Faculty Profiles - MATSUKAWA Akihiro

Papers - MATSUKAWA Akihiro

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Regulatory T cells function at the early stage of tumor progression in a mouse model of tongue squamous cell carcinoma Reviewed International journal

Kentaro Miki, Yorihisa Orita, Yuka Gion, Soshi Takao, Kyotaro Ohno, Mai Takeuchi, Toshihiro Ito, Hiroyuki Hanakawa, Tomoyasu Tachibana, Hidenori Marunaka, Takuma Makino, Akira Minoura, Akihiro Matsukawa, Kazunori Nishizaki, Tadashi Yoshino, Yasuharu Sato

CANCER IMMUNOLOGY IMMUNOTHERAPY 65 ( 11 ) 1401 - 1410 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The objective of this study was to observe the distribution of regulatory T cells (Tregs) in the development of tongue squamous cell carcinoma (SCC) and to determine the role of Tregs in the progression of tongue SCC. A mouse model of 4-nitroquinoline-1-oxide (4NQO)-induced-tongue SCC was established. The expression of Forkhead box P3 (Foxp3), interleukin 10, transforming growth factor-beta, chemokine CC motif ligands 17, 20, and CC chemokine receptor 4 was determined using real-time quantitative polymerase chain reaction. Foxp3 expression was also analyzed using immunohistochemistry. The results were compared with those of control mice and of 4NQO-treated mice treated with a cyclooxygenase-2 (COX-2) inhibitor. Well to moderately differentiated tongue SCC was induced in all of the experimental mice. The amount of Tregs of the experimental mice was over 10 times as much as control mice at the early stage of tumor progression. COX-2 inhibitor did not prevent the progression of tongue SCC and did not reduce the total amount of Tregs. Tregs function at the early stage of the development of tongue SCC, and it may be effective to suppress Tregs at the early stage of tumor progression for the treatment and/or prevention of tongue SCC.

DOI： 10.1007/s00262-016-1902-x

Sprouty-Related Ena/Vasodilator-Stimulated Phosphoprotein Homology 1-Domain-Containing Protein-2 Critically Regulates Influenza A Virus-Induced Pneumonia Reviewed International journal

Toshihiro Ito, Junya Itakura, Sakuma Takahashi, Miwa Sato, Megumi Mino, Soichiro Fushimi, Masao Yamada, Tuneo Morishima, Steven L. Kunkel, Akihiro Matsukawa

CRITICAL CARE MEDICINE 44 ( 7 ) E530 - E543 2016.7

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Objectives: Influenza A virus causes acute respiratory infections that induce annual epidemics and occasional pandemics. Although a number of studies indicated that the virus-induced intracellular signaling events are important in combating influenza virus infection, the mechanism how specific molecule plays a critical role among various intracellular signaling events remains unknown. Raf/MEK/extracellular signal-regulated kinase cascade is one of the key signaling pathways during influenza virus infection, and the Sprouty-related Ena/vasodilator-stimulated phos-phoprotein homology 1-domain-containing protein has recently been identified as a negative regulator of Raf-dependent extracellular signal-regulated kinase activation. Here, we examined the role of Raf/MEK/extracellular signal-regulated kinase cascade through sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein in influenza A viral infection because the expression of sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein was significantly enhanced in human influenza viral-induced pneumonia autopsy samples.
Design: Prospective animal trial.
Setting: Research laboratory.
Subjects: Wild-type and sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 knockout mice inoculated with influenza A.
Interventions: Wild-type or sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 knockout mice were infected by intranasal inoculation of influenza A (A/PR/8). An equal volume of phosphate-buffered saline was inoculated intranasally into mock-infected mice.
Measurements and Main Results: Influenza A infection of sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 knockout mice led to higher mortality with greater viral load, excessive inflammation, and enhanced cytokine production than wild-type mice. Administration of MEK inhibitor, U0126, improved mortality and reduced both viral load and cytokine levels. Furthermore, bone marrow chimeras indicated that influenza A-induced lung pathology was most severe when sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 expression was lacking in nonimmune cell populations. Furthermore, microarray analysis revealed knockdown of sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 led to enhanced phosphatidylinositol 3-kinase signaling pathway, resulting that viral clearance was regulated by sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 expression through the phosphatidylinositol 3-kinase signaling pathway in murine lung epithelial cells.
Conclusions: These data support an important function of sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 in controlling influenza virus-induced pneumonia and viral replication. Sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 may be a novel therapeutic target for controlling the immune response against influenza influenza A virus infection.

