64 results on '"Fukuishi N"'
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2. Antiallergic effect of ardisiaquinone A, a potent 5-lipoxygenase inhibitor
- Author
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Fukuishi, N., Takada, T., Fukuyama, Y., and Akagi, M.
- Published
- 2001
- Full Text
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3. Lipoteichoic Acid and Peptidoglycan Inhibit Fc Epsilon RI Expression by Mast Cells
- Author
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Yoshioka, M., primary, Iriguchi, S., additional, Imajo, N., additional, Akagi, M., additional, and Fukuishi, N., additional
- Published
- 2006
- Full Text
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4. Bacterial Components Enhance Mast Cell Phagocytosis through the Expression of Complement Receptor 3
- Author
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Imajo, N., Yoshioka, M., Inukai, A., Akagi, M., and Fukuishi, N.
- Published
- 2006
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5. Kamebakaurin Suppresses Antigen-Induced Mast Cell Activation by Inhibition of FcεRI Signaling Pathway.
- Author
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Asai H, Kato K, Miyasaka M, Hatsukawa K, Murakami N, Takeda N, Abe J, Aoyagi Y, Kohda Y, Gui MY, Jin YR, Li XW, Hitotsuyanagi Y, Takeya K, Andoh T, Kurosaki H, and Fukuishi N
- Subjects
- Animals, Mice, Interleukin-4 metabolism, Histamine Release drug effects, Antigens immunology, Anti-Allergic Agents pharmacology, Mice, Inbred BALB C, Phosphorylation drug effects, Hypersensitivity immunology, Hypersensitivity metabolism, Hypersensitivity drug therapy, Mast Cells immunology, Mast Cells metabolism, Mast Cells drug effects, Receptors, IgE metabolism, Signal Transduction drug effects, Cell Degranulation drug effects, Cell Degranulation immunology, Syk Kinase metabolism, Syk Kinase antagonists & inhibitors
- Abstract
Introduction: Kamebakaurin is an active constituent of both Rabdosia japonica and Rabdosia excisa, which are utilized in Chinese traditional medicine for improving symptoms in patients with allergies. We investigated the molecular mechanisms of the anti-allergic effects of kamebakaurin using BMMCs., Methods: The degranulation ratio, histamine release, and the interleukin (IL)-4, leukotriene B4 (LTB4), and cysteinyl leukotriene productions on antigen-triggered BMMC were investigated. Additionally, the effects of kamebakaurin on signal transduction proteins were examined by Western blot and binding to the Syk and Lyn kinase domain was calculated. The effects of kamebakaurin on antigen-induced hyperpermeability were investigated using mouse model., Results: At 10 μ
m , kamebakaurin partially inhibited degranulation, histamine release, and IL-4 production. At 30 μm , kamebakaurin partially reduced LTB4 and cysteinyl leukotriene productions and suppressed degranulation, histamine release, and IL-4 production. Phosphorylation of both Syk Y519/520 and its downstream protein, Gab2, was reduced by kamebakaurin, and complete inhibition was observed with 30 μm kamebakaurin. In contrast, phosphorylation of Erk was only partially inhibited, even in the presence of 30 μm kamebakaurin. Syk Y519/520 is known to be auto-phosphorylated via intramolecular ATP present in its own ATP-binding site, and this auto-phosphorylation triggers degranulation, histamine release, and IL-4 production. Docking simulation study indicated kamebakaurin blocked ATP binding to the ATP-binding site in Syk. Therefore, inhibition of Syk auto-phosphorylation by kamebakaurin binding to the Syk ATP-binding site appeared to cause a reduction of histamine release and IL-4 production. Kamebakaurin inhibited antigen-induced vascular hyperpermeability in a dose-dependent fashion but did not reduce histamine-induced vascular hyperpermeability., Conclusion: Kamebakaurin ameliorates allergic symptoms via inhibition of Syk phosphorylation; thus, kamebakaurin could be a lead compound for the new anti-allergic drug., (© 2024 S. Karger AG, Basel.)- Published
- 2024
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6. Difference in the Inhibitory Effect of Thiol Compounds and Demetallation Rates from the Zn(II) Active Site of Metallo-β-lactamases (IMP-1 and IMP-6) Associated with a Single Amino Acid Substitution.
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Yamaguchi Y, Kato K, Ichimaru Y, Uenosono Y, Tawara S, Ito R, Matsuse N, Wachino JI, Toma-Fukai S, Jin W, Arakawa Y, Otsuka M, Fujita M, Fukuishi N, Sugiura K, Imai M, and Kurosaki H
- Subjects
- Catalytic Domain, Amino Acid Substitution, beta-Lactams chemistry, Zinc chemistry, Sulfhydryl Compounds, beta-Lactamases metabolism, Anti-Bacterial Agents pharmacology
- Abstract
Gram-negative bacteria producing metallo-β-lactamases (MBLs) have become a considerable threat to public health. MBLs including the IMP, VIM, and NDM types are Zn(II) enzymes that hydrolyze the β-lactam ring present in a broad range of antibiotics, such as N -benzylpenicillin, meropenem, and imipenem. Among IMPs, IMP-1 and IMP-6 differ in a single amino acid substitution at position 262, where serine in IMP-1 is replaced by glycine in IMP-6, conferring a change in substrate specificity. To investigate how this mutation influences enzyme function, we examined lactamase inhibition by thiol compounds. Ethyl 3-mercaptopropionate acted as a competitive inhibitor of IMP-1, but a noncompetitive inhibitor of IMP-6. A comparison of the crystal structures previously reported for IMP-1 (PDB code: 5EV6) and IMP-6 (PDB code: 6LVJ) revealed a hydrogen bond between the side chain of Ser262 and Cys221 in IMP-1 but the absence of hydrogen bond in IMP-6, which affects the Zn2 coordination sphere in its active site. We investigated the demetallation rates of IMP-1 and IMP-6 in the presence of chelating agent ethylenediaminetetraacetic acid (EDTA) and found that the demetallation reactions had fast and slow phases with a first-order rate constant ( k
fast = 1.76 h-1 , kslow = 0.108 h-1 for IMP-1, and kfast = 14.0 h-1 and kslow = 1.66 h-1 for IMP-6). The difference in the flexibility of the Zn2 coordination sphere between IMP-1 and IMP-6 may influence the demetallation rate, the catalytic efficiency against β-lactam antibiotics, and the inhibitory effect of thiol compounds.- Published
- 2023
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7. Potential Anti-allergic Effects of Bibenzyl Derivatives from Liverworts, Radula perrottetii.
- Author
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Asai H, Kato K, Suzuki M, Takahashi M, Miyata E, Aoi M, Kumazawa R, Nagashima F, Kurosaki H, Aoyagi Y, and Fukuishi N
- Subjects
- Animals, Cell Degranulation, Immunoglobulin E, Interleukin-4 metabolism, Interleukin-4 pharmacology, Leukotriene B4 metabolism, Leukotriene B4 pharmacology, Mast Cells, Mice, Mice, Inbred C57BL, Phospholipase C gamma metabolism, Phospholipase C gamma pharmacology, Receptors, IgE metabolism, Anti-Allergic Agents pharmacology, Bibenzyls metabolism, Bibenzyls pharmacology, Hepatophyta
- Abstract
The liverwort Radula perrottetii contains various bibenzyl derivatives which are known to possess various biological activities, such as anti-inflammatory effects. Mast cells (MC) play crucial roles in allergic and inflammatory diseases; thus, inhibition of MC activation is pivotal for the treatment of allergic and inflammatory disorders. We investigated the effects of perrottetin D (perD), isolated from Radula perrottetii , and perD diacetate (Ac-perD) on antigen-induced activation of MCs. Bone marrow-derived MCs (BMMCs) were generated from C57BL/6 mice. The degranulation ratio, histamine release, and the interleukin (IL)-4 and leukotriene B
4 productions on antigen-triggered BMMC were investigated. Additionally, the effects of the bibenzyls on binding of IgE to Fc ε RI were observed by flow cytometry, and signal transduction proteins was examined by Western blot. Furthermore, binding of the bibenzyls to the Fyn kinase domain was calculated. At 10 µM, perD decreased the degranulation ratio (p < 0.01), whereas 10 µM Ac-perD down-regulated IL-4 production (p < 0.05) in addition to decreasing the degranulation ratio (p < 0.01). Both compounds tended to decrease histamine release at a concentration of 10 µM. Although 10 µM perD reduced only Syk phosphorylation, 10 µM Ac-perD diminished phosphorylation of Syk, Gab2, PLC- γ , and p38. PerD appeared to selectively bind Fyn, whereas Ac-perD appeared to act as a weak but broad-spectrum inhibitor of kinases, including Fyn. In conclusion, perD and Ac-perD suppressed the phosphorylation of signal transduction molecules downstream of the Fc ε RI and consequently inhibited degranulation, and/or IL-4 production. These may be beneficial potential lead compounds for the development of novel anti-allergic and anti-inflammatory drugs., Competing Interests: This work was partially supported by a Kinjo Gakuin University Research Grant., (Thieme. All rights reserved.)- Published
- 2022
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8. A Rapid and Sensitive Determination of Histamine in Mast Cells Using a Didansyl Derivatization Method.
- Author
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Asai H, Yamamoto R, Kuromiya K, Takamura R, Jin W, Kurosaki H, and Fukuishi N
- Subjects
- Animals, Cell Degranulation, Histamine, Histidine, Immunoglobulin E, Mice, Receptors, IgE, Hypersensitivity, Mast Cells
- Abstract
Background: Mast cells play a central role in allergic responses such as food allergy, asthma, allergic rhinitis, and allergic conjunctivitis. Symptoms in the early phase of these allergic diseases are primarily caused by histamine. However, due to the high histidine content in the cytosol and low histamine content in secretory granules, separating and quantifying histamine from histidine is often difficult., Objectives: We studied a method for rapid and sensitive quantitation of mast cell-derived histamine and evaluated its application to allergic disease research., Methods: Bone marrow-derived mouse mast cells (BMMCs) were employed in this study. IgE-sensitized BMMCs were activated by FcεRI cross-linking. After activation, both the histamine released to the supernatant and histamine remaining in BMMCs were didansylated and then analyzed by high-performance liquid chromatography with fluorescence detection (HPLC-FD). Didansyl histamine was synthesized as a standard material., Results: Synthetic didansyl histamine was detected by HPLC-FD with a peak retention time of 18.5 min. Very high linearity of the standard curve was maintained at concentrations of 10 pg/μL or less when the didansyl histamine method was used. This method enables detection of histamine released from 1 × 105 BMMCs. In addition, the histamine concentration in the supernatant due to spontaneous release was also determined. Finally, the ratio of histamine release was highly correlated with the degranulation ratio., Conclusion: These results indicate that the proposed method using didansylated histamine to determine mast cell-derived histamine is highly useful for allergy research applications., (© 2022 S. Karger AG, Basel.)
- Published
- 2022
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9. Crystal Structures of Metallo-β-Lactamase (IMP-1) and Its D120E Mutant in Complexes with Citrate and the Inhibitory Effect of the Benzyl Group in Citrate Monobenzyl Ester.
