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141.
Christopher J. Fowler Sandra Holt Gunnar Tiger 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):55-58
Previous studies have demonstrated that fatty acid amide hydrolase, the enzyme responsible for the metabolism of anandamide, is inhibited by the acidic non-steroidal anti-inflammatory drug (NSAID) ibuprofen with a potency that increases as the assay pH is reduced. Here we show that (R) -, (S) - and (R, S) -flurbiprofen, indomethacin and niflumic acid show similar pH-dependent shifts in potency to that seen with ibuprofen. Thus, (S) -flurbiprofen inhibited 2 μM [3 H]anandamide metabolism with IC 50 values of 13 and 50 μM at assay pH values of 6 and 8, respectively. In contrast, the neutral compound celecoxib was a weak fatty acid amide hydrolase inhibitor and showed no pH dependency (IC 50 values ~300 μM at both assay pH). The cyclooxygenase-2-selective inhibitors nimesulide and SC-58125 did not inhibit fatty acid amide hydrolase activity at either pH. The data are consistent with the conclusion that the non-ionised forms of the acidic NSAIDs are responsible for the inhibition of fatty acid amide hydrolase. 相似文献
142.
143.
Edmond M. Linossi Jeffrey J. Babon Douglas J. Hilton Sandra E. Nicholson 《Cytokine & growth factor reviews》2013,24(3):241-248
The discovery of the Suppressor of Cytokine Signaling (SOCS) family of proteins has resulted in a significant body of research dedicated to dissecting their biological functions and the molecular mechanisms by which they achieve potent and specific inhibition of cytokine and growth factor signaling. The Australian contribution to this field has been substantial, with the initial discovery of SOCS1 by Hilton, Starr and colleagues (discovered concurrently by two other groups) and the following work, providing a new perspective on the regulation of JAK/STAT signaling. In this review, we reflect on the critical discoveries that have lead to our current understanding of how SOCS proteins function and discuss what we see as important questions for future research. 相似文献
144.
Sandra M. Miltsch Jürgen Krücken Janina Demeler Sabrina Ramünke Achim Harder Georg von Samson-Himmelstjerna 《Parasitology international》2013,62(6):591-598
Due to the increasing development of anthelmintic resistance in nematodes worldwide, it is important to search for anthelmintic compounds with new modes of action and also to investigate the possibility to combine compounds with possible synergistic effects. There might also be the chance to take advantage of the fact that nematode populations which have developed resistance against one anthelmintic class might respond hypersusceptibly to another drug class. The aim of this study was to investigate responses of Caenorhabditis elegans populations with mutations in neuro-muscular ion channels to different anthelmintic classes. Furthermore, potential synergistic effects between two anthelmintic compounds from different classes, i.e. emodepside and tribendimidine, were studied. Although there was neither a synergistic nor an antagonistic effect between emodepside and tribendimidine, other types of interactions could be identified. The C. elegans GABAA-receptor (GABAA-R) unc-49 mutants, showing decreased emodepside susceptibility, were more susceptible to tribendimidine than wild-type C. elegans. In contrast, the reverse phenomenon – hypersusceptibility to emodepside in tribendimidine resistant acetylcholine-receptor (AChR) loss of function mutants – was not observed. Moreover, the slo-1 mutant strain (completely emodepside resistant) also showed hypersusceptibility to piperazine. Interestingly, neither the GABAA-R unc-49 mutants nor the AChR mutants showed decreased susceptibility against piperazine, although there were some studies that indicated an involvement of GABAA-R or AChR in the piperazine mode of action. In conclusion, the present study provides evidence suggesting that interactions between commercially available anthelmintic drugs with different modes of action might be a relatively common phenomenon but this has to be carefully worked out for each anthelmintic and each anthelmintic drug combination. Moreover, results obtained in C. elegans will have to be confirmed using parasitic nematodes in the future. 相似文献
145.
146.
