- 著者
- Hiroaki Shimokawa Tomohiko Shindo Aiko Ishiki Naoki Tomita Sadamitsu Ichijyo Tasuku Watanabe Takashi Nakata Kumiko Eguchi Yoku Kikuchi Takashi Shiroto Jun Takahashi Satoshi Yasuda Hiroyuki Arai
- 出版者
- Tohoku University Medical Press
- 雑誌
- The Tohoku Journal of Experimental Medicine (ISSN:00408727)
- 巻号頁・発行日
- pp.2022.J078, (Released:2022-09-15)
- 被引用文献数
- 9
- 著者
- Kentaro Matsumoto Shenwei Ni Hiroyuki Arai Takashi Toyama Yoshiro Saito Takehiro Suzuki Naoshi Dohmae Kojiro Mukai Tomohiko Taguchi
- 出版者
- Japan Society for Cell Biology
- 雑誌
- Cell Structure and Function (ISSN:03867196)
- 巻号頁・発行日
- vol.48, no.1, pp.59-70, 2023 (Released:2023-02-16)
- 参考文献数
- 43
Stimulator of interferon genes (STING) is an ER-localized transmembrane protein and the receptor for 2',3'-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), which is a second messenger produced by cGAMP synthase (cGAS), a cytosolic double-stranded DNA sensor. The cGAS-STING pathway plays a critical role in the innate immune response to infection of a variety of DNA pathogens through the induction of the type I interferons. Pharmacological activation of STING is a promising therapeutic strategy for cancer, thus the development of potent and selective STING agonists has been pursued. Here we report that mouse STING can be activated by phenylarsine oxide (PAO), a membrane permeable trivalent arsenic compound that preferentially reacts with thiol group of cysteine residue (Cys). The activation of STING with PAO does not require cGAS or cGAMP. Mass spectrometric analysis of the peptides generated by trypsin and chymotrypsin digestion of STING identifies several PAO adducts, suggesting that PAO covalently binds to STING. Screening of STING variants with single Cys to serine residues (Ser) reveals that Cys88 and Cys291 are critical to the response to PAO. STING activation with PAO, as with cGAMP, requires the ER-to-Golgi traffic and palmitoylation of STING. Our results identify a non-nucleotide STING agonist that does not target the cGAMP-binding pocket, and demonstrate that Cys of STING can be a novel target for the development of STING agonist.Key words: STING agonist, cysteine modification, innate immunity, phenylarsine oxide
- 著者
- Hiroaki Shimokawa Tomohiko Shindo Aiko Ishiki Naoki Tomita Sadamitsu Ichijyo Tasuku Watanabe Takashi Nakata Kumiko Eguchi Yoku Kikuchi Takashi Shiroto Jun Takahashi Satoshi Yasuda Hiroyuki Arai
- 出版者
- Tohoku University Medical Press
- 雑誌
- The Tohoku Journal of Experimental Medicine (ISSN:00408727)
- 巻号頁・発行日
- vol.258, no.3, pp.167-175, 2022 (Released:2022-10-25)
- 参考文献数
- 30
- 被引用文献数
- 9
The prevalence of Alzheimer’s disease (AD) has been rapidly increasing worldwide. We have developed a novel angiogenic therapy with low-intensity pulsed ultrasound (LIPUS), which is effective and safe in animal models of AD and vascular dementia. We performed two trials of LIPUS therapy for AD (mild cognitive impairment due to AD and mild AD); a roll-in open trial for safety, and a randomized, double-blind, placebo-controlled (RCT) trial for efficacy and safety. The LIPUS therapy was performed for whole brain through the bilateral temporal bones for one hour 3 times a week as one session under the special conditions (1.3 MPa, 32 cycles, 5% duty cycle) we identified. The LIPUS therapy was performed for one session in the roll-in trial, and 6 sessions in the RCT trial with 3-month intervals for 1.5 years. The primary endpoint was ADAS-J cog scores. The RCT trial was terminated prematurely due to the COVID-19 pandemic. In the roll-in trial (N = 5), no adverse effects were noted. In the RCT trial (N = 22), the worsening of ADAS-J cog scores tended to be suppressed in the LIPUS group compared with the placebo group at week 72 (P = 0.257). When responders were defined as those with no worsening of ADAS-J cog scores at week 72, the prevalence was 50% (5/10) and 0% (0/5) in the LIPUS and placebo groups, respectively (P = 0.053). No adverse effects were noted. These results suggest that the LIPUS therapy is safe and tends to suppress cognitive impairment although a next pivotal trial with a large number of subjects is warranted.
- 著者
- Hiroyuki Arai Shinya Yamamoto Takeshi Matsubara Takafumi Miyake Akira Tochio Akiko Mii Akira Shimizu Sachiko Minamiguchi Eri Muso Motoko Yanagita
- 出版者
- The Japanese Society of Internal Medicine
- 雑誌
- Internal Medicine (ISSN:09182918)
- 巻号頁・発行日
- pp.1283-22, (Released:2023-01-15)
- 参考文献数
- 28
- 被引用文献数
- 2
Ponatinib is a novel multi-tyrosine kinase inhibitor (TKI) with potent inhibitory activity against refractory chronic myeloid leukemia (CML). Despite its high clinical efficacy, ponatinib induces various adverse events due to its multi-target characteristic. However, renal complications associated with ponatinib are rare. A 76-year-old woman had a history of chronic myeloid leukemia (CML) resistant to imatinib and nilotinib. Our patient developed proteinuria and renal function deterioration during treatment with ponatinib but not with imatinib or nilotinib. We herein report the first case of a patient with secondary focal segmental glomerulosclerosis (FSGS) with partial glomerular collapse induced by ponatinib treatment.
