53 results on '"Onizawa M"'
Search Results
2. Antenna-Coupled Electrode Electro-Optic Modulator for 5G Mobile Applications
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Murata, H., primary, Yokohashi, H., additional, Matsukawa, S., additional, Sato, M., additional, Onizawa, M., additional, and Kurokawa, S., additional
- Published
- 2021
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3. P063 B-cell receptor signalling in lymphoid tissues may be regulated by CEACAM1
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Nagaishi, T, primary, Tsugawa, N, additional, Yamada, D, additional, Watabe, T, additional, Onizawa, M, additional, and Watanabe, M, additional
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- 2020
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4. P042 APL expression is down-regulated in an animal model of chronic colitis
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Nagaishi, T, primary, Kojima, Y, additional, Yamada, D, additional, Watabe, T, additional, Tsugawa, N, additional, Jose, N, additional, Onizawa, M, additional, and Watanabe, M, additional
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- 2019
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5. Optical fiber link port extender for vector network analyzer
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Kurokawa, S., primary, Hirose, M., additional, Toba, Y., additional, Onizawa, M., additional, and Ichijo, J., additional
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- 2017
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6. Physical properties of Mn oxypnictide (LaO)MnPn; Pn = P, As, Sb
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Onizawa, M., primary, Otsuka, S., additional, Takeda, R., additional, Kato, K., additional, Umeyama, N., additional, Ikeda, S., additional, Hiramoto, S., additional, Yoshida, F., additional, Moriyoshi, C., additional, Kuroiwa, Y., additional, Tobimatu, K., additional, Sato, H., additional, Sawada, M., additional, Namatame, H., additional, Taniguchi, M., additional, Watanabe, T., additional, Takano, Y., additional, Takase, K., additional, Ihm, Jisoon, additional, and Cheong, Hyeonsik, additional
- Published
- 2011
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7. Tumor necrosis factor receptor signaling in intestinal epithelia may be directly involved in colitis-associated carcinogenesis
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Nagaishi, T, primary, Onizawa, M, additional, Wang, S, additional, Suzuki, M, additional, Tsuge, N, additional, Yamaji, O, additional, Totsuka, T, additional, and Watanabe, M, additional
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- 2009
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8. A study on a long-distance transmission of terrestrial digital TV signals using optical fibers.
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Haeiwa, K., Toba, Y., Onizawa, M., and Nakamura, M.
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- 2006
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9. Computational method of three dimensional eddy current by using volume integral equation method
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Koizumi, M., primary and Onizawa, M., additional
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- 1991
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10. Development of a Microwave Receiving and Transmission System using an Optical Modulator
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Yamashita, T., primary, Haeiwa, K., additional, Negishi, T., additional, Toba, Y., additional, Murasaki, I., additional, and Onizawa, M., additional
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11. Optical RF-TV signal sensing and transmission for terrestrial TV relaying stations
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Haeiwa, K., primary, Yamashita, T., additional, Takeuchi, Y., additional, Toba, Y., additional, Torihata, S., additional, and Onizawa, M., additional
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12. Physical properties of Mn oxypnictide (LaO)MnPn; Pn = P, As, Sb.
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Onizawa, M., Otsuka, S., Takeda, R., Kato, K., Umeyama, N., Ikeda, S., Hiramoto, S., Yoshida, F., Moriyoshi, C., Kuroiwa, Y., Tobimatu, K., Sato, H., Sawada, M., Namatame, H., Taniguchi, M., Watanabe, T., Takano, Y., and Takase, K.
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- *
MAGNETIC semiconductors , *MANGANESE compounds , *ELECTRIC resistance , *MAGNETIZATION , *BAND gaps , *TEMPERATURE effect - Abstract
We have investigated physical properties of the layered Mn oxypnictides (LaO)MnPn; Pn = P, As, Sb. Electrical resistivity of three samples, indicting semiconducting behaviors, drastically increases with lowering temperature. The optical band gaps estimated from the diffusive reflectance are about 1.6 eV and they don't depend on pnictogen atoms even though the lattice constants widely change. Magnetizations of (LaO)MnAs and (LaO)MnSb show very weak temperature dependence with positive slope against temperature. Some magnetic order is expected to exist at higher temperature than room temperature. Consequently, the Mn oxypnictides (LaO)MnPn are magnetic semiconductors. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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13. Development of a microwave receiving and transmission system using an optical modulator.
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Yamashita, T., Haeiwa, K., Negishi, T., Murasaki, I., Toba, Y., and Onizawa, M.
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- 2005
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14. Optical RF-TV signal sensing and transmission for terrestrial TV relaying stations.
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Haeiwa, K., Yamashita, T., Takeuchi, Y., Toba, Y., Torihata, S., and Onizawa, M.
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- 2002
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15. C5a stimulation induces caspase-1 activation and mature IL-1β production in human peripheral blood mononuclear cells.
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Fujita Y, Matsumoto H, Inada K, Onizawa M, Saito K, Sumichika Y, Yoshida S, Temmoku J, Matsuoka N, Asano T, Sato S, Machida T, and Migita K
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- Humans, Inflammasomes metabolism, Inflammasomes immunology, Monocytes immunology, Monocytes metabolism, Cells, Cultured, Lipopolysaccharide Receptors metabolism, Enzyme Activation, Interleukin-1beta metabolism, Caspase 1 metabolism, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear immunology, Complement C5a
- Abstract
The complement component C5a contributes to the recruitment of immune cells to inflamed tissues and local inflammation. The proinflammatory cytokine interleukin (IL)-1β is also related to inflammatory disorders through inflammasome activation. However, the association between inflammasome activation and C5a is unclear. Human peripheral blood mononuclear cells (PBMCs) were stimulated with C5a and measured for IL-1β secretion by enzyme-linked immunosorbent assay (ELISA). The pro-IL-1β expression in cell lysates was also examined by Western blot analysis. Similarly, magnetic bead-isolated CD14
+ monocyte-depleted and lymphocyte-depleted PBMCs were stimulated with C5a, and immunoblot analysis was performed using an anti-cleaved-IL-1β (p17) antibody. FACS was performed to detect caspase-1-activated cells. C5a-stimulated PBMCs produced IL-1β in C5a concentration-dependent manner. The protein levels of pro-IL-1β in the cell lysates were significantly increased. Furthermore, the cleaved-IL-1β (p17) was faintly detected in the same lysates. Active caspase-1 was demonstrated in C5a-simulated CD14+ monocytes by FACS. Cleaved-IL-1β (p17) was demonstrated in the supernatant of C5a-stimulated PBMCs. Lymphocyte-depleted PBMCs stimulated with C5a but monocyte-depleted PBMCs produced cleaved-IL-1β (p17). C5a induced the production of mature IL-1β in PBMCs. The IL-1β production is mediated mainly by caspase-1 activation in CD14+ monocytes. These results suggest that C5a alone potentiates mature IL-1β production mainly in monocytes.- Published
- 2024
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16. Characteristics of positive horizontal margins in patients who underwent colorectal endoscopic submucosal dissection.
