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若山, 友彦 ; Wakayama, Tomohiko
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Wakayama, Tomohiko ; Mizushima, Seiichi ; Hirose, Jiro ; Iseki, Shoichi ; 若山, 友彦 ; 井関, 尚一
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金沢大学医薬保健研究域医学系<br />Human urinary trypsin inhibitor (UTI) is the functional domain of serum inter-a-trypsin inhibitor. R
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at urine also contains UTI-like immunoreactivity. To clarify the source of rat UTI, we performed a combination of reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization and immunohistochemistry. The expression of UTI mRNA was detected by RT-PCR only in the liver and not in any other rat organs, including the kidney. In situ hybridization revealed that UTI transcripts are located exclusively in the hepatocytes and not in the nonparenchymal cells of the liver. On light microscopic immunohistochemistry, not only the hepatocytes but also the Kupffer cells of liver and the proximal tubules of kidney were immunostained with anti-UTI antibody. Immunoelectron microscopy further demonstrated that hepatocyte UTI-immunoreactivity is localized primarily on the cell surface facing the sinusoidal capillary and is also found in the Golgi apparatus. In contrast, the reactivity of Kupffer cell and proximal tubular epithelial cell was found primarily in the lysosomes. These results indicated that the liver is the only site for production of rat UTI, and that the kidney does not produce rat UTI but reabsorbs it from the primary urine.<br />出版者許可を得て登録 20191114
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Wakayama, Tomohiko ; Iseki, Shoichi ; 若山, 友彦 ; 井関, 尚一
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金沢大学医薬保健研究域医学系<br />Urinary trypsin inhibitor (UTI) is an acidic protein with anti-proteolytic activity that constitutes
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the active domain of serum interα-trypsin inhibitor. UTI has been demonstrated not only in the adult urine but also in the amniotic fluid of late pregnancy. In order to examine the expression and localization of UTI in the rat embryo and placenta, we performed a combination of reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization and immunohistochemistry. UTI mRNA expression was detected by RT-PCR in the embryo on and after the day 12 of gestation (E12) but not in the placenta throughout the prenatal period. In situ hybridization revealed that UTI transcripts were localized in the liver but not in any other organs of embryo from E12 through E20. On the other hand, UTI immunoreactivity was detected not only in the liver from E12 but also in the kidney and intestine from E18. On electron microscopy, the immunoreactivity of liver was localized to the surface of hepatocytes and the lysozomes of Kupffer cells, whereas the endothelial cells and hematopoietic cells were free of the reaction. In contrast, the immunonoreactivities of kidney and intestine were localized exclusively to the apical lysosomes of proximal tubular epithelial cells and absorptive epithelial cells, respectively. These results indicated that in the rat embryo, as in the adult, the hepatocyte is the only site for production of UTI, that UTI is excreted into the urine and thereby into the amniotic fluid, and that a part of amniotic UTI is reabsorbed in the fetal intestine, suggesting a possible role of UTI in the protection of the fetus during the late pregnancy.<br />出版者許可を得て登録 20191114
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Wakayama, Tomohiko ; Sai, Yoshimichi ; Ito, Akihiko ; Kato, Yukio ; Kurobo, Miho ; Murakami, Yoshinori ; Nakashima, Emi ; Tsuji, Akira ; Kitamura, Yukihiko ; Iseki, Shoichi ; 若山, 友彦 ; 崔, 吉道 ; 加藤, 将夫 ; 辻, 彰 ; 井関, 尚一
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金沢大学医薬保健研究域医学系<br />The cell adhesion protein immunoglobulin superfamily 4A (IGSF4A) is expressed on the surfaces of spe
