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200901049373548801
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- Haga S, YiMin, Yamaki H, Jin S, Sogon T, Morita N, Ozaki MBioscience, biotechnology, and biochemistry 83 (11) 2110 - 2120 0916-8451 2019/11 [Refereed][Not invited]
ABSTRACT Bilberry has been reported to have anti-oxidant and anti-inflammatory properties. We studied the effect of bilberry (Vaccinium myrtillus L.) fruits extracts (BEs) on the pathogenesis caused by lipid accumulation in fatty liver and non-alcoholic steatohepatitis (NASH). 5 μg/ml of BEs was enough to suppress lipid accumulation in the fatty liver model of the mouse hepatic AML12 cells. BEs increased cell viability and anti-oxidant capacity, presumably by activating (phosphorylating) Akt/STAT3 and inducing MnSOD/catalase. BEs also significantly reduced Rubicon and induced p62/SQSTM1, possibly contributing to reduce cellular lipids (lipophagy). When the mice were fed supplemented with BEs (5% or 10%, w/w), hepatic steatosis, injury, and hypercholesterolemia/hyperglycemia were significantly improved. Furthermore, histological and cytokine studies indicated that BEs possibly suppress hepatic inflammation (hepatitis) and fibrosis. Therefore, BEs improved liver steatosis and injury, and potentially suppress fibrosis by suppressing inflammatory response, which therefore may prevent the progression of fatty liver to NASH. - Naznin Khadiza, Tomoka Hasegawa, Tomoya Nagai, Tomomaya Yamamoto, Yukina Miyamoto-Takasaki, Hiromi Hongo, Miki Abe, Mai Haraguchi, Tsuneyuki Yamamoto, Yimin, Zixuan Qiu, Muneteru Sasaki, Shinichiro Kuroshima, Hayato Ohshima, Paulo Henrique Luiz de Freitas, Minqi Li, Yasutaka Yawaka, Norio AmizukaBiomedical research (Tokyo, Japan) 40 (4) 133 - 143 0388-6107 2019 [Refereed][Not invited]
In this study, we attempted to localize the immunoreactivities of podoplanin/E11/gp38 and CD44, a counterpart possessing a high affinity to podoplanin/E11/gp38, as well as endomucin-immunoreactive blood vessels in the regions of odontoblast layers and the underlying sub-odontoblastic layers in murine tooth germs. Endomucin-reactive small blood vessels were scattered throughout the dental papillae of the tooth germs at postnatal day 1 but came to be localized close to the odontoblast/sub-odontoblastic layers until day 3. After postnatal day 5, small blood vessels were seen in odontoblast cell layers, while blood vessels with relatively larger diameters were seen forming in sub-odontoblastic layers. Immunoreactivities of podoplanin/E11/gp38 and CD44 were not detectable in the cells of dental papillae facing the inner enamel epithelium at postnatal day 1. However, at around postnatal days 3-5, podoplanin/E11/gp38 was localized in the odontoblast layer but not in the sub-odontoblastic layer, whereas CD44 was observed in the sub-odontoblastic layer but not in the odontoblast layer. The exclusive immunolocalization of podoplanin/E11/gp38 and CD44 in the odontoblast layers and sub-odontoblastic layers was seen after postnatal day 3 of the tooth germs, when the mesenchymal cells of dental papillae have already differentiated into mature odontoblasts at the cusp tip. Taken together, it seems likely that endomucin-reactive small blood vessels extended to the podoplanin/E11/gp38-positive odontoblast layers, whereas endomucin-reactive large blood vessels were already present in CD44-immmunopositive sub-odontoblastic layer, indicating the cellular regulation on the vascularization of endomucin-reactive endothelial cells during odontogenesis of the tooth germs. - Sanae Haga, Takeaki Ozawa, Naoki Morita, Mami Asano, Shigeki Jin, Yimin, Michitaka OzakiOncology Research 26 (3) 467 - 472 1555-3906 2018 [Refereed][Not invited]
Akt is commonly overexpressed and activated in cancer cells and plays a pivotal role in cell survival, protection, and chemoresistance. Therefore, Akt is one of the target molecules in understanding characters of cancer cells and developing anticancer drugs. Here we examined whether a newly developed photo-activatable Akt (PA-Akt) probe, based on a light-inducible protein interaction module of plant cryptochrome2 (CRY2) and cryptochrome-interacting basic helix–loop–helix (CIB1), can regulate Akt-associated cell functions. By illuminating blue light to the cells stably transfected with PA-Akt probe, CRY2-Akt (a fusion protein of CRY2 and Akt) underwent a structural change and interacted with Myr-CIBN (myristoylated N-terminal portion of CIB1), anchoring it at the cell membrane. Western blot analysis revealed that S473 and T308 of the Akt of probe-Akt were sequentially phosphorylated by intermittent and continuous light illumination. Endogenous Akt and GSK-3b, one of the main downstream signals of Akt, were also phosphorylated, depending on light intensity. These facts indicate that photo-activation of probe-Akt can activate endogenous Akt and its downstream signals. The photo-activated Akt conferred protection against nutritional deprivation and H2O2 stresses to the cells significantly. Using the newly developed PA-Akt probe, endogenous Akt was activated easily, transiently, and repeatedly. This probe will be a unique tool in studying Akt-associated specific cellular functions in cancer cells and developing anticancer drugs. - Sanae Haga, Yimin, Michitaka OzakiBMC GASTROENTEROLOGY 17 1471-230X 2017/01 [Refereed][Not invited]
Background: Liver injury and regeneration involve complicated processes and are affected by various physiopathological conditions. Surgically, severe liver injury after surgical resection often leads to fatal liver failure, especially with some underlying pathological conditions such as steatosis. Therefore, protection from the injury of hepatocytes and liver is a serious concern in various clinical settings. Methods: We studied the effects of the farnesoid X receptor (FXR) on cell survival and steatosis in mouse hepatocytes (AML12 mouse liver cells) and investigated their molecular mechanisms. We next studied whether or not FXR improves liver injury, regeneration and steatosis in a mouse model of partial hepatectomy (PH) with steatosis. Results: An FXR-specific agonist, GW4064, induced expressions of the p62/SQSTM1 gene and protein in AML12 mouse liver cells. Because we previously reported p62/SQSTM1 as a key molecule for antioxidation and cell survival in hepatocytes, we next examined the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) and induction of the antioxidant molecules by GW4064. GW4064 activated Nrf2 and subsequently induced antioxidant molecules (Nrf2, catalase, HO-1, and thioredoxin). We also examined expressions of pro-survival and cell protective molecules associated with p62/SQSTM1. Expectedly, GW4064 induced phosphorylation of Akt, expression of the anti-apoptotic molecules (Bcl-xL and Bcl-2), and reduced harmful hepatic molecules (Fas ligand and Fas). GW4064 promoted hepatocyte survival, which was cancelled by p62/SQSTM1 siRNA. These findings suggest the potential relevance of the FXR-p62/SQSTM1 pathway for the survival and protection of hepatocytes. Furthermore, GW4064 induced the expression of small heterodimer partners (SHP) and suppressed liver X receptor (LXR)-induced steatosis in hepatocytes, expecting the in vivo protective effect of FXR on liver injury especially with steatosis. In the hepatectomy model of db/db mice with fatty liver, pre-treatment by GW4064 significantly reduced post-PH liver injury (serum levels of LDH, AST & ALT and histological study) and improved steatosis. The key molecules, p62/SQSTM1, Nrf2 and SHP were upregulated in fatty liver tissue by GW4064 treatment. Conclusions: The present study is the first to demonstrate the relevance of FXR-p62/SQSTM1 and-SHP in the protection against injury of hepatocytes and post-PH liver, especially with steatosis. - Bo Liu, Jian Cui, Jing Sun, Juan Li, Xiuchun Han, Jie Guo, Min Yi, Norio Amizuka, Xin Xu, Minqi LiMOLECULAR MEDICINE REPORTS 14 (2) 1099 - 1106 1791-2997 2016/08 [Refereed][Not invited]