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Kawashima K, Hikichi T, Onizawa M, Gunji N, Watahiki Y, Sakuma C, Mochimaru T, Murakami M, Suzuki O, Hashimoto Y, Kobayakawa M, and Ohira H
- Abstract
Objectives: Endoscopic submucosal dissection (ESD) enables en bloc resection of colorectal neoplasms, but occasionally results in positive horizontal margins (HMs). However, the site of the resected specimen that tends to be positive for HM has not been investigated. We aimed to clarify the characteristics associated with HMs in lesions resected en bloc with ESD., Methods: Patients with colorectal neoplasms who underwent en bloc resection with ESD were included in this study. The patients were divided into negative HMs (HM0) and positive or indeterminate HMs (HM1) groups. The characteristics associated with HM1 resection were investigated. In addition, the local recurrence rate during endoscopic follow-up for >6 months after ESD was observed., Results: In total, 201 lesions were analyzed in 189 patients (HM0, 189 lesions; HM1, 12 lesions). The HM1 group had a significantly larger median lesion diameter (25 vs. 55 mm; p < 0.001) and more lesions with >50% circumference than did the HM0 group ( p < 0.001). Furthermore, the prevalence of severe fibrosis was significantly higher in the HM1 group than in the HM0 group ( p < 0.001). Positive horizontal sites of the resected specimens were more frequent at the oral and anal sites than at the lateral sites. No local recurrences were observed in either group., Conclusions: The characteristics associated with HM1 depended on lesion size, particularly lesions with >50% circumference, and submucosal fibrosis., Competing Interests: Authors declare no conflicts of interest for this article., (© 2023 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)
- Published
- 2023
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17. A balloon-assisted endoscopic submucosal dissection using long colonoscope and guidewire.
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Watahiki Y, Kawashima K, Hikichi T, Takagi T, Onizawa M, Gunji N, Watanabe C, Wada J, Oka Y, Hashimoto Y, and Ohira H
- Abstract
Balloon-assisted endoscopy enables stable endoscopic maneuverability. Balloon-assisted endoscopic submucosal dissection (BA-ESD) is useful in the treatment of proximal colorectal tumors where scope maneuverability is poor. Herein, we reported a case in which BA-ESD was successfully performed using a long colonoscope with a guidewire, although the lesion could not be reached using the balloon-assisted endoscopy technique with a therapeutic colonoscopy. A 50-year-old man underwent a colonoscopy that revealed a tumor in the ascending colon. BA-ESD was performed using a conventional therapeutic endoscope due to excessive intestinal elongation and poor endoscopic maneuverability. However, the transverse colon loop could not be reduced, and the total colonoscopy failed despite using balloon-assisted endoscopy. The scope was then changed from a conventional colonoscope to a long colonoscope, inserted into the terminal ileum, and the loop was reduced. After the guidewire was placed at the terminal ileum and the long colonoscope was removed, a therapeutic colonoscopy with an overtube was inserted into the ascending colon without reforming the colonic loop, allowing safe BA-ESD., Competing Interests: None., (© 2023 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)
- Published
- 2023
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18. Cecal Volvulus with Typical Whirlpool Sign.
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Watahiki Y, Kawashima K, Onizawa M, and Ohira H
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- 2023
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19. Apelin expression is downregulated in T cells in a murine model of chronic colitis.
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Yamada D, Kojima Y, Hosoya A, Suzuki M, Watabe T, Inoue T, Tsugawa N, Asakawa T, Yonemoto Y, Onizawa M, Nemoto Y, Oshima S, Shimonaka M, Kuba K, Ishida J, Fukamizu A, Penninger JM, Watanabe M, Okamoto R, and Nagaishi T
- Subjects
- Mice, Humans, Animals, T-Lymphocytes metabolism, Apelin metabolism, Disease Models, Animal, Dextran Sulfate, Mice, Inbred C57BL, CD4-Positive T-Lymphocytes, Colitis pathology, Inflammatory Bowel Diseases metabolism
- Abstract
Apelin (APL), an endogenous ligand for APJ, has been reported to be upregulated in a murine model of acute colitis induced by sodium dextran sulfate, as well as inflammatory bowel diseases (IBD) in humans. However, the mechanisms and functions of APL/APJ axis in the pathogenesis of IBD are unclear. We herein analyzed CD4
+ T cells to determine the functions of APL in a murine model of chronic colitis induced in Rag deficient mice (Rag-/- ). In colonic tissues of wild-type mice (WT), we found that APL was expressed especially in the lamina propria lymphocytes, where CD4+ T cells are dominant, rather than the epithelial cells. Unexpectedly, the APL expression was rather downregulated in the colonic tissue of the chronic colitis group compared to the control groups (Rag-/- before colitis induction and WT). The APL expression was downregulated when naïve T cells were differentiated into effecter T cells. A lack of APL resulted in decreased naïve T cells and increased effecter T cells in secondary lymphoid organs. A synthetic APL peptide, [Pyr1 ]-APL-13, increased IL-10 and decreased IFN-γ productions by effecter T cells. Administration of [Pyr1 ]-APL-13 improved survival rate in association with lessened colitis severity and decreased pro-inflammatory cytokine production. This is the first report showing immunological function of APL specifically on T cells, and these results indicate that APL/APJ axis may be a novel therapeutic target for IBD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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20. Electronic properties of DNA-related molecules containing a bromine atom.
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Hirato M, Onizawa M, Baba Y, Haga Y, Fujii K, Wada SI, and Yokoya A
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- Bromouracil, DNA, Bromine, Thymine
- Abstract
Purpose: To clarify the radiosensitization mechanism masking the Auger effect of the cells possessing brominated DNA, the electronic properties of DNA-related molecules containing Br were investigated by X-ray spectroscopy and specific heat measurement., Materials and Methods: X-ray absorption near-edge structure (XANES) and X-ray photoemission spectroscopy (XPS) were used to measure the electronic properties of the nucleotides with and without Br. We determined the specific heat of 5-bromouracil crystals with thymine as a reference molecule at low temperatures of 3-48 K to calculate the microscopic state numbers., Results: Obtained XANES and XPS spectra indicated that both the lowest unoccupied molecular orbital (LUMO) and the core-levels were not affected by the Br incorporation. The state numbers of 5-bromouracil calculated from the specific heats obtained around 25 K was about 1.5 times larger than that for thymine below 20 K, although the numbers were almost the same below 5 K., Discussion: Our results suggest that the Br atom may not contribute substantially to the LUMO and core-level electronic states of the molecule, but rather to the microscopic states related to the excitation of lattice vibrations, which may be involved in valence electronic states.
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- 2023
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21. Increased CEACAM1 expression on peripheral blood neutrophils in patients with rheumatoid arthritis.
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Matsumoto H, Fujita Y, Onizawa M, Saito K, Sumichika Y, Yoshida S, Temmoku J, Matsuoka N, Yashiro-Furuya M, Asano T, Sato S, Suzuki E, Machida T, Watanabe H, and Migita K
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- Humans, Inflammation genetics, Inflammation metabolism, Neutrophils metabolism, Antigens, CD genetics, Antigens, CD metabolism, Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid metabolism, Leukocytes, Mononuclear metabolism
- Abstract
Altered expression of adhesion molecules in immune cells has been demonstrated in rheumatoid arthritis (RA). Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is an adhesion molecule that acts as a coinhibitory receptor in the immune system. We investigated the role of CEACAM1 in immune cell subsets of patients with RA. Peripheral blood was obtained from 37 patients with RA and 20 healthy controls (HC). The expression of CEACAM1 and T-cell immunoglobulin mucin domain molecule (TIM) -3 on peripheral blood mononuclear cells and neutrophils was analyzed by flow cytometry. Intracellular TIM-3 expression was analyzed using cellular lysates by Western blot analysis. Serum levels of soluble CEACAM1 (sCEACAM1) were estimated by an enzyme-linked immunosorbent assay. CEACAM1 expression was not detected in peripheral blood mononuclear cells, including in CD14(+) monocytes and CD3(+) lymphocytes isolated from patients with RA or HC. However, substantial cell-surface expression of CEACAM1 was detected in peripheral blood neutrophils, and it was significantly elevated in samples from patients with RA without remission compared to those in remission. There was no significant difference in serum levels of sCEACAM1 between patients with RA and HC. Cell-surface expression of TIM-3 was not detected in peripheral blood neutrophils from patients with RA or HC but was seen in CD14(+) monocytes. However, there was no significant difference in TIM-3 expression on monocytes between patients with RA and HC. Our data indicate that cell-surface expression of CEACAM1 on peripheral blood neutrophils are higher in patients with RA and that it is associated with rheumatoid inflammation. Further studies are needed to explore the potential role of CEACAM1 in rheumatoid inflammatory pathways., 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 Matsumoto, Fujita, Onizawa, Saito, Sumichika, Yoshida, Temmoku, Matsuoka, Yashiro-Furuya, Asano, Sato, Suzuki, Machida, Watanabe and Migita.)