DOI： 10.1097/CCM.0000000000001562

Induction of Monocyte Chemoattractant Proteins in Macrophages via the Production of Granulocyte/Macrophage ColonyStimulating Factor by Breast Cancer Cells Reviewed International journal

Teizo Yoshimura, Tomozumi Imamichi, Jonathan M. Weiss, Miwa Sato, Liangzhu Li, Akihiro Matsukawa, Ji Ming Wang

FRONTIERS IN IMMUNOLOGY 7 ( JAN ) 1524 - 1524 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：FRONTIERS MEDIA SA

Monocyte chemoattractant protein-1 (MCP-1)/CCL2 plays an important role in the initiation and progression of cancer. We previously reported that in 4T1 murine breast cancer, non-tumor stromal cells, including macrophages, were the major source of MCP-1. In the present study, we analyzed the potential mechanisms by which MCP-1 is upregulated in macrophages infiltrating 4T1 tumors. We found that cell free culture supernatants of 4T1 cells (4T1-sup) markedly upregulated MCP-1 production by peritoneal inflammatory macrophages. 4T1-sup also upregulated other MCPs, such as MCP-3/CCL7 and MCP-5/CCL12, but modestly upregulated neutrophil chemotactic chemokines, such as KC/CXCL1 or MIP-2/CXCL2. Physicochemical analysis indicated that an approximately 2-3 kDa 4T1 cell product was responsible for the capacity of 4T1-sup to upregulate MCP-1 expression by macrophages. A neutralizing antibody against granulocyte/macrophage colony stimulating factor (GM-CSF), but not macrophage CSF, almost completely abrogated MCP-1-inducing activity of 4T1-sup, and recombinant GM-CSF potently upregulated MCP-1 production by macrophages. The expression levels of GM-CSF in 4T1 tumors in vivo were higher than other tumors, such as Lewis lung carcinoma. Treatment of mice with anti-GM-CSF antibody significantly reduced the growth of 4T1 tumors at the injection sites but did not reduce MCP-1 production or lung metastasis in tumor-bearing mice. These results indicate that 4T1 cells have the capacity to directly upregulate MCP-1 production by macrophages by releasing GM-CSF; however, other mechanisms are also involved in increased MCP-1 levels in the 4T1 tumor microenvironment.

DOI： 10.3389/fimmu.2016.00002

Iron depletion enhances the effect of sorafenib in hepatocarcinoma Reviewed International journal

Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Takayuki Ninomiya, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Kazuhiro Nouso, Akihiro Matsukawa, Kazuhide Yamamoto, Toshiyoshi Fujiwara

CANCER BIOLOGY & THERAPY 17 ( 6 ) 648 - 656 2016

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS INC

Human hepatocellular carcinoma (HCC) is known to have a poor prognosis. Sorafenib, a molecular targeted drug, is most commonly used for HCC treatment. However, its effect on HCC is limited in clinical use and therefore new strategies regarding sorafenib treatment are required. Iron overload is known to be associated with progression of chronic hepatitis and increased risk of HCC. We previously reported that iron depletion inhibited cancer cell proliferation and conversely induced angiogenesis. Indeed iron depletion therapy including iron chelator needs to be combined with anti-angiogenic drug for its anti-cancer effect. Since sorafenib has an anti-angiogenic effect by its inhibitory targeting VEGFR, we hypothesized that sorafenib could complement the anti-cancer effect of iron depletion. We retrospectively analyzed the relationship between the efficacy of sorafenib and serum iron-related markers in clinical HCC patients. In clinical cases, overall survival was prolonged in total iron binding capacity (TIBC) high- and ferritin low-patients. This result suggested that the low iron-pooled patients, who could have a potential of more angiogenic properties in/around HCC tumors, could be adequate for sorafenib treatment. We determined the effect of sorafenib (Nexavar (R)) and/or deferasirox (EXJADE (R)) on cancer cell viability, and on cell signaling of human hepatocarcinoma HepG2 and HLE cells. Both iron depletion by deferasirox and sorafenib revealed insufficient cytotoxic effect by each monotherapy, however, on the basis of increased angiogenesis by iron depletion, the addition of deferasirox enhanced anti-proliferative effect of sorafenib. Deferasirox was confirmed to increase vascular endothelial growth factor (VEGF) secretion into cellular supernatants by ELISA analysis. In in vivo study sorafenib combined with deferasirox also enhanced sorafenib-induced apoptosis. These results suggested that sorafenib combined with deferasirox could be a novel combination chemotherapy for HCC.

