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At least 505 records · Page 28Linked to original sources
PubMed2006

Toluene induces rapid and reversible rise of hippocampal glutamate and taurine neurotransmitter levels in mice.

Toluene, a widely used aromatic organic solvent, has been well characterized as a neurotoxic chemical. Although the neurobehavioral effects of toluene have been studied substantially, the mechanisms involved are not clearly understood. Hippocampus, which is one of the limbic areas of brain associated with neuronal plasticity, and learning and memory functions, may be a principal target of toluene. In the present study, to establish a mouse model for investigating the effects of acute toluene exposure on the amino acid neurotransmitter levels in the hippocampus, in vivo microdialysis study was performed in freely moving mice after a single intraperitoneal administration of toluene (150 and 300 mg/kg). Amino acid neurotransmitters in microdialysates were measured by a high performance liquid chromatography system. The extracellular levels of glutamate and taurine were rapidly and reversibly increased within 30 min after the toluene administration in a dose-dependent manner and returned to the basal level by 1h. Conversely, the extracellular level of glycine and GABA were stable, and no significant change was observed after the toluene administration. To further investigate the brain toluene level in the hippocampus of toluene-administered mice, we used a solid-phase microextraction (SPME) method and examined the time course changes of toluene in the hippocampus of living mice. The brain toluene level reached the peak at 30 min after injection and returned to the basal level after 2h. In the present study, we observed the relationship between brain toluene levels and amino acid neurotransmitter glutamate and taurine levels in the hippocampus. Therefore, we suggest that toluene may mediate its action through the glutamatergic and taurinergic neurotransmission in the hippocampus of freely moving mice.

Animals↗
PubMed1997

Effect of unilateral tympanotomy on auditory induced c-fos expression in cochlear nuclei.

The immediate early gene, c-fos, signals expression of target genes. Three natural occurring physiological entities: (1) learning, (2) plasticity, and (3) stress are proposed to use c-fos gene expression to signal molecular changes in neurons. The objective of this study was to determine whether c-fos expression is predominately activated by stress or by novel events associated with learning and plasticity. The approach was to quantitate the number of neurons in cochlear nuclei which express Fos protein following short-term novel sound stimuli together with either uni- or bilateral tympanotomy so as to differentiate novel sound stimuli from stress activation. The results show that routinely experienced sounds do not elicit c-fos expression in medullary cochlear nuclei, but novel sounds produced a 25-fold increase in the number of active cells. Following unilateral tympanotomy with novel sound stimulation, only a small number of cells were activated, ipsilaterally, (partially deafened side) while contralaterally, there was a 30-fold increase. After normalization of the data for control values, the data clearly indicate that novelty of sound stimuli induce c-fos gene expression. Furthermore, bilateral tympanotomy (bilateral partial deafening) with sound stimulation activated both sides by 20-fold, indicating that the c-fos response followed the sound stimulation. The data allow us to conclude that stress generates only a small contribution to c-fos gene expression while novel stimuli are potent signals, strongly implicating c-fos in novelty induced adaptation processes involved in learning and plasticity.

Acoustic Stimulation↗
PubMed2002

NGF-dependent and tissue-specific transcription of vgf is regulated by a CREB-p300 and bHLH factor interaction.

Neurotrophins support neuronal survival, development, and plasticity through processes requiring gene expression. We studied how vgf target gene transcription is mediated by a critical promoter region containing E-box, CCAAT and cAMP response element (CRE) sites. The p300 acetylase was present in two distinct protein complexes bound to this region. One complex, containing HEB (ubiquitous basic helix-loop-helix (bHLH)), bound the promoter in non-neuronal cells and was involved in repressing vgf expression. Neurotrophin-dependent transcription was mediated by the second complex, specific for neuronal cells, which included CRE binding protein and MASH1 (neuro-specific bHLH), bound the CCAAT motif, and was target of neurotrophin signalling. The interaction, mediated by p300, of different transcription factors may add specificity to the neurotrophin response.

3T3 Cells↗
PubMed2003

Regional and developmental regulation of syntaphilin expression in the brain: a candidate molecular element of synaptic functional differentiation.