- Published
- 2022
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22. Endoscopic submucosal dissection with the combination of a scissor-type knife and novel traction method for colonic neoplasm involving a diverticulum.
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Kawashima K, Hikichi T, Gunji N, Onizawa M, and Ohira H
- Abstract
Video 1A 35-mm laterally spreading tumor partially infiltrated the interior portion of the diverticular orifice in the ascending colon. Glycerol and hyaluronate solution were injected into the submucosa to maintain adequate mucosal elevation. Mucosal incision and submucosal dissection were performed using a DualKnife and insulation-tipped knife from the anal side; however, safe submucosal dissection was challenging with these knives because of severe fibrosis and abundant blood vessels in the diverticulum. Therefore, to improve the visibility of the submucosa, a scissor-type knife and a multiloop traction device was used to facilitate the submucosal dissection. Finally, en bloc resection was achieved in 117 minutes without adverse events. A part of the diverticular defect after endoscopic submucosal dissection was clipped to prevent delayed perforation., (© 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc.)
- Published
- 2022
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23. Colonic Endoscopic Submucosal Dissection for a Granular Cell Tumor with Insufficient Endoscopic Manipulation in the Hepatic Flexure.
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Kawashima K, Hikichi T, Onizawa M, Gunji N, Takeda Y, Mochimaru T, Ishizaki Y, Murakami M, Kobayashi R, Shioya Y, Suzuki O, Hashimoto Y, Kobayakawa M, and Ohira H
- Abstract
This report describes a granular cell tumor (GCT) with insufficient endoscopic manipulation in the hepatic flexure (HF) of the colon, which was treated by endoscopic submucosal dissection (ESD) using a splinting tube and the spring S-O clip traction method. A 44-year-old man presented with a 10 mm subepithelial tumor in the HF near the ascending colon on colonoscopy. The lesion had a smooth surface without erosion. The histology of biopsied specimen from the lesion was suspected as a GCT. Most GCTs are considered low-grade malignant, but ESD was chosen to treat the lesion due to the patient's insistence on endoscopic treatment. Because the lesion was located in the HF, it was assumed that the scope manipulation during ESD would be difficult. During ESD, a splinting tube was utilized to stabilize endoscopic manipulation and the spring S-O clip traction method to keep clear visualization of the submucosa, and the procedure was completed without adverse events. An 8 × 7 mm lesion with negative margins was removed by ESD. Hematoxylin and eosin staining showed atypical cells with round-to-oval nuclei and acidophilic vesicles, and immunohistochemical staining for S-100 protein was strongly positive with a Ki-67 labeling index of 5%. The lesion was pathologically confirmed as a GCT. This case showed the usefulness and safety of ESD for GCT with insufficient endoscopic manipulation in the HF., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2022 by S. Karger AG, Basel.)
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- 2022
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24. Trichuris trichiura Incidentally Detected by Colonoscopy and Identified by a Genetic Analysis.
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Ishizaki Y, Kawashima K, Gunji N, Onizawa M, Hikichi T, Hasegawa M, and Ohira H
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- Animals, Colon, Ascending, Colonoscopy, Humans, Zoonoses, Trichuriasis diagnosis, Trichuris genetics
- Abstract
Although trichuriasis, a zoonotic disease, has recently become rare in Japan due to improved environmental hygiene, we herein report a 79-year-old man in whom a worm was incidentally found in the ascending colon during colonoscopy for positive fecal occult blood and was endoscopically removed. A genetic analysis identified the worm as Trichuris trichiura possessing mixed sequences from non-human primate and human origins. Despite controversy regarding Trichuris trichiura infection originating from Japanese macaques, according to some studies, it originates primarily from humans. This report suggests the efficacy of a genetic analysis for identifying infection sources.
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- 2022
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25. Evaluation of the relationship between the spleen volume and the disease activity in ulcerative colitis and Crohn disease.
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Kawashima K, Onizawa M, Fujiwara T, Gunji N, Imamura H, Katakura K, and Ohira H
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- Adult, Body Weight, Female, Humans, Inflammatory Bowel Diseases, Male, Middle Aged, Pancreatic Cyst, Retrospective Studies, Colitis, Ulcerative diagnostic imaging, Crohn Disease diagnostic imaging, Spleen diagnostic imaging, Tomography, X-Ray Computed methods
- Abstract
Abstract: Inflammatory bowel disease (IBD) is caused by the activation of an abnormal immune response in the intestinal mucosa; the spleen is involved in the main immune response. Ulcerative colitis (UC) and Crohn disease (CD) have different inflammatory mechanisms; this study aimed to quantitatively measure and compare the spleen volumes between patients with UC and CD and examine the relationship between spleen volume and disease activity in both.We retrospectively analyzed 44 patients with IBD aged 30-60 years (UC group, n = 24; CD group, n = 20). The control group comprised 19 patients with pancreatic cysts that did not affect the spleen volume. All patients underwent computed tomography (CT) between April 2014 and March 2019. Using the Image J software, spleen volumes in the UC, CD, and control groups were measured accurately from the CT images and adjusted for the body weight.No significant differences in the sex, age, or body weight were noted between the UC and CD groups and the control group. The spleen volumes, adjusted for the body weight, were 2.2 ± 1.0 cm3/kg, 2.0 ± 1.0 cm3/kg, and 3.6 ± 1.7 cm3/kg in the control, UC, and CD groups, respectively. The volumes differed significantly between the CD and control groups (P = .01), but not between the UC and control groups (P = .43). Furthermore, a significant strong correlation was found between the disease activity and the body weight-adjusted spleen volume in patients with CD (P < .01).The spleen volume, adjusted for the body weight, was significantly larger in patients with CD than in the controls and was also strongly correlated with the CD activity. These results suggest that the immune response in CD may affect the spleen volume., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2022
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26. Endoscopic Images before the Onset of Cronkhite-Canada Syndrome.
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Kawashima K, Hikichi T, Onizawa M, and Ohira H
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- Endoscopy, Humans, Intestinal Polyposis diagnostic imaging
- Published
- 2021
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27. Correction to: Upregulation of complement C1q reflects mucosal regeneration in a mouse model of colitis.
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Gunji N, Katakura K, Abe K, Kawashima K, Fujiwara T, Onizawa M, Takahashi A, and Ohira H
- Published
- 2021
- Full Text
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28. Corrigendum to "CEACAM1 specifically suppresses B cell receptor signaling-mediated activation".
