Studies of the Effects of Fk506 on Renal Allografting in the Beagle Dog

Ochiai, Takenori; Nagata, Michio; Nakajima, Kiyokazu; Suzuki, Takao; Sakamoto, Kaoru; Enomoto, Kazuo; Gunji, Yoshio; Uematsu, Taro; Goto, Tatsuo; Hori, Seiji; Kenmochi, Takashi; Nakagouri, Toshio; Asano, Tomohiko; Isono, Kaichi; Hamaguchi, K; Tsuchida, Hiroki; Nakahara, Kazunari; Inamura, Naoki; Goto, Toshio

doi:10.1097/00007890-198712000-00001

Cited by 128 publications

(35 citation statements)

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“…2 We are using the numbering system in the literature (35) for consistency (see Figs. 1 and 4), that is, the N-terminal methionine of FKBP12 is designated as the 0 amino acid residue so that the Cterminal glycine is numbered 107.…”

Section: Methodsmentioning

confidence: 99%

“…The drug has been used both experimentally and clinically to prevent organ graft rejection and to treat autoimmune diseases (1)(2)(3)(4)(5). FK506 suppresses activation of human T-lymphocytes by blocking a key step required in the synthesis or activation of transcription factors (NF-AT, AP-3, and NF-B), which promote expression of lymphokine genes such as interleukin-2 (IL-2) (6).…”

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confidence: 99%

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Three Amino Acid Residues Determine Selective Binding of FK506-binding Protein 12.6 to the Cardiac Ryanodine Receptor

Xin

Rogers

et al. 1999

Journal of Biological Chemistry

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FK506-binding protein (FKBP12) has been found to be associated with the skeletal muscle ryanodine receptor (RyR1) (calcium release channel), whereas FKBP12.6, a novel isoform of FKBP, is selectively associated with the cardiac ryanodine receptor (RyR2). For both RyRs, the stoichiometry is 4 FKBP/RyR. Although FKBP12.6 differs from FKBP12 by only 18 of 108 amino acids, FKBP12.6 selectively binds to RyR2 and exchanges with bound FKBP12.6 of RyR2, whereas both FKBP isoforms bind to RyR1 and exchange with bound FKBP12 of RyR1. To assess the amino acid residues of FKBP12.6 that are critical for selective binding to RyR2, the residues of FKBP12.6 that differ with FKBP12 were mutated to the respective residues of FKBP12. FK506, a fungal macrolide antibiotic, possesses potent immunosuppressive activity. The drug has been used both experimentally and clinically to prevent organ graft rejection and to treat autoimmune diseases (1-5). FK506 suppresses activation of human T-lymphocytes by blocking a key step required in the synthesis or activation of transcription factors (NF-AT, AP-3, and NF-B), which promote expression of lymphokine genes such as interleukin-2 (IL-2) (6). The immunosuppressive action of the drug is related to its inhibition of calcineurin, a calciumdependent protein phosphatase involved in intracellular signaling transduction, by way of binding to FK506-binding proteins (FKBPs), 1 a family of related intracellular receptors including FKBP12 and FKBP12.6 (7-9).In skeletal muscle and heart, the ryanodine receptor (RyR)/ calcium release channel serves to release Ca 2ϩ from sarcoplasmic reticulum (SR), thereby triggering muscle contraction (10 -12). FKBP12 has been found to be tightly associated with skeletal muscle RyR (RyR1), and more recently its novel isoform, FKBP12.6, was found to be selectively associated with cardiac RyR (RyR2). Thus, the structural formulae for RyR1 and RyR2 are (RyR1 protomer) 4 (FKBP12) 4 and (RyR2 protomer) 4 (FKBP12.6) 4 , respectively (13-16). The ultrastructural localization of FKBP12 has been pinpointed within the three dimensional structure of RyR1 by cryoelectron microscopy and image enhancement analysis. There are four FKBPs/ receptor with 4-fold symmetry, and FKBP is located in the vicinity of RyR1 that is close to the transverse tubule, consistent with its serving a role in E-C coupling (17, 18). Both FKBP12 and FKBP12.6 share a number of structural and functional similarities, including: 1) 85% amino acid sequence homology (only 18 of 108 amino acid residues differ); 2) PPIase activity that is inhibited by FK506 or rapamycin; and 3) inhibition of calcineurin when the ternary complexes are formed with FKBP and FK506 (6 -8). FKBP12 appears to have a role in excitation-contraction coupling in skeletal muscle by modulating the release of Ca 2ϩ from SR (15,19,20). However, the action of FKBP12.6 on cardiac excitation-contraction coupling is less clear (16). Recently, it has been suggested that FKBP12.6 may be involved in the regulation of insulin biosynthesis and secretion by...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Three Amino Acid Residues Determine Selective Binding of FK506-binding Protein 12.6 to the Cardiac Ryanodine Receptor

