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Imaizumi, Tadaatsu ; Mori, Fumiaki ; Yagihashi, Norito ; Kitamura, Hideo ; Sashinami, Hiroshi ; Suzuki, Koichi ; Yamashita, Koji ; Taima, Kageaki ; Kubota, Kosei ; Tanji, Kunikazu ; Sakaki, Hirotaka ; Matsumiya, Tomoh ; Yoshida, Hidemi ; Mariya, Yasushi ; Nakane, Hajime ; Tanaka, Hiroshi ; Takanashi, Shingo ; Wakabayashi, Koichi ; Yagihashi, Soroku ; Nakane, Akio ; Ito, Etsuro ; Okumura, Ken ; Kimura, Hiroto ; Satoh, Kei
概要:
Retinoic acid-inducible gene-I （RIG-I） is a cytoplasmic protein regarded as putative RNA helicase.Immunohistochemical st
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udies revealed high levels of RIG-I expression in epidermic cells in psoriasis, in macrophagesin atherosclerotic lesions and in glomeruli of lupus nephritis. RIG-I expression was also demonstrated in macrophagesand vascular endothelial cells in experimental animals with Listeria or Hanta virus infection. In vitro studies using cellcultures revealed the expression of RIG-I, in various cells including endothelial cells, macrophages and astroglial cells, inresponse to the stimulation with cytokines, lipopolysaccharide, double-stranded RNA, Listeria monocytogenes, etc. Thestudies employing the overexpression or RNA interference suggested that RIG-I is involved in the regulation of cytokineexpression including CXCL10/IP-10 and CCL5/RANTES. These results suggest that RIG-I constitutes a part of theintracellular pathway for the regulation of infl ammatory and immune responses.
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| 2.
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Yoshida, Hidemi ; Mimura, Junsei ; Imaizumi, Tadaatsu ; Matsumiya, Tomoh ; Ishikawa, Akira ; Metoki, Norifumi ; Tanji, Kunikazu ; Ota, Ken ; Kosaka, Kunio ; Itoh, Ken ; Satoh, Kei
概要:
Optimization of neuronal function and survival is an important goal in the treatment of cerebrovascular diseases in orde
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r to avoid or improve devastating long-term sequelae. Nerve growth factor （NGF） is essential for neuronal growth and survival in the central nervous system （CNS）. Vascular endothelial growth factor （VEGF） is a potent mitogen specifi c for endothelial cells and a stimulator of neovascularization. VEGF also enhances vascular permeability, which may promote the development of brain edema during cerebral ischemia. These molecules aff ect the outcome of ischemia/reperfusion injury in the CNS. Edaravone, a brain-penetrant, free radical scavenger, is known to ameliorate postischemic neuronal dysfunction. Transcription factor Nrf2（ nuclear factor-erythroid 2-related factor 2）, a master regulator of antioxidant responses, plays an important role in the coordinated expressions of stress-inducible genes. Astrocytes express various genes involved in the regulation of neuronal functions, and the regulation of astrocyte gene expressions may be a potential therapeutic target in brain injury. This review aims to appraise the eff ects of radical scavenger edaravone and a natural Nrf2-inducer as neuroprotective agents in human astrocytes, particularly under an experimental model for hypoxia/reoxygenation.
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| 3.
