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Putluri N Shojaie A Vasu VT Nalluri S Vareed SK Putluri V Vivekanandan-Giri A Byun J Pennathur S Sana TR Fischer SM Palapattu GS Creighton CJ Michailidis G Sreekumar A 《PloS one》2011,6(7):e21417
Prostate cancer is the second leading cause of cancer related death in American men. Development and progression of clinically localized prostate cancer is highly dependent on androgen signaling. Metastatic tumors are initially responsive to anti-androgen therapy, however become resistant to this regimen upon progression. Genomic and proteomic studies have implicated a role for androgen in regulating metabolic processes in prostate cancer. However, there have been no metabolomic profiling studies conducted thus far that have examined androgen-regulated biochemical processes in prostate cancer. Here, we have used unbiased metabolomic profiling coupled with enrichment-based bioprocess mapping to obtain insights into the biochemical alterations mediated by androgen in prostate cancer cell lines. Our findings indicate that androgen exposure results in elevation of amino acid metabolism and alteration of methylation potential in prostate cancer cells. Further, metabolic phenotyping studies confirm higher flux through pathways associated with amino acid metabolism in prostate cancer cells treated with androgen. These findings provide insight into the potential biochemical processes regulated by androgen signaling in prostate cancer. Clinically, if validated, these pathways could be exploited to develop therapeutic strategies that supplement current androgen ablative treatments while the observed androgen-regulated metabolic signatures could be employed as biomarkers that presage the development of castrate-resistant prostate cancer. 相似文献
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Murine angiogenin-4 (mAng-4) is a member of the pancreatic ribonuclease superfamily that is expressed in some endodermally derived organs. We now show that mAng-4 is angiogenic using a thoracic aorta assay never before applied to the angiogenins. mAng-4, human angiogenin (hAng), and murine angiogenin-1 (mAng-1) stimulate the proliferation of IGR1 melanoma cells but do not stimulate the proliferation or migration of bovine corneal endothelial cells or primary mouse embryonic fibroblasts. In addition, we report the 3-D structure of mAng-4 at 2.02-A resolution. The structure shows that the residues forming the putative B1, P1, and B2 RNA-binding subsites occupy positions similar to their hAng counterparts. The B1 subsite is obstructed by Glu115 and Ile118. The obstruction is stabilized by a novel salt bridge between the C-terminal carboxyl group and the side chain of Arg99. Through mutational studies, we identify residues critical to the angiogenic function of mAng-4. The effect of H12A and H112A mutations in the catalytic site indicates that ribonucleolytic activity is essential to angiogenesis. The consequences of a nearby E115A mutation are consistent with a significant role for Glu115 in the attenuation of enzymatic activity but also suggest that sufficient suppression of catalysis is necessary for angiogenesis. The effect of an R32A mutation in the putative nuclear localization sequence indicates that this residue is crucial for angiogenesis. In the putative cell-binding segment, the replacement of Lys59 with Asn (its counterpart at position 61 of hAng) does not abrogate enzymatic activity but abolishes angiogenic activity, the reason for which is unclear. 相似文献
3.
During the process of angiogenesis, the normally quiescent endothelial cells that line the vasculature are induced to proliferate,
migrate and align to form new blood vessels by angiogenic stimuli. Assays for angiogenic factors mostly involve in vivo approaches.
The two most commonly used in vivo assays—the chick chorioallantoic membrane (CAM) assay and the rabbit corneal assay are
tedious to perform and are technically demanding. Several in vitro assays have also been developed, based on the ability of
endothelial cells to form tubes in 3-D matrices. Here, we describe the modification of a microcarrier bead-based assay. This
assay combines cells grown on Cytodex-3 microcarrier beads with Matrigel to provide an easy, rapid, and reliable method for
evaluating and measuring angiogenic activity. We also describe the differential behavior of normal and transformed endothelial
cells cultured in Matrigel. 相似文献
4.
