bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endocannabinoid metabolism in human glioblastomas and meningiomas compared to human non‐tumour brain tissue
Authors: Petersen Gitte , Moesgaard Birthe , Schmid Patricia C. , Schmid Harald H. O. , Broholm Helle , Kosteljanetz Michael , Hansen Harald S. 
Published: March 2005

AbstractThe endogenous levels of the two cannabinoid receptor ligands 2‐arachidonoyl glycerol and anandamide, and their respective congeners, monoacyl glycerols and N‐acylethanolamines, as well as the phospholipid precursors of N‐acylethanolamines, were measured by gas chromatography‐mass spectrometry in glioblastoma (WHO grade IV) tissue and meningioma (WHO grade I) tissue and compared with human non‐tumour brain tissue. Furthermore, the metabolic turnover of N‐acylethanolamines was compared by measurements of the enzymatic activity of N‐acyltransferase, N‐acylphosphatidylethanolamine‐hydrolysing phospholipase D and fatty acid amide hydrolase in the same three types of tissue. Glioblastomas were characterized by enhanced levels of N‐acylethanolamines (eightfold, 128 ± 59 pmol/μmol lipid phosphorus) including anandamide (17‐fold, 4.6 ± 3.1pmol/μmol lipid phosphorus) and several species of N‐acylphosphatidylethanolamines (three to eightfold). This was accompanied by a more than 60% reduction in the enzyme activities of N‐acylphosphatidylethanolamine‐hydrolysing phospholipase D and fatty acid amide hydrolase. By contrast, meningiomas were characterized by a massively enhanced level of 2‐monoacyl glycerols (20‐fold, 2293 ± 361 pmol/μmol lipid phosphorus) including 2‐arachidonoyl glycerol (20‐fold, 1524 ± 361 pmol/μmol lipid phosphorus). This was accompanied by an enhanced in vitro conversion of phosphatidylcholine to monoacyl glycerol (fivefold). The enhanced level of the 2‐arachidonoyl glycerol, anandamide and other N‐acylethanolamines detected in the two types of tumour tissue may possibly act as endogenous anti‐tumour mediators by stimulation of both cannabinoid and non‐cannabinoid receptor‐mediated mechanisms.
Alterations in the solubility and intracellular localization of parkin by several familial Parkinson's disease‐linked point mutations
Authors: Wang Cheng , Tan Jeanne M. M. , Ho Michelle W. L. , Zaiden Norazean , Wong Siew Heng , Chew Constance L. C. , Eng Pei Woon , Lim Tit Meng , Dawson Ted M. , Lim Kah Leong 
Published: March 2005

AbstractMutations in the parkin gene, which encodes a ubiquitin ligase, are currently recognized as the main contributor to familial forms of Parkinson's disease (PD). A simple assumption about the effects of PD‐linked mutations in parkin is that they impair or ablate the enzyme activity. However, a number of recent studies, including ours, have indicated that many disease‐linked point mutants of parkin retain substantial catalytic activity. To understand how the plethora of mutations on parkin contribute to its dysfunction, we have conducted a systematic analysis of a significant number of parkin point mutants (22 in total), which represent the majority of parkin missense/nonsense mutations reported to date. We found that more than half of these mutations, including many located outside of the parkin RING fingers, produce alteration in the solubility of parkin which influences its detergent extraction property. This mutation‐mediated alteration in parkin solubility is also associated with its propensity to form intracellular, aggresome‐like, protein aggregates. However, they do not represent sites where parkin substrates become sequestered. As protein aggregation sequesters the functional forms away from their normal sites of action, our results suggest that alterations in parkin solubility and intracellular localization may underlie the molecular basis of the loss of function caused by several of its mutations.
Cloning and characterization of a Family C orphan G‐protein coupled receptor
Authors: Kuang Donghui , Yao Yi , Lam Janice , Tsushima Robert G. , Hampson David R. 
Published: March 2005

