdown suppressed arthritis development and may be therapeutically beneficial for RA patients., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)
- Published
- 2017
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45. CRACM3 regulates the stability of non-excitable exocytotic vesicle fusion pores in a Ca(2+)-independent manner via molecular interaction with syntaxin4.
- Author
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Liu S, Sahid MN, Takemasa E, Kiyoi T, Kuno M, Oshima Y, and Maeyama K
- Subjects
- Animals, Calcium Channels genetics, Calcium Release Activated Calcium Channels metabolism, Cell Line, Tumor, Exocytosis drug effects, Membrane Fusion physiology, Qa-SNARE Proteins genetics, Rats, Secretory Vesicles metabolism, Single-Cell Analysis, Thapsigargin pharmacology, Calcium metabolism, Calcium Channels physiology, Exocytosis physiology, Qa-SNARE Proteins metabolism
- Abstract
Ca(2+) release-activated calcium channel 3 (CRACM3) is a unique member of the CRAC family of Ca(2+)-selective channels. In a non-excitable exocytosis model, we found that the extracellular L3 domain and the cytoplasmic C-terminus of CRACM3 interacted in an activity-dependent manner with the N-peptide of syntaxin4, a soluble N-ethylmaleimide-sensitive factor attachment receptor protein. Our biochemical, electrophysiological and single-vesicle studies showed that knockdown of CRACM3 suppressed functional exocytosis by decreasing the open time of the vesicle fusion pore without affecting Ca(2+) influx, the activity-dependent membrane capacitance (Cm) change, and the total number of fusion events. Conversely, overexpressing CRACM3 significantly impaired cell exocytosis independent of Ca(2+), led to an impaired Cm change, decreased the number of fusion events, and prolonged the dwell time of the fusion pore. CRACM3 changes the stability of the vesicle fusion pore in a manner consistent with the altered molecular expression. Our findings imply that CRACM3 plays a greater role in exocytosis than simply acting as a compensatory subunit of a Ca(2+) channel.
- Published
- 2016
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46. The protective role of protein L-isoaspartyl (D-aspartate) O-methyltransferase for maintenance of mitochondrial morphology in A549 cell.
- Author
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Ogasawara M, Otani M, Takano M, Shudou M, Inaba Y, Nirasawa S, Takahashi S, Kiyoi T, Tanaka Y, Kameda K, Kunugita N, Maeyama K, Sano K, Yamashita M, and Yamauchi K
- Subjects
- A549 Cells, Adenosine Triphosphate metabolism, Endoplasmic Reticulum Stress, Humans, Mitochondria ultrastructure, Mitochondrial Dynamics, Oxidative Stress, Prohibitins, Mitochondria enzymology, Protein D-Aspartate-L-Isoaspartate Methyltransferase metabolism, Repressor Proteins metabolism
- Abstract
Purpose: The increasing amounts of evidence with abnormal aging process have been involved in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Mice with deficient protein L-isoaspartate (D-aspartate) O-methyl transferase 1 (PCMT1) expression reveal acceleration of aging and result in the increased proportion of D-aspartate (D-Asp) residues and dysfunction in proteins. Furthermore, mitochondrial morphology and functions are associated with COPD and IPF pathogenesis. The purpose of the current study was to investigate the role of PCMT1 on mitochondrial morphology using A549 cells., Materials and Methods: We investigated PCMT1, prohibitin1 (PHB1), mitochondrial membrane proteins expression, mitochondrial morphology, and the proportion of D-Asp residues in PHB1 in A549 cells with (PCMT1-KD) and without the context of decreased PCMT1 expression (PCMT1-Cont) using electron microscopy, fluorescence staining, Western blot analysis, and the ATP content per cells. To investigate the effects of the PCMT1-KD cells, we developed double-transfected cell lines containing either the cytosolic or the endoplasmic isoform of PCMT1., Results: We found a significantly higher proportion of D-Asp residues in PHB1 in PCMT1-KD cells than that in PCMT1-Cont cells. The PCMT1-KD cells without cigarette smoke extract exposure were characterized by a significantly increased proportion of the D-Asp residues in PHB1, damaged mitochondrial ultrastructure, and a tendency toward the fission direction of the mitochondrial dynamics followed by a significant decrease in the cellular ATP content., Conclusions: The increased proportion of the D-Asp residues may contribute to COPD pathogenesis, via irreversible protein conformational changes, followed by mitochondrial dysfunction.
- Published
- 2016
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47. The α4β2 nicotinic acetylcholine receptor modulates autism-like behavioral and motor abnormalities in pentylenetetrazol-kindled mice.
