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Biomedical subjects

Robert J Parker

Publications and source records attributed to Robert J Parker.

8 recordsLinked to original sources
PubMed2006

Roles of glia in the Drosophila nervous system.

Glial cells have diverse functions that are necessary for the proper development and function of complex nervous systems. Various insects, primarily the fruit fly Drosophila melanogaster and the moth Manduca sexta, have provided useful models of glial function during development. The present review will outline evidence of glial contributions to embryonic, visual, olfactory and wing development. We will also outline evidence for non-developmental functions of insect glia including blood-brain-barrier formation, homeostatic functions and potential contributions to synaptic function. Where relevant, we will also point out similarities between the functions of insect glia and their vertebrate counterparts.

Animals↗
PubMed2006

Reaction of geldanamycin and C17-substituted analogues with glutathione: product identifications and pharmacological implications.

17-Dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and 17-allylamino-17-demethoxygeldanamycin (17-AAG) are two derivatives of geldanamycin (GA) that are currently undergoing clinical evaluation as anticancer agents. These agents bind to heat shock protein 90 (hsp90), resulting in the destabilization of client proteins and inhibition of tumor growth. In a search for the mechanism of hepatotoxicity, which is a dose-limiting toxicity for these agents, we found that GA and its derivatives, 17-AAG and 17-DMAG, react chemically (i.e., nonenzymatically) with glutathione (GSH). A combination of liquid chromatography/electrospray ionization/mass spectrometry and nuclear magnetic resonance analyses were used to identify the product of this reaction as a GSH adduct in which the thiol group of GSH is substituted in the 19-position of the benzoquinone ring. The reaction proceeds rapidly with GA and 17-DMAG (half-lives of approximately 1.5 and 36 min, respectively) and less rapidly with 17-AAG and its major metabolite, 17-AG (half-lives of approximately 9.8 and 16.7 h). The reaction occurs at pH 7.0, 37 degrees C, and a physiological concentration of GSH, indicating that cellular GSH could play a role in modulating the cellular toxicity of these agents and therefore be a factor in their mechanism of differential toxicity. Moreover, reactions with thiol groups of critical cellular proteins could be important to the mechanism of toxicity with this class of anticancer agents.

Antibiotics, Antineoplastic↗
PubMed2005

Snoring.

Explore the source record for details and available documents.

Behavior Therapy↗
PubMed2005

Stability and comparative metabolism of selected felbamate metabolites and postulated fluorofelbamate metabolites by postmitochondrial suspensions.

Evidence has been presented suggesting that a reactive metabolite, 2-phenylpropenal (ATPAL), may be responsible for the toxicities observed during therapy with the antiepileptic drug felbamate (FBM). Formation of ATPAL from its unstable immediate precursor, 3-carbamoyl-2-phenylpropionaldedhyde (CBMA) requires the loss of the hydrogen atom at position 2 in the propane chain, and it has been postulated that substitution of this atom with fluorine would prevent the formation of ATPAL. On the basis of this hypothesis, 2-fluoro-2-phenyl-1,3-propanediol dicarbamate (F-FBM) was synthesized and is presently undergoing drug development. To test this hypothesis, we compared the metabolism by human liver postmitochondrial suspensions (S9) in vitro of selected FBM and postulated F-FBM metabolites leading to formation of CBMA or 3-carbamoyl-2-fluoro-2-phenyl-propionaldehyde (F-CBMA). All S9 incubations included GSH as a trapping agent for any reactive metabolites formed. Our results indicated that, in phosphate buffer, pH 7.4, at 37 degrees C, the half-life for 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) was 2.8 and 3.6 h in the presence or absence of GSH, respectively; compared to 4-hydroxy-5-fluoro-5-phenyl-tetrahydro-1,3-oxazin-2-one (F-CCMF) which lost only 2.5% or 4.9% over 24 h under the same conditions. When incubated with S9 in the presence of the cofactor, NAD+, 2-phenyl-1,3-propanediol monocarbamate (MCF) was oxidized to CCMF which was further oxidized to 3-carbamoyl-2-phenylpropionic acid (CPPA). 2-Fluoro-2-phenyl-1,3-propanediol monocarbamate (F-MCF) under similar conditions was stable, and no metabolites were observed. When CCMF was incubated with S9 in the presence of NAD+ cofactor, oxidation to CPPA and reduction to MCF were observed. In addition, a new atropic acid GSH adduct (ATPA-GSH) was identified by mass spectrometry. When F-CCMF was incubated under the same conditions as CCMF, both reduced and oxidized metabolites, F-MCF and 3-carbamoyl-2-fluoro-2-phenylpropionic acid (F-CPPA), respectively, were formed but at significantly lower rates, and no GSH conjugates were identified. Our results support the hypothesis that F-FBM and F-CCMF are not metabolized by S9 in vitro to the known reactive FBM metabolite, ATPAL.