The aim of the present study was to investigate the expression of matrix metalloproteinase (MMP) 9 and MMP2, and their potential roles in bone metastasis nests using a well-standardized model of breast cancer bone metastasis in nude mice. BALB/c nu/nu mice (5-week-old; n=10) were subjected to intracardiac injection of MDA-MB-231 human breast cancer cells. After 4 weeks, the mice exhibiting radiolucent lesions in tibiae were sacrificed, and the tibiae were removed for histochemical analysis. The gene expression of MMP2 and MMP9 in the tumor cells, metaphysis and diaphysis of normal BALB/c nu/nu mice were determined using reverse transcription-polymerase chain reaction analysis. The metastatic tumor tissue occupied almost the entire bone marrow cavity. Numerous tartrate-resistant acid phosphatase-positive osteoclasts were found in the metastasized lesions. The invaded tumor cells positive for mammaglobin 1 exhibited different proliferation activities and apoptosis between the metaphysis and diaphysis. Proliferating cell nuclear antigen was expressed at high levels in the metaphyseal area, whereas TdT-mediated dUTP nick-end labeling (TUNEL) -positive cells were more evident in the diaphysis area. Of note, MMP9 was expressed predominantly in the proliferating cell nuclear antigen-positive area, whereas the expression of MMP2 was observed predominantly in the diaphysis, which had more TUNEL-positive cells. Taken together, the results suggested that MMP9 and MMP2 may have their own importance in extracellular matrix degradation and trabecular bone damage in different zones of bone metastasis, including the metaphysis and diaphysis. - Mitsugu Watanabe, Hirotoshi Fuda, Hiroaki Okabe, Sae Joko, Yusuke Miura, Shu-Ping Hui, Yimin, Naohiro Hamaoka, Emiko Miki, Hitoshi ChibaJOURNAL OF FUNCTIONAL FOODS 20 516 - 531 1756-4646 2016/01 [Refereed][Not invited]
The phenolic compound 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA) is a natural antioxidant recently isolated from the Pacific oyster. DHMBA, up to a concentration of 500 mu M, has demonstrated a strong in vitro hepatocyte-protective effect from oxidative stress without any cytotoxicity. This study investigated the in vivo potential of DHMBA-rich oyster extracts (DOE) for prevention or attenuation of non-alcoholic steatohepatitis (NASH). NASH-model mice, developed by supplementation of a high-fat diet for 23 weeks and intravenous injections of oxidised low-density lipoproteins, exhibited obesity, insulin resistance, hepatic steatosis, inflammation, fibrosis, and apoptosis. These changes were significantly moderated by supplementation of DOE. The search for an underlying mechanism determined that DOE significantly improved the redox status of DNA, proteins, and lipids. Moreover, DOE suppressed the increase of hepatic expression of PPARy and CD36 (fatty acid transporter) in the NASH-model mice. DOE might serve as a functional food for people at elevated risk for NASH. (C) 2015 The Authors. Published by Elsevier Ltd. - Wei Feng, Bo Liu, Di Liu, Tomoka Hasegawa, Wei Wang, Xiuchun Han, Jian Cui, Yimin, Kimimitsu Oda, Norio Amizuka, Minqi LiJOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY 64 (1) 42 - 53 0022-1554 2016/01 [Refereed][Not invited]
In this study, we aimed to evaluate the influence of diet-induced obesity on IL-6 deficiency-induced bone remodeling abnormality. Seven-week-old IL-6(-/-) mice and their wild type (WT) littermates were fed a standard diet (SD) or high-fat diet (HFD) for 25 weeks. Lipid formation and bone metabolism in mice tibiae were investigated by histochemical analysis. Both IL-6(-/-) and WT mice fed the HFD showed notable body weight gain, thickened cortical bones, and adipose accumulation in the bone marrow. Notably, the HFD normalized the bone phenotype of IL-6(-/-) mice to that of their WT counterpart, as characterized by a decrease in bone mass and the presence of an obliquely arranged, plate-like morphology in the trabecular bone. Alkaline phosphatase and osteocalcin expressions were attenuated in both genotypes after HFD feeding, especially for the IL-6(-/-) mice. Meanwhile, tartrate-resistant acid phosphatase staining was inhibited, osteoclast apoptosis rate down-regulated (revealed by TUNEL assay), and the proportion of cathepsin K (CK)-positive osteoclasts significantly increased in IL-6(-/-) mice on a HFD as compared with IL-6(-/-) mice on standard chow. Our results demonstrate that HFD-induced obesity reverses IL-6 deficiency-associated bone metabolic disorders by suppressing osteoblast activity, upregulating osteoclastic activity, and inhibiting osteoclast apoptosis. - Juan Li, Wei Feng, Bo Liu, Bao Sun, Xiuchun Han, Juan Du, Jing Sun, Yimin, Jian Cui, Jie Guo, Akira Kudo, Norio Amizuka, Minqi LiJOURNAL OF MOLECULAR HISTOLOGY 46 (3) 303 - 311 1567-2379 2015/06 [Refereed][Not invited]
Periostin is essential for the integrity and function of the periodontal ligament (PDL), and periostin knockout is related to an enhanced inflammatory status in PDL. High mobility group box 1 (HMGB1), a late inflammatory cytokine, is up-regulated in PDL cells in response to mechanical stress. This study aimed to investigate the effect of periostin deficiency (Pn-/-) on HMGB1 expression in PDL during orthodontic tooth movement. We used 8-week-old male mice homozygous for the disrupted periostin gene and their wild-type (WT) littermates. Tooth movement was performed according to Waldo's method, in which 0.5-mm-thick elastic bands were inserted between the first and second upper molars of anesthetized mice. After 3 days of mechanical loading, mice were fixed by transcardial perfusion of 4 % paraformaldehyde in phosphate buffer, and the maxilla was extracted for histochemical analyses. Compared with the WT group, Pn-/- mice showed higher basal expression of HMGB1 in the absence of mechanical loading. Following 3 days of orthodontic tooth movement, the PDL in the compression side of both groups was almost replaced by cell-free hyaline zones, and Pn-/- mice showed a much wider residual PDL than WT mice. In the tension side, the number of HMGB1-positive cells in PDL in both Pn-/- and WT groups increased remarkably without a significant difference between the two groups. Our findings suggest an inhibitory effect of periostin on HMGB1 production by PDL and confirmed the critical role of periostin in integrity of PDL collagen fibrils during orthodontic tooth movement, although mechanical loading is the predominant stimulant of HMGB1 expression relative to periostin deficiency. - Hongrui Liu, Jian Cui, Jing Sun, Juan Du, Wei Feng, Bao Sun, Juan Li, Xiuchun Han, Bo Liu, Yimin, Kimimitsu Oda, Norio Amizuka, Minqi LiJOURNAL OF MOLECULAR HISTOLOGY 46 (3) 313 - 323 1567-2379 2015/06 [Refereed][Not invited]