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rmatogenic cells in the mouse testis. During spermatogenesis, IGSF4A is considered to bind to the surface of Sertoli cells in a heterophilic manner. To identify this unknown partner of IGSF4A, we generated rat monoclonal antibodies against the membrane proteins of mouse Sertoli cells grown in primary culture. Using these monoclonal antibodies, we isolated a clone that immunostained Sertoli cells and reacted with the product of immunoprecipitation of the homogenate of mouse testis with anti-IGSF4A antibody. Subsequently, to identify the Sertoli cell membrane protein that is recognized by this monoclonal antibody, we performed expression cloning of a cDNA library from the mouse testis. As a result, we identified poliovirus receptor (PVR), which is another IGSF-type cell adhesion molecule, as the binding partner of IGSF4A. The antibodies raised against PVR and IGSF4A immunoprecipitated both antigens in the homogenate of mouse testis. Immunoreactivity for PVR was present in Sertoli cells but not in spermatogenic cells at all stages of spermatogenesis. Overexpression of PVR in TM4, a mouse Sertoli cell line, increased more than three-fold its capacity to adhere to Tera-2, which is a human cell line that expresses IGSF4A. These findings suggest that the heterophilic binding of PVR to IGSF4A is responsible, at least in part, for the interaction between Sertoli and spermatogenic cells during mouse spermatogenesis. © 2007 by the Society for the Study of Reproduction, Inc.<br />Embargo Period 12 months
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Watanabe, Toshifumi ; Tajima, Hidehiro ; Hayashi, Hironori ; Nakagawara, Hisatoshi ; Ohnishi, Ichiro ; Takamura, Hiroyuki ; Ninomiya, Itasu ; Kitagawa, Hirohisa ; Fushida, Sachio ; Tani, Takashi ; Fujimura, Takashi ; Ohta, Tetsuo ; Wakayama, Tomohiko ; Iseki, Shoichi ; Harada, Shinichi ; 田島, 秀浩 ; 林, 泰寛 ; 中川原, 寿俊 ; 高村, 博之 ; 二宮, 致 ; 北川, 裕久 ; 伏田, 幸夫 ; 谷, 卓 ; 藤村, 隆 ; 太田, 哲生 ; 若山, 友彦 ; 井関, 尚一 ; 原田, 真市
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金沢大学医薬保健研究域医学系<br />Histone acetylation and deacetylation have been thought to be related to gene expression, and there
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are many reports indicating that histone deacetylase inhibitors (HDACis) exert antifibrogenic effects in several organs. In injured livers, hepatic stellate cells (HSCs) are activated in response to profibrogenic mediators and produce large amounts of extracellular matrix. In particular, transforming growth factor-β1 (TGF-β1) is considered as a key factor in accelerating hepatic fibrosis because it is released from activated HSCs and further stimulates them. The present study aimed to clarify whether sodium valproate (VPA) has suppressive effects on cultured human HSCs (LI90). We showed that treatment with VPA had no significantly suppressive effect on cell proliferation at a concentration of 1 mM, which corresponded approximately to the serum concentration obtained by the administration of a clinical dose. However, VPA prevented the morphological changes characteristic for activation and inhibited the expression of collagen type 1 α1 (COL1A1) and TGF-β1 in activated LI90 cells at the mRNA and protein levels. Our results support the hypothesis that VPA exerts antifibrogenic activity with little cytotoxicity at 1 mM, and HDACis are expected to be used in clinical practice for the treatment of fibrotic diseases.<br />Embargo Period 6 months
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Nakanuma, Shinichi ; Tajima, Hidehiro ; Okamoto, Koichi ; Hayashi, Hironori ; Nakagawara, Hisatoshi ; Onishi, Ichiro ; Takamura, Hiroyuki ; Kitagawa, Hirohisa ; Fushida, Sachio ; Tani, Takashi ; Fujimura, Takashi ; Kayahara, Masato ; Ohta, Tetsuo ; Wakayama, Tomohiko ; Iseki, Shoichi ; Harada, Shinichi ; 中村, 信一 ; 田島, 秀浩 ; 岡本, 浩一 ; 林, 泰寛 ; 中川原, 寿俊 ; 高村, 博之 ; 北川, 裕久 ; 伏田, 幸夫 ; 谷, 卓 ; 藤村, 隆 ; 萱原, 正都 ; 太田, 哲生 ; 若山, 友彦 ; 井関, 尚一 ; 原田, 真市