Vasanta D 《Journal of biosciences》2005,30(1):129-137
The study of language knowledge guided by a purely biological perspective prioritizes the study of syntax. The essential process
of syntax is recursion — the ability to generate an infinite array of expressions from a limited set of elements. Researchers
working within the biological perspective argue that this ability is possible only because of an innately specified genetic
makeup that is specific to human beings. Such a view of language knowledge may be fully justified in discussions on biolinguistics,
and in evolutionary biology. However, it is grossly inadequate in understanding language-learning problems, particularly those
experienced by children with neurodevelopmental disorders such as developmental dyslexia, Williams syndrome, specific language
impairment and autism spectrum disorders. Specifically, syntax-centered definitions of language knowledge completely ignore
certain crucial aspects of language learning and use, namely, that language is embedded in a social context; that the role
of envrironmental triggering as a learning mechanism is grossly underestimated; that a considerable extent of visuo-spatial
information accompanies speech in day-to-day communication; that the developmental process itself lies at the heart of knowledge
acquisition; and that there is a tremendous variation in the orthographic systems associated with different languages. All
these (socio-cultural) factors can influence the rate and quality of spoken and written language acquisition resulting in
much variation in phenotypes associated with disorders known to have a genetic component. Delineation of such phenotypic variability
requires inputs from varied disciplines such as neurobiology, neuropsychology, linguistics and communication disorders. In
this paper, I discuss published research that questions cognitive modularity and emphasises the role of the environment for
understanding linguistic capabilities of children with neuro-developmental disorders. The discussion pertains to two specific
disorders, developmental dyslexia and Williams syndrome. 相似文献
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THE EFFECT OF ELECTRICAL STIMULATION AND HIGH POTASSIUM CONCENTRATIONS ON THE EFFLUX OF [3 H] γ-AMINOBUTYRIC ACID FROM BRAIN SLICES 总被引:10,自引:0,他引:10
Abstract— Brain slices were incubated with [3 H]GABA in a medium containing aminooxyacetic acid to prevent metabolism of [3 H]GABA by GABA-glutamate transaminase. The slices, which rapidly accumulated radioactivity, were then continuously perfused and the efflux of [3 H]GABA from the tissue was measured. The spontaneous efflux of [3 H]GABA consisted of an initial rapid phase followed by a much slower release of [3 [H]GABA. After 40 min perfusion 90 per cent of the radioactivity remained in the tissue.
The slices were depolarized by electrical stimulation or by perfusion with a medium containing a high potassium concentration (40 mM). These procedures caused a striking increase in the efflux of [3 H]GABA. The increased efflux produced by potassium, but not that produced by electrical stimulation, was dependent on calcium ions in the medium. The effect of electrical stimulation on [3 H]GABA release was considerably reduced by a raised concentration (10 mM) of magnesium in the medium.
High potassium concentrations and electrical stimulation did not cause an increase in the efflux of [14 C]urea, L-[3 H]leucine or [14 C]α-amino-isobutyric acid from brain slices. These results are consistent with the suggestion that GABA may be an inhibitory transmitter in the cerebral cortex. 相似文献
The slices were depolarized by electrical stimulation or by perfusion with a medium containing a high potassium concentration (40 mM). These procedures caused a striking increase in the efflux of [
High potassium concentrations and electrical stimulation did not cause an increase in the efflux of [
6.
Characterization of human angiogenin variants implicated in amyotrophic lateral sclerosis 总被引:1,自引:0,他引:1
Crabtree B Thiyagarajan N Prior SH Wilson P Iyer S Ferns T Shapiro R Brew K Subramanian V Acharya KR 《Biochemistry》2007,46(42):11810-11818
Human angiogenin (ANG), the first member of the angiogenin family (from the pancreatic ribonuclease A superfamily) to be identified, is an angiogenic factor that induces neovascularization. It has received much attention due to its involvement in the growth of tumors and its elevated expression level in pancreatic and several other cancers. Recently the biological role of ANG has been shown to extend to the nervous system. Mutations in ANG have been linked with familial as well as sporadic forms of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by selective destruction of motor neurons. Furthermore, mouse angiogenin-1 has been shown to be expressed in the developing nervous system and during the neuronal differentiation of pluripotent stem cells. We have now characterized the seven variants of ANG reported in ALS patients with respect to the known biochemical properties of ANG and further studied the biological properties of three of these variants. Our results show that the ribonucleolytic activity of six of the seven ANG-ALS implicated variants is significantly reduced or lost and some variants also show altered thermal stability. We report a significant reduction in the cell proliferative and angiogenic activities of the three variants that we chose to investigate further. Our studies on the biochemical and structural features of these ANG variants now form the basis for further investigations to determine their role(s) in ALS. 相似文献
7.