- Author
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Yamaguchi Y, Kato K, Ichimaru Y, Jin W, Sakai M, Abe M, Wachino JI, Arakawa Y, Miyagi Y, Imai M, Fukuishi N, Yamagata Y, Otsuka M, Fujita M, and Kurosaki H
- Subjects
- Benzyl Compounds chemistry, Citric Acid chemistry, Dose-Response Relationship, Drug, Esters chemistry, Humans, Molecular Docking Simulation, Molecular Structure, Mutation, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Structure-Activity Relationship, Benzyl Compounds pharmacology, Citric Acid pharmacology, Esters pharmacology, RNA-Binding Proteins antagonists & inhibitors
- Abstract
The emergence and rapid spread of carbapenem-resistant pathogens producing metallo-β-lactamases such as IMP-1 and NDM-1 have been of great concern in the global clinical setting. The X-ray crystal structures of IMP-1 from Serratia marcescens and its single mutant, D120E, in complexes with citrate were determined at resolutions of 2.00 and 1.85 Å, respectively. Two crystal structures indicate that a single mutation at position 120 caused a structural change around Zn1, where the geometry changes from a tetrahedron in the native IMP-1 to a square pyramid in D120E. Based on these two complex structures, the authors synthesized citrate monobenzyl ester 1 to evaluate the structural requirement for the inhibitory activity against IMP-1 and compared the inhibitory activities with nonsubstituted citrate. The introduction of a benzyl group into citrate enhanced the inhibitory activity in comparison to citrate (IC
50 > 5 mM).- Published
- 2021
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10. Suppression of IgE-Independent Degranulation of Murine Connective Tissue-Type Mast Cells by Dexamethasone.
- Author
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Yamada K, Sato H, Sakamaki K, Kamada M, Okuno Y, Fukuishi N, Furuta K, and Tanaka S
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- 3T3 Cells, Animals, Bone Marrow Cells cytology, Gene Expression Regulation drug effects, Histamine metabolism, Male, Mast Cells drug effects, Mast Cells metabolism, Mice, Mice, Inbred BALB C, RNA metabolism, Skin blood supply, Skin drug effects, Cell Degranulation drug effects, Connective Tissue Cells cytology, Dexamethasone pharmacology, Immunoglobulin E metabolism, Mast Cells physiology
- Abstract
Steroidal anti-inflammatory drugs are widely used for the treatment of chronic cutaneous inflammation, such as atopic dermatitis, although it remains unknown how they modulate cutaneous mast cell functions. We investigated the effects of prolonged treatment with a synthetic glucocorticoid, dexamethasone, on murine connective tissue-type mast cells using in vitro and in vivo models. Our connective tissue-type bone marrow-derived cultured mast cell model was found to be sensitive to mast cell secretagogues, such as compound 48/80 and substance P, and higher expression levels of α subunit of a trimeric G protein, G
i1 , and several Mas-related G protein-coupled receptor (Mrgpr) subtypes were observed in comparison with immature cultured mast cells. Secretagogue-induced degranulation and up-regulation of these genes was suppressed when cultured in the presence of dexamethasone. The profiles of granule constituents were drastically altered by dexamethasone. Topical application of dexamethasone down-modulated secretagogue-induced degranulation and the expression levels of several Mrgpr subtypes in cutaneous tissue. These results suggest that mast cell-mediated IgE-independent cutaneous inflammation could be suppressed by steroidal anti-inflammatory drugs through the down-regulation of Gαi1 and several Mrgpr subtypes in mast cells., Competing Interests: The authors declare no conflict of interest.- Published
- 2019
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11. 1O, 20O-diacetyl kamebakaurin protects against acetaminophen-induced hepatotoxicity in mice.
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Yoshioka H, Nonogaki T, Ohnishi H, Fukuishi N, Yoshikawa M, Gui MY, Jin YR, Li XW, Adachi Y, Ohno N, Takeya K, Hitotsuyanagi Y, Miura N, and Aoyagi Y
- Subjects
- Animals, Antioxidants chemistry, Antioxidants pharmacology, Biomarkers, Chemical and Drug Induced Liver Injury drug therapy, Cytokines metabolism, Disease Models, Animal, Diterpenes chemistry, Glutathione metabolism, Inflammation Mediators metabolism, Liver Function Tests, Male, Malondialdehyde metabolism, Mice, Molecular Structure, Oxidative Stress drug effects, Protective Agents chemistry, Protein Transport, Reactive Oxygen Species metabolism, Acetaminophen adverse effects, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Diterpenes pharmacology, Protective Agents pharmacology
- Abstract
The present study aimed to investigate the protective effects of kamebakaurin (KA) and 1O, 20O-diacetyl kamebakaurin (Ac
2 KA) on acetaminophen (APAP)-induced hepatotoxicity and compare the hepatoprotective mechanisms of the two chemicals. Seven-week-old male C57BL/6J mice were orally administered KA, Ac2 KA, or an ethanol/olive oil emulsion once per day for 7-days. Twenty-four hours after the final administration, the mice were fasted and then intraperitoneally injected with 450 mg/kg APAP or saline. At 16 h after injection, the mice were euthanized and blood samples were collected for plasma analysis. Pretreatment with KA and Ac2 KA significantly attenuated APAP-induced hepatic injury. The protective effect of Ac2 KA was stronger than that of KA. These two chemicals attenuated oxidative stress, inflammatory cytokine production, c-jun N-terminal kinase activation, and receptor-interacting protein (RIP)-3 activation. Ac2 KA also decreased APAP-induced RIP-1 activation and nuclear factor kappa B (NF-κB) p65 translocation. Moreover, Ac2 KA repressed mRNA expression of Cyp1a2/2e1 in the liver. Our results showed that KA and Ac2 KA exerted protective effects against APAP-induced hepatotoxicity. The responsible mechanisms may be related to the chemicals' antioxidant activity and the inhibition of c-jun N-terminal kinase activation and RIP-3 activation. The effects of Ac2 KA included those of KA, as well as RIP-1 inactivation, NF-κB inhibition, and Cyp inhibition.- Published
- 2018
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12. Suppressive effect of kamebakaurin on acetaminophen-induced hepatotoxicity by inhibiting lipid peroxidation and inflammatory response in mice.
- Author
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Yoshioka H, Aoyagi Y, Fukuishi N, Gui MY, Jin YR, Li XW, Adachi Y, Ohno N, Takeya K, Hitotsuyanagi Y, Miura N, and Nonogaki T
- Subjects
- Analgesics, Non-Narcotic, Animals, Antioxidants pharmacology, Diterpenes administration & dosage, Female, Inflammation drug therapy, Mice, Mice, Inbred C57BL, Acetaminophen toxicity, Chemical and Drug Induced Liver Injury prevention & control, Diterpenes pharmacology, Inflammation chemically induced, Lipid Peroxidation drug effects
- Abstract
Background: Kamebakaurin (KA) is an ent-kaurane diterpenoid known to have anti-inflammatory potential. In the current study, we investigated whether pretreatment with KA could ameliorate acetaminophen (APAP)-induced hepatotoxicity by inhibiting the anti-inflammatory response in mice., Methods: Seven-week-old C57BL/6J mice were orally administered KA or olive oil emulsion for seven days. Twenty-four hours after the last KA or olive oil administration, the mice were intraperitoneally injected with 400mg/kg APAP or saline under feed deprived condition. The mice from each group were euthanized and bled for plasma analysis 24h after the injection., Result: APAP increased plasma levels of hepatic injury markers (i.e., alanine aminotransferase and aspartate aminotransferase), lipid peroxidation, and pro-inflammatory cytokines. Pretreatment with KA reduced the magnitude of APAP-induced increases in plasma levels of hepatic injury markers, lipid peroxidation, and inflammatory response. In addition, KA exhibited antioxidant capacity in a dose-dependent manner, with slight reactive oxygen species scavenging activity., Conclusion: Our results indicate that KA has the ability to protect the liver from APAP-induced hepatotoxicity, presumably by both inhibiting the inflammatory response and oxidative stress., (Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)
- Published
- 2017
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13. Vitamin D3-induced hypercalcemia increases carbon tetrachloride-induced hepatotoxicity through elevated oxidative stress in mice.
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Yoshioka H, Usuda H, Miura N, Fukuishi N, Nonogaki T, and Onosaka S
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- Adenosine Triphosphate metabolism, Animals, Body Weight drug effects, Calcium blood, Calcium metabolism, Cytochrome P-450 CYP2E1 metabolism, Lipid Peroxidation drug effects, Male, Malondialdehyde metabolism, Mice, NADP metabolism, Carbon Tetrachloride toxicity, Cholecalciferol adverse effects, Hypercalcemia chemically induced, Hypercalcemia metabolism, Liver drug effects, Liver metabolism, Oxidative Stress drug effects
- Abstract
The aim of this study was to determine whether calcium potentiates acute carbon tetrachloride (CCl4) -induced toxicity. Elevated calcium levels were induced in mice by pre-treatment with cholecalciferol (vitamin D3; V.D3), a compound that has previously been shown to induce hypercalcemia in human and animal models. As seen previously, mice injected with CCl4 exhibited increased plasma levels of alanine aminotransferase, aspartate aminotransferase, and creatinine; transient body weight loss; and increased lipid peroxidation along with decreased total antioxidant power, glutathione, ATP, and NADPH. Pre-treatment of these animals with V.D3 caused further elevation of the values of these liver functional markers without altering kidney functional markers; continued weight loss; a lower lethal threshold dose of CCl4; and enhanced effects on lipid peroxidation and total antioxidant power. In contrast, exposure to V.D3 alone had no effect on plasma markers of liver or kidney damage or on total antioxidant power or lipid peroxidation. The potentiating effect of V.D3 was positively correlated with elevation of hepatic calcium levels. Furthermore, direct injection of CaCl2 also enhanced CCl4-induced hepatic injury. Since CaCl2 induced hypercalcemia transiently (within 3 h of injection), our results suggest that calcium enhances the CCl4-induced hepatotoxicity at an early stage via potentiation of oxidative stress.
- Published
- 2017
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14. Chronotoxicity of bromobenzene-induced hepatic injury in mice.
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Yoshioka H, Nonogaki T, Fukuishi N, Shinohara Y, Hwang GW, Ohtani K, and Miura N
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- Alanine Transaminase blood, Animals, Aspartate Aminotransferases blood, Blood Urea Nitrogen, Chemical and Drug Induced Liver Injury blood, Chemical and Drug Induced Liver Injury pathology, Creatinine blood, Kidney drug effects, Kidney metabolism, Kidney pathology, Liver drug effects, Liver metabolism, Liver pathology, Male, Malondialdehyde metabolism, Mice, Inbred ICR, Bromobenzenes toxicity, Circadian Rhythm, Solvents toxicity
- Abstract
The aim of the present study is to investigate whether or not bromobenzene (BB) toxicity varies with circadian periodicity. Seven-week-old male ICR mice were injected with 900 mg/kg (5.73 mmol/kg) BB intraperitoneally at 4 different time points of a day (zeitgeber time [ZT]: ZT0, ZT6, ZT12, and ZT18). Mortality was then monitored for 7 days after injection. Interestingly, mice were sensitive to BB acute toxicity at ZT6 while tolerant at ZT18. Moreover, in mice that were given a non-lethal dose of BB (540 mg (3.44 mmol)/kg), levels of alanine aminotransferase and aspartate aminotransferase, used as markers of hepatic injury, markedly increased in response to injection at ZT6, but did not increase significantly in response to injection at ZT18. In contrast, the markers of renal injury (creatinine and blood urea nitrogen), showed no significant difference in response to the two injection times. To further investigate this extreme circadian variation, we examined hepatic and renal lipid peroxidation levels, and conducted histopathological studies. Similar to our observation with alanine aminotransferase and creatinine, hepatic lipid peroxidation and histopathological changes were more pronounced than renal changes, and showed circadian variation. Our present investigation demonstrated that BB-induced mortality had clear circadian variation, and suggested that hepatic injury was one of the important factors for determination of this variation.
