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| 1.
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Kobayashi, Mio ; Kakuda, Yuko ; Harada, Kenichi ; Sato, Yasunori ; Sasaki, Motoko ; Ikeda, Hiroko ; Terada, Mitsuhiro ; Mukai, Munenori ; Kaneko, Shuichi ; Nakanuma, Yasuni ; 小林, 水緒 ; 原田, 憲一 ; 佐藤, 保則 ; 佐々木, 素子 ; 池田, 博子 ; 金子, 周一 ; 中沼, 安二
概要:
金沢大学医薬保健研究域医学系<br />AIM: To investigate histological and immunohistochemical differences in hepatitis between autoimmune
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hepatitis (AIH) and primary biliary cirrhosis (PBC) with AIH features. METHODS: Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were examined. The activity of periportal and lobular inflammation was scored 0 (none or minimal activity) to 4 (severe), and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored 0-3. The infiltration of mononuclear cells positive for CD20, CD38, CD3, CD4, and CD8 and positive for immunoglobulins (IgG, IgM, and IgA) at the periportal areas (interface hepatitis) and in the hepatic lobules (lobular hepatitis) were semiquantitatively scored in immunostained liver sections (score 0-6). Serum aspartate aminotransferase (AST), immunoglobulins, and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual lesions. RESULTS: Lobular hepatitis, hepatitic rosette formation, and emperipolesis were more extensive and frequent in AIH than in PBC. CD3+, CD4+, and CD8+ cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in PBC. The degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC, but to a lesser degree in AIH. CD20+ cells were mainly found in the portal tracts and, occasionally, at the interface in both diseases. Elevated AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration, specifically CD38+ cells in PBC. No correlation existed between autoantibodies and inflammatory cell infiltration in PBC or AIH. While most AIH cases were IgG-predominant at the interface, PBC cases were divided into IgM-predominant, IgM/IgGequal, and IgG-predominant types, with the latter sharing several features with AIH. CONCLUSION: These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
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| 2.
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Sato, Hirohide ; Sato, Yasunori ; Harada, Kenichi ; Sasaki, Motoko ; Hirano, Katsuyasu ; Nakanuma, Yasuni ; 佐藤, 保則 ; 原田, 憲一 ; 佐々木, 素子 ; 中沼, 安二
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金沢大学医薬保健研究域医学系<br />A 77-year-old woman complained of epigastralgia, and a tumor (5 cm in diameter) of the gallbladder n
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eck was detected by image analysis. Following cholecystectomy, the tumor was pathologically diagnosed as intraductal papillary neoplasm (IPN), gastric type, with associated invasive carcinoma. About 10 mo later, intraluminal multiple masses (3 foci, up to 1.8 cm) were noted in the extrahepatic bile duct, and the resected specimen showed that all tumors had similar gross and microscopic features as seen in gallbladder IPN without invasion, and they were synchronous multiple lesions. This case showed a papillary tumor of the gallbladder of gastric phenotype, and confirmed that the gallbladder is a target of IPN in addition to the bile ducts. © 2013 Baishideng. All rights reserved.
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| 3.
