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排序方式: 共有310条查询结果,搜索用时 15 毫秒
91.
An apoptosis targeted stimulus with nanosecond pulsed electric fields (nsPEFs) in E4 squamous cell carcinoma 总被引:1,自引:0,他引:1
Stimuli directed towards activation of apoptosis mechanisms are an attractive approach to eliminate evasion of apoptosis,
a ubiquitous cancer hallmark. In these in vitro studies, kinetics and electric field thresholds for several apoptosis characteristics
are defined in E4 squamous carcinoma cells (SCC) exposed to ten 300 ns pulses with increasing electric fields. Cell death
was >95% at the highest electric field and coincident with phosphatidylserine externalization, caspase and calpain activation
in the presence and absence of cytochrome c release, decreases in Bid and mitochondria membrane potential (Δψm) without apparent changes reactive oxygen species levels
or in Bcl2 and Bclxl levels. Bid cleavage was caspase-dependent (55–60%) and calcium-dependent (40–45%). Intracellular calcium
as an intrinsic mechanism and extracellular calcium as an extrinsic mechanism were responsible for about 30 and 70% of calcium
dependence for Bid cleavage, respectively. The results reveal electric field-mediated cell death induction and progression,
activating pro-apoptotic-like mechanisms and affecting plasma membrane and intracellular functions, primarily through extrinsic-like
pathways with smaller contributions from intrinsic-like pathways. Nanosecond second pulsed electric fields trigger heterogeneous
cell death mechanisms in E4 SCC populations to delete them, with caspase-associated cell death as a predominant, but not an
unaccompanied event. 相似文献
92.
Joel T. Arcari Jean S. Beebe Martin A. Berliner Vincent Bernardo Merin Boehm Gary V. Borzillo Tracey Clark Bruce D. Cohen Richard D. Connell Heather N. Frost Deborah A. Gordon William M. Hungerford Shefali M. Kakar Aaron Kanter Nandell F. Keene Elizabeth A. Knauth Susan D. LaGreca Yong Lu Jinshan M. Chen 《Bioorganic & medicinal chemistry letters》2013,23(10):3059-3063
The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models. 相似文献
93.
Andrews KM Beebe DA Benbow JW Boyer DA Doran SD Hui Y Liu S McPherson RK Neagu C Parker JC Piotrowski DW Schneider SR Treadway JL VanVolkenberg MA Zembrowski WJ 《Bioorganic & medicinal chemistry letters》2011,21(6):1810-1814
A 3-amino-4-substituted pyrrolidine series of dipeptidyl peptidase IV (DPP-4) inhibitors was rapidly developed into a candidate series by identification of a polar valerolactam replacement for the lipophilic 2,4,5-trifluorophenyl pharmacophore. The addition of a gem-difluoro substituent to the lactam improved overall DPP-4 inhibition and an efficient asymmetric route to 3,4-diaminopyrrolidines was developed. Advanced profiling of a subset of analogs identified 5o with an acceptable human DPP-4 inhibition profile based on a rat PK/PD model and a projected human dose that was suitable for clinical development. 相似文献
94.
Kostmann disease is an inherited severe congenital neutropenia syndrome associated with loss-of-function mutations in an adaptor protein HS1-associated protein X-1 (Hax1). How Hax1 regulates neutrophil function remains largely unknown. In this paper, we use ribonucleic acid interference to deplete Hax1 in the neutrophil-like cell line PLB-985 and identify Hax1 as a negative regulator of integrin-mediated adhesion and chemotaxis. Using microfluidics, we show that depletion of Hax1 impairs neutrophil uropod detachment and directed migration. Hax1-deficient cells also display increased integrin-mediated adhesion and reduced RhoA activity. Moreover, depletion of RhoA induces increased neutrophil adhesion and impaired migration, suggesting that Hax1 regulates neutrophil adhesion and chemotaxis through RhoA. Accordingly, activation of RhoA is sufficient to rescue adhesion of Hax1-deficient neutrophils. Together, our findings identify Hax1 as a novel regulator of neutrophil uropod detachment and chemotaxis through RhoA. 相似文献
95.
Beebe DC Holekamp NM Siegfried C Shui YB 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2011,366(1568):1293-1300
The lens is composed of a thin metabolically active outer layer, consisting of epithelial and superficial fibre cells. Lying within this outer shell are terminally differentiated, metabolically inactive fibre cells, which are divided into an outer cortex and central nucleus. Mature fibre cells contain a very high protein concentration, which is important for the transparency and refractive power of the lens. These proteins are protected from oxidation by reducing substances, like glutathione, and by the low-oxygen environment around the lens. Glutathione reaches the mature fibre cells by diffusing from the metabolically active cells at the lens surface. With age, the cytoplasm of the nucleus becomes stiffer, reducing the rate of diffusion and making nuclear proteins more susceptible to oxidation. Low pO(2) is maintained at the posterior surface of the lens by the physical and physiological properties of the vitreous body, the gel filling the space between the lens and the retina. Destruction or degeneration of the vitreous body increases exposure of the lens to oxygen from the retina. Oxygen reaches the lens nucleus, increasing protein oxidation and aggregation and leading to nuclear cataract. We suggest that maintaining low pO(2) around the lens should prevent the formation of nuclear cataracts. 相似文献
96.