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Imaizumi, Tadaatsu ; Aizawa, Tomomi ; Tanaka, Hiroshi ; Sato, Fuyuki ; Xing, Fei ; Matsumiya, Tomoh ; Yoshida, Hidemi ; Satoh, Kei
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Viral infection is important in renal pathology both as a trigger of chronic inflammatory diseases and as a complicatio
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n associated with organ transplantation. Glomerular mesangial cells produce a variety of functional molecules potentially involved in immune reactions, and we investigated anti-viral responses in normal human mesangial cells. Human mesangial cells were treated with polyinosinic-polycytidylic acid （poly IC）, an authentic double-stranded RNA that mimics viral RNA. Treatment of cells with poly IC induced interferon-β （IFN-β）, retinoic acid-inducible gene-I（ RIG-I）, CC chemokine ligand 5（ CCL5）, differentiated embryo-chondrocyte 2（ DEC2） and IFN-stimulated gene 20 （ISG20）. Knockdown of toll-like receptor 3 （TLR3）, by RNA interference （RNAi）, abolished the poly IC-induced expression of these molecules. RNAi against IFN-β inhibited the induction of RIG-I,CCL5 and ISG20, but not of DEC2. Knockdown of RIG-I resulted in the reduced expression of CCL5. RNAi against DEC2 enhanced the poly IC-induced expression of IFN-β, RIG-I and CCL5. Transfection of cells with a poly IC/cationic lipid complex induced IFN-β, RIG-I and ISG20. Knockdown of RIG-I decreased the expression of IFN-β and ISG20 induced by transfection with poly IC/cationic lipid. TLR3 and RIG-I may function as recognition receptors against double-stranded RNA, which induce IFN-β and its downstream IFN-inducible genes. In the signaling elicited by poly IC, the IFN-inducible genes include RIG-I and effector molecules as CCL5 with leukocyte chemotactic activity and ISG20 with exonuclease activity on single-stranded RNA. The poly IC-induced expression of DEC2 is independent on IFN-β and it may control the signaling elicited by double-stranded RNA. The poly IC-inducible molecules may mediate anti-viral innate responses in renal mesangial cells.
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| 4.
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Narita, Norihiko ; Matsumiya, Tomoh ; Kon, Takao ; Hayakari, Ryo ; Itoh, Ryohei ; Kubota, Kosei ; Sakaki, Hirotaka ; Furudate, Ken ; Yoshida, Hidemi ; Imaizumi, Tadaatsu ; Kobayashi, Wataru ; Kimura, Hiroto
概要:
The CXC chemokine growth-related oncogene protein-α （GRO-α） has a wide variety of biological activities including as neu
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trophil trafficking or migration of vascular endothelial cells. In addition, studies have shown a crosstalk between tumor cells and vascular endothelial cells; GRO-α released by endothelial cells induces invasion of tumor cells toward endothelial cells, indicating an importance of GRO-α in a tumor environment. Oral squamous cells are reported to produce GRO-α in response to cytokines such as tumor necrosis factor-α （TNF-α）. However, little is known about how GRO-α is involved in oral cancer. Here, we investigated the biological role of GRO-α for both tumor growth and angiogenesis in oral squamous cell carcinoma cells. We first evaluated the effect of TNF-α on GRO-α expression in three oral cancer cells from different origins. Among the cell lines we used, KOSC-2 cells expressed the highest amount of GRO-α mRNA in response to TNF-α. TNF-α-treated condition medium from KOSC-2 cells enhanced endothelial cell chemotaxis and the chemotactic activity was partially inhibited by the addition of neutralizing anti-GRO-α antibody. In addition, GRO-α exerted tumor cell migration of KOSC-2. From these results, we conclude that GRO-α may contribute to both angiogenesis and proliferation in oral cancer.
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Onda, Kaoru ; Yoshida, Hidemi ; Hayakari, Ryo ; Xing, Fei ; Wang, Lian ; Matsumiya, Tomoh ; Kawaguchi, Shogo ; Murakami, Manabu ; Imaizumi, Tadaatsu
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Dysregulation of iron homeostasis in brain causes various neurodegenerative disorders. In fact, high concentration of ir
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on is present in brains of patients with Alzheimer’s disease. It was previously reported that CXCL8 protects human neurons from amyloid-β-induced neurotoxicity and that astrocytes have the potential to play important roles in Alzheimer’s disease. In the present study, we examined the effect of desferrioxamine, an iron chelator, on the expression of CXCL8 in U373MG human astrocytoma cells used as a model of astrocytes. Treatment of the cells with desferrioxamine induced the expression of CXCL8. Pretreatment of the cells with FeSO4 counteracted the positive effect of desferrioxamine on CXCL8 production, suggesting that the effect of desferrioxamine was due to iron chelation. RNA interference experiments showed that HIF-1α was not involved in desferrioxamine-induced CXCL8 expression. We conclude that desferrioxamine induces CXCL8 in astrocytes and the chelation of iron may be a new therapeutic strategy for Alzheimer’s disease.