DOI： 10.1080/15384047.2016.1177677

Bone engineering by phosphorylated-pullulan and beta-TCP composite Reviewed International journal

Tomohiro Takahata, Takumi Okihara, Yasuhiro Yoshida, Kumiko Yoshihara, Yasuyuki Shiozaki, Aki Yoshida, Kentaro Yamane, Noriyuki Watanabe, Masahide Yoshimura, Mariko Nakamura, Masao Irie, Bart Van Meerbeek, Masato Tanaka, Toshifumi Ozaki, Akihiro Matsukawa

BIOMEDICAL MATERIALS 10 ( 6 ) 065009 - 065009 2015.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：IOP PUBLISHING LTD

A multifunctional biomaterial with the capacity bond to hard tissues, such as bones and teeth, is a real need for medical and dental applications in tissue engineering and regenerative medicine. Recently, we created phosphorylated-pullulan (PPL), capable of binding to hydroxyapatite in bones and teeth. In the present study, we employed PPL as a novel biocompatible material for bone engineering. First, an in vitro evaluation of the mechanical properties of PPL demonstrated both PPL and PPL/beta-TCP composites have higher shear bond strength than materials in current clinical use, including polymethylmethacrylate (PMMA) cement and a-tricalcium phosphate (TCP) cement, Biopex-R. Further, the compressive strength of PPL/beta-TCP composite was significantly higher than Biopex-R. Next, in vivo osteoconductivity of PPL/beta-TCP composite was investigated in a murine intramedular injection model. Bone formation was observed 5 weeks after injection of PPL/beta-TCP composite, which was even more evident at 8 weeks; whereas, no bone formation was detected after injection of PPL alone. We then applied PPL/beta-TCP composite to a rabbit ulnar bone defect model and observed bone formation comparable to that induced by Biopex-R. Implantation of PPL/beta-TCP composite induced new bone formation at 4 weeks, which was remarkably evident at 8 weeks. In contrast, Biopex-R remained isolated from the surrounding bone at 8 weeks. In a pig vertebral bone defect model, defects treated with PPL/beta-TCP composite were almost completely replaced by new bone; whereas, PPL alone failed to induce bone formation. Collectively, our results suggest PPL/beta-TCP composite may be useful for bone engineering.

DOI： 10.1088/1748-6041/10/6/065009

Early Growth Response-1 Plays an Important Role in Ischemia-Reperfusion Injury in Lung Transplants by Regulating Polymorphonuclear Neutrophil Infiltration. Reviewed International journal

Yamamoto S, Yamane M, Yoshida O, Waki N, Okazaki M, Matsukawa A, Oto T, Miyoshi S

Transplantation 99 ( 11 ) 2285 - 2293 2015.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Early growth response-1 (Egr-1) has been shown to be a trigger-switch transcription factor that is involved in lung ischemia-reperfusion injury (IRI). METHODS: Mouse lung transplants were performed in wild-type (WT) C57BL/6 and Egr1-knockout (KO) mice in the following donor → recipient combinations: WT → WT, KO → WT, WT → KO, and KO → KO to determine whether the presence of Egr-1 in the donor or recipient is the most critical factor for IRI. Pulmonary grafts were retrieved after 18 hours of ischemia after 4 hours of reperfusion. We analyzed graft function by analyzing arterial blood gas and histology in each combination and assessed the effects of Egr1 depletion on inflammatory cytokines that are regulated by Egr-1 as well on polymorphonuclear neutrophil (PMN) infiltration. RESULTS: Deletion of Egr1 improved pulmonary graft function in the following order of donor → recipient combinations: WT → WT < WT → KO < KO → WT < KO → KO. Polymerase chain reaction assays for Il1B, Il6, Mcp1, Mip2, Icam1, and Cox2 showed significantly lower expression levels in the KO → KO group than in the other groups. Immunohistochemistry demonstrated clear Egr-1 expression in the nuclei of pulmonary artery endothelial cells and PMN cytoplasm in the WT grafts. Flow cytometry analysis showed that Egr1 deletion reduced PMN infiltration and that the extent of reduction correlated with graft function. CONCLUSIONS: Both graft and recipient Egr-1 played a role in lung IRI, but the graft side contributed more to this phenomenon through regulation of PMN infiltration. Donor Egr-1 expression in pulmonary artery endothelial cells may play an important role in PMN infiltration, which results in IRI after lung transplantation.