- Author
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Takechi K, Suemaru K, Kiyoi T, Tanaka A, and Araki H
- Subjects
- Animals, Anxiety drug therapy, Anxiety metabolism, Behavior, Animal drug effects, Convulsants, Disease Models, Animal, Kindling, Neurologic, Male, Mice, Inbred ICR, Motor Activity drug effects, Pentylenetetrazole, Psychomotor Performance drug effects, Rotarod Performance Test, Social Behavior, Anti-Anxiety Agents pharmacology, Anti-Anxiety Agents therapeutic use, Autistic Disorder drug therapy, Autistic Disorder metabolism, Isoxazoles pharmacology, Isoxazoles therapeutic use, Nicotinic Agonists pharmacology, Nicotinic Agonists therapeutic use, Pyrrolidines pharmacology, Pyrrolidines therapeutic use, Receptors, Nicotinic metabolism, Seizures chemically induced, Seizures drug therapy, Seizures metabolism
- Abstract
Epilepsy is associated with several psychiatric disorders, including cognitive impairment, autism and attention deficit/hyperactivity disorder (ADHD). However, the psychopathology of epilepsy is frequently unrecognized and untreated in patients. In the present study, we investigated the effects of ABT-418, a neuronal nicotinic acetylcholine receptor agonist, on pentylenetetrazol (PTZ)-kindled mice with behavioral and motor abnormalities. PTZ-kindled mice displayed impaired motor coordination (in the rotarod test), anxiety (in the elevated plus maze test) and social approach impairment (in the three-chamber social test) compared with control mice. ABT-418 treatment (0.05 mg/kg, intraperitoneally) alleviated these behavioral abnormalities in PTZ-kindled mice. Immunolabeling of tissue sections demonstrated that expression of the α4 nicotinic acetylcholine receptor subunit in the medial habenula was similar in control and PTZ-kindled mice. However, expression was significantly decreased in the piriform cortex in PTZ-kindled mice. In addition, we examined the expression of the synaptic adhesion molecule neuroligin 3 (NLG3). NLG3 expression in the piriform cortex was significantly higher in PTZ-kindled mice compared with control mice. Collectively, our findings suggest that ADHD-like or autistic-like behavioral abnormalities associated with epilepsy are closely related to the downregulation of the α4 nicotinic receptor and the upregulation of NLG3 in the piriform cortex. In summary, this study indicates that ABT-418 might have therapeutic potential for attentional impairment in epileptic patients with psychiatric disorders such as autism and ADHD., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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48. Involvement of stimulation of α7 nicotinic acetylcholine receptors in the suppressive effect of tropisetron on dextran sulfate sodium-induced colitis in mice.
- Author
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Tasaka Y, Yasunaga D, Kiyoi T, Tanaka M, Tanaka A, Suemaru K, and Araki H
- Subjects
- Aconitine analogs & derivatives, Aconitine pharmacology, Animals, Colitis chemically induced, Colitis metabolism, Colitis, Ulcerative chemically induced, Colitis, Ulcerative metabolism, Colon metabolism, Cytokines metabolism, Disease Models, Animal, Indoles antagonists & inhibitors, Inflammation Mediators metabolism, Male, Mice, Inbred ICR, Peroxidase metabolism, Tropisetron, Colitis drug therapy, Colitis genetics, Colitis, Ulcerative drug therapy, Colitis, Ulcerative genetics, Dextran Sulfate, Indoles pharmacology, Indoles therapeutic use, alpha7 Nicotinic Acetylcholine Receptor physiology
- Abstract
Ulcerative colitis (UC) involves chronic inflammation of the large intestine. Several agents are used to treat UC, but adverse side effects are remaining problems. We examined the effect of tropisetron as a new type of drug for UC using a dextran sulfate sodium (DSS)-induced model of colitis in mice. We developed a DSS-induced model of colitis and calculated the Disease Activity Index and colon length. We measured myeloperoxidase activity and determined the protein level and mRNA level of cytokines in the colon. DSS-induced colitis was ameliorated by administration of tropisetron and PNU282987. Pre-administration of methyllycaconitine diminished the suppressive effect of tropisetron upon DSS-induced colitis. These findings suggested that α7 nicotinic acetylcholine receptors (α7 nAChRs) were related to the suppressive effect of tropisetron on DSS-induced colitis. Additionally, stimulation of α7 nAChRs decreased the colon level of interleukin-6 and interferon-γ upon DSS administration. Furthermore, stimulation of α7 nAChRs decreased macrophage infiltration, with expression of α7 nAChR increased by DSS administration. These results suggest that the underlying mechanism of this suppressive effect on DSS-induced colitis is via stimulation of α7 nAChRs and involves suppression of expression of pro-inflammatory cytokines. Tropisetron could be a new type of therapeutic agent for UC., (Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)
- Published
- 2015
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49. Evaluation of edaravone against radiation-induced oral mucositis in mice.
