Publications (26)80.45 Total impact
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Article: Effect of a peroxynitrite scavenger, a manganese-porphyrin compound on airway remodeling in a murine asthma.
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ABSTRACT: Airway remodeling, pathological changes in the lung structure, is a characteristic feature of chronic asthma. The changes include bronchial epithelial hyperplasia and hypertrophy, excess production of mucus, and fibroblast proliferation in the lung. On the other hand, it has been known that both nitric oxide and superoxide anion are increased in exhaled air of asthmatic patients. These molecules react with each other forming a powerful oxidant, peroxynitrite. In this study, effect of a peroxynitrite scavenger, a metalloporphyrin compound, [tetrakis(4-carboxylatophenyl)porphyrinato]manganese(III) (MnTBAP) on multiple antigen challenge-induced airway remodeling was evaluated in mice. When sensitized BALB/c mice were intratracheally challenged with an antigen, ovalbumin, for 3 times, bronchial epithelial thickening and mucus accumulation in the epithelium were histologically observed. Daily treatment with MnTBAP (3 and 10 mg/kg/time/twice a day, i.p.) dose-dependently suppressed both the epithelial thickening and mucus accumulation in the epithelium. On the other hand, TUNEL staining revealed that the multiple antigen challenges increased the number of apoptotic cells in the bronchial epithelium. The increase in apoptotic cells was also effectively suppressed by the treatment with MnTBAP. Taken together, it was suggested that peroxynitrite could be involved in the formation of epithelial hyperplasia associated with the mucus accumulation through induction of apoptosis of the epithelial cells. Thus, peroxynitrite can be a target molecule for development of new pharmacotherapy for asthma.Biological & Pharmaceutical Bulletin 02/2013; · 1.66 Impact Factor -
Article: Group IVA phospholipase A2 participates in the progression of hepatic fibrosis.
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ABSTRACT: Group IVA phospholipase A(2) (IVA-PLA(2)) is an enzyme that intiates the arachidonic acid pathway and plays an important role in inflammation. We demonstrate that IVA-PLA(2) deficiency suppresses lipid deposition in the liver, which was induced by administration of a high-fat and -cholesterol diet (HFCD) for 16 wk in mice. Herein, we performed 2-dimensional gel-based comparative proteomics to further define the suppressive effect of IVA-PLA(2) deficiency on fatty liver formation. In comparisons among 4 groups, wild-type (WT)/normal diet (ND), IVA-PLA(2)-deficient knockout (KO)/ND, WT/HFCD, and KO/HFCD, 4 proteins, 3 of which are associated with hepatic fibrosis, were identified as molecules, of which altered expression by HFCD was suppressed in KO mice compared to WT mice. Therefore, we assessed the effect of IVA-PLA(2) deficiency on hepatic fibrosis induced by HFCD or carbon tetrachloride (CCl(4)) in mouse models. Biochemical and histological analyses revealed that IVA-PLA(2) deficiency markedly reduced overall collagen accumulation in the liver of HFCD- and CCl(4)-derived mouse models. We found that IVA-PLA(2) deficiency prevented activation of hepatic stellate cells and infiltration of F4/80-positive macrophages without affecting other immunocytes such as CD8(+) lymphocytes and natural killer cells. In summary, IVA-PLA(2) deficiency attenuates not only lipid deposition in the liver but also hepatic fibrosis formation.-Ishihara, K., Miyazaki, A., Nabe, T., Fushimi, H., Iriyama, N., Kanai, S., Sato, T., Uozumi, N., Shimizu, T., Akiba, S. Group IVA phospholipase A(2) participates in the progression of hepatic fibrosis.The FASEB Journal 06/2012; 26(10):4111-21. · 5.71 Impact Factor -
Article: Regulatory role of antigen-induced interleukin-10, produced by CD4(+) T cells, in airway neutrophilia in a murine model for asthma.
