1.

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Uesato, Ryoko ; Ishibashi, Yasuyuki ; Ohshika, Shusa ; Naraoka, Takuya ; Toh, Satoshi
出版情報: 弘前医学.  59  pp.98-103,  2008-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/702
概要: Proteoglycans are one of the most important components of the extracellular matrix in the cartilage and the levels of proteoglycans. such as versican and aggrecan, increase during chondrogenesis. The purpose of this study was to investigate the effect of exogenous proteoglycans from salmon nasal cartilage on chondrogenesis of mesenchymal stem cells. Mesenchymal stem cells derived from bone marrow aspiration of rabbit femurs were induced to chondrogenic lineage using a pellet culture technique. Pellets were cultured in the medium with or without cell growth factors. with or without proteoglycans. or a combination of these agents. Pellets treated with cell growth factors became hypertrophic and showed lacuna formation. and synthesis of cartilage matrix was recognized histologically. The expression of type II collagen and aggrecan mRNA were decreased in pellets incubated with a combination of cell growth factors and proteoglycans, compared to those incubated with only cell growth factors. Exogenous proteoglycans may down-regulate the expression of cartilage-specific mRNA directly, or may interact with growth factors in the culture medium. As the increase of glycoprotein during chondrogenesis is important for determining the direction and degree of differentiation. exogenous proteoglycans may have a similar effect. 続きを見る
2.

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対馬, 史泰 ; 小野, 修一 ; 清野, 浩子 ; 森本, 公平 ; 大畑, 崇 ; 長畑, 守雄 ; 三浦, 弘行 ; 阿部, 由直 ; 対馬, 敬夫 ; 鎌田, 義正
出版情報: 弘前医学.  59  pp.104-109,  2008-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/703
概要: 肺癌診断に対して薄層CT (thin-sliceCT)による胸膜播種の術前診断が可能となってきたが,胸膜の良性病変との鑑別が困難な症例が存在する.肺癌の胸膜播種の診断能向上目的に.術前CTにて胸膜に病的所見の見られる症例について原発巣胸膜浸 潤所見を検討した.対象は2003年1月より2005年12月までに肺癌として手術が施行され,術前CTが施行された138例(男性84名,女性54名,38-82歳,平均66歳)である.肺癌の術前CTを2名の放射線科医で評価した.葉間あるいは胸壁胸膜(臓側/壁側)の病的所見(不整な肥厚,′ト粒状影,結節影)の有無を検討した.胸膜に所見の見られた症例について,原発巣の進展,周囲浸潤を示す所見を検討した.肺癌138例中,術中に播種の判明した例は6例(4.3%)であった.6例全例に病理組織学的に原発巣の胸膜浸潤が見られた.術前CTでは31例(22.5%)に胸隈に所見が見られ,実際に播種のあった6例中5例は葉間胸膜に小結節影を認めた.また,胸膜播種陽性例には術前の薄層CTにて全例に原発巣と胸膜との接触が認められ,特に原発巣の胸壁胸膜浸潤および肥厚所見は偽陽性例に対し胸膜播種例で高頻度であった.術前の薄層CTにおける播種陽性例と陰性例の原発巣胸膜所見に差を認めたことから,胸膜に病的所見が見られた場合,原発巣を詳細に評価することが肺癌術前の胸膜播種診断に有用と思われた. 続きを見る
3.

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佐藤, 江里 ; 田村, 綾女 ; 丹藤, 雄介 ; 須田, 俊宏 ; 中村, 光男 ; 山岸, 昌一
出版情報: 弘前医学.  59  pp.110-117,  2008-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/704
概要: 病歴の長い糖尿病患者において,アミラーゼ分泌の低下や障萎縮・線維化を呈する症例があることが報告されている.しかしこのような病態の動物モデルは現在確立されていない.また,終末糖化産物AGE,その受容体であるRAGEは糖尿病血管合併症に関与して いるとされているが,陣-の影響は不明である.糖尿病における障外分泌障害とその機序を明らかにするため,加齢により障ラ氏島の線維化を生じる自然発症2型糖尿病モデル,SpontaneouslyDiabeticTorii(SDT)ラットにcaerulein急性輝炎を発症させ,糖尿病の発症および程度,降の線維化に変化を生じるか否か,同時に,RAGEの発現をRT-PCRにより検討した.結果,障炎による糖尿病発症および降の線維化,糖尿病発症前後および輝炎の有無によるRAGEの発現に変化は認めず,糖尿病ラットモデルにおける障障害とRAGEの関連は明らかではなかった. 続きを見る
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Nakai, Makoto ; Yoshihara, Shuichi ; Morohashi, Hajime ; Ishido, Keinosuke ; Sasaki, Mutsuo
出版情報: 弘前医学.  59  pp.118-127,  2008-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/705
概要: Hyaluronan (HA) is a major component of the pericellular matrix, and is implicated in cell adhesion, invasion. and tumor metastasis. We have reported that 4-methylumbelliferone (MU) inhibits HA synthesis by cultured skin fibroblasts, melanoma cells, and pancreatic cancer cells. We focused in the present study, on mesothelioma which has an extremely poor prognosis, and in which no effective therapy has yet been established. We investigated dealing with this neoplasm whether MU and 4-methylesculetin (ME), a MU derivative, are able to inhibit HA synthesis by the mesothelioma cell line NCI-H2052. MU inhibited HA synthesis by about 20%, and ME by about 40%, in comparison with the control group. MU inhibited the adhesion of NCI-H2052 cells by about 30%, and ME by about 50%, compared with the untreated control. MU inhibited cell locomotion by about 30%. and ME by about 40%. It is suggested through these results suggest that MU and ME inhibit HA synthesis. adhesion, and locomotion by human mesothelioma cells and weaken their pericellular matrix, and that the inhibitory effect of ME on HA synthesis is stronger than that of MU. It is presumed that both MU and ME may have potential as new therapeutic or prophylactic medicines against mesothelioma. 続きを見る
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Matsukura, Daisuke ; Yokoyama, Yoshihito ; Tanaka, Kanji ; Ozaki, Takashi ; Mizunuma, Hideki
出版情報: 弘前医学.  59  pp.128-135,  2008-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/706
概要: The changes in proteoglycan (PG) expression and glycosaminoglycan (GAG) constituents in the intervillous space of the pregnancy-induced hypertension (PIR) placenta were investigated. PGs and GAGs were purified from the extract of the placental intervillous space by the DEAE-Sephacel column and salt-concentration gradient method. and the GAG sugar chains were released by the actinase and cellulase treatments. The sugar chains from the placentas of normal pregnancy and PIR were compared by cellulose-acetate membrane electrophoresis. No difference was observed in the expressions of hyaluronic acid. heparan sulfate, and chondroitin sulfate. but a clear increase in the expression of dermatan sulfate (DS) in the placenta of the PIR was confirmed. An increase of the DS that specifically activates anticoagulants can be a body reaction to counteract the hemostatic condition observed in PIR. 続きを見る
6.

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Maruyama, Ikuro ; Ito, Takashi ; Hashiguchi, Teruto
出版情報: 弘前医学.  59  pp.S1-S11,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2210
概要: Responses to stimuli in cellar level are diverse and such hierarchical as secretion of stored factors,synthesis of lipid mediators and protein synthesis through genomic transcription. However, how can the cellsrespond in the case of necrosis? Recently a characteristic intranuclear protein, high-mobility group box 1 protein(HMGB1) is released from necrotic cells. The protein is an abundant nuclear protein with a dual functionboth inside and outside the cells. In physiological state, HMGB1 is present in the nucleus, and binds to DNA,playing a variety of crucial functions, including transcription and keeping the characteristic DNA architecture.However, the protein is released to extracellular space from most of necrotic cells, activated macrophages anddendritic cells. Out of the cells, HMGB1 acts as a signal of tissue damage and can promote infl ammation, immuneresponses, and results tissue regeneration. During sepsis and/or disseminated intravascular coagulation (DIC),however, massive accumulation of HMGB1 in the systemic circulation will cause multiple organ failure (MOF)and subsequent lethal outcome. Thus HMGB1 in the systemic circulation has been considered as a lethalmediator of sepsis, and a promising therapeutic target for sepsis. Recently we identified that thrombomodulin(TM), a natural anticoagulant glycoprotein expressed on the surface of endothelial cells, plays an importantrole in sequestering HMGB1. TM may prevent HMGB1 from reaching remote organs, thereby restrictingthe spectrum of HMGB1 action in the site of injury. Here we review recent progress made in defining thephysiological and pathological roles of HMGB1 and therapeutic strategies aimed at blocking circulatory HMGB1. 続きを見る
7.

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Sasaki, Takeshi
出版情報: 弘前医学.  59  pp.S12-S18,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2211
概要: Human parvovirus B19 (B19) is single stranded DNA virus, that causes erythema infectinosum in infantand/or acute onset p olyarthritis in adult. We present the evidence showing the role of B19 on the etiopathogy ofrheumatoid arthritis( RA).( 1) B19 DNA could be frequently amplifi ed in the samples from rheumatoid joints. Thedetection B19 RNA and B19 protein VP1 was specific for RA, and positive at T cells, B cells, macrophages andfollicular dendritic cells in rheumatoid synovium. ( 2) B19 infection or transduction of B19 NS1gene caused TNFα,IL-6 and IL-8 production through activating AP1 and AP2 in macrophages or macrophage celll line U937. We alsofound Ku80 as a novel receptor for B19 on T cells, macrophages or erythroblasts. B19 used clathrin on the surface attheir cell entry and caused enhanced actin polymerization, resulting in the migration of T cells. ( 3) B19-transgenicmice became susceptible to type II collagen-induced polyarthritis that is a model of RA. We also experienced 12cases who developed RA after acute B19 infection. ( 4) Half of RA cases had a defective neutralizing ability to B19. 続きを見る
8.

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Kido, Hiroshi ; Mizuno, Dai ; Le, Quang Trong ; Chida, Junji ; Yamada, Hiroshi ; Okumura, Yuushi ; Yano, Mihiro
出版情報: 弘前医学.  59  pp.S19-S25,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2212
概要: Human infl uenza virus causes an annual epidemic infection. After infl uenza virus infection in the airway,infection som etimes spreads with severe neurologic complication and multiple organ failure, resulting in highmortality. In the process of viral spread from the lungs to other organs, signifi cant up-regulated trpsin was observedin various organs. Up-regulated trypsin eff ectively converted precursor of the viral envelope hemagglutinin( HA) intoHA1 and HA2 subunits. The proteolytic activation of HA is a prerequisite for virus multiplication. Administration ofthe inhibitors of trypsin as new approaches for the treatment of infl uenza virus infection eff ectively suppressed viralmultiplication. Almost vaccines for infl uenza virus infection are administered i.m. or s.c., which induce IgG-mediatedprotection in the systemic immune compartment, but this immunization off ers insuffi cient protection on the mucosalsurface at the initial site of viral multiplication. To improve protective mucosal immunity, intranasal vaccinationhas been studied. The powerful mucosal adjuvants reported are toxin based, such as cholera toxin and Escherichiacoli heat-labile toxin, but these enterotoxins cause severe side eff ects. We recently found natural mucosal adjuvant,pulmonary surfactant, in the lungs. Intranasal administration of infl uenza vaccine combined with Surfacten, a modifi edpulmonary surfactant free of antigenic c-type lectins, induced high protective mucosal immunity in the airway andsystemic immune responses in the blood, the effi cacy of both protective immunities by Surfacten being equivalent tothose by cholera toxin. In this symposium, we reported the eff ects of Surfacten on mucosal and systemic immunities. 続きを見る
9.

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Kurachi, Makoto ; Kakimi, Kazuhiro ; Ueha, Satoshi ; Matsushima, Kouji
出版情報: 弘前医学.  59  pp.S26-S34,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2213
概要: Memory CD8+ T cells generated during an immune response are long-lived and self-renewing, off eringenhanced host protect ion against re-infection. However, how an antigen-specific population of memory T cells ismaintained throughout repetitive infections over potentially a lifetime is not known. Here we review the generationand maintenance of antigen-specifi c CD8+ T cells and introduce our recent data showing dynamic turnover of anantigen-specific memory T cell population during repeated antigen challenge in vivo. We demonstrated that aprimary response potentially occurs upon every recall response and fi nd that the skewed T-cell receptor (TCR)repertoire of pre-existing memory T cells is partly corrected by diversity in a newly formed (primary) population.Importantly, memory T cells generated in a more recent antigen encounter expand more vigorously in a subsequentrecall response. A primary response during re-challenge therefore restores both the TCR diversity and proliferativepotential of the memory T cell population. These findings indicate that memory T cell populations evolve overmultiple challenges, favoring memory T cells generated in more recent encounters, and suggest that these primarypopulations have essential roles in the perpetuation of antigen-specifi c T cell populations. 続きを見る
10.

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Ohteki, Toshiaki ; Kuwajima, Seiichi
出版情報: 弘前医学.  59  pp.S35-S42,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2214
概要: Unmethylated CpG oligodeoxynucleotides (CpG) prevalent in bacteria and DNA viruses bind Toll-likereceptor( TLR) 9 and di rectly stimulate DCs, thereby activating the innate and adaptive immune responses. CpG ispotentially a powerful reagent for protective immunity against infection by a wide variety of pathogens, for cancerand allergy therapies, and for the development of prophylactic and therapeutic vaccines. Here we investigated therole of interleukin (IL)-15 in the activation of CpG-induced immune responses. We show that upon CpG-priming,both wild-type( WT) and NK cell-depleted WT mice produce interleukin( IL)-12 p70 and become resistant to a lethaldose of Listeria monocytogenes( LM), whereas IL-15-/- mice impair IL-12 p70 production and succumb to the infection.Notably, CpG-stimulated conventional dendritic cells (cDCs) are the major producer of both IL-15 and IL-12 p70,but cDCs do not produce IL-12 in the absence of plasmacytoid DCs( pDCs) in vivo. Importantly, cDC-derived IL-15induces CD40 expression on cDCs, which interacts with CD40 ligand on pDCs, leading to CD40 cross-linking and IL-12production. Collectively, these fi ndings show that IL-15-dependent cross-talk between cDCs and pDCs is essential forCpG-induced immune activation( recently published in Nat Immunol 2006;7:740-6) 続きを見る
11.

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Seya, Tsukasa ; Matsumoto, Misako ; Ebihara, Takashi ; Akazawa, Takashi
出版情報: 弘前医学.  59  pp.S43-S51,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2215
概要: Double-stranded (ds)RNA-recognition receptors reside in the cytoplasm and membranes of cells. Thesereceptors are implica ted in the differential screening of microbes by the host. Myeloid dendritic cells (mDCs)recognize and respond to polyI:C, an analog of dsRNA, by endosomal TLR3 and cytoplasmic MDA5. NK cells areinduced in vivo by the administration of polyI:C to mice and in vitro are reciprocally activated by mDCs, although themolecular mechanisms as yet undetermined. Here, we show that the TLR adapter TICAM-1 (TRIF) participates inmDC-derived antitumor NK activation. In a syngeneic mouse tumor implant model, intraperitoneal administration ofpolyI:C led to the retardation of tumor growth, which eff ect relied largely on NK activation. This NK-dependent tumorregression did not occur in TICAM-1-/- or IFNAR-/- mice, while a normal NK antitumor response was induced in PKR-/-,MyD88-/-, IFN-β-/- and wild-type mice. IFNAR was a prerequisite for the induction of IFN-α/β and TLR3. The lackof TICAM-1 did not aff ect IFN production but resulted in unresponsiveness to IL-12 production, mDC maturation andpolyI:C-mediated antitumor activity. This NK activation required NK-mDC contact in in vitro transwell analysis. NKantitumoractivity was successfully introduced into tumor-implanted mice by transferring mDCs expressing TICAM-1.Implanted tumor growth in IFNAR-/- mice was retarded by adoptively transferring polyI:C-treated TICACM-1-positivemDCs but not TICAM-1-/- mDCs. Thus, TICAM-1 rather than MDA5 in mDCs critically facilitated mDC-NK contactand activation of antitumor NK, resulting in the regression of low MHC-expressing tumors 続きを見る
12.

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Fujita, Takashi
出版情報: 弘前医学.  59  pp.S52-S57,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2216
概要: Recent studies show the involvement of cytoplasmic RNA helicase family, RIG-I, MDA5 and LGP2 inantiviral innate immune r esponses. RIG-I and MDA5 are primarily responsible for the detection of viral infectionand triggering activation cascade for type I interferon genes in many cell types. RIG-I consists of N-terminalCAspase Recruitment Domain (CARD) and a domain with signatures of DExD/H box helicase (helicase domain).Functional analyses revealed that the helicase domain detects viral RNA and CARD triggers the activation ofdownstream signaling cascade, including activation of transcription factors, NF-κB, IRF-3 and IRF-7. RIG-I bindsto double stranded (ds)RNA, however it does not simply function as a binding receptor for dsRNA, since RIG-Iwith disrupted ATP binding site is incapable of signaling. A model is proposed that in the absence of dsRNA,RIG-I forms “closed” conformation and upon binding to dsRNA, it conforms into “open” structure exposing CARD.We produced recombinant RIG-I protein using Baculo virus system and purified it to homogeneity. Biochemicalproperties, including dsRNA binding activity, ATPase activity and helicase activity, of recombinant RIG-I wereinvestigated. The results suggested that RIG-I requires certain structure of ligand RNA that is specifi c to viral (ornon-self) origin. Furthermore, we found evidence that RIG-I conforms a certain structure upon binding to dsRNA inthe presence of ATP. These results were consistent with the above model for activation of RIG-I. Furthermore, weobserved that RIG-I forms oligomers in virus-infected cells and artifi cial oligomerization of RIG-I CARD mimics virusinducedsignaling, resulting in the activation of interferon and other cytokine genes. These results highlight how viralreplication in cytoplasm is detected by RIG-I helicase and switch on signal cascades for initial antiviral responses. 続きを見る
13.

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Iwasaki, Yasumasa ; Tsugita, Makoto ; Taniguchi, Yoshimori ; Nigawara, Takeshi ; Takayasu, Shinobu ; Kawahara, Masayuki ; Suda, Toshihiro ; Hashimoto, Kozo
出版情報: 弘前医学.  59  pp.S58-S61,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2217
概要: Cytokines is known to infl uence hormone synthesis and secretion. Indeed, some of the proinfl ammatorycytokines stimulat e hormone release at the hypothalamic, pituitary, and peripheral endocrine organs. Recently, a newparadigm of immune-endocrine interaction has been emerging. We and others have shown that cytokines modify theeff ectiveness of hormone action. This is occurring via enhancement of receptor-mediated signaling, or modifi cation ofintracellular metabolism of hormones. In the latter case, we found that representative cytokines such as interleukin 1βand TNFα stimulate the expression of the glucocorticoid-activating enzyme 11β- ~ hydroxysteroid dehydrogenase type1( 11βHSD1) and suppress that of the inactivating enzyme 11βHSD2, thus increasing the intracellular concentrationand action of glucocorticoids. In vascular smooth muscle cells, this mechanism is advantageous in preventing vascularcollapse during sepsis. We also found that, in hepatocytes, cytokines suppress the expression of the thyroid hormoneactivatingenzyme 5’-deiodinase type I. This may be responsible for the low T3 syndrome in critical illness. 続きを見る
14.