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Tsugawa N, Yamada D, Watabe T, Onizawa M, Wang S, Nemoto Y, Oshima S, Tsubata T, Adachi T, Kawano Y, Watanabe M, Blumberg RS, Okamoto R, and Nagaishi T
- Published
- 2021
- Full Text
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29. Oral administration of D-serine prevents the onset and progression of colitis in mice.
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Asakawa T, Onizawa M, Saito C, Hikichi R, Yamada D, Minamidate A, Mochimaru T, Asahara SI, Kido Y, Oshima S, Nagaishi T, Tsuchiya K, Ohira H, Okamoto R, and Watanabe M
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- Administration, Oral, Animals, Colitis prevention & control, Disease Models, Animal, Disease Progression, Hydro-Lyases pharmacology, Mice, Mice, Inbred C57BL, Colitis drug therapy, Hydro-Lyases therapeutic use
- Abstract
Background: L-amino acids are the predominant forms of organic molecules on the planet, but recent studies have revealed that various foods contain D-amino acids, the enantiomers of L-amino acids. Though diet plays important roles in both the development and progression of inflammatory bowel disease (IBD), to our best knowledge, there has been no report on any potential interactions between D-amino acids and IBD. In this report, we aim to assess the effects of D-serine in a murine model of IBD., Materials and Methods: To induce chronic colitis, naïve CD4 T cells (CD4
+ CD62+ CD44low ) from wild-type mice were adoptively transferred into Rag2-/- mice, after or before the mice were orally administered with D-serine. In vitro proliferation assays were performed to assess naïve CD4 T cell activation under the Th-skewing conditions in the presence of D-serine., Results: Mice treated with D-serine prior to the induction of colitis exhibited a reduction in T-cell infiltration into the lamina propria and colonic inflammation that were not seen in mice fed with water alone or L-serine. Moreover, D-serine suppressed the progression of chronic colitis when administered after the disease induction. Under in vitro conditions, D-serine suppressed the proliferation of activated CD4 T cells and limited their ability to differentiate to Th1 and Th17 cells., Conclusion: Our results suggest that D-serine not only can prevent, but also has efficacious effects as a treatment for IBD., (© 2021. Japanese Society of Gastroenterology.)- Published
- 2021
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30. A potent endocytosis inhibitor Ikarugamycin up-regulates TNF production.
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Minamidate A, Onizawa M, Saito C, Hikichi R, Mochimaru T, Murakami M, Sakuma C, Asakawa T, Hiraoka Y, Oshima S, Nagaishi T, Tsuchiya K, Ohira H, Okamoto R, and Watanabe M
- Abstract
Ikarugamycin (IK) is an antibiotic which has been reported to have a variety of functions, such as inhibition of clathrin-mediated endocytosis (CME), anti-tumor effects and regulation of the immune system. Whether IK influences cytokine production is poorly understood. We have investigated the relationship between IK and production of tumor necrosis factor-α (TNF). TNF plays a pivotal role in pathogenesis of many diseases. Although the dynamics of soluble TNF (sTNF) has been widely explored so far, the functions of the membrane form of TNF (mTNF) have not been fully elucidated. We demonstrated that IK increases the amount of mTNF and prolongs the duration of TNF expression. This effect is unrelated to the shedding activity of disintegrin and metalloproteinase domain-containing protein 17 (ADAM 17). Our results revealed that there is a mechanism to terminate inflammation at the cellular level which IK dysregulates. Furthermore, IK can be a tool to study TNF signaling due to its effect of increasing mTNF expression., Competing Interests: The authors have declared that no competing interests exist., (© 2021 The Author(s).)
- Published
- 2021
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31. Upregulation of complement C1q reflects mucosal regeneration in a mouse model of colitis.
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Gunji N, Katakura K, Abe K, Kawashima K, Fujiwara T, Onizawa M, Takahashi A, and Ohira H
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- Animals, Colitis genetics, Colitis physiopathology, Disease Models, Animal, Female, Gene Expression Regulation, Inflammation, Macrophages immunology, Mice, Mice, Inbred C57BL, Up-Regulation, beta Catenin genetics, beta Catenin metabolism, Colitis metabolism, Complement C1q genetics, Intestinal Mucosa physiology, Macrophages metabolism, Regeneration, Wnt Signaling Pathway
- Abstract
Confirming mucosal healing is important in inflammatory bowel disease treatment. Complement C1q-mediated Wnt signaling activation has recently been suggested to mediate tissue repair and mucosal regeneration. We investigated the involvement of complement C1q and Wnt signaling in intestinal mucosal regeneration using a murine colitis model. The colitis model was established by providing C57BL/6J mice with 4% dextran sodium sulfate (DSS) for 1 week (inflammation phase) followed by regular water for 2 weeks (recovery phase). After 3 weeks, we investigated the relationship between C1q in serum and colonic tissue during the inflammation and recovery phases. We assessed Wnt signaling activity by evaluating β-catenin expression in mouse intestinal tissue. Serum C1q levels were elevated during the recovery phase. C1q-specific staining indicated high C1q expression in pathological intestinal tissue during the inflammation and recovery phases. C1q mRNA and protein expression was increased during both phases. Interestingly, C1q-expressing cells were consistent with macrophages (F4/80-positive cells). Moreover, the expression of β-catenin increased in the colonic tissues during the recovery phase of DSS-induced colitis but decreased during the inflammation phase of DSS-induced colitis. C1q expression may mediate Wnt signaling activity and intestinal epithelial regeneration.
- Published
- 2021
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32. Nickel ions attenuate autophagy flux and induce transglutaminase 2 (TG2) mediated post-translational modification of SQSTM1/p62.
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Aonuma E, Tamura A, Matsuda H, Asakawa T, Sakamaki Y, Otsubo K, Nibe Y, Onizawa M, Nemoto Y, Nagaishi T, Tsuchiya K, Nakamura T, Uo M, Watanabe M, Okamoto R, and Oshima S
- Abstract
Nickel, the most frequent contact allergy cause, is widely used for various metallic materials and medical devices. Autophagy is an intracellular protein degradation system and contributes to metal recycling. However, it is unclear the functions of nickel in autophagy. We here demonstrated that NiCl2 induced microtubule-associated protein 1 light chain 3 (LC3)-II and LC3 puncta, markers of autophagosomes. Bafilomycin A1 (BafA1) treatment did not enhance LC3 puncta under NiCl2 stimulation, suggesting that NiCl2 did not induce autophagic flux. In addition, NiCl2 promotes the accumulation of SQSTM1/p62 and increased SQSTM1/p62 colocalization with lysosomal-associated membrane protein 1 (LAMP1). These data indicated that NiCl2 attenuates autophagic flux. Interestingly, NiCl2 induced the expression of the high-molecular-weight (MW) form of SQSTM1/p62. Inhibition of NiCl2-induced reactive oxygen species (ROS) reduced the high-MW SQSTM1/p62. We also showed that NiCl2-induced ROS activate transglutaminase (TG) activity. We found that transglutaminase 2 (TG2) inhibition reduced high-MW SQSTM1/p62 and SQSTM1/p62 puncta under NiCl2 stimulation, indicating that TG2 regulates SQSTM1/p62 protein homeostasis under NiCl2 stimulation. Our study demonstrated that nickel ion regulates autophagy flux and TG2 restricted nickel-dependent proteostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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33. CEACAM1 specifically suppresses B cell receptor signaling-mediated activation.
