| 1.
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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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Kijima, Hiroshi ; Sato, Fuyuki ; Bhawal, Ujjal Kumar ; Kawamoto, Takeshi ; Fujimoto, Katsumi ; Imaizumi, Tadaatsu ; Imanaka, Tadanobu ; Kondo, Jun ; Koyanagi, Satoru ; Noshiro, Mitsuhide ; Yoshida, Hidemi ; Kato, Yukio
概要:
The circadian rhythms in mammals are regulated by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus
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. Five clock-gene families, i.e. Clock, Bmal, Per, Cry and Dec, have been found to be involved in a transcription-translation feedback loop that generates the circadian rhythm at the intracellular level. In this study, we examined functional analysis of the Dec gene. DEC1 and DEC2 are basic-helix-loop-helix （bHLH） transcription factors, involved in cellular diff erentiation, responses to hypoxia, and circadian rhythms. We recently showed that the expression of DEC1 and DEC2 was upregulated by hypoxia, however, the functions of these two factors under hypoxic conditions have not been elucidated in detail. It is well established that the expression of vascular endothelial growth factor （VEGF） is upregulated by hypoxia, and the expression of VEGF in response to hypoxia depends on transcriptional activation by a heterodimer comprising hypoxia-inducible factor 1 α （HIF-1α） and arylhydrocarbon receptor nuclear translocator 1 （ARNT1）. In the present study, we showed that DEC2, but not DEC1, suppressed VEGF gene expression under hypoxic conditions. DEC2 protein was co-immunoprecipitated with HIF-1α but not with ARNT1. The binding of HIF-1α to the hypoxia response element（ HRE） in the VEGF promoter was decreased by DEC2 overexpression, and increased by DEC2 knockdown. We also showed that the circadian expression of VEGF showed a reciprocal pattern to that of DEC2 in cartilage. DEC2 had a circadian oscillation in implanted Sarcoma 180 cells. We conclude that DEC2 negatively regulates VEGF expression and plays an important role in the pathological conditions in which VEGF is involved.
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| 3.
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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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| 4.
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Imaizumi, Tadaatsu ; Aizawa, Tomomi ; Tanaka, Hiroshi ; Sato, Fuyuki ; Xing, Fei ; Matsumiya, Tomoh ; Yoshida, Hidemi ; Satoh, Kei
概要:
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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| 5.
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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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| 6.
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Shintaku, Tomohiro ; Ohba, Takayoshi ; Niwa, Hidetoshi ; Kushikata, Tetsuya ; Hirota, Kazuyoshi ; Ono, Kyoichi ; Mariya, Yasushi ; Imaizumi, Tadaatsu ; Sawamura, Daisuke ; Murakami, Manabu
概要:
General anesthesia is important for pharmacological studies in laboratory animals. Although a number of transgenic anima
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ls have been reported, basic analyses concerning mouse ECG and heart rate variability（ HRV） have not been rigorously examined.
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| 7.
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Shintaku, Tomohiro ; Ohba, Takayoshi ; Niwa, Hidetoshi ; Kushikata, Tetsuya ; Hirota, Kazuyoshi ; Ono, Kyoichi ; Mariya, Yasushi ; Imaizumi, Tadaatsu ; Sawamura, Daisuke ; Murakami, Manabu
概要:
We compared the effects of inhalation anesthesia（ 2% isoflurane）, intraperitoneal injection of pentobarbital anesthesia
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（50 mg/kg）, and a combination anesthetic consisting of medetomidine, midazolam and butorphanol （MMB） on electrocardiograms in mice. Using either isoflurane inhalation anesthesia or pentobarbital anesthesia, heart rate （HR） was in the acceptable range （ca. 450-500 bpm）. In contrast, MMB anesthesia decreased HR significantly. Importantly, MMB anesthesia responded minimally to propranolol （β-blocker）, suggesting that MMB anesthesia affects sympathetic tonus and is not suitable for evaluation of the cardiovascular or sympathetic system. We confirmed that modified MMB, with a decreased dose of medetomidine from the original protocol（ an α2 agonist）, was associated with a HR of 400 bpm and a diminished response to propranolol. Our present results illustrate the importance of using an appropriate form of anesthesia suitable for experimental pharmacological studies.
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| 8.
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Onda, Kaoru ; Yoshida, Hidemi ; Hayakari, Ryo ; Xing, Fei ; Wang, Lian ; Matsumiya, Tomoh ; Kawaguchi, Shogo ; Murakami, Manabu ; Imaizumi, Tadaatsu
概要:
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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| 9.
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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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| 10.
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Chong, Han ; Ogata, Yoshiki ; Niwa, Hidetoshi ; Kushikata, Tetsuya ; Watanabe, Hiroyuki ; Imaizumi, Tadaatsu ; Hirota, Kazuyoshi ; Ono, Kyoichi ; Ohba, Takayoshi ; Murakami, Manabu
概要:
Transgenic mice experiments have become increasingly popular to research human inherited disease.However, a number of Ja
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panese researchers have difficulty with the selection of anesthesia, after the classificationof ketamine, probably the most used anesthesia, as a narcotic drug in 2006. Therefore, we compared the effects ofinhalation anesthesia （2% of isoflurane, sevoflurane and enflurane） and intraperitoneal pentobarbital anesthesia （50mg/kg） on the electrocardiogram（ ECG） and blood oxygen saturation（ SPO2） of mice. With inhalation anesthesia, theheart rate（ HR） and SPO2 were within an acceptable range. In contrast, the HR significantly decreased after initiationof pentobarbital anesthesia, and gradually returned to a low rate. Importantly, pentobarbital anesthesia significantlylowered SPO2, and heart rate variability analysis showed unstable beat-to-beat intervals during pentobarbitalanesthesia, suggesting that inhalation anesthesia is more suitable for evaluation of cardiorespiratory responsesthan pentobarbital anesthesia. During anesthesia, propranolol, a ????-adrenergic blocker, significantly decreased heartrate. Atropine, a parasympathetic blocker, also significantly increased heart rate. Our data suggest that inhalation anesthesia is suitable for cardiorespiratory analysis in mice.
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