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Kageyama, Kazunori ; Hanada, Komaki ; Iwasaki, Yasumasa ; Sakihara, Satoru ; Nigawara, Takeshi ; Kasckow, John ; Suda, Toshihiro
出版情報: 弘前医学.  59  pp.S62-S66,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2218
概要: Corticotropin-releasing factor (CRF) plays a central role in controlling the hypothalamic-pituitary-adrenalaxis during s tressful periods. CRF, produced in the hypothalamic paraventricular nucleus (PVN) in response tostress, stimulates adrenocorticotropic hormone (ACTH) release in the anterior pituitary. ACTH then stimulatesglucocorticoid release from the adrenal glands. Glucocorticoid in turn inhibits hypothalamic PVN production of CRFand pituitary production of ACTH. We previously demonstrated that protein kinase A( PKA) pathway takes a mainpart in producing CRF in the hypothalamus. A functional cAMP-response element( CRE) on the 5’-promoter region isimportant to increase CRF gene expression. Glucocorticoids inhibit CRF promoter activity in the pituitary cells, whilein the placenta and the bed nucleus of the stria terminalis, glucocorticoids stimulate it. The eff ect of glucocorticoids onCRF gene, therefore, would be tissue specifi c. Although to study the mechanism regulating CRF transcription in thePVN has been the lack of availability of a representative cell line, a rat fetal hypothalamic cell line has been recentlyavailable. We found that forskolin-stimulated CRF gene transcription is mediated by CRE on the CRF 5’-promoterregion in the hypothalamic cells. Both PKA and, in part, p38 mitogen-activated protein kinase pathways contribute tothe forskolin-induced CRF promoter activity. Glucocorticoid-dependent repression of forskolin-stimulated CRF promoteractivity was localized to promoter sequences between -278 and -249 bp. Taken together, these fi ndings indicate thata negative glucocorticoid regulatory element is critical for the repression of CRF gene in the hypothalamic cells. 続きを見る
15.

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Sashinami, Hiroshi ; Kageyama, Kazunori ; Suda, Toshihiro ; Nakane, Akio
出版情報: 弘前医学.  59  pp.S67-S76,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2219
概要: It is well known that corticotropin releasing factor (CRF) modulates immune response duringinfl ammation. We investigate d the eff ect of CRF family peptides on host resistance to Listeria monocytogenes infectionin mice. The numbers of L. monoctyogenes in the organs of Ucn2-treated mice were dramatically increased comparedwith CRF- or Ucn-treated mice. CRF receptor type 2 is involved in the suppressive eff ect of Ucn2 on L. monocytogenesinfection. Interferon (IFN)-γ and tumor necrosis factor (TNF)-α production were decreased and interleukin (IL)-10 production was signifi cantly increased in the spleens of Ucn2-treated mice compared with those in Ucn2-untreatedcontrol mice. The eff ect of Ucn2 was canceled by depleting endogenous IL-10 using anti-IL-10 monoclonal antibodyand in IL-10 deficient mice. The expression and activation of signal transducers and activators of transcription3 (STAT3) were up-regulated and the expression and activation of STAT1 were down-regulated in the spleensfrom Ucn2-treated mice compared with vehicle-treated mice. Moreover, suppression of TNF-α production andaugmentation of IL-10 production and expression and activation of STAT3 by Ucn2 treatment were observed in heatkilledL. monocytogenes-stimulated macrophages. These results suggested that Urn2 suppresses host resistance to L.monocytogenes infection via up-regulation of IL-10 production. 続きを見る
16.

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Warner, Margaret ; Gustafsson, Jan-Åke
出版情報: 弘前医学.  59  pp.S77-S81,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2220
概要: Estrogen has distinct functions in the immune system where it acts via ERα and HERβ respectively.Surprisingly, the defec ts in the immune system which develop in the absence of either ERα or ERβ are quitedistinct from what develops in the absence of estrogen. We have found by studying mice in which either or bothestrogen receptors have been inactivated that the two estrogen receptors play distinct roles in the immune system.Loss of ERβ leads to chronic myeloid leukemia and loss of ERα leads to autoimmune disease. In mice which cannotsynthesize estrogen there is also autoimmune disease resembling Sjögren’s Syndrome. We plan to study these micefurther with the aim of fi nding the exact sites of action of the two receptors in the immune system and by usingspecifi c ligands for ERα. or ERβ to examine how specifi c parts of the immune system can be modifi ed. These studiesshould lead to improved treatment of patients with diseases of the immune system. 続きを見る
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Cosgrove, Karen E. ; Shepherd, Ruth M. ; Dunne, Mark J.
出版情報: 弘前医学.  59  pp.S82-S88,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2221
概要: Congenital Hyperinsulinism in Infancy (HI) is a potentially-lethal condition of neonates and duringearly childhood. For many years the pathophysiology of this disorder was unknown. Recent advances in genetics,histopathology and molecule physiology have now revealed the causes of HI in a large cohort of patients. From defectsin ion channel subunit genes to lesions in the control of pancreatic B-cell metabolism and anaplerosis, the causes ofHI are both varied and numerous. However, in all cases they appear to share a common target protein - the ATPsensitiveK-channel. The function of these channels is not only critical to the control of healthy normal insulin-secretingcell function, but “activating” defects in these channels lead to permanent neonatal diabetes and type 2 diabetes. HIcan therefore arise through “channelopathies” of K-ATP channels: HI-KATP through gene defects in ABCC8 andKCNJ11 (Ch11.p15); or as a result of “metabolopathies” through defects in the genes encoding glucokinase HI-GK(GCK, Ch.7p15-p13), glutamate dehydrogenase HI-GDH (GLUD1, Ch.10q23.3) and Short-chain L-3-hydroxyacyl-CoAdehydrogenase HI-SCHAD( HADHSC, Ch.4q22-q26). Advances in the integration of genetic medicine and cell biologyhave provided key insights into the causes of HI, and this has been of key importance to the defi nition of pathogenesis.However, medical therapy for HI remains largely unchanged due to the availability of limited agents that are selectiveand specifi c for the termination of insulin release from β-cells. CHI can be a devastating disease, and in this reviewfocuses upon the relationship between the basis of HI and current / future therapies, including stem cells. 続きを見る
18.

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論文
Wakui, Makoto ; Misaki, Naoko ; Suga, Sechiko ; Mao, Xia ; Lin, Yu-Fung ; Wu, Jie
出版情報: 弘前医学.  59  pp.S89-S100,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2222
概要: Diabetes mellitus is a group of diseases characterized by high levels of blood glucose resulting from defectsin insulin production, insulin action, or both. Diabetes patients usually have accompanying cardiovascular disorders.Sulfonylureas have been the leading oral antihyperglycemic agents for type 2 diabetes treatment, which currently stillconstitute the most popular anti-diabetic drugs. Nevertheless, concern has arisen over the side eff ects of sulfonylureason the cardiovascular system. Here we report that iptakalim, a novel cardiovascular ATP-sensitive potassium( KATP)channel opener, closed rat pancreatic β-cell KATP channels and increased insulin release. Using whole-cell patch-clamprecordings, iptakalim depolarized β-cells, induced action potential fi ring and reduced pancreatic KATP channel currents.Using single-channel recordings, iptakalim reduced KATP channel open-probability independently of intracellular ATPconcentrations. We demonstrated that iptakalim elevated intracellular Ca2+ concentrations and increased insulin release asrevealed by fl uorescence imaging( fura-2) and biochemical measurements, respectively. In addition, iptakalim signifi cantlyinhibited the open-probability of recombinant Kir6.2/SUR1 and Kir6.2FL4A( a traffi cking mutant of the Kir6.2) channelsexpressed in transfected human embryonic kidney (HEK) 293 cells. Collectively, iptakalim, a cardiovascular KATPchannel opener, closes rat pancreatic β-cell KATP channels, which may result from direct inhibition of the Kir6.2 subunit.Therefore, iptakalim bi-directionally regulates KATP channels in cardiovascular and pancreatic tissues, and this uniquepharmacological property suggests iptakalim could be used as a new therapeutic strategy for the treatment of type 2diabetes with the potential benefi t in alleviating cardiac and/or vascular disorders frequently associated with diabetes. 続きを見る
19.

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論文
Yagihashi, Soroku ; Yamagishi, Shin-Ichiro ; Mizukami, Hiroki ; Wada, Ryuichi
出版情報: 弘前医学.  59  pp.S101-S108,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2223
概要: Accumulating evidence supports that proinflammatory processes are implicated in the establishmentof characteristic patho logy in diabetic vascular and neurological complications. Altered cellular signaling duringinflammatory processes is a new target for the treatment of diabetic complications and there appear to be someattempts to explore the eff ects of thiazolidinedione, a ligand of peroxisome proliferating activator receptor( PPAR)-γfor not only the treatment of diabetes itself but for the application to diabetic complications. We therefore explored theeff ects of PPAR-γ agonist, pioglitazone, on the experimental model of diabetic neuropathy. We found that pioglitazonesignifi cantly improved nerve conduction velocities and depressed protein kinase C activity. This is a new area for theexploration of eff ective treatment of diabetic complications that pose a considerable socioeconomic burden in the currentworld. 続きを見る
20.

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論文
Lambert, David G. ; Williams, John P. ; Thompson, Jonathan P.
出版情報: 弘前医学.  59  pp.S109-S118,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2224
概要: Clinically opioids are immunomodulatory where a general depression is reported. In addition, immunecells carry endogenou s opioid peptides to sites of inflammation where opioid receptors on peripheral nerves areupregulated. Release of these endogenous opioids produces a degree of analgesia and completes the neuroimmune axis.The expression of opioid receptors on immune cells that deliver these opioid peptides, is contentious and is the basis ofthis short review. There are several papers reporting expression of opioid receptors on peripheral blood mononuclearcells (PBMCs) using a variety of in vitro biochemical/pharmacological techniques. Equally there are studies failingto detect these receptors. We have recently undertaken a detailed volunteer study to determine the expression ofclassical naloxone sensitive MOP, DOP and KOP and non-classical naloxone insensitive NOP receptors. We initiallyfocused our attention on the MOP receptor as the main clinical analgesic target. Using radioligand binding, FACSwith opioid receptor antibodies and PCR we have failed to detect all classical opioid receptors. In contrast, using PCRtechniques the non-classical NOP receptor is present in all volunteer samples examined along with its endogenouspeptide ligand nociceptin/orphanin F/Q (N/OFQ). As both the peptide (N/OFQ) and receptor (NOP) are presentwe suggest that there may be a feedback loop such that peripherally delivered N/OFQ( to infl ammatory site) wouldproduce both a classical analgesic response and then feedback to modulate PMBC function. The nature of that functionremains to be determined but could include release of further N/OFQ, activation of other immune cells or chemotaxis.Opioids have been used by man for centuries for the relief of pain. Morphine is the most widely used opioid in theclinic and is considered the gold standard to which all others are compared. In addition to producing analgesia, opioidadministration also produces other eff ects including; respiratory depression, gastrointestinal-inhibition, tolerance anddependence and immunomodulationbasic summaries see1-4). Patients receiving long term opioid treatment display signs ofimmunodepression; it has been suggested that this may occur either as a direct eff ect of opioids on circulating immunecells or via a central action (see below). Neuronal opioid receptors are up-regulated in peripheral infl ammation andStein and colleagues( in particular) have shown that release of these endogenous opioids from circulating immune cellsproduces a degree of analgesia and complete the neuroimmune axis5), i.e., immunomodulation of neuronal activity. Theexpression of opioid receptors on the circulating immune cells that deliver these opioid peptides remains unclear and isthe focus of this short review. 続きを見る
21.

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論文
Hasan, Kazi N. ; Shoji, Masaru ; Sugimoto, Kazuhiro ; Tsutaya, Shoji ; Matsuda, Eriko ; Kudo, Ryoko ; Saito, Junko ; Nakaji, Shigeyuki ; Suda, Toshihiro ; Yasujima, Minoru
出版情報: 弘前医学.  59  pp.S119-S127,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2225
概要: Candidate gene SNP study is a promising genetic approaches to complex common disorders. Argininevasopressin (AVP), a pep tide hormone released from the posterior pituitary, has been suggested to play importantroles in the regulation of blood pressure, glycogenolysis and platelet aggregation through G protein coupled V1areceptor (V1aR). Thus, polymorphisms in the V1aR gene have been prospective as possible genetic markers foressential hypertension, type 2 diabetes mellitus and divergent platelet aggregation response to AVP. We identifi ed 4novel single nucleotide polymorphisms( SNPs) in the promoter region of the V1aR gene and named according to theupstream locations such as, -6951G/A, -4112A/T, -3860T/C, and -242C/T. We investigated the association of 4 SNPs ofthe V1aR gene in 365 hypertensive and 255 healthy subjects, 186 T2DM patients and 188 non-diabetic control subjects(CS), and 33 young healthy volunteers living in the Aomori prefecture. Signifi cant association was identifi ed betweenSNP at -6951 and hypertension in nonobese individuals, at -6951 and type 2 diabetes mellitus. Positive association wasalso identifi ed between nonobese hypertension and haplotype H3. Signifi cant association was demonstrated betweenSNP at -6951 and glycemic status in young healthy subjects. However, there was no signifi cant association in the AVPinducedplatelet aggregation with V1aR gene variants. The study suggests V1aR gene variants as increased riskfor hypertension in nonobese and type 2 diabetes mellitus in the Aomori population; however, might not be useful asgenetic markers for platelet aggregation heterogeneity. 続きを見る
22.

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論文
Tsubo, Toshihito ; Fujita, Ayaka ; Hashiba, Eiji ; Ishihara, Hironori ; Hirota, Kazuyoshi
出版情報: 弘前医学.  59  pp.S128-S136,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2226
概要: To investigated the eff ect of high volume continuous hemofi ltration( HVHF) on the lung lesion observedwith transesopha geal echocardiography (TEE) in endotoxin-induced acute lung injury in piglets. Piglets weighing20-30kg. Interventions: After endotoxin of 20 μg/kg intravenous administration, animals were randomly assigned tocontrol group( n=7) and HVHF group( n=7). In both group, fi ltration was performed for fi ve hours and zero balanced.Filtration fl ow was 150 ml/hr in HVHF group and 0ml/hr in control group. The area of the lesion, resistive indexand maximal blood velocity in regional pulmonary artery were estimated using TEE. High mobility group B1 protein(HMGB1), cortisol and catecholamine concentrations were measured in plasma at endotoxin 5 hours. Measurements ofblood gas, hemodynamics and TEE images were obtained every hour. The value of PaO2, density area and resistiveindex were 70.0±8.8 mmHg, 10.7±4.5 cm2 and 0.61±0.23 in control group and 120.4±20.3 mmHg, 3.3±2.0 cm2 and 0.88±0.22 in HVHF group at endotoxin 5 hours respectively( mean±SD). PaO2 and resistive index increased, and densityarea decreased in HVHF group than those of control group signifi cantly( p<0.05, respectively). There was signifi cantrelationship between PaO2 and density area (r=0.76, p<0.01). There was no signifi cant diff erence in hemodynamics,HMGB1, cortisol and catecholamines concentration in plasma and morphometry between control group and HVHFgroup. In conclusion, these results suggest that non-specifi c blood purifi cation with HVHF improves arterial oxygenationand lung image observed with TEE in endotoxin-induced acute lung injury in piglets. 続きを見る
23.

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論文
Imaizumi, Tadaatsu ; Mori, Fumiaki ; Yagihashi, Norito ; Kitamura, Hideo ; Sashinami, Hiroshi ; Suzuki, Koichi ; Yamashita, Koji ; Taima, Kageaki ; Kubota, Kosei ; Tanji, Kunikazu ; Sakaki, Hirotaka ; Matsumiya, Tomoh ; Yoshida, Hidemi ; Mariya, Yasushi ; Nakane, Hajime ; Tanaka, Hiroshi ; Takanashi, Shingo ; Wakabayashi, Koichi ; Yagihashi, Soroku ; Nakane, Akio ; Ito, Etsuro ; Okumura, Ken ; Kimura, Hiroto ; Satoh, Kei
出版情報: 弘前医学.  59  pp.S137-S142,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2227
概要: Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic protein regarded as putative RNA helicase.Immunohistochemical st udies revealed high levels of RIG-I expression in epidermic cells in psoriasis, in macrophagesin atherosclerotic lesions and in glomeruli of lupus nephritis. RIG-I expression was also demonstrated in macrophagesand vascular endothelial cells in experimental animals with Listeria or Hanta virus infection. In vitro studies using cellcultures revealed the expression of RIG-I, in various cells including endothelial cells, macrophages and astroglial cells, inresponse to the stimulation with cytokines, lipopolysaccharide, double-stranded RNA, Listeria monocytogenes, etc. Thestudies employing the overexpression or RNA interference suggested that RIG-I is involved in the regulation of cytokineexpression including CXCL10/IP-10 and CCL5/RANTES. These results suggest that RIG-I constitutes a part of theintracellular pathway for the regulation of infl ammatory and immune responses. 続きを見る
24.

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論文
Tanji, Kunikazu ; Mori, Fumiaki ; Takahashi, Hitoshi ; Kamitani, Tetsu ; Wakabayashi, Koichi
出版情報: 弘前医学.  59  pp.S143-S146,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2228
概要: NEDD8 is developmentally down-regulated ubiquitin-like protein, which can conjugate covalently to their target proteins . Recently, we identifi ed NUB1 as a NEDD8-interacting protein, which is composed of 601 amino acid residues with a calculated molecular mass of 69.1 kDa. More recently, we showed that NUB1 is an interferon-induced protein and also recruits NEDD8 to the proteasome for degradation. Here, we performed a yeast two-hybrid screening using NUB1 as bait and isolated the cDNA of synphilin-1 from a human testis cDNA library. Synphilin-1 is a major component of inclusion bodies found in the brains of patients with α-synucleinopathies, including Parkinson’s disease. Our biochemical study showed that NUB1 directly interacts with synphilin-1 through its NEDD8-binding site. In addition, our immunohistochemical study showed that NUB1, as well as synphilin-1, accumulates in the inclusion bodies found in the brains of patients with α-synucleinopathies. These fi ndings imply that NUB1 plays a role in the formation of synphilin-1-positive inclusions. 続きを見る
25.

