bluuebunny/crossref_metadata_2025_split huggingface dataset:
British Nutrition Foundation annual lecture: Chips with everything? Nutritional genomics and the application of diet in disease prevention
Authors: Williams Christine M. 
Published: May 2003

SummaryThe development of high throughput techniques (‘chip’ technology) for measurement of gene expression and gene polymorphisms (genomics), and techniques for measuring global protein expression (proteomics) and metabolite profile (metabolomics) are revolutionising life science research, including research in human nutrition. In particular, the ability to undertake large‐scale genotyping and to identify gene polymorphisms that determine risk of chronic disease (candidate genes) could enable definition of an individual's risk at an early age. However, the search for candidate genes has proven to be more complex, and their identification more elusive, than previously thought. This is largely due to the fact that much of the variability in risk results from interactions between the genome and environmental exposures. Whilst the former is now very well defined via the Human Genome Project, the latter (e.g. diet, toxins, physical activity) are poorly characterised, resulting in inability to account for their confounding effects in most large‐scale candidate gene studies. The polygenic nature of most chronic diseases offers further complexity, requiring very large studies to disentangle relatively weak impacts of large numbers of potential ‘risk’ genes. The efficacy of diet as a preventative strategy could also be considerably increased by better information concerning gene polymorphisms that determine variability in responsiveness to specific diet and nutrient changes. Much of the limited available data are based on retrospective genotyping using stored samples from previously conducted intervention trials. Prospective studies are now needed to provide data that can be used as the basis for provision of individualised dietary advice and development of food products that optimise disease prevention. Application of the new technologies in nutrition research offers considerable potential for development of new knowledge and could greatly advance the role of diet as a preventative disease strategy in the 21st century. Given the potential economic and social benefits offered, funding for research in this area needs greater recognition, and a stronger strategic focus, than is presently the case. Application of genomics in human health offers considerable ethical and societal as well as scientific challenges. Economic determinants of health care provision are more likely to resolve such issues than scientific developments or altruistic concerns for human health.
Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer's disease
Authors: Matsubara Etsuro , Bryant‐Thomas Tara , Pacheco Quinto Javier , Henry Tracey L. , Poeggeler Burkhard , Herbert Donald , Cruz‐Sanchez Felix , Chyan Yau‐Jan , Smith Mark A. , Perry George , Shoji Mikio , Abe Koji , Leone Anna , Grundke‐Ikbal Inge , Wilson Glen L. , Ghiso Jorge , Williams Christina , Refolo Lorenzo M. , Pappolla Miguel A. 
Published: May 2003

AbstractIncreased levels of a 40–42 amino‐acid peptide called the amyloid β protein (Aβ) and evidence of oxidative damage are early neuropathological markers of Alzheimer's disease (AD). Previous investigations have demonstrated that melatonin is decreased during the aging process and that patients with AD have more profound reductions of this hormone. It has also been recently shown that melatonin protects neuronal cells from Aβ‐mediated oxidative damage and inhibits the formation of amyloid fibrils in vitro. However, a direct relationship between melatonin and the biochemical pathology of AD had not been demonstrated. We used a transgenic mouse model of Alzheimer's amyloidosis and monitored over time the effects of administering melatonin on brain levels of Aβ, abnormal protein nitration, and survival of the mice. We report here that administration of melatonin partially inhibited the expected time‐dependent elevation of β‐amyloid, reduced abnormal nitration of proteins, and increased survival in the treated transgenic mice. These findings may bear relevance to the pathogenesis and therapy of AD.
A role for semaphorins and neuropilins in oligodendrocyte guidance
Authors: Cohen Rick I. , Rottkamp Daniele M. , Maric Dragan , Barker Jeffery L. , Hudson Lynn D. 
Published: May 2003

AbstractOligodendrocytes develop in defined CNS regions as progenitor cells, which migrate to their final destinations, encountering soluble and membrane‐bound signals that influence their differentiation and potential to myelinate axonal projections. To identify the regulatory genes that may be involved in this process, microarray analysis of developing oligodendroglia was performed. Several neural guidance genes, including members of the neuropilin (NP) and semaphorin families were detected. These findings were verified and expanded upon using RT–PCR with RNA from fluorescent activated cell sorted A2B5+ oligodendrocyte progenitors and O4+ pro‐oligodendrocytes isolated from in vitro and in vivo sources. RT–PCR, western and immunocytochemical analyses revealed that oligodendrocytes expressed NP1, several alternatively spliced isoforms of NP2, and a broad spectrum of both soluble (Class 3), membrane‐spanning (Class 4–6), and membrane‐tethered (Class 7) semaphorin ligands. Class 3 semaphorins, in a modified stripe assay, caused the collapse of oligodendrocyte progenitor growth cones, redirection of processes, and altered progenitor migration. Our data support a role for neuropilins and semaphorins in orchestrating the migration patterns of developing oligodendrocytes in the CNS.
Functional study of rat 5‐HT2A receptors using antisense oligonucleotides
Authors: Van Oekelen Dirk , Megens Anton , Meert Theo , Luyten Walter H. M. L. , Leysen Josée E. 
Published: May 2003