Validity of the Indicator Organism Paradigm for Pathogen Reduction in Reclaimed Water and Public Health Protection 总被引:3,自引:5,他引:3
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Valerie J. Harwood Audrey D. Levine Troy M. Scott Vasanta Chivukula Jerzy Lukasik Samuel R. Farrah Joan B. Rose 《Applied microbiology》2005,71(6):3163-3170
The validity of using indicator organisms (total and fecal coliforms, enterococci, Clostridium perfringens, and F-specific coliphages) to predict the presence or absence of pathogens (infectious enteric viruses, Cryptosporidium, and Giardia) was tested at six wastewater reclamation facilities. Multiple samplings conducted at each facility over a 1-year period. Larger sample volumes for indicators (0.2 to 0.4 liters) and pathogens (30 to 100 liters) resulted in more sensitive detection limits than are typical of routine monitoring. Microorganisms were detected in disinfected effluent samples at the following frequencies: total coliforms, 63%; fecal coliforms, 27%; enterococci, 27%; C. perfringens, 61%; F-specific coliphages, ~40%; and enteric viruses, 31%. Cryptosporidium oocysts and Giardia cysts were detected in 70% and 80%, respectively, of reclaimed water samples. Viable Cryptosporidium, based on cell culture infectivity assays, was detected in 20% of the reclaimed water samples. No strong correlation was found for any indicator-pathogen combination. When data for all indicators were tested using discriminant analysis, the presence/absence patterns for Giardia cysts, Cryptosporidium oocysts, infectious Cryptosporidium, and infectious enteric viruses were predicted for over 71% of disinfected effluents. The failure of measurements of single indicator organism to correlate with pathogens suggests that public health is not adequately protected by simple monitoring schemes based on detection of a single indicator, particularly at the detection limits routinely employed. Monitoring a suite of indicator organisms in reclaimed effluent is more likely to be predictive of the presence of certain pathogens, and a need for additional pathogen monitoring in reclaimed water in order to protect public health is suggested by this study. 相似文献
8.
Validity of the indicator organism paradigm for pathogen reduction in reclaimed water and public health protection 总被引:5,自引:0,他引:5
Harwood VJ Levine AD Scott TM Chivukula V Lukasik J Farrah SR Rose JB 《Applied and environmental microbiology》2005,71(6):3163-3170
The validity of using indicator organisms (total and fecal coliforms, enterococci, Clostridium perfringens, and F-specific coliphages) to predict the presence or absence of pathogens (infectious enteric viruses, Cryptosporidium, and Giardia) was tested at six wastewater reclamation facilities. Multiple samplings conducted at each facility over a 1-year period. Larger sample volumes for indicators (0.2 to 0.4 liters) and pathogens (30 to 100 liters) resulted in more sensitive detection limits than are typical of routine monitoring. Microorganisms were detected in disinfected effluent samples at the following frequencies: total coliforms, 63%; fecal coliforms, 27%; enterococci, 27%; C. perfringens, 61%; F-specific coliphages, approximately 40%; and enteric viruses, 31%. Cryptosporidium oocysts and Giardia cysts were detected in 70% and 80%, respectively, of reclaimed water samples. Viable Cryptosporidium, based on cell culture infectivity assays, was detected in 20% of the reclaimed water samples. No strong correlation was found for any indicator-pathogen combination. When data for all indicators were tested using discriminant analysis, the presence/absence patterns for Giardia cysts, Cryptosporidium oocysts, infectious Cryptosporidium, and infectious enteric viruses were predicted for over 71% of disinfected effluents. The failure of measurements of single indicator organism to correlate with pathogens suggests that public health is not adequately protected by simple monitoring schemes based on detection of a single indicator, particularly at the detection limits routinely employed. Monitoring a suite of indicator organisms in reclaimed effluent is more likely to be predictive of the presence of certain pathogens, and a need for additional pathogen monitoring in reclaimed water in order to protect public health is suggested by this study. 相似文献
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Ribonuclease A homologues of the zebrafish: polymorphism, crystal structures of two representatives and their evolutionary implications 总被引:1,自引:0,他引:1
Kazakou K Holloway DE Prior SH Subramanian V Acharya KR 《Journal of molecular biology》2008,380(1):206-222
The widespread and functionally varied members of the ribonuclease A (RNase A) superfamily provide an excellent opportunity to study evolutionary forces at work on a conserved protein scaffold. Representatives from the zebrafish are of particular interest as the evolutionary distance from non-ichthyic homologues is large. We conducted an exhaustive survey of available zebrafish DNA sequences and found significant polymorphism among its four known homologues. In an extension of previous nomenclature, the variants have been named RNases ZF-1a-c,-2a-d,-3a-e and-4. We present the first X-ray crystal structures of zebrafish ribonucleases, RNases ZF-1a and-3e at 1.35-and 1.85 Å resolution, respectively. Structure-based clustering with ten other ribonuclease structures indicates greatest similarity to mammalian angiogenins and amphibian ribonucleases, and supports the view that all present-day ribonucleases evolved from a progenitor with three disulphide bonds. In their details, the two structures are intriguing melting-pots of features present in ribonucleases from other vertebrate classes. Whereas in RNase ZF-1a the active site is obstructed by the C-terminal segment (as observed in angiogenin), in RNase ZF-3e the same region is open (as observed in more catalytically efficient homologues). The progenitor of present-day ribonucleases is more likely to have had an obstructive C terminus, and the relatively high similarity (late divergence) of RNases ZF-1 and-3 infers that the active site unblocking event has happened independently in different vertebrate lineages. 相似文献
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