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Tsugawa N, Yamada D, Watabe T, Onizawa M, Wang S, Nemoto Y, Oshima S, Tsubata T, Adachi T, Kawano Y, Watanabe M, Blumberg RS, Okamoto R, and Nagaishi T
- Subjects
- Animals, B-Lymphocytes metabolism, Cell Differentiation, Cell Lineage, Cells, Cultured, Cytokines biosynthesis, Female, Mice, Inbred C57BL, Mice, Antigens, CD metabolism, Cell Adhesion Molecules metabolism, Receptors, Antigen, B-Cell metabolism, Signal Transduction
- Abstract
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expressed in T cells may regulate immune responses in the gut. In addition to T cells, B cells are also an important population in the gut-associated lymphoid tissues that orchestrate mucosal homeostasis. However, the role of CEACAM1 in B cells has not been elucidated. We herein analyzed mature B cells to determine the functions of CEACAM1. Flow cytometry revealed high expression of CEACAM1 on B cells in secondary lymphoid tissues. Cytokine production induced by activation of B cell receptor (BCR) signaling was suppressed by CEACAM1 signaling in contrast to that associated with either Toll-like receptor 4 or CD40 signaling. Confocal microscopy revealed co-localization of CEACAM1 and BCR when activated with anti-Igμ F(ab')
2 fragment. Overexpression of CEACAM1 in a murine B cell line, A20, resulted in reduced expressions of activation surface markers with decreased Ca2+ influx after BCR signal activation. Overexpression of CEACAM1 suppressed BCR signal cascade in A20 cells in association with decreased spontaneous proliferation. Our results suggest that CEACAM1 can regulate BCR-mediated mature B cell activation in lymphoid tissues. Therefore, further studies of this molecule may lead to greater insights into the mechanisms of immune responses within peripheral tissues and the potential treatment of inflammatory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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34. A case of Takayasu arteritis complicated by refractory ulcerative colitis successfully treated with tofacitinib.
- Author
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Sato S, Matsumoto H, Temmoku J, Fujita Y, Matsuoka N, Furuya M, Gunji N, Fujiwara T, Asano T, Onizawa M, Kobayashi H, Watanabe H, Ohira H, and Migita K
- Subjects
- Adolescent, Female, Humans, Treatment Outcome, Colitis, Ulcerative drug therapy, Colitis, Ulcerative etiology, Piperidines therapeutic use, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use, Pyrroles therapeutic use, Takayasu Arteritis complications
- Published
- 2020
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35. Receptor-Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells.
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Otsubo K, Maeyashiki C, Nibe Y, Tamura A, Aonuma E, Matsuda H, Kobayashi M, Onizawa M, Nemoto Y, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Torii S, Itakura E, Watanabe M, and Oshima S
- Subjects
- Autophagosomes drug effects, Autophagosomes metabolism, Cell Line, Tumor, Epithelial Cells drug effects, Epithelial Cells metabolism, Humans, Lysosomes drug effects, Lysosomes metabolism, Microtubule-Associated Proteins metabolism, Oligopeptides pharmacology, Sequestosome-1 Protein metabolism, Tumor Necrosis Factor-alpha pharmacology, Autophagy drug effects, Epithelial Cells cytology, Epithelial Cells enzymology, Intestines cytology, Necroptosis drug effects, Receptor-Interacting Protein Serine-Threonine Kinases metabolism
- Abstract
Autophagy is an intracellular process that regulates the degradation of cytosolic proteins and organelles. Dying cells often accumulate autophagosomes. However, the mechanisms by which necroptotic stimulation induces autophagosomes are not defined. Here, we demonstrate that the activation of necroptosis with TNF-α plus the cell-permeable pan-caspase inhibitor Z-VAD induces LC3-II and LC3 puncta, markers of autophagosomes, via the receptor-interacting protein kinase 3 (RIPK3) in intestinal epithelial cells. Surprisingly, necroptotic stimulation reduces autophagic activity, as evidenced by enlarged puncta of the autophagic substrate SQSTM1/p62 and its increased colocalization with LC3. However, necroptotic stimulation does not induce the lysosomal-associated membrane protein 1 (LAMP1) nor syntaxin 17, which mediates autophagosome-lysosome fusion, to colocalize with LC3. These data indicate that necroptosis attenuates autophagic flux before the lysosome fusion step. Our findings may provide insights into human diseases involving necroptosis., (© 2020 Federation of European Biochemical Societies.)
- Published
- 2020
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36. A20 and ABIN-1 synergistically preserve intestinal epithelial cell survival.
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Kattah MG, Shao L, Rosli YY, Shimizu H, Whang MI, Advincula R, Achacoso P, Shah S, Duong BH, Onizawa M, Tanbun P, Malynn BA, and Ma A
- Subjects
- Animals, Apoptosis, Caspases metabolism, Cell Survival, Enterocolitis pathology, Gene Deletion, Mice, Organoids metabolism, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Signal Transduction, Tumor Necrosis Factor-alpha metabolism, Adaptor Proteins, Signal Transducing metabolism, Epithelial Cells cytology, Epithelial Cells metabolism, Intestines cytology, Tumor Necrosis Factor alpha-Induced Protein 3 metabolism
- Abstract
A20 ( TNFAIP3 ) and ABIN-1 ( TNIP1 ) are candidate susceptibility genes for inflammatory bowel disease and other autoimmune or inflammatory diseases, but it is unclear how these proteins interact in vivo to prevent disease. Here we show that intestinal epithelial cell (IEC)-specific deletion of either A20 or ABIN-1 alone leads to negligible IEC loss, whereas simultaneous deletion of both A20 and ABIN-1 leads to rapid IEC death and mouse lethality. Deletion of both A20 and ABIN-1 from enteroids causes spontaneous cell death in the absence of microbes or hematopoietic cells. Studies with enteroids reveal that A20 and ABIN-1 synergistically restrict death by inhibiting TNF-induced caspase 8 activation and RIPK1 kinase activity. Inhibition of RIPK1 kinase activity alone, or caspase inhibition combined with RIPK3 deletion, abrogates IEC death by blocking both apoptosis and necroptosis in A20 and ABIN-1 double-deficient cells. These data show that the disease susceptibility proteins A20 and ABIN-1 synergistically prevent intestinal inflammation by restricting IEC death and preserving tissue integrity., (© 2018 Kattah et al.)
- Published
- 2018
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37. B cell activation in the cecal patches during the development of an experimental colitis model.
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Watabe T, Nagaishi T, Tsugawa N, Kojima Y, Jose N, Hosoya A, Onizawa M, Nemoto Y, Oshima S, Nakamura T, Karasuyama H, Adachi T, and Watanabe M
- Subjects
- Animals, Appendix diagnostic imaging, Appendix pathology, B-Lymphocytes immunology, B-Lymphocytes pathology, Calcium Signaling, Cecum diagnostic imaging, Cecum pathology, Colitis chemically induced, Colitis diagnostic imaging, Colitis pathology, Colon diagnostic imaging, Colon pathology, Disease Models, Animal, Humans, Intravital Microscopy, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Oxazolone, Tertiary Lymphoid Structures diagnostic imaging, Tertiary Lymphoid Structures pathology, Appendix immunology, Cecum immunology, Colitis immunology, Colon immunology, Tertiary Lymphoid Structures immunology
- Abstract
Although previous studies have suggested that appendix seems to be involved in the colitis, the role of this in the pathogenesis remains unclear. In this study, we assessed the importance of appendiceal lymphoid follicles, specifically the cecal patches (CP) in mice, using an experimental colitis model. Treatment with oxazolone resulted in ulcerations particularly at CP with follicular expansion as well as colitis. The colitis was attenuated by either appendectomy or the absence of mature B cells. We therefore established an intravital imaging system accompanied by the fluorescence resonance energy transfer technology to analyze the dynamic immune response of CP B cells. Our observation revealed frequent Ca
2+ signaling in CP B cells during the early phase of colitis development. These findings suggested that the CP B cells may be involved in the pathogenesis of colitis including inflammatory bowel diseases in humans., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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38. HADHA, the alpha subunit of the mitochondrial trifunctional protein, is involved in long-chain fatty acid-induced autophagy in intestinal epithelial cells.