Xin

Rogers

et al. 1999

Journal of Biological Chemistry

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“…These data are in contrast with those of Takai et al (1990) who reported no weight loss in rats treated with I mg/kg FK506, although they did observe marked thymic changes. Studies of FK506 in dogs with renal allografts (Ochiai et al, 1987b;Collier et al, 1988) revealed that the drug was immunosuppressive orally at a dose of 1 mg/kg. In the study reported by Collier et al, animals suffered from nausea requiring treatment with metaclopramide and all animals surviving more than 84 days had histological evidence of acute vasculitis.…”

Section: Fk506mentioning

confidence: 99%

Untitled

1991

Clinical &Amp; Experimental Immunology

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“…The discovery and development of immunosuppressants from natural sources have an impressive record: mycophenolic acid (MPA) and cyclosporin A (CsA), the fungal metabolites isolated in 1932 [6] and 1970 [7] , respectively; rapamycin, found in 1975 [8] ; FK506, extracted from a culture filtrate of Streptomyces tsukubaensis in 1987 [9,10] ; and fingolimod (FTY720), described in 1995 [11] . Although the current industry model for drug discovery does not favor natural products, the resources are so vast as to seem unlimited, and these emerging tools will provide important discoveries, leading to new medicines [12] .…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressant discovery from Tripterygium wilfordii Hook f: the novel triptolide analog (5R)-5-hydroxytriptolide (LLDT-8)

Tang

Zuo

2012

Acta Pharmacol Sin

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The Chinese traditional herb Tripterygium wilfordii Hook f (TwHF) has been widely used in the treatment of autoimmune and inflammatory diseases. Over the past few decades, great efforts have been made to explore modern preparations of TwHF with higher efficacy, solubility, and lower toxicity. In this study, we reviewed several examples both of naturally occurring compounds and their derivatives in TwHF, and summarized the preclinical evaluations with regard to autoimmune and inflammatory diseases. All of the candidate compounds described herein have been or are currently in clinical trials. Although some studies encountered problems, the data still provided valuable references for future studies. (5R)-5-hydroxytriptolide (LLDT-8, Leitengshu) is a novel triptolide derivative with potent immunosuppressive and anti-inflammatory activities developed at Shanghai Institute of Materia Medica. Indeed, a Phase I clinical trial for this compound has been completed in rheumatoid arthritis patients. The results will provide the basis for the further exploration of this ancient herb and encourage the research and development of valuable traditional Chinese medicine. IntroductionFor thousands of years, natural products have played an important role throughout the world in treating and preventing human diseases [1][2][3][4][5] . The discovery and development of immunosuppressants from natural sources have an impressive record: mycophenolic acid (MPA) and cyclosporin A (CsA), the fungal metabolites isolated in 1932 [6] and 1970 [7] , respectively; rapamycin, found in 1975 [8] ; FK506, extracted from a culture filtrate of Streptomyces tsukubaensis in 1987 [9,10] ; and fingolimod (FTY720), described in 1995 [11] . Although the current industry model for drug discovery does not favor natural products, the resources are so vast as to seem unlimited, and these emerging tools will provide important discoveries, leading to new medicines [12] . Furthermore, the drugs already in use as immunosuppressants (eg, cyclophosphamide, methotrexate, azathioprine, cyclosporin) are associated with some significant problems, including toxicity, a lack of reversibility, and increased susceptibility to viral and other infections [13] . Indeed, exploring new and innovative immunosuppres-* To whom correspondence should be addressed.E-mail jpzuo@mail.shcnc.ac.cn Received 2012-06-11 Accepted 2012-07-04 sants from natural sources has now become a focus of intense research.Tripterygium wilfordii Hook f (TwHF) and its extracts have been widely used in the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and dermatomyositis (DM) [14][15][16][17][18] , and have beneficial effects on tissue and organ transplantation [19,20] . In 1993, the ethyl acetate (EA) extract of TwHF was entered into a Phase I study for the treatment of RA patients [21][22][23][24][25] , and many clinical trials have tested triptolide for the treatment of RA and psoriasis [26,27] . In addition, PG490-88/F60008 (F...

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Studies of the Effects of Fk506 on Renal Allografting in the Beagle Dog

Cited by 128 publications

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Three Amino Acid Residues Determine Selective Binding of FK506-binding Protein 12.6 to the Cardiac Ryanodine Receptor

Three Amino Acid Residues Determine Selective Binding of FK506-binding Protein 12.6 to the Cardiac Ryanodine Receptor

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Immunosuppressant discovery from Tripterygium wilfordii Hook f: the novel triptolide analog (5R)-5-hydroxytriptolide (LLDT-8)

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