Mikio Ito

Meijo University, Nagoya, Aichi, Japan

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Publications (49)41.4 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Butein (3,4,2′,4′-tetrahydroxychalcone), a flavonoid derivative, has been reported to show several biological actions, including anti-inflammatory and anti-cancer. However, the possible molecular mechanisms involved are poorly understood. Treatment of human umbilical vein endothelial cells (HUVECs) with butein significantly inhibited cell surface intercellular adhesion molecule-1 (ICAM-1) expression, ICAM-1 protein synthesis, and mRNA expression induced by tumor necrotic factor-α (TNF-α) and/or phorbol 12-myristate 13-acetate (PMA). Electrophoretic mobility shift assay revealed that butein blocked activation of transcription factors, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), induced by TNF-α and PMA. Moreover, butein abolished TNF-α- and PMA-induced IκBα phosphorylation, which participates in NF-κB activation, and PMA-induced phosphorylation of c-Jun, a subunit composed of AP-1. In vitro, butein inhibited the phosphorylation of c-Jun, binding to GST beads, mediated by JNK isolated from PMA-treated cells. The inhibitory action of butein on the JNK-mediated in vitro c-Jun phosphorylation was abrogated in the presence of ATP. These results indicate that in HUVEC, butein suppresses the expression of ICAM-1 mRNA and protein through the inhibition of the activation of NF-κB and AP-1 induced by TNF-α and PMA, that the inhibitory action of butein on NF-κB activation results from the inhibition of IκBα phosphorylation by IκB kinase (IKK), and that the inactivation of PMA-activated AP-1 by butein is due to the blocking of JNK-mediated c-Jun phosphorylation through the inhibition of ATP binding.
    International Immunopharmacology 12/2014; 24(2). DOI:10.1016/j.intimp.2014.12.016 · 2.71 Impact Factor
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    ABSTRACT: MCP1 is upregulated by various stimuli, including LPS, high glucose, and hyperosmolality. However, the molecular mechanisms of transcriptional regulation of the MCP1 gene under hyperosmolar conditions are poorly understood. Treatment of NRK52E cells with NaCl or mannitol resulted in significant elevation of MCP1 mRNA and protein in a time- and dose-dependent manner. Treatment with a p38MAPK inhibitor (SB203580), an ERK inhibitor (PD98059), or an MEK inhibitor (U0126), suppressed the increase in MCP1 expression caused by hypertonic NaCl, whereas a JNK inhibitor (SP600125) and an AP1 inhibitor (curcumin) failed to attenuate MCP1 mRNA expression by NaCl. In the 5'-flanking region of the MCP1 gene, there is a sequence motif similar to the consensus TonE/ORE as well as the consensus C/E binding protein (BP), NF-kappaB, and AP1/Sp1 sites. Luciferase activity in cells transfected with reporter constructs containing a putative TonE/ORE element (MCP1-TonE/ORE) enhanced reporter gene expression under hypertonic stress. Results of electrophoretic gel mobility shift assay showed a slow migration of the MCP1-TonE/ORE probe, representing the binding of TonEBP/OREBP/NFAT5 to this enhancer element. These results indicate that the 5'-flanking region of MCP1 contains a hypertonicity-sensitive cis-acting element, MCP1-TonE/ORE, as a novel element in the MCP1 gene. Furthermore, p38MAPK and MEK-ERK pathways appear to be, at least in part, involved in hypertonic stress-mediated regulation of MCP1 expression through the MCP1-TonE/ORE.
