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41.
The p38 MAPK inhibitor, PD169316, inhibits transforming growth factor beta-induced Smad signaling in human ovarian cancer cells 总被引:4,自引:0,他引:4
Fu Y O'Connor LM Shepherd TG Nachtigal MW 《Biochemical and biophysical research communications》2003,310(2):391-397
Transforming growth factor beta (TGFbeta) can signal through a variety of Smad-independent pathways, including the p38 MAPK pathway. Recent work has shown that inhibitors of p38 MAPK, such as SB203580 and SB202190, can inhibit signaling induced by TGFbeta. Here we show that another p38 MAPK inhibitor, PD169316, abrogates signaling initiated by both TGFbeta and Activin A, but not bone morphogenetic protein (BMP) 4. Inhibition of TGFbeta signaling is dose dependent and results in reduced Smad2 and Smad3 phosphorylation, nuclear translocation, and up-regulation of the TGFbeta target gene Smad7. Reduced TGFbeta signaling is not due to abrogation of p38 MAPK activity, since blocking p38 MAPK activity with a dominant negative form of p38 MAPK has no effect on TGFbeta/Smad signaling. Our results show that use of PD169316 at 5 MICROM or higher can block TGFbeta signaling activity and thus caution must be used when attributing cellular activities exclusively to p38 MAPK signaling when these inhibitors are used experimentally. 相似文献
42.
Khanh B. Tran Gregory Gimenez Peter Tsai Sharada Kolekar Euan J. Rodger Aniruddha Chatterjee Anower Jabed Jen‐Hsing Shih Wayne R. Joseph Elaine S. Marshall Qian Wang Cristin G. Print Michael R. Eccles Bruce C. Baguley Peter R. Shepherd 《Pigment cell & melanoma research》2021,34(1):136-143
Melanoma is a disease associated with a very high mutation burden and thus the possibility of a diverse range of oncogenic mechanisms that allow it to evade therapeutic interventions and the immune system. Here, we describe the characterization of a panel of 102 cell lines from metastatic melanomas (the NZM lines), including using whole‐exome and RNA sequencing to analyse genetic variants and gene expression changes in a subset of this panel. Lines possessing all major melanoma genotypes were identified, and hierarchical clustering of gene expression profiles revealed four broad subgroups of cell lines. Immunogenotyping identified a range of HLA haplotypes as well as expression of neoantigens and cancer–testis antigens in the lines. Together, these characteristics make the NZM panel a valuable resource for cell‐based, immunological and xenograft studies to better understand the diversity of melanoma biology and the responses of melanoma to therapeutic interventions. 相似文献
43.
Kendall JD O'Connor PD Marshall AJ Frédérick R Marshall ES Lill CL Lee WJ Kolekar S Chao M Malik A Yu S Chaussade C Buchanan C Rewcastle GW Baguley BC Flanagan JU Jamieson SM Denny WA Shepherd PR 《Bioorganic & medicinal chemistry》2012,20(1):69-85
We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC(50) 0.9nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model. 相似文献
44.
45.
Shepherd J.M. Large P.J. Midgley M. Ratledge C. 《World journal of microbiology & biotechnology》1998,14(4):535-541
On agar spread plates, N-octylethanolamine was biocidal at comparable minimum inhibitory concentration (MIC) values (3–4mm) against Pseudomonas aeruginosa (two strains), Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Candida tropicalis, and Acremonium sp. which had been grown on a number of different media. The inhibition was greater at higher pH values. In liquid culture, growth inhibition by 3mm N-octylethanolamine was accompanied by cell lysis. Both effects could be prevented by the presence of 1mm spermine or spermidine, but only in bacteria, and not at high pH values. These effects of the polyamines were shown to be non-specific, being shared by other polycations and Mg2+ ions. N-Octylethanolamine at concentrations above its MIC caused total inhibition of the oxidation of 1mm glucose by Ps. aeruginosa (CAS1 and PAO1), E. coli, or C. tropic an effect that was partially reversible by Mg2+ ions. At concentrations below the MIC, there was little inhibit ion of glucose oxidation but a potent inhibition of the extrusion of ethidium bromide from intact cells of E. coli, suggesting that at such concentrations N-octylethanolamine is uncoupling oxidative phosphorylation. The data presented confirm the view that the biocidal effects are due to action on the cytoplasmic membrane. 相似文献
46.