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ABSTRACT: It has been suggested that interleukin (IL)-10 exerts immunosuppressive effects on allergic inflammation, including asthma, mainly through inhibition of Th2 cell-mediated eosinophilic airway inflammation. In a model of experimental asthma utilizing multiple intratracheal antigen challenges in sensitized mice, IL-10 production as well as eosinophilia and neutrophilia in the lung were induced by the multiple challenges. In this study, we set out to reveal the cellular source of endogenously produced IL-10, and the roles of IL-10 in airway leukocyte inflammation using an anti-IL-10 receptor monoclonal antibody. Balb/c mice were sensitized i.p. with ovalbumin+Al(OH)(3), and then challenged by intratracheal administration of ovalbumin 4 times. Flow cytometric analyses revealed that the cellular source of IL-10 was CD4(+) T cells lacking the transcription factor, forkhead box P3. Treatment with anti-IL-10 receptor monoclonal antibody prior to the 4th challenge significantly augmented airway neutrophilia as well as the production of IL-1β, and CXC chemokines, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2, but not airway eosinophilia, Th2 cytokine (IL-4 and IL-5) production, or a late-phase increase in specific airway resistance. Approximately 40% of IL-10 receptor(+) cells expressed the macrophage marker F4/80, whereas only 3-4% of the IL-10 receptor(+) cells were granulocyte differentiation antigen (Gr)-1(high) cells (neutrophils). In conclusion, multiple airway antigen challenges induced the proliferation of IL-10-expressing CD4(+) T cells in regulating airway neutrophilia. Systemic blockade of IL-10 function coincided with increases in IL-1β and CXC chemokines. Thus, IL-1β and CXC chemokines may be targets for development of novel pharmacotherapy for neutrophilic asthma.European journal of pharmacology 12/2011; 677(1-3):154-62. · 2.59 Impact Factor -
Article: Regulation of macrophage differentiation and polarization by group IVC phospholipase A₂.
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ABSTRACT: Although the cellular function of group IVC phospholipase A(2) (IVC-PLA(2)) remains to be understood, the expression of IVC-PLA(2) in human monocytic THP-1 cells was increased during phorbol ester-induced macrophage differentiation. We therefore examined the role of IVC-PLA(2) in macrophage differentiation using THP-1 cells. Two THP-1 cell lines stably expressing IVC-PLA(2)-specific shRNA were established. Differentiation and maturation into macrophages on treatment with phorbol ester were facilitated by knockdown of IVC-PLA(2) without the compensatory induction of mRNA expression for other group IV and VI PLA(2)s. Furthermore, the enhancement of macrophage differentiation by IVC-PLA(2)-knockdown were abolished by treatment with lysophosphatidylcholine, a metabolite of phospholipids generated by PLA(2)-mediated hydrolysis, indicating that PLA(2) activity is necessary for the inhibition of macrophage differentiation by IVC-PLA(2). Additionally, we found that the differentiation into classically activated M1 macrophage was superior in IVC-PLA(2)-knockdown cells, whereas the differentiation into alternatively activated M2 macrophage was suppressed by IVC-PLA(2)-knockdown. These findings suggest that IVC-PLA(2) is involved in regulations of macrophage differentiation and macrophage polarization.Biochemical and Biophysical Research Communications 11/2011; 416(3-4):325-30. · 2.48 Impact Factor -
Article: Synthesis of N-(trifluoromethyl-2-pyridinyl)arenesulfonamides as an inhibitor of secretory phospholipase A₂.
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ABSTRACT: A series of N-(trifluoromethyl-2-pyridinyl)alkane- and arenesulfonamides 2-5 have been synthesized by the substitution reaction of 2-chloro(trifluoromethyl)pyridines 6 with alkane- and arenesulfonamides 7. Their inhibitory activities against secretory phospholipase A₂ of porcine pancreas were examined and the analog N-[4,5-bis(trifluoromethyl)-2-pyridinyl]-4-trifluoromethylbenzenesulfonamide 4i was shown to have the highest inhibitory activity, with an IC(50) value of 0.58 mM.Chemical & pharmaceutical bulletin 01/2011; 59(6):783-6. · 1.70 Impact Factor -
Article: Synthesis of N-[2-(2,4-Difluorophenoxy)trifluoromethyl-3-pyridyl]sulfonamides and their inhibitory activities against secretory phospholipase A₂.