The purpose of this study was to investigate the effect of zoledronate (ZA) on osteoclast functions and viability in the tibiae of 8-week-old male mice. After weekly intravenous administration of ZA (125 mu g/kg body weight) for 8 weeks, the mice were fixed by transcardial perfusion of 4 % paraformaldehyde under anesthesia, and their tibiae were extracted for histochemical analysis. Compared with the control group, many tartrate-resistant acidic phosphatase-positive osteoclasts were found on the surface of the trabecular bone, but cartilage cores were obviously increased in the metaphysis of the ZA group. Osteoclasts of both groups showed similar expression of cathepsin K and matrix metalloproteinase-9. However, hardly any expression of c-src, a gene necessary for ruffled border formation and bone resorption, was found in osteoclasts of the ZA group. Moreover, no expression of CD44 or osteopontin (OPN) was observed in osteoclasts of the ZA group. Taken together, our findings suggest that ZA administration decreases the bone resorption ability of osteoclasts by inhibiting c-src expression and suppressing osteoclast adhesion by interfering with CD44/OPN binding. - Hongrui Liu, Jian Cui, Wei Feng, Shengyu Lv, Juan Du, Jing Sun, Xiuchun Han, Zhenming Wang, Xiong Lu, Yimin, Kimimitsu Oda, Norio Amizuka, Minqi LiMATERIALS SCIENCE & ENGINEERING C-MATERIALS FOR BIOLOGICAL APPLICATIONS 49 14 - 24 0928-4931 2015/04 [Refereed][Not invited]
The aim of this study was to investigate the influence of calcitriol on osteoinduction following local administration into mandibular bone defects. Calcitriol-loaded absorbable collagen membrane scaffolds were prepared using the polydopamine coating method and characterized by scanning electron microscopy. Composite scaffolds were implanted into rat mandibular bone defects in the following groups: no graft material (control), bare collagen membrane (CM group), collagen membrane bearing polydopamine coating (DOP/CM group), and collagen membrane bearing polydopamine coating absorbed with calcitriol (CAL/DOP/CM group). At 1, 2, 4 and 8 weeks post-surgery, the osteogenic potential of calcitriol was examined by histological and immunohistochemical methods. Following in vivo implantation, calcitriol-loaded composite scaffolds underwent rapid degradation with pronounced replacement by new bone and induced reunion of the bone marrow cavity. Calcitriol showed strong potential in inhibiting osteoclastogenesis and promotion of osteogenic differentiation at weeks 1, and 2. Furthermore, statistical analysis revealed that the newly formed bone volume in the CAL/DOP/CM group was significantly higher than other groups at weeks 1, and 2. At weeks 4, and 8, the CAL/DOP/CM group showed more mineralized bone and uniform collagen structure. These data suggest that local administration of calcitriol is promising in promoting osteogenesis and mineralization for restoration of mandibular bone defects. (C) 2014 Elsevier B.V. All rights reserved. - Yimin, Masashi Kohanawa, Songji Zhao, Minqi Li, Yuji Kuge, Nagara Tamaki, Masahiko WatanabeJOURNAL OF INTERFERON AND CYTOKINE RESEARCH 35 (3) 222 - 231 1079-9907 2015/03 [Refereed][Not invited]
Interleukin (IL)-4 promotes the regression of granulomas during the late phase of Rhodococcus aurantiacus infection. In this study, the contribution of IL-4 to the initial response against this bacterium was investigated using IL-4-deficient mice. Compared with wild-type (WT) mice, IL-4-deficient mice displayed remarkably lower tumor necrosis factor (TNF)-alpha and IL-6 secretion in the liver, spleen, and blood at the initial phase of infection, along with improved survival. IL-4-deficient mice also showed diminished IL-10 secretion in the spleen and blood; however, hepatic IL-10 levels were similar to those observed in WT animals, and were concomitant with augmented interferon (IFN)-gamma production and decreased bacterial burden in the liver at the early infection phase. Histological examination revealed reduced hepatic granuloma formation in infected IL-4-deficient mice. On challenge with heat-killed R. aurantiacus, IL-4-deficient mouse macrophages showed reduced expression of TNF-alpha, IL-6, and IL-10 at both the gene and protein levels compared with WT mouse cells. These findings indicate that during the initiation of R. aurantiacus-induced inflammation, IL-4 deficiency attenuates cytokine responses in macrophages, which contributes to amelioration in mouse survival and reduction of granulomatous inflammation, and augments a hepatic IFN-gamma response which transiently accelerates bacterial elimination. - Chikayo Yamane, Tomohiro Yamazaki, Shinji Nakamura, Junji Matsuo, Kasumi Ishida, Sumire Yamazaki, Satoshi Oguri, Natsumi Shouji, Yasuhiro Hayashi, Mitsutaka Yoshida, Yimin, Hiroyuki YamaguchiPLOS ONE 10 (2) e0116486 1932-6203 2015/02 [Refereed][Not invited]
Ancient chlamydiae diverged into pathogenic and environmental chlamydiae 0.7-1.4 billion years ago. However, how pathogenic chlamydiae adapted to mammalian cells that provide a stable niche at approximately 37 degrees C, remains unknown, although environmental chlamydiae have evolved as endosymbionts of lower eukaryotes in harsh niches of relatively low temperatures. Hence, we assessed whether an environmental chlamydia, Parachlamydia Bn-9, could grow in human HEp-2 cells at a low culture temperature of 30 degrees C. The assessment of inclusion formation by quantitative RT-PCR revealed that the numbers of bacterial inclusion bodies and the transcription level of 16SrRNA significantly increased after culture at 30 degrees C compared to at 37 degrees C. Confocal microscopy showed that the bacteria were located close to HEp-2 nuclei and were actively replicative. Transmission electron microscopy also revealed replicating bacteria consisting of reticular bodies, but with a few elementary bodies. Cytochalasin D and rifampicin inhibited inclusion formation. Lactacystin slightly inhibited bacterial inclusion formation. KEGG analysis using a draft genome sequence of the bacteria revealed that it possesses metabolic pathways almost identical to those of pathogenic chlamydia. Interestingly, comparative genomic analysis with pathogenic chlamydia revealed that the Parachlamydia similarly possess the genes encoding Type III secretion system, but lacking genes encoding inclusion membrane proteins (IncA to G) required for inclusion maturation. Taken together, we conclude that ancient chlamydiae had the potential to grow in human cells, but overcoming the thermal gap was a critical event for chlamydial adaptation to human cells. - Staging liver fibrosis by analysis of non-linear normalization texture in gadolinium-enhanced magnetic resonance imaging.Mou W, Guo D, Liu H, Zhang p, Shao Y, Wang S, Yimin, Zheng LBiomedical Physics & Engineering Express (045012) 045012. 2015 [Refereed][Not invited]