    The Journal of Immunology 04/2010; 184(9):5253-62. DOI:10.4049/jimmunol.0901298 · 5.36 Impact Factor
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    ABSTRACT: The present study was designed to clarify the effects of an ethanol extract of artichoke leaf on acute gastric mucosal injury in rats. Oral administration of artichoke leaf extract dose-dependently prevented absolute ethanol-induced (125-500 mg/kg) or restraint plus water immersion stress-induced gastric mucosal injury (1000-2000 mg/kg). The artichoke leaf extract contains 1% cynaropicrin and 0.8% chlorogenic acid as main components and 70% dextrin as a vehicle. Cynaropicrin at doses of 1/100 of artichoke leaf extract [ethanol-induced mucosal injury: 5 mg/kg, per os (p.o.); stress-induced mucosal injury: 20 mg/kg, p.o.] also prevented gastric mucosal injury in both animal models. However, dextrin and chlorogenic acid at doses contained in the leaf extract were ineffective in both models. When artichoke leaf extract was given orally to normal rats, it (500-2000 mg/kg, p.o.) dose-dependently increased gastric mucus content. In addition, it (125-500 mg/kg, p.o.) dose-dependently prevented the decrease in gastric mucus content by absolute ethanol. When the effects of artichoke leaf extract on basal gastric acid secretion in rats were evaluated, it (500-2000 mg/kg, p.o.) dose-dependently increased the volume of gastric juice in normal rats. However, it was ineffective in decreasing basal gastric acid secretion in normal rats. These results indicate that artichoke leaf extract is effective against acute gastritis and its beneficial effect is due to that of cynaropicrin. The gastric mucus-increasing action of artichoke leaf extract may be, at least in part, related to the anti-gastritic action of the extract.
    Biological & Pharmaceutical Bulletin 02/2010; 33(2):223-9. DOI:10.1248/bpb.33.223 · 1.78 Impact Factor
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    ABSTRACT: In the present study, we compared the effects of alpha-tocopherol and probucol, antioxidants, on the healing of acetic acid-induced gastric ulcers in 8-, 48- and 96-week-old rats. The repeated oral administration of alpha-tocopherol (16 mg/kg twice daily) and probucol (1000 mg/kg twice daily) for 14 consecutive days markedly accelerated the gastric ulcer healing in 48- and 96-week-old rats as well as 8-week-old ones. The ulcer healing effects of both drugs were not significantly different among the rats at three different ages. The superoxide dismutase (SOD) activity in the ulcerated region of 8-, 48- and 96-week-old rats was markedly lower than that in the unulcerated region. In contrast, the thiobarbituric acid (TBA)-reactive substance content, an index of lipid peroxidation, in the ulcerated region of rats at three different ages markedly increased, as compared to that in the unulcerated region. The SOD activity tended to decrease with aging, while the TBA-reactive substance content gradually increased. The repeated administration of alpha-tocopherol and probucol accelerated the ulcer healing and inhibited the increase in the TBA-reactive substance content in the ulcerated region. These results suggest that alpha-tocopherol and probucol promote the ulcer healing by their potent antioxidant activities in 48- and 96-week-old rats as well as 8-week-old rats.
    European journal of pharmacology 11/2008; 601(1-3):143-7. DOI:10.1016/j.ejphar.2008.10.020 · 2.68 Impact Factor
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    ABSTRACT: We investigated participation of monocyte chemoattractant protein-1 (MCP-1) in tubulointerstitial fibrosis and correlation between MCP-1 and proteinuria in Wistar-Kyoto (WKY) rats with glomerulonephritis induced by anti-glomerular basement membrane (anti-GBM) antibody. WKY rats showed marked proteinuria and severe glomerular crescent formation at 7 days post antibody injection. At 28 days, tubulointerstitial fibrotic lesions were observed, followed by sustained heavy proteinuria and severe tubulointerstitial fibrosis at 56 days. Histological examination revealed that the overlapped immunoreactivities of MCP-1, rat albumin, and p65NF-kappaB were detected in the same tubular segments of nephritic kidney, and a significant positive correlation was observed between proteinuria and MCP-1 expression in the tubulointerstitial fibrosis. ED-1- and CD8-positive cells were also abundant, and there was a good correlation between monocyte/macrophage recruitment and MCP-1 expression in the tubulointerstitial area. These results suggest that MCP-1 participates in the progression of tubulointerstitial fibrosis, through massive albuminuria, which is accompanied by marked monocyte/macrophage recruitment.