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ABSTRACT: N-[2-(2,4-Difluorophenoxy)trifluoromethyl-3-pyridyl]sulfonamide derivatives 3-6 were prepared by the reaction of 3-pyridylamines and sulfonyl chlorides. Inhibitory activities of these compounds toward secretory phospholipase A₂ (sPLA₂) were examined and N-[2-(2,4-difluorophenoxy)-5-trifluoromethyl-3-pyridyl]-2-naphthalenesulfonamide (5c) was found to be the most potent against sPLA₂ with an IC₅₀ value of 90 µM.Chemical & pharmaceutical bulletin 01/2011; 59(8):1069-72. · 1.70 Impact Factor -
Article: Triacylglycerol deposition with group IVC phospholipase A2 expression in oleate- and linoleate-stimulated Huh-7 hepatocytes.
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ABSTRACT: The accumulation of hepatocellular triacylglycerol (TG), a major symptom of fatty liver, is associated with the excessive incorporation of exogenous free fatty acids into hepatocytes, the free fatty acids inducing an increase in TG bearing acyl chains derived from not only themselves but also endogenous fatty acids. However, the mechanisms responsible for the supply of endogenous fatty acids, which are mainly esterified into phospholipids, remain unclear. In the present study, we examined the possible involvement of intracellular phospholipase A(2) (PLA(2))s including group IVA, IVC, VIA, and VIB PLA(2)s, which catalyze the release of endogenous fatty acids, in the deposition of TG in hepatocytes. Stimulation of human hepatoma Huh-7 cells with oleate or linoleate for 48 h increased TG contents time-dependently. Under the conditions, increased expression of group IVC PLA(2) mRNA and protein was observed at 6-12 h and 24-48 h after the stimulation, respectively. However, mRNA levels of group IVA, VIA, or VIB PLA(2) did not change. When cells were treated with methyl arachidonyl fluorophosphonate used as an inhibitor of group IVC PLA(2), the fatty acid-induced deposition of TG was partially but significantly suppressed at 48 h, although no significant inhibition was observed at 24 h. Overexpression of wild-type group IVC PLA(2) but not a catalytically inactive mutant of group IVC PLA(2) tended to increase cellular TG levels. The present findings suggest that stimulation of Huh-7 hepatocytes with free fatty acids induces the expression of group IVC PLA(2), which is involved in the fatty acid-induced deposition of TG.Biological & Pharmaceutical Bulletin 01/2011; 34(2):191-6. · 1.66 Impact Factor -
Article: Alleviation of high-fat diet-induced fatty liver damage in group IVA phospholipase A2-knockout mice.
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ABSTRACT: Hepatic fat deposition with hepatocellular damage, a feature of non-alcoholic fatty liver disease, is mediated by several putative factors including prostaglandins. In the present study, we examined whether group IVA phospholipase A(2) (IVA-PLA(2)), which catalyzes the first step in prostanoid biosynthesis, is involved in the development of fatty liver, using IVA-PLA(2)-knockout mice. Male wild-type mice on high-fat diets (20% fat and 1.25% cholesterol) developed hepatocellular vacuolation and liver hypertrophy with an increase in the serum levels of liver damage marker aminotransferases when compared with wild-type mice fed normal diets. These high-fat diet-induced alterations were markedly decreased in IVA-PLA(2)-knockout mice. Hepatic triacylglycerol content was lower in IVA-PLA(2)-knockout mice than in wild-type mice under normal dietary conditions. Although high-fat diets increased hepatic triacylglycerol content in both genotypes, the degree was lower in IVA-PLA(2)-knockout mice than in wild-type mice. Under the high-fat dietary conditions, IVA-PLA(2)-knockout mice had lower epididymal fat pad weight and smaller adipocytes than wild-type mice. The serum level of prostaglandin E(2), which has a fat storage effect, was lower in IVA-PLA(2)-knockout mice than in wild-type mice, irrespective of the kind of diet. In both genotypes, high-fat diets increased serum leptin levels equally between the two groups, but did not affect the serum levels of adiponectin, resistin, free fatty acid, triacylglycerol, glucose, or insulin. Our findings suggest that a deficiency of IVA-PLA(2) alleviates fatty liver damage caused by high-fat diets, probably because of the lower generation of IVA-PLA(2) metabolites, such as prostaglandin E(2). IVA-PLA(2) could be a promising therapeutic target for obesity-related diseases including non-alcoholic fatty liver disease.PLoS ONE 01/2009; 4(12):e8089. · 4.09 Impact Factor -
Article: The phenylic hydroxyl group is essential for the induction of stress response by sodium salicylate.