AbstractMembers of the family C receptors within the G‐protein coupled receptor superfamily include the metabotropic glutamate receptors, GABAB receptors, the calcium‐sensing receptor (CaSR), the V2R pheromone receptors, the T1R taste receptors, and a small group of uncharacterized orphan receptors. We have cloned and studied the mouse GPRC6A family C orphan receptor. The open reading frame codes for a protein with highest sequence identity to the fish 5.24 odorant receptor and the mammalian CaSR. The gene structure shows a striking resemblance to that of the CaSR. Results from RT‐PCR analyses showed that mouse GPRC6A mRNA is expressed in mouse brain, skeletal muscle, heart, lung, spleen, kidney, liver, and in the early stage mouse embryo. Immunocytochemical analysis of the cloned mouse GPRC6A cDNA expressed in human embryonic kidney 293 cells demonstrated that GPRC6A was present on the plasma membrane, as well as in the endoplasmic reticulum and nuclear envelope membranes of transfected cells. A chimeric cDNA construct in which the extracellular ligand binding domain of the fish 5.24 amino acid‐activated odorant receptor was ligated to the complementary downstream sequence of the mouse GPRC6A receptor indicated that GPRC6A is coupled to phosphoinositol turnover and release of intracellular calcium. Further studies with mouse GPRC6A expressed in Xenopus laevis ooctyes demonstrated that this receptor possesses a pharmacological profile resembling that of the fish 5.24 odorant receptor. These findings suggest that GPRC6A may function as the receptor component of a novel cellular transmitter system in mammals.
Differential phosphodiesterase expression and cytosolic Ca2+ in human CNS tumour cells and in non‐malignant and malignant cells of rat origin
Authors: Vatter Sandra , Pahlke Gudrun , Deitmer Joachim W. , Eisenbrand Gerhard 
Published: March 2005

AbstractA promising attempt in the field of tumour therapy is the modulation of intracellular, proliferation‐associated signalling pathways. The role of cyclic nucleotide phosphodiesterases (PDEs), key enzymes in cAMP/cGMP signal transduction, was investigated in two human CNS tumour cell lines as well as in the rat glioblastoma cell line C6 in comparison with rat cerebellar astrocytes with the emphasis on target evaluation. We found differential PDE expression patterns in human CNS tumour cell lines as well as in CNS cells of rat origin. In human glioblastoma cells, intracellular cAMP and Ca2+ levels correlated well with the PDE expression pattern. There were, however, marked differences in PDE expression and Ca2+ kinetics between the human glioblastoma cell lines. In contrast to human epithelial tumour cells, shown earlier by us to express significantly enhanced cAMP‐specific PDE activity, this was not the case in rat glioblastoma cells compared with non‐malignant rat astrocytes. Despite different levels of PDE1 and PDE4 expression and activity, cyclic nucleotide and Ca2+ levels in non‐malignant and malignant rat CNS cells were similar. These in vitro data do not support the concept of PDE1C representing a target exploitable for drug treatment of malignant CNS tumours.
CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model
Authors: Chou Szu‐Yi , Lee Yi‐Chao , Chen Hui‐Mei , Chiang Ming‐Chang , Lai Hsing‐Lin , Chang Hao‐Hung , Wu Yi‐Chih , Sun Chung‐Nan , Chien Chen‐Li , Lin Yow‐Sien , Wang Shyi‐Chyi , Tung Yu‐Ying , Chang Chen , Chern Yijuang 
Published: March 2005

AbstractHuntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in exon 1 of the Huntingtin (Htt) gene. We show herein that in an HD transgenic mouse model (R6/2), daily administration of CGS21680 (CGS), an A2A adenosine receptor (A2A‐R)‐selective agonist, delayed the progressive deterioration of motor performance and prevented a reduction in brain weight. 3D‐µMRI analysis revealed that CGS reversed the enlarged ventricle‐to‐brain ratio of R6/2 mice, with particular improvements in the left and right ventricles. 1H‐MRS showed that CGS significantly reduced the increased choline levels in the striatum. Immunohistochemical analyses further demonstrated that CGS reduced the size of ubiquitin‐positive neuronal intranuclear inclusions (NIIs) in the striatum of R6/2 mice and ameliorated mutant Htt aggregation in a striatal progenitor cell line overexpressing mutant Htt with expanded polyQ. Moreover, chronic CGS treatment normalized the elevated blood glucose levels and reduced the overactivation of a major metabolic sensor [5′AMP‐activated protein kinase (AMPK)] in the striatum of R6/2 mice. Since AMPK is a master switch for energy metabolism, modulation of energy dysfunction caused by the mutant Htt might contribute to the beneficial effects of CGS. Collectively, CGS is a potential drug candidate for the treatment of HD.
Selective serotonin reuptake blockade increases extracellular dopamine in noradrenaline‐rich isocortical but not prefrontal areas: dependence on serotonin‐1A receptors and independence from noradrenergic innervation
Authors: Valentini V. , Cacciapaglia F. , Frau R. , Di Chiara G. 
Published: March 2005