- Hui Liu, Xiaomiao Shi, Dongmei Guo, Zuowei Zhao, YiminBIOMED RESEARCH INTERNATIONAL 2015 263586 2314-6133 2015 [Refereed][Not invited]
It is crucial to understand the specificity of HIV-1 protease for designing HIV-1 protease inhibitors. In this paper, a new feature selection method combined with neural network structure optimization is proposed to analyze the specificity of HIV-1 protease and find the important positions in an octapeptide that determined its cleavability. Two kinds of newly proposed features based on Amino Acid Index database plus traditional orthogonal encoding features are used in this paper, taking both physiochemical and sequence information into consideration. Results of feature selection prove that p2, p1, p1', and p2' are the most important positions. Two feature fusion methods are used in this paper: combination fusion and decision fusion aiming to get comprehensive feature representation and improve prediction performance. Decision fusion of subsets that getting after feature selection obtains excellent prediction performance, which proves feature selection combined with decision fusion is an effective and useful method for the task of HIV-1 protease cleavage site prediction. The results and analysis in this paper can provide useful instruction and help designing HIV-1 protease inhibitor in the future. - Hongrui Liu, Wei Feng, Yimin, Jian Cui, Shengyu Lv, Tomoka Hasegawa, Bao Sun, Juan Li, Kimimitsu Oda, Norio Amizuka, Minqi LiJOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY 62 (8) 556 - 564 0022-1554 2014/08 [Refereed][Not invited]
Interleukin-6 (IL-6) is a multifunctional cytokine considered to modulate bone homeostasis. Based on previous contradictory studies, we aimed to verify the influence of IL-6 deficiency on bone remodeling using an IL-6 knockout (IL-6-/-) murine model. Eight-month-old male mice, homozygous for the disrupted IL-6 gene, and their wild type (WT) littermates (control), were used. After transcardiac perfusion, tibiae were removed for histochemical analysis. Compared with the control group, IL-6 deficiency increased tartrate resistant acid phosphatase (TRAP)-positive osteoclast numbers and up-regulated the alkaline phosphatase (ALP) activity of osteoblasts in the metaphysis of the tibia. However, further analysis of serial histological sections from IL-6-/- ice found a significant discrepancy in osteoclast number, with the higher number of TRAP-positive osteoclasts conflicting with the lower number of cathepsin K-positive osteoclasts. Moreover, TUNEL staining identified a significantly higher rate of osteoclast apoptosis in IL-6-/- ice as compared with their WT controls. IL-6 deficiency induced abundant TRAP-positive osteoclasts but delayed bone remodeling by significantly inhibiting the bone resorption activity of osteoclasts and promoting osteoclast apoptosis. - Yimin, Masashi Kohanawa, Songji Zhao, Michitaka Ozaki, Sanae Haga, Guangxian Nan, Yuji Kuge, Nagara TamakiPLoS ONE 8 (9) e74287 1932-6203 2013/09/13 [Refereed][Not invited]
Staphylococcus aureus is a common pathogen that causes a wide range of infectious diseases. The function of TLRs, specifically TLR2, during S. aureus infection is still debated. In this study, we investigated the extent to which TLR2 contributes to the host innate response against the bacterial infection using TLR2-deficient mice. Intravenous inoculation with S. aureus resulted in all TLR2-deficient mice dying within 4 d, along with a high bacterial burden in the livers. However, histological examination showed the same degree of macrophage and neutrophil accumulation in the livers of infected TLR2-deficient mice as that in infected wild-type (WT) mice. TLR2-deficient mouse macrophages also showed normal phagocytic activity, although they failed to express CD36 that appeared on the surface of WT mouse cells upon challenge with heat-killed S. aureus. These data indicate that TLR2, as well as CD36, does not directly affect S. aureus clearance and that CD36 expression on macrophages depends on the presence of TLR2. In vivo infection with S. aureus caused significantly elevated production of TNF-α and IL-6 in the livers and blood of TLR2-deficient mice compared with those in WT mice, while the hepatic and serum levels of IL-10 decreased in these mice. In contrast, lower expression of IL-6 and IL-10, but not of TNF-α, at both the gene and protein levels was found in TLR2-deficient mouse macrophages compared to that in WT mouse cells, in response to challenge with heat-killed S. aureus. These findings suggest that the S. aureus-induced pro-inflammatory cytokine response is not dependent on macrophages and that TLR2 deficiency results in decreased IL-10 release by macrophages, which contributes to dysregulated cytokine balance, impaired bacterial clearance, and mouse death. Therefore, TLR2 possesses a protective function during S. aureus infection by regulating pro- and anti-inflammatory cytokine responses. © 2013 Yimin et al. - Kasumi Ishida, Takeru Kubo, Ayumi Saeki, Chikayo Yamane, Junji Matsuo, Yimin, Shinji Nakamura, Yasuhiro Hayashi, Miyuki Kunichika, Mitsutaka Yoshida, Kaori Takahashi, Itara Hirai, Yoshimasa Yamamoto, Ken-ichiro Shibata, Hiroyuki YamaguchiMICROBES AND INFECTION 15 (3) 192 - 200 1286-4579 2013/03 [Refereed][Not invited]
Lymphocytes are a potential host cell for Chlamydophila pneumoniae, although why the bacteria must hide in lymphocytes remains unknown. Meanwhile, interferon (IFN)-gamma is a crucial factor for eliminating chlamydiae from infected cells through indoleamine 2,3-dioxygenase (IDO) expression, resulting in depletion of tryptophan. We therefore assessed if lymphocytes could work as a shelter for the bacteria to escape IFN-gamma. C. pneumoniae grew normally in human lymphoid Jurkat cells, even in the presence of IFN-gamma or under stimulation with phorbol myristate acetate plus ionomycin. Although Jurkat cells expressed IFN-gamma receptor CD119, their lack of IDO expression was confirmed by RT-PCR and western blotting. Also, C. pneumoniae survived in enriched human peripheral blood lymphocytes, even in the presence of IFN-gamma. Furthermore, C. pneumoniae in spleen cells obtained from IFN-gamma knockout mice with C57BL16 background was maintained in a similar way to wild-type mice, supporting a minimal role of]FN-gamma-related response for eliminating C. pneumoniae from lymphocytes. Thus, we concluded that IFN-gamma did not remove C. pneumoniae from lymphocytes, possibly providing a shelter for C. pneumoniae to escape from the innate immune response, which has direct clinical significance. (C) 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. - Masanori Sato, Kazuaki Nakanishi, Sanae Haga, Masato Fujiyoshi, Motoi Baba, Kazuhiro Mino, Yimin, Haruki Niwa, Hideki Yokoo, Kazuo Umezawa, Yoshihiro Ohmiya, Toshiya Kamiyama, Satoru Todo, Akinobu Taketomi, Michitaka OzakiONCOLOGY RESEARCH 6 21 (6) 333 - 343 0965-0407 2013 [Refereed][Not invited]
