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排序方式: 共有5047条查询结果,搜索用时 15 毫秒
991.
Jiansong Fang Ping Wu Ranyao Yang Li Gao Chao Li Dongmei Wang Song Wu Ai-Lin Liu Guan-Hua Du 《药学学报(英文版)》2014,4(6):430-437
In this study two genistein derivatives (G1 and G2) are reported as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and differences in the inhibition of AChE are described. Although they differ in structure by a single methyl group, the inhibitory effect of G1 (IC50=264 nmol/L) on AChE was 80 times stronger than that of G2 (IC50=21,210 nmol/L). Enzyme-kinetic analysis, molecular docking and molecular dynamics (MD) simulations were conducted to better understand the molecular basis for this difference. The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE. The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area (MM/GBSA) method were consistent with the experimental data. The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions (ΔEele+ΔGGB) was responsible for the binding affinities of these two inhibitors. Additionally, analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124, Glu292, Val294 and Phe338 of AChE. In conclusion, the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds.KEY WORDS: Genistein derivatives, Acetylcholinesterase (AChE), Kinetics analysis, Molecular docking, Molecular dynamics simulation, MM/GBSAAbbreviations: ACh, acetylcholine; AChEIs, acetylcholinesterase inhibitors; AChE, acetylcholinesterase; AD, Alzheimer׳s disease; BuChE, butyrylcholinesterase; BuSCh, S-butyrylthiocholine chloride; CAS, catalytic active site; DTNB, 5,5′-dithiobis-(2-nitrobenzoic acid); GAFF, generalized AMBER force field; G1, 3-(4-methoxyphenyl)-7-(2-(piperidin-1-yl)ethoxy)-4H-chromen-4-one; G2, (S)-3-(4-methoxyphenyl)-7-(2-(2-methylpiperidin-1-yl)ethoxy)-4H-chromen-4-one; iso-OMPA, tetraisopropyl pyrophosphoramide; MD, molecular dynamics; MM/GBSA, molecular mechanics/generalized born surface area; PAS, peripheral anionic site; PDB, protein data bank; PME, particle mesh Ewald; RMSD, root-mean-square deviation; S-ACh, acetylthiocholine iodide; ΔEele, electrostatic energy contribution; ΔEMM, gas-phase interaction energy between receptor and ligand; ΔEvdw, van der Waals energy contribution; SASA, solvent accessible surface area; ΔGexp, experimental binding free energy; ΔGGB, polar desolvation energy term; ΔGpred, total binding free energy; ΔGSA, nonpolar desolvation energy term; ΔS, conformational entropy contribution 相似文献
992.
Evidence that genetic deletion of the TNF receptor p60 or p80 inhibits Fas mediated apoptosis in macrophages 总被引:3,自引:0,他引:3
Almost 19 members of the tumor necrosis factor (TNF) superfamily have been identified that interact with 29 different receptors. Whether these receptors communicate with each other is not understood. Recently, we have shown that receptor activator of NF-kappaB ligand signaling is modulated by genetic deletion of the TNF receptor. In the current report, we investigated the possibility of a cross-talk between Fas and TNF-alpha signaling pathway in macrophage cell lines derived from wild-type (WT) mice and from mice with genetic deletion of the type 1 TNF receptor (p60(-/-)), the type 2 TNF receptor (p80(-/-)), or both receptors (p60(-/-)p80(-/-)). We found that the macrophages expressing TNF receptors were highly sensitive to apoptosis induced by anti-Fas. The genetic deletion of TNF receptors, however, made the cells resistance to anti-Fas-induced apoptosis. Anti-Fas induced activation of caspase-3 and PARP cleavage in WT cells but not in TNF receptor-deleted cells. This difference was found to be independent of the expression of Fas, Fas-associated protein with death domain (FADD) or TNF receptor-associated death domain (TRADD). We found that anti-Fas induced recruitment of TNFR1 into Fas-complex. We also found that TRADD, which mediates TNF signaling, was constitutively bound to Fas receptor in TNF receptor-deleted cells but not in wild-type cells. Transient transfection of TNFR1 in TNFR1-deleted cells sensitized them to anti-Fas-induced apoptosis. Overall our results demonstrate that Fas signaling is modulated by the TNF receptors and thus provide the evidence of cross-talk between the receptors of two cytokines. 相似文献
993.
