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71.
Ajit G. Thomas Cliona M. O’Driscoll Joseph Bressler Walter E. Kaufmann Camilo J. Rojas Barbara S. Slusher 《Biochemical and biophysical research communications》2014
Glutaminase plays a critical role in the generation of glutamate, a key excitatory neurotransmitter in the CNS. Excess glutamate release from activated macrophages and microglia correlates with upregulated glutaminase suggesting a pathogenic role for glutaminase. Both glutaminase siRNA and small molecule inhibitors have been shown to decrease excess glutamate and provide neuroprotection in multiple models of disease, including HIV-associated dementia (HAD), multiple sclerosis and ischemia. Consequently, inhibition of glutaminase could be of interest for treatment of these diseases. Bis-2-(5-phenylacetimido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and 6-diazo-5-oxo-l-norleucine (DON), two most commonly used glutaminase inhibitors, are either poorly soluble or non-specific. Recently, several new BPTES analogs with improved physicochemical properties were reported. To evaluate these new inhibitors, we established a cell-based microglial activation assay measuring glutamate release. Microglia-mediated glutamate levels were significantly augmented by tumor necrosis factor (TNF)-α, phorbol 12-myristate 13-acetate (PMA) and Toll-like receptor (TLR) ligands coincident with increased glutaminase activity. While several potent glutaminase inhibitors abrogated the increase in glutamate, a structurally related analog devoid of glutaminase activity was unable to block the increase. In the absence of glutamine, glutamate levels were significantly attenuated. These data suggest that the in vitro microglia assay may be a useful tool in developing glutaminase inhibitors of therapeutic interest. 相似文献
72.
Youngil Cho Charles T. Driscoll Chris E. Johnson Thomas G. Siccama 《Biogeochemistry》2010,100(1-3):3-20
Liming has been used to mitigate effects of acidic deposition in forest ecosystems. This study was designed to examine the effects of calcium (Ca) supply on the spatial patterns and the relations between soil and soil solution chemistry in a base-poor forest watershed. Watershed 1 at the Hubbard Brook Experimental Forest in New Hampshire, USA was experimentally treated with wollastonite (CaSiO3) in October, 1999. Exchangeable Ca (Ex-Ca), soil pHs (in 0.01 M CaCl2), effective cation exchange capacity (CECe), and effective base saturation (BSe) increased, while exchangeable acidity (Ex-Acid) decreased in organic soil horizons in 2000 and 2002. Mineral soils experienced either small increases in Ex-Ca, pHs, CECe, BSe, small decreases in Ex-Acid or no changes. Thus, most of the added Ca remained in the forest floor during the study period. Prior to the treatment the BSe decreased with increasing elevation in organic and mineral soil horizons. This spatial pattern changed significantly in the forest floor after the treatment, suggesting that soils at higher elevations were more responsive to the chemical addition than at lower elevations. Soil solutions draining the forest floor responded to the treatment by increases in concentrations of Ca, dissolved silica, pH, and acid neutralizing capacity (ANC), and a decrease in inorganic monomeric Al (Ali). Treatment effects diminished with increasing soil depth and decreasing elevation. Positive correlations between Ca/total monomeric Al (Alm) in soil solution and Ex-Ca/Ex-Al ratios in soil indicated that changes in the chemistry of soils significantly influenced the chemistry of soil water, and that Ca derived from the dissolution of wollastonite mitigated the mobilization of Al within the experimental watershed. 相似文献
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Improving health of the rapidly growing aging population is a critical medical, social, and economic goal. Identification of genes that modulate healthspan, the period of mid‐life vigor that precedes significant functional decline, will be an essential part of the effort to design anti‐aging therapies. Because locomotory decline in humans is a major contributor to frailty and loss of independence and because slowing of movement is a conserved feature of aging across phyla, we screened for genetic interventions that extend locomotory healthspan of Caenorhabditis elegans. From a group of 54 genes previously noted to encode secreted proteins similar in sequence to extracellular domains of insulin receptor, we identified two genes for which RNAi knockdown delayed age‐associated locomotory decline, conferring a high performance in advanced age phenotype (Hpa). Unexpectedly, we found that hpa‐1 and hpa‐2 act through the EGF pathway, rather than the insulin signaling pathway, to control systemic healthspan benefits without detectable developmental consequences. Further analysis revealed a potent role of EGF signaling, acting via downstream phospholipase C‐γplc‐3 and inositol‐3‐phosphate receptor itr‐1, to promote healthy aging associated with low lipofuscin levels, enhanced physical performance, and extended lifespan. This study identifies HPA‐1 and HPA‐2 as novel negative regulators of EGF signaling and constitutes the first report of EGF signaling as a major pathway for healthy aging. Our data raise the possibility that EGF family members should be investigated for similar activities in higher organisms. 相似文献
76.
The most extensive regenerative ability in adult vertebrates is found in the salamanders. Although it is often suggested that regeneration is an ancestral property for vertebrates, our studies on the cell-surface three-finger-protein Prod 1 provide clear evidence for the importance of local evolution of limb regeneration in salamanders. Prod 1 is implicated in both patterning and growth in the regeneration of limbs. It interacts with well-conserved proteins such as the epidermal growth-factor receptor and the anterior gradient protein that are widely expressed in phylogeny. A detailed analysis of the structure and sequence of Prod 1 in relation to other vertebrate three-finger proteins in mammals and zebra fish supports the view that it is a salamander-specific protein. This is the first example of a taxon-specific protein that is clearly implicated in the mechanisms of regeneration. We propose the hypothesis that regeneration depends on the activity of taxon-specific components in orchestrating a cellular machinery that is extensively conserved between regenerating and non-regenerating taxa. This hypothesis has significant implications for our outlook on regeneration in vertebrates, as well as for the strategies employed in extending regenerative ability in mammals. 相似文献
77.
Donnacha O’Driscoll 《Cytotechnology》2007,53(1-3):127-130
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This article provides an overview of the development, theoretical basis, regulatory status, and application of the U.S. Environmental Protection Agency's (USEPA's) Equilibrium Partitioning Sediment Benchmarks (ESBs) for PAH mixtures. ESBs are compared to other sediment quality guidelines (SQGs) for PAHs. Data that examine the ability of the ESB approach to predict toxic effects to invertebrates are discussed. A USEPA draft methodology for the development of site-specific ESBs that takes into account the limited bioavailability of PAHs at certain sites is discussed. Research is presented that compares the ability of ESBs and site-specific ESBs to predict the toxicity of sediments collected from manufactured gas plants (MGPs). Site-specific ESBs that accounted for adsorption of PAHs onto black carbon were better predictors of the toxicity of sediments from MGP sites than ESBs that did not account for adsorption to black carbon. 相似文献
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