The transcription factor nuclear factor-kappa B (NF-kappa B) plays a crucial role in pancreatic cancer (PC) progression. NF-kappa B is also involved in resistance to anoikis, a special type of apoptosis induced when cells are detached from the extracellular matrix or other cells. Anoikis resistance is related to the metastatic abilities of tumor cells; however, little is known about anoikis induction as it relates to inhibition of PC metastasis by NF-kappa B inhibitors. Here we used a specific NF-kappa B inhibitor, (-)-dehydroxymethylepoxyquinomicin (DHMEQ), to investigate anoikis induction and peritoneal metastasis suppression following NF-kappa B inhibition. We transduced Glue, a secretory form of luciferase, into a PC cell line, AsPC-1 (AsPC-1-Gluc), for our in vivo experiments. (-)-DHMEQ induced anoikis in AsPC-1-Gluc cells as measured by cell survival assays and flow cytometry. The DNA-binding activity of p65 was enhanced immediately after cell detachment from culture dishes in ELISA assays. Some antiapoptotic proteins such as cellular inhibitor of apoptotic protein-1 were consequently upregulated on Western blots. (-)-DHMEQ prevented this increase in p65 activity and the subsequent expressions of antiapoptotic molecules. In a murine xenograft model, anoikis-resistant PC cell lines tended to metastasize to the peritoneum more than anoikis-sensitive cells, suggesting a correlation between anoikis sensitivity and peritoneal metastasis. (-)-DHMEQ successfully inhibited peritoneal metastasis of AsPC-1-Gluc cells. We monitored metastasis inhibition by ex vivo chemiluminescent detection of Glue secreted from tumor cells into murine plasma and by in vivo imaging. Our results suggest that (-)-DHMEQ inhibited peritoneal dissemination by preventing anoikis resistance of PC cells. - Yimin, Huirong Tao, Masashi Kohanawa, Songji Zhao, Yuji Kuge, Nagara TamakiBIOLOGICAL & PHARMACEUTICAL BULLETIN 35 (12) 2214 - 2223 0918-6158 2012/12 [Refereed][Not invited]
The healthy drink Pairogen is mainly composed of ferrous ferric chloride water that reportedly changes the status of intracellular water from oxidative to antioxidative. Here, we investigated whether Pairogen affects host immune function in a murine model of granulomatous inflammation in response to Rhodococcus aurantiacus (R. aurantiacus) infection. Longitudinal ingestion of Pairogen markedly improved the survival of infected mice in a concentration-dependent manner. Compared to mice received water, mice that ingested 10-fold-diluted Pairogen displayed rapid bacterial elimination, decreased production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and high levels of IL-10 in organs during the initial phase of infection. Moreover, histological studies showed significant reduction in the number and size of granulomas as well as amelioration of oxidative stress in the livers of mice ingested 10-fold-diluted Pairogen at 14d post-infection. These characteristics were further pronounced in first-generation (F1) mice that also ingested 10-fold-diluted Pairogen. Following stimulation with heat-killed R. aurantiacus, the production of TNF-alpha, IL-6, and IL-10 by macrophages from F1 mice was similar to that detected in vivo, while their gene expression levels in these cells were significantly lower than the levels in macrophages from mice received water. Heat-killed R. aurantiacus also induced the expression of heme oxygenase-1 mRNA in the cells from F1 mice. Taken together, these results indicate that Pairogen contributes to the negative regulation of the immuno-inflammatory response to R. aurantiacus infection in mice by modulating the cellular redox state. Longitudinal ingestion of Pairogen further enhances the defense function in mouse progeny. - Hiroshi Hirata, Yimin, Shuichi Segawa, Moeko Ozaki, Naoyuki Kobayashi, Tatsuro Shigyo, Hitoshi ChibaPLOS ONE 7 (11) e49415 1932-6203 2012/11 [Refereed][Not invited]
Background: Xanthohumol is expected to be a potent anti-atherosclerotic agent due to its inhibition of cholesteryl ester transfer protein (CETP). In this study, we hypothesized that xanthohumol prevents atherosclerosis in vivo and used CETP-transgenic mice (CETP-Tg mice) to evaluate xanthohumol as a functional agent. Methodology/Principal Findings: Two strains of mice, CETP-Tg and C57BL/6N (wild-type), were fed a high cholesterol diet with or without 0.05% (w/w) xanthohumol ad libitum for 18 weeks. In CETP-Tg mice, xanthohumol significantly decreased accumulated cholesterol in the aortic arch and increased HDL cholesterol (HDL-C) when compared to the control group (without xanthohumol). Xanthohumol had no significant effect in wild-type mice. CETP activity was significantly decreased after xanthohumol addition in CETP-Tg mice compared with the control group and it inversely correlated with HDL-C (%) (P<0.05). Furthermore, apolipoprotein E (apoE) was enriched in serum and the HDL-fraction in CETP-Tg mice after xanthohumol addition, suggesting that xanthohumol ameliorates reverse cholesterol transport via apoE-rich HDL resulting from CETP inhibition. Conclusions: Our results suggest xanthohumol prevents cholesterol accumulation in atherogenic regions by HDL-C metabolism via CETP inhibition leading to apoE enhancement. - Yasuhiro Hayashi, Yimin, Junji Matsuo, Shinji Nakamura, Miyuki Kunichika, Mitsutaka Yoshida, Kaori Takahashi, Hiroyuki YamaguchiMICROBIOLOGY-SGM 158 (6) 1607 - 1614 1350-0872 2012/06 [Refereed][Not invited]
Parachlamydia acanthamoebae is an obligate intracellular bacterium that infects free-living amoebae (Acanthamoeba), and is a potential human pathogen associated with hospital-acquired pneumonia. The attachment mechanism of this bacteria to host cells is crucial in bacterial pathogenesis, yet remains undetermined. Hence, we obtained monoclonal antibodies (mAbs) specific to either P. acanthamoebae or amoebae in an attempt to elucidate the attachment mechanism involved. Hybridomas of 954 clones were assessed, and we found that four mAbs (mAb38, mAb300, mAb311, mAb562) that were reactive to the amoebae significantly inhibited bacterial attachment. All mAbs recognized amoebal released molecules, and mAb311 also recognized the amoebal surface. mAbs reacted with the bacteria not only within amoebae, but also when they were released from amoebae (except mAb311). Furthermore, a serine protease inhibitor had an inhibitory effect on the bacterial attachment to amoebae, although none of the mAbs had any synergistic effect on the inhibition of attachment by the protease inhibitor. Taken together, we conclude that concurrent P. acanthoamebae attachment to amoebae is required for several amoebal released molecules and serine protease activity, implying the existence of a complicated host parasite relationship. - Yin Lin, Hiroaki Furumaki, Shiho Matsuoka, Toshihiro Sakurai, Masashi Kohanawa, Songji Zhao, Yuji Kuge, Nagara Tamaki, Hitoshi ChibaLABORATORY INVESTIGATION 92 (2) 265 - 281 0023-6837 2012/02 [Refereed][Not invited]
