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医学部 附属病院 総合周産期母子医療センター |
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講師 |
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Aoki Y., Dai H., Furuta F., Akamatsu T., Oshima T., Takahashi N., Goto Y.i., Oka A., Itoh M.
Cell Communication and Signaling 21 ( 1 ) 126 2023年6月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Cell Communication and Signaling
Background: Microglial cells play an important role in the immune system in the brain. Activated microglial cells are not only injurious but also neuroprotective. We confirmed marked lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression in microglial cells in pathological lesions in the neonatal hypoxic-ischemic encephalopathy (nHIE) model brain. LOX-1 is known to be an activator of cytokines and chemokines through intracellular pathways. Here, we investigated a novel role of LOX-1 and the molecular mechanism of LOX-1 gene transcription microglial cells under hypoxic and ischemic conditions. Methods: We isolated primary rat microglial cells from 3-day-old rat brains and confirmed that the isolated cells showed more than 98% Iba-1 positivity with immunocytochemistry. We treated primary rat microglial cells with oxygen glucose deprivation (OGD) as an in vitro model of nHIE. Then, we evaluated the expression levels of LOX-1, cytokines and chemokines in cells treated with or without siRNA and inhibitors compared with those of cells that did not receive OGD-treatment. To confirm transcription factor binding to the OLR-1 gene promoter under the OGD conditions, we performed a luciferase reporter assay and chromatin immunoprecipitation assay. In addition, we analyzed reactive oxygen species and cell viability. Results: We found that defects in oxygen and nutrition induced LOX-1 expression and led to the production of inflammatory mediators, such as the cytokines IL-1β, IL-6 and TNF-α; the chemokines CCL2, CCL5 and CCL3; and reactive oxygen/nitrogen species. Then, the LOX-1 signal transduction pathway was blocked by inhibitors, LOX-1 siRNA, the p38-MAPK inhibitor SB203580 and the NF-κB inhibitor BAY11-7082 suppressed the production of inflammatory mediators. We found that NF-κB and HIF-1α bind to the promoter region of the OLR-1 gene. Based on the results of the luciferase reporter assay, NF-κB has strong transcriptional activity. Moreover, we demonstrated that LOX-1 in microglial cells was autonomously overexpressed by positive feedback of the intracellular LOX-1 pathway. Conclusion: The hypoxic/ischemic conditions of microglial cells induced LOX-1 expression and activated the immune system. LOX-1 and its related molecules or chemicals may be major therapeutic candidates. [MediaObject not available: see fulltext.].
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Yoshinori Aoki, Tatsuo Kono, Mikako Enokizono, Kaoru Okazaki
BMC pediatrics 21 ( 1 ) 224 2021年5月
担当区分：筆頭著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
Background: Neonatal encephalopathy due to acute perinatal asphyxia is a major cause of perinatal brain damage. Moderate to severe neonatal encephalopathy is associated with high mortality and morbidity rates. However, the neurodevelopmental outcomes in neonates with mild neonatal encephalopathy are unclear. The primary aim of this single-center observational study was to assess the short-term outcomes in term neonates with mild neonatal encephalopathy due to perinatal asphyxia. A secondary aim was to identify predictors of poor prognosis by identifying the characteristics of these infants according to their short-term outcomes.
Methods: We retrospectively investigated all infants with perinatal asphyxia at Tokyo Metropolitan Children's Medical Center from January 2014 to December 2019. An abnormal short-term outcome was defined as any one of the following: seizures or abnormal electroencephalography, abnormal brain magnetic resonance imaging obtained within the first 4 weeks of life, and abnormal neurological examination findings at discharge.
Results: In total, 110 term infants with perinatal asphyxia during the study period were screened and 61 were diagnosed with mild neonatal encephalopathy. Eleven (18 %) of these infants had an abnormal short-term outcome. The median Thompson score at admission was significantly higher in infants with abnormal short-term outcomes than in those with normal short-term outcomes (5 [interquartile range, 4-5.5] vs. 2 [interquartile range, 1-3], p < 0.01). Receiver operating characteristic curve analysis showed that a cutoff value of 4 had high sensitivity and specificity (90.9 and 83.0 %, respectively) for prediction of an abnormal short-term outcome.
