1.

論文

論文
Nasti, Alessandro ; Sakai, Yoshio ; Seki, Akihiro ; Buffa, Geraldine Belen ; Komura, Takuya ; Mochida, Hatsune ; Yamato, Masatoshi ; Yoshida, Keiko ; Ho, Tuyen T. B. ; Takamura, Masayuki ; Usui, Soichiro ; Wada, Takashi ; Honda, Masao ; Kaneko, Shuichi ; 酒井, 佳夫 ; 餅田, 初音 ; 吉田, 佳子 ; 高村, 雅之 ; 薄井, 荘一郎 ; 和田, 隆志 ; 本多, 政夫 ; 金子, 周一
出版情報: European Journal of Immunology.  47  pp.2163-2174,  2017-12.  Wiley
URL: http://hdl.handle.net/2297/00050487
概要: 金沢大学医薬保健研究域医学系<br />Stromal cells in adipose tissue are useful for repair/regenerative therapy as they harbor a substant ial number of mesenchymal stem cells; therefore, freshly isolated autologous uncultured adipose tissue derived stromal cells (u-ADSCs) are useful for regenerative therapy, and obviate the need for mesenchymal stem cells. We evaluated the therapeutic effect of murine u-ADSCs and sorted subsets of u-ADSCs in a concanavalin A (ConA) induced murine model of hepatitis, as well as their characteristics. We found that 10–20% of u-ADSCs expressed the CD45 leukocyte-related antigen. CD68, which is a marker of macrophages (MΦs), was expressed by 50% of CD45+ u-ADSCs. About 90% of CD68+CD45+ cells expressed CD206 antigen, which is a marker of inhibitory M2-type MΦs. Genes related to M2-type MUs were especially more highly expressed by CD45+CD206+ u-ADSCs than by CD45− u-ADSCs. CD45+ u-ADSCs inhibited the expression of cytokines/chemokines and suppressed the proliferation of splenocytes stimulated with ConA. We observed that not only whole u-ADSCs, but also the CD45+ subset of u-ADSCs ameliorated the ConA-induced hepatitis in mice. In conclusion, we show that freshly isolated murine u-ADSCs were effective against acute hepatitis, and CD45+ u-ADSCs acting phenotypically and functionally like M2-type MΦs, contributed to the repair of liver tissue undergoing inflammation. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim<br />Embargo Period 12 months 続きを見る
2.

論文

論文
Honda, Masao ; Nakamura, Mikiko ; Tateno, Makoto ; Sakai, Akito ; Shimakami, Tetsuro ; Shirasaki, Takayoshi ; Yamashita, Tatsuya ; Arai, Kuniaki ; Yamashita, Taro ; Sakai, Yoshio ; Kaneko, Shuichi
出版情報: Journal of Hepatology.  53  pp.817-826,  2010-01-01.  European Association for the Study of the Liver / Elsevier
URL: http://hdl.handle.net/2297/25263
概要: 金沢大学医薬保健研究域医学系<br />Background & Aims: The mechanisms of treatment resistance to interferon (IFN) and ribavirin (Rib) co mbination therapy for hepatitis C virus (HCV) infection are not known. This study aims to gain insight into these mechanisms by exploring hepatic gene expression before and during treatment. Methods: Liver biopsy was performed in 50 patients before therapy and repeated in 30 of them 1 week after initiating combination therapy. The cells in liver lobules (CLL) and the cells in portal areas (CPA) were obtained from 12 patients using laser capture microdissection (LCM). Results: Forty-three patients were infected with genotype 1 HCV, 20 of who were viral responders (genotype 1-Rsp) with treatment outcome of SVR or TR, while 23 were non-responders (genotype 1-nonRsp) with NR. Only seven patients were infected with genotype 2. Before treatment, the expression of IFN and Rib-stimulated genes (IRSGs), apoptosis-associated genes, and immune reaction gene pathways was greater in genotype 1-nonRsp than in Rsp. During treatment, IRSGs were induced in genotype 1-Rsp, but not in nonRsp. IRSG induction was irrelevant in genotype 2-Rsp and was mainly impaired in CLL but not in CPA. Pathway analysis revealed that many immune regulatory pathways were induced in CLL from genotype 1-Rsp, while growth factors related to angiogenesis and fibrogenesis were more induced in CPA from genotype 1-nonRsp. Conclusions: Impaired IRSGs induction in CLL reduces the sensitivity to treatment for genotype 1 HCV infection. CLL and CPA in the liver might be differentially involved in treatment resistance. These findings could be useful for the improvement of therapy for HCV infection. © 2010 European Association for the Study of the Liver. 続きを見る
3.