DOI： 10.1097/TP.0000000000000783

Anti-high mobility group box-1 monoclonal antibody treatment provides protection against influenza A virus (H1N1)-induced pneumonia in mice Reviewed International journal

Nobuyuki Nosaka, Masato Yashiro, Mutsuko Yamada, Yosuke Fujii, Hirokazu Tsukahara, Keyue Liu, Masahiro Nishibori, Akihiro Matsukawa, Tsuneo Morishima

CRITICAL CARE 19 ( 249 ) s13054-0 - 249 2015.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Introduction: Provision for the emergence of an influenza pandemic is an urgent issue. The discovery of a novel anti-influenza therapeutic approach would increase the effectiveness of traditional virus-based strategies. This study was undertaken to evaluate the therapeutic effects of anti-high mobility group box-1 (HMGB1) monoclonal antibody (mAb) treatment on influenza A virus (H1N1)-induced pneumonia in mice.
Methods: Nine-week-old male C57BL/6 mice were inoculated with H1N1, then anti HMGB1 mAb or control mAb were administered intravenously at 1, 24 and 48 hours after H1N1 inoculation and the survival rate was analyzed. Lung lavage and histopathological analysis were performed on days 3, 5, 7 and 10 after inoculation.
Results: Anti-HMGB1 mAb significantly improved the survival rate of H1N1-inoculated mice (1 out of 15 versus 8 out of 15 deaths in the anti-HMGB1 mAb-treated group versus the control mAb-treated group, p < 0.01), although the treatment did not affect virus propagation in the lungs. The treatment also significantly attenuated histological changes and neutrophil infiltration in the lungs of H1N1-inoculated mice. This was associated with inhibition of HMGB1 and suppression of inflammatory cytokine/chemokine expression and oxidative stress enhancement, which were observed in H1N1-inoculated mice. The expression of receptor for advanced glycation end products and nuclear factor kappa B was attenuated by the treatment.
Conclusions: Anti-HMGB1 mAb may provide a novel and effective pharmacological strategy for severe influenza virus infection in humans by reducing the inflammatory responses induced by HMGB1.

DOI： 10.1186/s13054-015-0983-9

The anabolic effect of plasma-mediated ablation on the intervertebral disc: stimulation of proteoglycan and interleukin-8 production. Reviewed International journal

Fabrice A Kuelling, Kevin T Foley, Jane J Liu, Ellen Liebenberg, Anthony H Sin, Akihiro Matsukawa, Jeffrey C Lotz