    Journal of Clinical Immunology 08/2007; 27(4):409-29. DOI:10.1007/s10875-007-9085-z · 2.65 Impact Factor
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    ABSTRACT: Oral administration of tea catechin dose-dependently prevented absolute ethanol-induced (50, 100, 200 mg/kg) or restraint plus water immersion stress-induced acute gastric mucosal injury (300, 400 mg/kg) in rats. When the effect of test compound was evaluated on the 15th day after acetic acid injection to rats, repeated oral administration of tea catechin (25, 50, 100 mg/kg twice daily) dose-dependently accelerated the healing of acetic acid-induced chronic gastric ulcers. Tea catechin (10(-5)-10(-1) g/100 ml) concentration-dependently scavenged superoxide anions in vitro. Tea catechin (100, 200 mg/kg orally) markedly inhibited the increase in thiobarbituric acid-reactive substances in the injured mucosa of rats treated with 50% ethanol. Tea catechin (50, 100 mg/kg twice orally, daily) markedly inhibited the increase in content of thiobarbituric acid-reactive substances in the ulcerated region of acetic acid-induced gastric ulcers on the 7th and 15th days. In addition, at 50, 100 and 200 mg/kg orally, it dose-dependently prevented the decrease in gastric mucosal hexosamine content induced by absolute ethanol, although it failed to inhibit the basal gastric acid secretion. These results suggest that tea catechin may primarily protect gastric mucosa from acute gastric mucosal injury and promote the healing of chronic gastric ulcers by its antioxidant activity and gastric mucus-increasing actions.
    Biological & Pharmaceutical Bulletin 12/2006; 29(11):2206-13. DOI:10.1248/bpb.29.2206 · 1.78 Impact Factor
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    ABSTRACT: We investigated the effects of long-term treatment with probucol, a hypolipidemic agent with antioxidative action, insulin, or their combination on renal damage in streptozotocin-induced diabetic rats fed a high cholesterol diet. Increases in urinary albumin and lipid peroxide excretions were observed in these diabetic rats, when both urinary parameters were measured at 8 and 15 weeks after streptozotocin administration. Daily treatment with probucol, insulin, or their combination markedly suppressed the increase in the 24 h urinary albumin and lipid peroxide excretions. Furthermore, glycogen degeneration of distal tubules, fatty degeneration of glomerular endothelium, and hypertrophy of glomeruli and mesangium were observed in the kidneys of the diabetic animals, when histopathological evaluation was performed at 4, 8 and 15 weeks (glomerular and mesangial hypertrophy was observed only at 15 weeks). Combined probucol and insulin treatment was the most effective in suppressing these renal histopathological changes. These results indicate that combined treatment with probucol and insulin is useful in preventing the progression of renal damage in diabetic rats. The possible mechanisms for the preventive effect of this combined treatment will be discussed.
    European Journal of Pharmacology 11/2006; 548(1-3):174-80. DOI:10.1016/j.ejphar.2006.07.053 · 2.68 Impact Factor
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    ABSTRACT: In the present study, we investigated the effects of a long-term treatment with vitamin E, an antioxidant vitamin, insulin, or their combination on renal damage in streptozotocin (STZ)-induced diabetic rats fed a high cholesterol diet. Increases in urinary albumin and lipid peroxide (LPO) excretions were observed in these diabetic rats, when both urinary parameters were measured at 8 and 15 weeks after STZ administration. Daily treatment with vitamin E, insulin, or their combination markedly suppressed the increase in the 24 h urinary albumin and lipid peroxide excretions. Furthermore, glycogen degeneration of distal tubules, fatty degeneration of glomerular endothelium and hypertrophy of glomeruli and mesangium were observed in the kidneys of the diabetic animals when histopathological evaluation was performed at 4, 8, and 15 weeks (glomerular and mesangial hypertrophy were observed only at 15 weeks). Combined vitamin E and insulin treatment was the most effective at suppressing these renal histopathological changes. These results indicate that combined vitamin E and insulin treatment additively prevents the development and progression of renal damage in diabetic rats. Possible mechanisms for the preventive effect of this combined treatment are discussed.
