排序方式: 共有22条查询结果,搜索用时 15 毫秒
1.
Prasanna M. Chandramouleeswaran Dawen Shen Anna J. Lee Alain Benitez Kara Dods Fiona Gambanga Benjamin J. Wilkins Jamie Merves Yuliana Noah Sarit Toltzis Jennifer H. Yearley Jonathan M. Spergel Hiroshi Nakagawa Rene deWaal Malefyt Amanda B. Muir Mei-Lun Wang 《PloS one》2016,11(3)
Eosinophilic esophagitis (EoE) is a chronic Th2 and food antigen-mediated disease characterized by esophageal eosinophilic infiltration. Thymic stromal lymphopoetin (TSLP), an epithelial derived cytokine which bridges innate and Th2-type adaptive immune responses in other allergic conditions, is overexpressed in esophageal biopsies of EoE subjects. However, the triggers of TSLP expression in the esophageal epithelium are unknown. The objective of the current study was to characterize TSLP expression in human esophageal epithelium in EoE in vivo and to determine the role of food antigens upon epithelial TSLP expression in vitro. Using immunohistochemistry (IHC), we localized TSLP in esophageal biopsies of active EoE (≥15 eos/hpf), inactive EoE (<15 eos/hpf) and non-EoE control subjects, and found that TSLP expression was restricted to the differentiated suprabasal layer of the epithelium in actively inflamed EoE biopsies. Consistent with these results in vivo, inducible TSLP protein secretion was higher in CaCl2 differentiated telomerase-immortalized esophageal epithelial cells (EPC2-hTERT) compared to undifferentiated cells of the basal phenotype, following stimulation with the TLR3 ligand poly(I:C). To determine whether food antigens could directly induce epithelial TSLP secretion, differentiated and undifferentiated primary esophageal epithelial cells from EoE and non-EoE subjects were challenged with food antigens clinically relevant to EoE: Chicken egg ovalbumin (OVA), wheat, and milk proteins beta-lactoglobulin (blg) and beta-casein. Food antigens failed to induce TSLP secretion by undifferentiated cells; in contrast, only OVA induced TSLP secretion in differentiated epithelial cells from both EoE and control cell lines, an effect abolished by budesonide and NF-κb inhibition. Together, our study shows that specific food antigens can trigger innate immune mediated esophageal TSLP secretion, suggesting that esophageal epithelial cells at the barrier surface may play a significant role in the pathogenesis of EoE by regulating TSLP expression. 相似文献
2.
Chen P Norris D Das J Spergel SH Wityak J Leith L Zhao R Chen BC Pitt S Pang S Shen DR Zhang R De Fex HF Doweyko AM McIntyre KW Shuster DJ Behnia K Schieven GL Barrish JC 《Bioorganic & medicinal chemistry letters》2004,14(24):6061-6066
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy. 相似文献
3.
James Kempson Junqing Guo Jagabandhu Das Robert V. Moquin Steven H. Spergel Scott H. Watterson Charles M. Langevine Alaric J. Dyckman Mark Pattoli James R. Burke XiaoXia Yang Kathleen M. Gillooly Kim W. McIntyre Laishun Chen John H. Dodd Murray McKinnon Joel C. Barrish William J. Pitts 《Bioorganic & medicinal chemistry letters》2009,19(10):2646-2649
A new series of tricyclic-based inhibitors of IKK have been derived from an earlier lead compound. The synthesis and structure–activity relationships (SAR) are described. Compound 4k inhibited TNF production in rats stimulated with LPS. 相似文献
4.
Das J Lin J Moquin RV Shen Z Spergel SH Wityak J Doweyko AM DeFex HF Fang Q Pang S Pitt S Shen DR Schieven GL Barrish JC 《Bioorganic & medicinal chemistry letters》2003,13(13):2145-2149
A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in the T-cell proliferation assay. BMS-243117 (compound 2) is identified as a potent, and selective Lck inhibitor with good cellular activity (IC(50)=1.1 microM) against T-cell proliferation. 相似文献
5.
