T Muraki

Tokyo Women's Medical University, Edo, Tōkyō, Japan

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Publications (107)278.43 Total impact

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    ABSTRACT: Carbonyl stress is one of the important mechanisms of tissue damage in vascular complications of diabetes. In the present study, we observed that the plasminogen activator inhibitor-1 (PAI-1) levels in serum and its gene expression in adipose tissue were up-regulated in aged OLETF rats, model animals of obese type 2 diabetes. To study the mechanism of PAI-1 up-regulation, we examined the effect of advanced glycation end products (AGEs) and the product of lipid peroxidation (4-hydroxy-2-nonenal (HNE)), both of which are endogenously generated under carbonyl stress. Stimulation of primary white adipocytes by either AGE or HNE resulted in the elevation of PAI-1 in culture medium and at mRNA levels. The up-regulation of PAI-1 was also observed by incubating the cells in high glucose medium (30 mm, 48 h). The stimulatory effects by AGE or high glucose were inhibited by antioxidant, pyrrolidine dithiocarbamate, and reactive oxygen scavenger, probucol, suggesting a pivotal role of oxidative stress in white adipocytes. We also found that the effect by HNE was inhibited by antioxidant, N-acetylcysteine and that a specific inhibitor of glutathione biosynthesis, l-buthionine-S,R-sulfoximine, augmented the effect of subthreshold effect of HNE. Bioimaging of reactive oxygen species (ROS) by a fluorescent indicator, 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate, revealed ROS production in white adipocytes treated with AGE or HNE. These results suggest that cellular carbonyl stress induced by AGEs or HNE may stimulate PAI-1 synthesis in and release from adipose tissues through ROS formation.
    Journal of Biological Chemistry 03/2004; 279(6):4075-83. · 4.65 Impact Factor
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    ABSTRACT: Uremic toxins have been suggested to promote progression of chronic renal failure. We have shown that organic anion transporter-mediated uptake of uremic toxins induces oxidative stress in opossum kidney renal tubular cells overexpressing the transporter. Plasminogen activator inhibitor-1 (PAI-1) and nuclear factor-kappa B (NF-kappaB) are major factors known to promote tubulointerstitial fibrosis. The present study examined the signaling pathway that is activated by uremic toxins to induce PAI-1 and activate NF-kappaB in human renal proximal tubular cells (HK-2). Uremic toxins in the form of organic anion were examined their ability to induce oxidative stress, PAI-1 gene expression, and NF-kappaB activation in HK-2. PAI-1 expression was measured by enzyme-linked immunosorbent assay (ELISA) and the Northern blotting. Human PAI-1 promoter activity was estimated by luciferase reporter gene (NKkappaB-luc) assay. NF-kappaB activation was measured by the pNFkappaB-luc reporter gene and electrophretic gel mobility shift assay. Among organic anion species tested, indoxyl sulfate and indoleacetic acid induced free radical production in HK-2. A nonspecific transporter inhibitor (probenecid) suppressed the IS-stimulated radical production. Indoxyl sulfate and indoleacetic acid dose dependently increased the expressions of PAI-1 mRNA and protein in these cells. The luciferase reporter gene assay revealed that indoxyl sulfate and indoleacetic acid dose dependently activated NF-kappaB and PAI-1 promoter. Activation of NF-kappaB was also confirmed by an electrophoretic gel mobility shift assay. Both antioxidant and NF-kappaB inhibitors dose dependently inhibited the activation of PAI-1 promoter by indoxyl sulfate. Uremic toxins induce free radical production by renal tubular cells and activate NF-kappaB which, in turn, up-regulates PAI-1 expression. Thus, progression of chronic renal failure may be promoted by PAI-1 up-regulation induced by uremic toxins.