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論文
Suzuki, Yasuyuki ; Daitoku, Kazuyuki ; Minakawa, Masahito ; Fukui, Kozo ; Fukuda, Ikuo
出版情報: 弘前医学.  59  pp.S147-S153,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2229
概要: We have proved that Sivelestat preserved lung function after cardiopulmonary bypass( CPB) in the rabbit model. We now r eport the therapeutic efficacy of Sivelestat in the clinical case. From July 2005, 16 patients who underwent aortic arch replacements were enrolled in this study. Diagnosis included dissected aortic aneurysm in 6 patients, true aortic arch aneurysm in 8, and traumatic aortic arch aneurysm in 1 patient. We randomly divided these patients into two groups. In the Pre-Group( Pre:n=8), infusion of Sivelestat( 0.2mg/kg/hr) was started before the operation; in the Post-Group( Post:n=8), it was started after the operation. Serum elastase activity, interleukin-8( IL-8) levels were measured before the operation, before cessation of CPB and at the end of operation. Blood gas analyses were measured before the operation, at one and three hours after the CPB and the next morning. Because the preoperative P/F ratio( arterial PO2/FiO2) varies with each case, the value of the P/F ratio at one hour after the CPB was calculated for 100%. Elastase activity of both groups were increased at the end of CPB( Pre:8.9±10.6, Post:4.6± 3.5), then returned to baseline level at end of operation( NS). IL-8 of both groups were increased at end of CPB, then in the Pre-Group decreased to 59.3± 25.0 pg/ml, but in the Post-Group increased to 97.9±45.7 pg/ml( p=0.09). The P/F ratio in the Pre- Group was well maintained from post CPB to next morning, but in the Post-Group was decreased three hours after the CPB (p<0.05). In conclusion, these fi ndings showed that Sivelestat reduced the infl ammatory reaction associated with cardiopulmonary bypass, and prevented the pulmonary dysfunction caused by infl ammatory reaction. 続きを見る
26.

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論文
Kon, Atsushi ; Igarashi, Manami ; Yamaguchi, Masanori ; Kojima, Kaoru
出版情報: 弘前医学.  59  pp.S154-S161,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2230
概要: Chronic ultraviolet (UV) radiation results in photoaged skin characterized by deep wrinkle formation.Recent studies sugg est that diminishment of anchoring fi brils( AF), stabilizing the association of the basement membraneto the underlying dermis, are involved in photoaged skin. Expression of COL7A1, encoding type VII collagen that is amajor component of AF, is also decreased in photoaged skin. In this study, we have investigated COL7A1 transcriptionby UV and UV-related cytokines involved in photoaged skin. Nuclear run-on assay, luciferase assay and gel shift assayrevealed that UV and UV-related cytokines( TNF-α, IL-1β) tissue specifi cally downregulated COL7A1 transcription inepidermal keratinocytes, whereas COL7A1 transcription was upregulated by each modulator in dermal fi broblasts. Theresponsive element of each modulator was located between nucleotide -524 and -22 of COL7A1 promoter and AP-1 andNF-κB families band to this region. Taken together, these data strongly suggest that the downregulation of COL7A1transcription in epidermal keratinocytes, main cells expressing COL7A1 in the skin, and subsequent diminishment of AFare involved in photoaged skin. We also have discussed relation between these results and pathophysiology of wrinkleformation, characteristic feature of photoaged skin. 続きを見る
27.

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論文
Mori, Kazuyuki ; Yoshikawa, Kazuaki ; Saitoh, Hideki ; Kudoh, Seiji ; Okamoto, Akiko ; Imai, Atsushi ; Ishimura, Hirofumi ; Hatakeyama, Shingo ; Hagisawa, Shigeru ; Iwabuchi, Ikuya ; Yoneyama, Takahiro ; Koie, Takuya ; Yamato, Takashi ; Yokomizo, Hidehiro ; Naka, Takashi ; Yano, Ikuya ; Ohyama, Chikara
出版情報: 弘前医学.  59  pp.S162-S166,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2231
概要: Bacillus Calmette-Guerin( BCG) has been widely accepted as an eff ective treatment for CIS and superfi cial carcinoma o f the bladder. However, it has considerable side eff ects and toxicity. We thought if eff ective bacterial cell wall elements as substitutes for live bacteria were identifi ed, useful treatment with lower toxicity while maintaining strong anti-tumor eff ects might be possible. For these reasons we generated a nano-particulated BCG complex, which does not contain live bacteria. Here, we present its direct in vitro anti-tumor eff ect on bladder cancer cell lines. Tokyo 172 BCG sub-strain was disrupted by French press with monitoring the particle distribution by the particle analyzer. After removing the not-disrupted bacteria by centrifuge at 6,800×g, supernatant was centrifuged at 18,000×g. Then the supernatant( Sup) and the precipitate( CW) were lyophilyzed to obtain nano-particulated BCG complex. Bladder cancer cell lines, J82 and KK47, were co-cultured with BCG, Sup, CW or Sup+CW( mix) for 5 days, then viable cell numbers were counted. In J82 cells, when separately added to the culture medium, both CW and Sup reduced cell number to about 70% of control cells. While they were mixed together, they reduced cell number equally compared with BCG; 59.2% (mix) vs 60.2%( BCG) in J82 cells, 67.3% vs 68.8% in KK47 cells. These preliminary in vitro experiments demonstrated the identical direct anti-tumor eff ect of nano-particulated BCG to that of live BCG. In vivo tumor assays are warranted for clinical application of nano-particulated BCG. 続きを見る
28.

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論文
Maruyama, Atsushi ; Itoh, Ken
出版情報: 弘前医学.  59  pp.S167-S171,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2232
概要: NF-E2-related factor 2 (Nrf2) regulates the coordinate induction of phase 2 detoxifying and antioxidantenzymes in respon se to xenobiotics and oxidative stress via antioxidant responsive element. Nrf2 knockout mice arehighly susceptible to the acute toxicity generated by acetaminophen, butylated hydroxytoluene or hyperoxia and tocarcinogenesis induced by benzo[a]pyrene. Recently, it becomes increasingly evident that Nrf2 also plays essential rolesin the protection against infl ammation. Nrf2 regulates the infl ammation during carrageenin-induced pleurisy and lunginfl ammation, wound healing in skin, and dextran sulfate-induced colitis. Nrf2 knockout mice are also susceptible toendotoxin-induced septic shock and allergen-induced asthma. Using carrageenin-induced pleurisy and porcine neutrophilelastase-induced lung injury models, we proposed that this anti-infl ammatory action of Nrf2 relies on the activities inmacrophages. In macrophages, Nrf2 modulates the infl ammatory response by up-regulating a range of anti-oxidative andanti-infl ammatory enzymes, such as CD36 and secretory leukoprotease inhibitor( SLPI). CD36 is a macrophage classB scavenger receptor involved in the uptake of apoptotic neutrophils and microorganisms such as Staphylococcus aureus.Thus, Nrf2 may play important roles in the protection of infl ammation and innate immune response. 続きを見る
29.

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Kusumi, Akinori ; Sakaki, Hirotaka ; Kusumi, Tomomi ; Nakagawa, Hiroshi ; Kubota, Kosei ; Oda, Mitsuo ; Satoh, Hisashi ; Kimura, Hiroto
出版情報: 弘前医学.  59  pp.S172-S187,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2233
概要: The application of mechanical stress is known to be the unique method of analyses on bone metabolismand remodeling in vi tro and in vivo. We have investigated on the effects of the application of cyclic tensile strain(CTS) on the syntheses of bone metabolic factors from the normal human osteoblasts in vitro. In this study, we foundthat diff erent passage numbers aff ected synthesis of CTS-induced factors from osteoblasts in vitro. Osteoblasts werestimulated with the application of CTS for 3 days, 4 hrs a day. Then, it was found that the application of CTS increasednitric oxide( NO) production, the expression of cyclooxygenase 2( Cox-2) mRNA, and synthesis of osteopontin( OPN)from osteoblasts during serial passage. However, CTS-induced osteoprotegerin( OPG) synthesis from osteoblasts wasshown to change at diff erent passage numbers. In short, increasing at the 3rd passage, CTS-induced OPG synthesis fromosteoblasts decreased at the 5th passage. While, though soluble RANKL( sRANKL) release by the application of CTSdecreased at 1st passage and did not change at the 5th passage, the expression of receptor activator of nuclear factor-κBligand( RANKL) mRNA increased in osteoblasts at the 5th passage, decreasing in those at the 3rd passage. The increaseon OPN synthesis the expression of Cox-2 mRNA, and NO production from osteoblasts by the application of CTS wasnot aff ected during serial passage. Analyzing on the activity of the p38 mitogen-activated protein kinase( p38 MAPK)in osteoblasts with or without the application of CTS, the p38 MAPK activity in osteoblasts at the 3rd passage inhibitedin compared with that at the 3rd passage. From these results, we should use osteoblasts at the 1st passage whenanalyzing on CTS-induced OPG synthesis with normal human osteoblasts. It is suggested that the regulation of CTSinducedOPG synthesis might be aff ected by aging of osteoblasts. 続きを見る
30.

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論文
Noto, Yuka ; Kudo, Mihoko ; Sato, Tetsumi ; Ebina, Masako ; Hirota, Kazuyoshi
出版情報: 弘前医学.  59  pp.S188-S192,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2234
概要: Massage therapy promotes psychosocial relaxation and reduce stress. In addition, this therapy has beenreported to improv e immune function. Although evaluation of psychosocial status has been performed with subjectivepsychological tests such as State-Trait Anxiety Inventory (STAI), subjective psychological tests are of limited valueif the subjects fail to report reliably. Salivary biomarkers have been recently suggested as useful objective indicatorsfor assessing psychosocial status. To determine whether salivary biomarkers are useful objective indices for assessingeff ects of back massage on psychological status in 25 young healthy female volunteers, we measured heart rate andsalivary biomarkers( α-amylase, cortisol and chromogranin-A) and assessed STAI score before and after back massage.Back massage significantly reduced heart rate from 73.4±11.8 to 69.8±11.2 and STAI from 41.0±6.0 to 32.3±4.9. Incontrast salivary chromogranin-A signifi cantly increased from 2.93±2.21 to 5.29±5.46 pmol/mg protein whilst salivaryα-amylase and cortisol did not change. Therefore, salivary biomarkers tested may not indicate changes in psychologicalrelaxation following back massage. Massage therapy has been reported to not only reduce psychosocial stress butalso enhance immune functions in cancer patients. In the present study, massage therapy significantly increasedchromogranin-A release. As several reports clearly show that chromogranin-A has antibacterial and antifungalactivities, back massage may increase host defense with salivary chromogranin-A release against oral microbial invasion. 続きを見る
31.

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Sakihara, Satoru ; Kageyama, Kazunori ; Nigawara, Takeshi ; Hanada, Komaki ; Suda, Toshihiro
出版情報: 弘前医学.  59  pp.S193-S198,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2235
概要: Corticotropin-releasing factor (CRF) is primary regulator of hypothalamus-pituitary-adrenal( HPA) axis,which is activate d by various types of stress. Starvation is also a potent activating factor of CRF. Because theperipheral energy store refl ects on plasma levels of leptin, secreted from adipose tissue, it is presumed that leptin maybe involved in the CRF activity during starvation. Indeed, the attenuation of CRF or HPA axis activity by leptintreatment has been demonstrated in several reports. While many studies indicate the leptins involvement in CRFactivity, its precise regulation has not been elucidated. The aim of this study is to determine the impact of leptin onthe hypothalamic CRF neuron. To exclude the other hypothalamic factors, associated with leptins central eff ect, weemployed the in vitro study using immortalized CRF expressing neuron( IVB cell). Since the mRNA expression of longformleptin receptor was detected clearly in IVB cell with RT-PCR, we next investigated the impact of leptin on this cell.IVB cell was treated with leptin in diff erent concentrations and periods, then, the mRNA expression and the promoteractivity of CRF were analyzed with real-time PCR and luciferase assay, respectively. In result, leptin suppressed CRFpromoter activity with dose- and time- dependent manner in IVB cell. This indicates that leptin can suppress the CRFtranscription directly in hypothalamus. Our result might explain the mechanism partially how leptin attenuate theactivation of CRF or HPA axis induced by stress or starvation. 続きを見る
32.

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Nigawara, Takeshi ; Sakihara, Satoru ; Kageyama, kazunori ; Terui, Ken ; Fukuda, Yoshiko ; Kawashima, Shoko ; Takayasu, Shinobu ; Moriyama, Takako ; Kawahara, Masayuki ; Korekawa, Ayumi ; Yamashita, Maki ; Kohsaka, Akira ; Kakizaki, Yoshifumi ; Suda, Toshihiro
出版情報: 弘前医学.  59  pp.S199-S201,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2236
33.

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Tonosaki, Yoshikazu ; Sugiura, Yasuo ; Roubos, Eric W.
出版情報: 弘前医学.  59  pp.S202-S209,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2237
概要: It is well-known that α-melanophore-stimulating hormone (α-MSH) release from the amphibian parsintermedia( PI) depends o n the light condition of the animal’s background. In the present study, we present two newfunctions of α-MSH in amphibians and mammals. In Xenopus laevis, we show that temperatures below 8 ℃ stimulateα-MSH secretion of the PI and skin darkening, with a maximum at 5 ℃, under regulation of the hypothalamus rule,independently from the illumination state of the background. The cold-induced α-MSH release of the PI was inhibited byneuropeptide-Y-producing suprachiasmatic-melanotrope-inhibiting neurons in the ventrolateral area of the suprachiasmaticnucleus but increasely in thyrotropin-releasing-hormene-containing neurons of the magnocellular nucleus. It is knownthat intracerebroventricular( ICV) administration of a low dose of interleukin-1β( IL-1β) induces hyperalgesia in ratand that this eff ect can be inhibited by α-MSH. To identify the part of the brain that is aff ected by hyperalgesiainducingIL-1β and the site of α-MSH concerned, we have examined Fos expression in the brain in response to ICVmicroinjection of α-MSH and/or IL-1β. Following injection of 10 pg IL-1β, hyperalgesia was induced and Fos becameexpressed in the paraventricular nucleus( PVN) of the hypothalamus and in the arcuate nucleus( ARC), which containsα-MSH-producing neurons. ICV co-injection of IL-1β ・ with 30 ng α-MSH fully inhibited both hyperalgesia and Fosexpression in the PVN and the ARC. We conclude that PVN neurons are activated by hyperalgesic IL-1β and proposethat this eff ect is abolished by α-MSH released from the ARC but not from the pituitary gland. 続きを見る
34.

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論文
Hu, Dong-Liang ; Omoe, Katsuhiko ; Narita, Koji ; Shinagawa, Kunihiro ; Nakane, Akio
出版情報: 弘前医学.  59  pp.S210-S218,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2238
概要: To develop a Staphylococcus aureus vaccine, we constructed and expressed a non-toxic mutant staphylococcalenterotoxin C( mSEC) and investigated whether immunization with mSEC can protect against S. aureus infection. Micewere immunized with mSEC and challenged with viable S. aureus. Bacteria counts in the organs in mSEC-immunizedmice were significantly lower and the survival rate was higher than those of the control group. mSEC vaccinationinduced the production of T-helper 2 type antibodies. The production of interleukin-10( IL-10) and IL-4 in vaccinatedmice was signifi cantly higher compared with the control group, whereas the production of gamma interferon (IFN-γ.)was signifi cantly decreased in the vaccinated mice. Furthermore, IFN-γ.and tumor necrosis factor-α・ production in vitrowas signifi cantly inhibited by the sera from mSEC-vaccinated mice but not by those from control mice. These resultssuggest that vaccination with mSEC provides protection against S. aureus infection. SEC neutralizing antibodies and theIL-10 and IL-4 induction might play important role for the protection. 続きを見る
35.

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論文
Hu, Dong-Liang ; Suga, Yochiko ; Omoe, Katsuhiko ; Abe, Yoshinao ; Shinagawa, Kunihiro ; Wakui, Makoto ; Nakane, Akio
出版情報: 弘前医学.  59  pp.S219-S226,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2239
概要: To clarify whether SEA can aff ect any changes of cellular signalling pathways in intestinal epithelial cells, weperform ed experiments to see if SEA can modulate the intracellular signaling pathway in intestinal epithelial cells. Wedemonstrate here that SEA induces an increase in intracellular calcium( [Ca2+]i) in human intestinal epithelial cells andthe[ Ca2+]i is released from intracellular stores. SEA-induced increase of[ Ca2+]i was clearly inhibited by treatment witha nitric oxide synthase( NOS) inhibitor, NG-monomethyl-L-arginine. Intestinal epithelial cells express endothelial NOS(eNOS) in resting cell condition, and express inducible NOS( iNOS) after stimulating with tumor necrosis factor( TNF)-α. TNF-α-pretreated cells showed a signifi cant increase in[ Ca2+]i that was also inhibited by the NOS inhibitor. Theseresults demonstrate that SEA induces an increase in intracellular Ca2+ concentration in human intestinal epithelial cells,and the expressions of both eNOS and iNOS could be responsible for the increase in intracellular Ca2+ concentration inthe cells induced by SEA. It is important to study the relationship of NOS expression, Ca2+ signal pathway and emesisfor understanding the mechanism of SEA-induced food poisoning. 続きを見る
36.

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論文
Narita, Koji ; Hu, Dong-Liang ; Tsuji, Takao ; Nakane, Akio
出版情報: 弘前医学.  59  pp.S227-S234,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2240
概要: Infection caused by methicillin-resistant Staphylococcus aureus (MRSA) has been the most commonlyacquired types of nosoc omial infections. It was reported that anterior nares are the major reservoir of S. aureus andthe source of 80% of S. aureus bacteremia is endogenous. Considering these facts, elimination and reduction of nasalcarriage are thought to be eff ective protection against systemic S. aureus infection and nosocomial infection. Toxic shocksyndrome toxin 1( TSST-1) is one of superantigens secreted by S. aureus. Previously, it was reported that mutant form(H135A) of TSST-1( mTSST-1) was shown to be nontoxic, and subcutaneous vaccination with mTSST-1 could protectagainst systemic S. aureus infection in a mouse model. In this study, we investigated the protective eff ect of intranasalvaccination with mTSST-1 supplemented with non-toxic mutant( H44A) Escherichia coli heat labile toxin( mLT) as amucosal adjuvant. The results demonstrated that intranasal immunization with mTSST-1 plus mLT could efficientlyinduce production of anti-TSST-1 antibodies in sera and also induce anti-TSST-1 IgA production in bronchoalveolar lavagefl uids( BALF) of vaccinated mice. In nasal-associated lymphoid tissues( NALT) of vaccinated mice, anti-TSST-1 IgAsecreting cells were signifi cantly increased. To evaluate of the protective eff ect of this vaccine against systemic S. aureusinfection, BALB/c mice were vaccinated with mTSST-1 plus mLT and challenged with clinical isolated S. aureus 834intravenously. Bacterial numbers in spleen and liver, and cumulative mortality rate of vaccinated mice were lower thanthose of control mice. We further developed a mouse model of nasal S. aureus colonization. S. aureus bacterial numbers innasal cavity of vaccinated mice were signifi cantly reduced compared with those of control mice. These results indicatethat intranasal immunization with mTSST-1 plus mLT is able to induce systemic and mucous immune responses and ofprovide protection against systemic S. aureus infection and nasal colonization. 続きを見る
37.