AbstractWe studied the effects in rats of a 6‐day intracerebroventricular (i.c.v) infusion of four different end‐capped phosphorothioate‐modified antisense oligonucleotides (AOs), specifically targeting different regions of the 5‐hydroxytryptamine2A (5‐HT2A) receptor mRNA, on central 5‐HT2A receptor expression and 5‐HT2A receptor‐mediated behaviours. Only one of the AOs (sequence 4), directed against the 5′‐untranslated region (from + 557 to + 577), specifically affected central 5‐HT2A receptor expression and receptor‐mediated behaviour. This AO (sequence 4) reduced binding of the 5‐HT2A agonist 1‐(2,5‐dimethoxy‐4‐[125I]iodophenyl)‐2‐aminopropane ([125I]DOI) up to 25% in cortical areas, as measured by quantitative autoradiography. Cortical binding of the antagonist [3H]ketanserin was not affected. As the specific AO treatment presumably affects the synthesis of new receptor, we hypothesize that this newly synthesized receptor represents the major part of the functionally active, G protein coupled receptor. A 5‐day infusion of AO (sequence 4) resulted in profound inhibition of the head‐twitch response (HTR) to 1‐(2,5‐dimethoxy‐4‐methylphenyl)‐2‐aminopropane (DOM). In contrast, treatment with vehicle, sense oligonucleotides (SOs) and other AOs (sequences 1, 2 and 3) caused an increased DOM‐induced HTR as well as a spontaneous HTR. The latter was abolished by treatment with the 5‐HT2 receptor antagonist, ritanserin. Systematic investigation of the surgical and infusion procedures revealed that the enhanced HTR already appeared following drilling of the skull. This wounding can probably damage the blood–brain barrier and cause a stress‐induced increase in serotonergic transmission. AO (sequence 4) treatment also abolished the spontaneous HTR. AO (sequence 4) treatment allowed the identification of specific central 5‐HT2A receptor‐mediated behaviours in the complex serotonergic syndrome induced by tryptamine in rats. Only bilateral convulsions and body tremors were significantly inhibited. The backward locomotion, hunched back and Straub tail were not affected, nor was cyanosis, an index of vasoconstriction induced by peripheral 5‐HT2A receptor activation. Labelling of central 5‐HT2C receptors by [3H]mesulergine, and 5‐HT2C receptor‐mediated anxiety were not attenuated by AO or SO treatment. Rats treated with AO (sequence 4) showed increased locomotor activity and a strong reactivity towards touching. We hypothesize that the down‐regulation of functional 5‐HT2A receptors may shift the balance between various 5‐HT receptor subtypes. Our analysis of the behavioural consequences of AO treatment and the use of different AOs and SOs has shown that specific receptor‐mediated behaviour can be identified.
Pathogenic Aβ induces the expression and activation of matrix metalloproteinase‐2 in human cerebrovascular smooth muscle cells
Authors: Jung Sonia S. , Zhang Weibing , Van Nostrand William E. 
Published: May 2003

AbstractCerebral amyloid angiopathy (CAA) is a major pathological feature of Alzheimer's disease and related disorders. Human cerebrovascular smooth muscle (HCSM) cells, which are intimately associated with CAA, have been used as an in vitro model system to investigate pathologic interactions with amyloid β protein (Aβ). Previously we have shown that pathogenic forms of Aβ induce several pathologic responses in HCSM cells including fibril assembly at the cell surface, increase in the levels of Aβ precursor, and apoptotic cell death. Here we show that pathogenic Aβ stimulates the expression and activation of matrix metalloproteinase‐2 (MMP‐2). Furthermore, we demonstrate that the increase in MMP‐2 activation is largely caused by increased expression of membrane type‐1 (MT1)‐MMP expression, the primary MMP‐2 activator. Finally, treatment with MMP‐2 inhibitors resulted in increased HCSM cell viability in the presence of pathogenic Aβ. Our findings suggest that increased expression and activation of MMP‐2 may contribute to HCSM cell death in response to pathogenic Aβ. In addition, these activities may also contribute to loss of vessel wall integrity in CAA resulting in hemorrhagic stroke. Therefore, further understanding into the role of MMPs in HCSM cell degeneration may facilitate designing therapeutic strategies to treat CAA found in AD and related disorders.
Ethanol consumption and serotonin‐1A (5‐HT1A) receptor function in heterozygous BDNF (+/–) mice
Authors: Hensler J. G. , Ladenheim E. E. , Lyons W. E. 
Published: May 2003