Marie T. Thomas Mark Shepherd Robert K. Poole Arnoud H. M. van Vliet David J. Kelly Bruce M. Pearson 《Environmental microbiology》2011,13(1):48-61
Campylobacter jejuni, a major food‐borne intestinal pathogen, preferentially utilizes a few specific amino acids and some organic acids such as pyruvate and l ‐ and d ‐lactate as carbon sources, which may be important for growth in the avian and mammalian gut. Here, we identify the enzymatic basis for C. jejuni growth on l ‐lactate. Despite the presence of an annotated gene for a fermentative lactate dehydrogenase (cj1167), no evidence for lactate excretion could be obtained in C. jejuni NCTC 11168, and inactivation of the cj1167 gene did not affect growth on lactate as carbon source. Instead, l ‐lactate utilization in C. jejuni NCTC 11168 was found to proceed via two novel NAD‐independent l ‐LDHs; a non‐flavin iron–sulfur containing three subunit membrane‐associated enzyme (Cj0075c‐73c), and a flavin and iron–sulfur containing membrane‐associated oxidoreductase (Cj1585c). Both enzymes contribute to growth on l ‐lactate, as single mutants in each system grew as well as wild‐type on this substrate, while a cj0075c cj1585c double mutant showed no l ‐lactate oxidase activity and did not utilize or grow on l ‐lactate; d ‐lactate‐dependent growth was unaffected. Orthologues of Cj0075c‐73c (LldEFG/LutABC) and Cj1585c (Dld‐II) were recently shown to represent two novel families of l ‐ and d ‐lactate oxidases; this is the first report of a bacterium where both enzymes are involved in l ‐lactate utilization only. The cj0075c‐73c genes are located directly downstream of a putative lactate transporter gene (cj0076c, lctP), which was also shown to be specific for l ‐lactate. The avian and mammalian gut environment contains dense populations of obligate anaerobes that excrete lactate; our data indicate that C. jejuni is well equipped to use l ‐ and d ‐lactate as both electron‐donor and carbon source. 相似文献
47.
Pollinarium removal and pollinium insertion of seven Oxypetalum species (O. alpinum var. alpinum, O. appendiculatum, O. banksii subsp. banksii, O. jacobinae, O. mexiae, O. pachyglossum and O. subriparium) were recorded in Vi?osa. Minas Gerais. They presented a tendency of one or two pollinarium removals and one pollinium insertion (single insertion), except O. appendiculatum. In this species, mainly, two pollinia of the same pollinarium were inserted per stigmatic chamber (double insertion), resulting exceptionally in 6-10 inserted pollinia in a flower, an unusual occurrence among the Asclepiadaceae. No association between removal and insertion was found, e.g., O. subriparium and O. banksii subsp. banksii had the highest pollinarium removal (1.78 and 1.45, respectively) and one of the lowest pollinium insertions (0.02 in both species), per flower. Oxypetalum mexiae showed the lowest pollinarium removal and pollinium insertion per flower (0.09 and 0.01, respectively) among the studied species and other Asclepiadaceae. Oxypetalum subriparium, O. banksii subsp. banksii and O. mexiae might be having reproductive limitations. Pollinarium removal and pollinium insertion per flower of the studied species varied from site to site, similarly to what was recorded for other Asclepiadaceae. 相似文献
48.