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Maeyashiki C, Oshima S, Otsubo K, Kobayashi M, Nibe Y, Matsuzawa Y, Onizawa M, Nemoto Y, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, and Watanabe M
- Subjects
- Animals, Berberine Alkaloids pharmacology, Epithelial Cells metabolism, Epithelial Cells pathology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Protein Subunits, Autophagy physiology, Fatty Acids metabolism, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Microtubule-Associated Proteins metabolism, Mitochondrial Trifunctional Protein metabolism
- Abstract
Genome-wide association studies have identified autophagy-related susceptibility genes for inflammatory bowel disease (IBD); however, whether autophagy regulators can be utilized as therapeutic targets remains unclear. To identify novel microtubule-associated protein 1 light chain 3 (LC3)-interacting proteins in intestinal epithelial cells (IECs), we isolated primary IECs from green fluorescent protein (GFP)-LC3 mice. We performed immunoprecipitation with a GFP antibody and then analyzed co-immunoprecipitates by mass spectrometry. HADHA was identified as an LC3-interacting protein from primary IECs. The HADHA gene encodes the alpha subunit of the mitochondrial trifunctional protein. Given that HADHA catalyzes the last three steps of mitochondrial beta-oxidation of long-chain fatty acids, we investigated whether long-chain fatty acids induce autophagy in IECs. We found that palmitic acid induced autophagy in DLD-1, HT29, and HCT116 cells. HADHA was expressed in not only the mitochondria but also the cytosol. LC3 puncta co-localized with HADHA, which were enhanced by palmitic acid stimulation. However, LC3 puncta did not co-localize with Tom20, suggesting that HADHA was induced to associate with LC3 puncta at sites other than the mitochondria. Thus, HADHA may have extra-mitochondrial functions. Furthermore, we found that palmitic acid induced cell death in IECs, which was accelerated by bafilomycin A and chloroquine. These findings suggested that palmitic acid-induced autophagy supports the survival of IECs. Taken together, these results suggested that HADHA is involved in long-chain fatty acid-induced autophagy in IECs, thus providing new insights into the pathology of IBD and revealing novel therapeutic targets of IBD., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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39. Erratum: The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis.
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Onizawa M, Oshima S, Schulze-Topphoff U, Oses-Prieto JA, Lu T, Tavares R, Prodhomme T, Duong B, Whang MI, Advincula R, Agelidis A, Barrera J, Wu H, Burlingame A, Malynn BA, Zamvil SS, and Ma A
- Published
- 2015
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40. The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis.
- Author
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Onizawa M, Oshima S, Schulze-Topphoff U, Oses-Prieto JA, Lu T, Tavares R, Prodhomme T, Duong B, Whang MI, Advincula R, Agelidis A, Barrera J, Wu H, Burlingame A, Malynn BA, Zamvil SS, and Ma A
- Subjects
- Animals, Apoptosis genetics, Catalytic Domain genetics, Cysteine Endopeptidases genetics, Humans, Intracellular Signaling Peptides and Proteins genetics, Jurkat Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Multiprotein Complexes genetics, Necrosis genetics, Protein Binding, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Tumor Necrosis Factor alpha-Induced Protein 3, Ubiquitination genetics, Ubiquitins metabolism, Cysteine Endopeptidases metabolism, Fibroblasts physiology, Intracellular Signaling Peptides and Proteins metabolism, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, T-Lymphocytes physiology
- Abstract
A20 is an anti-inflammatory protein linked to multiple human diseases; however, the mechanisms by which A20 prevents inflammatory disease are incompletely defined. We found that A20-deficient T cells and fibroblasts were susceptible to caspase-independent and kinase RIPK3-dependent necroptosis. Global deficiency in RIPK3 significantly restored the survival of A20-deficient mice. A20-deficient cells exhibited exaggerated formation of RIPK1-RIPK3 complexes. RIPK3 underwent physiological ubiquitination at Lys5 (K5), and this ubiquitination event supported the formation of RIPK1-RIPK3 complexes. Both the ubiquitination of RIPK3 and formation of the RIPK1-RIPK3 complex required the catalytic cysteine of A20's deubiquitinating motif. Our studies link A20 and the ubiquitination of RIPK3 to necroptotic cell death and suggest additional mechanisms by which A20 might prevent inflammatory disease.
- Published
- 2015
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41. A20 restricts ubiquitination of pro-interleukin-1β protein complexes and suppresses NLRP3 inflammasome activity.
- Author
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Duong BH, Onizawa M, Oses-Prieto JA, Advincula R, Burlingame A, Malynn BA, and Ma A
- Subjects
- Animals, Cell Line, Cysteine Endopeptidases genetics, DNA Mutational Analysis, Immune Tolerance, Interleukin-1beta genetics, Intracellular Signaling Peptides and Proteins genetics, Mice, Mice, Inbred Strains, Mice, Knockout, Multiprotein Complexes metabolism, NLR Family, Pyrin Domain-Containing 3 Protein, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Tumor Necrosis Factor alpha-Induced Protein 3, Ubiquitination genetics, Carrier Proteins metabolism, Cysteine Endopeptidases metabolism, Inflammasomes immunology, Interleukin-1beta metabolism, Intracellular Signaling Peptides and Proteins metabolism, Macrophages physiology
- Abstract
Inappropriate inflammasome activation contributes to multiple human diseases, but the mechanisms by which inflammasomes are suppressed are poorly understood. The NF-κB inhibitor A20 is a ubiquitin-modifying enzyme that might be critical in preventing human inflammatory diseases. Here, we report that A20-deficient macrophages, unlike normal cells, exhibit spontaneous NLRP3 inflammasome activity to LPS alone. The kinase RIPK3, but not the adaptor MyD88, is required for this response. In normal cells, A20 constitutively associates with caspase-1 and pro-IL-1β, and NLRP3 activation further promotes A20 recruitment to the inflammasome. Pro-IL-1β also co-immunoprecipitates with RIPK1, RIPK3, caspase-1, and caspase-8 in a complex that is modified with K63-linked and unanchored polyubiquitin. In A20-deficient macrophages, this pro-IL-1β-associated ubiquitination is markedly increased in a RIPK3-dependent manner. Mass spectrometric and mutational analyses reveal that K133 of pro-IL-1β is a physiological ubiquitination site that supports processing. Our study reveals a mechanism by which A20 prevents inflammatory diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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42. Amelioration of DSS-induced murine colitis by VSL#3 supplementation is primarily associated with changes in ileal microbiota composition.
