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91.
Dhifaf Sarhan Padraig D’Arcy Andreas Lundqvist 《International journal of molecular sciences》2014,15(10):18557-18573
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand- receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of the death-inducing signaling complex (DISC), caspase activation and ultimately apoptosis. Conversely the decoy receptors TRAIL-R3 and TRAIL-R4, which lack the pro-apoptotic death domain, function to dampen the apoptotic response by competing for TRAIL ligand. The tissue restricted expression of the decoy receptors on normal but not cancer cells provides a therapeutic rational for the development of selective TRAIL-mediated anti-tumor therapies. Recent clinical trials using agonistic antibodies against the apoptosis-inducing TRAIL receptors or recombinant TRAIL have been promising; however the number of patients in complete remission remains stubbornly low. The mechanisms of TRAIL resistance are relatively unexplored but may in part be due to TRAIL-R down-regulation or shedding of TRAIL-R by tumor cells. Therefore a better understanding of the mechanisms underlying TRAIL resistance is required. The ubiquitin-proteasome system (UPS) has been shown to regulate TRAIL-R members suggesting that pharmacological inhibition of the UPS may be a novel strategy to augment TRAIL-based therapies and increase efficacies. We recently identified b-AP15 as an inhibitor of proteasome deubiquitinase (DUB) activity. Interestingly, exposure of tumor cell lines to b-AP15 resulted in increased TRAIL-R2 expression and enhanced sensitivity to TRAIL-mediated apoptosis and cell death in vitro and in vivo. In conclusion, targeting the UPS may represent a novel strategy to increase the cell surface expression of pro-apoptotic TRAIL-R on cancer cells and should be considered in clinical trials targeting TRAIL-receptors in cancer patients. 相似文献
92.
93.
报道一种新型含硫席夫碱的合成,结构表征,并测试了它对某些金属离子的配位性。 相似文献
94.
For development of an optimized red dopant in the organic light emitting devices (OLEDs), new iridium complexes containing 2,3-dpqx derivatives as a ligand were prepared. The ligands were prepared according to Friedlander reaction. The complexes, Ir(2,3-dpqx-F2)2(acac) (2,3-dpqx-F2 = 2,3-bis(4-fluorophenyl)-quinoxaline; acac = acetylacetonate) and Ir(6-Me-2,3-dpqx-F2)2(acac) (6-Me-2,3-dpqx-F2 = 2,3-bis(4-fluorophenyl)-6-methylquinoxaline) were synthesized from the two-step reactions of IrCl3·xH2O with the corresponding ligand and characterized by 1H NMR, mass spectrometry and elemental analysis. Ir(2,3-dpqx-F2)2(acac) and Ir(6-Me-2,3-dpqx-F2)2(acac) exhibited the luminescence peaks at 632 and 630 nm, respectively. Their UV-spectra showed the strong 3MLCT transition due to the strong coupling between the 5d orbital of the iridium center and the highest occupied molecular orbitals (HOMOs) of the ligands. The organic light emitting devices employing these compounds as the dopant were prepared and their electroluminescence was investigated. Both of the complexes exhibited the phosphorescence close to the saturated red emission at the CIE coordinate of x = 0.68, y = 0.31. 相似文献
95.
Intherecentyears ,thestudiesonthede signandsynthesisofthestablelanthanidecomplexeswithtripodalligandshaveattractedmuchattentionbecauseoftheiruniqueproper tiesandtheirpotentialapplicationsinthevari ousresearchfields[1 ,2 ] .It′sworthynotethatthelanthanidecom… 相似文献
96.
目的对重组2型腺相关病毒肿瘤坏死因子相关凋亡诱导配体(recombinant adeno-associated virus 2 encoding tumor necrosis factor-related apoptosis-induced ligand,r AAV2-TRAIL)基因治疗制剂进行质量分析,并针对其关键质量属性建立质控方法。方法采用PCR法对r AAV2-TRAIL基因治疗制剂中插入的启动子CAG和目的基因TRAIL进行鉴别;在腺病毒(Ad5)的辅助下,将r AAV2-TRAIL体外感染293T细胞后,采用ELISA法检测培养上清中目的蛋白TRAIL的表达量,检测r AAV2-TRAIL对神经胶质瘤U251细胞的体外杀伤活性;设计引物及探针,采用Q-PCR法检测r AAV2-TRAIL基因治疗制剂中的r AAV2-TRAIL滴度、可能存在的复制型rc AAV滴度以及残余辅助病毒1型单纯疱疹病毒(herpes simplex virus 1,HSV1)滴度。结果启动子CAG和目的基因TRAIL的PCR鉴定结果与理论及理化对照品相符;r AAV2-TRAIL感染293T细胞48 h后,上清中TRAIL表达量为(0.36±0.18)ng/ml,RSD为50.0%;r AAV2-TRAIL体外作用于神经胶质瘤细胞U251,细胞生长相对抑制率为(26.6±3.75)%,RSD为14.1%;制剂中r AAV2-TRAIL滴度为(4.72×1011±0.52×1011)copies/ml,RSD为11.0%,rc AAV滴度为(2.49×107±0.18×107)copies/ml,RSD为7.2%,HSV1滴度为(6.02×106±0.51×106)copies/ml,RSD为8.5%。r AAV2-TRAIL/rc AAV为1.90×104,r AAV2-TRAIL/HSV1为7.84×104。结论建立的质控方法可用于r AAV2-TRAIL的质量控制,为该产品质量标准的建立奠定了基础,同时对以AAV为载体的基因治疗制剂的质量研究提供参考。 相似文献
97.