AbstractHeterozygous brain‐derived neurotrophic factor (BDNF) (+/–) mice display abnormalities in central serotonergic neurotransmission, develop decrements in serotonergic innervation of the forebrain, and exhibit enhanced intermale aggressiveness. As disturbances of serotonin neurotransmission are implicated in alcohol abuse and aggression, we have examined in BDNF (+/–) mice alcohol drinking behavior, as well as central 5‐hydroxytryptamine (5‐HT)1A receptor function at the level of 5‐HT1A receptor–G protein interaction. BDNF (+/–) mice displayed increased ethanol intake in a two‐bottle choice procedure. There was no difference in the preference ratio for non‐alcoholic tastants (i.e. quinine or saccharin) between genotypes. In the brains of alcohol‐naive mice, we measured [35S]GTPγS binding stimulated by the 5‐HT1A receptor agonist (+/–)‐8‐hydroxy‐2‐dipropyl‐aminotetralin hydrobromide (8‐OH‐DPAT; 1 µm). In BDNF (+/–) versus wild‐type (WT) mice, 5‐HT1A receptor‐stimulated [35S]GTPγS binding was significantly attenuated in the median raphe nucleus. There was a decrease in (+/–)8‐OH‐DPAT‐stimulated [35S]GTPγS binding in the dorsal raphe, which did not reach statistical significance. In the hippocampus, 5‐HT1A receptor–stimulated [35S]GTPγS binding was significantly attenuated in BDNF (+/–) mice. 5‐HT1A receptor–stimulated [35S]GTPγS binding was attenuated in the anterior cingulate cortex and lateral septum, although these reductions did not reach statistical significance. 5‐HT1A receptor number was not different between genotypes in any area of brain examined, suggesting that 5‐HT1A receptor function, specifically the capacity of the 5‐HT1A receptor to activate G proteins, is attenuated in BDNF (+/–) mice.
Subtype‐specific coupling with ADP‐ribosyl cyclase of metabotropic glutamate receptors in retina, cervical superior ganglion and NG108‐15 cells
Authors: Higashida Haruhiro , Zhang Jia‐Sheng , Mochida Sumiko , Chen Xiao‐Liang , Shin Yeonsook , Noda Mami , Hossain Kazi Z. , Hoshi Naoto , Hashii Minako , Shigemoto Ryuichi , Nakanishi Shigetada , Fukuda Yutaka , Yokoyama Shigeru 
Published: May 2003

AbstractCyclic ADP‐ribose (cADP‐ribose) is a putative second messenger or modulator. However, the role of cADP‐ribose in the downstream signals of the metabotropic glutamate receptors (mGluRs) is unclear. Here, we show that glutamate stimulates ADP‐ribosyl cyclase activity in rat or mouse crude membranes of retina via group III mGluRs or in superior cervical ganglion via group I mGluRs. The retina of mGluR6‐deficient mice showed no increase in the ADP‐ribosyl cyclase level in response to glutamate. GTP enhanced the initial rate of basal and glutamate‐stimulated cyclase activity. GTP‐γ‐S also stimulated basal activity. To determine whether the coupling mode of mGluRs to ADP‐ribosyl cyclase is a feature common to individual cloned mGluRs, we expressed each mGluR subtype in NG108‐15 neuroblastoma × glioma hybrid cells. The glutamate‐induced stimulation of the cyclase occurs preferentially in NG108‐15 cells over‐expressing mGluRs1, 3, 5, and 6. Cells expressing mGluR2 or mGluRs4 and 7 exhibit inhibition or no coupling, respectively. Glutamate‐induced activation or inhibition of the cyclase activity was eliminated after pre‐treatment with cholera or pertussis toxin, respectively. Thus, the subtype‐specific coupling of mGluRs to ADP‐ribosyl cyclase via G proteins suggests that some glutamate‐evoked neuronal functions are mediated by cADP‐ribose.
Glutamate transport alteration triggers differentiation‐state selective oxidative death of cultured astrocytes: a mechanism different from excitotoxicity depending on intracellular GSH contents
Authors: Ré Diane B. , Boucraut José , Samuel Denise , Birman Serge , Kerkerian‐Le Goff Lydia , Had‐Aissouni Laurence 
Published: May 2003