Blair MW Rodriguez LM Pedraza F Morales F Beebe S 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2007,114(2):261-271
Bean golden yellow mosaic virus (BGYMV) is a whitefly-transmitted geminivirus of the Begomovirus family that causes important yield losses to common beans grown in tropical and sub-tropical countries of Latin America and
the Caribbean. A major resistance gene that has been widely deployed in this region is the recessive locus bgm-1 that prevents the development of severe yellowing typical of the disease. In this study, we developed a co-dominant sequence-characterized
amplified region (SCAR) marker, SR2, based on a previously identified random amplified polymorphic DNA (RAPD) marker that
is tightly linked to the bgm-1 resistance gene and identified the position of the locus in the common bean genome through comparative mapping using two
genetic maps for the species. The SR2 marker was mapped relative to bgm-1 in a segregating population of recombinant inbred lines developed from the resistant × susceptible cross of DOR476 × SEL1309.
Polymorphism was shown to be based on a 37 bp insertion event in the SR2 allele associated with susceptibility compared to
the allele associated with resistance and the marker mapped at a distance of 7.8 cM from the resistance gene. The SR2 marker
was significantly associated with overall disease symptoms and with three of the four symptoms associated with the disease
(yellowing or chlorosis, flower abortion, foliar deformation) in a greenhouse trial in Colombia with the mechanically transmissible
BGYMV–Guatemala strain. In both the DOR364 × G19833 and BAT93 × Jalo EEP558 mapping populations, SR2 was located near the
end of linkage group b03 (chromosome 5) suggesting a sub-telomeric position. The position of the bgm-1 resistance gene was estimated to be close to that of bc-1, a strain-specific resistance gene for Bean common mosaic virus (BCMV), based on linkage of SR2 with the SCAR marker SBD5 in the DOR364 × G19833 mapping population. The implications of
linkage between these two recessive resistance genes are discussed, as this is the first association between resistance genes
against both a begomovirus and a potyvirus.
Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users. 相似文献
97.
Chen N Garner AL Chen G Jing Y Deng Y Swanson RJ Kolb JF Beebe SJ Joshi RP Schoenbach KH 《Biochemical and biophysical research communications》2007,364(2):220-225
Nanosecond electric pulses generate nanopores in the interior membranes of cells and modulate cellular functions. Here, we used confocal microscopy and flow cytometry to observe Smith antigen antibody (Y12) binding to nuclear speckles, known as small nuclear ribonucleoprotein particles (snRNPs) or intrachromatin granule clusters (IGCs), in Jurkat cells following one or five 10 ns, 150 kV/cm pulses. Using confocal microscopy and flow cytometry, we observed changes in nuclear speckle labeling that suggested a disruption of pre-messenger RNA splicing mechanisms. Pulse exposure increased the nuclear speckled substructures by ∼2.5-fold above basal levels while the propidium iodide (PI) uptake in pulsed cells was unchanged. The resulting nuclear speckle changes were also cell cycle dependent. These findings suggest that 10 ns pulses directly influenced nuclear processes, such as the changes in the nuclear RNA-protein complexes. 相似文献
98.
JS Osombause SNM Mandiki JA-P Ulyel J-C Micha P Kestemont 《African Journal of Aquatic Science》2019,44(1):61-70
Distichodus antonii is an endemic fish species of the Congo River basin in which the stocks of wild populations are threatened by overfishing pressure. Knowledge of its reproductive biology would be useful in consideration of conservation and management options for the species. Therefore, this study investigated changes in ovarian activity and levels of steroid profiles in wild populations in relation to variation in temperature and rainfall. Adult females (n = 101, body weight of 3 183 ± 14.75 g, SE) were captured monthly over one year (2013–2014). Apart from evaluation of oocyte diameters and gonad developmental stages, gonado-, hepato-, lipososomatic indices (GSI, HSI, LSI) and plasma levels of sex steroids (testosterone-T, estradiol-17β-E2) were determined. The results suggested a synchronous development of oocytes with two annual reproductive seasons over the one-year study. Plasma T and E2 levels peaked during spawning periods likely reflecting active oogenesis. The highest values of morphosomatic indices were observed during the longest rainfall period in September, and were associated with high steroidogenic activity evidenced by increased E2 production. In addition, more vitellogenic oocytes (September and October) were observed during the latter season than during the short rainy season (in May). 相似文献
99.
Chu-Moyer MY Ballinger WE Beebe DA Coutcher JB Day WW Li J Oates PJ Weekly RM 《Bioorganic & medicinal chemistry letters》2002,12(11):1477-1480
SAR studies on the stereoisomers of CP-470,711 suggested that in vivo epimerization was taking place in rats. Further metabolism studies revealed that no epimerization was occurring in dogs, and that no epimerization was expected in humans. A mechanism for the in vivo epimerization is proposed involving an oxidation-reduction pathway of the secondary benzylic alcohol, in contrast to an acid/base-promoted epimerization of the same center during chemical synthesis. 相似文献
100.
Treatment of cancer often involves uses of multiple therapeutic strategies with different mechanisms of action. In this study we investigated combinations of nanosecond pulsed electric fields (nsPEF) with low concentrations of gemcitabine on human oral cancer cells. Cells (Cal-27) were treated with pulse parameters (20 pulses, 100 ns in duration, intensities of 10, 30 and 60 kV/cm) and then cultured in medium with 0.01 μg/ml gemcitabine. Proliferation, apoptosis/necrosis, invasion and morphology of those cells were examined using MTT, flow cytometry, clonogenics, transwell migration and TEM assay. Results show that combination treatments of gemcitabine and nsPEFs exhibited significant synergistic activities versus individual treatments for inhibiting oral cancer cell proliferation and inducing apoptosis and necrosis. However, there was no apparent synergism for cell invasion. By this we demonstrated synergistic inhibition of Cal-27 cells in vitro by nsPEFs and gemcitabine. Synergistic behavior indicates that these two treatments have different sites of action and combination treatment allows reduced doses of gemcitabine and lower nsPEF conditions, which may provide better treatment for patients than either treatment alone while reducing systemic toxicities. 相似文献