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Furudate, Ken ; Matsumiya, Tomoh ; Hayakari, Ryo ; Xing, Fei ; Kubota, Kosei ; Sakaki, Hirotaka ; Tamura, Yoshihiro ; Kijima, Hiroshi ; Imaizumi, Tadaatsu ; Kimura, Hiroto ; Kobayashi, Wataru
概要:
Tumor microenvironment is related to growth, survival, invasion, and metastasis of tumor cells. Several studies have pro
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ved that stromal fibroblasts play an important role in the tumor microenvironment to convert cancer-associated fibroblast （CAFs）. Clock genes are known to regulate circadian rhythms, angiogenesis, and immunoreaction. In addition, clock genes play an important role in cancer development. However, little has been shown about how these clock genes function in the tumor microenvironment. In the present study, we investigated to evaluate the effect of co-culture fibroblasts with oral cancer cells on the expression of clock genes. Following the coculture of human primary fibroblasts with human gingival carcinoma Ca9-22 cells, the expression levels of clock genes were analyzed by real-time quantitative PCR. We found that the rhythmic expression of clock genes were altered, enhanced, or disappeared by the co-culture. Such effect was observed not only in fibroblasts in the presence of Ca9-22 cells but also in Ca9-22 cells in the presence of fibroblasts. Our results suggested that clock genes might affect an important role in the tumor microenvironment.
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| 7.
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Imaizumi, Tadaatsu ; Hayakari, Ryo ; Watanabe, Shojiro ; Aizawa, Tomomi ; Matsumiya, Tomoh ; Yoshida, Hidemi ; Tsuruga, Kazushi ; Kawaguchi, Shogo ; Tanaka, Hiroshi
概要:
Cylindromatosis (CYLD), a deubiquitinase, negatively regulates nuclear factor-κB in various cells. However, its potentia
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l roles in glomerular inflammation remain unclear. Because the activation of the Toll-like receptor 3 (TLR3)/type I interferon (IFN) pathways plays a pivotal role in chronic kidney diseases (CKD), we examined the role of CYLD in the TLR3 signaling in cultured human mesangial cells (MCs).<br />We stimulated CYLD-silenced MCs with polyinosinic-polycytidylic acid (poly IC), a synthetic analogue of dsRNA, and studied representative TLR3/IFN-β pathways (i.e., TLR3/IFN-β/retinoic acid-inducible gene-I (RIG-I)/CCL5, and TLR3/IFN-β/melanoma differentiation associated gene 5 (MDA5)/CXCL10 axes) using RT-PCR, western blotting, and ELISA. We also used immunofluorescence staining and microscopy to examine mesangial CYLD expression in biopsied specimens from patients with CKD.<br />CYLD silencing resulted in an increase of poly IC-induced RIG-I and MDA5 protein levels and increased CCL5 and CXCL10 mRNA and protein expression, but unexpectedly decreased mRNA expressions of RIG-I and MDA5. Interestingly, CYLD silencing did not affect IFN-β or the phosphorylated STAT1 (signal transducers and activator of transcription protein 1). CYLD was highly expressed in biopsied specimens from patients with proliferative lupus nephritis (LN).<br />CYLD inhibits post-transcriptional regulation of RIG-I and MDA5 expression following TLR3 activation in MCs. CYLD may be involved in the pathogenesis of CKD, especially pathogenesis of LN.
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| 8.
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Imaizumi, Tadaatsu ; Yano, Chikashi ; Numata, Akiko ; Tsugawa, Koji ; Hayakari, Ryo ; Matsumiya, Tomoh ; Yoshida, Hidemi ; Watanabe, Shojiro ; Tsuruga, Kazushi ; Kawaguchi, Shogo ; Murakami, Manabu ; Tanaka, Hiroshi
概要:
Activation of Toll-like receptor 3 (TLR3) signaling followed by type I interferon (IFN) expression is crucial in antivir
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al and "pseudoviral" immune reactions in renal mesangial cells (MCs). These reactions are probably involved in the pathogenesis of chronic kidney disease (CKD). However, the role of IFN-induced 35-kDa protein 35 (IFI35), a type I IFN-dependent transcript, in glomerular inflammation is unclear. Here, we aimed to investigate the expression and the role of IFI35 in IFN-β/retinoic acid-inducible gene-I (RIG-I)/CCL5 and IFN-β/melanoma differentiation-associated gene 5 (MDA5)/CXCL10 axes in MCs.<br />We treated human MCs with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, then analysed the IFI35 expression by reverse transcription-polymerase chain reaction and western blotting. To examine the regulation of IFI35 expression, we subjected MCs to RNA interference (siRNA) against IFN-β, RIG-I, and MDA5.<br />Activation of TLR3 by poly IC induces the IFI35 expression in MCs. siRNA against IFN-β inhibited poly IC-induced IFI35 expression. Knockdown of IFI35 resulted in a decrease of poly IC-induced RIG-I and MDA5 protein as well as decreased CCL5 and CXCL10 mRNA and protein expression. However, it did not affect the expression of none of phosphorylated signal transducers or activator of transcription (STAT) 1 protein, or RIG-I and MDA5 in mRNA levels.<br />Regional expression of IFI35 and its dysregulation may be involved in the pathogenesis of glomerular inflammation in CKD.
