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991.
Yong-Jin Wu Huan He Robert Bertekap Ryan Westphal Snjezana Lelas Amy Newton Tanya Wallace Matthew Taber Carl Davis John E. Macor Joanne Bronson 《Bioorganic & medicinal chemistry》2013,21(8):2217-2228
This report describes the synthesis, structure–activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders. 相似文献
992.
David J. Richard Ryan Lena Thomas Bannister Noel Blake William E. Pierceall Nicole E. Carlson Christina Eberhart Keller Marcel Koenig Yuanjun He Dmitriy Minond Jitendra Mishra Michael Cameron Timothy Spicer Peter Hodder Michael H. Cardone 《Bioorganic & medicinal chemistry》2013,21(21):6642-6649
Anti-apoptotic Bcl-2 family proteins are important oncology therapeutic targets. To date, BH3 mimetics that abrogate anti-apoptotic activity have largely been directed at Bcl-2 and/or Bcl-xL. One observed mechanism of resistance to these inhibitors is increased Mcl-1 levels in cells exposed to such therapeutics. For this reason, and because Mcl-1 is important in the onset of lymphoid, myeloid, and other cancers, it has become a target of great interest. However, small molecule inhibitors displaying potency and selectivity for Mcl-1 are lacking. Identifying such compounds has been challenging due to difficulties in translating the target selectivity observed at the biochemical level to the cellular level. Herein we report the results of an HTS strategy coupled with directed hit optimization. Compounds identified have selective Mcl-1 inhibitory activity with greater than 100-fold reduced affinity for Bcl-xL. The selectivity of these compounds at the cellular level was validated using BH3 profiling, a novel personalized diagnostic approach. This assay provides an important functional biomarker that allows for the characterization of cells based upon their dependencies on various anti-apoptotic Bcl-2 proteins. We demonstrate that cells dependent on Mcl-1 or Bcl-2/Bcl-xL for survival are commensurately responsive to compounds that genuinely target those proteins. The identification of compound 9 with uniquely validated and selective Mcl-1 inhibitory activity provides a valuable tool to those studying the intrinsic apoptosis pathway and highlights an important approach in the development of a first-in-class cancer therapeutic. 相似文献
993.
994.
A direct electrochemical DNA biosensor based on zero current potentiometry was fabricated by immobilization of ssDNA onto gold nanoparticles (AuNPs) coated pencil graphite electrode (PGE). One ssDNA/AuNPs/PGE was connected in series between clips of working and counter electrodes of a potentiostat, and then immersed into the solution together with a reference electrode, establishing a novel DNA biosensor for specific DNA detection. The variation of zero current potential difference (ΔE(zcp)) before and after hybridization of the self-assembled probe DNA with the target DNA was used as a signal to characterize and quantify the target DNA sequence. The whole DNA biosensor fabrication process was characterized by cyclic voltammetry and electrochemical impedance spectroscopy with the use of ferricyanide as an electrochemical redox indicator. Under the optimized conditions, ΔE(zcp) was linear with the concentrations of the complementary target DNA in the range from 10nM to 1μM, with a detection limit of 6.9nM. The DNA biosensor showed a good reproducibility and selectivity. Prepared DNA biosensor is facile and sensitive, and it eliminates the need of using exogenous reagents to monitor the oligonucleotides hybridization. 相似文献
995.
PJ Cai X Xiao YR He WW Li GL Zang GP Sheng M Hon-Wah Lam L Yu HQ Yu 《Biosensors & bioelectronics》2013,39(1):306-310
The enhanced electricity generation in a biocathode bio-electrochemical system (BES) with Microcystis aeruginosa IPP as the cathodic microorganism under illumination is investigated. The results show that this cyanobacterium is able to act as a potential cathodic microorganism under illumination. In addition, M. aeruginosa IPP is found to produce reactive oxygen species (ROS) in its growth in the BES. ROS, as more competitive electron acceptors than oxygen, are utilized prior to oxygen. The BES current is substantially reduced when the ROS production is inhibited by mannitol, indicating that the ROS secreted by the cyanobacterium play an important role in the electricity generation of such a biocathode BES. This work demonstrates that the ROS released by cyanobacteria benefit for an enhanced electricity generation of BES. 相似文献
996.
997.
998.