Not-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome that is characterized by steritosis, inflammation, and fibrosis, and may progress to cirrhosis and carcinoma. To investigate its pathogenic processes, we established a novel murine model for NASH by combination of a high-fat diet (HFD) and oxidized low-density lipoprotein (oxLDL). Mice that received HFD for 23 weeks showed hepatic steatosis, slight fibrosis, and a high level of lipid peroxidation compared with a regular diet (RD)-fed mice. Hepatic injury and elevated tumor necrosis factoor (TNF)-alpha mRNA expression were also detected in these mice. Moreover, oxLDL administration to HFD-fed mice during weeks 21-23 not only aggravated hepatic steatosis, fibrosis, and lipid metabolism, but also resulted in intense inflammation, including severe hepatic injury and inflammatory cell infiltration, which are the typical histological features of NASH. Inflammation was accompanied by increased gene expression of TNF-alpha and interleukin (IL)-6. Additionally, the livers of RD-fed animals treated with oxLDL during weeks 21-23 were characterized by foamy macrophages and inflammatory cell infiltration along with an elevated IL-6 mRNA level. These results suggest that an increased oxidative state, including HFD-induced intracellular lipid peroxidation and its extracellular source from oxLDL, is the actual trigger for hepatic inflammation in which liver injury is mediated by TNF-alpha: and inflammatory cell accumulation is dependent on HFD and oxLDL also induced insulin resistance in mice; additionally, oxLDL downregulated insulin secretion. In his model, CD36 overexpression was observed in the hepatocytes of HFD-fed mice and those treated with HFD and oxl DL, and in the hepatic macrophages of RD-fed mice immediately after oxLDL treatment. In vitro experiments indicated a rapid and transient elevation of CD36 on macrophage plasma membrane in response to oxLDL. Our findings demonstrate that CD36 expressed on hepatocytes and hepatic macrophages mediates the pathophysiology of NASH. Laboratory Investigation (2012) 92, 265-281; doi:10.1038/labinvest.2011.159; published online 7 November 2011 - Songji Zhao, Yuji Kuge, Min Yi, Yan Zhao, Toshiyuki Hatano, Keiichi Magota, Ken-ichi Nishijima, Masashi Kohanawa, Nagara TamakiEUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 38 (10) 1876 - 1886 1619-7070 2011/10 [Refereed][Not invited]
We evaluated whether the dynamic profile of L-C-11-methionine (C-11-MET) may have an additional value in differentiating malignant tumors from granulomas in experimental rat models by small animal positron emission tomography (PET). Rhodococcus aurantiacus and allogenic rat C6 glioma cells were inoculated, respectively, into the right and left calf muscles to generate a rat model bearing both granulomas and tumors (n = 6). Ten days after the inoculations, dynamic C-11-MET PET was performed by small animal PET up to 120 min after injection of C-11-MET. The next day, after overnight fasting, the rats were injected with F-18-2-deoxy-2-fluoro-D-glucose (F-18-FDG), and dynamic F-18-FDG PET was performed up to 180 min. The time-activity curves, static images, and mean standardized uptake value (SUV) in the lesions were calculated. C-11-MET uptake in the granuloma showed a slow exponential clearance after an initial distribution, while the uptake in the tumor gradually increased with time. The dynamic pattern of C-11-MET uptake in the granuloma was significantly different from that in the tumor (p < 0.001). In the static analysis of C-11-MET, visual assessment and SUV analysis could not differentiate the tumor from the granuloma in all cases, although the mean SUV in the granuloma (1.48 +/- 0.09) was significantly lower than that in the tumor (1.72 +/- 0.18, p < 0.01). The dynamic patterns, static images, and mean SUVs of F-18-FDG in the granuloma were similar to those in the tumor (p = NS). Dynamic C-11-MET PET has an additional value for differentiating malignant tumors from granulomatous lesions, which deserves further elucidation in clinical settings. - Yimin, Masashi Kohanawa, Michitaka Ozaki, Sanae Haga, Keiko Fujikawa, Songji Zhao, Yuji Kuge, Nagara TamakiMICROBES AND INFECTION 10 (14-15) 1450 - 1458 1286-4579 2008/11 [Refereed][Not invited]
The interaction between interleukin-10 (IL-10) and interleukin-6 (IL-6) was investigated in the inflammatory response to Rhodococcus aurantiacus (R. aurantiacus) infection, in which both cytokines act as anti-inflammatory cytokines. Compared with wild-type (WT) counterparts, IL-6 gene-deficient (IL-6(-)/(-)) mice mounted a more robust production of IL-10 and tumor necrosis factor-alpha (TNF-alpha) during the initial phase of infection. Administration of anti-IL-10 antibody resulted in all the mice dying within 3 days post-infection as well as a further elevated TNF-alpha release. In vitro challenge of the macrophages from IL-6(-)/(-) and WT mice with heat-killed R. aurantiacus also showed similar results. Addition of exogenous IL-6 depressed IL-10 and TNF-alpha production by either IL-6(-)/(-) mice or IL-6(-)/(-) mouse macrophages. Likewise, WT mouse macrophages pretreated with anti-IL-10 or anti-IL-6 antibody exhibited increased production of TNF-alpha and IL-6 or IL-10 respectively. Moreover, neutralization of both IL-10 and IL-6 induced a further increase in TNF-alpha production by WT mouse cells. Overall, we conclude that IL-10 is a key element in protecting mice against mortality, and that IL-10 and IL-6 production are negatively regulated by each other although they are additive in suppressing TNF-alpha release in R. aurantiacus-infected mouse model. (C) 2008 Elsevier Masson SAS. All rights reserved. - Songji Zhao, Yuji Kuge, Masashi Kohanawa, Toshiyuki Takahashi, Yan Zhao, Min Yi, Kakuko Kanegae, Koh-ichi Seki, Nagara TamakiJOURNAL OF NUCLEAR MEDICINE 49 (1) 135 - 141 0161-5505 2008/01 [Refereed][Not invited]
Many clinical PET studies have shown that increased F-18-FDG uptake is not specific to malignant tumors. F-18-FDG is also taken up in inflammatory lesions, particularly in granulomatous lesions such as sarcoidosis or active inflammatory processes after chemoradiotherapy, making it difficult to differentiate malignant tumors from benign lesions, and is the main source of false-positive F-18-FDG PET findings in oncology. These problems may be overcome by multitracer studies using 3'-deoxy-3'-F-18-fluorothymidine (F-18-FLT) or L-C-11-methionine. However, F-18-FLT or C-11-methionine uptake in granulomatous lesions remains unclarified. In this study, the potentials of F-18-FLT and C-11-methionine in differentiating malignant tumors from granulomas were compared with F-18-FDG using experimental rat models. Methods: Dual-tracer tissue distribution studies using 18F-FDG and H-3-FLT (groups I and III) or F-18-FDG and C-11-methionine (groups II and IV) were performed on rats bearing both granulomas (Mycobacterium bovis bacillus Calmette-Guerin [BCG]-induced) and hepatomas (KDH-8-induced) (groups I and II) or on rats bearing both turpentine oil-induced inflammation and hepatomas (groups III and IV). One hour after the injection of a mixture of F-18-FDG and H-3-FLT or of F-18-FDG and C-14-methionine, tissues were