- Author
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Mar JS, Nagalingam NA, Song Y, Onizawa M, Lee JW, and Lynch SV
- Subjects
- Animals, Bacteria classification, Bacteria isolation & purification, Cecum microbiology, Cecum pathology, Colitis chemically induced, Colitis pathology, Colon microbiology, Colon pathology, Dextran Sulfate administration & dosage, Female, Gastrointestinal Tract microbiology, Histocytochemistry, Ileum microbiology, Ileum pathology, Mice, Inbred C57BL, Severity of Illness Index, Treatment Outcome, Biota drug effects, Colitis microbiology, Colitis therapy, Dextran Sulfate toxicity, Diet Therapy methods, Probiotics administration & dosage, Stem Cell Transplantation methods
- Abstract
Inflammatory bowel diseases encompass gastrointestinal illnesses typified by chronic inflammation, loss of epithelial integrity and gastrointestinal microbiota dysbiosis. In an effort to counteract these characteristic perturbations, we used stem cells and/or a probiotic therapy in a murine model of Dextran Sodium Sulfate induced colitis to examine both their efficacy in ameliorating disease and impact on niche-specific microbial communities of the lower GI tract. Colitis was induced in C57BL/6 mice by administering 3% DSS in drinking water for 10 days prior to administering one of three treatment plans: daily probiotic (VSL#3) supplementation for 3 days, a single tail vein injection of 1x10 (6) murine mesenchymal stem cells, or both. Ileal, cecal and colonic sections were collected for microbiota and histological analyses. Microbiota profiling revealed distinct bacterial community compositions in the ileum, cecum and colon of control untreated animals, all of which were predicted in silico to be enriched for a number of discrete KEGG pathways, indicating compositional and functional niche specificity in healthy animals. DSS-treatment perturbed community composition in all three niches with ileal communities exhibiting the greatest change relative to control animals. Each treatment group exhibited treatment-specific alterations in microbiota composition in the lower GI tract, though disease scores were only improved in VSL#3-treated animals. The ileal microbiota were most profoundly altered in composition in this group of animals and characterized by significant Enterobacteriaceae enrichment compared with colitic mice (P<0.05).
- Published
- 2014
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43. Negative regulation of Hif1a expression and TH17 differentiation by the hypoxia-regulated microRNA miR-210.
- Author
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Wang H, Flach H, Onizawa M, Wei L, McManus MT, and Weiss A
- Subjects
- Animals, CD4 Antigens metabolism, Cell Differentiation genetics, Cell Hypoxia immunology, Cells, Cultured, Cytokines metabolism, Disease Models, Animal, Disease Progression, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Lymphocyte Activation genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, MicroRNAs genetics, RNA Interference immunology, T-Lymphocyte Subsets cytology, Th17 Cells cytology, Colitis, Ulcerative immunology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, MicroRNAs metabolism, T-Lymphocyte Subsets immunology, Th17 Cells immunology
- Abstract
The microRNA miR-210 is a signature of hypoxia. We found robust increase in the abundance of miR-210 (>100-fold) in activated T cells, especially in the TH17 lineage of helper T cells. Hypoxia acted in synergy with stimulation via the T cell antigen receptor (TCR) and coreceptor CD28 to accelerate and increase Mir210 expression. Mir210 was directly regulated by HIF-1α, a key transcriptional regulator of TH17 polarization. Unexpectedly, we identified Hif1a as a target of miR-210, which suggested negative feedback by miR-210 in inhibiting HIF-1α expression. Deletion of Mir210 promoted TH17 differentiation under conditions of limited oxygen. In experimental colitis, miR-210 reduced the abundance of Hif1a transcripts and the proportion of cells that produced inflammatory cytokines and controlled disease severity. Our study identifies miR-210 as an important regulator of T cell differentiation in hypoxia, which can limit immunopathology.
- Published
- 2014
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44. Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis.
- Author
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Suzuki M, Nagaishi T, Yamazaki M, Onizawa M, Watabe T, Sakamaki Y, Ichinose S, Totsuka M, Oshima S, Okamoto R, Shimonaka M, Yagita H, Nakamura T, and Watanabe M
- Subjects
- Animals, Carcinogenesis drug effects, Carcinogenesis metabolism, Cell Line, Cell Proliferation drug effects, Colitis metabolism, Colon drug effects, Colon pathology, Colon ultrastructure, Cytokines metabolism, Disease Models, Animal, Epithelial Cells metabolism, Epithelial Cells pathology, Epithelial Cells ultrastructure, Female, Inflammation pathology, Inflammation Mediators metabolism, Interferon-gamma pharmacology, Intestinal Mucosa drug effects, Intestinal Mucosa pathology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Tight Junctions drug effects, Tight Junctions metabolism, Tumor Necrosis Factor-alpha pharmacology, Up-Regulation drug effects, Carcinogenesis pathology, Colitis pathology, Epithelial Cells enzymology, Myosin-Light-Chain Kinase metabolism, Receptors, Tumor Necrosis Factor, Type II metabolism, Signal Transduction drug effects
- Abstract
It has been suggested that prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). We previously observed that the NF-κB activation in colonic epithelial cells is associated with increased tumor necrosis factor receptor 2 (TNFR2) expression in CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC is still unclear. Myosin light chain kinase (MLCK) has been reported to be responsible for the epithelial permeability associated with TNF signaling. Therefore we focused on the role of MLCK expression via TNFR2 signaling on CAC development. Pro-tumorigenic cytokines such as IL-1β, IL-6 and MIP-2 production as well as INF-γ and TNF production at the lamina propria were increased in the setting of colitis, and further in tumor tissues in associations with up-regulated TNFR2 and MLCK expressions in the epithelial cells of a CAC model. The up-regulated MLCK expression was observed in TNF-stimulated colonic epithelial cells in a dose-dependent fashion in association with up-regulation of TNFR2. Silencing TNFR2, but not TNFR1, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. Antibody-mediated blockade of TNF signaling also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results were observed with suppressing TNFR2 and MLCK expressions by inhibiting MLCK in the epithelial cells. Silencing of MLCK also resulted in suppressed TNFR2, but not TNFR1, expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in restored TJ, decreased pro-tumorigenic cytokines and reduced CAC development. These results suggest that MLCK may be a potential target for the prevention of IBD-associated tumor development.
- Published
- 2014
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45. Dimerization and ubiquitin mediated recruitment of A20, a complex deubiquitinating enzyme.
- Author
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Lu TT, Onizawa M, Hammer GE, Turer EE, Yin Q, Damko E, Agelidis A, Shifrin N, Advincula R, Barrera J, Malynn BA, Wu H, and Ma A
- Subjects
- Animals, Cells, Cultured, Colitis chemically induced, Colitis genetics, Cysteine Endopeptidases, Mice, Mice, Inbred C57BL, Mice, Transgenic, Protein Multimerization, Signal Transduction genetics, Tumor Necrosis Factor alpha-Induced Protein 3, Ubiquitin metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitination, Zinc Fingers genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, GTPase-Activating Proteins metabolism, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
A20 is an anti-inflammatory protein linked to multiple human autoimmune diseases and lymphomas. A20 possesses a deubiquitinating motif and a zinc finger, ZF4, that binds ubiquitin and supports its E3 ubiquitin ligase activity. To understand how these activities mediate A20's physiological functions, we generated two lines of gene-targeted mice, abrogating either A20's deubiquitinating activity (Tnfaip3(OTU) mice) or A20's ZF4 (Tnfaip3(ZF4) mice). Both Tnfaip3(OTU) and Tnfaip3(ZF4) mice exhibited increased responses to TNF and sensitivity to colitis. A20's C103 deubiquitinating motif restricted both K48- and K63-linked ubiquitination of receptor interacting protein 1 (RIP1). A20's ZF4 was required for recruiting A20 to ubiquitinated RIP1. A20(OTU) proteins and A20(ZF4) proteins complemented each other to regulate RIP1 ubiquitination and NFκB signaling normally in compound mutant Tnfaip3(OTU/ZF4) cells. This complementation involved homodimerization of A20 proteins, and we have defined an extensive dimerization interface in A20. These studies reveal how A20 proteins collaborate to restrict TNF signaling., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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46. The development of colitogenic CD4(+) T cells is regulated by IL-7 in collaboration with NK cell function in a murine model of colitis.
