http://hdl.handle.net/10564/2756 2012年度博士論文（要旨） Fri, 10 Apr 2026 13:43:20 GMT 2026-04-10T13:43:20Z http://hdl.handle.net/10564/2790 タイトル: ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia-reperfusion injury. 著者: Fujioka, Masayuki; Nakano, Takafumi; Hayakawa, Kazuhide; Irie, Keiichi; Akitake, Yoshiharu; Sakamoto, Yuya; Mishima, Kenichi; Muroi, Carl; Yonekawa, Yasuhiro; Banno, Fumiaki; Kokame, Koichi; Miyata, Toshiyuki; Nishio, Kenji; Okuchi, Kazuo; Iwasaki, Katsunori; Fujiwara, Michihiro; Siesjö, Bo K. 抄録: Highly adhesive glycoprotein von Willebrand factor (VWF) multimer induces platelet aggregation and leukocyte tethering or extravasation on the injured vascular wall, contributing to microvascular plugging and inflammation in brain ischemia–reperfusion. A disintegrin and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) cleaves the VWF multimer strand and reduces its prothrombotic and proinflammatory functions. Although ADAMTS13 deficiency is known to amplify post-ischemic cerebral hypoperfusion, there is no report available on the effect of ADAMTS13 on inflammation after brain ischemia. We investigated if ADAMTS13 deficiency intensifies the increase of extracellular HMGB1, a hallmark of post-stroke inflammation, and exacerbates brain injury after ischemia–reperfusion. ADAMTS13 gene knockout (KO) and wild-type (WT) mice were subjected to 30-min middle cerebral artery occlusion (MCAO) and 23.5-h reperfusion under continuous monitoring of regional cerebral blood flow (rCBF). The infarct volume, plasma high-mobility group box1 (HMGB1) level, and immunoreactivity of the ischemic cerebral cortical tissue (double immunofluorescent labeling) against HMGB1/NeuN (neuron-specific nuclear protein) or HMGB1/MPO (myeloperoxidase) were estimated 24 h after MCAO. ADAMTS13KO mice had larger brain infarcts compared with WT 24 h after MCAO (p < 0.05). The rCBF during reperfusion decreased more in ADAMTS13KO mice. The plasma HMGB1 increased more in ADAMTS13KO mice than in WT after ischemia–reperfusion (p < 0.05). Brain ischemia induced more prominent activation of inflammatory cells co-expressing HMGB1 and MPO and more marked neuronal death in the cortical ischemic penumbra of ADAMTS13KO mice. ADAMTS13 deficiency may enhance systemic and brain inflammation associated with HMGB1 neurotoxicity, and aggravate brain damage in mice after brief focal ischemia. We hypothesize that ADAMTS13 protects brain from ischemia–reperfusion injury by regulating VWF-dependent inflammation as well as microvascular plugging. 内容記述: 博士（医学）・乙第1310号・平成25年3月15日; © Springer International Publishing AG,2012 Sun, 30 Sep 2012 15:00:00 GMT http://hdl.handle.net/10564/2790 2012-09-30T15:00:00Z http://hdl.handle.net/10564/2789 タイトル: The dichotomy in the histogenesis of endometriosis-associated ovarian cancer: clear cell-type versus endometrioid-type adenocarcinoma. 著者: Kajihara, Hirotaka; Yamada, Yoshihiko; Shigetomi, Hiroshi; Higashiura, Yumi; Kobayashi, Hiroshi 抄録: The histogenesis of endometriosis and endometriosis-associated ovarian cancer is one of the most mysterious aspects of pathology. To better understand the histogenesis of endometriosis and endometriosis-associated ovarian cancer, we analyzed the possibility of a link of endometrium, ovarian surface epithelium, and a cortical inclusion cyst to ovarian endometriosis and endometriosis-associated ovarian cancer by immunohistochemistry using the epithelial membrane antigen (an epithelial marker), calretinin (a mesothelial marker), and hepatocyte nuclear factor (HNF)-1β (a clear cell carcinoma-specific transcription factor). During ovarian surface epithelium invagination, cortical inclusion cyst epithelial cells may, in some cases, undergo mesothelial–epithelial transition and subsequently differentiate into endometriosis. This case of endometriosis that has undergone Müllerian metaplasia arises from the HNF-1β-negative cells. The remaining endometriosis may develop from the late secretory and menstrual endometria, with HNF-1β-positive staining, by retrograde menstruation. Endometrioid adenocarcinoma and clear cell carcinoma arise from the HNF-1β-negative and HNF-1β-positive epithelial cells of endometriosis, respectively. It has been proposed that clear cell and endometrioid-type adenocarcinomas arise from distinct types of endometriosis with different cells of origin. 