The spine journal : official journal of the North American Spine Society 14 ( 10 ) 2479 - 87 2014.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND CONTEXT: Plasma-mediated radiofrequency-based ablation (coblation) is an electrosurgical technique currently used for tissue removal in a wide range of surgical applications, including lumbar microdiscectomy. In vitro and in vivo studies have shown the technique to alter the expression of inflammatory cytokines in the disc, increasing the levels of interleukin-8 (IL-8), which may promote maturation and remodeling of the disc matrix. PURPOSE: To better understand the effect of coblation treatment, this study characterizes the temporal and spatial pattern of healing after stab injury to the rabbit intervertebral disc, with and without plasma-mediated radiofrequency treatment. PATIENT SAMPLE: A total of 23 New Zealand white rabbits. STUDY DESIGN: Annular and nuclear stab injuries. OUTCOME MEASURES: Sandwich enzyme-linked immunosorbent assay evaluated the concentrations of cytokines tumor necrosis factor-α, IL-1β, and IL-8. Histopathologic evaluations were performed on whole discs and end plates. Tissue sections were stained with Safranin-O to evaluate nucleus pulposus and annulus fibrosus proteoglycan content and with Alcian blue for extracellular proteoglycan content. Intradiscal leakage pressure was evaluated by injecting methylene blue dye into the nucleus. METHODS: Animals underwent annular and nuclear stab injuries on three consecutive lumbar discs (L2-L3 to L4-L5). The three levels were randomly assigned into one of the three groups for treatment with a plasma-mediated radiofrequency ablation device (TOPAZ; ArthroCare Corp., Austin, TX, USA): active treatment of the nucleus only (SN); active treatment of both nucleus and annulus (SNA); sham treatment. Unstabbed/untreated discs from L5-L6 (n=5) served as normal controls. Animals were euthanized at 4, 8, and 28 days postsurgery. RESULTS: Tumor necrosis factor-α was detected in sham discs at 4 and 8 days, but not in coblation groups (SN or SNA); IL-1β was below detection in all three treatment groups. Interleukin-8 levels increased in all treatment groups at 4 and 8 days compared with normal control, peaking at 4th day for sham and SN groups and 8th day (p>.3) for the SNA group (a 2.5-fold increase). Pressure measurements revealed higher leakage in the SN group, but no statistically significant differences. Histopathology showed higher proteoglycan production by 28 days in the SNA and SN groups compared with sham. All three treatment groups showed ruptured annular fibers from the stab injury, but maintained the overall architecture. Remnants of notochordal tissue within the nucleus were evident in all treatment groups at 4 and 8 days, but were only found in sham group by 28 days. At this time, unlike the normal or sham controls, the nucleus of SN and SNA discs had fibrocartilaginous tissue with chondrocyte-like cells. Significant differences in the disc architecture grade were only noted when comparing normal controls with other groups by 28 days (p<.001). CONCLUSIONS: Plasma-mediated radiofrequency ablation appears to have an anabolic effect on disc cells, stimulating proteoglycan and IL-8 production and maintaining annulus architecture. Coblation treatment appears to reduce cellular response to proinflammatory stimuli and restore overall disc architecture that may prove beneficial in a number of degenerative disc paradigms. Further studies are encouraged to investigate the therapeutic effect of the technique.

DOI： 10.1016/j.spinee.2014.04.010

Metastasis of 4T1 murine breast cancer cells to the lung is dependent on the chemokine CCL2/MCP-1 produced by stromal cells in the primary tumor Reviewed

Teizo Yoshimura, O. M. Zack Howard, Toshihiro Ito, Masaki Kuwabara, Akihiro Matsukawa, Keqiang Chen, Ying Liu, Mingyong Liu, Ji Ming Wang

CANCER RESEARCH 74 ( 19 ) 2014.10

Spred-2 Deficiency Exacerbates Lipopolysaccharide-Induced Acute Lung Inflammation in Mice Reviewed International journal

Yang Xu, Toshihiro Ito, Soichiro Fushimi, Sakuma Takahashi, Junya Itakura, Ryojiro Kimura, Miwa Sato, Megumi Mino, Akihiko Yoshimura, Akihiro Matsukawa

PLOS ONE 9 ( 10 ) e108914 2014.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background: Acute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred)-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK)-MAPK pathway, in lipopolysaccharide (LPS)-induced acute lung inflammation.
Methods: Wild-type (WT) mice and Spred-2(-/-) mice were exposed to intratracheal LPS (50 mu g in 50 mu L PBS) to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2(-/-) mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells.
Results: LPS- induced acute lung inflammation was significantly exacerbated in Spred-2(-/-) mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-alpha, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2(-/-) mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells.
Conclusions: The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls the development of LPS-induced lung inflammation by negatively regulating the ERK-MAPK pathway. Thus, Spred-2 may represent a therapeutic target for the treatment of ALI.