論文

論文
Tang, Yaliang ; Masuo, Yusuke ; Sakai, Yoshio ; Wakayama, Tomohiko ; Sugiura, Tomoko ; Harada, Ryuichi ; Futatsugi, Azusa ; Komura, Takuya ; Nakamichi, Noritaka ; Sekiguchi, Hirotaka ; Sutoh, Keita ; Usumi, Koji ; Iseki, Shoichi ; Kaneko, Shuichi ; Kato, Yukio
出版情報: Journal of Pharmaceutical Sciences.  105  pp.1779-1789,  2016-05-01.  American Pharmacists Association / Elsevier
URL: http://hdl.handle.net/2297/45429
概要: Xenobiotic transporters play key roles in disposition of certain therapeutic agents, although limited information is ava ilable on their roles other than pharmacokinetic issues. Here, suppressive effect of multispecific organic cation transporter OCTN1/SLC22A4 on liver fibrosis was proposed in liver injury models. After injection of hepatotoxins such as dimethylnitrosamine (DMN) or concanavalin A, hepatic fibrosis, and oxidative stress, evaluated in terms of Sirius red and 4-hydroxy-2-nonenal staining, respectively, were more severe in liver of octn1/slc22a4 gene knockout (octn1-/-) mice than that in wild-type mice. DMN treatment markedly increased α-smooth muscle actin and F4/80, markers of activated stellate and Kupffer cells, respectively, in liver of octn1-/-, but had less effect in wild-type mice. Thus, octn1/slc22a4 gene deletion results in more severe hepatic fibrosis, oxidative stress, and inflammation. DMN-treated wild-type mice showed increased Octn1 staining and hepatic concentration of its food-derived antioxidant ergothioneine (ERGO). The upregulated Octn1 was co-localized with α-smooth muscle actin. Functional expression of Octn1 was demonstrated in activated human hepatic stellate cell lines, LI90 and LX-2. Provision of ERGO-rich feed ameliorated DMN-induced liver fibrosis and oxidative stress. Overall, Octn1 is upregulated in activated stellate cells, resulting in increased delivery of its substrate antioxidant ERGO and a protective effect against liver fibrosis. © 2016 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.<br />Embargo Period 12 months 続きを見る
4.

論文

論文
Honda, Masao ; Sakai, Yoshio ; Yamashita, Taro ; Yamashita, Tatsuya ; Sakai, Akito ; Mizukoshi, Eishiro ; Nakamoto, Yasunari ; Tatsumi, Isamu ; Miyazaki, Yoshitaka ; Tanno, Hiroshi ; Kaneko, Shuichi ; Hokuriku Liver Study Group
出版情報: Biochemical and Biophysical Research Communications.  400  pp.7-15,  2010-09-01.  Elsevier
URL: http://hdl.handle.net/2297/25265
概要: 金沢大学医薬保健研究域医学系<br />To develop a non-invasive and sensitive diagnostic test for cancer using peripheral blood, we evalua ted gene expression profiling of blood obtained from patients with cancer of the digestive system and normal subjects. The expression profiles of blood-derived total RNA obtained from 39 cancer patients (11 colon cancer, 14 gastric cancer, and 14 pancreatic cancer) was clearly different from those obtained from 15 normal subjects. By comparing the gene expression profiles of cancer patients and normal subjects, 25 cancer-differentiating genes (p<5.0×10-6 and fold differences >3) were identified and an " expression index" deduced from the expression values of these genes differentiated the validation cohort (11 colon cancer, 8 gastric cancer, 18 pancreatic cancer, and 15 normal subjects) into cancer patients and normal subjects with 100% (37/37) and 87% (13/15) accuracy, respectively. Although, the expression profiles were not clearly different between the cancer patients, some characteristic genes were identified according to the stage and species of the cancer. Interestingly, many immune-related genes such as antigen presenting, cell cycle accelerating, and apoptosis- and stress-inducing genes were up-regulated in cancer patients, reflecting the active turnover of immune regulatory cells in cancer patients. These results showed the potential relevance of peripheral blood gene expression profiling for the development of new diagnostic examination tools for cancer patients. © 2010 Elsevier Inc. 続きを見る
5.