    Kidney International 06/2003; 63(5):1671-80. · 8.52 Impact Factor
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    ABSTRACT: The effect of heat shock protein (hsp) induction on lipopolysaccharide (LPS)-induced increase in vascular permeability was studied in mice as a model of inflammatory mediator-induced inflammatory response. Mice were exposed to an ambient temperature of 43 degrees C for 1 h and then returned to 23 degrees C to recover up to 24 h. Dermal contents of hsp70 and hsp90 but not heat shock cognate protein (hsc)70 increased at 6 h after heat exposure and returned to the basal level at 24 h. LPS was injected subcutaneously at 0, 2, 4, 6, or 24 h after heat exposure. Two hours after LPS injection, vascular permeability was assessed by dermal accumulation of intravenously injected dye. LPS-induced dye leakage was reduced by 42 and 49% in heat-exposed mice after recovery for 4 and 6 h, respectively. Increases in dermal tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) contents induced by LPS were significantly reduced in the heat-stressed mice recovered for 6 h. LPS-induced increase in cyclooxygenase-2 but not TNF-alpha mRNA was attenuated in heat-stressed mice. Deoxyspergualin, an inhibitor of hsc70 and hsp90, and geldanamycin, a specific hsp90 inhibitor, dose dependently reversed the inhibitory effect of heat stress on LPS-induced dye leakage and dermal TNF-alpha content but not PGE(2) content. These results suggest that heat stress attenuated LPS-induced vascular permeability change by inducing hsp90, leading to inhibition of TNF-alpha production.
    Journal of Pharmacology and Experimental Therapeutics 12/2002; 303(2):656-63. · 3.89 Impact Factor
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    ABSTRACT: A direct effect of uraemic toxins in promoting progression of chronic renal disease has not been established. In this study, we investigated the toxic effects of organic anions which characteristically appeared in the patients with progressive renal disease on renal proximal tubular cells expressing human organic anion transporter (hOAT) 1. A renal proximal tubular cell line, opossum kidney (OK) cells, was transformed with hOAT1. Among the organic anions examined, hippuric acid, para-hydroxyhippuric acid, ortho-hydroxyhippuric acid, indoxyl sulphate and indoleacetic acid showed a high affinity for hOAT1 expressed in the OK cells. Indoxyl sulphate and indoleacetic acid concentration-dependently inhibited proliferation of the hOAT1-transformed cells. The h.p.l.c. analysis demonstrated that cellular uptake of these organic anions was significantly elevated in hOAT1-transformed cells. These organic anions also concentration-dependently stimulated cellular free radical production. The degrees of inhibition of cell proliferation and the stimulation of free radical production induced by the organic anions were significantly higher in the hOAT1-transformed cells than vector-transformed cells. The stimulatory effect of indoxyl sulphate on free radical production was abolished by anti-oxidants and probenecid. Less free radical production was observed in the hOAT1-transformed cells treated with p-hydroxyhippuric acid, o-hydroxyhippuric acid compared with indoxyl sulphate and indoleacetic acid. Hippuric acid had little effect on free radical production. Organic anions present in the serum of patients with progressive renal disease may cause proximal tubular injury via hOAT1-mediated uptake. The mechanism of cellular toxicity by these uraemic toxins involves free radical production. Thus, some uraemic toxins may directly promote progression of chronic renal disease.
    British Journal of Pharmacology 02/2002; 135(2):555-63. · 5.07 Impact Factor
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    ABSTRACT: The effects of pretreatment with ONO-4007, a lipid A analog, on cutaneous plasma leakage induced by ONO-4007, lipopolysaccharide (LPS) and inflammatory mediators were investigated. Male ddY strain mice. Mice were pretreated with ONO-4007 (up to 6 mg/kg i.p.), 0-24 h prior to plasma leakage study. Plasma extravasation was determined by dye leakage. Systemic ONO-4007 (6 mg/kg i. p.) pretreatment for 2 to 12 h inhibited plasma extravasation in the mouse skin elicited by ONO-4007 and LPS. The inhibition was dose-dependent. Plasma leakage induced by platelet-activating factor (PAF), histamine and 5-hydroxytryptamine (5-HT) was also inhibited by ONO-4007 pretreatment. Plasma corticosterone levels increased 2 and 4 h after systemic ONO-4007 (6 mg/kg) administration and returned to the control level 24 h later. Adrenalectomy and metyrapone but not propranolol reversed the inhibition by ONO-4007 pretreatment of LPS-induced plasma leakage. A single injection of ONO-4007 in mice induced transient tolerance to plasma leakage elicited by LPS, ONO-4007 and inflammatory mediators. Endogenous corticosterone, at least in part, plays a role in the development of tolerance.