- Author
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Yamaji O, Nagaishi T, Totsuka T, Onizawa M, Suzuki M, Tsuge N, Hasegawa A, Okamoto R, Tsuchiya K, Nakamura T, Arase H, Kanai T, and Watanabe M
- Subjects
- Animals, Cell Separation, Colitis pathology, Disease Models, Animal, Flow Cytometry, Mice, Mice, Inbred C57BL, Mice, Knockout, CD4-Positive T-Lymphocytes immunology, Colitis immunology, Interleukin-7 immunology, Killer Cells, Natural immunology, T-Lymphocyte Subsets immunology
- Abstract
We previously reported that IL-7(-/-)RAG(-/-) mice receiving naive T cells failed to induce colitis. Such abrogation of colitis may be associated with not only incomplete T cell maintenance due to the lack of IL-7, but also with the induction of colitogenic CD4(+) T cell apoptosis at an early stage of colitis development. Moreover, NK cells may be associated with the suppression of pathogenic T cells in vivo, and they may induce apoptosis of CD4(+) T cells. To further investigate these roles of NK cells, RAG(-/-) and IL-7(-/-)RAG(-/-) mice that had received naive T cells were depleted of NK cells using anti-asialo GM1 and anti-NK1.1 Abs. NK cell depletion at an early stage, but not at a later stage during colitogenic effector memory T cell (T(EM)) development, resulted in exacerbated colitis in recipient mice even in the absence of IL-7. Increased CD44(+)CD62L(-) T(EM) and unique CD44(-)CD62L(-) T cell subsets were observed in the T cell-reconstituted RAG(-/-) recipients when NK cells were depleted, although Fas, DR5, and IL-7R expressions in this subset differed from those in the CD44(+)CD62L(-) T(EM) subset. NK cell characteristics were the same in the presence or absence of IL-7 in vitro and in vivo. These results suggest that NK cells suppress colitis severity in T cell-reconstituted RAG(-/-) and IL-7(-/-)RAG(-/-) recipient mice through targeting of colitogenic CD4(+)CD44(+)CD62L(-) T(EM) and, possibly, of the newly observed CD4(+)CD44(-)CD62L(-) subset present at the early stage of T cell development.
- Published
- 2012
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47. [Innate and acquired immunity in inflammatory bowel disease].
- Author
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Onizawa M, Ma A, and Watanabe M
- Subjects
- Animals, Antigen-Presenting Cells immunology, Humans, Intestinal Mucosa immunology, Mice, Adaptive Immunity immunology, Immunity, Innate immunology, Inflammatory Bowel Diseases immunology
- Published
- 2012
48. Signaling pathway via TNF-alpha/NF-kappaB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis.
- Author
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Onizawa M, Nagaishi T, Kanai T, Nagano K, Oshima S, Nemoto Y, Yoshioka A, Totsuka T, Okamoto R, Nakamura T, Sakamoto N, Tsuchiya K, Aoki K, Ohya K, Yagita H, and Watanabe M
- Subjects
- Animals, Antibodies, Monoclonal, Carcinoma, Cell Line, Colitis chemically induced, Dextran Sulfate toxicity, Female, Gene Expression Regulation physiology, Inflammation chemically induced, Inflammation metabolism, Intestinal Mucosa cytology, Mice, Mice, Inbred C57BL, Receptors, Tumor Necrosis Factor, Type I genetics, Receptors, Tumor Necrosis Factor, Type I metabolism, Receptors, Tumor Necrosis Factor, Type II genetics, Receptors, Tumor Necrosis Factor, Type II metabolism, Signal Transduction, Up-Regulation, Colitis complications, Colonic Neoplasms complications, Epithelial Cells metabolism, NF-kappa B metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
Treatment with anti-TNF-alpha MAb has been accepted as a successful maintenance therapy for patients with inflammatory bowel diseases (IBD). Moreover, it has been recently reported that blockade of TNF receptor (TNFR) 1 signaling in infiltrating hematopoietic cells may prevent the development of colitis-associated cancer (CAC). However, it remains unclear whether the TNF-alpha signaling in epithelial cells is involved in the development of CAC. To investigate this, we studied the effects of anti-TNF-alpha MAb in an animal model of CAC by administration of azoxymethane (AOM) followed by sequential dextran sodium sulfate (DSS) ingestion. We observed that the NF-kappaB pathway is activated in colonic epithelia from DSS-administered mice in association with upregulation of TNFR2 rather than TNFR1. Immunoblot analysis also revealed that the TNFR2 upregulation accompanied by the NF-kappaB activation is further complicated in CAC tissues induced in AOM/DSS-administered mice compared with the nontumor area. Such NF-kappaB activity in the epithelial cells is significantly suppressed by the treatment of MP6-XT22, an anti-TNF-alpha MAb. Despite inability to reduce the severity of colitis, sequential administration of MP6-XT22 reduced the numbers and size of tumors in association with the NF-kappaB inactivation. Taken together, present studies suggest that the TNFR2 signaling in intestinal epithelial cells may be directly involved in the development of CAC with persistent colitis and imply that the maintenance therapy with anti-TNF-alpha MAb may prevent the development of CAC in patients with long-standing IBD.
- Published
- 2009
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49. Autoimmune hepatitis complicated by late-onset systemic lupus erythematosus.
- Author
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Takahashi A, Rai T, Onizawa M, Monoe K, Kanno Y, Saito H, Abe K, Yokokawa J, Irisawa A, and Ohira H
- Abstract
A 69-year-old man with autoimmune hepatitis (AIH) was admitted to hospital with high fever and cough. Chest roentgenogram and computed tomography showed pleural and pericardial effusion. Serological tests showed a high titer of antinuclear antibodies and positive anti-DNA antibody and lymphocytopenia. He fulfilled the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). After administration of corticosteroids, his symptoms and liver dysfunction improved. To the authors' knowledge, this is the first male case of overlap between AIH and late-onset SLE.
- Published
- 2007
- Full Text
- View/download PDF
50. A recovery case of acute-onset autoimmune hepatitis presenting as fulminant hepatic failure [corrected], who received living donor-liver transplantation.
- Author
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Takahashi A, Ohira H, Onizawa M, Monoe K, Kanno Y, Saito H, Abe K, Takiguchi J, Rai T, Kimura T, Kenjo A, Tsuchiya T, Saito T, and Gotoh M
- Subjects
- Acute Disease, Adult, Anti-Obesity Agents adverse effects, Diagnosis, Differential, Female, Humans, Liver Failure, Acute chemically induced, Hepatitis, Autoimmune diagnosis, Hepatitis, Autoimmune surgery, Liver Failure, Acute diagnosis, Liver Failure, Acute surgery, Liver Transplantation, Living Donors
- Abstract
A 23-year-old woman was admitted to our hospital with jaundice and hepatic coma. She had taken a weight-loss supplement for one month before admission. Her clinical and laboratory findings were consistent with fulminant hepatic failure and fulfilled the criteria of autoimmune hepatitis. Despite corticosteroid pulse therapy and plasma exchange, her symptoms and laboratory findings deteriorated. Her condition improved after she received a living donor-liver transplant from her sister. Autoimmune hepatitis usually follows a chronic course, but it should be considered a type of fulminant hepatic failure and treated promptly.
- Published
- 2006
- Full Text
- View/download PDF
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