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91.
In this study, the effects of the FK506-mPEG on immune cell activity, skin grafting rejection, and Freund’s complete adjuvant
arthritis were investigated. The proliferation of T cells was inhibited with increase with the FK506 and FK506-mPEG concentrations.
FK506 and FK506-mPEG at concentrations between 0.01 nM and 1000 nM had very similar effects on the proliferation of the T
cells. On the other hand, in the case of the proliferation of T cells by calcium ionophore A23187 (1 μM), when the FK506-mPEG
concentration was increased from 0.01 to 1000 mM, the proliferation was decreased from 90.8 to 40.3%. This was 1.8-fold higher
than that of paramethoxyamphetamine (PMA). The inhibitory effect of FK506-mPEG on mast cell proliferation was higher than
that of FK506. When B cells were cultured for 7 days in basal medium with no pokeweed mitogen (PWM), the IgG production was
156.2 ng/mL. On the other hand, in the case of the same treatment with 0.25% of PWM, it was 876.4 ng/mL. This is about 5.6-fold
higher than with no PWM. These results show that FK506-mPEG may be practically applicable as a prodrug for the immunosuppressant
FK506. 相似文献
92.
The role protein phosphatase 2B (calcineurin, CaN) plays in learning and memory has received a significant amount of attention due to its promotion of the dephosphorylation of 3′-5′-cyclic AMP response element binding protein (CREB). Researchers have ascertained that overexpression of CaN is associated with memory retention deficits [Foster TC, Sharrow KM, Masse JR, Norris CM, Kumar A (2001) Calcineurin links Ca2+ dysregulation with brain aging. J Neurosci 21:4066–4073; Mansuy IM, Mayford M, Jacob B, Kandel ER, Bach ME (1998) Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory. Cell 92:39–49], while CaN inhibition enhances learning and memory [Gerdjikov TV, Beninger RJ (2005) Differential effects of calcineurin inhibition and protein kinase A activation on nucleus accumbens amphetamine-produced conditioned place preference in rats. Eur J Neurosci 22:697–705; Ikegami S, Inokuchi K (2000) Antisense DNA against calcineurin facilitates memory in contextual fear conditioning by lowering the threshold for hippocampal long-term potentiation induction. Neuroscience 98:637–646]. The present study hypothesized that infusion of a CaN inhibitor (FK506) bilaterally into the olfactory bulbs of postnatal day 6 Sprague Dawley rat pups would prolong the duration of a conditioned odor preference and retard cyclic AMP response element binding protein dephosphorylation. A 2 mg/kg s.c. injection of isoproterenol (ISO, β-adrenoceptor agonist) was paired with a 10 min exposure to peppermint and subsequently an infusion of FK506. Immunohistochemistry for phosphorylated 3′-5′-cyclic AMP response element binding protein (pCREB) revealed that unilateral infusion of FK506 resulted in an amplification of phosphorylated CREB in the olfactory bulb 40 min after training compared with saline-infused bulbs. Pups infused bilaterally with FK506 maintained a learned preference for peppermint 48, 72 and 96 h after training. CaN inhibition also modified the conventional inverted U curve obtained when ISO is used to replace stroking, as the unconditioned stimulus. When pups were infused with FK506, learning occurred with sub- and supra-optimal doses of ISO indicating that CaN overcomes non-optimal effects ISO may have on learning. We demonstrate that CaN inhibition can extend the duration of conditioned olfactory memory and may provide a target for memory prolongation that is superior to even phosphodiesterase inhibition observed in previous studies. 相似文献
93.
94.
Background and purpose:
The sarcoplasmic reticulum (SR), regulates the cytoplasmic Ca2+ concentration ([Ca2+]cyto) in vascular smooth muscle. Release from the SR is controlled by two intracellular receptor/channel complexes, the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP3R). These receptors may be regulated by the accessory FK506-binding protein (FKBP) either directly, by binding to the channel, or indirectly via FKBP modulation of two targets, the phosphatase, calcineurin or the kinase, mammalian target of rapamycin (mTOR).Experimental approach:
Single portal vein myocytes were voltage-clamped in whole cell configuration and [Ca2+]cyto measured using fluo-3. IP3Rs were activated by photolysis of caged IP3 and RyRs activated by hydrostatic application of caffeine.Key results:
FK506 which displaces FKBP from each receptor (to inhibit calcineurin) increased the [Ca2+]cyto rise evoked by activation of either RyR or IP3R. Rapamycin which displaces FKBP (to inhibit mTOR) also increased the amplitude of the caffeine-evoked, but reduced the IP3-evoked [Ca2+]cyto rise. None of the phosphatase inhibitors, cypermethrin, okadaic acid or calcineurin inhibitory peptide, altered either caffeine- or IP3-evoked [Ca2+]cyto release; calcineurin did not contribute to FK506-mediated potentiation of RyR- or IP3R-mediated Ca2+ release. The mTOR inhibitor , like rapamycin, decreased IP3-evoked Ca2+ release. LY294002Conclusions and implications:
Ca2+ release in portal vein myocytes, via RyR, was modulated directly by FKBP binding to the channel; neither calcineurin nor mTOR contributed to this regulation. However, IP3R-mediated Ca2+ release, while also modulated directly by FKBP may be additionally regulated by mTOR. Rapamycin inhibition of IP3-mediated Ca2+ release may be explained by mTOR inhibition. 相似文献95.