DOI： 10.1371/journal.pone.0108914

CPC解説(第59回) シュウ酸カルシウム結晶沈着を伴ったAspergillus nigerによる侵襲性肺アスペルギルス症の1例

板倉淳哉, 伏見聡一郎, 荻野哲也, 伊藤利洋, 小田晋輔, 河原明奈, 萩谷英大, 桑原宏子, 松川昭博

病理と臨床 32 ( 6 ) 669 - 675 2014.6

Chemokine Receptor CCR8 Is Required for Lipopolysaccharide-Triggered Cytokine Production in Mouse Peritoneal Macrophages Reviewed International journal

Tomoyuki Oshio, Rei Kawashima, Yuki I. Kawamura, Teruki Hagiwara, Noriko Mizutani, Toshihiko Okada, Takeshi Otsubo, Kyoko Inagaki-Ohara, Akihiro Matsukawa, Tatsuya Haga, Shigeru Kakuta, Yoichiro Iwakura, Seijiro Hosokawa, Taeko Dohi

PLOS ONE 9 ( 4 ) e94445 2014.4

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Chemokine (C-C motif) receptor 8 (CCR8), the chemokine receptor for chemokine (C-C motif) ligand 1 (CCL1), is expressed in T-helper type-2 lymphocytes and peritoneal macrophages (PM phi) and is involved in various pathological conditions, including peritoneal adhesions. However, the role of CCR8 in inflammatory responses is not fully elucidated. To investigate the function of CCR8 in macrophages, we compared cytokine secretion from mouse PM phi or bone marrow-derived macrophages (BMM phi) stimulated with various Toll-like receptor (TLR) ligands in CCR8 deficient (CCR8(-/-)) and wild-type (WT) mice. We found that CCR8(-/-) PM phi demonstrated attenuated secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10 when stimulated with lipopolysaccharide (LPS). In particular, LPS-induced IL-10 production absolutely required CCR8. CCR8-dependent cytokine secretion was characteristic of PM phi but not BMM phi. To further investigate this result, we selected the small molecule compound R243 from a library of compounds with CCR8-antagonistic effects on CCL1-induced Ca2+ flux and CCL1-driven PM phi aggregation. Similar to CCR8(-/-) PM phi, R243 attenuated secretion of TNF-alpha, IL-6, and most strikingly IL-10 from WT PM phi, but not BMM phi. CCR8(-/-)PM phi and R243-treated WT PM phi both showed suppressed c-jun N-terminal kinase activity and nuclear factor-kappa B signaling after LPS treatment when compared with WT PM phi. A c-Jun signaling pathway inhibitor also produced an inhibitory effect on LPS-induced cytokine secretion that was similar to that of CCR8 deficiency or R243 treatment. As seen in CCR8(-/-) mice, administration of R243 attenuated peritoneal adhesions in vivo. R243 also prevented hapten-induced colitis. These results are indicative of cross talk between signaling pathways downstream of CCR8 and TLR-4 that induces cytokine production by PMQ. Through use of CCR8(-/-) mice and the new CCR8 inhibitor, R243, we identified a novel macrophage innate immune response pathway that involves a chemokine receptor.

DOI： 10.1371/journal.pone.0094445

A novel, visible light-induced, rapidly cross-linkable gelatin scaffold for osteochondral tissue engineering Reviewed International journal

Tetsuro Mazaki, Yasuyuki Shiozaki, Kentaro Yamane, Aki Yoshida, Mariko Nakamura, Yasuhiro Yoshida, Di Zhou, Takashi Kitajima, Masato Tanaka, Yoshihiro Ito, Toshifumi Ozaki, Akihiro Matsukawa

SCIENTIFIC REPORTS 4 4457 - 302 2014.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Osteochondral injuries remain difficult to repair. We developed a novel photo-cross-linkable furfurylamine-conjugated gelatin (gelatin-FA). Gelatin-FA was rapidly cross-linked by visible light with Rose Bengal, a light sensitizer, and was kept gelled for 3 weeks submerged in saline at 37 degrees C. When bone marrow-derived stromal cells (BMSCs) were suspended in gelatin-FA with 0.05% Rose Bengal, approximately 87% of the cells were viable in the hydrogel at 24 h after photo-cross-linking, and the chondrogenic differentiation of BMSCs was maintained for up to 3 weeks. BMP4 fusion protein with a collagen binding domain (CBD) was retained in the hydrogels at higher levels than unmodified BMP4. Gelatin-FA was subsequently employed as a scaffold for BMSCs and CBD-BMP4 in a rabbit osteochondral defect model. In both cases, the defect was repaired with articular cartilage-like tissue and regenerated subchondral bone. This novel, photo-cross-linkable gelatin appears to be a promising scaffold for the treatment of osteochondral injury.