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金沢大学医薬保健研究域医学系<br />In primary malignant liver tumors, trypsinogen-immunoreactivity was present in 70% of intrahepatic c
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holangiocarcinoma (ICC) specimens, but absent in hepato-cellular carcinoma (HCC) specimens. We suggest the secretion of trypsinogen to be a key difference in biological behavior between ICC and HCC cells. The purpose of this study was to investigate the secretion of tumor-derived trypsin and the expression of its specific receptor, protease-activated receptor-2 (PAR-2), in ICC using cell lines and surgical specimens. The expression of trypsinogen-1 mRNA was observed in three of four ICC cell lines, but none of three HCC cell lines. Western blot analysis detected trypsinogen-1 in serum-free conditioned medium from one of the ICC cell lines positive for the mRNA. Gelatin zymography revealed a gelatinolytic activity for trypsin, the activated form of trypsinogen, in the same conditioned medium. PAR-2 mRNA and protein were observed in ICC cell lines. The proliferative activity of ICC cells was increased by concentrations of trypsin as low as 10 nM, and peaked at 100 nM. The effect of trypsin was suppressed by a serine protease inhibitor, gabexate mesilate. PAR-2 expression was detected in 64% of ICC surgical specimens immunohistochemically. In addition, stroma fibroblasts expressed PAR-2 in 52% of ICC specimens. These results suggest that trypsinogen-1 contributes to the growth of ICC cells and also tumor-associated fibroblasts.<br />Embargo Period 6 months
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Okamoto, Koichi ; Tajima, Hidehiro ; Nakanuma, Shinichi ; Sakai, Seisho ; Makino, Isamu ; Kinoshita, Jun ; Hayashi, Hironori ; Nakamura, Keishi ; Oyama, Katsunobu ; Nakagawara, Hisatoshi ; Fujita, Hideto ; Takamura, Hiroyuki ; Ninomiya, Itasu ; Kitagawa, Hirohisa ; Fushida, Sachio ; Fujimura, Takashi ; Harada, Shinichi ; Wakayama, Tomohiko ; Iseki, Shoichi ; Ohta, Tetsuo ; 岡本, 浩一 ; 田島, 秀浩 ; 中村, 信一 ; 牧野, 勇 ; 木下, 淳 ; 林, 泰寛 ; 中村, 慶史 ; 尾山, 勝信 ; 中川原, 寿俊 ; 藤田, 秀人 ; 高村, 博之 ; 二宮, 致 ; 北川, 裕久 ; 伏田, 幸夫 ; 藤村, 隆 ; 原田, 真市 ; 若山, 友彦 ; 井関, 尚一 ; 太田, 哲生
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金沢大学医薬保健研究域医学系<br />We previously reported that hepatic stellate cells (HSCs) activated by angiotensin II (AngII) facili
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tate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma (ICC). AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition (EMT) in renal epithelial cells, alveolar epithelial cells and peritoneal mesothelial cells. However, in the past, the relationship between AngII and stromal cell-derived factor-1 (SDF-1) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail. SDF-1 and its specific receptor, CXCR4, are now receiving attention as a mechanism of cell progression and metastasis. In this study, we examined whether activated HSCs promote tumor fibrogenesis, tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor (AT-1) and the SDF-1/CXCR4 axis. Two human ICC cell lines and a human HSC line, LI-90, express CXCR4. Significantly higher concentration of SDF-1αwas released into the supernatant of LI-90 cells to which AngII had been added. SDF-1α increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor. Furthermore, addition of SDF-1α and AngII enhanced the increase of the migratory capability and vimentin expression, reduced E-cadherin expression, and translocated the expression of β-catenin into the nucleus and cytoplasm in ICC cells. Co-culture with HSCs also enhanced the migratory capability of ICC cells. These findings suggest that SDF-1α, released from activated HSCs and AngII, play important roles in cancer progression, tumor fibrogenesis, and migration in autocrine and paracrine fashion by mediating EMT. Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1α-initiated signaling pathway that regulates fibrogenesis in cancerous stroma, tumor progression and metastasis of tumor cells expressing AT-1 and CXCR4.<br />Embargo Period 6 months