    Inflammation Research 02/2002; 51(1):38-43. · 1.96 Impact Factor
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    ABSTRACT: Anti-inflammatory effects of cyclic AMP elevating agents were examined in a mouse model of lipopolysaccharide (LPS)-induced microvascular permeability change. Vascular permeability on the back skin was measured by the local accumulation of Pontamine sky blue (PSB) after subcutaneous injection of LPS (400 microg site-1) from Salmonella typhimurium. Dye leakage in the skin was significantly increased 2 h after injection of LPS. This LPS-induced dye leakage was suppressed by phosphodiesterase inhibitors, including pentoxifylline (160 mg kg-1), milrinone (5 - 10 mg kg-1), rolipram (0.5 - 10 mg kg-1) and zaprinast (5 - 10 mg kg-1). The dye leakage was also inhibited by beta-adrenoceptor agonists, including isoproterenol (0.5 - 5 mg kg-1) and salbutamol (0.05 - 5 mg kg-1), an adenylate cyclase activator, forskolin (5 mg kg-1), and a cell permeable cyclic AMP analogue, 8-bromo-cyclic AMP (8-Br-cAMP, 10 mg kg-1). LPS caused a transient increase in serum TNF-alpha level peaking at 1 h after the injection. This increase in serum TNF-alpha was completely blocked by a pretreatment with pentoxifylline (160 mg kg-1), milrinone (5 mg kg-1), rolipram (1 mg kg-1), zaprinast (10 mg kg-1), salbutamol (0.5 mg kg-1), forskolin (1 mg kg-1) and 8-Br-cAMP (10 mg kg-1). LPS caused an increase in serum IL-1alpha level peaking at 3 h after injection. This increase in serum IL-1alpha was not significantly suppressed by the cyclic AMP elevating agents. Our study suggests that cyclic AMP elevating agents attenuate LPS-induced microvascular permeability change by suppressing TNF-alpha up regulation.
    British Journal of Pharmacology 06/2001; 133(2):237-42. · 5.07 Impact Factor
  • K Ohba, T Yoshioka, T Muraki
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    ABSTRACT: Human type II iodothyronine deiodinase (hDII) belongs to a family of selenoproteins. It catalyzes 5'-deiodination of thyroxine to generate an active thyroid hormone, 3,3',5-triiodothyronine. Two novel splice variants of hDII gene transcript; namely hDII-b and hDII-c, were identified. Three distinct DNA fragments (hDII-a-c) were amplified by a reverse transcription-polymerase chain reaction (RT-PCR) with hDII intron-spanning primers using total-RNA from human umbilical vein endothelial cell line, ECV304. The sequence of hDII-a was identical to that of previously reported hDII. hDII-b and hDII-c had an additional insertion of 108 and 242 bp, respectively. The insertion sequences were found in the intron of hDII gene, therefore, two novel exons exist between exons 1 and 2 of hDII gene. The splice sites of new exons (b and c) conserved the consensus sequences of splice acceptor and donor sites. hDII-b contains exon b with an in-frame TGA codon that may encode an extra selenocysteine. hDII-c contained exons b and c and the predicted open reading frame is interrupted by a stop codon (TAA) produced by a frame shift. RT-PCR analysis showed that hDII-a and hDII-b mRNAs are expressed in human tissues including brain, kidney, lung and trachea. The mRNA abundance of hDII-c was lower than that of hDII-a or hDII-b. Thus, the new variants of hDII transcripts suggest the presence of two short exons between exons 1 and 2 of hDII gene, and of functional variant of hDII.