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ABSTRACT: We have shown that sodium salicylate (SA) activates the heat shock promoter and induces the expression of heat shock proteins (Hsps) with a concomitant increase in the thermotolerance of cells. To identify the functional groups of SA necessary for the induction of Hsps, we evaluated the effect of various derivatives of SA using a mammalian cell line containing a reporter gene downstream of an hsp105 promoter. Among the derivatives, the compounds in which the carboxyl group of SA was substituted activated the hsp105 promoter at 37 degrees C as SA did, but the compounds in which the hydroxyl group was substituted did not. Thus, the phenylic hydroxyl group but not the carboxyl group of SA seemed to be necessary for a stress-induced response. In addition, the orientation of two functional groups on the benzene ring of SA derivatives was also important for the induction of a response. Among these compounds, salicylalcohol which strongly induced the expression of Hsps suppressed the protein aggregation and apoptosis caused by an expanded polyglutamine tract in a cellular model of polyglutamine disease. These findings may aid in the development of novel effective Hsp-inducers.Biochemical and Biophysical Research Communications 12/2006; 350(1):131-7. · 2.48 Impact Factor -
Article: Hsp105 family proteins suppress staurosporine-induced apoptosis by inhibiting the translocation of Bax to mitochondria in HeLa cells.
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ABSTRACT: Hsp105 (Hsp105alpha and Hsp105beta), major heat shock proteins in mammalian cells, belong to a subgroup of the HSP70 family, HSP105/110. Previously, we have shown that Hsp105alpha has completely different effects on stress-induced apoptosis depending on cell type. However, the molecular mechanisms by which Hsp105alpha regulates stress-induced apoptosis are not fully understood. Here, we established HeLa cells that overexpress either Hsp105alpha or Hsp105beta by removing doxycycline and examined how Hsp105 modifies staurosporine (STS)-induced apoptosis in HeLa cells. Apoptotic features such as the externalization of phosphatidylserine on the plasma membrane and nuclear morphological changes were induced by the treatment with STS, and the STS-induced apoptosis was suppressed by overexpression of Hsp105alpha or Hsp105beta. In addition, we found that overexpression of Hsp105alpha or Hsp105beta suppressed the activation of caspase-3 and caspase-9 by preventing the release of cytochrome c from mitochondria. Furthermore, the translocation of Bax to mitochondria, which results in the release of cytochrome c from the mitochondria, was also suppressed by the overexpression of Hsp105alpha or Hsp105beta. Thus, it is suggested that Hsp105 suppresses the stress-induced apoptosis at its initial step, the translocation of Bax to mitochondria in HeLa cells.Experimental Cell Research 11/2006; 312(17):3215-23. · 3.58 Impact Factor -
Article: Arctigenin from Fructus Arctii is a novel suppressor of heat shock response in mammalian cells.
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ABSTRACT: Because heat shock proteins (Hsps) are involved in protecting cells and in the pathophysiology of diseases such as inflammation, cancer, and neurodegenerative disorders, the use of regulators of the expression of Hsps in mammalian cells seems to be useful as a potential therapeutic modality. To identify compounds that modulate the response to heat shock, we analyzed several natural products using a mammalian cell line containing an hsp promoterregulated reporter gene. In this study, we found that an extract from Fructus Arctii markedly suppressed the expression of Hsp induced by heat shock. A component of the extract arctigenin, but not the component arctiin, suppressed the response at the level of the activation of heat shock transcription factor, the induction of mRNA, and the synthesis and accumulation of Hsp. Furthermore, arctigenin inhibited the acquisition of thermotolerance in mammalian cells, including cancer cells. Thus, arctigenin seemed to be a new suppressive regulator of heat shock response in mammalian cells, and may be useful for hyperthermia cancer therapy.Cell Stress and Chaperones 02/2006; 11(2):154-61. · 3.01 Impact Factor -
Article: DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4 T cells and CD8 T cells.