- Published
- 2017
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15. Bromobenzene-induced lethal toxicity in mouse is prevented by pretreatment with zinc sulfate.
- Author
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Yoshioka H, Fukaya S, Fukuishi N, Nagatsu A, Nonogaki T, and Onosaka S
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- Alanine Transaminase blood, Animals, Antioxidants analysis, Aspartate Aminotransferases blood, Calcium metabolism, Injections, Intraperitoneal, Kidney drug effects, Kidney metabolism, Kidney pathology, Liver drug effects, Liver metabolism, Liver pathology, Male, Malondialdehyde metabolism, Mice, Bromobenzenes toxicity, Protective Agents pharmacology, Zinc Sulfate pharmacology
- Abstract
In the current study, we evaluated the protective effect of zinc (Zn) against bromobenzene (BB) -induced lethal toxicity. We used Zn because this element is known to be an inducer of metallothionein (MT), which is in turn known to serve as an endogenous scavenger of free radicals. We administered Zn (as ZnSO4) at 50 mg/kg subcutaneously once-daily for 3 successive days prior to a single intraperitoneal administration of 1.2 g/kg BB in male ddY mice. Our results showed that pretreatment with Zn completely abolished the BB-induced mortality of mice until 48 h. We also found that pretreatment of mice with Zn significantly decreased the functional marker levels and reduced the histological damage both in liver and kidney as assessed at 18 h post-BB. We also showed that pretreatment with Zn enhanced antioxidative activity, resulting in decreased lipid peroxidation in both liver and kidney. Moreover, BB-induced calcium levels were downregulated by pretreatment with Zn. In addition, Zn-induced MT was decreased in Zn + BB-treated animals, implying that MT was consumed by BB-induced radicals. These findings suggest that prophylaxis with Zn protects mice from BB-induced lethal toxicity by decreasing oxidative stress in liver and kidney, presumably by induction of MT, which scavenges radicals induced by BB exposure., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2016
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16. Calcium-deficient diet attenuates carbon tetrachloride-induced hepatotoxicity in mice through suppression of lipid peroxidation and inflammatory response.
- Author
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Yoshioka H, Nonogaki T, Fukuishi N, and Onosaka S
- Abstract
The aim of this study is to investigate whether a Ca-deficient diet has an attenuating effect on carbon tetrachloride (CCl4)-induced hepatotoxicity. Four-week-old male ddY mice were fed a Ca-deficient diet for 4 weeks as a part of the experimental protocol. While hypocalcemia was observed, there was no significant change in body weight. The CCl4-exposed hypocalcemic mice exhibited a significant decrease in alanine aminotransferase and aspartate aminotransferase activities at both 6 h and 24 h even though markers of renal function remained unchanged. Moreover, lipid peroxidation was impaired and total antioxidant power was partially recovered in the liver. Studies conducted in parallel with the biochemical analysis revealed that hepatic histopathological damage was attenuated 24 h post CCl4 injection in hypocalcemic mice fed the Ca-deficient diet. Finally, this diet impaired CCl4-induced inflammatory responses. Although upregulation of Ca concentration is a known indicator of terminal progression to cell death in the liver, these results suggest that Ca is also involved in other phases of CCl4-induced hepatotoxicity, via regulation of oxidative stress and inflammatory responses.
- Published
- 2016
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17. Carbon Tetrachloride-Induced Nephrotoxicity in Mice Is Prevented by Pretreatment with Zinc Sulfate.
- Author
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Yoshioka H, Usuda H, Fukuishi N, Nonogaki T, and Onosaka S
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- Animals, Blood Urea Nitrogen, Carbon Tetrachloride, Creatinine blood, Kidney drug effects, Kidney metabolism, Kidney pathology, Kidney Diseases chemically induced, Kidney Diseases metabolism, Kidney Diseases pathology, Male, Malondialdehyde metabolism, Metallothionein metabolism, Mice, Zinc Sulfate pharmacology, Kidney Diseases prevention & control, Zinc Sulfate therapeutic use
- Abstract
Carbon tetrachloride (CCl4) is commonly used as a chemical inducer of experimental liver injury. In addition, many studies showed that CCl4 can induce kidney damage. In the current study, we evaluated the protective effect of zinc (Zn) against CCl4-induced nephrotoxicity. We hypothesized that this protective effect would result from the ability of Zn to serve as an inducer of metallothionein (MT), a known endogenous scavenger of free radicals. We administered Zn (as ZnSO4) 50 mg/kg subcutaneously once daily for 3 successive days prior to a single intraperitoneal administration of CCl4 4 g/kg in male ddY mice. Our results showed that Zn pretreatment significantly decreased creatinine and blood urea nitrogen levels and reduced renal histopathological damage at 6 h post-CCl4 injection, observations consistent with enhanced antioxidative activity in the kidney. Moreover, kidney MT levels in the Zn+CCl4-treated group decreased by greater than 70% compared with levels in the Zn-alone group, implying that MT was consumed by CCl4-induced radicals. These findings suggest that prophylaxis with Zn protects mice from CCl4-induced acute nephrotoxicity, presumably by induction of MT, which in turn scavenges radicals induced by CCl4 exposure.
- Published
- 2016
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18. CD72 negatively regulates mouse mast cell functions and down-regulates the expression of KIT and FcεRIα.
- Author
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Kataoka TR, Kumanogoh A, Fukuishi N, Ueshima C, Hirata M, Moriyoshi K, Tsuruyama T, and Haga H
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Antibodies, Neutralizing pharmacology, Cell Line, Tumor, Down-Regulation drug effects, Humans, Mast Cells cytology, Mice, NIH 3T3 Cells, Proto-Oncogene Proteins c-cbl, Semaphorins immunology, Antigens, CD immunology, Antigens, Differentiation, B-Lymphocyte immunology, Down-Regulation immunology, Mast Cells immunology, Proto-Oncogene Proteins c-kit immunology, Receptors, IgE immunology
- Abstract
CD72 is a transmembrane protein belonging to the C-type lectin family that is expressed by various hematopoietic cells. When bound to its natural ligand, CD100 (semaphorin 4D), CD72 inhibits the KIT-mediated responses of human mast cells, but not IgE/FcεRI-mediated mast cell degranulation. We extended these findings to examine the role of CD72 in mouse mast cells. CD72 expression was detected in mouse bone marrow-derived mast cells (mBMMCs). As for human mast cells, an agonistic antibody against CD72 (K10.6) suppressed the KIT-mediated cell growth of, IL-6 production by and chemotaxis of mBMMCs. However, in contrast to human mast cells, the IgE-triggered degranulation of mBMMCs was suppressed by K10.6. K10.6 did not affect the phosphorylation of SHP-1 in mBMMCs, although SHP-1 mediated the inhibitory effects of CD72 in human mast cells. Administration of K10.6 induced phosphorylation of the ubiquitin ligase Cbl-b and decreased the expression of KIT and FcεRIα on the surface of murine mast cells. We also observed expression of CD72 in a mouse neoplastic cell line, P815, harboring gain-of-function mutations in KIT genes. In addition, we found that K10.6 activated Cbl-b, down-regulated KIT expression and suppressed the mutated KIT-driven growth of these cells. Thus, the mechanism by which CD72 mediates inhibitory effects in mast cells is species-dependent., (© The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
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19. Nonpeptide neurotrophic agents useful in the treatment of neurodegenerative diseases such as Alzheimer's disease.
- Author
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Akagi M, Matsui N, Akae H, Hirashima N, Fukuishi N, Fukuyama Y, and Akagi R
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- Alzheimer Disease pathology, Animals, Biphenyl Compounds pharmacology, Cells, Cultured, Hippocampus pathology, Humans, Lignans pharmacology, Magnolia chemistry, Mice, Molecular Weight, Nerve Growth Factors pharmacology, Neurodegenerative Diseases pathology, Neurogenesis drug effects, Rats, Structure-Activity Relationship, Zingiberales chemistry, Alzheimer Disease drug therapy, Biphenyl Compounds therapeutic use, Dietary Supplements, Lignans therapeutic use, Nerve Growth Factors therapeutic use, Neurodegenerative Diseases drug therapy, Phytotherapy, Polyphenols pharmacology, Polyphenols therapeutic use
- Abstract
Developed regions, including Japan, have become "aged societies," and the number of adults with senile dementias, such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease, has also increased in such regions. Neurotrophins (NTs) may play a role in the treatment of AD because endogenous neurotrophic factors (NFs) prevent neuronal death. However, peptidyl compounds have been unable to cross the blood-brain barrier in clinical studies. Thus, small molecules, which can mimic the functions of NFs, might be promising alternatives for the treatment of neurodegenerative diseases. Natural products, such as or nutraceuticals or those used in traditional medicine, can potentially be used to develop new therapeutic agents against neurodegenerative diseases. In this review, we introduced the neurotrophic activities of polyphenols honokiol and magnolol, which are the main constituents of Magnolia obovata Thunb, and methanol extracts from Zingiber purpureum (BANGLE), which may have potential therapeutic applications in various neurodegenerative disorders., (Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.)
- Published
- 2015
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20. Compound 48/80, a Mast Cell Stimulator, Enhances Synthesis of IgE and IgG Induced by Intranasal Application of Ovalbumin in Mice.
- Author
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Matsui N, Ito D, Takabatake Y, Nashioka E, Tada S, Kanagawa M, Fukuishi N, and Akagi M
- Subjects
- Administration, Intranasal, Animals, Female, Interleukin-4 metabolism, Mast Cells metabolism, Mice, Inbred BALB C, Mucous Membrane metabolism, Rhinitis, Allergic metabolism, Immunoglobulin E metabolism, Immunoglobulin G metabolism, Mast Cells drug effects, Nasal Mucosa metabolism, Ovalbumin immunology, Rhinitis, Allergic immunology, p-Methoxy-N-methylphenethylamine pharmacology
- Abstract
Mast cells are well established effector cells of type I hypersensitivity reactions such as allergic rhinitis. However, recent studies have suggested that activated mast cells enhance local immunoglobulin E (IgE) synthesis in the nasal mucosa of allergic rhinitis patients. Therefore, we hypothesized that non-immunological mast cell activators may have the potential to enhance local IgE synthesis. Here, we examined the effect of compound 48/80 (C48/80), a mast cell activator, on IgE and immunoglobulin G (IgG) synthesis. Female Balb/c mice were intranasally administered a mixture of ovalbumin (OVA) (1-10 µg/nose) and C48/80 (1-100 µg/nose) on days 0, 7, 14 and 21 and on consecutive days from day 28 to day 42. Intranasal administration of C48/80 with OVA increased serum OVA-specific IgE and IgG. Double staining with fluorescent-labeled OVA and fluorescent-labeled IgE- or IgG-specific antibody demonstrated the presence of OVA-specific IgE- or IgG-producing cells in the nasal mucosa of sensitized mice. Moreover, intranasal administration of C48/80 with OVA increased the nasal mucosal interleukin (IL)-4 level and enhanced the OVA-induced symptom of sneezing. These results suggested that simultaneous activation of mast cells with antigen exposure enhances local IgE and IgG synthesis.
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- 2015
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21. Does β-hexosaminidase function only as a degranulation indicator in mast cells? The primary role of β-hexosaminidase in mast cell granules.
