排序方式: 共有24条查询结果,搜索用时 15 毫秒
1.
Genetic relationships among actinomycetes that produce the immunosuppressant macrolides FK506, FK520/FK523 and rapamycin 总被引:1,自引:0,他引:1
George M. Garrity Brain K. Heimbuch Haideh Motamedi Ali Shafiee 《Journal of industrial microbiology & biotechnology》1993,12(1):42-47
Summary A polyphasic taxonomic study was undertaken to establish the genetic and phenotypic relationships among six actinomycetes that produce the immunosuppressant macrolides FK506, FK520/FK523 and rapamycin. Chemotaxonomic studies reveal that all have Type I cell walls. Gas chromatography (GC) of fatty acid methyl esters revealed patterns consistent for strains ofStreptomyces with 160 and 150anteiso predominating. Principal component analysis of GC data revealed distinct profiles for each culture. Reciprocal DNA homology studies atT
m
-25 showed the rapamycin-producing strain and one FK506-producing strain to have 38–50% homology with the type strain ofStreptomyces hygroscopicus (ATCC 27438). The remaining strains exhibited 6–17% homology. To further explore the relationships among these strains all were probed for the presence of anO-methyltransferase gene specific to this biosynthetic pathway. Among the strains of interest, onlyStreptomyces hygroscopicus subsp.yakushimaensis, the patent strain for FK520/FK523, failed to hybridize with the probes. 相似文献
2.
Immunosuppressants inhibit hormone-stimulated Mg2+ uptake in mouse distal convoluted tubule cells 总被引:3,自引:0,他引:3
Kim SJ Kang HS Jeong CW Park SY Kim IS Kim NS Kim SZ Kwak YG Kim JS Quamme GA 《Biochemical and biophysical research communications》2006,341(3):742-748
Immunosuppressants such as cyclosporinA and FK506 (tacrolimus) are widely prescribed to treat numerous disorders and to treat organ transplant recipients. However, cyclosporine A and FK506 are both known to produce hypomagnesaemia. The mechanism of this effect is still unclear. The present study determined the effects of immunosuppressant treatment on the parathyroid hormone (PTH) mediated Mg(2+) uptake and the mitogen-activated protein kinase (MAPK) activation in mouse distal convoluted tubule (MDCT) cells. The intracellular Ca(2+) and Mg(2+) concentrations in a single MDCT cell were measured by using the fluorescentdye Fura-2 AM and Mag-fura-2 AM, respectively. Cyclosporine A and FK506 illicited a transient increase of intracellular Ca(2+) from a basal level of 99 +/- 16 nM to 685 +/- 105 and 608 +/- 96 nM, respectively. In order to determine the Mg(2+) transport, the MDCT cells were Mg(2+)-depleted by culturing them in Mg(2+)-free media for 16 h, and the Mg(2+) uptake was measured by microfluorescence after placing the depleted cells in 1.5mM MgCl(2). The mean rate of Mg(2+) uptake, d([Mg(2+)](i))/dt, was 140 +/- 16 nM/s in the control MDCT cells. PTH increased the Mg(2+) uptake more than 2 times in this cell. Cyclosporine A (10 microM) and FK506 (0.1 microM) did not affect the basal Mg(2+)uptake (140 +/- 16 and 142 +/- 14 nM/s, respectively), but they inhibited the PTH-stimulated Mg(2+) entry, decreasing it from 248+/-12 to 147 +/- 7 and 148 +/- 14 nM/s, respectively. These effects were inhibited by L685818, which is a potent competitive antagonist of FK506. PTH stimulated the extracellular signal-regulated kinase1/2 (ERK1/2) protein synthesis. This PTH-stimulated ERK1/2 activation was inhibited by cyclosporine A and FK506. In the present study, the role of ERK1/2 activation on the PTH-dependent magnesium uptake was examined in MDCT cells, and we showed that immunosuppressants inhibit the hormone-stimulated Mg(2+) uptake into the MDCT cells by inhibiting the MAPK pathway. 相似文献
3.
Shigeki Kunikawa Akira Tanaka Yuji Takasuna Mamoru Tasaki Noboru Chida 《Bioorganic & medicinal chemistry》2018,26(20):5499-5509
Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and is an attractive target for the treatment of T cell-mediated diseases such as transplant rejection and autoimmune disease. To identify PKCθ inhibitors, we focused on the 2,6-diamino-3-carbamoyl-5-cyanopyrazine derivative 2, which exhibited moderate PKCθ inhibitory activity. Optimization of 2 identified the 2,4-diamino-5-cyanopyrimidine derivative 16c, which exhibited potent PKCθ inhibitory activity and showed good selectivity against other PKC isozymes. Compound 16c prolonged graft survival in an in vivo rat heterotopic cardiac transplant model. 相似文献
4.
Sugawara A Torigoe T Tamura Y Kamiguchi K Nemoto K Oguro H Sato N 《Cell stress & chaperones》2009,14(2):133-139
Polyamine compound deoxyspergualin (DSG) is a potent immunosuppressive agent that has been applied clinically for protecting
graft rejection and treatment of Wegener's granulomatosis. Though DSG can bind to heat-shock proteins (HSPs) in cells, its
mechanism of immunosuppressive action remains unknown. It is widely accepted that extracellular HSPs are capable of stimulating
dendritic cells (DC) through cell surface receptors, leading to DC activation and cytokine release. In this study, we examined
if DSG analogs could inhibit HSP70-induced DC activation. Bone marrow derived immature mouse DCs and peripheral blood mononuclear
cell-derived immature human DCs were generated and incubated with Alexa 488-labeled Hsp70 in the presence of methoxyDSG (Gus-1)
that had comparable HSP70-binding affinity to DSG or DSG analog GUS-7, which had much more reduced binding affinity for HSP70.
