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1. Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice
Yamamoto, Yasuhiko ; Liang, Mingkun ; Munesue, Seiichi ; Deguchi, Kisaburo ; Harashima, Ai ; Furuhara, Kazumi ; Yuhi, Teruko ; Zhong, Jing ; Akther, Shirin ; Goto, Hisanori ; Eguchi, Yuya ; Kitao, Yasuko ; Hori, Osamu ; Shiraishi, Yoshitake ; Ozaki, Noriyuki ; Shimizu, Yu ; Kamide, Tomoya ; Yoshikawa, Akifumi ; Hayashi, Yasuhiko ; Nakada, Mitsutoshi ; Lopatina, Olga ; Gerasimenko, Maria ; Komleva, Yulia ; Malinovskaya, Natalia ; Salmina, Alla B. ; Asano, Masahide ; Nishimori, Katsuhiko ; Shoelson, Steven E. ; Yamamoto, Hiroshi ; Higashida, Haruhiro ; 山本, 靖彦 ; 棟居, 聖一 ; 古原, 和美 ; 堀, 修 ; 白石, 昌武 ; 尾﨑, 紀之 ; 吉川, 陽文 ; 中田, 光俊 ; 東田, 陽博
概要:
金沢大学医薬保健研究域医学系<br />Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bo
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nding behaviours. Mice lacking secreted oxcytocin (Oxt -/-, Cd38 -/-) or its receptor (Oxtr -/-) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in Oxt -/- and Cd38 -/-, but not Oxtr -/- mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in Ager -/- male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in Ager -/- mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding.<br />30820471
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El‑Far, Ali Hafez Ali MohammedTsuchiya Hiroshi Yamamoto Hazem M.E. Shaheen Yasser S. El‑Sayed Shuhei Kawano Sei‑Ichi Tanuma Yasuhiko Yamamoto ; Munesue, Seiichi ; Harashima, Ai ; Satoh, Akira ; Shindo, Mika ; Nakajima, Shingo ; Inada, Mana ; Tanaka, Mariko ; Takeuchi, Akihiko ; Tsuchiya, Hiroyuki ; Yamamoto, Hiroshi ; Shaheen, Hazem M.E. ; El‑Sayed, Yasser S. ; Kawano, Shuhei ; Tanuma, Sei‑Ichi ; Yamamoto, Yasuhiko ; 棟居, 聖一 ; 原島, 愛 ; 武内 , 章彦 ; 土屋, 弘行 ; 山本, 靖彦
概要:
金沢大学医薬保健研究域医学系<br />Receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in
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the pathogenesis of certain types of cancer. In the present study, papaverine was identified as a RAGE inhibitor using the conversion to small molecules through optimized‑peptide strategy drug design system. Papaverine significantly inhibited RAGE‑dependent nuclear factor κ‑B activation driven by high mobility group box‑1, a RAGE ligand. Using RAGE‑ or dominant‑negative RAGE‑expressing HT1080 human fibrosarcoma cells, the present study revealed that papaverine suppressed RAGE‑dependent cell proliferation and migration dose‑dependently. Furthermore, papaverine significantly inhibited cell invasion. The results of the present study suggested that papaverine could inhibit RAGE, and provided novel insights into the field of RAGE biology, particularly anticancer therapies.<br />Embargo Period 6 months
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| 3.
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山田, 外史 ; 橋口, 敬 ; 細野, 隆次 ; 山本, 博 ; 別所, 一夫 ; 上野, 照剛 ; 谷本, 能文 ; Yamada, Sotoshi ; Hashiguchi, Takashi ; Hosono, Ryuji ; Yamamoto, Hiroshi ; Bessho, Kazuo ; Ueno, Shoogo ; Tanimoto, Yoshifumi
概要:
金沢大学理工研究域電子情報学系<br />Electromagnetic devices such as superconducting magnets, magnetically levitated vehicles and magnet
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ic resonance imaging(MRI) create strong magnetic fields within their immediate vicinity. This has generated some concerns over the effects that these fields may have on the outside environment and in particular on living organisms. 50/60Hz magnetic fields are of special concern because living organisms are exposed to them on a continuing basis.We investigate the influence of a strong 60Hz AC magnetic field of 1.2T on organisms. The high AC magnetic field is generated by using a multilayer eddy-current type AC magnetic generator developed in our laboratory. In this paper, in vitro experiments were performed with biochemical reactions, enzyme and restriction endonuclese activities.As a result, the magnetic field inhibited catalase activity slightly only in biochemical reactions. Other reactions such as β-galactosidase activity and restriction endonuclese activity were not influenced at all. The results suggest that high 60Hz AC magnetic fields may influence biological functions in some organisms.