    Biological & Pharmaceutical Bulletin 12/2005; 28(11):2080-6. DOI:10.1248/bpb.28.2080 · 1.78 Impact Factor
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    ABSTRACT: We investigated the effects of long-term treatment with probucol, a hypolipidemic agent with antioxidative action, insulin, or their combination on cataracts of streptozotocin-induced diabetic rats fed a high cholesterol diet. Each rat was checked for cataracts at 0, 1, 2, 4, 8, 12 and 15 weeks after streptozotocin injection. Cataracts were observed from 8 weeks in untreated hypercholesterolemic and diabetic rats and the incidence of catarats increased to 100% by 15 weeks. The incidence of cataracts in rats treated with probucol, insulin and their combination was first seen at 12, 12 and 15 weeks, respectively, and was 86%, 63% and 33%, respectively, at 15 weeks. The preventive effects of both agents alone and their combination on the cataracts were confirmed by histopathological evaluation of eyeballs. The combined treatment with both agents markedly improved hyperglycemia, hyperlipidemia and increased serum lipid peroxide levels. These results indicate that the combined treatment with probucol and insulin is useful in preventing the development and progression of diabetic cataracts.
    European Journal of Pharmacology 05/2005; 513(1-2):159-68. DOI:10.1016/j.ejphar.2005.03.004 · 2.68 Impact Factor
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    ABSTRACT: In the present study we investigated the effects of a long-term treatment with vitamin E, an antioxidant vitamin, insulin or their combination on cataracts of streptozotocin (STZ)-induced diabetic rats fed a high cholesterol diet. Each rat was checked for cataracts at 0, 1, 2, 4, 8, 12 and 15 weeks after STZ injection. Cataracts were observed from 8 weeks in the control diabetic rats and their incidence of catarats increased to 100% by 12 weeks. The incidence of cataracts in rats treated with vitamin E, insulin and their combination was first seen at 12 weeks and 56%, 20% and 10%, respectively, at 12 weeks and 78%, 50% and 20%, respectively, at 15 weeks. The preventive effects of either agent alone and their combination on the cataracts were in agreement with those obtained by histopathological evaluation of eyeballs. The combined treatment with both agents markedly improved hyperglycemia, hyperlipidemia and increased serum lipid peroxide levels. These results indicate that the combined treatment with vitamin E and insulin is useful in preventing the development and progression of diabetic cataracts.
    Biological & Pharmaceutical Bulletin 04/2004; 27(3):338-44. DOI:10.1248/bpb.27.338 · 1.78 Impact Factor
  • Masashi Ishihara, Mikio Ito
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    ABSTRACT: In this study, we compared the effects of cimetidine and omeprazole on the healing of acetic acid-induced gastric ulcers in 8-, 48-, and 96-week-old rats. The repeated oral administration of cimetidine or omeprazole for 14 consecutive days markedly accelerated the ulcer healing in 8- and 48-week-old rats. However, both drugs were ineffective in 96-week-old rats. The basal gastric acid secretion of 8-, 48-, and 96-week-old rats decreased with aging. A single oral administration of cimetidine or omeprazole strongly decreased basal gastric acid secretion in the three different ages of rats. Cimetidine and omeprazole produced a potent and sustained serum gastrin-elevating action in 8- and 48-week-old rats. However, the gastrin-elevating actions of both drugs in 96-week-old rats were much weaker than in the 8- and 48-week-old rats. These results indicate that cimetidine and omeprazole have potent gastric ulcer healing actions in 8- and 48-week-old rats, as well as potent serum gastrin-elevating actions, but both drugs are ineffective in 96-week-old rats, which have lost their gastrin-elevating actions.