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Fukuishi N, Murakami S, Ohno A, Yamanaka N, Matsui N, Fukutsuji K, Yamada S, Itoh K, and Akagi M
- Subjects
- Animals, Asthma immunology, Cell Degranulation, Cell Wall immunology, Disease Models, Animal, Glycoproteins metabolism, Lysosomes enzymology, Mast Cells transplantation, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptidoglycan immunology, Peptidoglycan metabolism, Staphylococcal Infections mortality, Staphylococcus epidermidis immunology, Cytoplasmic Granules enzymology, Mast Cells enzymology, Mast Cells immunology, Staphylococcal Infections immunology, beta-N-Acetylhexosaminidases metabolism
- Abstract
β-Hexosaminidase, which is generally present in the lysosome, is essential for glycoprotein metabolism in the maintenance of cell homeostasis. In mast cells (MCs), large amounts of β-hexosaminidase are present in the granules as opposed to the lysosome, and the biological role of MC β-hexosaminidase has yet to be fully elucidated. Therefore, we investigated the biological role of β-hexosaminidase in MC granules. Bone marrow-derived MCs from C57BL/6 (BL/6-BMMC) or β-hexosaminidase gene-deficient (hexb(-/-)-BMMC) mice were transplanted into MC-deficient (WBB6F1/J-Kit(W)/Kit(W-v) [W/W(v)]) mice to generate MC-reconstituted models. In asthma model experiments, no differences were observed in the symptoms of BL/6, W/W(v), BL/6-BMMC-reconstituted W/W(v), or hexb(-/-)-BMMC-reconstituted W/W(v) mice. In Staphylococcus epidermidis experimental infection model experiments, the severity of symptoms and frequency of death were markedly higher in W/W(v) and hexb(-/-)-BMMC-reconstituted W/W(v) mice than in BL/6 and BL/6-BMMC-reconstituted W/W(v) mice. The growth of S. epidermidis in an in vitro study was clearly inhibited by addition of BL/6-BMMC lysate, but not by addition of hexb(-/-)-BMMC lysate. Moreover, suppression of bacterial proliferation was completely recovered when bacteria were incubated with hexb(-/-)-BMMC lysate plus β-hexosaminidase. Transmission electron microscopy indicated that the cell wall of S. epidermidis was heavily degraded following coincubation of bacteria with BL/6-BMMC lysate, but not following coincubation with hexb(-/-)-BMMC lysate. These findings strongly suggest that MC granule β-hexosaminidase is crucial for defense against bacterial invasion, but is not involved in the allergic response. Our results also suggest that the bactericidal mechanism of β-hexosaminidase involves degradation of bacterial cell wall peptidoglycan., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2014
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22. Generation of mast cells from mouse fetus: analysis of differentiation and functionality, and transcriptome profiling using next generation sequencer.
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Fukuishi N, Igawa Y, Kunimi T, Hamano H, Toyota M, Takahashi H, Kenmoku H, Yagi Y, Matsui N, and Akagi M
- Subjects
- Animals, Bone Marrow Cells physiology, Cell Degranulation, Cells, Cultured, Cytokines genetics, Cytokines metabolism, Fetus cytology, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Mice, Mice, Inbred C57BL, Peptide Hydrolases genetics, Peptide Hydrolases metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Chemokine genetics, Receptors, Chemokine metabolism, Sequence Analysis, DNA, Cell Differentiation, Mast Cells physiology, Stem Cells physiology, Transcriptome
- Abstract
While gene knockout technology can reveal the roles of proteins in cellular functions, including in mast cells, fetal death due to gene manipulation frequently interrupts experimental analysis. We generated mast cells from mouse fetal liver (FLMC), and compared the fundamental functions of FLMC with those of bone marrow-derived mouse mast cells (BMMC). Under electron microscopy, numerous small and electron-dense granules were observed in FLMC. In FLMC, the expression levels of a subunit of the FcεRI receptor and degranulation by IgE cross-linking were comparable with BMMC. By flow cytometry we observed surface expression of c-Kit prior to that of FcεRI on FLMC, although on BMMC the expression of c-Kit came after FcεRI. The surface expression levels of Sca-1 and c-Kit, a marker of putative mast cell precursors, were slightly different between bone marrow cells and fetal liver cells, suggesting that differentiation stage or cell type are not necessarily equivalent between both lineages. Moreover, this indicates that phenotypically similar mast cells may not have undergone an identical process of differentiation. By comprehensive analysis using the next generation sequencer, the same frequency of gene expression was observed for 98.6% of all transcripts in both cell types. These results indicate that FLMC could represent a new and useful tool for exploring mast cell differentiation, and may help to elucidate the roles of individual proteins in the function of mast cells where gene manipulation can induce embryonic lethality in the mid to late stages of pregnancy.
- Published
- 2013
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23. Phenylbutenoid dimers isolated from Zingiber purpureum exert neurotrophic effects on cultured neurons and enhance hippocampal neurogenesis in olfactory bulbectomized mice.
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Matsui N, Kido Y, Okada H, Kubo M, Nakai M, Fukuishi N, Fukuyama Y, and Akagi M
- Subjects
- Animals, Butyrates isolation & purification, Cell Survival drug effects, Cells, Cultured, Chromatography, High Pressure Liquid, Female, Hippocampus cytology, Immunohistochemistry, Magnetic Resonance Spectroscopy, Mice, Neurites drug effects, Neuroprotective Agents, PC12 Cells, Plant Roots chemistry, Pregnancy, Rats, Rats, Sprague-Dawley, Butyrates pharmacology, Zingiber officinale chemistry, Hippocampus drug effects, Hippocampus growth & development, Neurogenesis drug effects, Neurons drug effects, Olfactory Bulb physiology
- Abstract
Trans-3-(3'4'-dimethoxyphenyl)-4-[(E)-3",4"-dimethoxystyryl]cyclohex-1-ene (Comp.1) and cis-3-(3'4'-dimethoxyphenyl)-4-[(E)-3",4"-dimethoxystyryl]cyclohex-1-ene (Comp.2), phenylbutenoid dimers, have been isolated as neurotrophic molecules from an Indonesian medicinal plant, Zingiber purpureum. The aim of this study was to explore the neurotrophic effects of Comp.1 and Comp.2 in vitro and in vivo. Comp.1 (10-30 μM) or Comp.2 (30 μM) significantly induced neurite sprouting in PC12 cells. Comp.1 (0.03-3 μM) or Comp.2 (0.3-3 μM) significantly increased the neurite length and number of neurites in primary cultured rat cortical neurons. Comp.1 (30 μM) and Comp.2 (3-30 μM) also provided significant protection against cell death caused by deprivation of serum. The in vivo effects of both Comp.1 and Comp.2 were evaluated on hippocampal neurogenesis in olfactory bulbectomized (OBX) mice, an experimental depression and dementia animal model. Comp.1 (50mg/kg p.o.), Comp.2 (50mg/kg p.o.), or fluoxetine (10mg/kg i.p.), an antidepressant, were administrated once a day on days 15-28 after OBX. Neurogenesis was assessed by analysis of cells expressing NeuN, a neuronal marker, and 5-bromo-2'-deoxyuridine (BrdU) uptake. Immunohistochemical analysis showed that the number of BrdU/NeuN double-labeled cells in the dentate gyrus was significantly decreased 30 days after OBX. Chronic treatment with Comp.1, Comp.2 or fluoxetine significantly increased the number of BrdU/NeuN double-labeled cells. These results indicate that Comp.1 and Comp.2 have neurotrophic effects, and have the potential for disease modification in depression and dementia., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)
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- 2012
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24. Magnolol and honokiol prevent learning and memory impairment and cholinergic deficit in SAMP8 mice.
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Matsui N, Takahashi K, Takeichi M, Kuroshita T, Noguchi K, Yamazaki K, Tagashira H, Tsutsui K, Okada H, Kido Y, Yasui Y, Fukuishi N, Fukuyama Y, and Akagi M
- Subjects
- Acetylcholine metabolism, Analysis of Variance, Animals, Blotting, Western, Cell Count, Dose-Response Relationship, Drug, Drugs, Chinese Herbal pharmacology, Immunohistochemistry, Male, Mice, Neurons drug effects, Neurons metabolism, Nitric Oxide Synthase antagonists & inhibitors, Phosphorylation drug effects, Plant Extracts administration & dosage, Prosencephalon drug effects, Prosencephalon metabolism, Proto-Oncogene Proteins c-akt metabolism, Aging drug effects, Avoidance Learning drug effects, Biphenyl Compounds administration & dosage, Lignans administration & dosage, Recognition, Psychology drug effects
- Abstract
The therapeutic use of neurotrophic factors to treat neurodegenerative disorders, including Alzheimer's disease, is considered feasible. Magnolol and honokiol, constituents of the Magnolia plant, are small organic compounds with neurotrophic activity. We investigated whether magnolol and honokiol can prevent age-related learning and memory impairment and cholinergic deficits in senescence-accelerated mice (SAM). Magnolol (1, 10 mg/kg) or honokiol (0.1, 1 mg/kg) were orally administered to SAMP8 mice once a day for 14 days in 2-month-old mice. Learning and memory performance were evaluated by passive avoidance tests and location and object novelty recognition tests. SAMP8 mice showed significant impairment of learning and memory at 4 and 6 months of age. This age-related learning and memory impairment was prevented by pretreatment with either magnolol (10 mg/kg) or honokiol (1 mg/kg). Cholinergic neuron densities in the medial septum and vertical limb of the diagonal band of the forebrain were evaluated by an immunohistochemical analysis of choline acetyltransferase (ChAT). SAMP8 mice showed a significant cholinergic deficit at 6 months of age. These age-related cholinergic deficits were prevented by treatment with either magnolol (10 mg/kg) or honokiol (1 mg/kg). Moreover, SAMP8 mice showed decreased activity of Akt, a member of the prosurvival pathway, in the forebrain at 2 months of age. A 14-day treatment with either magnolol (10 mg/kg) or honokiol (1 mg/kg) enhanced phosphorylation of Akt in the forebrain at 2 months of age. These results suggest that magnolol and honokiol prevent age-related learning and memory impairment by preserving cholinergic neurons in the forebrain. These compounds may have potential therapeutic applications to various neurodegenerative disorders.
- Published
- 2009
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25. Human mast cells synthesize and release angiogenin, a member of the ribonuclease A (RNase A) superfamily.
- Author
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Kulka M, Fukuishi N, and Metcalfe DD
- Subjects
- Animals, Asthma blood, Asthma enzymology, Chickens, Escherichia coli physiology, Flow Cytometry, Humans, Inflammation blood, Inflammation physiopathology, Inflammation prevention & control, Mast Cells cytology, Mast Cells microbiology, Neoplasms blood, Neoplasms enzymology, Neovascularization, Physiologic, Oligonucleotide Array Sequence Analysis, Ribonuclease, Pancreatic biosynthesis, Ribonuclease, Pancreatic genetics, Ribonuclease, Pancreatic metabolism, Wound Healing physiology, Mast Cells enzymology, Ribonuclease, Pancreatic blood
- Abstract
ANG is a plasma protein with angiogenic and ribonucleolytic activity implicated in tumor growth, heart failure, wound healing, asthma, and the composition of the adult gut microflora. Human mast cells (HuMC) are similarly associated with modulation of vascular permeability, angiogenic processes, wound healing, and asthma. We hypothesized that HuMC express and secrete ANG in response to divergent stimuli. ANG expression was evaluated in the LAD2 HMC, the HMC-1, and CD34+-derived HuMC, following exposure to live Escherichia coli, TLR ligands, or neuropeptides and following FcepsilonRI aggregation. Expression and production of ANG were determined by microarray analysis, qRT-PCR, confocal microscopy, and ELISA. Microarray analysis showed that ANG is up-regulated by LAD2 cells exposed to live E. coli. qRT-PCR analysis revealed that LAD2, HMC-1, and HuMC constitutively expressed ANG mRNA and that it was up-regulated by exposure to E. coli. Activation of HuMC by FcepsilonRI aggregation resulted in release of small amounts of ANG (<100 pg/mL), whereas compound 48/80, NGF, LPS, PGN, and flagellin activated HuMC to secrete >160 pg/mL ANG. These observations demonstrate that HuMC store and secrete ANG to a variety of stimuli and suggest that MC-derived ANG is available in the subsequent inflammatory response.