内容記述: 博士（医学）・乙第1309号・平成25年3月15日; ©2012 International Society of Gynecological Pathologists Thu, 31 May 2012 15:00:00 GMT http://hdl.handle.net/10564/2789 2012-05-31T15:00:00Z http://hdl.handle.net/10564/2788 タイトル: Positive effect of daylight exposure on nocturnal urinary melatonin excretion in the elderly: a cross-sectional analysis of the HEIJO-KYO study. 著者: Obayashi, Kenji; Saeki, Keigo; Iwamoto, Junko; Okamoto, Nozomi; Tomioka, Kimiko; Nezu, Satoko; Ikada, Yoshito; Kurumatani, Norio 抄録: CONTEXT:Melatonin is involved in a variety of diseases, including cancer, insomnia, depression, dementia, hypertension, and diabetes; its secretion is influenced by environmental light. Although daylight exposure increases nocturnal melatonin secretion in a controlled laboratory setting, whether it increases nocturnal melatonin secretion in an uncontrolled daily life setting remains unclear.OBJECTIVE:We aimed to determine the association between daylight exposure in an uncontrolled daily life setting and urinary 6-sulfatoxymelatonin excretion.DESIGN AND PARTICIPANTS:A cross-sectional study was conducted in 192 elderly individuals (mean age, 69.9 yr).MEASURES:We measured ambulatory daylight exposure using a wrist light meter in two 48-h sessions; furthermore, we measured overnight urinary 6-sulfatoxymelatonin excretion, an index of melatonin secretion, on the second night of each session.RESULTS:The median duration of daylight exposure of at least 1000 lux was 72 min (interquartile range, 37-124). Univariate linear regression analysis showed marginal to significant associations between log-transformed urinary 6-sulfatoxymelatonin excretion and age, current smoking status, benzodiazepine use, day length, log-transformed duration of daylight exposure of at least 1000 lux, and daytime physical activity. In a multivariate model, log-transformed duration of daylight exposure of at least 1000 lux was significantly associated with log-transformed urinary 6-sulfatoxymelatonin excretion (regression coefficient, 0.101; 95% confidence interval, 0.003-0.199; P = 0.043). Furthermore, an increase in the duration of daylight exposure of at least 1000 lux from 37 to 124 min (25th to 75th percentiles) was associated with a 13.0% increase in urinary 6-sulfatoxymelatonin excretion (6.8 to 7.7 μg).CONCLUSIONS:Daylight exposure in an uncontrolled daily life setting is positively associated with urinary 6-sulfatoxymelatonin excretion in the elderly. 内容記述: 博士（医学）・乙第1308号・平成25年3月15日; Copyright © 2012 by The Endocrine Society Wed, 31 Oct 2012 15:00:00 GMT http://hdl.handle.net/10564/2788 2012-10-31T15:00:00Z http://hdl.handle.net/10564/2787 タイトル: Advanced glycation end products (AGE) induce the receptor for AGE in the colonic mucosa of azoxymethane-injected Fischer 344 rats fed with a high-linoleic acid and high-glucose diet. 著者: Shimomoto, Takasumi; Luo, Yi; Ohmori, Hitoshi; Chihara, Yoshitomo; Fujii, Kiyomu; Sasahira, Tomonori; Denda, Ayumi; Kuniyasu, Hiroki 抄録: BACKGROUND:Advanced glycation end products (AGE) and the receptor for advanced glycation end products (RAGE) are closely associated with colorectal cancer progression. The association between RAGE and AGE in colon carcinogenesis needs to be clarified.METHODS:Levels of RAGE and AGE were examined in azoxymethane (AOM)-injected Fischer 344 rats fed a control diet (Group C), a 15 % linoleic acid (LA) diet (Group L), a control diet with 10 % glucose drink (Group G), and a 15 % LA diet with 10 % glucose drink (Group L + G). Group L + G showed the most pronounced increase of body weight, blood sugar, and serum insulin.RESULTS:The rats in Group L + G showed the most pronounced multiplicity of aberrant crypt foci (ACF) and carcinomas with increased mucosal RAGE and AGE. IEC6 rat intestinal epithelial cells treated with AGE showed increased RAGE expression, which was inhibited by treatment with metformin or losartan. In the AOM-injected rat colon cancer model, the levels of RAGE and AGE, and the multiplicity of ACF and carcinomas, in Group L + G rats were suppressed by treatment with metformin or losartan.CONCLUSIONS:These results suggest that AGE-RAGE induced by high-LA and high-glucose diets substantially enhances colon cancer development; thus, suppression of AGE-RAGE could be a potential target for colon cancer chemoprevention. 内容記述: 博士（医学）・乙第1307号・平成25年3月15日; © Springer International Publishing AG,2012; © Japanese Society of Gastroenterology 2012 Sun, 30 Sep 2012 15:00:00 GMT http://hdl.handle.net/10564/2787 2012-09-30T15:00:00Z