    Molecular and Cellular Endocrinology 03/2001; 172(1-2):169-75. · 4.04 Impact Factor
  • F Tsukahara, T Yoshioka, T Muraki
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    ABSTRACT: A novel variant of human heat-shock cognate protein 70 (HSC70) transcript, named heat-shock cognate protein 54 (HSC54), was identified and characterized. The transcript encodes the protein lacking 153 amino acid residues of HSC70 in a part of the protein-binding and variable domains, resulting in a calculated molecular mass of 53.5 kDa. HSC54 mRNA was detected in all human cells and tissues examined. The protein was also detected in peripheral mononuclear cells and U937 human histiocytic lymphoma cells. Heat treatment of U937 cells up-regulated the expression of HSC54. The chaperoning activity of HSC54 was examined by luciferase renaturation assay. HSC70 recovered the luciferase activity in the presence of reticulocyte lysate as a source of cochaperones. However, HSC54 did not facilitate the recovery of denatured luciferase; besides, HSC54 significantly inhibited the HSC70-mediated chaperoning activity. In pull-down experiments, HSC54 interacted with cochaperones, p60, HSP40, and p48, as HSC70 did. The resonant mirror detection analysis showed that p60 binds to HSC54 with a higher association rate constant than HSC70 with a similar affinity constant. These results suggest that HSC54 is constitutively expressed and also inducible by stress and may function as an endogenous inhibitory regulator of HSC70 by competing the cochaperones.
    Molecular Pharmacology 01/2001; 58(6):1257-63. · 4.41 Impact Factor
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    ABSTRACT: Effects of dehydrocurdione, a zedoary-derived sesquiterpene, on smooth muscle were investigated by recording the mechanical activity of intestines and aorta from guinea pigs and rats. Dehydrocurdione (0.1-3 mM) induced a sustained relaxation of rat duodenum and inhibited spontaneous motility. Dehydrocurdione (0.1-1 mM) inhibited the contractile response of guinea pig ileum induced by acetylcholine (0.01-10 microM), histamine (0.03-10 microM) and substance P (0.1-30 nM) in a non-competitive manner. Acetylcholine (0.5 microM) elicited a transient contraction followed by a sustained contraction of guinea pig ileum, and dehydrocurdione pretreatment inhibited the sustained component, which depends on Ca(2+) entry from the extracellular space. The high K(+)-induced contraction of rat aortic ring is reported to be blocked by Ca(2+) channel blockers, while the norepinephrine-induced contraction includes a Ca(2+) channel blocker-resistant component. Dehydrocurdione (1 mM) blocked the high K(+) (60 mM)-induced contraction of rat aortic ring by 81%, while it inhibited the norepinephrine (1 microM)-induced contraction by only 28%. Dehydrocurdione (1 mM) significantly reduced the high K(+)-stimulated increase in cytosolic Ca(2+) level of Fura-2-loaded mesenteric artery from rats. These results suggest that the inhibitory effects of dehydrocurdione on intestinal and vascular smooth muscle are mediated by blockade of Ca(2+) entry from the extracellular space.
    European Journal of Pharmacology 10/2000; 403(3):235-42. · 2.59 Impact Factor
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    ABSTRACT: 1. Endotoxin shock is accompanied by an increase in peripheral vascular permeability. It has been postulated that most biological activities of LPS are derived from lipid A moiety. Here we examined the effect of lipid A analogue ONO-4007 in increasing vascular permeability and the possible mediators in mouse skin by a dye leakage method. 2. Subcutaneous injection of ONO-4007 (1 - 2 mg site(-1)) induced a dose-dependent increase in vascular permeability which was evident after 120 min. 3. ONO-4007-induced dye leakage was significantly attenuated by pretreatments with anti-tumour necrosis factor-alpha (TNF-alpha) and anti-interleukin-1alpha (IL-1alpha) antibodies, but not with indomethacin (5 mg kg(-1)) or diphenhydramine (10 mg kg(-1)). ONO-4007-induced dye leakage was significantly inhibited by a pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) (10 mg kg(-1)) but not with aminoguanidine (50 mg kg(-1)). In inducible nitric oxide synthase (iNOS)-deficient mice, ONO-4007 significantly increased the dye leakage, while ONO-4007 dilated rat thoracic aortic rings pre-contracted with phenylephrine, and the L-NAME pretreatment inhibited the dilation. 4. Thus, TNF-alpha, IL-1alpha and constitutive NOSs-derived nitric oxide but not prostaglandins or histamine play a role in ONO-4007-induced increase in vascular permeability. Although ONO-4007 mimics LPS in increasing vascular permeability, mechanisms of permeability change elicited by ONO-4007 were not identical to those of LPS.