excised to determine the radioactivities of F-18-FDG, H-3-FLT, and C-14-methionine (differential uptake ratio). Results: Mature epithelioid cell granuloma formation and massive lymphocyte infiltration were observed in the granuloma tissue induced by BCG, histologically similar to sarcoiclosis. The granulomas showed high F-18-FDG uptake comparable to that in the hepatomas (group I, 8.18 +/- 2.40 vs. 9.13 +/- 1.52, P = NS; group II, 8.43 +/- 1.45 vs. 8.91 +/- 2.32, P = NS). C-14-Methionine uptake in the granuloma was significantly lower than that in the hepatoma (1.31 +/- 0.22 vs. 2.47 +/- 0.60, P < 0.01), whereas H-3-FLT uptake in the granuloma was comparable to that in the hepatoma (1.98 +/- 0.70 vs. 2.30 +/- 0.67, P = NS). Mean uptake of F-18-FDG, H-3-FLT, and C-14-methionine was markedly lower in the turpentine oil-induced inflammation than in the tumor. Conclusion: C-14-Methionine uptake was significantly lower in the granuloma than in the tumor, whereas F-18-FDG and H-3-FLT were not able to differentiate granulomas from tumors. These results suggest that C-14-methionine has the potential to accurately differentiate malignant tumors from benign lesions, particularly granulomatous lesions, providing a biologic basis for clinical PET studies. - Yimin, Kohanawa MJournal of immunology (Baltimore, Md. : 1950) 1 177 (1) 642 - 650 0022-1767 2006/07 [Refereed][Not invited]
- Yimin, M Kohanawa, T MinagawaIMMUNOLOGY 110 (4) 501 - 506 0019-2805 2003/12 [Refereed][Not invited]
After intravenous injection of Rhodococcus aurantiacus normal mice develop non-necrotic granulomas, the formation of which is dependent on endogenous interferon-gamma (IFN-gamma). In the early phase of R. aurantiacus infection a high level of endogenous interleukin-6 (IL-6) is detected in the spleen extracts, though its importance is unknown. Using IL-6 knockout (IL-6(-/-)) mice, we studied the role of IL-6 in granulomatous inflammation induced by R. aurantiacus. The size of granulomas generated in IL-6(-/-) mice was significantly larger than that of wild-type (IL-6(+/+)) mice at 2 weeks postinjection (p.i). Moreover, central necrosis of the granuloma was observed in IL-6(-/-) mice but not in IL-6(+/+) controls. Titres of endogenous IFN-gamma and tumour necrosis factor-alpha (TNF-alpha) were markedly increased in the spleens and livers of IL-6(-/-) mice in comparison with IL-6(+/+) mice at days 1 through 3 p.i. In vivo administration of either an anti-IFN-gamma monoclonal antibody (mAb) or anti-TNF-alpha mAb to IL-6(-/-) mice reduced the number and size of granulomas, and prevented formation of necrotic granulomas. In addition, the production of endogenous IFN-gamma and TNF-alpha in the early phase of R. aurantiacus infection by IL-6(-/-) mice was suppressed by treatment with recombinant IL-6 (rIL-6). This suppression of IFN-gamma and TNF-alpha production was followed by a reduction in the number and size of central necrotic granulomas at 2 weeks p.i. These findings suggest that overproduction of IFN-gamma and TNF-alpha induces central necrotic granuloma formation in IL-6(-/-) mice, and that IL-6 down-regulates granulomatous inflammation reaction in response to R. aurantiacus infection by modulating production of IFN-gamma and TNF-alpha. - HY Diao, M Kohanawa, Yimin, F Nakajima, Y Sato, T Minagawa, A NakaneIMMUNOLOGY 105 (3) 344 - 349 0019-2805 2002/03 [Refereed][Not invited]
Streptococcus pyogenes sometimes induces invasive streptococcal infection, including streptococcal toxic shock syndrome (STSS). Muscular necrosis is one of the peculiar symptoms of invasive streptococcal infection and STSS. We inoculated S. pyogenes into the muscles of mice. To do so, 5 x 10(8) bacteria in 0.2 ml phosphate-buffered saline were injected into the right hind thigh. None of the mice injected with the bacteria showed muscular necrosis and none died. Tumour necrosis factor-alpha (TNF-alpha) and infiltration of leucocytes were detected in the muscles of infected sites, although the condition of the infected mice did not deteriorate after anti-TNF-alpha monoclonal antibody treatment. The infected mice treated intraperitoneally with Escherichia coli lipopolysaccharide (LPS) showed augmentation of bacterial growth, muscular necrosis and death. TNF-alpha was detected in the sera of the infected mice treated with LPS. but not in the muscles of the infected sites. Infiltration of leucocytes into the infected muscle was not observed in the infected mice treated with LPS. Anti-TNF-alpha monoclonal antibody treatment decreased mortality in the infected mice treated with LPS. Moreover, the infected mice treated with recombinant TNF-alpha showed augmentation of muscular necrosis and death. These results suggest that systemic production of TNF-alpha induced by stimulation with LPS inhibits infiltration of leucocytes into the infected site and exacerbates muscular infection. and that TNF-alpha produced in streptococcal infection is not a defence factor for the host. Invasive streptococcal infection and STSS appear to be induced by both S. pyogenes and the host's immune system. - Yimin, M Kohanawa, Y Sato, T MinagawaJOURNAL OF MEDICAL MICROBIOLOGY 50 (8) 688 - 694 0022-2615 2001/08 [Refereed][Not invited]
Intravenous injection of Rhodococcus aurantiacus into mice causes granulomatous inflammation dependent on endogenous interferon-gamma (IFN-gamma), This study investigated the mechanism of granuloma formation with an adoptive transfer system in IFN-gamma knockout (IFN-gamma (-/-)) mice. IFN-gamma (-/-) mice infected with R. aurantiacus did not develop granulomas, and high titres of endogenous interleukin-10 (IL-10) were detected in spleen extracts at 2 weeks after infection, The adoptive transfer of splenocytes from infected wild-type (IFN-gamma (+/+)) mice did not restore granuloma formation, although this treatment diminished IL-10 production in IFN-gamma (-/-) mice, Adoptive transfer of splenocytes from infected IFN-gamma (-/-) mice into infected IFN-gamma (+/+) reduced granuloma formation, These results suggest that splenocytes of IFN-gamma (-/-) mice suppress granuloma formation. On the other hand, although IFN-gamma production induced by R. aurantiacus infection was detected in nude mice, which are deficient in T cells, granuloma formation was not induced in them, However, adoptive transfer of immune splenocytes from either IFN-gamma (+/+) mice or IFN-gamma (-/-) mice could induce granuloma formation. This means that splenocytes of IFN-gamma (-/-) mice have the ability to both induce and suppress granuloma formation. Induction of granuloma is probably dependent on both T cells and IFN-gamma produced by non-T cells, It is suggested that the role of T cells in granuloma formation is not dependent on their IFN-gamma production. - Y Satoh, K Kasama, M Kuwabara, Yimin, HY Diao, H Nakajima, M Kohanawa, T MinagawaJOURNAL OF INTERFERON AND CYTOKINE RESEARCH 19 (8) 887 - 894 1079-9907 1999/08 [Refereed][Not invited]