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論文
Sashinami, Hiroshi ; Takagaki, Keiichi ; Nakane, Akio
出版情報: 弘前医学.  59  pp.S235-S243,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2241
概要: Proteoglycans (PGs) are complex glycohydrates, which are widely distributed in connective tissues andon the cell surface of mammalian tissues. We investigated the effect of PG extracted from salmon cartilage oncytokine responses to stimulation with heat-killed Escherichia coli( HKEC) in a mouse macrophage cell line, RAW264.7.PG exhibited the suppression of tumor necrosis factor( TNF)-α production and enhancement of interleukin( IL)-10production compared with chondroitin 4 sulfate( C4S) and chondroitin 6 sulfate( C6S). PG, C4S and C6S suppressedHKEC-induced Toll-like receptor 4( TLR4) and inducible nitric oxide synthase( iNOS) expression dose-dependentlyand the PG showed the strongest suppressive effect among 3 compounds. Only PG dramatically up-regulated theexpression of signal transducers and activators of transcription 3( STAT3) and the phosphorylation of STAT3 in mousemacrophages. Our results showed strong suppression of PG on infl ammatory response and suggested that the novelinteraction might exist between the extracellular matrix and immune system. 続きを見る
38.

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論文
Hiraga, Hiroto ; Sashinami, Hiroshi ; Hu, Dong-Liang ; Ishiguro, Yoh ; Wakabayashi, Koichi ; Munakata, Akihiro ; Nakane, Akio
出版情報: 弘前医学.  59  pp.S244-S252,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2242
概要: Dietary vitamin A is an essential precursor of tissue retinol, which participates in a variety of biological processes including innate immunity. Functions of vitamin A mainly depend on retinoic acid( RA), principally all-trans- RA (atRA) and 9-cis-RA. We assessed whether atRA is benefi cial in host resistance against bacterial infections or not. Vitamin A-defi cient( VAD) mice were highly susceptible to infection with Listeria monocytogenes. Pre-treatment with atRA enhanced host resistance against L. monocytogenes infection in both VAD and VAS mice. Interferon( IFN) -γ production in atRA pre-treated VAS mice was not higher compared with the control VAD mice. The eff ect of atRA was independent of T cells and B cells. The bactericidal activity in macrophages obtained from atRA pre-treated VAS mice was almost the same level compared with the control VAS mice. Our results demonstrated that the treatment with atRA is benefi cial for host resistance against L. monocytogenes infection in the early phase and suggested a new therapeutic possibility of atRA in bacterial infections. 続きを見る
39.

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論文
Kachi, Takashi
出版情報: 弘前医学.  59  pp.S262-S277,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1889
概要: Various aspects of pineal structures and functions have been reviewed. mainly relating to our ownobservations and experiments. The pineal gland shows high amplitude circadian rhythms in cellular and metabolicactivities. which are changeable under various circumstances. The pineal hormone appears to participate in the body'sadaptive regulatory system mostly by cooperative and modulatory mechanisms. particularly in relation to environmentalchanges including stress/invasion. timing of physiological processes including reproductive activities. and possiblyexogenous and endogenous pathological changes such as inflammatory disease and tumor. Pineal effects are variabledue to the sensitivity/state of target mechanisms. For example. the pinealectomy effects on adreno-medullary adrenalinecells were more evident in comparison with the 'sham-pinealectomy' group than the normal group, and the pinealectomyeffects on female reproductive activities were age-dependent. In any case, the pineal hormone retains physiologicalfunctions at least till middle age. Pineal actions are mainly inhibitory. but can be also stimulatory as shown in immuneregulatory mechanisms. It has long been known that big differences in pineal structures and functions exist betweenmammals and submammals and that mammals show characteristic development of the brain, autonomic nervous systemand unique style of reproduction including pregnancy and suckling. These and other related results seem to support ahypothetical view that the pineal hormone was involved in drastic reorganization of the regulatory system occurred inthe evolutional process from submammals to mammals and became participated in the system which regulates complexbody mechanisms in mammals. 続きを見る
40.

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論文
Sakuma, Yasuo
出版情報: 弘前医学.  59  pp.S253-S261,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2243
概要: Distinctive sex diff erences in reproductive behavior and physiology have been attributed not to diff erencesin hormones gonad secretes in each sex but differences in particular brain structures. Interestingly enough, brainsex difference is determined mostly by gonadal hormones during ontogeny independent of genetic sex. In manylaboratory mammals, brain sex can be manipulated at a particular stage of ontogeny called critical period for brain sexdiff erentiation, by endocrine treatments. Thus, neonatal orchidectomy or administration of gonadal hormones to femalepups reverses brain sex phenotype which culminates in sex-specifi c functions. The early, transient exposure to gonadalhormones or its absence leaves indelible marks on brain phenotype. This organizing action of gonadal hormones,combined with activational action of the hormones after puberty, accomplishes sex specific functions. Brain wouldundergo sex diff erentiation through neurogenesis, migration, or survival in addition to regulation of ion channels andother functional molecule. Two distinct structures, the sexually dimorphic nucleus of the preoptic area, which is largerin male rats than in males and the anteroventral periventricular nucleus, which furnish opposite characteristics, willprovide good opportunity to understand the mechanism of brain sex diff erentiation. 続きを見る
41.

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論文
Kachi, Takashi ; Kachi, Hitomi
出版情報: 弘前医学.  59  pp.S278-S287,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1890
概要: Our primary concern in this review is to give possible explanations and pose new questions on the phenomenaconcerning effects of neonatal estrogen exposure on the development and functions of reproductive organs and immunemechanisms particularly in male animals, in the light of new findings and cencepts. At first, our own experimental resultson the pathological changes in the epididymis and testis in neonatally estrogenized mice have been presented. The resultsof our first experiment showed that neonatal single injection of 10 flg of estradiol benzoate induced marked inflammatorychanges in the epididymis and testis, in which the initial pathological change occurred concomitantly with the appearanceof sperms in the epididymal duct. The second experiment showed that such epididymo-testicular changes did not occurwhen the testis was removed or neonatal estrogen was followed by testosterone. From these results, a possibility wassuggested that a hormone-related autoimmune mechanism might participate in such changes. Relating to these, variousreports concerning effects of neonatal estrogen treatment, either alone or with concommitent treatment with androgen.on the development and functions of reproductive organs and immune mechanisms in the adolescent or adult have beenreviewed. In addition, advances in the related areas, such as estrogen-related mechanisms in the development andfunctions of reproductive organs and immune mechanisms including autoimmune disease mechanisms. gender differencesand the role of CD25+ CD4+ T lymphocytes have also been reviewed briefly. 続きを見る
42.

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論文
Takemori, Nobuo
出版情報: 弘前医学.  59  pp.S288-S291,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2244
概要: The omentum contains peculiar lymphoid tissues termed omental milky spots. In NZB mice, omental milkyspots show extramed ullary neutrophilic myelopoiesis and mgakaryopoiesis. Similar milky spots( splenoportal milkyspots), which also show similar hematopoiesis, are present in the splenoportal fat band developing along the splenicartery. The splenoportal fat band contains sporadic aberrant spleens. In addition, transitional forms between splenoportalmilky spots and aberrant spleens are occasionally present in the fat band. These three types of lymphoid tissues inthe fat band are supplied by branches of the splenic artery. Based upon the blood vessel supply, the extramedullaryhematopoiesis and the morphological transition from aberrant spleens via transitional forms to splenoportal milky spots,splenoportal milky spots seem to represent splenoid lymphoid tissues. Taking into account the similarity betweenomental and splenoportal milky spots, the deduction that omental milky spots also represent splenoid lymphoid tissuesmay be made. The function and the signifi cance of milky spots are described in this paper. 続きを見る
43.

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論文
Takano, Hiroko
出版情報: 弘前医学.  59  pp.S292-S301,  2007-11-29.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/2245
概要: We divided the mouse epididymis into 5 segments( Segments I-V) based on regional diff erences in histologyto obtain a fu ndamental division that refl ects the functions of this organ. Segments I-III are contained in the caputepididymidis, Segment IV in the corpus epididymidis, and Segment V in the cauda epididymidis. For this classifi cation,we observed morphological features of the epididymal duct in adult mice by light and electron microscopy, and examinedpostnatal development of the epididymal duct qualitatively and quantitatively. We also performed experimental studiesto examine the eff ects of ligation/cutting of the eff erent ducts, epididymal duct ligation at the border between SegmentsIII-IV, testis irradiation, cryptorchidism, and estrogen administration on epididymis histology. In these studies, we foundthat the epididymal duct in each segment responds as a functional unit when the epididymis is subjected to pathologicalconditions. In conclusion, the present histological division is useful as a basic division for studies on the mouse epididymis. 続きを見る
44.

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論文
Akita, Miki ; Nanashima, Naoki ; Yamada, Toshiyuki ; Nakano, Hajime ; Shimizu, Takeshi ; Fan, Yang ; Tsuchida, Shigeki
出版情報: 弘前医学.  60  pp.1-11,  2009-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1792
概要: The Hirosaki hairless rat (HHR) is a mutant strain spontaneously derived from the Sprague-Dawley rat(SDR) and its inheri tance is autosomal recessive. Our recent study has revealed that an 80-kb genomic DNA on 7q36containing basic hair keratin genes, Kb21, Kb23, Kb26 and Krt2-25, is deleted in HHR. To characterize hair follicles inHHR, progression of hair cycle and expression profi les of basic hair keratins were immunohistochemically studied andcompared with those of SDR. The HHR exhibited sparse hairs and their twisted hairs were shorter than SDR hairs.HHR hair follicles entered the catagen phase earlier than SDR and massive destruction of HHR hair follicles andinfi ltration of infl ammatory cells occurred in the catagen phase. In HHR the hair medulla was enlarged and the innerroot sheath was thinned while the hair cortex was formed where Kb25 was expressed. In SDR Kb25 was expressedin the hair matrix and medulla. Electron microscopy indicated loss of the cuticle in HHR. These results suggest thathypotrichosis of HHR is due to the deletion of hair keratin genes and expression of a keratin fusion gene. Thus, HHRseems to be a useful model to examine the role of hair keratins in the hair follicle formation. 続きを見る
45.

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論文
千葉, 貴子 ; 大森, 厚子 ; 高橋, 賢次 ; 柏倉, 幾郎
出版情報: 弘前医学.  60  pp.12-17,  2009-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1793
概要: 全ての血球の源となる造血幹細胞を豊富に含む臍帯血は,幹細胞研究,再生医療研究さらには臍帯血移植へとその応用が進み,今や単なる医療廃棄物ではなく,社会の多様な需要の中でその重要性は益々高まっている.本研究では,造血幹細胞の基礎医学研究に資した 臍帯血採取を実施した単一助産所における過去10年間の取組みから,助産所の臍帯血採取施設としての可能性の可否を含め,その内容を検討した.研究には,1998年から2007年の単胎正期産児を経膣分娩した585名を対象とした.その結果,助産所出産の母子の概要は,国内における平均的な出産と大差なかった.平均臍帯血採取量は54.2 g であり,重回帰分析の結果,胎盤重量,胎盤体積,出生体重,羊水混濁及び臍帯の長さと採取臍帯血量との間に関連が見られ,これまでの報告と一致した.以上の結果から,助産所においても安全かつ確実に臍帯血採取が行えることが実証された. 続きを見る
46.

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論文
Ashitate, Toshihiro ; Osanai, Tomohiro ; Tanaka, Makoto ; Magota, Koji ; Echizen, Takashi ; Tomita, Hirofumi ; Okumura, Ken
出版情報: 弘前医学.  60  pp.18-26,  2009-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1794
概要: We showed that endogenous prostacyclin inhibitor coupling factor 6 (CF6) is released from vascularendothelial cells and its release is stimulated by tumor necrosis factor-α, which is related to congestive heart failure(CHF). We also showed that CF6 increases the gene expression related to CHF. To investigate the role of CF6 inthe genesis of CHF, we generated CF6-overexpressing transgenic( TG) mice, and characterized the phenotype. DNAfragment consisting of human elongation factor 1α promoter, and human calcitonin/CF6 fused gene was injected intothe embryo of C57BL/6J mouse, and homozygous TG mice were generated. In TG mice, CF6 gene was overexpressedby two fold in overall tissues compared with wild type( WT) mice. Under normal salt diet, blood pressure, heart rate,and the expression of energy metabolism-related genes were similar between TG and WT mice. When the mice werefed with 8% -salt diet for 35 weeks, the mortality of TG mice was higher than that of WT mice( survival rate; 50% inTG versus 92% in WT, p<0.05 by log-rank test). This preliminary report indicates that further examination, especiallyanalysis of the cardiac function, is needed to clarify the cause of high mortality of TG mice under high salt intake. 続きを見る
47.

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論文
Niwa, Hidetomo ; Sakai, Tetsuhiro ; Furukawa, Ken-Ichi ; Kanemaru, Kota ; Hirota, Kazuyoshi
出版情報: 弘前医学.  60  pp.27-35,  2009-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1795
概要: In the present study, we have conducted cDNA microarray in C6, rat brain glioma cell line, to assess anti-infl ammatory eff ects of ketamine and sevofl urane in the central nervous system. The cultured C6 cells were treated with ketamine (0-100 μM) and sevofl urane (0 and 0.66 mM). Total RNA was extracted from the cells and labeled with fl uorescent dye and then hybridized with microarray slide, containing 1936 genes. Quantitative analysis of each gene expression was confi rmed by real-time polymerase chain reaction (PCR). Microarray analyses showed that ketamine downregulated the expression of 4 proinfl ammatory cytokine genes and upregulated that of 2 antiinfl ammatory cytokine genes. On the other hand, sevofl urane downregulated the expression of 2 proinfl ammatory cytokines but upregulated that of two other proinfl ammatory cytokines. Furthermore, sevofl urane failed to stimulate the expressions of anti-infl ammatory cytokines. Although patterns of cytokine expression in response to ketamine and sevofl urane were diff erent from each other described above, both anesthetics downregulated a key cytokine, interleukin( IL)-1β remarkably in microarray analysis, which was confi rmed by real time PCR. These results suggest that both ketamine and sevofl urane show mainly anti-infl ammatory properties through the inhibition of IL-1β. 続きを見る
48.

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論文
Kato, Chisato ; Osanai, Tomohiro ; Shibutani, Shuji ; Hanada, Kenji ; Okumura, Ken
出版情報: 弘前医学.  60  pp.36-44,  2009-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1796
概要: Insulin-like growth factor (IGF)-1 is known to exert benefi cial eff ects on the heart, but its source andfunction under hypoxia are unknown. We investigated the eff ect of hypoxia on IGF-1 expression and its role in theregeneration in the heart. Cardiac myocytes and fi broblasts obtained from neonate mice heart were cultured andexposed to hypoxia. mRNA of IGF-1, IGF-binding protein 3 (IGFBP3), and vascular endothelial growth factor-A(VEGF-A) was measured by real-time PCR. In cardiac myocytes, IGF-1 mRNA was increased by 3.5±1.1 fold at 3hours after hypoxia concomitantly with the increase in IGFBP3 and VEGF-A mRNA, and returned to the baseline at24 hours. In contrast, IGF-1 mRNA in cardiac fi broblasts was unchanged by hypoxia, although VEGF-A mRNA wasincreased. To investigate the role of IGF-1 in the heart regeneration, we measured the gene expressions of stromalcell-derived factor-1( SDF-1), its receptor CXCR4, and matrix metalloproteinase( MMP)-14 related to cell homing. Incardiac myocytes, SDF-1 and MMP-14 mRNA were increased at 3 hours after hypoxia and tended to be positivelycorrelated with IGF-1 mRNA. These suggest that hypoxia increases IGF-1 expression in cardiac myocytes, and thisendogenous IGF-1 may exert benefi cial eff ects on regeneration in the heart. 続きを見る
49.

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論文
Horiuchi, Daisuke ; Osanai, Tomohiro ; Echizen, Takashi ; Ashitate, Toshihiro ; Kato, Chisato ; Yokoyama, Hiroaki ; Hanada, Kenji ; Shibutani, Shuji ; Itoh, Taihei ; Okumura, Ken
出版情報: 弘前医学.  60  pp.45-53,  2009-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1797
概要: Structural remodeling occurs in diverse heart diseases and affects their clinical courses. We reportedthat amiodarone su ppresses both electrical and structural remodeling in a canine persistent atrial fi brillation model.As a mechanism for amiodarone’s effect on structural remodeling, we suggested its inhibitory effect on matrixmetalloproteinase( MMP) activity. To elucidate it, we investigated the eff ect of amiodarone on MMP activity in a ratmyocardial infarction model created by left coronary artery( LCA) ligation. Adult Sprague-Dawley rats were dividedinto sham-operated (Sham), sham-operated with amiodarone (Sham+AMD), LCA-ligated without amiodarone (MI)and LCA-ligated with amiodarone rats (MI+AMD). Amiodarone (20 mg/kg/day) was administered for 2 weeksbefore and for 4 weeks after operation. The hearts were excised at 4 weeks after operation. MMP-2 activity wasmeasured by gelatin zymography. At 4 weeks after surgery, left ventricular fractional shortening was decreased inMI but not in MI+AMD rats. There was no diff erence in the infarct size between MI and MI+AMD rats (P=NS).As compared with Sham, MMP-2 activity was increased in MI (P<0.01), but not in MI+AMD (P=NS versus Sham;P<0.05 versus MI). MMP-2 activity was not increased in Sham+AMD( P=NS). Thus, amiodarone exerts an inhibitoryeff ect on MMP activity. This may be related to the improvement left ventricular function in MI rats. 続きを見る
50.

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論文
Tomotsune, Ken ; Ogawa, Yoshiji ; Hasegawa, Noriyuki ; Kudo, Takanori ; Naraoka, Maki ; Chikazawa, Shinji ; Tamasawa, Naoki ; Suda, Toshihiro
出版情報: 弘前医学.  60  pp.54-62,  2009-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1798
概要: The aim of this study was to determine the time course and mechanism of hypoxia-induced pancreaticislet dysfunction. Isl ets isolated from Sprague Dawley rats were cultured in 1% O2( hypoxia). Glucose stimulatedinsulin secretion( GSIS) was then examined for islets in either static or perifused cultures, followed by an evaluation ofmitochondrial activity and islet cell death. Additionally, we examined the eff ect of culturing previously hypoxic islets foran additional 24 h under normoxia to determine whether the hypoxic eff ects were reversible and to assess the eff ects ofre-oxygenation on GSIS. In the static islet culture, insulin secretion declined signifi cantly after 24 h. In perifused islets,the area under the curve( AUC) of fi rst-phase GSIS declined signifi cantly after 6 h, while the AUC of second-phase GSISdecreased signifi cantly after 12 h. Mitochondrial activity dropped markedly after 48 h, but cell death assays revealedthat apoptosis did not increase in the time period from 6 h to 48 h. However, necrosis increased signifi cantly after 24 h.In the re-oxygenation study, the return to normoxia signifi cantly worsened the decline in GSIS. In conclusion, exposureto hypoxia fi rst causes functional disorder in the islets, followed by cell death due to necrosis rather than apoptosis.Furthermore, re-oxygenation aggravated islet dysfunction. 続きを見る
51.