Hans M. Ockenfels Gregor Nußbaum Thomas Schultewolter Peter M. Burger Manfred Goos 《Archives of dermatological research》1995,287(3-4):304-309
Protein tyrosine kinases (PTKs) are closely related to cell growth, proliferation and differentiation. In keratinocytes, various growth factor receptors and cytosolic proteins, including the EGF and IGF receptors, the proteins of the src family and others, exhibit PTK activity. In psoriatic epidermis an increased level of EGF receptors and their ligand TGF-alpha has been found, and this is thought to be one reason for the pathological hyperproliferation of keratinocytes in this disease. Oral treatment with cyclosporin A (CsA) and FK506 or topical treatment with dithranol lead to an improvement in psoriasis. In the present study we examined the effect of these three drugs on the cellular content of phosphorylated tyrosines in highly proliferative HaCaT keratinocytes. HaCaT keratinocytes can be used as a model for highly proliferative epidermis, e.g. psoriatic epidermis. CsA had no effect whereas FK506 and dithranol reduced the phosphorylation of tyrosine residues in HaCaT keratinocytes. The activation of serine/threonine protein kinase C (PKC) is known to downregulate PTKs. Therefore we incubated keratinocytes with the selective PKC inhibitor Ro 31-8220 in addition to the other drugs. Only after the addition of Ro 31-8220 to FK506-treated keratinocytes was the phosphotyrosine (p-tyr) level elevated, but this was only one-third of the increase measured without additional therapeutic drugs. We assume that an induction of PKC alone is not responsible for the reduced p-tyr level after treatment with dithranol and FK506. FK506 and CsA affect the p-tyr signal transduction pathways of HaCaT keratinocytes in different ways, indicating distinct mechanisms of action of these drugs on keratinocytes. 相似文献
96.
France Massicot Chantal Martin Hélène Dutertre-Catella Sophie Ellouk-Achard Chuong Pham-Huy Marc Thevenin Pierre Rucay Jean-Michel Warnet Jean-Roger Claude 《Archives of toxicology》1997,71(8):529-531
FK506 and cyclosporin A (CsA) are two potent immunosupressants with similar toxicity profile. Nephrotoxicity is the main
adverse effect of both compounds. The aim of this study is to compare the in vitro nephrotoxic effects on renal epithelial
cell line LLC-PK1 by measuring cell viability and energy status as evaluated by concentrations of ATP and ATP metabolites.
Cell viability (expressed as IC50 was assessed via thiazolyl blue (MTT) assay after incubation for 4–24 h with FK506 or CsA. ATP and its metabolites were determined
by HPLC after 4 and 6 h incubation with FK506 or CsA alone at the respective IC50. Both FK506 and CsA decreased cell viability to similar extents, in a dose- and time-dependent manner. After 4 h incubation,
both drugs decreased ATP levels (−25%) and increased uric acid levels. However, the latter percentage increase was twofold
higher with CsA (18%) than with FK506 (9%). The energy charge, calculated according to levels of adenine nucleotides, was
decreased by 10% in FK506-treated cells and by 27% in CsA-treated cells. At the end of 6-h incubation, FK506-treated cells
maintained ATP levels coupled with energy charge at near control levels whereas the levels were 32% lower in CsA treated cells.
Compared to the 4 h-incubation, the increase in uric acid was similar for FK506 but was doubled with CsA. The decrease in
cell integrity and ATP depletion induced by CsA in LLC-PK1 cells was only transiently observed with FK506. By preserving energy
status, FK506 leads to fewer metabolic disturbances than CsA in the renal epithelial cell line LLC-PK1, demonstrating a minor
potential nephrotoxicity.
Received: 8 January 1997 / Accepted: 6 March 1997 相似文献
97.
98.