論文

論文
Komura, Takuya ; Sakai, Yoshio ; Honda, Masao ; Takamura, Toshinari ; Matsushima, Kouji ; Kaneko, Shuichi
出版情報: Diabetes.  59  pp.634-643,  2010-03-01.  American Diabetes Association
URL: http://hdl.handle.net/2297/23966
概要: 金沢大学医薬保健研究域医学系<br />OBJECTIVE - Although patients with diabetes suffer from increased infections and a higher incidence of cancer due to impaired immune function, details on diabetes-induced decrease in immunity are lacking. We assessed how immune-mediating peripheral blood mononuclear cells (PBMCs) are affected in diabetes. RESEARCH DESIGN AND METHODS - From 33 patients with type 2 diabetes and 28 healthy volunteers, we obtained PBMCs and investigated their susceptibility to apoptosis and functional alteration. RESULTS - In a subpopulation of PBMCs, monocytes derived from patients with diabetes were more susceptible to apoptosis than monocytes from healthy volunteers. Monocytes from patients with diabetes had decreased phagocytotic activity and were less responsive to Toll-like receptor (TLR) ligands, although the expression of TLRs did not differ significantly between the two groups. Furthermore, monocytes from patients with diabetes had a distinctly different gene expression profile compared with monocytes from normal volunteers as assessed with DNA microarray analysis. Specifically, quantitative real-time detection PCR measurements showed an elevated expression of the markers of endoplasmic reticulum (ER) stress in diabetic monocytes, and electron microscopic examination of monocytes revealed morphologic alterations in the ER of cells derived from patients with diabetes. Consistently, the ER stress inducer tunicamycin increased apoptosis of otherwise healthy monocytes and attenuated the proinflammatory responses to TLR ligands. CONCLUSIONS - These data suggest that monocytes comprise a substantially impaired subpopulation of PBMCs in patients with diabetes and that ER stress is involved in these pathologic changes mechanistically. This implies that the affected monocytes should be investigated further to better understand diabetic immunity. © 2010 by the American Diabetes Association. 続きを見る
6.

論文

論文
Honda, Masao ; Sakai, Akito ; Yamashita, Tatsuya ; Nakamotoa, Yasunari ; Mizukoshi, Eishiro ; Sakai, Yoshio ; Yamashita, Taro ; Nakamura, Mikiko ; Shirasaki, Takayoshi ; Horimoto, Katsuhisa ; Tanaka, Yasuhito ; Tokunaga, Katsushi ; Mizokami, Masashi ; Kaneko, Shuichi ; Hokuriku Liver Study Group
出版情報: Gastroenterology.  139  pp.499-509,  2010-08-01.  Elsevier
URL: http://hdl.handle.net/2297/25264
概要: 金沢大学医薬保健研究域医学系<br />Background & Aims: Multiple viral and host factors are related to the treatment response to pegylate d-interferon and ribavirin combination therapy; however, the clinical relevance and relationship of these factors have not yet been fully evaluated. Methods: We studied 168 patients with chronic hepatitis C who received pegylated-interferon and ribavirin combination therapy. Gene expression profiles in the livers of 91 patients were analyzed using an Affymetrix genechip (Affymetrix, Santa Clara, CA). The expression of interferon-stimulated genes (ISGs) was evaluated in all samples by real-time polymerase chain reaction. Genetic variation in interleukin 28B (IL28B; rs8099917) was determined in 91 patients. Results: Gene expression profiling of the liver differentiated patients into 2 groups: patients with up-regulated ISGs and patients with down-regulated ISGs. A high proportion of patients with no response to treatment was found in the up-regulated ISGs group (P = .002). Multivariate logistic regression analysis showed that ISGs (<3.5) (odds ratio [OR], 16.2; P < .001), fibrosis stage (F1-F2) (OR, 4.18; P = .003), and ISDR mutation (<2) (OR, 5.09; P = .003) were strongly associated with the viral response. The IL28B polymorphism of 91 patients showed that 66% were major homozygotes (TT), 30% were heterozygotes (TG), and 4% were minor homozygotes (GG). Interestingly, hepatic ISGs were associated with the IL28B polymorphism (OR, 18.1; P < .001), and its expression was significantly higher in patients with the minor genotype (TG or GG) than in those with the major genotype (TT). Conclusions: The expression of hepatic ISGs is strongly associated with treatment response and genetic variation of IL28B. The differential role of host and viral factors as predicting factors may also be present. © 2010 AGA Institute. 続きを見る
7.

論文

論文
Nakamoto, Yasunari ; Mizukoshi, Eishiro ; Kitahara, Masaaki ; Arihara, Fumitaka ; Sakai, Yoshio ; Kakinoki, Kaheita ; Fujita, Yui ; Marukawa, Yohei ; Arai, Kuniaki ; Yamashita, Tatsuya ; Mukaida, Naofumi ; Matsushima, Kouji ; Matsui, Osamu ; Kaneko, Shuichi
出版情報: Clinical and Experimental Immunology.  163  pp.165-177,  2011-02-01.  Blackwell Publishing
URL: http://hdl.handle.net/2297/26396
概要: 金沢大学医薬保健研究域医学系<br />Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0.1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 106 of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0.046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer. © 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology. 続きを見る
8.