AbstractThe present study investigated the effects of two serotonin (5‐HT) uptake inhibitors, citalopram and paroxetine, and of a non‐selective noradrenaline (NA) and 5‐HT uptake blocker, imipramine, on extracellular NA and dopamine (DA) in the prefrontal cortex (PfCX), parietal cortex (ParCX) and occipital cortex (OccCX). Citalopram, the most selective 5‐HT uptake blocker, increased dialysate DA in the OccCX and ParCX but not in the PfCX and this effect was prevented in the OccCX by WAY‐100635, an antagonist of serotonin‐1A (5‐HT1A) receptors, but not by dorsal noradrenergic bundle (DNAB) lesions that reduced to unmeasurable levels basal dialysate NA but did not affect dialysate DA. Paroxetine, a less selective 5‐HT uptake inhibitor than citalopram, at the dose of 5 mg/kg, increased DA in the OccCX but not in the PfCX; however, at doses of 10 mg/kg, which increase PfCX NA, paroxetine increased DA also in this area. Imipramine increased dialysate DA and NA both in the PfCX and in the OccCX and this effect was abolished by DNAB lesions and was reduced but not abolished by WAY‐100635. Administration of doses of reboxetine and citalopram that do not increase DA release in the OccCX if given separately, markedly increased DA when combined. These results indicate that endogenous 5‐HT, raised by selective blockade of the 5‐HT carrier, can increase extracellular DA in the OccCX and in the ParCX by stimulating 5‐HT1A receptors independently from the presence of NA terminals, although blockade of 5‐HT and NA carrier can strongly interact to raise extracellular DA in this area. These observations are consistent with the existence of DA neurons separate from the NA ones contributing to extracellular DA even in NA‐rich/DA poor isocortical areas.
Stage‐ and site‐specific DNA demethylation during neural cell development from embryonic stem cells
Authors: Shimozaki Koji , Namihira Masakazu , Nakashima Kinichi , Taga Tetsuya 
Published: March 2005

AbstractActivation of the transcription factor STAT3 is important for astrocyte differentiation during neural development. Demethylation of the methyl‐CpG dinucleotide in the STAT3 binding site in the promoter of the glial fibrillary acidic protein (GFAP) gene, a marker for astrocytes, was previously shown to be a crucial cue for neural progenitors to express this gene in response to astrogenic signals during brain development. In this study, we analyzed the methylation status of the STAT3 binding site in the GFAP gene promoter during neural cell development from mouse embryonic stem (ES) cells in vitro. The CpG dinucleotide in the STAT3 binding site in the GFAP gene promoter exhibited a high incidence of cytidine‐methylation in undifferentiated pluripotent ES cells. The high incidence of methylation of this particular cytidine was maintained in ES cell‐derived neuroectoderm‐like cells, but it underwent demethylation when the neural lineage cells became competent to express GFAP in response to a STAT3 activation signal. In contrast, hypermethylation of the CpG site was maintained in non‐neural cells generated from the same ES cells. Progressive demethylation of the STAT3 binding site in the GFAP gene promoter was also observed in primary embryonic neuroepithelial cells during in vitro culture, whereas non‐neural cells maintained hypermethylation of this site even after culture. Taken together, these results demonstrate that the astrocyte gene‐specific cytidine‐demethylation is programmed when neural progenitors from pluripotent cells are committed to a neural lineage that is capable of producing astrocytes.
Impaired long‐term potentiation in c‐Jun N‐terminal kinase 2‐deficient mice
Authors: Chen Ju‐Tao , Lu Da‐Hua , Chia Chern‐Pang , Ruan Di‐Yun , Sabapathy Kanaga , Xiao Zhi‐Cheng 
Published: March 2005

Abstractc‐Jun N‐terminal kinases (JNKs) are thought to be involved in regulating synaptic plasticity. We therefore investigated the specific role of JNK2 in modulating long‐term potentiation (LTP) in hippocampus during development, using JNK2‐deficient mice. The morphological structure and the numbers of both NeuN, a specific neuronal marker, and GABA‐positive neurons in the hippocampal areas were similar in wild‐type and Jnk2–/– mice. Western blot analysis revealed that JNK2 expression was higher and stable at 1 and 3 months of age, but JNK1 levels were lower at 1 month of age and almost undetectable in 3‐month‐old wild‐type mice. In contrast to wild‐type mice, there was a significant increase in JNK1 expression in JNK2 mutant mice, especially at 1 month of age. Electrophysiological studies demonstrated that LTP was impaired in both the CA1 and CA3 regions in 1‐month‐old, but not in adult, Jnk2–/– mice, probably owing to decreased presynaptic neurotransmitter release. Moreover, late‐phase LTP, but not early‐phase LTP, was impaired in the Jnk2–/– adult mice, suggesting that JNK2 plays a role in transforming early LTP to late LTP. Together, the data highlight the specific role of JNK2 in hippocampal synaptic plasticity during development.
Astroglial cytoprotection by erythropoietin pre‐conditioning: implications for ischemic and degenerative CNS disorders
Authors: Diaz Zuanel , Assaraf Michael I. , Miller Wilson H. , Schipper Hyman M. 
Published: March 2005