Conclusions: 18 % of infants with mild encephalopathy had an abnormal short-term outcome, such as abnormal brain magnetic resonance imaging findings. The Thompson score at admission may be a useful predictor of an abnormal short-term outcome in infants with mild neonatal encephalopathy. -
Arima M., Inoue H., Misumi A., Tsukamoto S., Matsushita I., Araki S., Ohta M., Takahashi K., Imazato M., Goto T., Aoki Y., Tagawa K., Hirose M., Fujita Y., Yoshida N., Nakao S., Kondo H., Kusuhara K., Kimura K., Hasegawa S., Ikeda Y., Kodama Y., Moritake H., Ochiai M., Ohga S., Kishimoto J., Todaka K., Ieiri I., Sonoda K.H.
Japanese Journal of Ophthalmology 68 ( 5 ) 490 - 499 2024年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
Purpose: To assess the safety and efficacy of ripasudil for retinopathy of prematurity (ROP). Study design: Phase 1/2, multicenter, open-label, single-arm, 12-week clinical trial. Methods: Infants born with gestational age (GA) of ≤ 32 weeks or weight of ≤ 1500 g with zone I or II, ≥ stage 1, ROP in both eyes were enrolled. Ripasudil eye drops were administered to patients in both eyes. Phase 1 was a dose-escalation study (once daily for 1 week, then twice daily for 2 weeks); an additional dosing up to 9 weeks was allowed if no safety issues occurred. In phase 2, ripasudil was administered twice daily for up to 12 weeks. Adverse events were assessed. The proportion of patients with type 1 ROP progression, number of days for type 1 ROP progression, and progression to the most advanced ROP stage were estimated. Results: Twenty-four infants were enrolled (phase 1, n = 3; phase 2, n = 21). Nineteen and four patients experienced systemic and ocular adverse events, respectively. Efficacy endpoints were not different between the ripasudil and historical control groups. However, in the GA ≤ 27 weeks subgroup, fewer patients progressed to type 1 ROP in the ripasudil than in the historical control group (P = 0.09). In the GA ≤ 27 weeks subgroups, the 25th percentile for the number of days for type 1 ROP progression was 22 days in the historical control group and 44 days in the ripasudil group. Conclusion: Ripasudil was safe and inhibited/delayed type 1 ROP progression, especially in infants with short GA.
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ウレアプラズマ肺炎を契機に顕在化した超早産児肺リンパ管拡張症の一例
榊原 康平, 山田 直史, 児玉 由紀, 小畑 静, 都築 康恵, 村岡 純輔, 青木 良則, 山下 理絵, 中目 和彦, 金子 政時, 桂木 真司, 都築 諒, 佐藤 勇一郎
日本周産期・新生児医学会雑誌 59 ( 1 ) 116 - 121 2023年
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：一般社団法人 日本周産期・新生児医学会
肺リンパ管拡張症（Pulmonary lymphangiectasia；PL）は肺リンパ管拡張を特徴とし，肺胞拡張障害をきたして重篤な呼吸不全を起こす疾患である．今回，ウレアプラズマ肺炎を契機に呼吸状態が増悪し，剖検でPLと診断された症例を報告する． 症例は超低出生体重児（在胎23週2日，610g，男児）．母体は，妊娠23週1日に胎胞形成，23週2日に経腟分娩となった．児はサーファクタント投与後，安定化した状態で人工呼吸管理を行っていた．日齢15にCRP上昇と肺野の透過性低下が認められた．各種抗菌薬治療では改善なく，日齢30の気管内分泌物ウレアプラズマ培養陽性により，アジスロマイシン水和物を開始した．CRPは著減したが，呼吸不全は悪化して日齢44に死亡した．病理解剖では，肺リンパ管がびまん性に拡張したPLと診断した．臨床的にはウレアプラズマ肺炎を契機に顕在化したPLと考えられた．
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Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1-Related Microglial Activation in Neonatal Hypoxic-Ischemic Encephalopathy: Morphologic Consideration.
Akamatsu T, Sugiyama T, Oshima T, Aoki Y, Mizukami A, Goishi K, Shichino H, Kato N, Takahashi N, Goto YI, Oka A, Itoh M
The American journal of pathology 191 ( 7 ) 1303 - 1313 2021年7月
科研費（文科省・学振・厚労省）獲得実績 【 表示 ／ 非表示 】
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低酸素性虚血性脳症におけるミクログリアでのLOX-1の役割解明と新規治療法の開発
研究課題/領域番号：20K16875 2020年04月 - 2023年03月
独立行政法人日本学術振興会 科学研究費補助金 若手研究
担当区分：研究代表者