The conserved nature of the basic machinery underlying synaptic function makes it necessary to search for other factors--structural and molecular--that could account for the tremendous diversity found among synapses even within a single neuron. Syntaphilin is a presynaptic membrane protein previously described as a molecular clamp that controls free syntaxin-1A and dynamin-1 availability, and thereby regulates synaptic vesicle exocytosis and endocytosis at the nerve terminal. In this study, we report our finding that syntaphilin expression is developmentally regulated, and show that syntaphilin is expressed most prominently in the mature rat brain, in areas that have been previously characterized to undergo synaptic plastic change. We also find that syntaphilin undergoes divergent subcellular targeting to the mitochondrial outer membrane and the synaptic plasma membrane, giving rise to two neuronal subpopulations of the protein that are modified in their relative enrichment with synaptic maturation and with the formation of cell contacts. Finally, we demonstrate that syntaphilin expression is initiated with induction of neuronal differentiation in PC12 cells. Given its biochemical and functional properties, the spatially and temporally limited nature of syntaphilin expression provides evidence that syntaphilin could be a molecular element of synaptic functional differentiation.

Animals↗
PubMed2003

The anterogradely transported BDNF promotes retinal axon remodeling during eye specific segregation within the LGN.

Neurotrophins have been implicated in regulating many aspects of neuronal development and plasticity, including dendritic and axonal elaboration, by acting primarily as target derived trophic factors. Recently, we have shown that brain-derived neurotrophic factor (BDNF) is produced by retinal ganglion cells (RGCs) and travels in an anterograde direction along the optic nerve in neonatal rats. Here, we have assessed whether the anterogradely transported BDNF plays a role in shaping the retinogeniculate connectivity during development. We used intraocular injections of antisense oligonucleotides to suppress selectively retinal synthesis and anterograde transport of BDNF in rat pups. We found that in the absence of endogenous BDNF, RGC axons retract from their target in the dorsal lateral geniculate nucleus (dLGN). The blockade of BDNF action at the retinal level with the tyrosine kinase inhibitor, K252a, failed to produce this effect, suggesting an anterograde action of the endogenous BDNF. Moreover, the effects of BDNF removal on RGC fibers were evident only during a narrow temporal window coincident with the critical period for the retinothalamic refinement, indicating a role for BDNF on growth and elaboration of RGC axons rather than on their maintenance. Altogether these results propose a novel role for BDNF in the elaboration of retinogeniculate axons.

Animals↗
PubMed2005

Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus.

The functions of 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid found in the brain, remain largely unknown. Here we show that two previously unknown inhibitors of monoacylglycerol lipase, a presynaptic enzyme that hydrolyzes 2-AG, increase 2-AG levels and enhance retrograde signaling from pyramidal neurons to GABAergic terminals in the hippocampus. These results establish a role for 2-AG in synaptic plasticity and point to monoacylglycerol lipase as a possible drug target.

Aniline Compounds↗
PubMed2006

The structure of p53 tumour suppressor protein reveals the basis for its functional plasticity.

p53 major tumour suppressor protein has presented a challenge for structural biology for two decades. The intact and complete p53 molecule has eluded previous attempts to obtain its structure, largely due to the intrinsic flexibility of the protein. Using ATP-stabilised p53, we have employed cryoelectron microscopy and single particle analysis to solve the first three-dimensional structure of the full-length p53 tetramer (resolution 13.7 A). The p53 molecule is a D2 tetramer, resembling a hollow skewed cube with node-like vertices of two sizes. Four larger nodes accommodate central core domains, as was demonstrated by fitting of its X-ray structure. The p53 monomers are connected via their juxtaposed N- and C-termini within smaller N/C nodes to form dimers. The dimers form tetramers through the contacts between core nodes and N/C nodes. This structure revolutionises existing concepts of p53's molecular organisation and resolves conflicting data relating to its biochemical properties. This architecture of p53 in toto suggests novel mechanisms for structural plasticity, which enables the protein to bind variably spaced DNA target sequences, essential for p53 transactivation and tumour suppressor functions.

Cryoelectron Microscopy↗
PubMed2004

Direct interactions between NMDA and D1 receptors: a tale of tails.

Considerable evidence has accumulated describing a complex interaction between the dopaminergic and glutamatergic pathways. Efforts to describe the mechanisms underlying this complex interaction have implicated a functional interaction between dopamine and glutamate receptors. Classically, the interaction between D(1) and NMDA (N-methyl-D-aspartate) receptors has been proposed to involve the activation of second-messenger signalling cascades after receptor stimulation. However, in recent years, another paradigm has emerged which involves the direct interaction between D(1) and NMDA receptors. The physical association between D(1) and NMDA receptors is unique in that two different regions of the D(1) C-terminus are able to couple specifically and physically with two different NMDA subunits. The selective modulation of multiple NMDA receptor-mediated functions by direct interactions with D(1) receptors may form a new avenue to identify specific targets for therapeutics to modulate NMDA receptor-governed synaptic plasticity, neuronal development and disease states.