    British Journal of Pharmacology 08/2000; 130(6):1235-40. · 5.07 Impact Factor
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    ABSTRACT: Lipoteichoic acid (LTA), the cell wall component of Gram-positive bacteria, has been shown to cause inflammatory responses comparable to lipopolysaccharide (LPS) of Gram-negative bacteria. This study examined the activity of LTA to induce dermal microvascular permeability changes in mice. Vascular permeability was assessed by extravasation of Pontamine sky blue. Subcutaneous injection of LTA (200-400 microg/site) in mice that were preinjected i.v. with the dye increased local dye leakage in the skin at 1 to 3 h. The LTA-induced dye leakage was inhibited by indomethacin, valeryl salicylate, diphenhydramine, and a platelet-activating factor antagonist but not by inhibitors of nitric-oxide synthase, cyclooxygenase-2, or guanylate cyclase or by antibodies against tumor necrosis factor-alpha or interleukin-1alpha. LTA induced comparable increases in dye leakage in inducible nitric-oxide synthase-deficient mice and wild-type controls. Pretreatment of normal mice with i.v. LTA did not confer tolerance to LTA- or LPS-induced dye leakage. In contrast, systemic LPS administration induced tolerance against subsequent challenge with LPS but not LTA. Serum corticosterone levels, which were suggested to induce tolerance, were not increased by LTA pretreatment but were increased by LPS. Thus, LTA increases dermal microvascular permeability in mice. Among the inflammatory mediators, eicosanoids, platelet-activating factor, and histamine mediate the effect of both LTA and LPS, whereas nitric oxide, tumor necrosis factor-alpha, and interleukin-1alpha may not play a major role in LTA-induced dye leakage. The difference between LTA and LPS to stimulate corticosterone may partially explain the failure of LTA to induce tolerance against vascular dye leakage.
    Journal of Pharmacology and Experimental Therapeutics 08/2000; 294(1):280-6. · 3.89 Impact Factor
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    ABSTRACT: 1. Subcutaneous injection of lipopolysaccharide (LPS) increases plasma leakage in mouse skin. Pretreatment with LPS conditions mice tolerant to the LPS-induced plasma leakage. Nitric oxide (NO) has been suggested to be involved in these LPS effects. A specific role of inducible NO synthase (iNOS) was investigated in the LPS-induced plasma leakage using iNOS deficient mice. 2. Plasma leakage in mouse skin was measured by the local accumulation of Pontamine sky blue at the site of subcutaneous injection of LPS (Sal. typhimurium). LPS (100 - 400 microg site(-1)) produced a dose-related increase in dye leakage in both iNOS deficient and wild-type mice with about 40% less dye leakage in iNOS deficient mice. 3. Indomethacin (5 mg kg(-1)), N-[-2-cyclohexyloxy]-4-nitrophenyl methanesulphonamide (NS-398) (1 mg kg(-1)), diphenhydramine (10 mg kg(-1)) and anti-TNF-alpha antibody (dilution 1 : 400, 10 ml kg(-1)) inhibited the LPS-induced dye leakage in both iNOS deficient and wild-type mice, whereas N(G)-nitro-L-arginine methyl ester (L-NAME) (10 mg kg(-1)) or aminoguanidine (10 mg kg(-1)) inhibited that in wild-type but not in iNOS deficient mice. 4. Pretreatment with LPS (0.15 mg kg(-1) i.p.) 4 h before decreased the LPS-induced dye leakage in wild-type but not in iNOS deficient mice. LPS pretreatment increased serum corticosterone levels in both mice, while it increased the serum nitrate/nitrite levels in wild-type but not in iNOS deficient mice. 5. These studies indicate that an increase in vascular permeability induced by LPS is mediated by NO produced by iNOS, eicosanoids, histamine and TNF-alpha. The tolerance against LPS-induced vascular permeability change may be mediated by iNOS induction but not by an increased release of endogenous corticosteroids.