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ABSTRACT: We report that HSP105, identified by serological identification of antigens by recombinant expression cloning (SEREX), is overexpressed in a variety of human cancers, including colorectal, pancreatic, thyroid, esophageal, and breast carcinoma, but is not expressed in normal tissues except for the testis. The amino acid sequences and expression patterns of HSP105 are very similar in humans and mice. In this study, we set up a preclinical study to investigate the usefulness of a DNA vaccine producing mouse HSP105 whole protein for cancer immunotherapy in vivo using BALB/c and C57BL/6 mice, Colon26, a syngeneic endogenously HSP105-expressing colorectal cancer cell line, and B16.F10, a melanoma cell line. The DNA vaccine was used to stimulate HSP105-specific T-cell responses. Fifty percent of mice immunized with the HSP105 DNA vaccine completely suppressed the growth of subcutaneous Colon26 or B16.F10 cells accompanied by massive infiltration of both CD4+ T cells and CD8+ T cells into tumors. In cell transfer or depletion experiments we proved that both CD4+ T cells and CD8+ T cells induced by these vaccines play critical roles in the activation of antitumor immunity. Evidence of autoimmune reactions was not present in surviving mice that had rejected tumor cell challenges. We found that HSP105 was highly immunogenic in mice and that the HSP105 DNA vaccination induced antitumor immunity without causing autoimmunity. Therefore, HSP105 is an ideal tumor antigen that could be useful for immunotherapy or the prevention of various human tumors that overexpress HSP105, including colorectal cancer and melanoma.Cancer Science 11/2005; 96(10):695-705. · 3.33 Impact Factor -
Article: A comparative proteomic analysis of the rat brain during rebound hyperphagia induced by space-restriction.
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ABSTRACT: Although neurochemical changes have been reported in the brain in animal models of binge eating, biochemical changes of specific proteins in the brain are unknown. Our aim was to elucidate brain proteins altered in rats during enhanced rebound hyperphargia. Rats were deprived of food for 22 h/day for 6 days, then allowed free access to food for 24 h in normal cages (rebound hyperphargia) or in space-restricted cages (enhanced rebound hyperphargia). Proteins extracted from the rat brain were separated by two-dimensional gel electrophoresis, and compared with those from control rats freely fed for 7 days in normal cages. Proteins expressed differently from controls were identified by N-terminal amino acid sequencing and mass fingerprinting using a MALDI-TOF mass spectrometer. Among proteins in the corpus striatum, frontal lobe, hippocampus and thalamus/hypothalamus, ubiquitin C-terminal hydrolase L1 and peroxiredoxin 2 decreased in the hippocampus and phosphatidylethanolamine-binding protein increased in the thalamus/hypothalamus of rats with the enhanced rebound hyperphargia induced by space-restriction. In this study, we first demonstrated that three brain proteins changed in rats during enhanced rebound hyperphagia. These proteins might have pathophysiologic relevance to binge eating.Molecular and Cellular Biochemistry 09/2005; 276(1-2):21-9. · 2.06 Impact Factor -
Article: Suppression of heat- and polyglutamine-induced cytotoxicity by nonsteroidal anti-inflammatory drugs.
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ABSTRACT: We have shown that sodium salicylate activates the heat shock promoter and induces the expression of heat shock proteins (hsps), with a concomitant increase in the thermotolerance of cells. To determine whether these effects are generally displayed by nonsteroidal anti-inflammatory drugs (NSAIDs), we examined the effects of a cyclooxygenase inhibitor, indomethacin, and a lipoxygenase inhibitor, nordihydroguaiaretic acid. Both inhibitors up-regulated the hsp promoter at 37 degrees C through the activation of heat shock factors, and increased cellular levels of hsps in mammalian cells, although the degree of the expression of hsps and thermotolerance of cells differed depending on the drugs. Furthermore, NSAIDs such as sodium salicylate and indomethacin suppressed the protein aggregation and apoptosis caused by an expanded polyglutamine tract in a cellular model of polyglutamine disease. These findings suggest that NSAIDs generally induce the expression of hsps in mammalian cells and may be used for the protection of cells against deleterious stressors and neurodegenerative diseases.European Journal of Biochemistry 12/2004; 271(22):4552-8. · 3.58 Impact Factor -
Article: Hsp105alpha suppresses Hsc70 chaperone activity by inhibiting Hsc70 ATPase activity.