994.
Sato H Kato Y Hayasi E Tabata T Suzuki M Takahara Y Sugiyama Y 《Pharmaceutical research》2002,19(11):1736-1744
Purpose. To demonstrate the utilities of a synthetic low-affinity ligand ((Gal)3) for the asialoglycoprotein receptor (ASGP-R) as a hepatic targeting device for therapeutic cytokines.
Methods. The site-specific incorporation of (Gal)3 or a typical high-affinity ligand (GalNAc)3 into IL-2 was catalyzed by microbial transglutaminase. The anti-tumor activities, pharmacokinetic profiles and receptor-mediated endocytosis in hepatocytes of the ligand-IL-2 conjugates were examined in mouse.
Results. The (Gal)3 has approximately 50 times lower affinity to ASGP-R than (GalNAc)3. Nevertheless, the antitumor effects were in the order of (Gal)3—IL-2 > unmodified IL-2 > (GalNAc)3—IL-2. The systemic elimination and the hepatic uptake of (GalNAc)3—IL-2 were more rapid than (Gal)3—IL-2. The ratio of the rate constant representing dissociation from the cell-surface receptor (koff) to that representing endocytosis of the ligand (kint) was greater for (Gal)3—IL-2 than (GalNAc)3—IL-2, suggesting that (Gal)3—IL-2 preferably avoids internalization due to its lower affinity to the receptor. The simulation studies demonstrated that (Gal)3—IL-2 was present in the hepatic extracellular space for a longer period than (GalNAc)3 IL-2.
Conclusions. The (Gal)3 ligand increases the therapeutic efficacy of IL-2 by enhancing its exposure to the cell-surface. The koff/kint affects the targeting efficacy of the conjugates to ASGP-R. 相似文献
995.
Shuting Qiu Jiajia Chen Yan Bai Jincan He Hua Cao Qishi Che Jiao Guo Zhengquan Su 《Nutrients》2022,14(13)
The treatment of nonalcoholic fatty liver disease (NAFLD) remains very challenging. This study investigated the therapeutic effect of galactose oligosaccharide (GOS), an important prebiotic, on NAFLD through in vivo and in vitro experiments and preliminarily explored the mechanism by which GOS improves liver lipid metabolism and inflammation through liver and intestinal microbiological analysis. The results of mouse liver lipidomics showed that GOS could promote body thermogenesis in mice with high-fat and high-sugar diet (HFHSD)-induced NAFLD, regulate lipolysis in liver fat cells, and accelerate glycine and cholesterol metabolism. GOS dose-dependently reduced the contents of total cholesterol (TC) and triglyceride (TG) in cells and reduced the accumulation of lipid droplets in cells. GOS also reduced the Firmicutes/Bacteroidetes ratio and altered the composition of the intestinal microbiota in mice fed a HFHSD. GOS can improve liver lipid metabolism and intestinal structure of NAFLD. These results provide a theoretical and experimental basis supporting the use of GOS as a health food with anti-NAFLD functions. 相似文献
996.
目的 探讨急性缺血性脑卒中患者血清OX40配体(OX40L)、闭合蛋白(Occludin)的水平,分析其与患者病情严重程度及预后的关系。方法 选取2016年1月至2020年1月在该院接受治疗的135例急性缺血性脑卒中患者为观察组。另选取同期该院体检健康者100例为对照组。采用酶联免疫吸附试验检测血清OX40L、Occludin水平差异。患者出院后6个月采用改良Rankin量表(mRS)评估预后状况,并分为预后良好组93例(mRS评分≤2分)和预后不良组42例(mRS评分>2分)。采用多因素Logistic回归分析影响急性缺血性脑卒中患者预后不良的危险因素。结果 观察组血清OX40L、Occludin水平与对照组相比,差异有统计学意义(P<0.05)。急性缺血性脑卒中重度组血清OX40L、Occludin水平高于中度组、轻度组,中度组血清OX40L、Occludin水平高于轻度组,差异有统计学意义(P<0.05)。预后不良组血清OX40L、Occludin水平明显高于预后良好组,差异有统计学意义(P<0.05)。多因素Logistic回归分析结果显示,美国国立卫生... 相似文献
997.
