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111.
Boys ML Bian F Kramer JB Chio CL Ren XD Chen H Barrett SD Sexton KE Iula DM Filzen GF Nguyen MN Angell P Downs VL Wang Z Raheja N Ellsworth EL Fakhoury S Bratton LD Keller PR Gowan R Drummond EM Maiti SN Hena MA Lu L McConnell P Knafels JD Thanabal V Sun F Alessi D McCarthy A Zhang E Finzel BC Patel S Ciotti SM Eisma R Payne NA Gilbertsen RB Kostlan CR Pocalyko DJ Lala DS 《Bioorganic & medicinal chemistry letters》2012,22(10):3392-3397
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFβ receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFβ induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring. 相似文献
112.
Powell NA Kohrt JT Filipski KJ Kaufman M Sheehan D Edmunds JE Delaney A Wang Y Bourbonais F Lee DY Schwende F Sun F McConnell P Catana C Chen H Ohren J Perrin LA 《Bioorganic & medicinal chemistry letters》2012,22(1):190-193
We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall. 相似文献
113.
Lunasin is a peptide derived from the soybean 2S albumin seed protein that has both anticancer and anti-inflammatory activities. Large-scale animal studies and human clinical trials to determine the efficacy of lunasin in vivo have been hampered by the cost of synthetic lunasin and the lack of a method for obtaining gram quantities of highly purified lunasin from plant sources. The goal of this study was to develop a large-scale method to generate highly purified lunasin from defatted soy flour. A scalable method was developed that utilizes the sequential application of anion-exchange chromatography, ultrafiltration, and reversed-phase chromatography. This method generates lunasin preparations of >99% purity with a yield of 442 mg/kg defatted soy flour. Mass spectrometry of the purified lunasin revealed that the peptide is 44 amino acids in length and represents the original published sequence of lunasin with an additional C-terminal asparagine residue. Histone-binding assays demonstrated that the biological activity of the purified lunasin was similar to that of synthetic lunasin. This study provides a robust method for purifying commercial-scale quantities of biologically-active lunasin and clearly identifies the predominant form of lunasin in soy flour. This method will greatly facilitate the development of lunasin as a potential nutraceutical or therapeutic anticancer agent. 相似文献
114.
As the microenvironment of a cell changes, associated mechanical cues may lead to changes in biochemical signaling and inherently mechanical processes such as mitosis. Here we explore the effects of confined mechanical environments on cellular responses during mitosis. Previously, effects of mechanical confinement have been difficult to optically observe in three-dimensional and in vivo systems. To address this challenge, we present a novel microfluidic perfusion culture system that allows controllable variation in the level of confinement in a single axis allowing observation of cell growth and division at the single-cell level. The device is capable of creating precise confinement conditions in the vertical direction varying from high (3 μm) to low (7 μm) confinement while also varying the substrate stiffness (E = 130 kPa and 1 MPa). The Human cervical carcinoma (HeLa) model with a known 3N+ karyotype was used for this study. For this cell line, we observe that mechanically confined cell cycles resulted in stressed cell divisions: (i) delayed mitosis, (ii) multi- daughter mitosis events (from 3 up to 5 daughter cells), (iii) unevenly sized daughter cells, and (iv) induction of cell death. In the highest confined conditions, the frequency of divisions producing more than two progeny was increased an astounding 50-fold from unconfined environments, representing about one half of all successful mitotic events. Notably, the majority of daughter cells resulting from multipolar divisions were viable after cytokinesis and, perhaps suggesting another regulatory checkpoint in the cell cycle, were in some cases observed to re-fuse with neighboring cells post-cytokinesis. The higher instances of abnormal mitosis that we report in confined mechanically stiff spaces, may lead to increased rates of abnormal, viable, cells in the population. This work provides support to a hypothesis that environmental mechanical cues influences structural mechanisms of mitosis such as geometric orientation of the mitotic plane or planes. 相似文献
115.
Many marine vertebrates, including pinnipeds, turtles and birds, spend periods of time ashore during their life cycles. Quantification of time spent ashore is important for estimating population parameters such as abundance and productivity in some species, but can prove to be a difficult task. Here we describe a novel telemetry system based on Global Systems for Mobile Communications (GSM), to provide detailed information on the haul-out behaviour of tagged animals. We tested the system on harbour seals in southwest Ireland. The GSM telemetry system proved an effective means of obtaining information on the haul-out activity of harbour seals in the study area and of providing crude movement information that was less labour intensive than VHF telemetry and provides an alternative means of data acquisition offering some advantages over satellite telemetry. The GSM tag with its internal antennae is more robust than a satellite tag. The GSM networks allow more information to be relayed, so the “cost per bit of data” is reduced. Moreover, the large global investment in GSM networks have resulted in a telemetry technology with low running costs and therefore with significantly lower costs of data acquisition via GSM relative to Argos systems. With the ever-expanding global GSM network coverage the system has significant potential applications in behavioural studies of amphibious vertebrates, such as estimating clutch frequency in sea turtles. 相似文献
116.