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ABSTRACT: Hsp105alpha is a mammalian member of the HSP105/110 family, a diverged subgroup of the HSP70 family. Hsp105alpha associates with Hsp70/Hsc70 as complexes in vivo and regulates the chaperone activity of Hsp70/Hsc70 negatively in vitro and in vivo. In this study, we examined the mechanisms by which Hsp105alpha regulates Hsc70 chaperone activity. Using a series of deletion mutants of Hsp105alpha and Hsc70, we found that the interaction between Hsp105alpha and Hsc70 was necessary for the suppression of Hsc70 chaperone activity by Hsp105alpha. Furthermore, Hsp105alpha and deletion mutants of Hsp105alpha that interacted with Hsc70 suppressed the ATPase activity of Hsc70, with the concomitant appearance of ATPase activity of Hsp105alpha. As the ATPase activity of Hsp70/Hsc70 is essential for the efficient folding of nonnative protein substrates, Hsp105alpha is suggested to regulate the substrate binding cycle of Hsp70/Hsc70 by inhibiting the ATPase activity of Hsp70/Hsc70, thereby functioning as a negative regulator of the Hsp70/Hsc70 chaperone system.Journal of Biological Chemistry 11/2004; 279(40):41727-33. · 4.77 Impact Factor -
Article: Screening of Hsp105alpha-binding proteins using yeast and bacterial two-hybrid systems.
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ABSTRACT: Hsp105alpha is a 105-kDa stress protein, which is expressed constitutively at especially high levels in the brain compared with other tissues in mammals, and is also induced by a variety of stressors. Recently, we have shown that Hsp105alpha binds to alpha-tubulin and prevents the heat-induced disaggregation of microtubules. To further elucidate the function of Hsp105alpha, we searched for Hsp105alpha-binding proteins by screening a mouse FM3A cell library and human and mouse brain cDNA libraries using the yeast and bacterial two-hybrid systems. We showed here that Hsp105alpha interacted with several cellular proteins, such as cofilin, dynein light chain 2A, alpha-adducin, ubiquitin activating enzyme E1, phosphoglycerate kinase 1, and platelet-activating factor acethylhydrolase alpha1-subunit. The interaction was validated by the results of a pull-down assay and indirect immunofluorescence analysis. The significance of Hsp105alpha and Hsp105alpha-binding proteins in cells was discussed.Biochemical and Biophysical Research Communications 03/2004; 314(2):396-402. · 2.48 Impact Factor -
Article: Hsp105 but not Hsp70 family proteins suppress the aggregation of heat-denatured protein in the presence of ADP.
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ABSTRACT: Hsp105alpha and Hsp105beta are mammalian members of the Hsp105/110 family, a diverged subgroup of the Hsp70 family. Here, we show that Hsp105alpha and Hsp105beta bind non-native protein through the beta-sheet domain and suppress the aggregation of heat-denatured protein in the presence of ADP rather than ATP. In contrast, Hsc70/Hsp40 suppressed the aggregation of heat-denatured protein in the presence of ATP rather than ADP. Furthermore, the overexpression of Hsp105alpha but not Hsp70 in COS-7 cells rescued the inactivation of luciferase caused by ATP depletion. Thus, Hsp105/110 family proteins are suggested to function as a substitute for Hsp70 family proteins to suppress the aggregation of denatured proteins in cells under severe stress, in which the cellular ATP level decreases markedly.FEBS Letters 01/2004; 555(2):390-6. · 3.54 Impact Factor -
Article: Identification of sodium salicylate as an hsp inducer using a simple screening system for stress response modulators in mammalian cells.
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ABSTRACT: As heat shock proteins (Hsps) are involved in protecting cells and also in the pathophysiology of diseases such as inflammation, cancer and neurodegenerative disorders, modulators of Hsp expression in mammalian cells would seem to be useful for the treatment of various diseases. In this study, we isolated mammalian cell lines for screening of Hsp modulators; mouse C3H10T1/2 cells stably transfected with a plasmid containing the mouse Hsp105 or human Hsp70B promoter upstream of a luciferase or beta-galactosidase reporter gene, respectively. Using these cells, we examined the effect of sodium salicylate (SA), which may induce the transcription of hsp genes, on stress response in mammalian cells. When these cells were treated with SA for 1 h at 37 degrees C, both promoter activities were up-regulated by SA at concentrations of more than 45 mm. The activation of heat shock factor and the subsequent accumulation of Hsp105alpha and Hsp70 were detected in cells treated with SA at concentrations of more than 20 and 45 mm, respectively. Furthermore, SA induced resistance against a subsequent lethal stress. These findings suggested that SA is a potent hsp inducer, and may be used to protect cells against deleterious stressors.European Journal of Biochemistry 09/2003; 270(16):3461-8. · 3.58 Impact Factor -
Article: Hsp105alpha suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity.