    European Journal of Pharmacology 06/2002; 444(3):209-15. DOI:10.1016/S0014-2999(02)01651-5 · 2.68 Impact Factor
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    ABSTRACT: In this study, we compared the effects of low molecular weight (LMW) chitosan (MW: 25,000-50,000), high molecular weight (HMW) chitosan (MW: 500,000-1000,000) and chitin on ethanol-induced gastric mucosal injury and on the healing of acetic acid-induced gastric ulcers in rats. Oral administration of LMW chitosan (250, 500 and 1000 mg/kg) dose-dependently prevented ethanol-induced gastric mucosal injury. Repeated oral administration of LMW chitosan (100, 200 and 400 mg/kg twice daily) also dose-dependently accelerated the gastric ulcer healing. However, the effects of HMW chitosan and chitin on the gastric mucosal injury formation and the gastric ulcer healing were less potent than those of LMW chitosan. LMW chitosan (250 and 500 mg/kg, orally) was ineffective in inhibiting gastric acid secretion in pylorus-ligated rats, although it had a weak acid-neutralizing action. LMW-chitosan (250, 500 and 1000 mg/kg orally) dose-dependently prevented the decrease in gastric mucus content induced by ethanol. These results indicate that of the three compounds, LMW chitosan has the most potent gastric cytoprotective and ulcer healing-promoting actions. In addition, gastric mucus-increasing action of LMW-chitosan may be, at least in part, related to the anti-ulcer effect of this compound.
    The Japanese Journal of Pharmacology 04/2000; 82(3):218-25. DOI:10.1254/jjp.82.218
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    ABSTRACT: In the present study, we investigated the susceptibility to restraint plus water-immersion stress (RWIS) in rats with daunomycin-induced nephrosis in comparison to that in normal rats. The severity of RWIS-induced gastric lesions was significantly less in nephrotic rats on the 20th and 40th days after a single i.v. injection of daunomycin (12 mg/kg) than in the respective control rats. Acid secretion in pylorus-ligated rats significantly decreased under the 3-h stress. On the 20th day after treatment with daunomycin, acid secretion was significantly less in nephrotic rats than in control rats under both stress and unstressed conditions. Pretreatment of normal rats with methylene blue, a guanylate cyclase inhibitor, or phenylephrine, a vasoconstrictor, significantly prevented the stress-induced gastric lesions and decreased acid secretion. N(omega)-Nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor, prevented the stress-induced gastric lesion formation only. These results indicate that nephrotic rats are more resistant to RWIS-induced gastric lesions than normal rats. In addition, these results suggest that the decrease in acid secretion related to the decrease in the release of NO from endothelial cells may contribute, at least in part, to the prevention of the stress-induced gastric lesion formation in nephrotic rats.
    The Japanese Journal of Pharmacology 11/1999; 81(2):230-6. DOI:10.1254/jjp.81.230
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    ABSTRACT: When free radical-scavenging activities of quercetin, alpha-tocopherol, nifedipine and tetracycline were measured by an electron spin resonance technique, all test compounds (10(-5) to 10(-3) M) scavenged both superoxide anions and hydroxyl radicals. The oral administration of quercetin (50 and 100 mg/kg), alpha-tocopherol (8 and 16 mg/kg), nifedipine (20 and 40 mg/kg) or tetracycline (10 and 20 mg/kg) markedly prevented the HCl plus ethanol-induced gastric mucosal injury and the increase in the content of thiobarbituric acid-reactive substances in the injured mucosa in rats. In addition, quercetin (25, 50 and 100 mg/kg), alpha-tocopherol (4, 8 and 16 mg/kg), nifedipine (10, 20 and 40 mg/kg) and tetracycline (5, 10 and 20 mg/kg), given orally, twice daily for 14 consecutive days from the day after acetic acid injection, dose-dependently promoted the ulcer healing and inhibited the increase in the content of thiobarbituric acid-reactive substances in the ulcerated mucosa. These results indicate that quercetin, alpha-tocopherol, nifedipine and tetracycline possess gastric cytoprotective and gastric ulcer healing-promoting actions. In addition, the free radical-scavenging properties of these compounds may be partly related to their anti-ulcer effects.