Carlos L Del Rio Patrick I McConnell Monica Kukielka Roger Dzwonczyk Bradley D Clymer Michael B Howie George E Billman 《Journal of applied physiology》2008,104(2):386-393
Passive electrical remodeling following myocardial infarction (MI) is well established. These changes can alter electrotonic loading and trigger the remodeling of repolarization currents, a potential mechanism for ventricular fibrillation (VF). However, little is known about the role of passive electrical markers as tools to identify VF susceptibility post-MI. This study investigated electrotonic remodeling in the post-MI ventricle, as measured by myocardial electrical impedance (MEI), in animals prone to and resistant to VF. MI was induced in dogs by a two-stage left anterior descending (LAD) coronary artery ligation. Before infarction, MEI electrodes were placed in remote (left circumflex, LCX) and infarcted (LAD) myocardium. MEI was measured in awake animals 1, 2, 7, and 21 days post-MI. Subsequently, VF susceptibility was tested by a 2-min LCX occlusion during exercise; 12 animals developed VF (susceptible, S) and 12 did not (resistant, R). The healing infarct had lower MEI than the normal myocardium. This difference was stable by day 2 post-MI (287 +/- 32 Omega vs. 425 +/- 62 Omega, P < 0.05). Significant differences were observed between resistant and susceptible animals 7 days post-MI; susceptible dogs had a wider electrotonic gradient between remote and infarcted myocardium (R: 89 +/- 60 Omega vs. S: 180 +/- 37 Omega). This difference increased over time in susceptible animals (252 +/- 53 Omega at 21 days) due to post-MI impedance changes on the remote myocardium. These data suggest that early electrotonic changes post-MI could be used to assess later arrhythmia susceptibility. In addition, passive-electrical changes could be a mechanism driving active-electrical remodeling post-MI, thereby facilitating the induction of arrhythmias. 相似文献
117.
Matsunaga I Naka T Talekar RS McConnell MJ Katoh K Nakao H Otsuka A Behar SM Yano I Moody DB Sugita M 《The Journal of biological chemistry》2008,283(43):28835-28841
Trehalose dimycolate (TDM), also known as cord factor, is a major surface glycolipid of the cell wall of mycobacteria. Because of its potent biological functions in models of infection, adjuvancy, and immunotherapy, it is important to determine how its biosynthesis is regulated. Here we show that glucose, a host-derived product that is not readily available in the environment, causes Mycobacterium avium to down-regulate TDM expression while up-regulating production of another major glycolipid with immunological roles in T cell activation, glucose monomycolate (GMM). In vitro, the mechanism of reciprocal regulation of TDM and GMM involves competitive substrate selection by antigen 85A. The switch from TDM to GMM biosynthesis occurs near the physiological concentration of glucose present in mammalian hosts. We further demonstrate that GMM is produced in vivo by mycobacteria growing in mouse lung. These results establish an enzymatic pathway for GMM production. More generally, these observations provide a specific enzymatic mechanism for dynamic alterations of cell wall glycolipid remodeling in response to the transition from noncellular to cellular growth environments, including factors that are monitored by the host immune system. 相似文献
118.
Du JX Bialkowska AB McConnell BB Yang VW 《The Journal of biological chemistry》2008,283(46):31991-32002
SUMOylation is a form of post-translational modification shown to control nuclear transport. Krüppel-like factor 5 (KLF5) is an important mediator of cell proliferation and is primarily localized to the nucleus. Here we show that mouse KLF5 is SUMOylated at lysine residues 151 and 202. Mutation of these two lysines or two conserved nearby glutamates results in the loss of SUMOylation and increased cytoplasmic distribution of KLF5, suggesting that SUMOylation enhances nuclear localization of KLF5. Lysine 151 is adjacent to a nuclear export signal (NES) that resembles a consensus NES. The NES in KLF5 directs a fused green fluorescence protein to the cytoplasm, binds the nuclear export receptor CRM1, and is inhibited by leptomycin and site-directed mutagenesis. SUMOylation facilitates nuclear localization of KLF5 by inhibiting this NES activity, and enhances the ability of KLF5 to stimulate anchorage-independent growth of HCT116 colon cancer cells. A survey of proteins whose nuclear localization is regulated by SUMOylation reveals that SUMOylation sites are frequently located in close proximity to NESs. A relatively common mechanism for SUMOylation to regulate nucleocytoplasmic transport may lie in the interplay between neighboring NES and SUMOylation motifs. 相似文献
119.
120.
Kristi A Miller Daniel M Yoshikawa Ian R McConnell Robin Clark David Schild Joanna S Albala 《The Journal of biological chemistry》2002,277(10):8406-8411
RAD51B and RAD51C are two of five known paralogs of the human RAD51 protein that are thought to function in both homologous recombination and DNA double-strand break repair. This work describes the in vitro and in vivo identification of the RAD51B/RAD51C heterocomplex. The RAD51B/RAD51C heterocomplex was isolated and purified by immunoaffinity chromatography from insect cells co-expressing the recombinant proteins. Moreover, co-immunoprecipitation of the RAD51B and RAD51C proteins from HeLa, MCF10A, and MCF7 cells strongly suggests the existence of an endogenous RAD51B/RAD51C heterocomplex. We extended these observations to examine the interaction between the RAD51B/RAD51C complex and the other RAD51 paralogs. Immunoprecipitation using protein-specific antibodies showed that RAD51C is central to a single large protein complex and/or several smaller complexes with RAD51B, RAD51D, XRCC2, and XRCC3. However, our experiments showed no evidence for the inclusion of RAD51 within these complexes. Further analysis is required to elucidate the function of the RAD51B/RAD51C heterocomplex and its association with the other RAD51 paralogs in the processes of homologous recombination and DNA double-strand break repair. 相似文献