Sandra D. Taylor Kristine K. Barlow‐Stewart Susan A. Treloar Mark Stranger Kellie Chenoweth 《New genetics and society》2013,32(2):225-239
Genetic discrimination, defined as the differential treatment of individuals or their relatives on the basis of actual or presumed genetic differences, is an emerging issue of interest in academic, clinical, social and legal contexts. While its potential significance has been discussed widely, verified empirical data are scarce. Genetic discrimination is a complex phenomenon to describe and investigate, as evidenced by the recent Australian Law Reform Commission inquiry in Australia. The authors research project, which commenced in 2002, aims to document the multiple perspectives and experiences regarding genetic discrimination in Australia and inform future policy development and law reform. Data are being collected from consumers, employers, insurers and the legal system. Attempted verification of alleged accounts of genetic discrimination will be a novel feature of the research. This paper overviews the early stages of the research, including conceptual challenges and their methodological implications. 相似文献
147.
Flooding is often considered a stimulus for production of fish in floodplain rivers. In the southern Murray–Darling Basin (MDB), Australia, however, few native fish species have been shown to use the floodplain for spawning, and recruitment has been positively and negatively associated with flooding. In 2010/11, extensive flooding in the lower River Murray provided an opportunity to investigate the recruitment response of Golden Perch (Macquaria ambigua ambigua) following 10 years of drought and floodplain isolation. Annual variation in Golden Perch abundance and recruitment were investigated in anabranch and main channel habitats at Chowilla in the floodplain geomorphic region of the lower River Murray over a 7‐year period incorporating the flood and 6 years of in‐channel flow. Spatial variation in recruitment in the lower River Murray was also investigated by comparing the age structure of Golden Perch in the swamplands/lakes, gorge and floodplain geomorphic regions. Golden Perch abundance in the Chowilla region increased significantly postflooding compared with drought years. Age structures indicated that increased abundance was due predominantly to fish spawned during the flood (2010/11) and the previous year (2009/10), which was characterised by in‐channel flows. Age structure was similar in the nearby Katarapko Anabranch system indicating a uniform postflood recruitment response in the floodplain geomorphic region. Juvenile Golden Perch from the 2010/11 and 2009/10 cohorts were less apparent in the gorge and swamplands/lakes regions. Golden Perch have flexible life histories and will spawn and recruit in association with in‐channel rises in flow and overbank flows, but significant increases in abundance in the lower River Murray may result from overbank flooding. Contemporary approaches to flow restoration in the MDB emphasise overbank flows and floodplain processes. We suggest, however, that environmental flow management that incorporates floodplain and in‐channel processes, at appropriate spatio‐temporal scales, will result in more robust populations of Golden Perch. 相似文献
148.
Greg Hodge Mark Holmes Hubertus Jersmann Paul N Reynolds Sandra Hodge 《Respiratory research》2013,14(1):63
Background
Pro-inflammatory/cytotoxic T cells (IFNγ, TNFα, granzyme B+) are increased in the peripheral circulation in COPD. NKT-like and NK cells are effector lymphocytes that we have also shown to be major sources of pro-inflammatory cytokines and granzymes. P-glycoprotein 1 (Pgp1) is a transmembrane efflux pump well characterised in drug resistant cancer cells. We hypothesized that Pgp1 would be increased in peripheral blood T, NKT-like and NK cells in patients with COPD, and that this would be accompanied by increased expression of IFNγ, TNFα and granzyme B. We further hypothesized that treatment with cyclosporine A, a Pgp1 inhibitor, would render cells more sensitive to treatment with corticosteroids.Methods
Pgp1, granzyme B, IFNγ and TNFα expression were measured in peripheral blood T, NK and NKT-like cells from COPD patients and control subjects (± cyclosporine A and prednisolone) following in vitro stimulation and results correlated with uptake of efflux dye Calcein-AM using flow cytometry.Results
There was increased Pgp1 expression by peripheral blood T, NKT-like and NK cells co-expressing IFNγ, TNFα and granzyme B in COPD patients compared with controls (e.g. %IFNγ/Pgp1 T, NKT-like, NK for COPD (Control): 25(6), 54(27), 39(23)). There was an inverse correlation between Pgp1 expression and Calcein-AM uptake. Treatment with 2.5 ng/ml cylosporin A and10-6 M prednisolone resulted in synergistic inhibition of pro-inflammatory cytokines in Pgp1 + cells (p < 0.05 for all).Conclusions
Treatment strategies that target Pgp1 in T, NKT-like and NK cells may reduce systemic inflammatory mediators in COPD and improve patient morbidity. 相似文献149.
Maja Klug Sandra Schmidhofer Claudia Gebhard Reinhard Andreesen Michael Rehli 《Genome biology》2013,14(5):R46