Xiao-long Tang Feng Yue Jian-zheng He Ning-bo Wang Ming Ma Jia-run Mo Qiang Chen 《Zoology (Jena, Germany)》2013,116(6):331-335
A viviparous lizard, Eremias multiocellata, was used to investigate the possible sexual and ontogenetic effects on selected body temperature, thermal tolerance range and the thermal dependence of locomotor performance. We show that adults are sexually dimorphic and males have larger bodies and heads than females. Adults selected higher body temperatures (34.5 vs. 32.4 °C) and could tolerate a broader range of body temperatures (8.1–46.8 vs. 9.1–43.1 °C) than juveniles. The sprint speed and maximum sprint distance increased with temperature from 21 °C to 33 °C, but decreased at 36 °C and 39 °C in both juveniles and adults. Adults ran faster and longer than juveniles at each tested temperature. Adult locomotor performance was not correlated with snout–vent length (SVL) or sex, and sprint speed was positively correlated with hindlimb length. Juvenile locomotor performance was positively correlated with both SVL and hindlimb length. The ontogenetic variation in selected body temperature, thermal tolerance and locomotor performance in E. multiocellata suggests that the effects of morphology on temperature selection and locomotor performance vary at different ontogenetic stages. 相似文献
999.
Yi He Qinlong Zheng Ole Simonsen Kristian K. Petersen Thorbjørn G. Christiansen Morten A. Karsdal Anne C. Bay-Jensen 《Matrix biology》2013,32(3-4):143-151
ADAMTS-4 (aggrecanase1) is believed to play an important role in the degradation of aggrecan during the progression of joint diseases. ADAMTS-4 is synthesized as a latent pro-enzyme that requires the removal of the pro-domain, exposing the N-terminal neoepitope, to achieve activity. We developed a monoclonal antibody against this neoepitope of active ADAMTS-4. Furthermore, we established and characterized a competitive ELISA for measuring active ADAMTS-4 form applying the specific antibody. We used this assay to profile the presence of active ADAMTS-4 and its aggrecan degradation product (NITEGE373) in a bovine cartilage ex vivo model. We found that after stimulation with catabolic factors, the cartilage initially released high levels of aggrecanase-derived aggrecan fragments into supernatant but subsequently decreased to background levels. The level of active ADAMTS-4 released into the supernatant and retained in the cartilage matrix increased continuously throughout the 21 days of the study. The activity of ADAMTS-4 on the last day of catabolic stimulation was verified in vitro by adding deglycosylated or native aggrecan to the conditioned medium. Samples of human cartilage affected by varying degrees of osteoarthritis stained strongly for active ADAMTS-4 where surface fibrillation and clustered chondrocytes were observed. This assay could be an effective tool for studying ADAMTS-4 activity and for screening drugs regulating ADAMTS-4 activation. Moreover, it could be a potential biomarker for degenerative joint disease. 相似文献
1000.
F. Houben W. H. De Vos I. P. C. Krapels M. Coorens G. J. J. Kierkels M. A. F. Kamps V. L. R. M. Verstraeten C. L. M. Marcelis A. van den Wijngaard F. C. S. Ramaekers J. L. V. Broers 《Histochemistry and cell biology》2013,139(1):119-134
There is growing evidence that laminopathies, diseases associated with mutations in the LMNA gene, are caused by a combination of mechanical and gene regulatory distortions. Strikingly, there is a large variability in disease symptoms between individual patients carrying an identical LMNA mutation. This is why classical genetic screens for mutations appear to have limited predictive value for disease development. Recently, the widespread occurrence of repetitive nuclear ruptures has been described in fibroblast cultures from various laminopathy patients. Since this phenomenon was strongly correlated with disease severity, the identification of biomarkers that report on these rupture events could have diagnostic relevance. One such candidate marker is the PML nuclear body, a structure that is normally confined to the nuclear interior, but leaks out of the nucleus upon nuclear rupture. Here, we show that a variety of laminopathies shows the presence of these cytoplasmic PML particles (PML CPs), and that the amount of these protein aggregates increases with severity of the disease. In addition, between clinically healthy individuals, carrying LMNA mutations, significant differences can be found. Therefore, we postulate that detection of PML CPs in patient fibroblasts could become a valuable marker for diagnosis of disease development. 相似文献