目的:观察慢病毒表达载体介导的RNA干扰(RNAi)对人胰腺癌细胞株CFPAC-1增殖诱导配体(a proliferation-inducing ligand,APRIL)表达的影响,为后续的以APRIL基因为靶点的胰腺癌基因治疗研究奠定基础.方法:应用基因工程技术,筛选出3条针对APRIL基因的RNAi靶序列,分别与pGCL-GFP载体连接,构建3个重组慢病毒表达载体LV-APRIL shRNA1、LV-APRIL shRNA2、LV-APRIL shRNA3;将连接产物转化到DH5 α感受态细胞,经PCR筛选阳性克隆、测序鉴定.将LV-APRIL shRNA、pHelper 1.0、pHelper 2.0共转染293T细胞,包装产生慢病毒颗粒并测定病毒滴度.将包装产生的3种重组慢病毒分别感染CFPAC-1细胞,实时定量PCR和Western印迹检测CFPAC-1细胞APRIL mRNA和蛋白的表达,并与未转染及空转染细胞进行比较.结果:3个慢病毒载体PCR和测序结果与预期结果一致,经包装产生的病毒滴度分别为5×107、6×107、4×107 TU/ml.感染CFPAC-1细胞后,APRIL基因mRNA和蛋白的表达量与未感染慢病毒的细胞组及空载体感染组相比均明显下降(P<0.05),其中LV-APRIL shRNA1、LV-APRIL shRNA2作用较明显,使mRNA表达分别下降73%和68%,蛋白表达分别下降66%和59%(P<0.05);而未感染慢病毒的细胞组与空载体组相比无统计学差异.结论:成功构建针对APRIL基因的3个慢病毒载体LV-APRILshRNA,体外感染CFPAC-1细胞后可有效抑制APRIL基因和蛋白的表达. 相似文献
998.
《中国药理学通报》1996,(6)
目的:探讨伴刀豆蛋白A(ConA)对人胃癌细胞肿瘤坏死因子受体(TNFR)的调节机制及肿瘤坏死因子突变体(TNF-m)细胞毒效应与TNFR之间的关系。方法:以125I-TNF-m作为放射配体,用放射配体结合分析法、MTT比色法对ConA作用前后的人胃癌细胞(SGC7901)TNFR的数目,亲和力,以及TNF-m的细胞毒效应进行了检测,结果:ConA可快速增加细胞表面TNF-m的结合位点(0.56×10-11对0.91×10-11nmol·细胞-1,P<0.01)而不影响受体的亲和力(Kd:2.78×10-10对2.63×10-10mol·L-1,P>0.5)。ConA不增加受体蛋白的合成和胞浆受体的数目;ConA作用组TNF-m的内化和降解(分别为1.24×10-6和0.18×10-6nmol)显著低于对照组的内化和降解(分别为0.6×10-6和0.07×10-6nmol);ConA作用组TNF-m对胃癌细胞的最大抑制率(8.4%)显著低于对照组TNF-m的最大抑制率(60%)、P<0.01。结论:伴刀豆蛋白A通过抑制TNFR的内化而增加膜TNFR的数目;TNF-m的生物效应与TNFR介导的信号传递(受体后? 相似文献
999.
1000.
目的研究重组人可溶性肿瘤坏死因子相关凋亡诱导配体 (TRAIL)巴斯德毕赤酵母工程菌发酵工艺。方法首先用摇瓶对工程菌的甲醇诱导周期、甲醇浓度、pH进行研究 ,在此基础上 ,采用 5L发酵罐补料培养进行中试研究。结果人可溶性TRAIL巴斯德毕赤酵母菌在pH 6 .0、甲醇诱导浓度 1%的条件下诱导 96h ,目标蛋白质浓度最高 ,可达 72 .8mg/L。 5L发酵罐培养放大 ,可以达到 184mg/L。结论此发酵工艺可以较好地提高人可溶性TRAIL工程菌的分泌表达。 相似文献