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| 9.
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Yoshida, Hidemi ; Hashimoto, Yuko ; Fukushima, Takashi ; Tanji, Kunikazu ; Matsumiya, Tomoh ; Seya, Kazuhiko ; Kawaguchi, Shogo ; Imaizumi, Tadaatsu
概要:
Toxic amyloid-beta （Aβ） is known to generate symptoms of Alzheimer’s disease （AD）; however, less is known regarding the
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neurotoxicity of Aβ at lower concentrations. Moreover, the neuroprotective potential of combination treatment with plant biophenols and existing drugs is not well understood. In this study, we estimated the no-observed adverse effect level （NOAEL） of Aβ 1–42 （Aβ42） against cultured human neuroblastoma SHSY5Y cells, and examined the neuroprotective effect of combination pretreatment with 10 μM carnosic acid, 30 nM rebamipide, 10 μM edaravone, and 10 μM of resveratrol （the “CRER” blend） on weak but toxic Aβ42-treated SH-SY5Y cells. We evaluated the NOAEL of Aβ42 at 500 nM in these cells. Aβ42 at 1–8 μM reduced cell viability; however, the “CRER” blend ameliorated this Aβ42-induced decrease in viability. The “CRER” blend induced the expression of Aβ-degrading enzymes including matrix metalloproteinase-14 （MMP-14） and neprilysin, while also enhancing the expression of the inducible α-secretase TACE （tumor necrosis factor-α-converting enzyme）, sirtuin 1 （SIRT1）, and brain-derived neurotrophic factor（ BDNF）. Collectively, our results indicate that the “CRER” may aid in the prevention of Aβ toxicity by enhancing MMP-14, neprilysin, TACE, SIRT1, and BDNF. Thus, the “CRER” blend may prove to be a promising strategy for the prevention of Aβ-mediated disorders, particularly AD.
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| 10.
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Akiyama, Natsumi ; Kubota, Kosei ; Komatsu, Shotaro ; Itoh, Ryohei ; Chang, Hao Chi ; Yamazaki, Shunya ; Imaizumi, Tadaatsu ; Matsumiya, Tomoh ; Kobayashi, Wataru
概要:
Objective: Medication-related osteonecrosis of the jaw （MRONJ） is a complication of bisphosphonate （BP） therapy. The pat
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hophysiology of MRONJ remains unclear. Extensive studies have been performed to examine the effect of BPs on bone metabolism. Breakdown of mucosa is a factor classified into five stages in MRONJ, indicating an important role of oral soft tissue in the pathogenesis of MRONJ.Methods: We investigated the effect of alendronate, one of the most commonly used BPs worldwide, on the proliferation of human gingival fibroblasts by MTT assay, western blotting, and wound healing assay.Results: We observed time- and concentration-dependent inhibition of fibroblast proliferation by alendronate. Wound healing assays also showed that alendronate prolonged wound healing in a concentration-dependent manner. MAP kinase signaling pathway exhibits a cardinal role in cell proliferation; however, little is known about whether BPs affect classical MAP kinase ERK in fibroblasts. We found that U0126, a selective inhibitor of MAP kinase kinase （MEK1/2）, inhibited fibroblast proliferation similarly to alendronate. Alendronate was also found to inactivate ERK1/2, both of which are downstream molecules of MEK1/2.Conclusion: our findings indicated that alendronate inhibits the proliferation of human gingival fibroblasts via inactivation of ERK1/2.
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