論文

論文
Wada, Takashi ; Sakai, Norihiko ; Sakai, Yoshio ; Matsushima, Kouji ; Kaneko, Shuichi ; Furuichi, Kengo
出版情報: Clinical and Experimental Nephrology.  15  pp.8-13,  2011-02-01.  Japanese Society of Nephrology / Springer Verlag (Germany)
URL: http://hdl.handle.net/2297/26306
概要: 金沢大学医薬保健研究域医学系<br />Cellular mechanisms have been proposed in the pathogenesis of fibrotic processes in the kidney. In t his setting, cell sources underlying the generation of matrix-producing cells in diseased kidneys have been categorized as activated resident stromal cells (e.g., fibroblasts, pericytes), infiltrating bone-marrow-derived cells (e.g., fibrocytes, T cells, macrophages), and cells derived from epithelial-mesenchymal transition/endothelial-mesenchymal transition. Among these cell sources, accumulating evidence has shed light on the involvement of bone-marrow-derived cells, including monocytes/macrophages, and a circulating mesenchymal progenitor cell, fibrocyte, in the progression of fibrosis in kidney. Bone-marrow-derived cells positive for CD45 or CD34, and type 1 (pro)collagen dependent on the chemokine and renin-angiotensin systems migrate into diseased kidneys and enhance synthesis matrix protein, cytokines/chemokines, and profibrotic growth factors, which may promote and escalate chronic inflammatory processes and possible interaction with resident stromal cells, thereby perpetuating kidney fibrosis. © 2010 Japanese Society of Nephrology. 続きを見る
9.

論文

論文
Kakinoki, Kaheita ; Nakamoto, Yasunari ; Kagaya, Takashi ; Tsuchiyama, Tomoya ; Sakai, Yoshio ; Nakahama, Tohru ; Mukaida, Naofumi ; Kaneko, Shuichi
出版情報: Journal of Gene Medicine.  12  pp.1002-1013,  2010-12-01.  Wiley-Blackwell
URL: http://hdl.handle.net/2297/26395
概要: 金沢大学医薬保健研究域医学系<br />The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, largely as a result of i ntrahepatic metastasis. Using a mouse model of intrahepatic metastasis, we investigated whether chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) could potentiate the antitumor effects of the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system.Methods: Mouse hepatoma cells infected with recombinant adenovirus vectors expressing HSV-tk, CCL2/MCP-1 and LacZ at multiplicities of infection of Ad-tk/Ad-MCP1 = 3/0.03 (T/MLow), 3/3 (T/MHigh) and Ad-tk/Ad-LacZ = 3/3 (T/L) were injected into BALB/c mice.Results: Intrahepatic tumor growth was significantly lower in T/MLow mice. By contrast, no tumor suppression was observed in T/MHigh mice. The tumor-specific cytolytic activities of splenocytes from T/MLow and T/MHigh mice were comparable. Immunohistochemical analysis of liver tissues showed similar infiltration by Mac-1+ and T cells in these animals, whereas the proportions of classical activated (M1) monocytes/macrophages were significantly higher in T/MLow mice. In addition, interleukin-12 production was elevated in these tissues. Vascular endothelial growth factor-A expression and CD31+ microvessels were increased in T/MHigh mice.Conclusions: Collectively, these results demonstrate that an adequate amount of CCL2/MCP-1, together with the HSV-tk/GCV system, may induce T helper 1-polarized antitumor effects without inducing tumor angiogenesis in the microenvironment of intrahepatic HCC progression. © 2010 John Wiley & Sons, Ltd. 続きを見る
10.

論文

論文
Sunagozaka, Hajime ; Honda, Masao ; Yamashita, Taro ; Nishino, Ryuhei ; Takatori, Hajime ; Arai, Kuniaki ; Yamashita, Tatsuya ; Sakai, Yoshio ; Kaneko, Shuichi
出版情報: International Journal of Cancer.  129  pp.1576-1585,  2011-11-01.  Wiley-Blackwell
URL: http://hdl.handle.net/2297/29268
概要: The identification of genes involved in tumor growth is crucial for the development of inventive anticancer treatments. Here, we have cloned a 17-kDa secretory protein encoded by c19orf10 from hepatocellular carcinoma (HCC) serial analysis of gene expression libraries. Gene expression analysis indicated that c19orf10 was overexpressed in approximately two-thirds of HCC tissues compared to the adjacent noncancerous liver tissues, and its expression was significantly positively correlated with that of alpha-fetoprotein (AFP). Overexpression of c19orf10 enhanced cell proliferation of AFP-negative HLE cells, whereas knockdown of c19orf10 inhibited cell proliferation of AFP-positive Hep3B and HuH7 cells along with G1 cell cycle arrest. Supplementation of recombinant c19orf10 protein in culture media enhanced cell proliferation in HLE cells, and this effect was abolished by the addition of antibodies developed against c19orf10. Intriguingly, c19orf10 could regulate cell proliferation through the activation of Akt/mitogen-activated protein kinase pathways. Taken together, these data suggest that c19orf10 might be one of the growth factors and potential molecular targets activated in HCC. Copyright © 2010 UICC. 続きを見る