AbstractRecent evidence has been provided for astrocyte degeneration in experimental models of neurodegenerative insults associated with glutamate transport alteration. To determine whether astrocyte death can directly result from altered glutamate transport, we here investigated the effects of l‐trans‐pyrrolidine‐2,4‐dicarboxylate (PDC) on undifferentiated or differentiated cultured rat striatal astrocytes. PDC induced death of differentiated astrocytes without affecting undifferentiated astrocyte viability. Death of differentiated astrocytes was also triggered by another substrate inhibitor but not by blockers of glutamate transporters. The PDC‐induced death was delayed and apoptotic, and death rate was dose and treatment duration‐dependent. Although preceded by extracellular glutamate increase, this death was not mediated through glutamate receptor stimulation, as antagonists did not provide protection. It involves oxidative stress, as a decrease in glutathione contents and a dramatic raise in reactive oxygen species preceded cell loss, and as protection was provided by antioxidants. PDC induced a similar percentage of GSH depletion in the undifferentiated astrocytes, but only a slight increase in reactive oxygen species. Interestingly, undifferentiated astrocytes exhibited twofold higher basal GSH content compared with the differentiated ones, and depleting their GSH content was found to render them susceptible to PDC. Altogether, these data demonstrate that basal GSH content is a critical factor of astrocyte vulnerability to glutamate transport alteration with possible insights onto concurrent death of astrocytes and gliosis in neurodegenerative insults.
Gene profiling of hippocampal neuronal culture
Authors: Dabrowski Michal , Aerts Stein , Van Hummelen Paul , Craessaerts Katleen , De Moor Bart , Annaert Wim , Moreau Yves , De Strooper Bart 
Published: May 2003

AbstractWe performed mRNA expression profiling of mouse primary hippocampal neurones undergoing differentiation in vitro. We show that 2314 genes significantly changed expression during neuronal differentiation. The temporal resolution of our experiment (six time points) permits us to distinguish between gene expression patterns characteristic for the axonal and for the dendritic stages of neurite outgrowth. Cluster analysis reveals that, in the process of in vitro neuronal differentiation, a high level of expression of genes involved in the synthesis of DNA and proteins precedes the up regulation of genes involved in protein transport, energy generation and synaptic functions. We report in detail changes in gene expression for genes involved in the synaptic vesicle cycle. Data for other genes can be accessed at our website. We directly compare expression of 475 genes in the differentiating neurones and the developing mouse hippocampus. We demonstrate that the program of gene expression is accelerated in vitro as compared to the situation in vivo. When this factor is accounted for, the gene expression profiles in vitro and in vivo become very similar (median gene‐wise correlation 0.787). Apparently once the cells have taken a neuronal fate, the further program of gene expression is largely independent of histological or anatomical context. Our results also demonstrate that a comparison across the two experimental platforms (cDNA microarrays and oligonucleotide chips) and across different biological paradigms is feasible.
Heterologous µ‐opioid receptor adaptation by repeated stimulation of κ‐opioid receptor: up‐regulation of G‐protein activation and antinociception
Authors: Narita Minoru , Khotib Junaidi , Suzuki Masami , Ozaki Satoru , Yajima Yoshinori , Suzuki Tsutomu 
Published: May 2003

AbstractThe present study was designed to investigate the effect of repeated administration of a selective κ‐opioid receptor agonist (1S‐trans)‐3,4‐dichloro‐N‐methyl‐N‐[2‐(1‐pyrrolidinyl)cyclohexyl]‐benzeneacetamide hydrochloride [(–)U‐50,488H] on antinociception and G‐protein activation induced by µ‐opioid receptor agonists in mice. A single s.c. injection of (–)U‐50,488H produced a dose‐dependent antinociception, and this effect was reversed by a selective κ‐opioid receptor antagonist nor‐binaltorphimine (nor‐BNI). Furthermore, a single s.c. pre‐treatment with (–)U‐50,488H had no effect on the µ‐opioid receptor agonist‐induced antinociception. In contrast, repeated s.c. administration of (–)U‐50,488H resulted in the development of tolerance to (–)U‐50,488H‐induced antinociception. Under these conditions, we demonstrated here that repeated s.c. injection of (–)U‐50,488H significantly enhanced the antinociceptive effect of selective µ‐opioid receptor agonists endomorphin‐1, endomorphin‐2 and [d‐Ala2,N‐MePhe4,Gly‐ol5] enkephalin (DAMGO). Using the guanosine‐5′‐o‐(3‐[35S]thio) triphosphate ([35S]GTPγS) binding assay, we found that (–)U‐50,488H was able to produce a nor‐BNI‐reversible increase in [35S]GTPγS binding to membranes of the mouse thalamus, which has a high level of κ‐opioid receptors. Repeated administration of (–)U‐50,488H caused a significant reduction in the (–)U‐50,488H‐stimulated [35S]GTPγS binding in this region, whereas chronic treatment with (–)U‐50,488H exhibited the increase in the endomorphin‐1‐, endomorphin‐2‐ and DAMGO‐stimulated [35S]GTPγS bindings in membranes of the thalamus and periaqueductal gray. These results suggest that repeated stimulation of κ‐opioid receptors leads to the heterologous up‐regulation of µ‐opioid receptor functions in the thalamus and periaqueductal gray regions, which may be associated with the supersensitivity of µ‐opioid receptor‐mediated antinociception.
Hydrogen peroxide induces association between glyceraldehyde 3‐phosphate dehydrogenase and phospholipase D2 to facilitate phospholipase D2 activation in PC12 cells
Authors: Kim Jung Hwan , Lee Sukmook , Park Jong Bae , Lee Sang Do , Kim Jong Hyun , Ha Sang Hoon , Hasumi Keiji , Endo Akira , Suh Pann‐Ghill , Ryu Sung Ho 
Published: May 2003