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論文
Li, Chengtai ; Odagiri, Saori ; Meguro, Reiko ; Asano, Yoshiya ; Shoumura, Kazuhiko
出版情報: 弘前医学.  60  pp.63-76,  2009-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1799
概要: The localizations of nonheme-Fe( III) and Fe( II) were studied in the hypothalamo-neurohypophysealsystem of the rat brai n by light and electron microscopic nonheme iron-histochemistry. Fe (III)-deposit was heavilyaccumulated in the parvocellular part of the hypothalamic paraventricular nucleus( HPV), where numerous glias werestained. Fe( III)-deposit heavily fi lled the cytosol and lysosomes of microglia-, oligodendrocyte- and astrocyte-like cells,while neurons contained only a small number of Fe( III)-laden lysosomes. Fine processes of Fe( III)- laden microglia- andoligodendrocyte-like cells closely ensheathed the cell body and proximal dendrites of neurons. Fe (III)-laden astrocytelikecells tightly enclosed the capillary wall. The magnocellular part of the HPV and the supraoptic nucleus were lessintensely stained than the parvocellular part of the HPV. The secretory axon terminals in the outer lamina of the medianeminence( ME) and the posterior pituitary including the Herring bodies contained Fe( III)-laden small lysosomes amongdensely aggregated secretory granules. The secretory axon terminals in the ME were tightly enclosed by heavily Fe(III)-laden processes of tanycyte. The heavily Fe( III)-laden pituicytes and interstitial, pericapillary phagocytes closelyapproached the secretory axon terminals in the posterior pituitary. Fe (II) was largely localized in the lysosomesthroughout the hypothalamo-neurohypophyseal system. 続きを見る
52.

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Hayashi, Yoshimitsu ; Ishibashi, Yasuyuki ; Tsuda, Eiichi ; Yamamoto, Yuji ; Tsukada, Haruhiko ; Kimura, Yuka ; Toh, Satoshi
出版情報: 弘前医学.  60  pp.77-85,  2009-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1800
概要: Two- and three-dimensional motion analysis methods are commonly used for the measurement of dynamic lower limb alignment. However, there has been very few comparative studies between these two methods. The purpose of the present study was to investigate the correlation of the biomechanical data between two- and three-dimensional motion analysis methods for the evaluation of dynamic knee alignment. Seven female and 7 male college asketball players were recruited to perform a drop jump test. The Knee/Hip ratio for evaluation of valgus alignment of the knee in the coronal plane was measured by a two-dimensional motion analysis system with a digital video camera. The joint kinematics and kinetics of the knee were evaluated by a three-dimensional motion analysis system. From toe touch to maximum knee flexion, the knee/hip ratio decreased significantly both in males and females. However, the knee valgus angle and the peak knee valgus moment were not correlated with change in the knee/hip ratio. Both males and females showed a similar change in the knee/hip ratio in the two-dimensional motion analysis during the drop jump, but signifi cant diff erences in joint kinematic and kinetic patterns were seen in the three-dimensional motion analysis. These diff erences should be taken into account when using the two diff erent motion analysis systems. 続きを見る
53.

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Hasegawa, Kazushi ; Oikawa, Koichi ; Yoshida, Ikko ; Ishizaka, Hiroshi ; Osanai, Tomohiro ; Motomura, Shigeru ; Okumura, Ken
出版情報: 弘前医学.  60  pp.86-95,  2009-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1801
概要: To examine the effect of chronic hypertension on endothelium-derived hyperpolarizing factor( EDHF)responses, the hearts of Wistar-Kyoto rats( WKY) and spontaneously hypertensive rats( SHR) were isolated andperfused using Langendorff system with constant perfusion pressure. Bradykinin increased coronary fl ow( CF) dosedependentlyand this was not aff ected by NG-nitro-L-arginine methyl ester or indomethacin, indicating that bradykinin’seff ect on CF was not mediated by nitric oxide or prostacyclin but by EDHF. Bradykinin-induced CF increase was smallerin SHR than in WKY. Tetrabutylammonium( a non-specific KCa channel blocker) abolished bradykinin-induced CFincrease in both rats. 1-Ethyl-2-benzimedazolinone( 1-EBIO, an agonist of intermediate conductance KCa channel)-inducedincrease in CF was smaller in SHR than in WKY. 1,3-Dihydro-1-[2-hydroxy-5(- trifl uoromethyl) phenyl]-5(- trifl uoromethyl)-2H-benzimidazol-2-one( NS1619, an agonist of large conductance KCa channel)-induced increase in CF did not differbetween SHR and WKY. In early stage of hypertension, there was no signifi cant diff erence between SHR and WKY inbradykinin- and 1-EBIO-induced increases in CF. In conclusion, EDHF response in coronary microcirculation is impairedin SHR due to dysfunction of intermediate-conductance calcium-activated potassium channels. 続きを見る
54.

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Fujita, Wakako ; Fukuda, Ikuo ; Kitagawa, Reiko ; Kimura, Daisuke ; Yamada, Yoshitsugu ; Tsushima, Takao
出版情報: 弘前医学.  60  pp.96-99,  2009-03-31.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/1802
概要: We report a rare case of esophageal schwannoma. The patient was a 41-year-old man who was admittedto our hospital due to chest oppression. Chest imaging showed a solid mass in the middle mediastinum compressingthe esophagus and the trachea. Neurogenic tumor was suspected and the patient underwent extirpation of thetumor through right thoracotomy. The tumor, 4.5×4.3×3.4 cm in size, was strongly attached to the esophageal wall.Pathological examination revealed myxomatous pattern in the tumor. Immunohistochemical staining for S-100 proteinwas positive and the diagnosis of schwannoma was made. The majority of mediastinal schwannomas arise fromsympathetic nerve cells in the posterior mediastinum. Esophageal schwannoma is rare and only 27 cases were reportedin literature to date. 続きを見る
55.

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Itabashi, Yukihiro ; Baba, Toshiaki ; Kato, Satoru ; Hakamada, Kenichi
出版情報: 弘前医学.  61  pp.1-7,  2010-03-25.  弘前大学出版会
URL: http://hdl.handle.net/10129/3274
概要:  Forty patients with an average age of 64.6 years (range: 45-83) with early gastric cancer of cT1 (M,SM) underwent a cur ative-intended laparoscopy-assisted distal gastrectomy (LADG) where laparoscopic D1+αnodal clearance and extra-abdominal Billroth-I stapled anastomosis were performed. There was no conversionto open gastrectomy. The operation time for the 40 cases ranged 150 - 482 min (median: 285), while that for thelatest 10 cases reduced to 154-278 min (median: 216). The length of hospital stay of the patients varied 10-85 days(median: 17). Postoperative complications encountered were anastomosis-related: 2 anastomotic bleeding and 2anastomotic passage disturbance( 1 stricture and 1 temporary stenosis) occurred but no dehiscence. Four inaccuratepreoperative diagnoses of tumor invasion depth were revealed by postoperative pathology of the resected specimens.Thereafter the accuracy in the preoperative diagnosis was highly enhanced with implementation of endoscopicultrasound. Recurrence occurred in one patient with pT2( SS) pN2, who died of pleural carcinomatosis 4 years and 3months after surgery.  As the reduced operation time in LADG came closer to that in open distal gastrectomy, we will continuethis procedure for early gastric cancer. For this, the importance of an accurate preoperative diagnosis can’t beoveremphasized. 続きを見る
56.

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Yoshida, Ikko ; Ishizaka, Hiroshi ; Hasegawa, Kazushi ; Satoh, Kiyohiko ; Osanai, Tomohiro ; Motomura, Shigeru ; Okumura, Ken
出版情報: 弘前医学.  61  pp.8-18,  2010-03-25.  弘前大学出版会
URL: http://hdl.handle.net/10129/3275
概要: Objectives The purpose of this study was to test the hypothesis that adenosine-induced coronarymicrovascular dilation is blunted in the animals with diabetes mellitus( DM) through the impairment of KATP channelfunction.  Background Adenosine-induced coronary vasodilation is demonstrated to be mediated by activation of ATPsensitivepotassium( KATP) channels and nitric oxide( NO). Methods The hearts of Otsuka Long-Evans Tokushima fatty rats (OLETF, type 2 DM rats), and control Long-Evans Tokushima fatty rats( LETO) at the ages of 32 and 8 weeks were perfused using a Langendorff system withconstant perfusion pressure (80 mmHg). Changes in coronary fl ow to adenosine, pinacidil and sodium nitroprusside(SNP) were examined before and after administration of glibenclamide( 10-7 M), or NG-nitro-L-arginine methyl ester(L-NAME, 10-4 M).  Results At the age of 32 weeks, adenosine- and pinacidil-induced increases in coronary fl ow were blunted in OLETFas compared with those in LETO (both p<0.05). Glibenclamide attenuated adenosine-induced increase in coronaryfl ow in LETO (p<0.05), but not in OLETF. In contrast, L-NAME attenuated adenosine-induced increase in coronaryflow in OLETF (p<0.05), but not in LETO. SNP-induced increases in coronary flow in LETO and OLETF werecomparable and were not aff ected by glibenclamide. In 8-week-old OLETF and LETO, no diff erence was observed inadenosine-, pinacidil- and SNP-induced increases in coronary fl ow between OLETF and LETO. Conclusions In this type 2 DM model, KATP channel function in coronary microcirculation is impaired. Adenosineinducedincrease in coronary fl ow is mediated mainly by NO mechanism. 続きを見る
57.

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Sutoh, Takemichi ; Fukuda, Ikuo ; Kimura, Daisuke ; Tsushima, Takao
出版情報: 弘前医学.  61  pp.19-25,  2010-03-25.  弘前大学出版会
URL: http://hdl.handle.net/10129/3276
概要: Nafamostat mesilate( FUT-175), a synthetic serine protease inhibitor, has been reported to have antitumouractivities tow ard solid tumours. The objective of this study was to characterize the biological activities of FUT-175 ina malignant mesothelioma cell line. We used MSTO-211H, a biphasic-type human malignant pleural mesothelioma cellline. The effect on cell growth was evaluated by 3(- 4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Secretion of urokinase-type plasminogen activator( u-PA) and plasminogen activator inhibitor-1( PAI-1) was analysedby enzyme-linked immunosorbent assay. The eff ects on relative mRNA expression levels were measured by reversetranscription polymerase chain reaction. The eff ect on cell invasiveness was evaluated by cell invasion assay. FUT-175at 10-5 M signifi cantly inhibited cell growth and cell invasiveness. Cell growth reduced to 47.0 ± 2.1% compared withthe control. The number of invasive cells also reduced to 16.0 ± 0.7 cells/hpf, while that of control cells was 41.4 ± 8.0cells /hpf. U-PA and PAI-1 secreted from the cells were also reduced by FUT-175 in a dose-dependent manner. Theseresults suggest that FUT-175 has the potential to act as a therapeutic agent against local growth and invasion, andfunctions by reducing PAI-1 and u-PA production of the human malignant mesothelioma(195 words) 続きを見る
58.

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Nodagashira, Tatsuya ; Odagiri, Hiroki ; Ikenaga, Shojiro-Kazunori ; Maruyama, Masateru ; Sato, Toshiyuki ; Hakamada, Kenichi
出版情報: 弘前医学.  61  pp.26-34,  2010-03-25.  弘前大学出版会
URL: http://hdl.handle.net/10129/3277
概要:  Tissue-specifi c promoter has been used for cancer-specifi c suicide gene therapy, but its transcriptionalactivity is r elatively low. For more effi cient gene therapy of HER2-expressing tumor, a double adenovirus infectionsystem was established, in which a ‘regulator’ vector carried Cre gene under the control of HER2 promoter and ‘target’vectors carried target genes activated by Cre. We constructed a Cre recombinase expression vector, AxHER2Cre, forthe ‘regulator’ vector. By the combination of this vector and AxCALNLZ, β-D-galactosidase was induced in 90% and70% of MKN7 and MDA-MB-453, HER2‒overexpressing cell lines, but only about 20% and 10% of MKN28 and MCF7,low HER2-expressing cell lines. By the quantifi cation analysis, the β-galactosidase activities induced by this systemwere comparable to those by the combination of AxCANCre and AxCALNLZ. These results indicated that Cre/loxP system under the regulation of HER2 promoter could induce effi cient gene expression, maintaining the HER2-expression specifi city. Breast cancer with HER2 overexpression is treated with trastuzumab. However, refractoryor resitance of HER2 positive breast cancer against trastuzumab becomes a severe clinical problem, recently. Thissystem seemed to be another therapeutic option. 続きを見る
59.

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Sato, Hideaki ; Sato, Masashi ; Chiba, Makie ; Ito, Kyoko ; Ito, Koichi
出版情報: 弘前医学.  61  pp.35-45,  2010-03-25.  弘前大学出版会
URL: http://hdl.handle.net/10129/3278
概要: The ability of murine allogeneic umbilical cord blood cells (UCBCs) to reconstitute the immune systemwas investigated. U CBCs obtained from fetuses of C57BL/6 (B6; H-2b) mice, which were transgenic for greenfluorescent protein (GFP), were transplanted into RAG2 (-/-) BALB/c mice (H-2d). After transplantation, flowcytometric analysis revealed successful reconstitution of phenotypically mature GFP-positive immune cells of donororigin, including T cells, B cells, monocytes, and granulocytes in the peripheral blood of the recipient mice. Analysisof functional maturation of lymphocytes revealed that 2,4,6-trinitrophenyl-keyhole limpet hemocyanin (TNP-KLH)-immunized UCBC-transplanted recipients produced both TNP-specific IgM and IgG antibodies. These resultsindicated that the recipient mice were capable of mounting antibody responses to T-dependent antigens; further, Igclass switching from IgM to IgG confi rmed that both B cells and CD4+ helper T cells derived from allogeneic UCBCswere immunologically competent. Furthermore, mice transplanted with allogeneic UCBCs accepted skin grafts fromboth B6 and BALB/c mice. However, these chimeric mice completely rejected skin grafts from third party C3H/HeJ (H-2k) mice, indicating the presence of functional CD8+ killer T cells as well as CD4+ helper T cells. In termsof potential clinical application, our results indicate that allogeneic UCBC transplantation can enable recovery of thenormal immune system in recipients. 続きを見る
60.

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Ito, Kyoko ; Masuko, Kazutaka ; Ito, Koichi
出版情報: 弘前医学.  61  pp.46-57,  2010-03-25.  弘前大学出版会
URL: http://hdl.handle.net/10129/3279
概要: Contact between dendritic cells( DCs) and resting T cells is essential for initiation of the primary immuneresponse. In this study, we examined whether neuronal leucine-rich repeat protein 3 (NLRR3), a receptor involvedin nerve system development, participates in DC-T cell binding and T-cell activation. We confirmed that NLRR3is expressed on naive T cells. NLRR3 contains an Arg-Gly-Asp (RGD) motif in its amino acid sequence, for whichseveral integrins can be considered as potential ligands. Indeed, monocyte-derived DCs expressed several integrinsthat can bind to the RGD motif. Functionally, DC-induced resting allogeneic T-cell proliferation was partially inhibitedby addition of integrin-specific antibodies and synthetic RGD peptides, indicating that RGD-containing molecules,including NLRR3 and several integrins, at least participate in the events of the initial primary immune responseinvolving naive T cells and DCs. Furthermore, DCs were shown to bind directly to NLRR3-transfected Chinesehamster ovary cells in a NLRR3-dependent manner, and the binding was removed in the presence of integrin-specifi cantibodies. These data suggest that NLRR3 plays an important role in initiation of the primary immune response. 続きを見る
61.

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Yokoyama, Hiroaki ; Saito, Shin ; Higuma, Takumi ; Hanada, Hiroyuki ; Osanai, Tomohiro ; Daitoku, Kazuyuki ; Fukuda, Ikuo ; Okumura, Ken
出版情報: 弘前医学.  61  pp.58-64,  2010-03-25.  弘前大学出版会
URL: http://hdl.handle.net/10129/3280
概要: Adipose tissue secretes various bioactive molecules (adipokines), and apelin is one kind of adipokines.Recently, it was shown that plasma apelin level is decreased in patients with chronic heart failure, and apelin mightplay an important role in the pathogenesis of cardiovascular disease. However, plasma apelin level in coronary arterydisease( CAD) or other heart disease such as valvular heart disease( VHD) has not been elucidated. We enrolled 31patients with CAD and 14 patients with VHD who underwent elective cardiac surgery. We also examined plasmaapelin level in 20 healthy subjects (Control). Blood samples were obtained before the surgery. Paired samples ofvisceral and subcutaneous adipose tissues were harvested during surgery. Plasma apelin level was lower in both CADand VHD than in Control. When compared between CAD and VHD, it was lower in CAD than in VHD, and was notaff ected by treatment with HMG-CoA reductase inhibitors (statins) which was shown to increase adiponectin level.Left ventricular ejection fraction( LVEF) was lower in CAD than in VHD. There was no correlation between plasmaapelin level and LVEF. Gene expression of apelin in visceral adipose tissue was higher than that in subcutaneousadipose tissue, but it was similar between two groups. These suggest that plasma apelin level was decreased inpatients with cardiac diseases, especially in those with CAD. Its role in the pathophysiology of CAD remains to beelucidated. 続きを見る
62.

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Lee, Sangun ; Umeda, Takashi ; Takahashi, Ippei ; Matsuzaka, Masashi ; Danjo, Kazuma ; Iwane, Kaori ; Iwasaki, Hiroki ; Nakaji, Shigeyuki
出版情報: 弘前医学.  61  pp.87-96,  2011-01-17.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/4345
概要: The changes in the anthropometric and blood biochemical parameters, neutrophil functions such asreactive oxygen species (ROS) production capability, phagocytic activity (PA) and the profile of mood state (POMS)were measured after 2-hours of judo training session for 24 male university freshmen judoists who had not done anytraining for a long period. As for neutrophil function, PA significantly decreased after the training compared with thepre-value, though ROS production capability did not change. The Depression, Tension and total mood disturbance (TMD) decreased significantly after the training. Furthermore, the change in blood sugar correlated positively withthe changes in the Depression, Fatigue and TMD. The change in creatine kinase was positively associated with thechange in the Confusion. The training negatively acted on the appearance of physiological fatigue, and positivelyacted on the appearance of mental fatigue, and some relationship between both. Furthermore, the typical responseof the neutrophil function (PA decrease and no change in ROS) does not coincide with the typical neutrophilcompensation pattern e.g. PA decrease and ROS increase may be due to the lack of training on the part of the subjects for the last 6 months. 続きを見る
63.