AbstractErythropoietin (Epo) is a glycoprotein secreted by the kidney in response to hypoxia that stimulates erythropoiesis through interaction with cell surface Epo receptors. Pre‐treatment with Epo has been shown to protect neurons in models of ischemic injury. The mechanism responsible for this neuroprotection and the effects of Epo on astroglial and other non‐neuronal cell populations remain unknown. In the present study, we determined whether Epo pre‐treatment protects neonatal rat astrocytes from apoptotic cell death resulting from treatment with nitric oxide, staurosporine (STS) and arsenic trioxide and possible mechanisms mediating Epo‐related cytoprotection. Epo (5–20 U/mL) significantly attenuated multiple hallmarks of apoptotic cell death in astroglia exposed to nitric oxide and STS but not arsenic trioxide. Epo (20 U/mL) induced mild oxidative stress as shown by increases in heme oxygenase (HO)‐1 mRNA and protein expression that could be suppressed by antioxidant coadministration. Moreover, coincubation with tin‐mesoporphyrin, a competitive inhibitor of HO activity, abrogated the cytoprotective effects of Epo (20 U/mL) in the face of STS treatment. Thus, induction of the ho‐1 gene may contribute to the glioprotection accruing from high‐dose Epo exposure. Epo may augment astroglial resistance to certain chemical stressors by oxidative stress‐dependent and ‐independent mechanisms.
Histone deacetylase inhibitors decrease reelin promoter methylation in vitro
Authors: Mitchell Colin P. , Chen Ying , Kundakovic Marija , Costa Erminio , Grayson Dennis R. 
Published: March 2005

AbstractWe investigated the effects of agents that induce reelin mRNA expression in vitro on the methylation status of the human reelin promoter in neural progenitor cells (NT2). NT2 cells were treated with the histone deacetylase inhibitors, trichostatin A (TSA) and valproic acid (VPA), and the methylation inhibitor aza‐2′‐deoxycytidine (AZA) for various times. All three drugs reduced the methylation profile of the reelin promoter relative to untreated cells. The acetylation status of histones H3 and H4 increased following treatment with VPA and TSA at times as short as 15 min following treatment; a result consistent with the reported mode of action of these drugs. Chromatin immunoprecipitation experiments showed that these changes were accompanied by changes occurring at the level of the reelin promoter as well. Interestingly, AZA decreased reelin promoter methylation without concomittantly increasing histone acetylation. In fact, after prolonged treatments with AZA, the acetylation status of histones H3 and H4 decreased relative to untreated cells. We also observed a trend towards reduced methylated H3 after 18 h treatment with TSA and VPA. Our data indicate that while TSA and VPA act to increase histone acetylation and reduce promoter methylation, AZA acts only to decrease the amount of reelin promoter methylation.
Sp1 and Sp3 activate transcription of the human dopamine transporter gene
Authors: Wang Jun , Bannon Michael J. 
Published: March 2005

AbstractThe dopamine transporter is a plasma membrane protein that controls extracellular concentrations of the neurotransmitter dopamine. The physiological importance of the DAT provides the impetus for studies aimed at understanding the molecular mechanisms underlying regulation of the DAT gene. In this study, we identified a DAT‐expressing neuroblastoma cell line (SK‐N‐AS) and employed it to investigate the transcriptional regulation of the human DAT gene. Two GC boxes (located at −130 and −60, respectively, relative to the transcriptional start site) were identified as important cis‐acting elements mediating DAT promoter activity in dopaminergic SK‐N‐AS cells. Utilizing Sp‐deficient Drosophila Schneider line (SL‐2) cells, we showed that both Sp1 and Sp3 are strong activators of DAT transcriptional activity. Differential binding of Sp1 and Sp3 to the two GC boxes was demonstrated by electrophoretic mobility shift assays and super‐shift assays. Our results indicate that the Sp1 family of proteins plays an important role in controlling the expression of the dopamine transporter gene within dopaminergic neurons.
Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6‐methyl‐phenyl‐tetrahydropyridine toxicity
Authors: Conti Bruno , Sugama Shuei , Lucero Jacinta , Winsky‐Sommerer Raphaelle , Wirz Sebastian A. , Maher Pamela , Andrews Zane , Barr Alasdair M. , Morale Maria C. , Paneda Covadonga , Pemberton Janell , Gaidarova Svetlana , Behrens M. Margarita , Beal Flint , Sanna Pietro Paolo , Horvath Tamas , Bartfai Tamas 
Published: March 2005