- Published
- 2009
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26. Lipoteichoic acid improves the capability of mast cells in the host defense system against bacteria.
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Imajo N, Kurihara D, Fukuishi N, Inukai A, Matsushita S, Noda S, Toyoda M, Yoshioka M, Teruya H, Nishii Y, Matsui N, and Akagi M
- Subjects
- Animals, CD11b Antigen immunology, Cells, Cultured, Chemokines immunology, Cytokines immunology, Endocytosis physiology, Humans, Macrophage-1 Antigen immunology, Peptidoglycan immunology, Receptors, IgG immunology, Toll-Like Receptor 2 genetics, Toll-Like Receptor 2 immunology, Toll-Like Receptor 9 genetics, Toll-Like Receptor 9 immunology, Lipopolysaccharides pharmacology, Mast Cells drug effects, Mast Cells immunology, Mast Cells physiology, Staphylococcus aureus metabolism, Teichoic Acids pharmacology
- Abstract
Objectives and Design: We investigated the effects of microbial components on the uptake of microbes by mast cells (MCs), and studied the change in cytokine production in MCs after bacterial uptake., Material or Subjects: LAD2 human mast cells, cord-blood and peripheral-blood derived MCs were employed to analyze their surface molecule expression and cytokine generation by flow cytometry. Bacterial internalization in these MCs was observed by confocal microscopy and flow cytometry., Results: Complement receptor 3 expression was augmented by LTA but not by PGN or 3CpG-oligodeoxynucleotide. LTA also enhanced the uptake of opsonized bacteria (over twofold augmentation). After bacterial uptake, MCs augmented the production of chemoattractant cytokines for neutrophils, while Th1 and Th2 cytokine production showed little or no change., Conclusions: LTA increases the capability of the MC as a sentinel in the host immune response, and some bacterial components direct human MC function towards innate immunity after pathogen infection.
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- 2009
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27. Human cathelicidin CAP18/LL-37 changes mast cell function toward innate immunity.
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Yoshioka M, Fukuishi N, Kubo Y, Yamanobe H, Ohsaki K, Kawasoe Y, Murata M, Ishizumi A, Nishii Y, Matsui N, and Akagi M
- Subjects
- Blotting, Western, Cell Line, Chemokines metabolism, Cytokines biosynthesis, DNA, Complementary biosynthesis, DNA, Complementary genetics, Flow Cytometry, Humans, Immunoprecipitation, Lipopolysaccharides pharmacology, Phosphorylation drug effects, RNA, Messenger biosynthesis, Reverse Transcriptase Polymerase Chain Reaction, Th2 Cells drug effects, Th2 Cells metabolism, Toll-Like Receptor 4 biosynthesis, Toll-Like Receptor 4 genetics, Transcription, Genetic drug effects, Up-Regulation drug effects, beta-N-Acetylhexosaminidases metabolism, Cathelicidins, Anti-Bacterial Agents pharmacology, Antimicrobial Cationic Peptides pharmacology, Immunity, Innate drug effects, Mast Cells drug effects, Mast Cells immunology
- Abstract
The antimicrobial peptide LL-37 is generated from skin keratinocytes during infection of Gram-negative bacteria and exerts a microbicidal effect. LL-37 also causes functional changes in mast cells. Mast cells in the skin are involved in the innate immune system response against microbial infections via Toll-like receptors (TLRs), such as TLR4, which that is known to recognize lipopolysaccharide (LPS), a bacterial component. Thus, in the present study, we examined the effects of LL-37 on the expression of TLRs and the generation of cytokines on mast cells, and considered functional changes in the host defense system against bacteria. We observed that LL-37 increased the level of TLR4 mRNA and TLR4 protein, and that LL-37 induced the release of IL-4, IL-5 and IL-1beta from mast cells. Cross-interaction between LL-37-triggered TLR4 augmentation and LL-37-inducible cytokine generation was also examined. Although the up-regulation of LL-37-inducible Th2 cytokines was cancelled by LPS, the augmentation of pro-inflammatory cytokine production was still observed. These findings indicate that LL-37 co-existing with the bacterial component switches mast cell function and directs human mast cells toward innate immunity. In conclusion, LL-37 may be a candidate modifier of the host defense against bacterial entry by serving as an alarm for sentinels such as mast cells.
- Published
- 2008
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28. Lipoteichoic acid downregulates FcepsilonRI expression on human mast cells through Toll-like receptor 2.
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Yoshioka M, Fukuishi N, Iriguchi S, Ohsaki K, Yamanobe H, Inukai A, Kurihara D, Imajo N, Yasui Y, Matsui N, Tsujita T, Ishii A, Seya T, Takahama M, and Akagi M
- Subjects
- Cell Degranulation drug effects, Cell Line, Cell Membrane metabolism, Dose-Response Relationship, Drug, Humans, Ligands, Lipopolysaccharides administration & dosage, Lung cytology, Mast Cells cytology, Mast Cells physiology, Peptidoglycan administration & dosage, Peptidoglycan pharmacology, RNA, Messenger metabolism, Receptors, IgE genetics, Teichoic Acids administration & dosage, Toll-Like Receptors metabolism, Down-Regulation physiology, Lipopolysaccharides pharmacology, Mast Cells metabolism, Receptors, IgE metabolism, Teichoic Acids pharmacology, Toll-Like Receptor 2 physiology
- Abstract
Background: FcepsilonRI on the surface of mast cells (MCs) plays a central role in allergic responses. Recent evidence shows that exposure to microbial components corresponds with a significant reduction in the risk for allergic diseases. Although many reports suggest that this is due to changes in T-cell functions, how MC functions are altered by bacterial infection remains unknown., Objective: We sought to elucidate the effect of bacterial infection on MC function and expression of Fc receptors, such as FcepsilonRI., Methods: Isolated human pulmonary MCs and a human MC line (LAD2) were stimulated with bacterial components, and the function and surface expression of Fc receptors were measured., Results: Lipoteichoic acid (LTA) and peptidoglycan, but not LPS, flagellin, or 3CpG-oligodeoxynucleotide, reduced the expression of FcepsilonRI on LAD2 cells. An antibody to Toll-like receptor (TLR) 2 partially blocked the effect of LTA but not peptidoglycan. Both LTA and peptidoglycan reduced MC degranulation caused by an antigen-specific IgE. Furthermore, exposure of pulmonary MCs to LTA reduced both FcepsilonRI expression and IgE-induced degranulation. None of the bacterial components affected the expression of other Fc receptors, such as Fcgamma receptors or Fcalpha receptor I., Conclusions: Our results indicate that LTA reduces the surface expression of FcepsilonRI through TLR2 and suggests that TLR2 ligands could be used as a novel therapy for controlling allergic disorders., Clinical Implications: By knowing how bacterial components modulate MC function, we can expand our possibilities for therapeutic interventions of allergic diseases.
- Published
- 2007
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29. Heme oxygenase-1 inhibits cytokine production by activated mast cells.
- Author
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Yasui Y, Nakamura M, Onda T, Uehara T, Murata S, Matsui N, Fukuishi N, Akagi R, Suematsu M, and Akagi M
- Subjects
- Animals, Cell Line, Tumor, Heme Oxygenase-1 genetics, Hypersensitivity enzymology, Hypersensitivity immunology, Hypersensitivity pathology, Inflammation enzymology, Inflammation immunology, Mast Cells metabolism, Rats, Rats, Inbred BN, Transcription Factor AP-1 physiology, Cytokines antagonists & inhibitors, Cytokines biosynthesis, Heme Oxygenase-1 physiology, Mast Cells enzymology, Mast Cells immunology
- Abstract
Heme oxygenase-1 (HO-1) is thought to contribute to host defense reactions against various stresses. In addition, recent reports have suggested that HO-1 modulates immunocyte activation and functions. HO-1 suppresses mast cell degranulation, but whether HO-1 suppresses cytokine synthesis as well is not yet known. We examined whether rat HO-1 cDNA transfected rat basophilic leukemia (RBL)-2H3 cells have altered cytokine production in response to stimulation with anti-ovalbumin (OA) serum/OA compared to Mock transfected RBL-2H3 cells. HO-1 inhibited anti-OA serum/OA-induced IL-3 and TNF-alpha production. Inhibition of HO-1 activity by Zn (II) protoporphyrin IX, a specific HO-1 inhibitor, prevented the suppression of TNF-alpha production. The cytokine inhibition by HO-1 was associated with selective suppression of the DNA-binding activity of AP-1 transcription factors. The suppression of mast cell cytokine production by HO-1 may be an important aspect of the processes that lead to resolution of allergic inflammation.
- Published
- 2007
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30. Upregulation of heme oxygenase-1 by degranulation in rat basophilic leukemia cells.
- Author
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Yasui Y, Sasao E, Sakata M, Matsui N, Fukuishi N, Akagi R, and Akagi M
- Subjects
- Acetylcysteine pharmacology, Animals, Azo Compounds metabolism, Blotting, Northern, Blotting, Western, Cell Line, Tumor, Cell Survival drug effects, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Fluoresceins metabolism, Fluorescence, Free Radical Scavengers pharmacology, Heme Oxygenase-1 antagonists & inhibitors, Heme Oxygenase-1 genetics, Leukemia, Basophilic, Acute pathology, Leukemia, Basophilic, Acute physiopathology, Metalloporphyrins pharmacology, Ovalbumin immunology, Ovalbumin pharmacology, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Inbred BN, Reactive Oxygen Species metabolism, Up-Regulation, Cell Degranulation, Heme Oxygenase-1 metabolism, Leukemia, Basophilic, Acute metabolism
- Abstract
Heme oxygenase (HO)-1, which is a rate-limiting enzyme involved in the catabolism of heme, is upregulated by a variety of stresses including oxidative stresses and inflammatory cytokines, in many cell types. Recent studies have suggested that upregulation of HO-1 might provide cytoprotection and immunomodulatory functions in addition to its obvious role in heme metabolism. In this study, we examined whether HO-1 was upregulated following degranulation in mast cells that initiate vigorous immunity reactions. To trigger degranulation, rat basophilic leukemia (RBL)-2H3 cells were passively sensitized using an antiserum collected from ovalbumin (OA) immunized-Brown Norway rats, and the cells were stimulated by treatment with OA. Degranulation was confirmed by measuring the release of beta-hexosaminidase. HO-1 mRNA and presence of HO-1 protein were detected using Northern blot and Western blot analyses, respectively. The effect of the antioxidant N-acetyl-L-cysteine (NAC) on HO-1 expression was also tested. HO-1 mRNA transiently increased at 1--2 h after RBL-2H3 cells were stimulated to degranulate. Its mRNA increases were dependent on the extent of degranulation. Following the upregulation of HO-1 mRNA, HO-1 protein was also increased. We also detected intracellular production of reactive oxygen species following degranulation in RBL-2H3 cells. NAC attenuated the HO-1 expression in a dose-dependent manner. This is the first report to reveal induction of both HO-1 mRNA and protein by degranulation in RBL-2H3 cells. We showed that NAC inhibited HO-1 upregulation. These results suggest that oxidative stress in activated RBL-2H3 cells results in the upregulation of HO-1.