    The Japanese Journal of Pharmacology 12/1998; 78(4):435-441. DOI:10.1254/jjp.78.435
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    ABSTRACT: We investigated the effect of probucol, a lipid-lowering agent with antioxidant properties, on HCl plus ethanol-induced gastric mucosal injury and on the healing of acetic acid-induced gastric ulcers in rats. When the free radical-scavenging activity of probucol was measured by an electron spin resonance technique, the agent (10(-5)-10(-3) M) scavenged both superoxide anions and hydroxyl radicals. Oral administration of probucol (250-1000 mg/kg) dose dependently prevented the HCl plus ethanol-induced gastric mucosal injury and the increase in thiobarbituric acid-reactive substances, an index of lipid peroxidation, in the injured mucosa. Repeated oral administration of probucol (250-1000 mg/kg twice daily) dose dependently accelerated the healing of acetic acid-induced gastric ulcers. In addition, probucol already inhibited the increase in the content of thiobarbituric acid-reactive substances in the ulcerated region before the ulcer-healing effect of this agent was recognized. These results suggest that probucol may partly protect gastric mucosa from acute gastric mucosal injury and promote the healing of chronic gastric ulcers by its antioxidant activity.
    European Journal of Pharmacology 09/1998; 354(2-3):189-96. DOI:10.1016/S0014-2999(98)00448-8 · 2.68 Impact Factor
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    ABSTRACT: This study was performed to evaluate the effect of nephrosis on gastric lesions in the rats. A single i.v. injection of daunomycin (12 mg/kg) into rats produced severe proteinuria and hypercholesterolemia on the 20th and 40th days after the administration. The severity of HCl-ethanol-induced gastric lesions was significantly greater in nephrotic rats than in control animals on the 20th and 40th days. The gastric mucosal blood flow on the 40th day was significantly lower in nephrotic rats. Pretreatment of normal rats withN -nitro-l-arginine or N-nitro-l-arginine methyl ester, a nitric oxide (NO) synthase inhibitor, methylene blue, a guanylate cyclase inhibitor, or phenylephrine, a vasoconstrictor, significantly aggravated the HCl-ethanol-induced gastric lesions and reduced the blood flow. WhenN -nitro-l-arginine methyl ester was given to nephrotic rats on the 40th day, it further increased the aggravation of the gastric lesions caused by nephrosis. These results suggest that the aggravation of HCl-ethanol-induced gastric lesions observed in nephrotic rats may be, at least in part, related to the decrease in the release of NO from endothelial cells.
    Environmental Toxicology and Pharmacology 04/1996; 1(2). DOI:10.1016/1382-6689(95)00019-4 · 2.08 Impact Factor
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    ABSTRACT: It is known that adhesion molecules play a crucial role in the development of glomerulonephritis. Therefore, we investigated the effects of acteoside on the expression of intercellular adhesion molecule-1 (ICAM-1) in nephritic glomeruli, in vivo, and human umbilical vein endothelial cells (HUVECs) and rat mesangial cells, in vitro. Aceteoside treatment significantly decreased the up-regulation of ICAM-1 expression in nephritic glomeruli. Acteoside prevented the up-regulation of ICAM-1 expression mediated by inflammatory cytokines or phorbol 12-myristate 13-acetate on HUVECs and rat mesangial cells. Adhesion of neutrophils and macrophages to acteoside-treated HUVECs was suppressed to one half of that in untreated HUVECs. These data support the finding that acteoside inhibits the up-regulation of ICAM-1 in the nephritic glomeruli. Additionally, it is suggested that the antinephritic action of acteoside is due to the inhibition of intraglomerular accumulation of leukocytes through the prevention of the up-regulation of ICAM-1. This is the first paper demonstrating that the up-regulation of ICAM-1 in nephritic glomeruli is inhibited by a natural product, acteoside.