AbstractOxidative stress is implicated in the death of dopaminergic neurons in sporadic forms of Parkinson's disease. Because oxidative stress can be modulated endogenously by uncoupling proteins (UCPs), we hypothesized that specific neuronal expression of UCP2, one member of the UCP family that is rapidly induced in the CNS following insults, could confer neuroprotection in a mouse model of Parkinson's disease. We generated transgenic mice overexpressing UCP2 in catecholaminergic neurons under the control of the tyrosine hydroxylase promoter (TH‐UCP2). In these mice, dopaminergic neurons of the substantia nigra showed a twofold elevation in UCP2 expression, elevated uncoupling of their mitochondria, and a marked reduction in indicators of oxidative stress, an effect also observed in the striatum. Upon acute exposure to 1,2,3,6‐methyl‐phenyl‐tetrahydropyridine, TH‐UCP2 mice showed neuroprotection and retention of locomotor functions. Our data suggest that UCP2 may represent a drug target for slowing the progression of Parkinson's disease.
Control of cyclin‐dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability
Authors: Wei Fan‐Yan , Tomizawa Kazuhito , Ohshima Toshio , Asada Akiko , Saito Taro , Nguyen Chan , Bibb James A. , Ishiguro Koichi , Kulkarni Ashok B. , Pant Harish C. , Mikoshiba Katsuhiko , Matsui Hideki , Hisanaga Shin‐ichi 
Published: March 2005

AbstractAlthough the roles of cyclin‐dependent kinase 5 (Cdk5) in neurodevelopment and neurodegeneration have been studied extensively, regulation of Cdk5 activity has remained largely unexplored. We report here that glutamate, acting via NMDA or kainate receptors, can induce a transient Ca2+/calmodulin‐dependent activation of Cdk5 that results in enhanced autophosphorylation and proteasome‐dependent degradation of a Cdk5 activator p35, and thus ultimately down‐regulation of Cdk5 activity. The relevance of this regulation to synaptic plasticity was examined in hippocampal slices using theta burst stimulation. p35–/– mice exhibited a lower threshold for induction of long‐term potentiation. Thus excitatory glutamatergic neurotransmission regulates Cdk5 activity through p35 degradation, and this pathway may contribute to plasticity.
Sex‐specific foraging behaviour in tropical boobies: does size matter?
Authors: LEWIS SUE , SCHREIBER E. A. , DAUNT FRANCIS , SCHENK GARY A. , ORR KATE , ADAMS AILEEN , WANLESS SARAH , HAMER KEITH C. 
Published: March 2005

Sex differences in the foraging behaviour of adults have been observed in a number of sexually size‐dimorphic birds, and the usual inference has been that these sex‐specific differences are driven primarily by differences in body size. An alternative explanation is that foraging differences result from sex differences unrelated to size, such as sex‐specific nutritional requirements. To examine these alternative hypotheses, the foraging behaviour of parents was compared between two sympatric and congeneric species of seabird, the Brown Booby Sula leucogaster, which is highly sexually size‐dimorphic (females 38% larger) and the Red‐footed Booby S. sula, in which sex differences in body size are less marked (females 15% larger). Using temperature and depth loggers, we found that there were highly significant differences in the foraging trip durations and diving behaviour of male and female Brown Boobies. These sex differences were less marked in Red‐footed Boobies. Thus, our interspecies comparison revealed that the magnitude of the difference between the sexes matched the sexual size dimorphism of the species, providing support for the size hypothesis.
X‐linked Reticulate Pigmentary Disorder with Systemic Manifestations: Report of a Third Family and Literature Review
Authors: Anderson Robert C. , Zinn Andrew R. , Kim June , Carder K. Robin 
Published: March 2005

Abstract:  Three siblings, two boys and one girl, presented with pigmentary abnormalities. The brothers, ages 11 and 6 years, had diffuse reticulate macular hyperpigmentation with onset in early childhood. In addition, these boys had hypohydrosis, coarse hair with an upswept frontal hairline, failure to thrive, and chronic pulmonary disease. The older boy also had corneal dystrophy and marked photophobia. A punch biopsy specimen from the 11‐year‐old showed melanophages and necrotic keratinocytes. Stains for amyloid were negative. The sister, age 2 years, had congenital linear hyperpigmented patches involving the intertrigenous areas, but was otherwise normal. The clinical findings of these children were consistent with X‐linked reticulate pigmentary disorder with systemic manifestations. We present a summary of the clinical manifestations of this rare disorder and discuss efforts to identify the causative gene.