The Use of Thermodynamic and Kinetic Data in Drug Discovery: Decisive Insight or Increasing the Puzzlement?
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Prof. Dr. Gerhard Klebe 《ChemMedChem》2015,10(2):229-231
The prime property to rate the success of hit‐to‐lead‐to‐drug optimization in drug discovery is binding affinity. Rational approaches try to relate this property with structure. Affinity can be linked to the thermodynamic property, Gibbs free energy of binding, which itself factorizes into enthalpy and entropy. With respect to kinetic properties, affinity can be associated with the ratio of koff and kon of complex formation. Do these features help to obtain better insight into affinity? The present viewpoint assesses our current understanding of thermodynamics– or kinetics–structure relationships and questions the accuracy of data collected to learn about the thermodynamic and kinetic basis to comprehend affinity. 相似文献
98.
Jun-Jen Liu Hsueh-Hsia Wu Tzu-Ho Chen Wan Leung Yu-Chih Liang 《International journal of molecular sciences》2015,16(8):19387-19400
15,16-Dihydrotanshinone I (DHTS) is extracted from Salvia miltiorrhiza Bunge which is a functional food in Asia. In this study, we investigated the apoptotic effect of DHTS on the human acute myeloid leukemia (AML) type III HL-60 cell line. We found that treatment with 1.5 μg/mL DHTS increased proapoptotic Bax and Bad protein expressions and activated caspases-3, -8, and -9, thus leading to poly ADP ribose polymerase (PARP) cleavage and resulting in cell apoptosis. DHTS induced sustained c-Jun N-terminal kinase (JNK) phosphorylation and Fas ligand (FasL) expression. The anti-Fas blocking antibody reversed the DHTS-induced cell death, and the JNK-specific inhibitor, SP600125, inhibited DHTS-induced caspase-3, -8, -9, and PARP cleavage. In a xenograft nude mice model, 25 mg/kg DHTS showed a great effect in attenuating HL-60 tumor growth. Taken together, these results suggest that DHTS can induce HL-60 cell apoptosis in vitro and inhibit HL-60 cell growth in vivo; the underlying mechanisms might be mediated through activation of the JNK and FasL signal pathways. 相似文献
99.
Supramolecular Ligands for Histone Tails by Employing a Multivalent Display of Trisulfonated Calix[4]arenes
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Dr. Yasuaki Kimura Nae Saito Kayo Hanada Jiaan Liu Prof. Takayoshi Okabe Dr. Shigehiro A. Kawashima Dr. Kenzo Yamatsugu Prof. Motomu Kanai 《Chembiochem : a European journal of chemical biology》2015,16(18):2599-2604
Post‐translational modification of histone tails plays critical roles in gene regulation. Thus, molecules recognizing histone tails and controlling their epigenetic modification are desirable as biochemical tools to elucidate regulatory mechanisms. There are, however, only a few synthetic ligands that bind to histone tails with substantial affinity. We report CA2 and CA3, which exhibited sub‐micromolar affinity to histone tails (especially tails with a trimethylated lysine). Multivalent display of trisulfonated calix[4]arene was important for strong binding. CA2 was applicable not only to synthetic tail peptides but also to endogenous histone proteins, and was successfully used to pull‐down endogenous histones from nuclear extract. These findings indicate the utility of these supramolecular ligands as biochemical tools for studying chromatin regulator protein and as a targeting motif in ligand‐directed catalysis to control epigenetic modifications. 相似文献
100.
Molecular docking is a widely-used computational tool for the study of molecular recognition, which aims to predict the binding mode and binding affinity of a complex formed by two or more constituent molecules with known structures. An important type of molecular docking is protein-ligand docking because of its therapeutic applications in modern structure-based drug design. Here, we review the recent advances of protein flexibility, ligand sampling, and scoring functions-the three important aspects in protein-ligand docking. Challenges and possible future directions are discussed in the Conclusion. 相似文献