- Published
- 2007
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31. Mast cells, which interact with Escherichia coli, up-regulate genes associated with innate immunity and become less responsive to Fc(epsilon)RI-mediated activation.
- Author
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Kulka M, Fukuishi N, Rottem M, Mekori YA, and Metcalfe DD
- Subjects
- Cell Adhesion Molecules immunology, Cells, Cultured, Chemokines genetics, Chemokines immunology, Gene Expression Regulation immunology, Humans, Immunoglobulin E immunology, Oligonucleotide Array Sequence Analysis methods, RNA, Messenger genetics, Receptors, IgE genetics, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha immunology, Up-Regulation immunology, Escherichia coli immunology, Immunity, Innate, Mast Cells immunology, Receptors, IgE immunology
- Abstract
Mast cells, which are associated with T helper cell type 2-dependent inflammation, have now been implicated in the innate immune response. To further characterize how mast cells are programmed to respond to infectious organisms, we used expression profiling using DNA microarray analysis of gene expression by human mast cells (huMC) during ingestion of Escherichia coli and examined immunoglobulin E (IgE)-mediated degranulation. Analysis of data revealed that specific groups of genes were modulated, including genes encoding transcription factors, cell signaling molecules, cell cycle regulators, enzymes, cytokines, novel chemokines of the CC family, adhesion molecules, and costimulatory molecules. Enzyme-linked immunosorbent assay analysis confirmed the production of tumor necrosis factor and the chemokines CC chemokine ligand (CCL)-1/I-309, CCL-19/macrophage-inflammatory protein-3beta (MIP-3beta), and CCL-18/MIP-4; flow cytometry confirmed the up-regulation of carcinoembryonic antigen-related cell adhesion molecule 1, the integrin CD49d, and CD80. Coincubation with E. coli down-regulated Fc receptor for IgE I (FcepsilonRI) expression and FcepsilonRI-mediated huMC degranulation. These data are consistent with the concept that bacterial exposure directs mast cell responses toward innate immunity and away from IgE-mediated effects.
- Published
- 2006
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32. The protective effect of H2-receptor activation against the duration of myocardial hypoxia/reoxygenation-induced ventricular fibrillation in sensitized guinea-pig hearts.
- Author
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Imajo N, Matsui S, Yasui Y, Matsui N, Fukuishi N, and Akagi M
- Subjects
- Adrenergic beta-Antagonists pharmacology, Animals, Atenolol pharmacology, Cytoplasmic Granules drug effects, Dimaprit analogs & derivatives, Dimaprit pharmacology, Electrocardiography drug effects, Enzyme Inhibitors pharmacology, Female, Guinea Pigs, Histamine pharmacology, Histamine Antagonists pharmacology, Histamine N-Methyltransferase antagonists & inhibitors, Histamine Release drug effects, Immunoglobulin E metabolism, In Vitro Techniques, Mast Cells drug effects, Perfusion, Histamine Agonists pharmacology, Myocardial Reperfusion Injury complications, Receptors, Histamine H2 drug effects, Ventricular Fibrillation etiology, Ventricular Fibrillation prevention & control
- Abstract
Patients with high serum immunoglobulin E levels were reported to be protected against sudden death during acute myocardial infarction. The protection mechanism might be attributed to the facilitation of histamine release from sensitized mast cells; however, this remains to be clarified. In this study, we examined the influence of sensitization on ventricular fibrillation (VF) induced by myocardial hypoxia/reoxygenation (H/R). Guinea pigs were actively sensitized by subcutaneous injection of ovalbumin in Bordetella pertussis vaccine. Hearts isolated from non-sensitized and sensitized guinea pigs were subjected to 30-min hypoxia / 30-min reoxygenation using a Langendorff apparatus. The amount of histamine released in the sensitized guinea-pig hearts was elevated, and the duration of VF was found to be reduced. The treatment with a histamine H2-receptor antagonist inhibited the reduction of VF duration. Treatment of the non-sensitized hearts with the histamine H2-receptor agonist resulted in the decrease of VF duration to the same level as that in the sensitized hearts. In conclusion, these results suggest that the risk of sudden death during myocardial H/R may be attenuated in the sensitized hearts and that histamine H2-receptor activation due to the released histamine may be involved in the protective effect.
- Published
- 2005
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33. Enzymatic measurement of tryptase-like protease release from isolated perfused guinea pig heart during ischemia-reperfusion.
- Author
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Matsui N, Okikawa T, Imajo N, Yasui Y, Fukuishi N, and Akagi M
- Subjects
- Animals, Creatine Kinase metabolism, Cysteine Proteinase Inhibitors pharmacology, Female, Guinea Pigs, Histamine Release drug effects, In Vitro Techniques, Leupeptins pharmacology, Tryptases, Myocardial Reperfusion Injury enzymology, Myocardium enzymology, Serine Endopeptidases metabolism
- Abstract
To elucidate the details of tryptase release from the heart during ischemia-reperfusion (I/R), we attempted the enzymatic measurement of tryptase release from the isolated guinea pig heart perfused by the Langendorff mode I/R model. Tryptase-like activity in the effluent was monitored by the hydrolysis of L-Pyr-Gly-Arg-MCA. Tryptase-like protease and histamine were rapidly released from heart during ischemia within 10 min. After reperfusion, tryptase-like protease levels decreased, achieving stabilization. The tryptase-like protease activity in the effluent was inactivated by serine protease inhibitors. The pattern of inhibition was similar to those of guinea pig and human lung tryptase. In conclusion, tryptase was released into the coronary effluent during ischemia, but not during reperfusion in guinea pig heart.
- Published
- 2005
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34. Neurotrophic effect of magnolol in the hippocampal CA1 region of senescence-accelerated mice (SAMP1).
- Author
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Matsui N, Nakashima H, Ushio Y, Tada T, Shirono A, Fukuyama Y, Nakade K, Zhai H, Yasui Y, Fukuishi N, Akagi R, and Akagi M
- Subjects
- Aging pathology, Animals, Cell Count, Hippocampus cytology, Hippocampus pathology, Mice, Mice, Inbred Strains, Nerve Degeneration pathology, Neurites drug effects, Neurofibrils drug effects, Tissue Embedding, Aging drug effects, Aging genetics, Biphenyl Compounds pharmacology, Hippocampus drug effects, Lignans pharmacology
- Abstract
Magnolol has neurotrophic effects in primary cultured rat cortical neurons, which are expressed as the promotion of neurite outgrowth and neuronal survival. In this study, we investigated the protective effect of magnolol against age-related neuronal loss in the hippocampus using senescence-accelerated mouse (SAMP1). Magnolol (5, 10 mg/kg) was orally administered once a day for 14 d to 2- or 4-month-old mice, and evaluation was carried out when the mice were 4 or 6 months old. The density of neurofibrils decreased with aging in the stratum radiatum of the CA1 region in the hippocampus of SAMP1, not SAMR1. Treatment with magnolol significantly prevented the decrease of neurofibrils in the CA1, when it was administered in 2-month-olds. However, administration at 4 months of age did not result in a preventive effect. These findings suggest that the administration of magnolol before the initiation of neuronal loss may result in a protective effect in the hippocampus.
- Published
- 2005
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35. Protective effect of the 5-lipoxygenase inhibitor ardisiaquinone A on hepatic ischemia-reperfusion injury in rats.
- Author
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Matsui N, Fukuishi N, Fukuyama Y, Yasui Y, and Akagi M
- Subjects
- Animals, Benzoquinones administration & dosage, Benzoquinones therapeutic use, Dose-Response Relationship, Drug, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors therapeutic use, Liver Diseases enzymology, Liver Diseases prevention & control, Male, Plant Extracts administration & dosage, Plant Extracts pharmacology, Plant Extracts therapeutic use, Protective Agents administration & dosage, Protective Agents therapeutic use, Rats, Rats, Wistar, Ardisia, Benzoquinones pharmacology, Enzyme Inhibitors pharmacology, Lipoxygenase Inhibitors, Phytotherapy, Protective Agents pharmacology, Reperfusion Injury prevention & control
- Abstract
The protective effects of the 5-lipoxygenase inhibitor ardisiaquinone A, a compound isolated from Ardisia sieboldii, on hepatic ischemia-reperfusion (I/R) injury was studied in rats. Hepatic I/R injury was induced by occlusion of the portal vein and the hepatic artery for 60 min, followed by reperfusion for 24 h. The content of leukotriene B (4) (LTB (4)) in the liver increased during ischemia. Serum alanine aminotransferase (ALT) levels, a marker of hepatic parenchymal cell injury, and hepatic myeloperoxidase (MPO) activity, a marker of neutrophil accumulation, significantly increased 6 - 9 h after reperfusion. Treatment with ardisiaquinone A (0.1 - 2 mg/kg, i. p.) 30 min prior to ischemia dose-dependently prevented the increase in LTB (4) content during ischemia (ID (50) = 0.645 mg/kg) with a slightly higher potency than that of AA-861 (ID (50) = 0.728 mg/kg), a known reference 5-lipoxygenase inhibitor. Ardisiaquinone A also attenuated the increase in MPO activity and serum ALT levels at 6 h after reperfusion (ID (50) = 1.71 mg/kg and 4.28 mg/kg, respectively). These protective effects were more efficient than those of AA-861 (ID (50) = 1.86 mg/kg and no effect, respectively), LY255283 (ID (50) = 18.1 mg/kg and 11.5 mg/kg, respectively), and ONO-4057 (ID (50) = 8.38 mg/kg and 9.44 mg/kg, respectively), which are LTB (4) receptor antagonists. These results suggest that ardisiaquinone A may protect the liver against damage due to I/R in rats.
- Published
- 2005
- Full Text
- View/download PDF
36. Inhibiton of NF-kappaB activation during ischemia reduces hepatic ischemia/reperfusion injury in rats.
- Author
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Matsui N, Kasajima K, Hada M, Nagata T, Senga N, Yasui Y, Fukuishi N, and Akagi M
- Subjects
- Alanine Transaminase blood, Animals, Male, NF-kappa B metabolism, Peroxidase metabolism, Proline pharmacology, Rats, Rats, Wistar, Sulfobromophthalein metabolism, Thiocarbamates pharmacology, Ischemia metabolism, Liver blood supply, NF-kappa B antagonists & inhibitors, Proline analogs & derivatives, Reperfusion Injury prevention & control
- Abstract
The aim of this study was to determine whether nuclear factor-kappaB (NF-kappaB) inhibitors are efficient against hepatic ischemia/reperfusion (I/R) injury. We previously demonstrated that xanthine oxidase-derived reactive oxygen species activate NF-kappaB during ischemia. However, the role of NF-kappaB activation during ischemia in post-reperfusion injury remains unclear. Therefore, while we examined the effects of NF-kappaB inhibitors, sulfasalazine and pyrrolidinedithiocarbamate on hepatic I/R injury using a rat lobar hepatic I/R model, we estimated the relationship between NF-kappaB activation during ischemia and following hepatic damage caused by reperfusion. The portal vein and the hepatic artery were clamped for 1 hr followed by reperfusion for up to 24 hr. NF-kappaB activation was determined by Western blot analysis. NF-kappaB activation was observed in the ischemic lobe of the liver, and the activation was prevented by pre-administration with NF-kappaB inhibitors. Although the serum ALT level, hepatic MPO activity and BSP clearance, as an index of hepatic injury, were increased after reperfusion, the increase was attenuated by pre-administration with NF-kappaB inhibitors. These findings suggest that NF-kappaB activation during ischemia is relevant to hepatic I/R injury. Moreover, we first showed that pre-administration with NF-kappaB inhibitors is effective against hepatic I/R injury.