Shinji Uemoto Koichi Tanaka Yukihiko Tokunaga Takashi Nishizawa Hisashi Sawada Hironori Katoh Eisi Yamamoto Yoshio Yamaoka Kame Ozawa 《Transplant international》1994,7(S1):81-84
Abstract FK 506 (Tacrolimus) was used with steroids to treat 61 pediatric patients who received living related partial liver transplantation. Fifty-two recipients survived and 9 died between 6 months and 3 years after transplantation. In the surviving patients, oral doses of Tacrolimus were tapered from 0.298 ± 0.277 mg/kg daily at 1 month after transplantation to 0.078 ± 0.054 at 24 months after transplantation. The 12 h trough levels of Tacrolimus were 12.6 ± 7.1 ng/ml and 4.1 ± 2.4 at 1 and 24 months after transplantation, respectively. The percentage of recipients free from steroids was 77%, 97%, and 94% at 6, 12, and 24 months after transplantation, respectively. Liver allograft rejection was encountered in seven recipients, five of whom were treated by steroid pulse therapy and a dose increase of Tacrolimus; the remaining two required OKT3. However, there was no episode of rejection that required retransplantation. Infectious complications encountered in 34 patients included 12 bacterial, 3 fungal, and 19 viral infections. Two recipients died one of fungal pneumonia and one of Epstein-Barr virus-associated lymphoproliferative disorder. Regarding adverse reactions of Tacrolimus, hypertension was observed in 28 patients, diabetes mellitus in 3, pancreatitis in 3, convulsion in 1, tremor in 12, itching in 5, and pigmentation in the oral mucosa in 2. Slightly increased values of creatinine were observed in most of the patients; however, an abnormal increase of serum of serum creatinine (> 1.0 mg/dl) was confined to the complicated cases. Improvement of somatic growth was observed in 21 patients (62%) and 13 (75%) at 12 and 24 months after transplantation, respectively. The long-term use of Tacrolimus is highly effective in terms of its immunosuppressive potential and reduced adverse reaction. Steady growth development can be expected in pediatric recipients free from steroids. 相似文献
99.
羊膜移植重建眼表治疗陈旧性化学伤的临床研究 总被引:6,自引:0,他引:6
目的 :探讨羊膜移植术重建眼表治疗陈旧性化学伤的临床价值。方法 :对 2 8例 (2 8只眼 )有严重睑球粘连及假性胬内的陈旧性化学伤患者应用羊膜移植手术重建眼表 ,术后局部应用FK -5 0 6、CsA及rhEGF等药物 ,观察其临床效果。结果 :在随访期内 (平均 11± 4个月 ) ,所有术眼睑球粘连均得到明显改善。 60 9%的患眼恢复正常的眼球运动 ;假性胬肉复发率较低 ;角膜新生血管及角膜透明度较术后明显好转。结论 :对于陈旧性化学伤造成的睑球粘连及假性胬肉 ,羊膜移植重建眼表是目前较理想的治疗手段。 相似文献
100.
D. Candinas O. Achilleos S. J. Lee A. Dalgic C. Miki A. D. Mayer P. McMaster 《Transplant international》1994,7(S1):378-380
Abstract We assessed the immunomodulatory effect of leflunomide (LEF) in a heterotopic abdominal model of rat heart transplantation using a major histocom-patibility mismatch (DA X LEW). The endpoint of this study was cardiac rejection assessed by abdominal palpation of the ventricular impulse and confirmed by laparotomy and histology. In this study, LF was investigated using four dosages (5, 10, 20 and 30 mg/kg per day orally) against cyclosporine (CsA) (15 mg/kg per day orally) and FK506 (1 mg/kg per day orally). The ability of LEF to prevent rejection and reverse ongoing acute rejection was assessed. The results showed that untreated hearts were fully rejected by day 5 and that LEF at 5 mg/kg was significantly better than any other dose tested, was superior to FK 1 mg/kg, and was as effective as CsA 15 mg/kg in preventing rejection after a short course of treatment. After a longer course, 10 and 20 mg/kg LEF proved more effective than 5 mg/kg in controlling rejection and as efficacious as 1 mg/kg FK and 15 mg/kg CsA. In the control of ongoing established early rejection. LEF proved to be equally effective, even at lower doses (5 mg/kg), to CsA 15 mg/kg and FK 1 mg/kg. In the control of ongoing established late rejection, 20 mg/kg LEF proved to be superior to 10 mg/kg LEF and 15 mg/kg CsA, and was as effective as FK 1 mg/kg. However, when higher doses of CsA (25 mg/kg) and FK (2 mg/kg) were tested against 20 mg/kg LEF in this mode of rescue, LEF proved as effective as CsA and superior to FK. In the assessment of drug toxicity using body weight as a parameter, 20 mg/kg LEF proved safer than any other LEF dose tested, and safer than 15 mg/kg CsA and 1 mg/kg FK in both short- and long term administration. We conclude that LEF is a relatively safe and potent immunosuppressant with promising clinical potential. 相似文献