- 著者
- Kentaro Matsumoto Shenwei Ni Hiroyuki Arai Takashi Toyama Yoshiro Saito Takehiro Suzuki Naoshi Dohmae Kojiro Mukai Tomohiko Taguchi
- 出版者
- Japan Society for Cell Biology
- 雑誌
- Cell Structure and Function (ISSN:03867196)
- 巻号頁・発行日
- pp.22085, (Released:2022-12-28)
Stimulator of interferon genes (STING) is an ER-localized transmembrane protein and the receptor for 2’,3’-cyclic guanosine monophosphate&endash;adenosine monophosphate (cGAMP), which is a second messenger produced by cGAMP synthase (cGAS), a cytosolic double-stranded DNA sensor. The cGAS-STING pathway plays a critical role in the innate immune response to infection of a variety of DNA pathogens through the induction of the type I interferons. Pharmacological activation of STING is a promising therapeutic strategy for cancer, thus the development of potent and selective STING agonists has been pursued. Here we report that mouse STING can be activated by phenylarsine oxide (PAO), a membrane permeable trivalent arsenic compound that preferentially reacts with thiol group of cysteine residue (Cys). The activation of STING with PAO does not require cGAS or cGAMP. Mass spectrometric analysis of the peptides generated by trypsin and chymotrypsin digestion of STING identifies several PAO adducts, suggesting that PAO covalently binds to STING. Screening of STING variants with single Cys to serine residues (Ser) reveals that Cys88 and Cys291 are critical to the response to PAO. STING activation with PAO, as with cGAMP, requires the ER-to-Golgi traffic and palmitoylation of STING. Our results identify a non-nucleotide STING agonist that does not target the cGAMP-binding pocket, and demonstrate that Cys of STING can be a novel target for the development of STING agonist.Key words: STING agonist, cysteine modification, innate immunity, phenylarsine oxide
- 著者
- Etsuo HORIKAWA Toshifumi MATSUI Hiroyuki ARAI Takashi SEKI Koh IWASAKI Hidetada SASAKI
- 出版者
- The Japanese Society of Internal Medicine
- 雑誌
- Internal Medicine (ISSN:09182918)
- 巻号頁・発行日
- vol.44, no.7, pp.717-721, 2005 (Released:2005-08-06)
- 参考文献数
- 16
- 被引用文献数
- 64 88
Objective Falls are common in patients with Alzheimer’s disease (AD). Identification of the potential risk factors and developing preventive strategies for falls will have a significant impact in maintaining the quality of life in AD.Patients Clinical follow-up of 124 (74.1±6.1 years, range 62-88) mild to moderate AD patients in an outpatient memory clinic.Methods Postural sway, cognitive function, use of neuroleptics, severity of periventricular and deep white matter lesions, and the presence or absence of silent brain infarctions on magnetic resonance imaging were assessed at baseline.Results A total of 104 patients (84%) completed the study. Fall events were confirmed in 42.3% (44/104). After adjustment for age, gender, and cognitive status, a high grade of periventricular white matter lesions (odds ratio 8.7 [95%CI 1.5 to 51.8], p=0.017) and neuroleptic drug use (odds ratio 3.5 [95%CI 1.2 to 10.5], p=0.027) were significantly associated with an increased risk of falls.Conclusion Our results suggest that periventricular white matter lesions and the use of neuroleptics may be related to falls in mild to moderate AD. A comprehensive risk management of brain ischemia as well as the use of the smallest efficacious dose of neuroleptics in the treatment of behavioral and psychiatric symptoms of AD should be recommended to help reduce the risk of unexpected falls.
- 著者
- Hiroyuki Arai Mutsuo Yamaya Takashi Ohrui Satoru Ebihara Takae Ebihara Kazushi Nakajo Hidetada Sasaki
- 出版者
- The Japan Society of Logopedics and Phoniatrics
- 雑誌
- The Japan Journal of Logopedics and Phoniatrics (ISSN:00302813)
- 巻号頁・発行日
- vol.43, no.4, pp.467-472, 2002-10-20 (Released:2010-06-22)
- 参考文献数
- 19
- 被引用文献数
- 1 2
誤嚥性肺炎を発症する高齢者では, 高率に脳血管障害, 特に大脳基底核領域に脳梗塞が見出される.この場合の脳梗塞は, 新しいものであっても陳旧性のものであっても, また症候性であっても無症候性であっても構わない.このような患者では, 嚥下反射と咳反射の両者の低下により, 誤嚥特に夜間の不顕性誤嚥により肺炎の成立にいたると考えられる.嚥下反射と咳反射は, 少なくとも2つの神経伝達物質, すなわちドーパミンとサブスタンス-Pによって支えられている.進行したアルツハイマー病患者も大脳基底核障害などにより誤嚥性肺炎を発症する.進行したアルツハイマー病患者において, major tranquilizerの使用と無症候性脳梗塞の合併は誤嚥性肺炎を誘発する危険因子であるため問題行動に対するmajor tranquilizerの使用には細心の注意が要求される.塩酸アマンタジン, ACE阻害薬, 抗血小板剤の使用また歯ブラシなどによる簡便な口腔ケアは肺炎の予防に役立つばかりでなく高齢者医療費削減にも貢献すると思われる.