- Published
- 2005
- Full Text
- View/download PDF
37. [The role of mast cells in allergic inflammation--from the view point of innate immune system involvement].
- Author
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Fukuishi N, Yoshioka M, and Akagi M
- Subjects
- Animals, Immunity, Innate physiology, Inflammation immunology, Membrane Glycoproteins physiology, Phagocytosis physiology, Receptors, Cell Surface physiology, Toll-Like Receptors, Hypersensitivity immunology, Mast Cells physiology
- Published
- 2005
- Full Text
- View/download PDF
38. Identification of Fyn-binding proteins in MC/9 mast cells using mass spectrometry.
- Author
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Nahm DH, Tkaczyk C, Fukuishi N, Colucci-Guyon E, Gilfillan AM, and Metcalfe DD
- Subjects
- Animals, Carrier Proteins isolation & purification, Cell Line, Electrophoresis, Polyacrylamide Gel, Mice, Phosphorylation, Pyruvate Kinase metabolism, Signal Transduction, Tyrosine metabolism, Vimentin metabolism, Adaptor Proteins, Signal Transducing, Carrier Proteins metabolism, Mass Spectrometry methods, Mast Cells metabolism
- Abstract
Fyn is a Src kinase known to have an essential role in mast cell degranulation induced following aggregation of the high affinity IgE-receptor. Although Fyn possesses SH2 and SH3 protein binding domains, the molecules that interact with Fyn have not been characterized in mast cells. We thus analyzed Fyn-binding proteins in MC/9 mast cells to explore the Fyn-mediated signaling pathway. On mass spectrometric analysis of proteins binding to the SH2 and SH3 domains of Fyn, we identified six proteins that bind to Fyn including vimentin, pyruvate kinase, p62 ras-GAP associated phosphoprotein, SLP-76, HS-1, and FYB. Among these proteins, vimentin and pyruvate kinase have not been shown to bind to Fyn. After IgE-receptor mediated stimulation, binding of vimentin to Fyn was increased; and this interaction was via binding to the SH2, but not the SH3, domain of Fyn. Mast cells from vimentin-deficient mice showed enhanced mediator release and tyrosine phosphorylation of intracellular proteins including NTAL and LAT. The observation that vimentin and pyruvate kinase bind to Fyn provides additional insight into Fyn-mediated signaling pathways, and suggests a critical role for Fyn in mast cell degranulation in interacting with both cytosolic and structural proteins.
- Published
- 2003
- Full Text
- View/download PDF
39. Involvement of arachidonic acid in nonimmunologic production of superoxide in mast cells.
- Author
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Sakaguchi M, Fukuishi N, Teramoto K, Miyazaki M, Huh NH, Namba M, and Akagi M
- Subjects
- Animals, Histamine Agonists pharmacology, Male, Mast Cells ultrastructure, Microscopy, Electron, Scanning, Rats, Rats, Wistar, Signal Transduction drug effects, Signal Transduction immunology, Arachidonic Acid pharmacology, Mast Cells drug effects, Mast Cells metabolism, Superoxides metabolism
- Abstract
Background: A number of different molecules are known to be involved in the signal pathway to release histamine from mast cells, among which arachidonic acid (AA) is one of the key mediators. On the other hand, we found that the application of compound 48/80, a typical histamine liberator, generated superoxide in mast cells. In the present study, we investigated the mechanism of superoxide production in mast cells with respect to AA signaling in conjunction with a fine structural analysis., Methods: Superoxide production was monitored by chemiluminescence in rat peritoneal mast cells and their subfractions after various treatments. For scanning electron micrography, the conditions for fixation and freeze-fracture were optimized to get natural fine images., Results: Compound 48/80 induced superoxide production in the isolated mast cells and some of their subfractions possibly through intracellular increase in Ca(2+) concentration, activation of cytosolic phospholipase A(2), and release of AA., Discussion: The present results indicate the critical role of AA in the signal pathway to generate superoxide from mast cells in response to compound 48/80., (Copyright 2003 S. Karger AG, Basel)
- Published
- 2003
- Full Text
- View/download PDF
40. Inhibitory effect of olopatadine on antigen-induced eosinophil infiltration and the LFA-1 and Mac-1 expression in eosinophils.
- Author
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Fukuishi N, Matsuhisa M, Shimono T, Murata N, Iwanaga M, Sagara H, Matsui N, and Akagi M
- Subjects
- Administration, Oral, Animals, Cell Movement drug effects, In Vitro Techniques, Integrin alpha4beta1 biosynthesis, Male, Nasal Mucosa pathology, Olopatadine Hydrochloride, Phthalazines pharmacology, Rats, Rhinitis, Allergic, Perennial drug therapy, Rhinitis, Allergic, Perennial pathology, Anti-Allergic Agents pharmacology, Dibenzoxepins pharmacology, Eosinophils drug effects, Histamine H1 Antagonists pharmacology, Lymphocyte Function-Associated Antigen-1 drug effects, Macrophage-1 Antigen biosynthesis
- Abstract
The inhibitory effect of olopatadine, a new antiallergic drug, on antigen-induced eosinophil infiltration and its mechanisms were examined using the local sensitized rat allergic rhinitis model and isolated IL-5-stimulated rat peritoneal eosinophils. Olopatadine dose-dependently inhibited antigen-induced eosinophil infiltration in the nasal mucosa. Olopatadine dose-dependently repressed the IL-5-induced expressions of CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) on rat peritoneal eosinophils. However, olopatadine had no effect on IL-5-induced CD49d/CD29 (VLA-4) expression. These results suggest that olopatadine may inhibit antigen-induced eosinophil infiltration through repression of LFA-1 and Mac-1 expression.
- Published
- 2002
- Full Text
- View/download PDF
41. Roles of superoxide dismutase in rat mast cell granules.
- Author
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Fukuishi N, Takahashi H, Harada N, Kanoh R, Matsui N, and Akagi M
- Subjects
- Animals, Calcium pharmacology, Cells, Cultured, Chemokine CCL4, Cytoplasmic Granules physiology, Hydrogen Peroxide pharmacology, Inflammation physiopathology, Macrophage Inflammatory Proteins metabolism, Male, Mast Cells ultrastructure, Rats, Rats, Wistar, Subcellular Fractions, Cytoplasmic Granules enzymology, Mast Cells enzymology, Superoxide Dismutase metabolism
- Abstract
Background: It has been suggested that in the granules of rat mast cells there is some kind of superoxide dismutase (SOD), but details of this SOD in mast cells remain unclear. In the present study, we studied the mode of existence of SOD in mast cells and its releasing mechanism from the granules. In addition, we discussed the physiological role of SOD in allergic events., Methods: Purified rat mast cells were disrupted with a sonic disrupter and granules (sample I) were separated from supernatant (sample II) by centrifugation. The granules were treated with 1 mM Ca(2+), and the supernatant (sample III) was separated from the pellet (sample IV). Sample III was applied to a heparin column and the eluate was used as sample V. SOD activity was measured in these samples., Results: SOD existed in mast cell granules as a heparin-binding and an inactive form. However, when granules were released and exposed to high Ca(2+) concentration, SOD was discharged from heparin and shifted to the active form. The expression of macrophage inflammatory protein-1 alpha mRNA was enhanced when hydrogen peroxide (H(2)O(2)) or sample III with the xanthine-xanthine oxidase system were added to the culture media., Conclusions: These findings suggest that in stimulated rat mast cells, the released SOD may transform the generated superoxide anion into H(2)O(2), and the generated H(2)O(2) may enhance the expression of chemokine mRNA in the mast cells., (Copyright 2001 S. Karger AG, Basel)
- Published
- 2001
- Full Text
- View/download PDF
42. Xanthine oxidase-derived reactive oxygen species activate nuclear factor kappa B during hepatic ischemia in rats.
- Author
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Matsui N, Satsuki I, Morita Y, Inaizumi K, Kasajima K, Kanoh R, Fukuishi N, and Akagi M
- Subjects
- Animals, Male, Rats, Rats, Wistar, Thiobarbituric Acid Reactive Substances metabolism, Ischemia metabolism, Liver blood supply, NF-kappa B metabolism, Reactive Oxygen Species metabolism, Xanthine Oxidase metabolism
- Abstract
The present study was carried out to elucidate the relationship between the generation of reactive oxygen species (ROS) and an activation of nuclear factor (NF) kappa B in a hepatic ischemia-reperfusion model. During the ischemic period, the contents of xanthine oxidase (XOD) metabolites and thiobarbituric acid-reactive substances were significantly increased, and NF-kappa B was activated in the liver of rats. The activation of NF-kappa B was inhibited by pretreatment of allopurinol (10-100 mg/kg, i.p.) in a dose-dependent manner. In conclusion, this suggests that the XOD-derived ROS may activate NF-kappa B during ischemia.
- Published
- 2000
- Full Text
- View/download PDF
43. Novel action of quinolones on osteoclast-like cells.
- Author
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Fukuishi N, Matsui N, Kanoh R, and Akagi M
- Subjects
- Animals, Cells, Cultured, Dinoprostone biosynthesis, Histocytochemistry, Male, Mice, Nalidixic Acid pharmacology, Norfloxacin pharmacology, Ofloxacin pharmacology, Spleen cytology, Tumor Necrosis Factor-alpha biosynthesis, Osteoclasts drug effects, Quinolones pharmacology
- Abstract
Quinolones have a broad antibacterial spectrum against Gram-negative and Gram-positive bacteria. The compounds, however, have a few adverse effects, such as convulsion and toxicity to articular cartilage. We observed that some quinolones such as Naldixic acid, Ofloxacin, and Norfloxacin have osteoclast-inducing effects. All quinolones we tested produced tumor necrosis factor-alpha and prostaglandin E2, and have potency as osteoclast inducers to cultured cells. These results suggest that some quinolones affect osteoclast induction or activation, and this may be related to the production of tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2).
- Published
- 1999
- Full Text
- View/download PDF
44. [Role of superoxide generation and degradation system of mast cells in allergic inflammation].
- Author
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Akagi M, Fukuishi N, Sakaguchi M, Matsui N, and Takahashi H
- Subjects
- Animals, Ascitic Fluid cytology, Calcimycin pharmacology, Inflammation physiopathology, Male, NADPH Oxidases, Phosphoproteins analysis, Rats, Rats, Wistar, Superoxide Dismutase metabolism, p-Methoxy-N-methylphenethylamine pharmacology, Hypersensitivity physiopathology, Mast Cells physiology, Superoxides metabolism
- Abstract
Rat peritoneal mast cells are stimulated to generate superoxide anion (O2) by the addition of compound 48/80 and A23187. Recently, we demonstrated by immunohistochemical and Western blot analysis that the mast cells contained the p47phox protein, which was one of cytosolic component of the NADPH oxidase system. In the present study, it was demonstrated that the mast cells contained the p47phox mRNA, much similar to that of mouse leukocyte. The permeabilized mast cells were stimulated to generate O2- by the addition of Ca2+, phospholipase A2 (PLA2) and arachidonic acid. Our data suggest the following:(1) cytosolic PLA2 may be activated by the elevation of [Ca2+]i; (2) the conjugation of membrane component with cytosolic component may be stimulated by the released arachidonic acid. The mast cell granules contained superoxide dismutase (SOD)-like enzyme, which degradated O2-, generated in xanthine-xanthinoxidase system. SOD-like enzyme was released from the granules by the treatment with Ca2+ and trapped by the treatment with heparin. In conclusion, our studies suggest that the disorder of the degradation system of O2- may contribute to the development of allergic inflammation.