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Yoshikawa, Seiichi ; Zen, Yoh ; Fujii, Takahiko ; Sato, Yasunori ; Ohta, Tetsuo ; Aoyagi, Yutaka ; Nakanuma, Yasuni ; 全, 陽 ; 佐藤, 保則 ; 太田, 哲生 ; 中沼, 安二
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金沢大学医薬保健研究域医学系<br />AIM: To reveal the characteristics of CD133+ cells in the liver. METHODS: This study examined the hi
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stological characteristics of CD133 + cells in non-neoplastic and neoplastic liver tissues by immunostaining, and also analyzed the biological characteristics of CD133 + cells derived from human hepatocellular carcinoma (HCC) or cholangiocarcinoma cell lines. RESULTS: Immunostaining revealed constant expression of CD133 in non-neoplastic and neoplastic biliary epithelium, and these cells had the immunophenotype CD133+/CK19+/HepPar -1-. A smal l number of CD133+/CK19-/HepPar-1+ cells were also identified in HCC and combined hepatocellular and cholangiocarcinoma. In addition, small ductal structures, resembling the canal of Hering, partly surrounded by hepatocytes were positive for CD133. CD133 expression was observed in three HCC (HuH7, PLC5 and HepG2) and two cholangiocarcinoma cell lines (HuCCT1 and CCKS1). Fluorescence-activated cell sorting (FACS) revealed that CD133+ and CD133-cells derived from HuH7 and HuCCT1 cells similarly produced CD133+ and CD133- cells during subculture. To examine the relationship between CD133+ cells and the side population (SP) phenotype, FACS was performed using Hoechst 33342 and a monoclonal antibody against CD133. The ratios of CD133+/CD133-cells were almost identical in the SP and non-SP in HuH7. In addition, four different cellular populations (SP/CD133+, SP/CD133-, non-SP/CD133+, and non-SP/CD133-) could similarly produce CD133+ and CD133- cells during subculture. CONCLUSION: This study revealed that CD133 could be a biliary and progenitor cell marker in vivo. However, CD133 alone is not sufficient to detect tumor-initiating cells in cell lines. © 2009 The WJG Press and Baishideng. All rights reserved.
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| 4.
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佐藤, 保則 ; Sato, Yasunori
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Sasaki, Motoko ; Ikeda, Hiroko ; Sawada, Seiko ; Sato, Yasunori ; Nakanuma, Yasuni
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金沢大学医薬保健研究域医学系<br />Background: Primary biliary cirrhosis (PBC) is an autoimmune liver disease targeting the intrahepati
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c small bile ducts showing chronic non-suppurative destructive cholangitis (CNSDC). Recent studies suggest that naturally-occurring CD4+CD25high regulatory T cells (Tregs) expressing Forkhead box P3 (Foxp3) play an active role in immunological self-tolerance. Aims: To investigate whether Foxp3+Tregs are involved in the pathogenesis of PBC. Methods: Foxp3+Tregs was detected immunohistochemically in livers from patients with PBC (n = 27), chronic viral hepatitis (CVH) (n = 15), and normal subjects (n = 10). The distribution of Tregs in portal tracts was semi-quantitatively evaluated in each groups. Levels of Foxp3, IL-10, TGFβ, IFNγ and TNFα mRNA was evaluated in PBC (n= 15) and control livers (n = 21) using semi-quantitative reverse transcriptase-PCR. Results: In PBC and CVH livers, the amounts of infiltrating Foxp3+Tregs in portal tracts were in parallel with the degree of portal inflammation irrespective of disease. The infiltration of Foxp3+Tregs into portal tracts with CNSDC in PBC was foremost in comparison with inflamed portal tracts in CVH or those without CNSDC in PBC (p<0.05). Focally, Tregs infiltrated into the biliary epithelial layer at the site of CNSDC. The level of Foxp3, IL-10 and TGFβ mRNA expression was high in PBC compared with normal livers (p<0.05). IFNγ and TNFα mRNA was high in early PBC and CVH livers. Conclusion: Results of this evaluation of Foxp3+Tregs do not suggest that the reduced regulatory function accounts for the development of CNSDC in PBC.