Animals↗
PubMed1999

CaMKII-dependent phosphorylation of NR2A and NR2B is decreased in animals characterized by hippocampal damage and impaired LTP.

The calcium-calmodulin-dependent protein kinase II (CaMKII) subserves activity-dependent plasticity in central neurons. To examine in vivo the implication of CaMKII activity in synaptic plasticity, we used an animal model characterized by developmentally induced targeted neuronal ablation within the cortex and the hippocampus, and showing, at presynaptic level, molecular alterations leading to facilitation of glutamate release in hippocampal synapses (methylazoxymethanol-treated rats, MAM-rats). We report here that at the postsynaptic side, the activity of CaMKII is markedly decreased in MAM-rats when compared to controls, although the concentration of the enzyme in Post Synaptic Density (PSD) is not altered. This effect is confined to PSD-associated CaMKII, as enzyme activity tested in the soluble fraction is unchanged in MAM-rats. In addition, the decreased activity is not due to inhibition by autophosphorylation in specific sites within the calmodulin-binding domain, as preincubation with purified phosphatases 1 and 2A failed to restore CaMKII activity in PSD of MAM-rats. The CaMKII-dependent phosphorylation of NR2A/B subunits of NMDA receptor is lower in MAM-rats when compared to controls (51.77 +/- 7.39% of controls level), as revealed in back-phosphorylation experiments. In addition, a treatment able to restore long-term potentiation (LTP) in hippocampal slices from MAM-rats, e.g. exposure to D-serine, is able to restore CaMKII activity to the control value.

Animals↗
PubMed2002

Generation and characterization of human hematopoietic cell lines expressing factor VIII.

Considering the plasticity of hematopoietic stem cells (HSC), they would be ideal targets for gene therapy of hemophilia A by virtue of their progeny providing immediate access to the bloodstream. However, several attempts to show expression of recombinant factor VIII (rFVIII) by primary hematopoietic cells and cell lines have failed; this failure was attributed to the inability of HSC to secrete rFVIII. Here we describe the generation of stable, FVIII-secreting hematopoietic cell lines representing different blood-cell types using a bicistronic lentiviral vector encoding for a B-domain-deleted FVIII (FVIII Delta B) and enhanced green fluorescence protein (EGFP). Transduced cell lines with erythroid and/or megakaryocytic background, (K562-F8 and TF-1-F8) secrete high levels of FVIII in the order of 76.4 and 41.6 ng FVIII:C/ml, whereas moderate and low levels are observed in B lymphoblastoid Raji-F8 cells and the T leukemia line Jurkat-F8 which secrete 6.73 and 1.83 ng FVIII:C/ml, respectively. The capacity to secrete rFVIII appeared to depend on factors related to the cell lineage rather than on the transduction efficacy. Stimulation of transduced cells with the protein kinase C (PKC)-activator phorbol myristate acetate (PMA) resulted in a marked augmentation of rFVIII secretion and enhanced green fluorescent protein (EGFP). Incubation with 0.1 and 1 ng/ml PMA resulted in up to 2.7-fold (K562-F8, Raji-F8) and 1.8-fold (293T-F8) increased rFVIII secretion. The established cell lines should be helpful in further elucidating mechanisms that are able to improve FVIII secretion in hematopoietic cells on a post-translational level and suggest reanalysis of hematopoietic cells as target for gene therapy of hemophilia.

Base Sequence↗
PubMedDate not supplied

The epigenetic reprogramming of poorly aggressive melanoma cells by a metastatic microenvironment.