- Author
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Nakajima N, Watanabe S, Kiyoi T, Tanaka A, Suemaru K, and Araki H
- Subjects
- Animals, Antipyrine pharmacology, Antipyrine therapeutic use, Edaravone, Mice, Inbred ICR, Peroxidase metabolism, Radiation Dosage, Radiation Injuries, Experimental etiology, Radiation Injuries, Experimental metabolism, Reactive Oxygen Species metabolism, Stomatitis metabolism, Thiobarbiturates metabolism, Antioxidants, Antipyrine analogs & derivatives, Radiation Injuries, Experimental prevention & control, Stomatitis etiology, Stomatitis prevention & control
- Abstract
Oral mucositis induced by radiotherapy for cancers of the head and neck reduce the quality of life of patients. However, effective therapeutic agents are lacking. Symptomatic treatment involves local anesthesia and analgesia. We focused on the antioxidant effects of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; Radicut(®)). Oral mucositis was induced on the tongue tips of mice using a single dose of X-rays (20 Gy). To evaluate the protective effect of edaravone (30 and 300 mg/kg), administration was carried out 30 min before irradiation. Survival, oral mucositis score, myeloperoxidase activity, and levels of 2-Thiobarbituric acid reactive substances were measured, and all were improved compared with those of control mice. A significant difference was not found in terms of survival due to edaravone. Histopathologic findings also highlighted the beneficial features of edaravone. Edaravone reduced the production of reactive oxygen species. These findings suggest that the protective effect of edaravone against radiation-induced oral mucositis is through an antioxidant effect., (Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
50. Systemic lentivirus-mediated delivery of short hairpin RNA targeting calcium release-activated calcium channel 3 as gene therapy for collagen-induced arthritis.
- Author
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Liu S, Kiyoi T, Takemasa E, and Maeyama K
- Subjects
- Animals, Calcium Signaling genetics, Cytokines biosynthesis, Cytokines blood, Cytosol metabolism, HEK293 Cells, Humans, Knee Joint metabolism, Lentivirus, Male, Mice, Mice, Inbred DBA, Osteoclasts metabolism, RNA Interference, Spleen cytology, Synovial Fluid cytology, T-Lymphocytes immunology, Thymocytes metabolism, Arthritis, Experimental therapy, Arthritis, Rheumatoid therapy, Calcium metabolism, Calcium Channels genetics, Genetic Therapy methods, RNA, Small Interfering genetics
- Abstract
Immune cells, including T cells, B cells, and osteoclasts, in conjunction with their associated cytokines, have been studied as primary molecular therapeutic targets for the management of rheumatoid arthritis (RA) patients. The increase in cytosolic Ca(2+) levels through the activation of store-operated Ca(2+) release-activated channels (CRACs) is involved in mediating a disparate array of cellular responses by these immune cells. This study was undertaken to investigate the feasibility and efficiency of the regulation of Ca(2+) entry in the treatment of RA. To moderately suppress Ca(2+) entry via CRACs, we gene silenced CRACM3, which was induced by systemic application of specific short hairpin RNAs (shRNAs) using a lentiviral-delivery system, in a murine model of collagen-induced arthritis (CIA). The inflammatory responses were determined by measuring the levels of a panel of cytokines and chemokines in the joints and serum. Ag-specific responses were evaluated by determining the cytokine profile of T cells stimulated with autoantigen. We also analyzed the ability of specific CRACM3-shRNA to regulate mature osteoclast function in CIA mice. The therapeutic effect of lentiviral-delivered CRACM3-shRNA was associated with gene silencing of CRACM3, along with the successful biodistribution of the virus. Extracellular Ca(2+) influx in the splenocytes, thymocytes, and knee joint synovial cells was moderately suppressed. Inflammatory responses and autoimmune responses were reduced by CRACM3 gene silencing. A decrease in mature osteoclast activity also was observed in CRACM3-shRNA-treated CIA mice. These results indicate that regulation of Ca(2+) entry through lentivirus-mediated CRACM3 gene silencing is beneficial in the treatment of RA., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
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