In vitro perfused-superfused cat carotid body for physiological and pharmacological studies 总被引:2,自引:0,他引:2
R Iturriaga W L Rumsey A Mokashi D Spergel D F Wilson S Lahiri 《Journal of applied physiology》1991,70(3):1393-1400
An in vitro perfused carotid body preparation was developed to study its chemosensory responses to physiological and pharmacological stimuli. The carotid bifurcation with the carotid body was vascularly isolated and excised from pentobarbital sodium-anesthetized cats. The CB was perfused in a chamber by gravity (80 Torr) with modified Tyrode's solution (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-NaOH at pH 7.40) equilibrated at a given Po2 and superfused with the same medium at (Po2 of 20 Torr). The temperature was maintained at 35.5 +/- 0.5 degrees C. The frequency of chemosensory discharges (CD) was recorded from the whole carotid sinus nerve (n = 24), and the responses were tested by repeated interruptions of perfusate flow (SF), perfusion with hypoxic medium, and injections of nicotine and cyanide (0.1 nmol to 1 mumol) and hypercapnic medium. During hyperoxic perfusion, SF resulted in a sigmoidal increase in CD, reaching a maximum that was 23.6 +/- 4.4-fold greater than the basal activity. Restoration of flow returned CD promptly to basal values. After normoxic perfusion, SF led to a similar maximal activity more rapidly, but the duration was shorter. Reduction of the perfusate PO2 (Po2 from 450 Torr to 150, 30, and less than 10 Torr) caused a nonlinear increase in CD. CO2 stimuli (PCo2 38-110 Torr) resulted in a linear increase in CD. Nicotine or cyanide increased CD in a dose-dependent manner. The preparation retained its initial responsiveness for 2-3 h, making extensive experimental studies feasible.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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7.
Dyckman AJ Langevine CM Quesnelle C Kempson J Guo J Gill P Spergel SH Watterson SH Li T Nirschl DS Gillooly KM Pattoli MA McIntyre KW Chen L McKinnon M Dodd JH Barrish JC Burke JR Pitts WJ 《Bioorganic & medicinal chemistry letters》2011,21(1):383-386
The synthesis, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis. 相似文献
8.
James Kempson Damaso Ovalle Junqing Guo Stephen T. Wrobleski Shuqun Lin Steven H. Spergel James J.-W. Duan Bin Jiang Zhonghui Lu Jagabandhu Das Bingwei V. Yang John Hynes Hong Wu John Tokarski John S. Sack Javed Khan Gary Schieven Yuval Blatt William J. Pitts 《Bioorganic & medicinal chemistry letters》2017,27(20):4622-4625
A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads. 相似文献
9.
Murugesan N Gu Z Stein PD Spergel S Bisaha S Liu EC Zhang R Webb ML Moreland S Barrish JC 《Bioorganic & medicinal chemistry letters》2002,12(4):517-520
A number of 4'-heterocyclic biphenylsulfonamide derivatives, formally derived from BMS-193884 (1) by replacing the oxazole ring with other heterocyclic rings, are potent and selective endothelin A (ET(A)) receptor antagonists. Among the analogues examined, the pyrimidine derivative 18 is the most potent (K(i)=0.9 nM) and selective for the ET(A) receptor, approximately equivalent to 1. 相似文献
10.
Chen P Iwanowicz EJ Norris D Gu HH Lin J Moquin RV Das J Wityak J Spergel SH de Fex H Pang S Pitt S Shen DR Schieven GL Barrish JC 《Bioorganic & medicinal chemistry letters》2002,12(21):3153-3156
A series of anilino(imidazoquinoxaline) analogues bearing solubilizing side chains at the 6- and 7-positions of the fused phenyl ring has been prepared and evaluated for inhibition against Lck enzyme and of T-cell proliferation. Significant improvement of the cellular activity was achieved over the initial lead, compound 2. 相似文献