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Harada, Kenichi ; Chiba, Mayumi ; Okamura, Atsushi ; Hsu, Maylee ; Sato, Yasunori ; Igarashi, Saya ; Ren, Xiang Shan ; Ikeda, Hiroko ; Ohta, Hajime ; Kasashima, Satomi ; Kawashima, Atsuhiro ; Nakanuma, Yasuni
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金沢大学医薬保健研究域医学系<br />Aims: Monocyte chemoattractant protein-1 (MCP-1) is a major chemotactic factor for hepatic stellate
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cells (HSCs) associated with hepatic fibrosis. In this study, among several fibrogenetic factors derived from biliary epithelial cells (BECs), MCP-1 produced by the biliary innate immune system was found to be most critical in the histogenesis of hepatic fibrogenesis. Methods: Using cultured human BECs, the expression of five fibrogenetic factors including MCP-1 on stimulation with Toll-like receptor ligands, inflammatory cytokines or bile acids was examined. Moreover, in situ detection of MCP-1 and α-smooth muscle actin proteins was performed using sections from normal and diseased livers by immunohistochemistry. Results: All fibrogenetic factors were detected in BECs, but only MCP-1 expression was upregulated, by all the Toll-like receptor ligands, IL-1β, and tumour necrosis factor-alpha. Proliferating bile ductules in interface areas expressed MCP-1 in diseased livers accompanying α-smooth muscle actin-positive activated HSCs. Conclusions: Bile ductules proliferate in various hepatobiliary diseases, and its significance is still unknown. This study demonstrated that BECs in bile ductules could produce MCP-1, particularly, via biliary innate immunity, suggesting that MCP-1 derived from BECs plays an important role in the recruitment of HSCs to interface areas and the activation of HSCs resulting in the progression of periportal fibrosis. Copyright Article author (or their employer) 2011.
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| 7.
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Harada, Kenichi ; Isse, Kumiko ; Sato, Yasunori ; Ozaki, Satoru ; Nakanuma, Yasuni
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金沢大学大学院医学系研究科がん細胞学<br />Background/Aim: Biliary epithelial cells possess an innate immune system consisting of Toll-like
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receptors (TLRs). Although the human bile contains lipopolysaccharide (LPS) in normal as well as diseased livers, LPS physiologically does not elicit an inflammatory response in the biliary tree. This absence of a response to LPS could be due to the 'endotoxin tolerance'speculated to maintain innate immune homeostasis in organs. Our aim here is to clarify the presence and molecular mechanisms of endotoxin tolerance of biliary epithelium. Methods and Results: In nuclear factor-κB (NF-κB)-DNA binding assays using three-cultured human intrahepatic biliary epithelial cell (HIBEC) lines, all the cells responded to LPS (TLR4 ligand) by activating NF-κB, but pretreatment with LPS for 24h effectively induced tolerance against any subsequent stimulation with LPS (endotoxin tolerance). This tolerance was also induced by pretreatment with Pam3Cys-Ser-(Lys)4 trihydrochloride (Pam3CKS4, TLR1/2 ligand). Then, real-time polymerase chain treaction and Western blotting revealed that LPS treatment upregulated the expression of IRAK-M (a negative regulator of TLR signaling), but did not affect interleukin-1 receptor-associated kinase-1 (IRAK-1, an essential molecule of TLR signaling), in HIBECs. Moreover, immunohistochemistry revealed that IRAK-M was diffusely expressed in intrahepatic bile ducts. Conclusions: This study showed that the mechanism of endotoxin tolerance exists in the intrahepatic biliary tree and is possibly induced by the expression of IRAK-M in the intrahepatic biliary epithelium, suggesting that the endotoxin tolerance is important in maintaining innate immune biliary homeostasis. © 2006 Blackwell Munksgaard.
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| 8.
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Ohira, Shusaku ; Itatsu, Keita ; Sasaki, Motoko ; Harada, Kenichi ; Sato, Yasunori ; Zen, Yoh ; Ishikawa, Akira ; Oda, Koji ; Nagasaka, Tetsuro ; Nimura, Yuji ; Nakanuma, Yasuni
概要:
金沢大学大学院医学系研究科がん細胞学<br />Tumor-stromal interactions are important for the progression of malignant tumors. The purpose of
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the present study was to examine interactions of cholangiocarcinoma (CC) cells and stromal fibroblasts with respect to stromal-derived factor-1 (SDF-1) and transforming growth factor (TGF)-β1. Two cell lines of CC (HuCCT-1 and CCKS-1) and WI-38 fibroblast cell line were used for cell culture, and 12 CC tissue specimens for immunohistochemical studies. Invasion of CC cells was increased significantly by the supernatant from fibroblast cultures, but not by the supernatant from fibroblasts cocultured with CC cells. Expression of SDF-1 in cultured fibroblasts was downregulated by TGF-β1 treatment, and coculture with CC cells and anti-TGF-β1 neutralizing antibody restored the decreased SDF-1 expression, suggesting that TGF-β1 secreted from CC cells might have reduced the expression of SDF-1 by fibroblasts and might have reduced the increased invasion of CC cells induced by the supernatant from fibroblasts. Immunohistochemical expression of TGF-β1 in CC cells was focal or negative and that of SDF-1 was evident in stromal fibroblasts at the invasive front of CC. In conclusion, local mutual influence of TGF-β1 secreted from carcinoma cells and SDF-1 expressed by stromal fibroblasts may be involved in invasion of CC cells. © 2006 Japanese Society of Pathology.