DOI： 10.1038/srep04457

Erythroid and megakaryocytic differentiation of K562 erythroleukemic cells by monochloramine Reviewed

T. Ogino, H. Kobuchi, H. Fujita, A. Matsukawa, K. Utsumi

FREE RADICAL RESEARCH 48 ( 3 ) 292 - 302 2014.3

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

The induction of leukemic cell differentiation is a hopeful therapeutic modality. We studied the effects of monochloramine (NH2Cl) on erythroleukemic K562 cell differentiation, and compared the effects observed with those of U0126 and staurosporine, which are known inducers of erythroid and megakaryocytic differentiation, respectively. CD235 (glycophorin) expression, a marker of erythroid differentiation, was significantly increased by NH2Cl and U0126, along with an increase in c mRNA levels. Other erythroid markers such as. gamma-globin and CD71 (transferrin receptor) were also increased by NH2Cl and U0126. In contrast, CD61 (integrin beta 3) and CD42b (GP1b alpha) expression, markers of megakaryocytic differentiation, was increased by staurosporine, but did not change significantly by NH 2 Cl and U0126. NH2Cl retarded cell proliferation without a marked loss of viability. When ERK phosphorylation (T202/ Y204) and CD235 expression were compared using various chemicals, a strong negative correlation was observed (r =-0.76). Paradoxically, NH2Cl and staurosporine, but not U0126, induced large cells with multiple or lobulated nuclei, which was characteristic to megakaryocytes. NH 2 Cl increased the mRNA levels of gata1 and scl, decreased that of gata2, and did not change those of pu.1 and klf1. The changes observed in mRNA expression were different from those of U0126 or staurosporine. These results suggest that NH2Cl induces the bidirectional differentiation of K562. Oxidative stress may be effective in inducing leukemic cell differentiation.

DOI： 10.3109/10715762.2013.865840

In vitro and in vivo enhanced osteogenesis by kaempferol found by a high-throughput assay using human mesenchymal stromal cells Reviewed

Tetsuro Mazaki, Takashi Kitajima, Yasuyuki Shiozaki, Miwa Sato, Megumi Mino, Aki Yoshida, Mariko Nakamura, Yasuhiro Yoshida, Masato Tanaka, Toshifumi Ozaki, Akihiro Matsukawa, Yoshihiro Ito

JOURNAL OF FUNCTIONAL FOODS 6 241 - 247 2014.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

High-throughput screening was performed as a phenotypic screening on clinically relevant human mesenchymal stem cells to identify small molecules that affect stem cell fate. From a library of pharmacologically active small molecules, we identified kaempferol, which is a natural flavonol, with a high osteogenic activity. Kaempferol achieved the highest levels of bone-specific markers among the chemicals tested in vitro. The osteogenic activity of kaempferol was the same as that of ipriflavone, which is a synthetic isoflavone, in ovariectomized mouse experiments. Considering that kaempferol is present in various foods such as vegetables and fruits, it will be useful as a new preventive medicine for osteoporosis. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jff.2013.10.013

Galectin-9 prolongs the survival of septic mice by expanding tim-3-expressing natural killer T cells and PDCA-1⁺ CD11c⁺ macrophages Reviewed International journal

Takashi Kadowaki, Asahiro Morishita, Toshiro Niki, Junko Hara, Miwa Sato, Joji Tani, Hisaaki Miyoshi, Hirohito Yoneyama, Tsutomu Masaki, Toshio Hattori, Akihiro Matsukawa, Mitsuomi Hirashima

Critical Care 17 ( 6 ) R284 2013.12

Language：English Publishing type：Research paper (scientific journal)