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Abe, Kazuhiro ; Higuchi, Tsuyoshi ; Mizunuma, Hideki ; Kakizaki, Ikuko ; Endo, Masahiko ; Suto, Shinichiro
出版情報: 弘前医学.  61  pp.97-103,  2011-01-17.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/4346
概要: The aim of study is to analyze functional sugar chains, glycosaminoglycans (GAGs) in urine frompostmenopausal women with osteoporosis. A 24-hour urine was collected from 15 osteoporotic women and normalwomen. All women were postmenopausal and aged at 60 to 70 years old. Diagnosis of osteoporosis was based onthe diagnosis criteria proposed by the Japan Osteoporosis Society after measurement of lumbar spine bone mineraldensity by dual energy X-ray absorptiometry. The urine was concentrated by dialysis and evaporation, thenprecipitated with ethanol. The precipitate was then reconstituted into NaCl solution, precipitated again by adding 10% cetylpyridinium chloride and the precipitation was used as complex GAGs fraction. The yield of complex fractionwas significantly higher in osteoporotic subjects than that in normal control. Then, the complex GAGs fraction wasanalyzed by cellulose acetate membrane electrophoresis and high performance liquid chromatography (HPLC),respectively. Cellulose acetate membrane electrophoresis has revealed that GAGs in urine contained partiallydesulfated chondroitin sulfate. However, further analysis by HPLC has shown that the excretion of desulfated GAGswas rather less in osteoporotic women, indicating that urinary GAGs fraction from osteoporotic women containsunknown acidic polysaccharides as well as GAGs. 続きを見る
64.

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大久保, 愉一 ; 松坂, 方士 ; 高橋, 一平 ; 檀上, 和真 ; 中路, 重之 ; 梅田, 孝
出版情報: 弘前医学.  61  pp.104-113,  2011-01-17.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/4347
概要: 労働者のメンタルヘルスと社会環境学的要因を調査し,メンタルヘルスに及ぼすこれらの影響を調査した.東北,北海道の労働者6310名に家族構成,生活習慣,健康度,職場環境,抑うつ度(CES-D)をアンケートで聞き取り,CES-D と他の項目の関係 を検討した.その結果,「仕事・職業満足度」「仕事裁量度」「仕事士気度」「上司関係満足度」「自己評価点」「健康度」「生活習慣点」「家族・友人満足度」で,低得点群に比較し高得点群でオッズ比が小さく,「悪対処数(問題となるストレス解消行動の数)」ではその逆であった.一方,「勤務時間」「時間外勤務」「仕事量質負担度」では有意な結果は得られなかった.以上より,わが国の労働者は地域社会・家庭のストレスを職場に持ち込み,さらにうつに対する感受性がうつ度に大きく影響していることが示唆された.また,仕事量質の影響は大きくなく,労働者のメンタルヘルス改善を考えた場合,社会精神文化を考慮した職場環境を構築することが重要と考えられた. 続きを見る
65.

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川口, 英夫 ; 青木, 昌彦 ; 畑山, 佳臣 ; 小野, 修一
出版情報: 弘前医学.  61  pp.114-121,  2011-01-17.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/4348
概要: 【目的】4D-CTを用いて呼吸性移動の線量計算に対する影響を検討した.【対象・方法】4D-CTを撮像した14例を対象に平均画像を用いて非対向6門で治療計画を作成した.計画を各呼吸位相のCTに貼り付けMU値を計算し,呼吸位相毎に平均画像のMU 値と比較した(MUdiff ).また,各門毎の変動を計算した(⊿MU).呼吸性移動をビームの平面方向と垂直方向に分離し,それぞれ⊿MUとの相関を検討した.線量計算はClarkson法(C法), superposition法(S法)の2つを用い比較した.【結果】MUdiff はC法では吸気相以外で,S法では終末吸気・呼気のみで有意差を認めた.⊿MUはC法では平面上方向・垂直方向に中等度相関を認めたが,S法では垂直方向のみに弱い相関を認めた.【結論】C法は呼吸性移動の影響を受けやすく,S法は影響が少なかった.呼吸性移動を加味した線量計算はS法が有用と考えられた. 続きを見る
66.

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Zheng, Zhongxi ; Miura, Tomisato ; Nozaka, Hiroyuki ; Takamatsu, Terumasa ; Sato, Tatsusuke
出版情報: 弘前医学.  61  pp.122-130,  2011-01-17.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/4349
概要: To date, digital pathology is based on single focal plane images, and with its rapid development, image quality and information are becoming critical concern in the field. This paper presents a new multiple focal-plane based focus image fusion algorithm to enhance the image quality. First of all, we will introduce a new focus image fusion lgorithm; next, we will demonstrate some experimental data and results on cytopathology slide images; and finally, we will verify the effectiveness of this algorithm using computer vision techniques and cytopathology diagnosis, and draw the conclusions. 続きを見る
67.

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Numazawa, Satomi ; Matsuzaka, Masashi ; Iwane, Kaori ; Inoue, Ryo ; Danjo, Kazuma ; Takahashi, Ippei ; Umeda, Takashi ; Nakaji, Shigeyuki
出版情報: 弘前医学.  61  pp.131-137,  2011-01-17.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/4350
概要: The present study investigated the relationship between obesity and atherosclerosis according to agein the general femal e population. Six hundred fifty-five females were divided into 3 different age groups and therelationship between brachial-ankle pulse wave velocity (baPWV) and various obesity indices were investigated.In the youngest age group (20-39 years), BMI, percentage body fat and abdominal circumference were positivelycorrelated with baPWV. In the middle-aged group (40-59 years), all four obesity indices (BMI, percentage bodyfat, abdominal circumference and the waist-to-hip ratio (WHR)) were positively correlated with baPWV. However,baPWV was found to be negatively correlated with BMI only in the oldest age group (60 years and over), thoughit was still positively correlated with WHR (but not abdominal circumference). The reason for this may be due to agradual reduction of body weigh caused by some lifestyle-related diseases or aging. In this study, it was confirmedthat abdominal obesity is a key indicator of arteriosclerosis, though the importance of BMI (general obesity) as anindicator may depend on the generation. Furthermore, our results suggested that abdominal circumference and WHRmay have different significance as the indicators of arteriosclerosis. 続きを見る
68.

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Yamai, Kiyonori ; Umeda, Takashi ; Matsuzaka, Masashi ; Danjo, Kazuma ; Takahashi, Ippei ; Tsuya, Ryosuke ; Hasebe, Tatsuya ; Nakaji, Shigeyuki
出版情報: 弘前医学.  61  pp.138-149,  2011-01-17.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/4351
概要: We examined the effects of vitamin C supplementation on neutrophil function during exercise loading.Neutrophil functions , namely the reactive oxygen species (ROS) production capability, neutrophil phagocytic activity(PA) and serum opsonic activity (SOA) were measured before and after a 2-hour unified loading exercise (ULE)both before and after a 7-day intensified training camp for 22 male judoists. The parameters were assessed neutrophilcount, myogenic enzymes, vitamin C in serum, SOA, PA, ROS production capability, body composition, and so on.Subjects were randomly assigned to two groups; the VC group (daily diet supplementation of 1,500 mg vitamin C)and the Control group (no vitamin C supplementation). The post-camp pre-ULE vitamin C level was higher in theVC group than in the Control group, though no such difference was seen at pre-camp. As for neutrophil function,although the typical changes seen following a single bout of normal exercise, namely an increase in SOA and ROS,and a decrease in PA, were recorded following the pre- and post-camp ULEs in both groups, significant differencein change rates were not seen between both groups. In conclusion, vitamin C supplementation had no significantinfluence on changes in neutrophil function. 続きを見る
69.

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Maruyama, Masateru ; Odagiri, Hiroki ; Ikenaga, Shojiro-Kazunori ; Nodagashira, Tatsuya ; Sato, Toshiyuki ; Hakamada, Kenichi ; Munakata, Hirofumi
出版情報: 弘前医学.  61  pp.150-158,  2011-01-17.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/4352
概要: We examined the therapeutic efficacy for the suicide gene introduction using two recombinant adenovirusvectors with HER2 promoter and Cre/loxP system in human gastric cancer cell lines, MKN-7 and MKN-28. HER2protein level was more expressed in MKN-7 than in MKN-28. Next, we constructed a Cre recombinae expressionvector in HER2-producing cell specifically, AxHER2NCre and AxCALNCD expressing cytosine deaminase (CD)gene under the control of the CAG promoter by the Cre switching system. Much higher CD messenger RNA (CDmRNA) and CD protein expression were induced in cells by the double infection method than by AxCALNCD only.Furthermore, CD mRNA and CD protein expression were induced higher in HER2-overexpressing cell line, MKN-7 than in MKN-28. We examined the efficacy of cell growth inhibition using 5-fluorocytosine (5-FC) as anti-tumorprodrug. Inhibition effect was dose-dependent at each cell line and rate was more in MKN-7 in comparison withMKN-28. This system can be applied for HER2-overexpressing cancer specific gene therapy. 続きを見る
70.

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論文
Kawaguchi, Yoko ; Hashiba, Eiji ; Kitayama, Masatou ; Hirota, Kazuyoshi
出版情報: 弘前医学.  61  pp.159-162,  2011-01-17.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/4353
概要: A 30-year-old woman underwent an emergency cesarean section because of fetal distress involveduterine rupture. As the pl acenta was firmly adhered to the uterine wall, following safe delivery, it took over one hour and more than 10000 ml blood loss until the placenta was removed. Additional blood was ordered, but there was delay in delivery. Bleeding was extremely beyond our estimation, and hardly controlled despite of transfusing1400 ml of prepared blood. With stopping operation and continuing hyperoxic ventilation, we decided to start intraoperative blood salvage. Though hemoglobin, platelet, and base excess decreased to 2.7 g/dl, 1000/μl, and -11.2,hemodynamics could be maintained with use of a blood salvage system. Salvaged blood was very helpful to manage critical hemodilution until additional blood was reached. Overall estimated blood loss was 20190 ml and massive blood transfusion was needed. The patient emerged from anesthesia with no neurological complication. Rarely but actually cesarean section resulted in life-threatening hemorrhage. Blood salvage systems is safe and useful during cesareansection. Blood salvage should be usually considered one of the suitable choices in cesarean section patients when supply of homologous blood is limited. 続きを見る
71.

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論文
Oomura, Yutaka ; Aou, Shuji ; Fukunaga, Kouji ; Moriguchi, Sigeki ; Sasaki, Kazuo
出版情報: 弘前医学.  61  pp.S1-S10,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3664
概要: Leptin is well known to be involved in the inhibition of feeding, thermogenesis, reproduction and neuroendocrine functio ns through its actions on the rodent hypothalamic receptors. Leptin facilitated the presynaptic transmitter release and postsynaptic sensitivity to the transmitters in the hippocampal CA1 neurons. Thus longterm potentiation (LTP) and the phosphorylation of Ca2+/calmodulin protein kinase II (CaMK II) were facilitated in the CA1 neurons. Therefore behavioral performance related to spatial learning and memory was improved by leptin in vivo applications. Orexin-A produced by glucose-sensitive neurons in the lateral hypothalamic area (LHA)and released during food intake facilitates feeding. Orexin-A suppressed LTP and CaMK II phosphorylation without affecting the presynaptic transmitter release. Therefore behavioral performance on learning and memory was impaired. The present studies suggest that leptin and orexin signalings in the brain may have important implications for cognitive function. 続きを見る
72.

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論文
Herman, Peter ; Sanganahalli, Basavaraju G. ; Coman, Daniel ; Blumenfeld, Hal ; Hyder, Fahmeed
出版情報: 弘前医学.  61  pp.S11-S22,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3665
概要: Neuronal activity mapping of cerebral functions using oxidative energetics has become an accepted functional magnetic re sonance imaging (fMRI) technique, termed calibrated fMRI. It requires calculation of oxygen consumption (CMRO2) from blood oxygenation level dependent (BOLD) signal using multi-modal measurements of blood flow (CBF) and volume (CBV). This approach is based on a biophysical model which describes tissue oxygen extraction at steady-state, therefore it is unclear if this conventional steady-state BOLD model can be applied transiently for calculating dynamic CMRO2 changes. In particular, it is unknown whether calculation of CMRO2 from calibrated fMRI differs between brief and long stimuli. In this study linearity was experimentally demonstrated between BOLD-related components and neural activity. We used multi-modal fMRI (at 11.7T) and neuronal signal measurements of local fi eld potential (LFP) and multi-unit activity (MUA) in α-chloralose anesthetized rats during forepaw stimulation to show that respective transfer functions (of BOLD, CBV, CBF) generated by deconvolution with LFP( or MUA) are time invariant, for events in the millisecond to minute range. Since the transfer functions are time invariant for event-related and steady-state stimuli, it is possible to use calibrated fMRI in a dynamic manner. The multi-modal results allowed assignment of a significant component of the BOLD signal that can be ascribed to CMRO2 transients. Here we discuss the importance of minimizing residual signal, represented by the diff erence between modeled and raw signals, in convolution analysis using multi-modal fMRI and neural signals. 続きを見る
73.

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論文
Yamada, Katsuya ; Yamamoto, Toshihiro ; Watanabe, Seiji ; Nishiuchi, Yuji ; Teshima, Tadashi ; Matsuoka, Hideaki ; Suga, Sechiko
出版情報: 弘前医学.  61  pp.S23-S25,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3666
概要: Glucose transport activity in mammalian cells has been monitored by radiolabeled tracers such as [14C] 2-deoxy-D-glucose . However, due to their limited spatial and temporal resolution, measuring glucose uptake in single, living cells was diffi cult. We have developed a fl uorescent D-glucose derivative, 2-[N(- 7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG), that allows a more sensitive measurement of glucose uptake in live cells. Indeed, the uptake of 2-NBDG takes place through glucose transporters (GLUTs) in a concentration-, time-, and temperature-dependent manner. Kinetic analysis revealed that apparent Km values for the uptake were similar to those reported by D-glucose and the nonmetabolizable glucose analogue, 3-O-methyl-D-glucose, found in pancreatic islet cells. This method can be combined with Ca2+ imaging and subsequent immunocytochemical identifi cation of cells. So far, 2-NBDG has been used for monitoring glucose uptake into a wide variety of mammalian cells including astrocytes and neurons. However, it has been pointed out that 2-NBDG method requires very accurate procedures, since the fl uorescence intensity is an arbitrary measure. In addition, temporal changes in health of cells in question should be verifi ed throughout the experiment by an independent way such as using patch clamp. To overcome the diffi culty, we synthesized transporter- unrecognizable glucose analogues as control for 2-NBDG uptake. These include 2-[N(- 7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-L-glucose [2-NBDLG], the antipode of 2-NBDG. A combined use of transporter-recognizable( D-isomer) and unrecognizable( L-isomer) fl uorescent analogues allows us to investigate not only net stereospecifi c transport of glucose in live cells but also ligand-transporter interactions and non-transportermediated glucose movement. 続きを見る
74.

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論文
Yamazaki, Daisuke ; Horiuchi, Junjiro ; Saitoe, Minoru
出版情報: 弘前医学.  61  pp.S26-S33,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3667
概要: Age-related memory impairment (AMI) is an important phenotype of brain aging. Understanding the molecular mechanisms und erlying AMI is important not only from a scientific viewpoint but also for the development of therapeutics that may eventually lead to developing drugs to combat memory loss. AMI has been generally considered to be an overall or nonspecifi c decay of memory processes that results from dysfunction of neural networks. However, extensive behavioral genetic characterization of AMI with Drosophila demonstrated that AMI results from disruption in specifi c memory process. In Drosophila, memory acquired after a single olfactory conditioning paradigm has three distinct phases: short-term memory (STM), middle-term memory (MTM), and longer-lasting anesthesia-resistant memory (ARM). Significantly, AMI results from the specific decay of only one memory component, amn-dependent MTM, and not other components. Since amnesiac encodes peptides that regulate adenylyl cyclase activity, these studies suggest the importance of the cAMP signaling pathway in AMI in Drosophila, a fi nding consistent with several models of AMI in mammals. In fact, hypomorphic mutations in PKA catalytic subunit signifi cantly suppress AMI. As cAMP signaling is an essential signaling for learning and memory, these studies suggest antagonistic pleiotropic eff ect of cAMP signaling. Due to its short lifespan, powerful genetics, and well-characterized and conserved pathways involved in memory and lifespan, Drosophila will be a useful model system for studying the molecular mechanisms underlying this process. 続きを見る
75.

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論文
Kato, Yukio ; Noshiro, Mitsuhide ; Fujimoto, Katsumi ; Kawamoto, Takeshi
出版情報: 弘前医学.  61  pp.S34-S42,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3668
概要: We cloned Dec1 (Differentiated embryonic chondrocyte-1) and a similar gene, Dec2, in 1997 and 2000, respectively. DEC st ructure is similar to that of HES1 and HAIRY, and we observed circadian rhythms of Dec1 mRNA levels in chondrocytes in vitro and rat liver in vivo. We then attempted to fi nd out whether these genes are implicated in the circadian pacemaker: We found that a mutation of Clock abolishes or shifts circadian expression of Dec1 and/or Dec2 in most tissues, including the suprachiasmatic nucleus( SCN), and that DEC1 and DEC2 modulate their own circadian expression and that of some other clock genes by auto-regulatory and interlocked feedback mechanisms. Studies on defi ciencies of these genes indicate that Dec1 and Dec2 play roles in the phase shift and maintenance of accurate circadian rhythms and clock outputs to some physiological activities. We speculate that clock genes, including Dec, are involved in the pathology of various diseases and aging. 続きを見る
76.

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論文
Kijima, Hiroshi ; Sato, Fuyuki ; Bhawal, Ujjal Kumar ; Kawamoto, Takeshi ; Fujimoto, Katsumi ; Imaizumi, Tadaatsu ; Imanaka, Tadanobu ; Kondo, Jun ; Koyanagi, Satoru ; Noshiro, Mitsuhide ; Yoshida, Hidemi ; Kato, Yukio
出版情報: 弘前医学.  61  pp.S43-S52,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3669
概要: The circadian rhythms in mammals are regulated by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus . Five clock-gene families, i.e. Clock, Bmal, Per, Cry and Dec, have been found to be involved in a transcription-translation feedback loop that generates the circadian rhythm at the intracellular level. In this study, we examined functional analysis of the Dec gene. DEC1 and DEC2 are basic-helix-loop-helix (bHLH) transcription factors, involved in cellular diff erentiation, responses to hypoxia, and circadian rhythms. We recently showed that the expression of DEC1 and DEC2 was upregulated by hypoxia, however, the functions of these two factors under hypoxic conditions have not been elucidated in detail. It is well established that the expression of vascular endothelial growth factor (VEGF) is upregulated by hypoxia, and the expression of VEGF in response to hypoxia depends on transcriptional activation by a heterodimer comprising hypoxia-inducible factor 1 α (HIF-1α) and arylhydrocarbon receptor nuclear translocator 1 (ARNT1). In the present study, we showed that DEC2, but not DEC1, suppressed VEGF gene expression under hypoxic conditions. DEC2 protein was co-immunoprecipitated with HIF-1α but not with ARNT1. The binding of HIF-1α to the hypoxia response element( HRE) in the VEGF promoter was decreased by DEC2 overexpression, and increased by DEC2 knockdown. We also showed that the circadian expression of VEGF showed a reciprocal pattern to that of DEC2 in cartilage. DEC2 had a circadian oscillation in implanted Sarcoma 180 cells. We conclude that DEC2 negatively regulates VEGF expression and plays an important role in the pathological conditions in which VEGF is involved. 続きを見る
77.

