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      Saireito and Saikosaponin D Prevent Urinary Protein Excretion via Glucocorticoid Receptor in Adrenalectomized WKY Rats with Heterologous-Phase Anti-GBM Nephritis

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          Abstract

          Aims: In order to clarify the antinephritic mechanisms of saireito, the glucocorticoid receptor agonistic effect of saireito was evaluated in adrenalectomized rats with anti-glomerular basement membrane (anti-GBM) nephritis. Methods: Rats with anti-GBM nephritis were subjected to adrenalectomy to exclude the effects of endogenous steroid hormones to investigate effects of saireito on the nephritis. The suppressive effects of saireito and saikosaponin D on the production of cytokines were investigated in vitro andin vivo. Results: Administration of saireito or saikosaponin D significantly suppressed the increase of urinary protein excretion and histopathological changes in adrenalectomized nephritic rats. Coadministration of saireito or saikosaponin D and RU-38486, a glucocorticoid receptor antagonist, did not suppress the increase of urinary protein excretion. Saikosaponin D inhibited the glucocorticoid receptor binding of [<sup>3</sup>H]dexamethasone in anin vitro assay (IC<sub>50</sub> ratio 5.8 µmol/l). The IC<sub>50</sub> values of saikosaponin D for the release of IL-2 and IL-10 were 13.4 and 12.3 µmol/l, respectively. Administration of saireito and saikosaponin D prevented an increase in IL-2 levels in the renal cortex of anti-GBM nephritic rats. Conclusion: These results suggest that the antinephritic effects of saireito may be partly attributable to an agonistic action on the glucocorticoid receptor by saikosaponin D, a component of saireito.

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          Most cited references 14

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          Effects of dexamethasone on the profile of cytokine secretion in human whole blood cell cultures.

          The interaction between the endocrine and immune systems is a very intriguing area. Endogenous glucocorticoids, as end-effectors of the hypothalamo-pituitary-adrenal axis, inhibit the immune and inflammatory responses and are used as immunosuppressive drugs in many inflammatory, autoimmune and allergic diseases. The aims of this study were to investigate the effects of dexamethasone on the profile of cytokine secretion in whole blood cell cultures from healthy subjects and to analyse the gender-related sensitivity to dexamethasone on each cytokine secretion. There was a significant inhibition by dexamethasone (from 1 to 100 nM) on the secretion of monokines (IL-1beta, IL-6, IL-8 and TNF alpha) and lymphokines (IL-2, IL-4, IL-10 and IFN gamma), either after LPS or PHA stimulation (P < 0.01). Interleukin 4 and IL-10 were less inhibited than IFN gamma (P < 0.05 at 1 nM, P < 0.01 at 10 nM and P < 0.001 from 100 nM to 10 microM). No gender difference was observed in the rate of inhibition of the secretion of each cytokine. This study shows that the inhibition of cytokine secretion by dexamethasone is more marked on Th1-type cytokines than on Th2-type cytokines. These data support the idea that glucocorticoids may induce a shift from the Th1 to Th2 profile of cytokine secretion.
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            Regulation of glucocorticoid receptors by glucocorticoids in cultured HeLa S3 cells.

            HeLa S3 cells contain high affinity, saturable receptors specific for glucocorticoids (congruent to 20,000 per cell). Growth of HeLa S3 cells in media containing dexamethasone (10(-6) M) results in a pronounced (congruent to 70%) reduction in the total cellular level of nuclear or cytoplasmic dexamethasone receptor number without any alteration in steroid-receptor dissociation constant (Kd congruent to 1 X 10(-9) M). This reduction in receptor number is not the result of simple receptor occupation, since this effect also occurs when receptor number is modulated by the direct addition of [3H]dexamethasone. Both control and dexamethasone-treated cells attain equilibrium states of receptor binding by 120 min at 0 C and by 60 min at 37 C, enabling estimation of receptor number and affinity by Scatchard analysis of saturation curves. Down-regulation of glucocorticoid receptor occurs at steroid concentrations as low as 10(-9) M (40% reduction). This alteration in receptor occurs after 24 h of hormone but not after either 2 or 6 h. Only the active glucocorticoids, (dexamethasone, cortisol) down-regulate glucocorticoid receptors. Cortexolone, estradiol, and 5 alpha-dihydrotestosterone have no apparent effect on this process, whereas progesterone (10(-7) M) is partially effective. Subcellular distribution studies indicate that glucocorticoids affect only that population of receptors capable of nuclear translocation at 37 C. We conclude that glucocorticoids can regulate the metabolism of their own receptors, via undefined mechanisms.
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              FK506 ameliorates proteinuria and glomerular lesions induced by anti-Thy 1.1 monoclonal antibody 1-22-3

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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2008
                July 2008
                04 July 2008
                : 109
                : 2
                : p19-p27
                Affiliations
                Tsumura & Co., Central Research Laboratories and Ibaraki Plant, Ami-machi, Japan
                Article
                142397 Nephron Physiol 2008;109:p19
                10.1159/000142397
                18600032
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 3, References: 28, Pages: 1
                Categories
                Original Paper

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