Shepherd EG Zhao Q Welty SE Hansen TN Smith CV Liu Y 《The Journal of biological chemistry》2004,279(52):54023-54031
Mitogen-activated protein (MAP) kinases play a pivotal role in the macrophages in the production of proinflammatory cytokines triggered by lipopolysaccharides. However, their function in the responses of macrophages to Gram-positive bacteria is poorly understood. Even less is known about the attenuation of MAP kinase signaling in macrophages exposed to Gram-positive bacteria. In the present study, we have investigated the regulation of MAP kinases and the role of MAP kinase phosphatase (MKP)-1 in the production of pro-inflammatory cytokines using murine RAW264.7 and primary peritoneal macrophages after peptidoglycan stimulation. Treatment of macrophages with peptidoglycan resulted in a transient activation of JNK, p38, and extracellular signal-regulated kinase. Most interestingly, MKP-1 expression was potently induced by peptidoglycan, and this induction was concurrent with MAP kinase dephosphorylation. Triptolide, a diterpenoid triepoxide, potently blocked the induction of MKP-1 by peptidoglycan and prolonged the activation of JNK and p38. Overexpression of MKP-1 substantially attenuated the production of tumor necrosis factor (TNF)-alpha induced by peptidoglycan, whereas knockdown of MKP-1 by small interfering RNA substantially increased the production of both TNF-alpha and interleukin-1 beta. Finally, we found that in primary murine peritoneal macrophages, MKP-1 induction following peptidoglycan stimulation also coincided with inactivation of JNK and p38. Blockade of MKP-1 induction resulted in a sustained activation of both JNK and p38 in primary macrophages. Our results reveal that MKP-1 critically regulates the expression of TNF-alpha and interleukin-1 beta in RAW264.7 cells and further suggest a central role for this phosphatase in controlling the inflammatory responses of primary macrophages to Gram-positive bacterial infection. 相似文献
49.
Anita Shepherd Danny Awty-Carroll Jason Kam Chris Ashman Elena Magenau Enrico Martani Mislav Kontek Andrea Ferrarini Stefano Amaducci Chris Davey Vanja Jurišić Gert-Jan Petrie Mohamad Al Hassan Isabelle Lamy Iris Lewandowski Emmanuel de Maupeou Jon McCalmont Luisa Trindade Kasper van der Cruijsen Philip van der Pluijm Rebecca Rowe Andrew Lovett Iain Donnison Andreas Kiesel John Clifton-Brown Astley Hastings 《Global Change Biology Bioenergy》2023,15(4):444-461
New biomass crop hybrids for bioeconomic expansion require yield projections to determine their potential for strategic land use planning in the face of global challenges. Our biomass growth simulation incorporates radiation interception and conversion efficiency. Models often use leaf area to predict interception which is demanding to determine accurately, so instead we use low-cost rapid light interception measurements using a simple laboratory-made line ceptometer and relate the dynamics of canopy closure to thermal time, and to measurements of biomass. We apply the model to project the European biomass potentials of new market-ready hybrids for 2020–2030. Field measurements are easier to collect, the calibration is seasonally dynamic and reduces influence of weather variation between field sites. The model obtained is conservative, being calibrated by crops of varying establishment and varying maturity on less productive (marginal) land. This results in conservative projections of miscanthus hybrids for 2020–2030 based on 10% land use conversion of the least (productive) grassland and arable for farm diversification, which show a European potential of 80.7–89.7 Mt year−1 biomass, with potential for 1.2–1.3 EJ year−1 energy and 36.3–40.3 Mt year−1 carbon capture, with seeded Miscanthus sacchariflorus × sinensis displaying highest yield potential. Simulated biomass projections must be viewed in light of the field measurements on less productive land with high soil water deficits. We are attempting to model the results from an ambitious and novel project combining new hybrids across Europe with agronomy which has not been perfected on less productive sites. Nevertheless, at the time of energy sourcing issues, seed-propagated miscanthus hybrids for the upscaled provision of bioenergy offer an alternative source of renewable energy. If European countries provide incentives for growers to invest, seeded hybrids can improve product availability and biomass yields over the current commercial miscanthus variety. 相似文献
50.
Isabelle Defourny Andrea Minetti Géza Harczi Stéphane Doyon Susan Shepherd Milton Tectonidis Jean-Hervé Bradol Michael Golden 《PloS one》2009,4(5)