A dynamic, complex relationship exists between tumor cells and their microenvironment, which plays a pivotal role in cancer progression, yet remains poorly understood. Particularly perplexing is the finding that aggressive melanoma cells express genes associated with multiple cellular phenotypes, in addition to their ability to form vasculogenic-like networks in three-dimensional matrix--called vasculogenic mimicry, which is illustrative of tumor cell plasticity. This study addressed the unique epigenetic effect of the microenvironment of aggressive melanoma cells on the behavior of poorly aggressive melanoma cells exposed to it. The data show significant changes in the global gene expression of the cells exposed to 3-D matrices preconditioned by aggressive melanoma cells, including the acquisition of a vasculogenic cell phenotype, upregulation of ECM remodeling genes, and increased invasive ability--indicative of an epigenetic, microenvironment-induced reprogramming of poorly aggressive melanoma cells. However, this epigenetic effect was completely abrogated when a highly cross-linked collagen matrix was used, which could not be remodeled by the aggressive melanoma cells. These findings offer an unique perspective of the inductive properties associated with an aggressive melanoma microenvironment that might provide new insights into the epigenetic regulation of tumor cell plasticity and differentiation, as well as mechanisms that could be targeted for novel therapeutic strategies.

Cell Line, Tumor↗
PubMed2001

Cross-resistance between triclosan and antibiotics in Pseudomonas aeruginosa is mediated by multidrug efflux pumps: exposure of a susceptible mutant strain to triclosan selects nfxB mutants overexpressing MexCD-OprJ.

Triclosan is an antiseptic frequently added to items as diverse as soaps, lotions, toothpaste, and many commonly used household fabrics and plastics. Although wild-type Pseudomonas aeruginosa expresses the triclosan target enoyl-acyl carrier protein reductase, it is triclosan resistant due to expression of the MexAB-OprM efflux system. Exposure of a susceptible Delta(mexAB-oprM) strain to triclosan selected multidrug-resistant bacteria at high frequencies. These bacteria hyperexpressed the MexCD-OprJ efflux system due to mutations in its regulatory gene, nfxB. The MICs of several drugs for these mutants were increased up to 500-fold, including the MIC of ciprofloxacin, which was increased 94-fold. Whereas the MexEF-OprN efflux system also participated in triclosan efflux, this antimicrobial was not a substrate for MexXY-OprM.

Amino Acid Sequence↗
PubMed1977

Effect of chemotherapy and immunotherapy on tumor-specific immunity in melanoma.

The effects of chemotherapy, with nitrosoureas or dimethyl-triazeno-imidazole-carboxamide (DTIC), or immunotherapy with Bacillus Calmette-Guérin (BCG), on cell-mediated immunity (CMI), and serum blocking factor (BF) to melanoma cells were studied in 23 patients. Studies were performed with autologous or allogenic melanoma target cells obtained from recent biopsy, in 16 mm diameter plastic wells. Assays for lymphocyte-mediated cytotoxicity and BF were performed at weekly intervals over the course of 3-4 mo, with some studies extending beyond 3 yr. The specificity of cytotoxicity was good with these methods. Nine patients given nitrosoureas, predominantly methyl-chloroethyl-cyclohexyl-nitrosourea, showed a transient decline in CMI from 42.2 to 14% 3 wk after administration of a single dose of the agent, with a rapid recovery within 1 week. 10 patients given 5-day courses of DTIC at 3-wk intervals showed no decline in CMI after two courses, and 7 of the 10 had no decline even after three courses. Three of the four patients who achieved a remission lost BF previously present: BF reappeared in both patients studied during a subsequent relapse. BCG intradermally or intralesionally elevated CMI within 2 mo after initiation of therapy, but despite continuation of the injections CMI returned to base line in all but two of the nine patients studied. These results indicate that chemotherapy for melanoma with nitrosoureas or DTIC at these schedules is not profoundly immunosuppressive towards tumor-specific immunity, as measured by our procedures. Putative immunotherapy with BCG at these schedules was likewise only transiently stimulatory.

Adult↗
PubMed2006

Regulatory mechanisms of cardiac development and repair.