We investigated the anti-asthmatic effects of low-dose oral and subcutaneous administration of interferon-beta (IFN-beta) on an ovalbumin (OVA)-sensitized and challenged guinea pig model of asthma. Subcutaneous administration of IFN-beta suppressed the eosinophil infiltration by 14.2% of the control and the respiratory resistance (Rrs) by 58.2% at 2.0 MIU/kg. Oral administration of IFN-beta inhibited the late asthmatic response (LAR) by suppressing the increase of Rrs by 29% of the control at 1 IU/ml and the eosinophil infiltration into the trachea and lung by 34.6% at the optimum dosage of 10 IU/ml. Both subcutaneous and oral administration could not inhibit the early asthmatic response (EAR). Additionally we found 2',5'-oligoadenylate synthetase (2',5'-OAS) induction by low-dose oral administration (LDOA) of IFN-beta to the same extent as by subcutaneous administration in whole blood in vivo. These data suggest that LDOA of IFN-beta would have some clinical benefit for patients with asthma. - Y Min, M Asano, M Kohanawa, T MinagawaIMMUNOLOGY 96 (1) 10 - 15 0019-2805 1999/01 [Refereed][Not invited]
Mice injected with Rhodococcus aurantiacus by the intravenous (i.v.) route show neurological disorders, hemiparesis, vertical headshake and turn-round gait after day 7 postinfection (p.i.). Neurological symptoms caused by i.v. inoculation of R. aurantiacus were relieved by treatment with levodopa (L-dopa). R. aurantiacus was isolated from the brain and was found td be completely eliminated at day 7 p.i. Focal encephalitis was mainly observed in the brain stem, and T cells could be isolated from the brain after day 7 p.i. Administration of both an anti-CD4 monoclonal antibody (mAb) and an anti-CD8 mAb suppressed neurological symptoms. These results suggest that R aurantiacus induces movement disorders in mice, and that the symptoms are mediated by T cells infiltrating the brain, rather than directly by the bacterium. - Kohanawa M, Asano M, Min Y, Minagawa T, Nakane AThe Journal of general virology 76 ( Pt 9) 2251 - 2256 0022-1317 1995/09 [Refereed][Not invited]
MISC
- HY Diao, M Kohanawa, Yimin, F Nakajima, Y Sato, T Minagawa, A Nakane IMMUNOLOGY 105- (3) 344 -349 2002/03 [Not refereed][Not invited]
Streptococcus pyogenes sometimes induces invasive streptococcal infection, including streptococcal toxic shock syndrome (STSS). Muscular necrosis is one of the peculiar symptoms of invasive streptococcal infection and STSS. We inoculated S. pyogenes into the muscles of mice. To do so, 5 x 10(8) bacteria in 0.2 ml phosphate-buffered saline were injected into the right hind thigh. None of the mice injected with the bacteria showed muscular necrosis and none died. Tumour necrosis factor-alpha (TNF-alpha) and infiltration of leucocytes were detected in the muscles of infected sites, although the condition of the infected mice did not deteriorate after anti-TNF-alpha monoclonal antibody treatment. The infected mice treated intraperitoneally with Escherichia coli lipopolysaccharide (LPS) showed augmentation of bacterial growth, muscular necrosis and death. TNF-alpha was detected in the sera of the infected mice treated with LPS. but not in the muscles of the infected sites. Infiltration of leucocytes into the infected muscle was not observed in the infected mice treated with LPS. Anti-TNF-alpha monoclonal antibody treatment decreased mortality in the infected mice treated with LPS. Moreover, the infected mice treated with recombinant TNF-alpha showed augmentation of muscular necrosis and death. These results suggest that systemic production of TNF-alpha induced by stimulation with LPS inhibits infiltration of leucocytes into the infected site and exacerbates muscular infection. and that TNF-alpha produced in streptococcal infection is not a defence factor for the host. Invasive streptococcal infection and STSS appear to be induced by both S. pyogenes and the host's immune system. - Role of T cells in granuloma formation induced by [i] Rhodococcus aurantiacus [/i] is independent of their interferon-gamma productionMICROBIAL PATHOGENICITY 50- 688 -694 2001 [Not refereed][Not invited]
- Immunology 96- (1) 10 -15 1999 [Not refereed][Not invited]
- Paralysis caused by acnte myelitis in theiler's murine encephalomyelitis virus strain GDVII infection is induced by CD4+ lymphocytes infiltrating the spinal card(jointly worked)Journal of General Virology 76- 2251 1995 [Not refereed][Not invited]
Books etc
Presentations
- Regulatory action of toll-like receptor 2 in a non-alcoholic steatohepatitis mouse model [Not invited]伊 敏5th Annual Meeting of the International Cytokine and interferon Society 2017/10
- Function of Toll-like receptor 2 in the murine inflammatory response to Rhodococcus aurantiacus infection [Not invited]伊 敏4th Annual Meeting of the International Cytokine and interferon Society, San Francisco 2016/10
- Regulatory effect of interleukin-4 in the innate immune and inflammatory responses to Rhodococcus aurantiacus infection in mice [Not invited]伊 敏2th Annual Meeting of the International Cytokine and Interferon Society 2014/10
- Down-regulatory effect of Pairogen, a health drink, on inflammatory response to Rhodococcus aurantiacus infection in mice [Not invited]伊 敏10th Joint Meeting of International Cytokine Society and International Society for Interferon and Cytokine Research 2012/09
- The roles of TLR2 and CD36 in response to Staphylococcus aureus in vivo [Not invited]伊敏8th Joint Meeting of International Cytokine Society and International Society for Interferon and Cytokine Research 2010/10
- CD36 function in a novel non-alcoholic steatohepatitis model in mice [Not invited]Yimin14th international congress of immunology 2010/08
- Interaction between IL-10 and IL-6 in mice infected with Rodococcus aurantiacus. [Not invited]Yimin4th Congress of the Federation of Immunology societies of Asia-Oceania 2008/10
- A regulatory effect of the balance between tumor necrosis factor-alpha and interleukine-6 in inflammatory response. [Not invited]Yimin6th Joint Meeting of International Cytokine Society 2006/08
Association Memberships
- 日本インターフェロンサイトカイン学会 THE JAPANESE SOCIETY FOR IMMUNOLOGY THE JAPANESE ASSOCIATION FOR INFECTIOUS DISEASES
Research Projects
- 自然免疫異常によるグラム陽性菌感染症の重症化機序についての解析日本学術振興会：基盤研究（C）Date (from‐to) : 2017/04 -2020/03Author : 伊敏
- 細胞死による積極的な肝機能維持・再生制御機構の解明と臨床応用に向けた研究日本学術振興会：挑戦的萌芽研究Date (from‐to) : 2014/04 -2015/03Author : 伊敏
- パイロゲンの免疫防御反応への制御について伊藤医薬学術交流財団：交流助成金Date (from‐to) : 2012/04 -2013/03Author : 伊敏
- 炎症性サイトカインと抗炎症性サイトカインのバランスの制御機構の解明に関する研究日本ワックスマン財団：学術研究助成奨励金Date (from‐to) : 2008/04 -2009/03Author : 伊敏
- 文部科学省：科学研究費補助金(基盤研究(B))Date (from‐to) : 1996 -1998Author : 皆川 知紀, 佐藤 雄一郎, 小華和 柾志, 伊 敏サルコイドーシスは、非壊死性肉芽腫が各種臓器に形成される原因不明全身性炎症性疾患である。これまで患者病的材料を用いて、病因の追求及び患者の免疫学的側面をサイトカインネットワークから追求してきた。一方で、マウスを用いた実験的肉芽腫形成モデルについて追求してきた。1.病因については結核説、プロピオニバクテリウム説が現在の所有力であるが、それらのいずれかが単独で発症させる可能性は少なく、むしろ多因子の背景があるところへある種の感染が引き金となつている可能性が強い。我々は非病原性であり、土壌細菌(環境細菌)出来でもあるRhodococcus aurantiacusも原因の一つになりえるとの立場から検索したが、患者リンパ節からは有意には分離されなかった。2.サルコイドーシス患者の免疫学的特性としてツベルクリン反応が陰性であるアネルギーがあるが、それは全身性の肉芽腫反応の結果であり、免疫不全を意味しない。患者リンパ節の肉芽腫病変よりIL-1、TNFα、IFN-γが検出されるが中でもIFN―γは血中レベル、病勢と相関している事を明らかにした。免疫組織染色などからもサルコイドーシス肉芽腫形成はThlタイプの反応の結果であることを明らかにした。3.Rhodococcusをマウスに静注すると肝臓、牌臓、肺などに典型的な非壊死性肉芽腫が形成されるが、これもサルコイドーシス同様Th1タイプの反応の結...
- Study on Mechanism of Granuloma Formation