AbstractOxidative stress or signaling is widely implicated in apoptosis, ischemia and mitogenesis. Previously, our group reported that the hydrogen peroxide (H2O2)‐dependent activation of phospholipase D2 (PLD2) in PC12 cells is involved in anti‐apoptotic effect. However, the precise mechanism of PLD2 activation by H2O2 was not revealed. To find H2O2‐dependent PLD2‐regulating proteins, we immunoprecipitated PLD2 from PC12 cells and found that glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) coimmunoprecipitated with PLD2 upon H2O2 treatment. This interaction was found to be direct by in vitro reconstitution of purified GAPDH and PLD2. In vitro studies also indicated that PLD2‐associated GAPDH was modified on its reactive cysteine residues. Koningic acid, an alkylator of GAPDH on catalytic cysteine residue, also increased interaction between the two proteins in vitro and enhanced PLD2 activity in PC12 cells. Blocking H2O2‐dependent modification of GAPDH with 3‐aminobenzamide resulted in the inhibition of the GAPDH/PLD2 interaction and attenuated H2O2‐induced PLD2 activation in PC12 cells. From the results, we suggest that H2O2 modifies GAPDH on its catalytic cysteine residue not only to inactivate the dehydrogenase activity of GAPDH but also to endow GAPDH with the ability to bind PLD2 and the resulting association is involved in the regulation of PLD2 activity by H2O2.
Cloning, characterization and expression of two alternatively splicing isoforms of Ca2+/calmodulin‐dependent protein kinase Iγ in the rat brain
Authors: Nishimura Hideki , Sakagami Hiroyuki , Uezu Akiyoshi , Fukunaga Kohji , Watanabe Makoto , Kondo Hisatake 
Published: May 2003

AbstractCa2+/calmodulin‐dependent protein kinase I (CaMKI), originally identified as a protein kinase phoshorylating synapsin I, has been shown to constitute a family of closely related isoforms (α, β and γ). Here, we have isolated and determined the complete primary structures of two alternatively splicing isoforms of CaMKI termed CaMKIγ1 and ‐γ2. CaMKIγ1 and ‐γ2 contain an identical N‐terminal catalytic domain with different C‐terminal regions due to the deletion of the 425‐bp nucleotide sequence of CaMKIγ1 in CaMKIγ2. In vitro kinase assay has demonstrated the marked enhancement of the Ca2+/CaM‐dependent activity of CaMKIγ1 by the preincubation with Ca2+/calmodulin‐dependent protein kinase kinase (CaMKK), but no significant activation of CaMKIγ2. Northern blot analysis has demonstrated the predominant expression of CaMKIγ in the brain. RT‐PCR analysis has revealed similar expression patterns between CaMKIγ1 and CaMKIγ2 in various brain regions. In situ hybridization analysis has demonstrated that CaMKIγ mRNA is expressed in a distinct pattern from other isoforms of CaMKI with predominant expression in some restricted brain regions such as the olfactory bulb, hippocampal pyramidal cell layer of CA3, central amygdaloid nuclei, ventromedial hypothalamic nucleus and pineal gland. In the primary hippocampal neurons and NG108‐15 cells, transfected CaMKIγ1 and ‐γ2 are localized primarily in the cytoplasm and neurites but not in the nucleus. These findings suggest that both isoforms of CaMKIγ may be involved in Ca2+ signal transduction in the cytoplasmic compartment of certain neuronal population.