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論文
Wakamori, Minoru ; Uriu, Yoshitsugu ; Miki, Takafumi ; Kiyonaka, Shigeki ; Mori, Yasuo
出版情報: 弘前医学.  61  pp.S53-S62,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3670
概要: Active zones are highly specialized sites for release of neurotransmitter in presynaptic nerve terminals. The spacing be tween voltage-dependent calcium channels( VDCCs) and synaptic vesicles at active zones is thought to infl uence the dynamic properties of synaptic transmission. Recently we have demonstrated a novel molecular interaction between VDCCs and an active zone scaffolding protein, rab3-interacting molecule 1 (RIM1). The RIM1 induced a pronounced deceleration of inactivation rate and a depolarizing shift of the inactivation curve of recombinant P/Q-type VDCC expressed as α1Aα2/δβ1a complex in baby hamster kidney cells. During 2-s voltagedisplacement to -30 mV, which is the threshold of the P/Q-type VDCC activation, almost all channels were inactivated in the absence of the RIM1 (closed-state inactivation), but less than 20% of the channels were inactivated in the presence of the RIM1. Thus, the RIM1 coordinates calcium signaling and spatial organization of molecular constituents at presynaptic active zone. A mutation has been identified for an autosomal dominant cone-rod dystrophy CORD7 in the RIM1 gene. Interestingly, the aff ected individuals showed signifi cantly enhanced cognitive abilities across a range of domains. The mouse RIM1 arginine-to-histidine substitution (R655H), which corresponds to the human CORD7 mutation, modifi es RIM1 function in regulating VDCC currents elicited by the P/Q-type Cav2.1 and L-type Cav1.4 channels. The data can raise an interesting possibility that CORD7 phenotypes including retinal defi cits and enhanced cognition are at least partly due to altered regulation of presynaptic VDCC currents. 続きを見る
78.

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論文
Itoh, Ken ; Kosaka, Kunio ; Mimura, Junsei ; Satoh, Takumi
出版情報: 弘前医学.  61  pp.S63-S69,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3671
概要: Electrophilic compounds, such as curcumin and neurite outgrowth-promoting prostaglandins (NEPPs), have been known to enh ance neurite outgrowth in the presence of small amounts of nerve growth factor (NGF)in PC12 cells. However, the redox-sensitive molecular target for enhanced neurite outgrowth is largely unknown. NGF exerts its function by binding to the cell surface tyrosine kinase receptor, TrkA. Recently, Shibata et al. reported that PTP1B catalyses the dephosphorylation of TrkA. They also demonstrated that an electrophile from Japanese horseradish Wasabi, 6-methylsulfi nylhexyl isothiocyanate (6-HITC), inactivates PTP1B causing sustained phosphorylation and activation of TrkA and promoting neural diff erentiation of PC12 cells. Further, we recently discovered that carnosic acid (CA), a catechol-type electrophilic compound that is a major ingredient in the herb rosemary, strongly promotes neurite outgrowth of PC12h cells by activating the redox-sensitive transcription factor, Nrf2. Activation of Nrf2 by CA caused a marked induction of p62/ZIP, an important signaling scaff old protein for NGF signaling. Unexpectedly, NGF also activates Nrf2, which is essential for NGF-mediated neural diff erentiation. Thus, electrophiles may enhance neural diff erentiation by both TrkA-dependent and -independent mechanisms. 続きを見る
79.

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論文
Nakabeppu, Yusaku ; Sheng, Zijing ; Oka, Sugako
出版情報: 弘前医学.  61  pp.S70-S79,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3672
概要: Oxidative DNA lesions, such as 8-oxoguanine( 8-oxoG), accumulate in nuclear and mitochondrial genomes during aging, and such accumulation is known to dramatically increase in patient brains with Parkinson’s disease( PD)or Alzheimer’s disease( AD). To counteract oxidative damage to nucleic acids, human and rodents are equipped with three distinct enzymes, MTH1, OGG1 and MUTYH. MTH1 hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP to their monophosphate forms. OGG1 and MUTYH are DNA glycosylases excising 8-oxoG opposite cytosine and adenine opposite 8-oxoG in DNA, respectively. We showed a signifi cant increase in 8-oxoG in cellular DNA as well as altered expression of MTH1, OGG1 and MUTYH in PD and AD brains, suggesting that the buildup of 8-oxoG may cause neurodegeneration. We have shown that buildup of 8-oxoG in either nuclear or mitochondrial DNA causes MUTYH-dependent cell death through two distinct pathways, and that accumulation of oxidized nucleotides in nucleotide pools also causes MUTYH-dependent cell death. MTH1-null mice exhibited an increased buildup of 8-oxoG in striatal mitochondrial DNA followed by more extreme neuronal dysfunction after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, while hMTH1-transgenic mice are resistant to a mitochondrial neurotoxin, 3-nitropropionic acid (3-NP)-induced striatal degeneration, in comparison to wild-type mice. We found that doubleknockout (DKO) mice lacking OGG1 and MTH1, and to a lesser extent OGG1-KO mice, are signifi cantly sensitive to 3-NP-induced striatal degeneration, in comparison to MTH1-KO or wild-type mice, while MUTYH defi ciency increases resistance to 3-NP in OGG1-KO or wild-type background. We thus demonstrated that 8-oxoG accumulated in brain genomes causes neurodegeneration in a MUTYH-dependent manner, and which is effi ciently suppressed by MTH1 and OGG1. 続きを見る
80.

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Wakabayashi, Koichi ; Miki, Yasuo ; Tanji, Kunikazu ; Mori, Fumiaki
出版情報: 弘前医学.  61  pp.S80-S88,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3673
概要: α-Synucleinopathies comprise a group of neurodegenerative disorders that share α-synuclein (αS)accumulation in selected vulnerable neurons and glia, i.e. Parkinson’s disease (PD), dementia with Lewy bodies and multiple system atrophy( MSA). The histological hallmark of PD is neuronal αS aggregates called Lewy bodies( LBs). LB formation has been considered to be a marker for neuronal degeneration, because neuronal loss is found in the predilection sites for LBs. However, recent studies have suggested that oligomers and protofi brils of αS are cytotoxic, and that LBs may represent a cytoprotective mechanism in PD. The histological hallmark of MSA is αS aggregates in the oligodendrocytes referred to as glial cytoplasmic inclusions( GCIs). αS inclusions are also found in the neuronal somata, axons and nucleus. At present, two degenerative processes have been considered in this disease; one is due to the widespread occurrence of GCIs associated with oligodendroglia-myelin degeneration, and the other is due to the aggregation of αS in neurons in several brain regions. These two processes might synergistically cause neuronal depletion in MSA. 続きを見る
81.

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Tanji, Kunikazu ; Mori, Fumiaki ; Wakabayashi, Koichi
出版情報: 弘前医学.  61  pp.S89-S96,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3674
概要: NEDD8 ultimate buster-1 (NUB1) is a potent down-regulator of the ubiquitin-like protein NEDD8, because it directly inter acts with NEDD8 and targets it and its conjugates to the 26S proteasome for proteolytic degradation. Recently, we found that NUB1 physically interacts with synphilin-1 through its NEDD8-binding site, implying that NUB1 also targets synphilin-1 to the 26S proteasome for proteolytic degradation. Synphilin-1 is an α-synuclein-interacting protein and is a major component of inclusion bodies found in the brains of patients with neurodegenerative α-synucleinopathies, including Parkinson’s disease. In our recent studies, we immunostained sections of brains from patients with Parkinson’s disease and other α-synucleinopathies and demonstrated that NUB1, as well as synphilin-1, accumulates in the inclusion bodies. To defi ne the role of NUB1 in the formation of these inclusion bodies, we performed a co-transfection assay using cultured HEK293 cells. This assay showed that NUB1 suppresses the formation of synphilin-1-positive inclusions. Further biochemical assays revealed that NUB1 overexpression leads to the proteasomal degradation of synphilin-1. These results and our previous observations suggest that NUB1 indeed targets synphilin-1 to the proteasome for its effi cient degradation, which, because of the resultant reduction in synphilin-1, suppresses the formation of synphilin-1-positive inclusions. In addition to these basic science aspects, our fi ndings on NUB1 have two important bearings clinically. First, they suggest that NUB1 could serve as a neuropathological marker in patients with α-synucleinopathies because it is strongly accumulated with synphilin-1 in the inclusions of their brain cells. Second, they suggest that NUB1 could be a potential therapeutic target for α-synucleinopathies. 続きを見る
82.

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Younkin, Steven
出版情報: 弘前医学.  61  pp.S97-S104,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3675
概要: Like my presentation, this article focuses exclusively on the role of the amyloid ß protein in Alzheimer’s Disease. I fi rst provide an overview of the research fi ndings that have made Aß, more specifi cally Aß42, a compelling therapeutic target for AD that is being pursued by virtually all pharmaceutical companies. I then discuss specifi capproaches to Aß-centered therapy. It is widely believed that the best way to manage AD will be through preventive therapy. To implement preventive therapy, it is critically important to be able to identify normal subjects who are at imminent risk for AD. In the last part of this article, I review recent evidence indicating that the measurement of Aß40 and Aß42 in plasma may be useful for identifying those normal subjects who will develop AD. 続きを見る
83.

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Mori, Hiroshi ; Tomiyama, Takami ; Ishibashi, Kennichi ; Ohnishi, Kiyouhisa ; Teraoka, Rie ; Fukushima, Akiko ; Takuma, Hiroshi ; Shimada, Hiroyuki ; Ataka, Suzuka ; Umeda, Tomohiro ; Kitajima, Erika ; Fujita, Yuki ; Yamashita, Yuki ; Yamamoto, Keiichi ; Miki, Takami ; Matsuyama, Shogo ; Iso, Hiroyuki ; Nagata, Tetsu ; Nishizaki, Tomoyuki ; Wada, Yasuhiro ; Yoshioka, Eito ; Watanabe, Yasuyoshi
出版情報: 弘前医学.  61  pp.S105-S110,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3676
概要: Alzheimer's disease (AD) is the major and common disease usually for aged people to show progressive neurodegenerative d isorder with the dementia. Amyloid-beta (also β-protein and referred here to as Aβ) is a wellestablished seminal peptide in AD that is produced from the amyloid precursor protein (APP) by consecutive digestions with β-secretase of BACE and gamma-secretase of the presenilin complex. Abnormal cerebral accumulation of Aβ such as insoluble fi brils in senile plaques and cerebral amyloid angiopathy (CAA) are observed as a neuropathological hallmark of AD. In contrast to such insoluble fi brillary Aβ, a soluble oligomeric complex is discussed as ADDLs, Aβ oligomer, low-n oligomer Aβ, Aβ*56 or so. Despite their diff erent names, it is proposed as the current hypothesis that oligomeric Aβ is the direct molecule to cause synaptic toxicity and cognitive dysfunction in the early stages of AD. We identifi ed a novel APP mutation (E693delta; referred to as the Osaka mutation) in a pedigree with probable AD resulting in a variant Aβ lacking glutamate at position 22. Based on theoretical prediction and in vitro studies on synthetic mutant Aβ peptides, the mutated Aβ peptide showed a unique aggregation property of enhanced oligomerization but no fi brillization. This was further confi rmed by PiB-PET analysis on the proband patient. Collectively together, we conclude that the Osaka mutation is the fi rst human evidence for the hypothesis that oligomeric Aβ is involved in AD. 続きを見る
84.

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論文
Ghiso, Jorge ; Tomidokoro, Yasushi ; Revez, Tamas ; Frangione, Blas ; Rostagno, Agueda
出版情報: 弘前医学.  61  pp.S111-S124,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3677
概要: Cerebral amyloid angiopathy (CAA) is increasingly recognized as a major contributor of Alzheimer’s disease( AD) pathogen esis. To date, vascular deposits and not parenchymal plaques appear more sensitive predictors of dementia. Amyloid deposition in and around cerebral blood vessels plays a central role in a series of response mechanisms that lead to changes in the integrity of the blood-brain barrier, extravasations of plasma proteins, edema formation, release of inflammatory mediators and matrix metalloproteases which, in turn, produce partial degradation of the basal lamina with the potential to develop hemorrhagic complications. The progressive buildup of amyloid deposits in and around blood vessels chronically limits blood supply and causes focal deprivation of oxygen, triggering a secondary cascade of metabolic events several of which involve the generation of nitrogen and oxygen free radicals with consequent oxidative stress and cell toxicity. Many aspects of CAA in early- and lateonset AD ‒the special preference of Aβ40 to deposit in the vessel walls, the favored vascular compromise associated with many Aβ genetic variants, the puzzling observation that some of these vasculotropic variants solely manifest with recurrent hemorrhagic episodes while others are mainly associated with dementia‒ await clarifi cation. Non-Aβ cerebral amyloidoses reinforce the viewpoint that plaque burden is not indicative of dementia while highlighting the relevance of non-fi brillar lesions and vascular involvement in the disease pathogenesis. The lessons learned from the comparative study of Aβ and non-Aβ cerebral amyloidosis provide new avenues and alternative models to study the role of amyloid in the molecular basis of neurodegeneration. 続きを見る
85.

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Carrasquillo, Minerva M. ; Zou, Fanggeng ; Pankratz, V. Shane ; Wilcox, Samantha L. ; Ma, Li ; Walker, Louise P. ; Younkin, Samuel G. ; Younkin, Curtis S. ; Younkin, Linda H. ; Bisceglio, Gina D. ; Ertekin-Taner, Nilufer ; Crook, Julia E. ; Dickson, Dennis W. ; Peterson, Rnald C. ; Graff-Radford, Neill R. ; Younkin, Steven G.
出版情報: 弘前医学.  61  pp.S125-S134,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3678
概要: By analyzing late onset Alzheimer’s disease (LOAD) in a genome wide association study of 3 American Caucasian series and evaluating the 25 SNPs with most significant allelic association in 4 additional series, we identifi ed a SNP (rs5984894) on Xq21.3 in PCDH11X that is strongly associated with LOAD in American Caucasians (total n=4,855; AD:2,391; control:2,464). Analysis of rs5984894 by logistic regression using sex as a covariate gave a global p value of 3.9 x 10-12 in the combined series. Odds ratios were 1.75( 95% CI 1.42-2.16) for female homozygotes (P=2.0x10-7) and 1.26 (95% CI 1.05-1.51) for female heterozygotes (P=0.01) compared to female non-carriers. For male hemizygotes (P=0.07) compared to male non-carriers the odds ratio was 1.18 (95% CI 0.99-1.41). The eff ect of this variant was dose dependent, as females homozygotes for the minor allele were at signifi cantly greater risk than heterozygous females and hemizygous males. We tested additional variants in PCDH11X for association with LOAD. One of these variants, rs2573905, showed association with LOAD similar to that for rs5984894, albeit with a slightly more significant p-value (5.4x10-13). This is not surprising since these two variants are in near perfect linkage disequilibrium (r2 = 0.98, D’ = 0.99), and the minor allele of these two SNPs occur on the same haplotype. However, rs2573905 is in a sequence that has been evolutionarily conserved between human and mice, with 70% sequence identity over 100bp, suggesting a possible functional role for this SNP. Joint analysis of APOE and rs2573905 genotypes showed that 75 women with LOAD (4.9%) were homozygous both for APOE e4 and for rs2573905 whereas only 2 unaff ected women (0.15%), both age 73, were double homozygotes. These fi nding suggest that the double homozygote may be fully penetrant in women over the age of 73 and that this combination may account for ~5% of the AD that occurs in women. 続きを見る
86.

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論文
Shoji, Mikio
出版情報: 弘前医学.  61  pp.S135-S141,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3679
概要: Antibodies to amyloid β protein( Aβ) are present naturally or after Aß vaccine therapy in human plasma. To clarify their clinical role, we examined plasma samples from 113 patients with Alzheimer’s disease( AD) and 205 normal controls using the tissue amyloid plaque immunoreactivity (TAPIR) assay. A high positive rate of TAPIR was revealed in AD (45%) and age-matched controls (41%), however, no signifi cance was observed. No signifi cant difference was observed in the MMS score or disease duration between TAPIR-positive and negative samples. TAPIR-positive plasma reacted with the Aß40 monomer and dimer, and the Aβ42 monomer weakly, but not with the Aβ42 dimer. TAPIR was even detected in samples from young normal subjects and young Tg2576 transgenic mice. Although the Aβ40 level and Aβ40/42 ratio increased, and Aβ42 was significantly decreased in plasma from AD groups when compared to controls, no signifi cant correlations were revealed between plasma Aß levels and TAPIR grading. Thus an immune response to Aβ40 and immune tolerance to Aβ42 occurred naturally in humans without a close relationship to the Aβ burden in the brain. Clarifi cation of the mechanism of the immune response to Aβ42 is necessary for realization of an immunotherapy for AD. 続きを見る
87.

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Shimamura, Norihito ; Ohkuma, Hiroki
出版情報: 弘前医学.  61  pp.S142-S146,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3680
概要: We developed a novel trans-femoral artery approach to the rat middle cerebral artery occlusion model (TF-MCAO) without s acrifi cing the external carotid artery (ECA) with/without the pterygopalatine artery, which is important for chewing food. To make the TF-MCAO we fi rst dissect the left common carotid artery( CCA), ECA, and internal carotid artery( ICA). Transient occlusion clips are applied to the proximal ECA and the pterygopalatine artery; we never sacrifi ce the ECA branch. A 24-gage catheter is inserted into the left femoral artery. We insert a slightly bent 0.014 inch hydrophilically-coated guide wire via a haemostasis valve. Anatomically, the left common carotid artery is located rostral to the descending aorta, permitting a straight-forward, blind approach to the CCA. The guide wire is gently advanced about 17 mm from the bifurcation of the CCA until slight resistance is encountered. The guide wire and temporary occlusion clips are withdrawn after 90 minutes. Rats were sacrifi ced 24h after reperfusion. Eleven rats were examined. One rat died before occlusion due to deep anesthesia. The success rate for producing infarction was 80%. The mean infarction volume of the basal ganglia was 94.4 ㎣ ± 9.4 se and mean infarction volume of the cerebral cortex was 124.2 ㎣ ± 21.6 se. No rat died due to cerebral infarction and no rat suff ered subarachnoid hemorrhage. We conclude that TF-MCAO was useful for producing a cerebral infarction. 続きを見る
88.