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Akhter, Hashina ; Hayashida, Yumiko ; Yoshida, Yumi ; Ohkuma, Shoji ; Yamamoto, Hiroshi ; Nakamura, Nobuhiro
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原著 ; 平成19年11月1日受付，平成19年11月20日受理
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Yamamoto, Yasuhiko ; Kato, Ichiro ; Doi, Toshio ; Yonekura, Hideto ; Ohashi, Seiji ; Takeuchi, Masayoshi ; Watanabe, Takuo ; Sakurai, Shigeru ; Yasui, Kiyoshi ; Ralica, Petrova G ; Joynal, Abedin ; Hui, Li ; A.K.M.Azadur, Rahman ; Takasawa, Shin ; Okamoto, Hiroshi ; Yamamoto, Hiroshi
概要:
金沢大学大学院医学部医学系研究科<br />Vascular complications are what eventually threaten the lives of diabetic patients. Here we show d
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irect in vivo evidence that the interaction between advanced glycation end products (AGE), the formation of which is accelerated during prolonged hyperglycemic exposure, and a cell surface receptor for AGE (RAGE) is the major cause of such complications. We created transgenic mice that overexpress human RAGE in vascular cells and crossbred them with another transgenic line which develops insulin-dependent diabetes early after birth. The resultant double transgenic mice exhibited accelerated kidney changes compared with single transgenic littermates, and the nephropathy was ameliorated by an inhibitor of AGE formation. The AGE–RAGE system will thus be a promising target for overcoming diabetic complications.
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Yamamoto, Yasuhiko ; Yonekura, Hideto ; Sakurai, Shigeru ; Tanaka, Nobushige ; Hui, Li ; Khin-Mar, Myint ; Chul-Hee, Kim ; Harashima, Ai ; Osawa, Mari ; Takeuchi, Masayoshi ; Watanabe, Takuo ; Yamamoto, Hiroshi
概要:
金沢大学大学院医学部医学系研究科<br />As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies conducted in this l
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ab revealed advanced glycation endproducts (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes, and the receptor for AGE (RAGE) as the major genetic factor that responds to them. AGE fractions that caused the vascular derangement were proven to be RAGE ligands. When made diabetic, RAGE-overexpressing transgenic mice exhibited the exacerbation of the indices of nephropathy, and this was prevented by the inhibition of AGE formation. We also created RAGE-deficient mice. They showed marked amelioration of diabetic nephropathy. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A)+ RNA, we came across a novel splice variant coding for a soluble RAGE protein, and named it endogenous secretory RAGE (esRAGE). esRAGE was able to capture AGE ligands and neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE–RAGE system should thus be regarded as a candidate molecular target for overcoming this life- and quality of life (QOL)-threatening disease.
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| 7.
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Nozaki, Ichiro ; Watanabe, Takuo ; Kawaguchi, Makoto ; Akatsu, Hiroyasu ; Tsuneyama, Koichi ; Yamamoto, Yasuhiko ; Ohe, Kazuyo ; Yonekura, Hideto ; Yamada, Masahito ; Yamamoto, Hiroshi
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Ohe, Kazuyo ; Watanabe, Takuo ; Harada, Shinichi ; Munesue, Seiichi ; Yamamoto, Yasuhiko ; Yonekura, Hideto ; Yamamoto, Hiroshi
概要:
金沢大学医薬保健研究域医学系<br />Receptor for advanced glycation endproducts (RAGE) is a cell-surface receptor. The binding of ligand
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s to membrane-bound RAGE (mRAGE) evokes cellular responses involved in various pathological processes. Previously, we identified a novel soluble form, endogenous secretory RAGE (esRAGE) generated by alternative 5′ splice site selection in intron 9 that leads to extension of exon 9 (exon 9B). Because esRAGE works as an antagonistic decoy receptor, the elucidation of regulatory mechanism of the alternative splicing is important to understand RAGE-related pathological processes. Here, we identified G-rich cis-elements within exon 9B for regulation of the alternative splicing using a RAGE minigene. Mutagenesis of the G-rich cis-elements caused a drastic increase in the esRAGE/mRAGE ratio in the minigene-transfected cells and in loss of binding of the RNA motif to heterogenous nuclear ribonucleoprotein (hnRNP) H. On the other hand, the artificial introduction of a G-stretch in exon 9B caused a drastic decrease in the esRAGE/mRAGE ratio accompanied by the binding of hnRNP H to the RNA motif. Thus, the G-stretches within exon 9B regulate RAGE alternative splicing via interaction with hnRNP H. The findings should provide a molecular basis for the development of medicines for RAGE-related disorders that could modulate esRAGE/mRAGE ratio. © The Authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.