Aldehydes↗
PubMed2004

Signaling in glial development: differentiation migration and axon guidance.

Glial cells have diverse functions that are necessary for the proper development and function of complex nervous systems. During development, a variety of reciprocal signaling interactions between glia and neurons dictate all parts of nervous system development. Glia may provide attractive, repulsive, or contact-mediated cues to steer neuronal growth cones and ensure that neurons find their appropriate synaptic targets. In fact, both neurons and glia may act as migrational substrates for one another at different times during development. Also, the exchange of trophic signals between glia and neurons is essential for the proper bundling, fasciculation, and ensheathement of axons as well as the differentiation and survival of both cell types. The growing number of links between glial malfunction and human disease has generated great interest in glial biology. Because of its relative simplicity and the many molecular genetic tools available, Drosophila is an excellent model organism for studying glial development. This review will outline the roles of glia and their interactions with neurons in the embryonic nervous system of the fly.

Animals↗
PubMed2003

Developing a charter of physical activity and sport for children and youth.

OBJECTIVES: The purpose of this project was to develop a Charter of Physical Activity and Sport for Children and Youth. Its primary purpose is to provide a philosophical framework to support participation, enjoyment and safety in physical activity and sport for all Australian children and youth. METHODS: The development of the charter was initiated by The Children's Hospital at Westmead, New South Wales (NSW) and was developed in consultation with 60 parent and community groups, sporting and recreational clubs and organisations, professional associations, schools, local and state government organisations and national sporting bodies. RESULTS: The charter emphasises that physical activity and sport should be a fundamental right of all children and youth; be enjoyable; enhance health and well-being; be available for children and youth with disabilities and chronic illness; include those who are geographically isolated; be safe and free from physical and psychological abuse; be free from exploitation for political, commercial or financial gain; avoid elitism; and be encouraged by a wide cross section of the community. CONCLUSIONS: Broad consensus has been reached by most organisations with a role or interest in child and youth sport and physical activity on the foundations for participation in these activities by young people living in NSW. IMPLICATIONS: Research and evaluation of practice in Australia is essential and will allow development of evidence-based guidelines for participation in physical activity and sport for young Australians, based on the philosophy of the charter.

Adolescent↗
PubMed2002

Production of intracellular 35S-glutathione by rat and human hepatocytes for the quantification of xenobiotic reactive intermediates.

The quantification and identification of xenobiotic reactive intermediates is difficult in the absence of highly radiolabeled drug. We have developed a method for identifying these intermediates by measuring the formation of adducts to intracellularly generated radiolabeled glutathione (GSH). Freshly isolated adherent rat and human hepatocytes were incubated overnight in methionine and cystine-free ('thio-free') medium. They were then exposed to 100 microM methionine and 10 microCi 35S-labeled methionine in otherwise thio-free medium to replete cellular GSH pools with intracellularly generated 35S-labeled GSH. After 3 h, acetaminophen was added as a test compound and the cells were incubated for an additional 24 h. Intracellular GSH and its specific activity were quantified after reaction with monobromobimane followed by HPLC analysis with fluorescence and radiochemical detection. Radiolabeled GSH was detectable at 3 h and maintained high specific activity and physiological concentrations for up to 24 h. Incubation medium from acetaminophen treated and nontreated hepatocytes were analyzed for radiolabeled peaks by HPLC using radiochemical detection. Radiolabeled peaks not present in nontreated hepatocytes were identified as acetaminophen GSH adducts by LC-MS. Formation of acetaminophen 35S-GSH adducts by rat hepatocytes containing endogenously synthesized 35S-GSH was increased with acetaminophen concentrations ranging from 500 to 2 mM.

Acetaminophen↗