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Yoshida, Hidemi ; Mimura, Junsei ; Imaizumi, Tadaatsu ; Matsumiya, Tomoh ; Ishikawa, Akira ; Metoki, Norifumi ; Tanji, Kunikazu ; Ota, Ken ; Kosaka, Kunio ; Itoh, Ken ; Satoh, Kei
出版情報: 弘前医学.  61  pp.S147-S156,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3681
概要: Optimization of neuronal function and survival is an important goal in the treatment of cerebrovascular diseases in orde r to avoid or improve devastating long-term sequelae. Nerve growth factor (NGF) is essential for neuronal growth and survival in the central nervous system (CNS). Vascular endothelial growth factor (VEGF) is a potent mitogen specifi c for endothelial cells and a stimulator of neovascularization. VEGF also enhances vascular permeability, which may promote the development of brain edema during cerebral ischemia. These molecules aff ect the outcome of ischemia/reperfusion injury in the CNS. Edaravone, a brain-penetrant, free radical scavenger, is known to ameliorate postischemic neuronal dysfunction. Transcription factor Nrf2( nuclear factor-erythroid 2-related factor 2), a master regulator of antioxidant responses, plays an important role in the coordinated expressions of stress-inducible genes. Astrocytes express various genes involved in the regulation of neuronal functions, and the regulation of astrocyte gene expressions may be a potential therapeutic target in brain injury. This review aims to appraise the eff ects of radical scavenger edaravone and a natural Nrf2-inducer as neuroprotective agents in human astrocytes, particularly under an experimental model for hypoxia/reoxygenation. 続きを見る
89.

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Cahill, Julian ; Zhang, John H.
出版情報: 弘前医学.  61  pp.S157-S163,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3682
概要: Background ̶Subarachnoid hemorrhage (SAH) remains a disease without any definitive treatment options. Research, to date, has concentrated on the pathophysiology of vasospasm. Recent evidence supports the concept of Early Brain Injury (EBI), a phenomena which may help to explain the complex pathophysiology seen in patients after a SAH. Summary ̶EBI aims to describe the pathophysiological events that occur in the brain within the first seventy two hours after a SAH, before the onset of vasospasm. A number of pathways have been identifi ed which may play a role in the etiology of EBI. This review provides a brief synopsis of EBI and its implications for the future. Conclusions ̶EBI may represent a key event in the development of both vasospasm and Delayed Ischemic Neurological Deficit (DIND) after subarachnoid hemorrhage. Additional studies are required to determine the pathophysiology of EBI and to examine its role as a possible precursor to both vasospasm and DIND. 続きを見る
90.

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Urade, Yoshihiro
出版情報: 弘前医学.  61  pp.S164-S173,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3683
概要: Prostaglandin( PG) D2 is the most potent endogenous sleep-promoting substance thus far reported and its sleep-inducing m echanism is the best characterized at the molecular level. PGD2 is produced by lipocalin-type PGD synthase (L-PGDS) localized in the leptomeninges, choroid plexus, and oligodendrocytes in the brain and is secreted into the cerebrospinal fluid as a sleep hormone. PGD2 stimulates DP1 receptors localized in the arachnoid membrane at the basal forebrain to release adenosine as a paracrine sleep-promoting molecule, which activates adenosine A2A receptor-expressing neurons located in the basal forebrain. These cells subsequently excite the sleep-active neurons in the ventrolateral preoptic area and concomitantly suppress the tuberomammillary nucleus, a histaminergic arousal center, through GABAergic and galaninergic inhibitory projection, to induce sleep. The administration of a PGD synthase inhibitor (SeCl4), DP1 antagonist (ONO-4127Na) or adenosine A2 receptor antagonist (caffeine) induces insomnia, indicating that the PGD2-adenosine system is crucial for the maintenance of physiological sleep. 続きを見る
91.

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Yamazaki, Yoshihiko ; Hozumi, Yasukazu ; Kaneko, Kenya ; Fujiwara, Hiroki ; Kato, Hiroshi ; Fujii, Satoshi
出版情報: 弘前医学.  61  pp.S174-S180,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3684
概要: Action potentials are the fundamental signals for relaying information from one region to another in the nervous system. Action potentials are propagated along axons without decrease of their amplitudes and are conducted with constant velocity depending on axonal diameter and myelin. It is considered that the modulation of firing patterns of action potentials in the neural circuit infl uences the information processing in the brain. We investigated the modulatory eff ects of glial cells on the fi ring pattern and the axonal conduction of action potentials using rat hippocampal slice preparation. In our previous study, we focused on interneuron / perineuronal glial cell pairs in CA1 region and reported that perineuronal glial cells could be classifi ed into two groups, one group belong astrocytes (perineuronal astrocytes) and the other group oligodendrocytes (perineuronal oligodendrocytes), based on their membrane properties and immunohistochemical study. Direct depolarization of perineuronal astrocytes modulated the directly induced fi ring pattern of the interneuron, with initial facilitation and subsequent suppression. We also studied the oligodendrocytes in the alveus and examined their modulatory effects on the conduction of action potentials along axons of CA1 pyramidal cells. Direct repetitive depolarization of oligodendrocytes shortened the latencies of action potentials evoked by antidromic stimulation. These results indicate that glial cells infl uence the firing pattern and axonal conduction of action potentials, and that their effects involve both facilitation and suppression. 続きを見る
92.

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Masamoto, Kazuto ; Obata, Takayuki ; Kanno, Iwao
出版情報: 弘前医学.  61  pp.S181-S186,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3685
概要: Cerebral blood flow is tightly regulated, and local metabolic demands are met by adjustments to the regional density of microvascular networks and by temporal and spatial changes in microvascular blood flow. Cerebral blood flow regulation may involve communication between and across the vascular cells and neural or glial cells in either rapid or slow conduits. In the present study, we report distinct diff erences between the dynamic reactions of cerebral arterial networks in cortical surface and in intracortical tissue regions in response to sensory stimulation. Using confocal and multi-photon excitation laser scanning fluorescence microscopy, we imaged the cortical surface and subsurface vascular networks in the somatosensory cortex of isoflurane-anesthetized rats. Changes in lumen diameter were imaged at a rate of 13 frames per second with a fi eld of view of 512 by 512 pixels. We consistently observed a stimulus-dependent increase in the lumen diameter of arterial networks in both cortical surface and subsurface regions. The onset time of vasodilation was observed to be ~0.8 sec for the subsurface arterioles( <40 μm), which was signifi cantly shorter than the ~1.1 sec vasodilation onset time of the surface arteries (20-120 μm). The peak dilation accounted for 10% of the pre-stimulus baseline diameter. Further, the propagation of surface arterial vasodilation increased in a stimulus-dependent manner. The results indicate that global vasodilation of upstream parent arteries may be necessary to prevent “blood steal” by inactive regions nearby. Further studies are needed to elucidate the physiological mechanisms underlying the propagation of vasodilation induced by neural stimulation. 続きを見る
93.

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Yamamoto, Toshihiro ; Nishiuchi, Yuji ; Teshima, Tadashi ; Watanabe, Seiji ; Suga, Sechiko ; Matsuoka, Hideaki ; Yamada, Katsuya
出版情報: 弘前医学.  61  pp.S187-S191,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3686
概要: D-Glucose is one of the most important energy sources for the survival of various organisms, from E. coli to mammals. Fo r live-cell monitoring of glucose uptake at the single-cell level, a fl uorescent D-glucose derivative 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4- yl)amino]-2-deoxy-D-glucose [2-NBDG], which we developed, has been widely used in various research fi elds. For the last ten years, however, researchers have awaited an optical control substance for evaluating the extent of non-specifi c adsorption of 2-NBDG upon plasma membrane and/or the rate of unhealthy 2-NBDG uptake through partially( or transiently) damaged membrane. Here we introduce a fluorescent L-glucose derivative, 2-[N(- 7-Nitrobenz-2-oxa- 1,3-diazol-4-yl)amino]- 2-deoxy-Lglucose [2-NBDLG]. L-Glucosamine is a key intermediate toward the synthesis of 2-NBDLG, but not commercially available. Although a few papers on the synthesis of L-glucosamine have been reported, a new synthetic method of L-glucosamine should be absolutely required in practical view of optical purity and preparative scale. We converted commercially available L-mannose into desired L-glucosamine by 10 steps in 14% of overall yield. The 1H-NMR data of synthetic L-glucosamine were completely identical with those of commercially available D-glucosamine. On the other hand, optical purity of L-glucosamine was confi rmed by comparison of specifi c rotation with that of D-glucosamine. L-Glucosamine thus obtained was coupled with NBD-halide to give 2-NBDLG. Use of transporterrecognizable (D-isomer) and unrecognizable (L-isomer) fluorescent analogues combined with real-time confocal microscopy, should provide valuable information on dynamism of glucose transport. 続きを見る
94.

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Takuwa, Hiroyuki ; Masamoto, Kazuto ; Obata, Takayuki ; Kanno, Iwao
出版情報: 弘前医学.  61  pp.S192-S196,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3687
概要: The mechanism regulating cerebral blood fl ow (CBF) during brain function (neurovascular coupling)has been widely invest igated in animals under anesthetized conditions, though anesthesia is known to greatly aff ect neurovascular physiology. The present study aims to develop a novel model for neurovascular coupling studies in awake-behaving mice. Male C57BL/6J mice were initially anesthetized with isofl urane in preparation for attaching the study apparatus to the head. The animal was tethered to the study apparatus but allowed to move spontaneously on a floated ball. The animal behavior and regional CBF in the somatosensory barrel cortex were simultaneously measured with optical motion sensor and laser-Doppler fl owmetry (LDF), respectively. Anesthesia was discontinued during recovery, while whisker stimulation (frequency 10 Hz and duration 10 or 20 sec) was induced at either the contralateral or ipsilateral side of the LDF recording site. During the experiments, the animals showed no signs of struggling against the head restraint. The intensity of baseline CBF was higher while the animal was under 2% isoflurane aesthesia than it was after anesthesia was stopped. CBF response to stimulation was not observed under anesthesia. After the animal was recovered from anesthesia, an increase in CBF (34 ± 18%) was observed during contralateral stimulation but not during ipsilateral stimulation. The fl uctuation levels of CBF baseline during resting and walking conditions were ±2.7% and ±3.5%, respectively. We observed that these fl uctuations were not due to vibration noises caused by such as air-puff and animal motion in our experimental conditions. 続きを見る
95.

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Munakata, Akira
出版情報: 弘前医学.  61  pp.S197-S203,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3688
概要: OBJECTIVE: It is hypothesized that free radical reactions evoked by oxyhemoglobin (oxyHb) cause cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH), even though the detailed mechanisms have not yet been fully established. The aims of this study were thus to investigate, through the use of the doublehemorrhage rabbit model, the possibility that using a potent free radical scavenger, edaravone, will show amelioration of cerebral vasospasm, and to delineate the mechanism of signal transduction that causes cerebral vasospasm.METHODS: In the SAH group, SAH was simulated using the double-hemorrhage rabbit model. In the treatment group, edaravone (0.6 mg/kg) was injected into the central ear vein. Ninety-six hours after SAH, the basilar artery was excised. The degree of cerebral vasospasm was evaluated by measuring the diameter of each basilar artery, and the expression of Rho-kinase in the vascular wall was examined by Western blotting. RESULTS: The diameter of the basilar artery in the edaravone-treated group was 0.71 ± 0.06 mm, which was statistically signifi cantly larger than that in the nontreated SAH group (0.50 ± 0.03 mm; P < 0.01). The expression of Rho-kinase in the edaravonetreated group was statistically signifi cantly reduced in comparison to that of the nontreated SAH group (P < 0.01).CONCLUSION: Results from this study indicate that edaravone may potentially serve as an agent in the prevention of cerebral vasospasm in patients after SAH. In addition, it might be suggested that the free radical reaction mediated by oxyHb is concerned with the regulation of the Rho/Rho-kinase pathway. 続きを見る
96.

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Zhang, Hai-xin ; Tanji, Kunikazu ; Yoshida, Hidemi ; Hayakari, Makoto ; Mori, Fumiaki ; Wakabayashi, Koichi
出版情報: 弘前医学.  61  pp.S204-S210,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3689
概要: TDP-43 proteinopathy (amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclus ions) is a newly categorized group of neurodegenerative disorders characterized by abnormal accumulation and mislocalization of nuclear TDP-43 protein in the neuronal cytoplasm. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is non-enzymatically produced from PGD2, and plays roles in infl ammation and oxidative stress responses. Indeed, 15d-PGJ2 is up-regulated in the spinal motor neurons in ALS. In this study, biochemical and fluorescent staining analyses showed that 15d-PGJ2 modifi es expression, solubility, and subcellular localization of TDP-43. This alteration was at least partly related to a cyclopentenone ring structure containing an electrophilic carbon of 15d-PGJ2, because 15d-PGJ2 analogue, which lacks an cyclopentenone ring structure, had almost no eff ect on TDP-43 protein. Finally in vitro binding experiment indicated that 15d-PGJ2 is covalently bound to TDP-43 protein. These fi ndings suggest that a sustained high level of 15d-PGJ2 is involved in the pathogenesis of neurodegenerative disorders related to abnormal TDP-43 protein. 続きを見る
97.

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Mori, Fumiaki ; Tanji, Kunikazu ; Miki, Yasuo ; Wakabayashi, Koichi
出版情報: 弘前医学.  61  pp.S211-S214,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3690
概要: Cystatin C (CC), a cysteine protease inhibitor involved in protein degradation, is a marker of Bunina bodies in lower mo tor neurons in amyotrophic lateral sclerosis (ALS). TDP-43-immunoreactive inclusions are also histological hallmark of ALS. However, immunohistochemical localization of CC in ALS motor neurons with or without inclusions is uncertain. Recently, we demonstrated that the majority of anterior horn cells showed moderate to intense immunoreactivity for CC in controls and that CC immunoreactivity was severely decreased in anterior horn cells in ALS. The proportion of CC-immunolabeled anterior horn cells was reduced regardless of whether those neurons contained Bunina bodies or not. In contrast, the proportion of CC-immunolabeled anterior horn cells was signifi cantly reduced owing to the presence of TDP-43 inclusions. These fi ndings suggest that the formation of TDP-43 inclusions, but not of Bunina bodies, reduces the content of CC in spinal motor neurons and that perturbations in endogenous levels of CC in neurons may participate in neurodegenerative process in ALS. 続きを見る
98.

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Hu, Dong-Liang ; Omoe, Katsuhiko ; Sashinami, Hiroshi ; Shinagawa, Kunihiro ; Nakane, Akio
出版情報: 弘前医学.  61  pp.S215-S223,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3691
概要: Background. Staphylococcal enterotoxins (SEs) are the most common cause of food-borne diseases and toxic shock syndrome throughout the world. However, little is known about the mechanism of emesis induced by SEs and no vaccine that prevents SE-induced emesis has been described. Methods. A nontoxic mutant SEA, SEAD227A, was constructed by site-directed mutagenesis and purified from Escherichia coli expression system. House musk shrews, a small emetic animal model, were immunized with SEAD227A and then challenged with wild-type SEA. SEA-induced emesis was recorded for 3 h. Antibody production was analyzed by gel double-immunodiff usion assay. Neutralizing activities of the antibodies to superantigenic and emetic activities were analyzed in vitro and in vivo. Results. SEAD227A was devoid of both superantigenic and emetic activities, but still retained its immunological activity. Immunization with SEAD227A strongly induced specifi c antibody production and signifi cantly provided the protection against SEA-induced emesis. The antibodies from immunized shrews markedly inhibited the SEA-induced proliferation of spleen cells and also significantly ablated the SEA-induced vomiting in the animals. Conclusions. These results suggest that vaccination with SEAD227A devoid of toxic properties provides protection against SEAinduced emesis. This nontoxic mutant and its specifi c antibodies might be useful in the prevention and treatment of staphylococcal food poisoning 続きを見る
99.

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Sashinami, Hiroshi ; Hu, Dong-Liang ; Li, Sheng-Jun ; Mitsui, Toshihito ; Hakamada, Kenichi ; Ishiguro, Yoh ; Fukuda, Shinsaku ; Nakane, Akio
出版情報: 弘前医学.  61  pp.S224-S231,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3692
概要: We investigated the eff ect of p60 that is one of virulence factors of Listeria monocytogenes on host immune response in vitro and in vivo. C57BL/6 mice immunized with p60 showed antigen-specifi c T-helper I type immune response. Mouse macrophage RAW264.7 cells produced tumor necrosis factor alpha (TNF-α), interleukin-12 and interferon beta (IFN-β) in response to stimulation with recombinant p60. Administration of p60 prior to a sublethal infection with L. monocytogenes enhanced innate host resistance in naïve mice. TNF-α and IFN-β production from RAW264.7 cells and bone marrow-derived macrophages were Toll-like receptor 4 (TLR4)-dependent. The enhanced clearance of L. monocytogenes by p60 administration was not shown in C3H/HeJ mice. Our fi ndings demonstrated that p60 enhances host resistance against L. monocytngenes infection through both activation and attenuation of host innate immune response in the TLR4-dependent manner. 続きを見る
100.

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Osanai, Arihiro ; Li, Sheng-Jun ; Nakane, Akio
出版情報: 弘前医学.  61  pp.S232-S237,  2010-07-08.  弘前大学大学院医学研究科・弘前医学会
URL: http://hdl.handle.net/10129/3693
概要: Peptidoglycan recognition proteins (PGRPs) are pattern recognition receptors which are conserved from insects to humans. PGRPs can recognize bacteria and their cell wall components, peptidoglycans. Human PGRPs have bactericidal activities that can be accomplished by their amidase activities. Insect PGRPs consist of 16 subtypes and some have eff ector functions as the activation of Toll pathway (PGRP-SA), the activation of Imd pathway (PGRPLC)and induction of autophagosome formation (PGRP-LE), thus contribute to the elimination of bacteria. However, the role of mammalian PGRPs in bacterial infection remains unclear. In this study, we report the function of mouse PGRP-S, the homologue of PGRP-SA, in bacterial infection. The recombinant protein was produced in Escherichia coli overexpression system and used for specifi cantibody production. We investigated the role of PGRP-S in infection with Listeria monocytogenes, a facultative Gram-positive bacterium that can grow intracellularly. The administration of recombinant PGRP-S before L. monocytogenes infection decreased the number of bacteria in the organs of infected mice. When endogenous PGRP-S was neutralized by antibodies specifi c to PGRP-S, the bacterial number increased. The levels of proinfl ammatory cytokines that are essential in the protection against L. monocytogenes infection were lower when the specific antibody was administered prior to infection. Together with these, it is suggested that PGRP-S plays a role in the protection against L. monocytogenes infection. 続きを見る