    The Japanese Journal of Pharmacology 03/1996; 70(2):157-68. DOI:10.1254/jjp.70.157
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    ABSTRACT: The possibility that hyperlipidemia and an increase of mononuclear cells in the glomeruli could participate in the pathogenesis of minimal change glomerulopathy was evaluated in puromycin aminonucleoside (PAN) nephrosis in rats. Significant increases in intraglomerular CD4-, IL-2-receptor (R)- and ED-1-positive cells were found in PAN rats. Urinary protein excretion and mononuclear cells in the glomeruli of 1% cholesterol diet-fed rats significantly increased, compared with standard diet feeding. Moreover, administration of a subnephrogenic dose of PAN in cholesterol diet-fed rats substantially increased urinary protein excretion and mononuclear cells in the glomeruli. Additionally, antihyperlipidemia agents and immunosuppressive agents prevented urinary protein excretion and increases of CD4-, IL-2R- and ED-1-positive cells in the glomeruli of PAN nephrotic rats. Monoclonal antibodies directed against these cells also prevented urinary protein excretion. These results suggest that CD4-, IL-2R- and ED-1-positive cells and hyperlipidemia are involved in the progression, but not the pathogenesis, of PAN.
    The Japanese Journal of Pharmacology 02/1996; 70(1):25-33. DOI:10.1254/jjp.70.25
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    ABSTRACT: The effect of FK506 (tacrolims hydrate), an immunosuppressive agent produced by Streptomyces tsukubaensis, on crescentic-type anti-glomerular basement membrane (GBM) nephritis in rats was investigated. When rats were treated with FK506 from 1 or 20 days after the anti-GBM serum injection, FK506 inhibited the increase in urinary protein excretion. Histological observation demonstrated that FK506 suppressed glomerular alterations. In the FK506-treated rats, antibody production and rat-IgG and C3 deposits on the GBM were significantly less than those in the nephritic control group. FK506 treatment suppressed the accumulation of ED-1-positive cells, CD4-positive cells, CD8-positive cells, interleukin-2 (IL-2)-receptor-positive cells, leukocyte-function-associated antigen-1 (LFA-1)-positive cells and intercellular adhesion molecule-1 (ICAM-1)-expression in nephritic glomeruli. However, in the in vitro study, FK506 failed to inhibit the up-regulated ICAM-1 expression on endothelial cells in response to tumor necrosis factor (TNF)-alpha. On the other hand, IL-2 production from the spleen cells isolated from nephritic rats treated with FK506 was lower than that in the nephritic control rats. These results suggest that FK506 is effective against crescentic-type anti-GBM nephritis and that the antinephritic mechanisms of FK506 is due to the inhibition of intraglomerular accumulation and activation of leukocytes through the suppression of ICAM-1 expression and IL-2 production.
    The Japanese Journal of Pharmacology 02/1996; 70(1):43-54. DOI:10.1254/jjp.70.43
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    ABSTRACT: The effects of cimetidine, omeprazole and atropine sulfate on the healing of acetic acid-induced gastric ulcers in rats with limited food intake time (9:00-10:00 a.m. and 5:00-6:00 p.m.) were evaluated 15 days after the acid injection. Oral repeated administration of cimetidine (25-100 mg/kg twice daily) or omeprazole (10-50 mg/kg once daily) dose dependently accelerated ulcer healing. Atropine sulfate (10 mg/kg twice daily, p.o.) was ineffective. A single oral administration of omeprazole (50 mg/kg) or cimetidine (100 mg/kg) resulted in potent and long-lasting anti-acid secretory and gastrin-releasing actions. The degree and duration of anti-acid secretion by atropine sulfate were equal to those of cimetidine, but the elevation of gastrin release by atropine sulfate was weak and temporary. These results indicate that the gastric ulcers of rats with a limited food intake time are useful for evaluating the healing effects of cimetidine and omeprazole on gastric ulcers. In addition, the effects of both drugs may be related to the increased gastrin release rather than to the reduced acid secretion.
    European Journal of Pharmacology 11/1994; 263(3):245-51. DOI:10.1016/0014-2999(94)90719-6 · 2.68 Impact Factor