| 1.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 2.
論文 |
論文
|
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
…
. 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.
続きを見る
|
||||
| 3.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 4.
論文 |
論文
|
Zhang, Hai-xin ; Tanji, Kunikazu ; Yoshida, Hidemi ; Hayakari, Makoto ; Mori, Fumiaki ; Wakabayashi, Koichi
概要:
TDP-43 proteinopathy （amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclus
…
ions） is a newly categorized group of neurodegenerative disorders characterized by abnormal accumulation and mislocalization of nuclear TDP-43 protein in the neuronal cytoplasm. 15-deoxy-Δ12,14-prostaglandin J2 （15d-PGJ2） is non-enzymatically produced from PGD2, and plays roles in infl ammation and oxidative stress responses. Indeed, 15d-PGJ2 is up-regulated in the spinal motor neurons in ALS. In this study, biochemical and fluorescent staining analyses showed that 15d-PGJ2 modifi es expression, solubility, and subcellular localization of TDP-43. This alteration was at least partly related to a cyclopentenone ring structure containing an electrophilic carbon of 15d-PGJ2, because 15d-PGJ2 analogue, which lacks an cyclopentenone ring structure, had almost no eff ect on TDP-43 protein. Finally in vitro binding experiment indicated that 15d-PGJ2 is covalently bound to TDP-43 protein. These fi ndings suggest that a sustained high level of 15d-PGJ2 is involved in the pathogenesis of neurodegenerative disorders related to abnormal TDP-43 protein.
続きを見る
|
||||
| 5.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 6.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 7.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 8.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 9.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 10.
論文 |
論文
|
Aizawa, Tomomi ; Imaizumi, Tadaatsu ; Tsuruga, Kazushi ; Watanabe, Shojiro ; Yoshida, Hidemi ; Kumagai, Naonori ; Ito, Etsuro ; Tanaka, Hiroshi
概要:
Renal biopsy is the gold standard for confirmation of disease severity and diagnosis of glomerulonephritis (GN), but its procedure is invasive with a risk of complications. Thus, a non-invasive monitoring method is desirable especially
…
in pediatric patients. Fractalkine and monocyte chemoattractant protein-1 (MCP-1) are proinflammatory chemokines, and both have been reported to be involved in the pathogenesis of immunocomplex-mediated GN. Recently, it has been reported that urinary fractalkine and MCP-1 may serve as possible predictors of disease activity of adult patients with GN. We, therefore, examined whether urinary levels of fractalkine and MCP-1 correlate with clinical and histologic parameters. Twenty-six consecutive children with various types of GN were enrolled in this study, including lupus nephritis, IgA nephropathy, membranous nephropathy, acute GN, and thin basement membrane disease (served as a non-inflammatory control). Urinary fractalkine and MCP-1 concentrations in the first morning urine samples obtained at the time of renal biopsy were measured by enzyme-linked immunosorbent assay, and standardized for urinary creatinine concentrations. Urinary fractalkine concentration differed significantly among the disease categories. Urinary concentrations of fractalkine and MCP-1 showed a significant positive correlation with the degree of occult blood in urine and a significant inverse correlation with the estimated glomerular filtration rate. Furthermore, the urinary MCP-1 concentration was significantly correlated with histological chronicity indices in patients with lupus nephritis and IgA nephropathy. Measurement of urinary fractalkine and MCP-1 concentrations may be useful as a non-invasive method for predicting the disease activity of GN in children.
続きを見る
|