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ABSTRACT: Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The N-terminal fragment of AR containing the expanded polyglutamine tract aggregates in cytoplasm and/or in nucleus and induces cell death. Some chaperones such as Hsp40 and Hsp70 have been identified as important regulators of polyglutamine aggregation and/or cell death in neuronal cells. Recently, Hsp105alpha, expressed at especially high levels in mammalian brain, has been shown to suppress apoptosis in neuronal cells and prevent the aggregation of protein caused by heat shock in vitro. However, its role in polyglutamine-mediated cell death and toxicity has not been studied. In the present study, we examined the effects of Hsp105alpha on the aggregation and cell toxicity caused by expansion of the polyglutamine tract using a cellular model of SBMA. The transient expression of truncated ARs (tARs) containing an expanded polyglutamine tract caused aggregates to form in COS-7 and SK-N-SH cells and concomitantly apoptosis in the cells with the nuclear aggregates. When Hsp105alpha was overexpressed with tAR97 in the cells, Hsp105alpha was colocalized to aggregates of tAR97, and the aggregation and cell toxicity caused by expansion of the polyglutamine tract were markedly reduced. Both beta-sheet and alpha-helix domains, but not the ATPase domain, of Hsp105alpha were necessary to suppress the formation of aggregates in vivo and in vitro. Furthermore, Hsp105alpha was found to localize in nuclear inclusions formed by ARs containing an expanded polyglutamine tract in tissues of patients and transgenic mice with SBMA. These findings suggest that overexpression of Hsp105alpha suppresses cell death caused by expansion of the polyglutamine tract without chaperone activity, and the enhanced expression of the essential domains of Hsp105alpha in brain may provide an effective therapeutic approach for CAG repeat diseases.Journal of Biological Chemistry 08/2003; 278(27):25143-50. · 4.77 Impact Factor -
Article: Hsp105α Suppresses the Aggregation of Truncated Androgen Receptor with Expanded CAG Repeats and Cell Toxicity
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ABSTRACT: Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The N-terminal fragment of AR containing the expanded polyglutamine tract aggregates in cytoplasm and/or in nucleus and induces cell death. Some chaperones such as Hsp40 and Hsp70 have been identified as important regulators of polyglutamine aggregation and/or cell death in neuronal cells. Recently, Hsp105α, expressed at especially high levels in mammalian brain, has been shown to suppress apoptosis in neuronal cells and prevent the aggregation of protein caused by heat shock in vitro. However, its role in polyglutamine-mediated cell death and toxicity has not been studied. In the present study, we examined the effects of Hsp105α on the aggregation and cell toxicity caused by expansion of the polyglutamine tract using a cellular model of SBMA. The transient expression of truncated ARs (tARs) containing an expanded polyglutamine tract caused aggregates to form in COS-7 and SK-N-SH cells and concomitantly apoptosis in the cells with the nuclear aggregates. When Hsp105α was overexpressed with tAR97 in the cells, Hsp105α was colocalized to aggregates of tAR97, and the aggregation and cell toxicity caused by expansion of the polyglutamine tract were markedly reduced. Both β-sheet and α-helix domains, but not the ATPase domain, of Hsp105α were necessary to suppress the formation of aggregates in vivo and in vitro. Furthermore, Hsp105α was found to localize in nuclear inclusions formed by ARs containing an expanded polyglutamine tract in tissues of patients and transgenic mice with SBMA. These findings suggest that overexpression of Hsp105α suppresses cell death caused by expansion of the polyglutamine tract without chaperone activity, and the enhanced expression of the essential domains of Hsp105α in brain may provide an effective therapeutic approach for CAG repeat diseases.Journal of Biological Chemistry 07/2003; 278(27):25143-25150. · 4.77 Impact Factor
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2002–2012
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Kyoto Pharmaceutical University
Kyoto, Kyoto-fu, Japan
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