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| 9.
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Yamamoto, Yasuhiko ; Kato, Ichiro ; Doi, Toshio ; Yonekura, Hideto ; Ohashi, Seiji ; Takeuchi, Masayoshi ; Watanabe, Takuo ; Yamagishi, Shoichi ; Sakurai, Shigeru ; Takasawa, Shin ; Okamoto, Hiroshi ; Yamamoto, Hiroshi
概要:
金沢大学医薬保健研究域医学系<br />Vascular complications arising from multiple environmental and genetic factors are responsible for m
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any of the disabilities and short life expectancy associated with diabetes mellitus. Here we provide the first direct in vivo evidence that interactions between advanced glycation end products (AGEs; nonenzymatically glycosylated protein derivatives formed during prolonged hyperglycemic exposure) and their receptor, RAGE, lead to diabetic vascular derangement. We created transgenic mice that overexpress human RAGE in vascular cells and crossbred them with another transgenic line that develops insulin-dependent diabetes shortly after birth. The resultant double transgenic mice exhibited increased hemoglobin A1c and serum AGE levels, as did the diabetic controls. The double transgenic mice demonstrated enlargement of the kidney, glomerular hypertrophy, increased albuminuria, mesangial expansion, advanced glomerulosclerosis, and increased serum creatinine compared with diabetic littermates lacking the RAGE transgene. To our knowledge, the development of this double transgenic mouse provides the first animal model that exhibits the renal changes seen in humans. Furthermore, the phenotypes of advanced diabetic nephropathy were prevented by administering an AGE inhibitor, (±)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195), thus establishing the AGE-RAGE system as a promising target for overcoming this aspect of diabetic pathogenesis.
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Matsuoka, Nobuhide ; Itoh, Takeshi ; Watarai, Hiroshi ; Sekine-Kondo, Etsuko ; Nagata, Naoki ; Okamoto, Kohji ; Mera, Toshiyuki ; Yamamoto, Hiroshi ; Yamada, Shingo ; Maruyama, Ikuro ; Taniguchi, Masaru ; Yasunami, Yohichi
概要:
金沢大学医薬保健研究域医学系<br />Islet transplantation for the treatment of type 1 diabetes mellitus is limited in its clinical appli
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cation mainly due to early loss of the transplanted islets, resulting in low transplantation efficiency. NKT cell-dependent IFN-γ production by Gr-1+CD11b+ cells is essential for this loss, but the upstream events in the process remain undetermined. Here, we have demonstrated that high-mobility group box 1 (HMGB1) plays a crucial role in the initial events of early loss of transplanted islets in a mouse model of diabetes. Pancreatic islets contained abundant HMGB1, which was released into the circulation soon after islet transplantation into the liver. Treatment with an HMGB1-specific antibody prevented the early islet graft loss and inhibited IFN-γ production by NKT cells and Gr-1+CD11b + cells. Moreover, mice lacking either of the known HMGB1 receptors TLR2 or receptor for advanced glycation end products (RAGE), but not the known HMGB1 receptor TLR4, failed to exhibit early islet graft loss. Mechanistically, HMGB1 stimulated hepatic mononuclear cells (MNCs) in vivo and in vitro; in particular, it upregulated CD40 expression and enhanced IL-12 production by DCs, leading to NKT cell activation and subsequent NKT cell-dependent augmented IFN-γ production by Gr-1+CD11b+ cells. Thus, treatment with either IL-12- or CD40L-specific antibody prevented the early islet graft loss. These findings indicate that the HMGB1-mediated pathway eliciting early islet loss is a potential target for intervention to improve the efficiency of islet transplantation.
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