    British Journal of Pharmacology 06/2000; 130(1):90-4. · 5.07 Impact Factor
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    ABSTRACT: 1. Carvedilol, an adrenoceptor blocker with antioxidant activity, was studied for its ability to interact with NO in a cell-free condition and in an endothelial cell line (ECV304). 2. In a cell-free system, carvedilol attenuated NO-dependent reduction of carboxy-2-phenyl-4,4, 5,5-tetramethyl-imidazoline-1-oxyl-3-oxide induced by a NO donor, 1-hydroxy-2-oxo-3-(aminopropyl)-3-isopropyl-1-triazene (NOC5), which was determined by electron paramagnetic resonance (EPR) spectrometry. The EPR study also showed that nitrosylhaemoglobin formation in rat red blood cells by the addition of NO-saturated solution was attenuated by prior incubation with 0.1 - 10 microM carvedilol. 3. NO-induced fluorescence in 4,5-diaminofluorescein-2 diacethyl (DAF-2DA)-loaded ECV304 cells was attenuated by carvedilol but not by labetalol. The IC(50) of carvedilol for NOC5 or sodium nitroprusside-induced fluorescence of DAF-2DA in ECV304 cells was 1. 0x10(-7) M, which was similar to the reported IC(50) of carvedilol for the antioxidant effect. 4. Cell toxicity induced by a NO donor determined by the number of viable cells after 24 h treatment with 2-2'(hydroxynitrosohydrazino)bis-ethanamine was significantly attenuated by pretreatment with 1 microM carvedilol. 5. Both free and cell-associated carvedilol quenched NO. Because NO mediates both physiological and pathophysiological processes, NO quenching by the drug may have diverse clinical implications depending upon specific functions of local NO in tissues where carvedilol is distributed.
    British Journal of Pharmacology 05/2000; 129(7):1530-5. · 5.07 Impact Factor
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    ABSTRACT: A natural tetrapeptide, acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a physiological negative regulator of hematopoiesis. The precursor of AcSDKP, thymocin beta 4, is expressed in many tissues including kidney. The present study examined the antiproliferative effect of AcSDKP in two renal cell lines, namely, renal interstitial fibloblasts cell line (NRK 49F) and renal proximal tubular epitherial cells (LLC-PK1). An addition of AcSDKP for 48 hours in theses cells resulted in a concentration-dependent attenuation in the proliferation rate (significant difference to non-treated cells was observed at 10(-9) to 10(-5) M AcSDKP) determined by a colorimetry of alamer blue oxidation. The cell cycle analysis of NRK 49F cells treated with AcSDKP showed that AcSDKP significantly reduced the ratio of S-phase to G2/M-phases. Thus, physiological concentrations of AcSDKP is capable of altering cell cycle to inhibit the proliferation of renal cells.
    Life Sciences 04/2000; 66(15):PL221-6. · 2.56 Impact Factor
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    ABSTRACT: Previously we showed that tumor necrosis factor-alpha (TNF-alpha) inhibits lipoprotein lipase (LPL) activity and its gene expression, an early marker of adipocyte differentiation, in cultured brown adipocytes. To know whether TNF-alpha also affects late events in brown adipocyte maturation, we examined the effect of TNF-alpha on obese gene expression and leptin secretion in mouse brown adipocytes differentiated in culture. TNF-alpha caused a concentration-dependent decrease in leptin accumulation in culture medium and leptin mRNA amount in brown adipocytes which constitutively express the ob gene. Time-course study showed that TNF-alpha significantly suppressed leptin secretion during incubation for 16, 24 and 48 h. Since some effect of TNF-alpha is mediated by activation of protein kinase C (PKC), the role of PKC in TNF-alpha-induced downregulation of ob gene expression and leptin secretion was studied. The suppressive effect of TNF-alpha on both ob gene expression and leptin secretion was blocked by PKC inhibitors such as bisindolylmaleimide I (BIM) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7). Incubation of brown adipocytes with TNF-alpha (20 ng/ml, 15 min) caused a rapid shift of PKC activity from the cytosolic to the membrane fraction, suggesting an activation of PKC by TNF-alpha in brown adipocytes. This effect of TNF-alpha was blocked by a selective PKC inhibitor, BIM. These results suggest that TNF-alpha promotes dedifferentiation of the brown adipocytes as evidenced by a downregulation in ob gene expression and leptin secretion via PKC-dependent mechanisms.