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| 9.
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Kakuda, Yuko ; Harada, Kenichi ; Sawada-Kitamura, Seiko ; Ikeda, Hiroko ; Sato, Yasunori ; Sasaki, Motoko ; Okafuji, Hirofumi ; Mizukoshi, Eishiro ; Terasaki, Shuichi ; Ohta, Hajime ; Kasashima, Satomi ; Kawashima, Atsuhiro ; Kaizaki, Yasuharu ; Kaneko, Shuichi ; Nakanuma, Yasuni
概要:
Recently, our research team proposed a new histologic staging and grading system for primary biliary cirrhosis (PBC) tha
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t takes into account necroinflammatory activity and histologic heterogeneity. The present study aimed to confirm the usefulness of the new evaluation system. A total of 152 liver biopsy specimens and clinical data (including outcomes in patients with PBC before treatment with ursodeoxycholic acid) were analyzed with respect to the new system. Staging was evaluated on the basis of 3 histologic components (fibrosis, bile duct loss, and deposition of orcein-positive granules), and grading was assessed on the basis of chronic cholangitis activity and hepatitis activity. Concurrently, the classical systems, that is, the Scheuer and Ludwig staging systems, were also assessed and compared with our new system. PBC cases showed different distributions in each stage of the 3 systems. The new staging and grading system reflected liver dysfunctions before specific treatment. This was on a par with the results obtained using the classical systems. Development of cirrhosis-related conditions correlated well with the new staging system compared with the 2 classical staging systems, and in particular, the amount of deposition of orcein-positive granules could reflect development of cirrhosis-related conditions (scores 0-1 versus scores 2-3 groups, P < .0001). In conclusion, the new PBC staging system was demonstrated to reflect clinicolaboratory features, and its progression was associated with the development of cirrhosis-related conditions. © 2013 Elsevier Inc. All rights reserved.
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| 10.
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Sasaki, Motoko ; Miyakoshi, Masami ; Sato, Yasunori ; Nakanuma, Yasuni
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Background and Aim: Recent studies disclosed that autophagy facilitates the process of senescence. Given that cellular s
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enescence is involved in the pathophysiology of ductular reaction (DR) in primary biliary cirrhosis (PBC), we examined an involvement of autophagy in DRs in PBC and control livers. Methods: We examined immunohistochemically the expression of microtubule-associated proteins light chain 3β (LC3) as autophagy marker, p62/sequestosome-1 (p62) as autophagy-related marker in bile ductular cells in livers taken from the patients with PBC (n = 42), and control livers (n = 100). The expression of senescent markers (p16INK4a and p21WAF1/Cip1) in bile ductular cells and their correlation with autophagy was also evaluated. Results: The expression of LC3 was seen in coarse vesicles in the cytoplasm of bile ductular cells and significantly more frequently in PBC of both early and advanced stages when compared to control livers (p < 0.01). The expression of p62 was seen as intracytoplasmic aggregates and significantly more frequently in PBC when compared to control livers (p < 0.05). The expression of LC3 and p62 significantly correlated with each other (p < 0.01). The expression of LC3 and p62 significantly correlated with the expression of p16INK4a, p21WAF1/Cip1 (p < 0.05). Conclusions: Autophagy is frequently seen in bile ductular cells in DRs in PBC. Since cellular senescence of bile ductular cells is rather frequent in the advanced stage of PBC, autophagy may precede cellular senescence of bile ductular cells in DRs in PBC. © 2011 Springer Science+Business Media, LLC.
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