- Published
- 1998
- Full Text
- View/download PDF
45. Inhibitor effect of apafant on bronchopulmonary responses to platelet activating factor and to antigen in rats.
- Author
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Akagi M, Nishioka E, Kanoh R, Tachibana M, and Fukuishi N
- Subjects
- Animals, Histamine metabolism, Histamine physiology, Hypersensitivity, Immediate physiopathology, In Vitro Techniques, Male, Organ Size drug effects, Organ Size physiology, Platelet Activating Factor pharmacology, Pulmonary Circulation drug effects, Rats, Rats, Inbred BN, Rats, Wistar, Azepines pharmacology, Bronchi drug effects, Hypersensitivity, Immediate drug therapy, Lung drug effects, Platelet Activating Factor antagonists & inhibitors, Platelet Aggregation Inhibitors pharmacology, Triazoles pharmacology
- Abstract
Apafant (4-(2-chlorophenyl)-9-methyl-2-(3-morpholino-3-oxopropyl)-6H-thieno[3,2- f] [1,2,4]triazolo[4,3-a][1,4] diazepine, CAS 105219-56-5, WEB 2086), as a specific platelet activating factor (PAF) antagonist, inhibited PAF-induced increases of bronchial inflation pressure (delta Pi), pulmonary artery perfusion pressure (delta Pp) and microvascular permeability (wet-to-dry lung weight ratios), dose-dependently, in rats. Apafant also inhibited antigen-induced increase of delta pi, delta Pp and microvascular permeability in passively sensitized rats. Ozagrel also inhibited PAF- and antigen-induced increase of delta Pi, delta Pp and microvascular permeability. Apafant almost completely inhibited the increase of intratracheal pressure and microvascular permeability, but incompletely inhibited the increase of pulmonary artery pressure. At 1 microgram/ml, the effects of ozagrel were almost comparable to that of apafant at the same concentration, but the inhibitory effect on intratracheal pressure was less than that of apafant. Apafant inhibited PAF-induced increase in perfusate of thromboxane (TX) B2 and leukotrine C4/D4E4 (LTs), and antigen-induced increase of TXB2, LTs, PAF and histamine. Ozagrel also inhibited the PAF-induced increase of TXB2, but not the increase of LTs. Apafant inhibited antigen-induced increase of TXB2 and LTs more strongly than PAF-induced increase. The order of inhibitory effects of apafant against generation and release of chemical mediators was TXB2, LTs, PAF and histamine. These findings suggest that TXA2, LTs and PAF may contribute to the increase of intratracheal pressure and microvascular permeability, and histamine may contribute to the increase of vascular resistance in rats. Apafant may inhibit bronchopulmonary responses through PAF receptor antagonism. In addition, apafant can be considered to be useful for the treatment of some allergic diseases when the drug is employed in clinical use.
- Published
- 1997
46. The mechanisms of compound 48/80-induced superoxide generation mediated by A-kinase in rat peritoneal mast cells.
- Author
-
Fukuishi N, Sakaguchi M, Matsuura S, Nakagawa C, Akagi R, and Akagi M
- Subjects
- Animals, Arachidonic Acid pharmacology, Arachidonic Acids pharmacology, Blotting, Western, Bucladesine pharmacology, Colforsin pharmacology, Cyclic AMP-Dependent Protein Kinases antagonists & inhibitors, Granulomatous Disease, Chronic, Immunohistochemistry, Indoles pharmacology, Isoproterenol pharmacology, Male, NADPH Oxidases, Phosphoproteins chemistry, Phosphoproteins immunology, Protein Kinase C antagonists & inhibitors, Pyrroles pharmacology, Rats, Rats, Wistar, Recombinant Proteins, Terpenes pharmacology, Carbazoles, Cyclic AMP-Dependent Protein Kinases drug effects, Cyclic AMP-Dependent Protein Kinases metabolism, Mast Cells drug effects, Mast Cells metabolism, Superoxides metabolism, p-Methoxy-N-methylphenethylamine pharmacology
- Abstract
This investigation was undertaken to clarify the mechanisms of superoxide anion (O2-) generation in rat peritoneal mast cells. Compound 48/80, a typical histamine liberator mediated by calcium influx, elicited O2- generation from the mast cells in a dose-dependent fashion. It was demonstrated by immunohistochemical study and Western blot analysis that the mast cells contained the 47-kDa phagocyte oxidase (p47phox) protein, which was one cytosolic component of the NADPH oxidase system. Arachidonic acid stimulated O2- generation in the mast cells, but other unsaturated fatty acids had no effect. On the other hand, 48/80-induced O2- generation was inhibited by phospholipase A2 inhibitors, such as arachidonyl trifluoromethyl ketone and manoalide. Forskolin, isoprenaline, and dibutyryl cyclic AMP inhibited the O2- generation, and KT-5720, a cyclic AMP-dependent protein kinase (A-kinase) inhibitor, markedly enhanced the O2- generation. These findings suggest that O2- is generated by a NADPH oxidase-like enzyme system in mast cells and that this enzyme system is activated by arachidonic acid released by cytosolic phospholipase A2. Thus, it is regulated by the cyclic AMP-A kinase system.
- Published
- 1997
- Full Text
- View/download PDF
47. Anti-allergic effect of tea-leaf saponin (TLS) from tea leaves (Camellia sinensis var. sinensis).
- Author
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Akagi M, Fukuishi N, Kan T, Sagesaka YM, and Akagi R
- Subjects
- Airway Resistance drug effects, Animals, Guinea Pigs, Histamine Release drug effects, Leukotriene C4 antagonists & inhibitors, Male, Mast Cells drug effects, Mast Cells metabolism, Passive Cutaneous Anaphylaxis drug effects, Rats, Rats, Inbred BN, ortho-Aminobenzoates pharmacology, Anti-Allergic Agents pharmacology, Anti-Asthmatic Agents pharmacology, Saponins pharmacology, Tea
- Abstract
We investigated the anti-allergic effect of tea-leaf saponin (TLS), which was a mixture of saponins separated from the leaves of Camellia sinensis var. sinensis, in guinea pigs and rats. TLS (20-100 mg/kg) dose-dependently inhibited experimentally-induced asthma, and ID50 was 61.7 mg/kg. TLS (20-100 mg/kg) dose-dependently inhibited a 48 h homologous PCA (passive cutaneous anaphylaxis) reaction, and the inhibitory effect was similar to that of tranilast. TLS (1-100 microg/ml) also inhibited the release of antigen-induced leukotriene (LT) C4 from sensitized guinea pig lung samples in a dose-dependent fashion, but did not prevent histamine release. TLS (0.01-0.5 microg/ml) inhibited histamine release from rat peritoneal mast cells induced by compound 48/80. At higher concentrations, TLS elicited histamine release. These findings suggest that TLS may be a useful protective agent against clinical allergy, and that the inhibitory effects of TLS on mediator release are in some way related to its inhibitory effect on experimentally-induced asthma and PCA reaction.
- Published
- 1997
- Full Text
- View/download PDF
48. Role of histamine H3 receptor on hypoxia-reoxygenation-induced cardiac dysfunction in guinea pigs.
- Author
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Akagi M, Hamada K, Nishioka E, Fukuishi N, and Akagi R
- Subjects
- Adenosine Triphosphate analysis, Animals, Cell Hypoxia, Creatine Kinase metabolism, Female, Guinea Pigs, Histamine analysis, Histamine metabolism, In Vitro Techniques, Heart Rate, Myocardial Contraction, Myocardial Ischemia physiopathology, Receptors, Histamine H3 physiology
- Abstract
Hypoxia elicited a remarkable decrease in contractility and heart rate in isolated right atria from guinea pigs, a decrease which recovered partially during reoxygenation. Histamine content increased during hypoxia and decreased during reoxygenation. However, hypoxia induced a marked degranulation of mast cells. Pretreatment with alpha-methylhistamine (100-300 nM) recuperated control level contractility and heart rate, and prevented the hypoxia-reoxygenation-induced leakage of creatine phosphokinase (CPK). On the other hand, pretreatment with thioperamide (100-300 nM) decreased contractility and heart rate dose-dependently, and prevented recovery during reoxygenation. These data shows that cardiac histamine may play an important role in the protection against hypoxia-reoxygenation injury through the H3 receptor.
- Published
- 1995
49. Inhibitory effect of epinastine on superoxide generation by rat neutrophils.
- Author
-
Fukuishi N, Kan T, Hirose K, Akagi R, and Akagi M
- Subjects
- Animals, Dose-Response Relationship, Drug, Ketotifen pharmacology, Male, NADH, NADPH Oxidoreductases drug effects, NADPH Oxidases, Piperazines pharmacology, Rats, Rats, Wistar, Anti-Allergic Agents pharmacology, Dibenzazepines pharmacology, Imidazoles pharmacology, Neutrophils drug effects, Superoxides metabolism
- Abstract
We studied the effects of antiallergic drugs, epinastine, ketotifen, oxatomide, mequitazine and cromolyn sodium on superoxide anion (O2-) generation from rat neutrophils. Epinastine, ketotifen, oxatomide and mequitazine dose-dependently prevented the N-formyl-Met-Leu-Phe- and phorbol 12-myristate 13-acetate-induced O2- generation, but cromolyn sodium did not prevent it. When membrane and cytosol fractions were incubated with each drug, epinastine, ketotifen and mequitazine prevented O2- generation. On the other hand, when only the membrane fraction was incubated with each drug, ketotifen and mequitazine prevented O2- generation, but epinastine did not. Epinastine may inhibit the NADPH oxidase system through the obstruction of NADPH oxidase-associated cytosol components.
- Published
- 1995
- Full Text
- View/download PDF
50. Contribution of platelet activating factor (PAF) in histamine-induced model of nasal allergy in rats.
- Author
-
Akagi M, Kanoh R, Fukuishi N, Tachibana M, and Akagi R
- Subjects
- Animals, Disease Models, Animal, Male, Nasal Mucosa drug effects, Nasal Mucosa metabolism, Permeability, Rats, Rats, Wistar, Rhinitis, Allergic, Perennial chemically induced, Histamine pharmacology, Platelet Activating Factor physiology, Rhinitis, Allergic, Perennial metabolism
- Abstract
Histamine-induced nasal hyperpermeability was measured in rats. Perfusion of histamine elicited a biphasic increase of nasal vascular permeability, and an increase of concentration of platelet-activating factor (PAF) in the perfusate. Both phases were prevented by pretreatment with diphenhydramine (1 mg/kg, p.o.), a histamine H1-receptor antagonist, and the second increase of vascular permeability was prevented by pretreatment with 3-[4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f] [1,2,4]-triazolo [4,3-alpha] [1,4] diazepin-2-yl]-1-(4-morpholinyl)-1-propane (WEB 2086) (10 mg/kg, p.o.), an anti PAF agent. The time-course of PAF-induced nasal hyperpermeability was similar to that of the second increase induced by histamine. These findings suggest that PAF released by histamine from nasal mucosa plays an important role in nasal allergy, especially in the late phase.
- Published
- 1995
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