    Archiv für Experimentelle Pathologie und Pharmakologie 12/1999; 360(6):691-8. · 2.15 Impact Factor
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    ABSTRACT: A novel insulin sensitizing agent, thiazolidine, has been demonstrated to inhibit the growth of cultured vascular smooth muscle cells (VSMC) in vitro. This study was undertaken to examine the in vivo effects of the thiazolidine compound pioglitazone (PIO) on carotid neointimal thickening, after endothelial injury in Wistar rats and vascular hypertrophy in stroke-prone spontaneously hypertensive rats (SHR-SP/Izm). PIO treatment (3 mg/kg/day for 1 week prior to endothelial injury and 2 weeks postendothelial injury) remarkably decreased neointimal cross-sectional areas in treated animals (63.8 +/- 4.9 x 10(3) microm2) versus controls (196 +/- 7.6 x 10(3) microm2, P < 0.05). Bromodeoxyuridine uptake in the neointima, a marker of DNA synthesis, was also decreased after treatment compared with controls. In SHR-SP/Izm but not in Wistar rats, PIO treatment decreased blood pressure and plasma insulin levels. PIO treatment in SHR-SP/Izm (3 mg/kg/day from 4 weeks of age for 7 weeks) significantly decreased the medial wall thickness of the mesenteric artery (10.4 +/- 1.2 x 10(3) microm2 versus control, 21.2 +/- 2.4 x 10(3) microm2, P < 0.05). In addition, PIO treatment significantly decreased the expression of EIIIA fibronectin both in the carotid neointima of Wistar rats and the media of the mesenteric artery in SHR-SP/Izm compared with their respective controls (P < 0.05). These results suggest that PIO has vasculo-protective effects in both acute and chronic vascular injury in vivo through inhibition of VSMC proliferation.
    Atherosclerosis 09/1999; 145(2):333-40. · 3.71 Impact Factor
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    ABSTRACT: The role of endogenous nitric oxide (NO) and prostanoids in the increase in microvascular permeability induced by NO donors was investigated in the mouse skin by a dye leakage method. Subcutaneous (s.c.) injection of 1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene (NOC 5), 1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene (NOC 18) and sodium nitroprusside dose-dependently increased local dye leakage. While indomethacin inhibited the dye leakage elicited by these NO donors, N(G)-nitro-L-arginine methyl ester (L-NAME) inhibited the effect of NOC 5 and NOC 18 but not of sodium nitroprusside. These results suggest that endogenous NO, in addition to the prostanoid biosynthesis, is involved in the dermal microvascular permeability increase induced by the NOC series NO donors.
    European Journal of Pharmacology 08/1999; 377(2-3):219-22. · 2.59 Impact Factor
  • Microvascular Research 08/1999; 58(1):74-8. · 2.93 Impact Factor
  • In Vitro Cellular & Developmental Biology - Animal 07/1999; 35(6):307-10. · 1.29 Impact Factor
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    ABSTRACT: Dehydrocurdione, a sesquiterpene isolated from zedoary, was tested for in vivo and in vitro antiinflammatory actions. Analgesic effect was tested in ICR mice by the acetic acid-induced writhing method. Antipyretic effect was studied in Sprague-Dawley rats treated with baker's yeast. Antiinflammatory activities were tested in Wistar rats with carrageenan-induced paw edema and adjuvant-induced chronic arthritis. In vitro analyses included the capabilities to inhibit cyclooxygenase activity, and to scavenge free radicals as determined by electron paramagnetic resonance (EPR). Oral administration of dehydrocurdione (40 to 200 mg/kg) mitigated the writhing reflex. induced by acetic acid and the fever elicited by baker's yeast. A higher dose (200 mg/kg) of dehydrocurdione was required to inhibit the carrageenan-induced paw edema. Oral administration of dehydrocurdione at 120 mg/kg/day for 12 days significantly reduced chronic adjuvant arthritis. Unlike indomethacin (IC50: 0.1 microM), dehydrocurdione showed minimal cyclooxygenase inhibition. However, dehydrocurdione (100 microM to 5 mM) significantly reduced free radical formation from hydrogen peroxide and ferrous iron determined by EPR spectrometry using 5,5'-dimethyl-1-pyrroline-N-oxide as a spin trap agent. In addition to the well-known effect of zedoary as a stomachic, dehydrocurdione, the major component of Curcuma zedoaria Roscoe has antiinflammatory potency related to its antioxidant effect.
    Inflammation Research 01/1999; 47(12):476-81. · 1.96 Impact Factor