Introduction: Galectin-9 ameliorates various inflammatory conditions including autoimmune diseases by regulating T cell and macrophage/dendritic cell (DC) functions. However, the effect of galectin-9 on polymicrobial sepsis has not been assessed.Methods: We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in mice. The survival rate was compared between galectin-9- and PBS-treated CLP mice. An ELISA was used to compare the levels of various cytokines in the plasma and culture supernatants. Fluorescence-activated cell sorting analysis was further performed to compare the frequencies of subpopulations of spleen cells.Results: Galectin-9 exhibited a protective effect in polymicrobial sepsis as demonstrated in galetin-9 transgenic mice and therapeutic galectin-9 administration. In contrast, such effect was not observed in nude mice, indicating the involvement of T cells in galectin-9-mediated survival prolongation. Galectin-9 decreased TNFα, IL-6, IL-10 and, high mobility group box 1 (HMGB1) and increased IL-15 and IL-17 plasma and spleen levels. Galectin-9 increased the frequencies of natural killer T (NKT) cells and PDCA-1+ CD11c+ macrophages (pDC-like macrophages) but did not change the frequency of CD4 or CD8 T cells, γδT cells or conventional DC. As expected, galectin-9 decreased the frequency of Tim-3+ CD4 T cells, most likely Th1 and Th17 cells. Intriguingly, many spleen NK1.1+ NKT cells and pDC-like macrophages expressed Tim-3. Galectin-9 increased the frequency of Tim-3-expressing NK1.1+ NKT cells and pDC-like macrophages. Galectin-9 further increased IL-17+ NK1.1+ NKT cells.Conclusion: These data suggest that galectin-9 exerts therapeutic effects on polymicrobial sepsis, possibly by expanding NKT cells and pDC-like macrophages and by modulating the production of early and late proinflammatory cytokines. © 2013 Kadowaki et al.; licensee BioMed Central Ltd.

DOI： 10.1186/cc13147

Oxaliplatin-induced liver injury mimicking metastatic tumor on images: a case report. Reviewed International journal

Kaori Uchino, Masayoshi Fujisawa, Takanori Watanabe, Yoshikatsu Endo, Tetsuji Nobuhisa, Yusuke Matsumoto, Kyohei Kai, Shiso Sato, Kenji Notohara, Akihiro Matsukawa

Japanese journal of clinical oncology 43 ( 10 ) 1034 - 8 2013.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatin-induced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such non-neoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment.

DOI： 10.1093/jjco/hyt113

小腸腸間膜嚢胞腺癌の1例

宇田征史, 吉岡貴裕, 伏見卓郎, 佐々木洸太, 松本朝子, 村田年弘, 松川昭博

日本臨床外科学会雑誌 74 ( 4 ) 968 - 972 2013.4

Language：Japanese Publisher：日本臨床外科学会

症例は80歳,男性.直腸S状部癌の精査目的CT検査,MRI検査にて回腸腸間膜に長径12cmの一部に石灰化を伴い造影効果のある充実性成分を伴う嚢胞性腫瘤を認めた.小腸腸間膜嚢胞腺癌,重複腸管,変性したGIST等を鑑別診断とし手術を行った.腫瘤は回腸末端から40から50cmの腸間膜に位置し浸潤傾向はなく腸管切除することなく核出術にて完全切除を行えた.摘出した腫瘤は13×6×5cm,256gで病理検査にて充実性腫瘤部に癌細胞を認め他部位の嚢胞壁には正常の円柱上皮,高円柱状異型細胞への移行像を認め嚢胞腺癌と診断された.腸間膜嚢胞に発生する腸間膜嚢胞腺癌は極めてまれな疾患であるが,今回われわれは直腸S状部癌の術前精査にて偶然発見された小腸腸間膜嚢胞腺癌の1例を経験したので若干の文献的考察を加え報告する.(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J03156&link_issn=&doc_id=20130507160021&doc_link_id=10.3919%2Fjjsa.74.968&url=https%3A%2F%2Fdoi.org%2F10.3919%2Fjjsa.74.968&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

In reply. Reviewed International journal

Yoshimasa Takeda, Hiroshi Hashimoto, Koji Fumoto, Tetsuya Danura, Hiromichi Naito, Naoki Morimoto, Hiroshi Katayama, Soichiro Fushimi, Akihiro Matsukawa, Aiji Ohtsuka, Kiyoshi Morita

Anesthesiology 118 ( 2 ) 469 - 70 2013.2

Pharyngeal Cooling, Brain Temperature Reduction and a Neglect of History Reply Reviewed

Yoshimasa Takeda, Hiroshi Hashimoto, Koji Fumoto, Tetsuya Danura, Hiromichi Naito, Naoki Morimoto, Hiroshi Katayama, Soichiro Fushimi, Akihiro Matsukawa, Aiji Ohtsuka, Kiyoshi Morita

ANESTHESIOLOGY 118 ( 2 ) 469 - 470 2013.2

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