The binding of HSP70 to immature DCs was analyzed by laser microscopy and flow cytometry. HSP70-induced DC activation was
assessed by TNF-α release by enzyme-linked immunosorbent assay. Binding of Hsp70 to the cell surface of immature DCs was inhibited
under the presence of Gus-1, but not under the presence of Gus-7. Immature DCs were activated and released TNF-α by the stimulation
with HSP70 for 12 hours; however, the HSP70-induced TNF-α release was suppressed under the presence of Gus-1, and partially
suppressed under the presence of Gus-7. Similar results were observed when immature human DCs were stimulated under the same
conditions. Immunosuppressive mechanism of DSG may be explained, at least in part, by the inhibition of extracellular HSP70-DC
interaction and HSP70-induced activation of immature DCs.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
5.
6.
Inflammatory bowel disease (IBD), as a representative inflammatory disease, currently has multiple effective treatment options available and new therapeutic strategies are being actively explored to further increase the treatment options for patients with IBD. Furthermore, biologic agents and small molecule drugs developed for ulcerative colitis (UC) and Crohn's disease (CD) have evolved toward fewer side effects and more accurate targeting. Novel inhibitors that target cytokines (such as IL-12/23 inhibitors, PDE4 inhibitors), integrins (such as integrin inhibitors), cytokine signaling pathways (such as JAK inhibitors, SMAD7 blocker) and cell signaling receptors (such as S1P receptor modulator) have become the preferred treatment choice for many IBD patients. Conventional therapies such as 5-aminosalicylic acid, corticosteroids, immunomodulators and anti-tumor necrosis factor agents continue to demonstrate therapeutic efficacy, particularly in combination with drug therapy. This review integrates research from chemical, biological and adjuvant therapies to evaluate current and future IBD therapies, highlighting the mechanism of action of each therapy and emphasizing the potential of development prospects. 相似文献
7.
Gonzalo Carrau Carine C. Drewes Ana Lúcia B. Shimada Ana Bertucci Sandra H.P. Farsky Helio A. Stefani David Gonzalez 《Bioorganic & medicinal chemistry》2013,21(14):4225-4232
A small library of compounds was prepared by a combination of toluene dioxygenase (TDO)-catalyzed enzymatic dihydroxylation and copper(I)-catalyzed Hüisgen cycloaddition. Some compounds were obtained by coupling an alkyne and a conduritol derivative, while more complex structures were obtained by a double Hüisgen reaction of a dialkyne and two molecules of the cyclitol. The compounds were fully characterized and subjected to preliminary biological screening. 相似文献
8.
疫苗是目前公认的预防传染病的有效手段,接种疫苗可极大降低人群传染病的发病率和病死率。随着现代医学的进展,接受免疫抑制剂治疗肿瘤、器官移植、造血干细胞移植及慢性病的患儿生存率有了很大提高,但免疫抑制剂的使用会影响疫苗诱导的免疫保护效果及儿童时期疫苗接种的安全性,使这部分免疫低下的特殊儿童成为疫苗可预防疾病的高危易感人群。本文综述了免疫抑制剂对儿童疫苗免疫保护性的影响及其相关机制。 相似文献
9.
Julie A. Spicer Christian K. Miller Patrick D. OConnor Jiney Jose Kristiina M. Huttunen Jagdish K. Jaiswal William A. Denny Hedieh Akhlaghi Kylie A. Browne Joseph A. Trapani 《Bioorganic & medicinal chemistry letters》2017,27(4):1050-1054
The pore-forming protein perforin is a key component of mammalian cell-mediated immunity and essential to the pathway that allows elimination of virus-infected and transformed cells. Perforin activity has also been implicated in certain auto-immune conditions and therapy-induced conditions such as allograft rejection and graft versus host disease. An inhibitor of perforin activity could be used as a highly specific immunosuppressive treatment for these conditions, with reduced side-effects compared to currently accepted therapies. Previously identified first-in-class inhibitors based on a 2-thioxoimidazolidin-4-one core show suboptimal physicochemical properties and toxicity toward the natural killer (NK) cells that secrete perforin in vivo. The current benzenesulphonamide-based series delivers a non-toxic bioisosteric replacement possessing improved solubility. 相似文献
10.
目的:比较激素联合不同免疫抑制剂治疗高危因素特发性膜性肾病临床疗效,以探讨合理的治疗方案。方法:随机将2001年5月至2011年5月在我院确诊的46例高危因素的特发性膜性肾病患者分为3组,分别给予甲基泼尼松龙与环磷酰胺、环孢素A或霉酚酸酯中的一种联合使用,总疗程12个月,比较各组治疗方案的临床疗效。结果:(1)治疗前3组患者血压、血肌酐和24 h尿蛋白定量比较无显著性(P〉0.05)。(2)甲基泼尼松龙+环磷酰胺、甲基泼尼松龙+环孢素A和甲基泼尼松龙+霉酚酸酯总缓解率分别为53.3%、80.0%和43.8%,甲基泼尼松龙+环孢素A与其余两组比较总缓解率较高,且有显著性(P〈0.05);甲基泼尼松龙+环磷酰胺和甲基泼尼松龙+霉酚酸酯两组之间总缓解率无明显差异(P〉0.05)。结论:激素联合免疫抑制剂治疗高危因素的特发性膜性肾病,可明显地提高患者的蛋白尿缓解率,其中甲基泼尼松龙+环孢素A总缓解率较高,且优于其他免疫抑制剂,但其复发率较高,肾脏药物不良反应大,临床选用时需谨慎。 相似文献