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Tajima, Hidehiro ; Takamura, Hiroyuki ; Kitagawa, Hirohisa ; Nakayama, Akira ; Shoji, Masatoshi ; Watanabe, Toshifumi ; Tsukada, Tomoya ; Nakanuma, Shinichi ; Okamoto, Koichi ; Sakai, Seisho ; Kinoshita, Jun ; Makino, Isamu ; Nakamura, Keishi ; Hayashi, Hironori ; Oyama, Katsunobu ; Inokuchi, Masafumi ; Nakagawara, Hisatoshi ; Miyashita, Tomoharu ; Ninomiya, Itasu ; Fushida, Sachio ; Fujimura, Takashi ; Wakayama, Tomohiko ; Iseki, Shoichi ; Ikeda, Hiroko ; Ohta, Tetsuo ; 田島, 秀浩 ; 高村, 博之 ; 北川, 裕久 ; 中村, 信一 ; 岡本, 浩一 ; 木下, 淳 ; 牧野, 勇 ; 中村, 慶史 ; 林, 泰寛 ; 尾山, 勝信 ; 井口, 雅史 ; 中川原, 寿俊 ; 宮下, 知治 ; 二宮, 致 ; 若山, 友彦 ; 藤村, 隆 ; 井関, 尚一 ; 池田, 博子 ; 太田, 哲生
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金沢大学医薬保健研究域医学系<br />A 33-year-old female was diagnosed with a solid pseudopapillary tumor (SPT) of the pancreas and mult
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iple liver metastases at the Department of Gastroenterological Surgery, Ishikawa Prefectural Central Hospital (Kanazawa, Japan). Distal pancreatectomy and postoperative systemic chemotherapy with gemcitabine (GEM) and S-1, an oral fluoropyrimidine derivative, was administered, however, liver metastases became enlarged and local recurrence occurred. Therefore, the patient was referred to the Department of Gastroenterologic Surgery at the Graduate School of Medicine (Kanazawa, Japan) for hepatic arterial infusion (HAI) chemotherapy. Oral S-1 (80 mg/m2) was administered as well as HAI chemotherapy with GEM (1,000 mg/standard liver volume). Following 18 cycles, tumor sizes were reduced and 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) examination revealed obvious reduction of tumor FDG uptake. Transarterial tumor embolization (TAE) was performed for the previously unresectable right subphrenic liver tumor, and the other tumors were surgically resected. The resected tumors were diagnosed as liver metastases and a local recurrence of SPT in the postoperative pathological examination, which revealed that the resected tumors were composed of sheets of bland cells, which were positive for CD10, CD56, vimentin, neuron-specific enolase and α-antitrypsin. The postoperative course was uneventful, and the patient is currently under observation at an outpatient clinic; postoperative adjuvant chemotherapy with oral S-1 has continued, and additional TAE is planned. In the future, if the middle segment of the liver becomes enlarged, surgery for the residual right lobe tumor may be possible. This case demonstrates one method of SPT treatment: Preoperative HAI chemotherapy with GEM, plus oral S-1 and TAE. If complete resection can be achieved, the majority of patients with SPT have a favorable prognosis. In patients with unresectable metastases from SPT, it is crucial to conduct systematic multimodal treatment to maximize treatment success. © 2015, Spandidos Publications. All Rights Reserved.<br />Embargo Period 6 months
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Yoshimoto, Katsuhiro ; Tajima, Hidehiro ; Ohta, Tetsuo ; Okamoto, Koichi ; Sakai, Seisho ; Kinoshita, Jun ; Furukawa, Hiroyuki ; Makino, Isamu ; Hayashi, Hironori ; Nakamura, Keishi ; Oyama, Katsunobu ; Inokuchi, Masafumi ; Nakagawara, Hisatoshi ; Itoh, Hiroshi ; Fujita, Hideto ; Takamura, Hiroyuki ; Ninomiya, Itasu ; Kitagawa, Hirohisa ; Fushida, Sachio ; Fujimura, Takashi ; Wakayama, Tomohiko ; Iseki, Shoichi ; Shimizu, Koichi ; 田島, 秀浩 ; 太田, 哲生 ; 岡本, 浩一 ; 木下, 淳 ; 古川, 裕之 ; 牧野, 勇 ; 林, 泰寛 ; 中村, 慶史 ; 尾山, 勝信 ; 井口, 雅史 ; 中川原, 寿俊 ; 藤田, 秀人 ; 高村, 博之 ; 二宮, 致 ; 藤村, 隆 ; 若山, 友彦 ; 井関, 尚一 ; 清水, 康一
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金沢大学医薬保健研究域医学系<br />Several recent studies have reported that selectins are produced during ischemia-reperfusion injury,
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and that selectin ligands play an important role in cell binding to the endothelium and in liver metastasis. Portal clamping during pancreaticoduodenectomy with vessel resection for pancreatic head cancer causes hepatic ischemia-reperfusion injury, which might promote liver metastasis. We investigated the liver colonization of pancreatic cancer cells under hepatic ischemia-reperfusion and examined the involvement of E-selectin and its ligands. A human pancreatic cancer cell line (Capan-1) was injected into the spleen of mice after hepatic ischemia-reperfusion (I/R group). In addition, to investigate the effect of an anti-E-selectin antibody on liver colonization in the IR group, mice received an intraperitoneal injection of the anti-E-selectin antibody following hepatic ischemia-reperfusion and tumor inoculation (IR+Ab group). Four weeks later, mice were sacrificed and the number of tumor nodules on the liver was compared to mice without hepatic ischemia-reperfusion (control group). The incidence of liver metastasis in the I/R group was significantly higher (16 of 20, 80%) than that in the control group (6 of 20, 30%) (P<0.01). Moreover, mice in the I/R group had significantly more tumor nodules compared to those in the control group (median, 9.9 vs. 2.7 nodules) (P<0.01). In the I/R+Ab group, only 2 of 5 (40%) mice developed liver metastases. RT-PCR and southern blotting of the liver extracts showed that the expression of IL-1 and E-selectin mRNA after hepatic ischemia-reperfusion was significantly higher than the basal levels. Hepatic ischemia-reperfusion increases liver metastases and E-selectin expression in pancreatic cancer. These results suggest that E-selectin produced due to hepatic ischemia-reperfusion is involved in liver metastasis.<br />Embargo Period 6 months
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10. Coexpression of menin and JunD during the duct cell differentiation in mouse submandibular gland
Hipkaeo, Wiphawi ; Sakulsak, Natthiya ; Wakayama, Tomohiko ; Yamamoto, Miyuki ; Nakaya, Masaaki ; Keattikunpairoj, Sunisa ; Kurobo, Miho ; Iseki, Shoichi
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金沢大学医薬保健研究域医学系<br />In the submandibular gland (SMG) of mice, a duct portion called the granular concvoluted tubule (GCT
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) is developed preferentially in males with puberty. This sexual dimorphism is androgen-dependent, but the underlying molecular mechanisms are unclear. We have demonstrated that the expression of a transcription factor JunD is regulated in association with the androgen-induced differentiation of GCT cells from striated duct (SD) cells. Menin, a nuclear protein encoded by the MEN1 tumor-suppressor gene, is known to bind JunD, thereby inhibiting its activity. In the present study, we examined the expression of menin in the mouse SMG by use of Northern blotting, Western blotting, and immunohistochemistry. Immunoreactivity for menin was higher in the female than male gland, and localized to the nuclei of intercalated duct cells and a subpopulation of SD cells. In contrast, GCT cells in males appeared negative for menin. The levels of menin in the SMG were increased with castration in males and decreased by repeated administration of testosterone to females or to castrated males. After a single administration of testosterone to females, many SD cells newly gained nuclear menin, which was lost as the cells converted to GCT cells by 48 hrs. These patterns of the expression and localization of menin were quite similar to those of JunD. Furthermore, the coimmunoprecipitation analysis of the SMG homogenates indicated that menin binds JunD in vivo. The present study suggests that the JunD-menin complex plays significant roles in the androgen-dependent differentiation of the duct system in the mouse SMG. © 2008 Tohoku University Medical Press.
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