The heart originates from bilateral primordia that eventually fuse in the embryonic midline leading to a linear tube. Soon after, the heart bends to the right and atrial and ventricular chambers are formed. Progressively each embryonic compartment initiates a process of septation that eventually leads to a four chambered heart with a double circuitry and synchronous contraction. During these developmental events, the growth of the heart and in particular of its myocardial component gradually increases. However, as the heart gets into its mature stage, myocardial growth ceases and concomitantly the myocardium looses its proliferative capacity. In the adult human population, the most frequent cardiac pathologies emanate from a decompensated lost of myocardial function. Therapeutical approaches aiming to add or replace new myocytes to the failing heart are thus highly desired. Embryonic stem cells have a high capacity to give rise to multiple cell types, including myocardial cells, opening new therapeutical possibilities. Unexpectedly discrete adult cell populations have also shown a greater cell plasticity than previously thought, earning therefore much attention as therapeutic targets. These observations have launched initial clinical trials with great hope of clinical benefit. However, it is essential in this respect to initially understand, and eventually control myogenic cell fate determination. Developmental biology of the heart provides a very suitable model for this end. Over the last decade there has been a considerable advance in the understanding of the molecular mechanisms that lead to the determination of the cardiomyocyte lineage and the regulatory mechanisms by which morphogenesis of the heart takes place. Growth factor signalling and transcriptional events controlling cardiac myogenesis have been progressively unravelled. In this review we aim to summarise current data concerning the cardiomyogenic cell fate determination pathways occurring during the natural process of cardiogenesis as compared to the myogenic lineages obtained from embryonic and adult stem cells. Identification of key elements provides important resources to which drugs can be targeted and eventually can result in promising tools to control and expand cardiomyocyte determination.

Animals↗
PubMed2026

Non-coding RNAs in cancer: multi-omics insights, liquid biopsy advances, drug resistance mechanisms, and the road to clinical translation.

For most of the twentieth century, the transcriptional output of the human genome was thought to be biologically inert-a characterization that has been proven wrong in almost every important respect. Non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), small nucleolar RNAs (snoRNAs) and PIWI-interacting RNAs (piRNAs) are now thought of as vital regulators of gene expression in all the stages of cancer pathogenesis, including the initial epigenetic changes, metastatic spread and the development of therapeutic resistance. This review highlights four areas where the clinical potential of ncRNAs is most promising: reconstruction of ncRNA regulatory networks by multi-omics integration; circulating ncRNAs as minimally invasive cancer biomarkers; causal roles of ncRNAs in drug resistance through epithelial-mesenchymal plasticity, metabolic reprogramming, and stromal communication; and translation of ncRNA targeting strategies to clinical trials. We will need to invest equally in mechanistic rigor and translational infrastructure to move forward.

antisense oligonucleotides↗
PubMed2001

Ontogeny of modulatory inputs to motor networks: early established projection and progressive neurotransmitter acquisition.

Modulatory information plays a key role in the expression and the ontogeny of motor networks. Many developmental studies suggest that the acquisition of adult properties by immature networks involves their progressive innervation by modulatory input neurons. Using the stomatogastric nervous system of the European lobster Homarus gammarus, we show that contrary to this assumption, the known population of projection neurons to motor networks, as revealed by retrograde dye migration, is established early in embryonic development. Moreover, these neurons display a large heterogeneity in the chronology of acquisition of their full adult neurotransmitter phenotype. We performed retrograde dye migration to compare the neuronal population projecting to motor networks located in the stomatogastric ganglion in the embryo and adult. We show that this neuronal population is quantitatively established at developmental stage 65%, and each identified projection neuron displays the same axon projection pattern in the adult and the embryo. We then combined retrograde dye migration with FLRFamide-like, histamine, and GABA immunocytochemistry to characterize the chronology of neurotransmitter expression in individual identified projection neurons. We show that this early established population of projection neurons gradually acquires its neurotransmitter phenotype complement. This study indicates that (1) the basic architecture of the known population of projection inputs to a target network is established early in development and (2) ontogenetic plasticity may depend on changes in neurotransmitter phenotype expression within preexisting neurons rather than in the addition of new projection neurons or fibers.

Animals↗
PubMed1993

Saccadic underaction in concomitant strabismus and Hering's law: a new neurophysiologic model for binocular motor correspondence.

Hering's law of equal innervation has remained so far as an universal truth with no scientific basis. However, recent reports of Saccadic underactions in concomitant strabismus indicating asymmetric ocular motor innervation is in contradiction to the law. In an effort to understand the inequalities of binocular movements, we propose a neurophysiologic model for both normal and abnormal eye movements. The model hypothesizes that any binocular movement results from the yoking of two monocular reflex loops corresponding to the two eyes, during the plastic stage of development of ocular motor reflexes. The retinal target discrepancy triggers the reflex loop resulting in a monocular corrective movement. As there is a common binocular field, the stimuli to the two eyes are similar causing a similar binocular corrective movement. In abnormal cases coupling of asymmetric motor loops may occur resulting in alternate or unilateral saccadic underactions.

Electrooculography↗
PubMed1996

The dynamics of dendritic structure in developing hippocampal slices.

Time-lapse fluorescence confocal microscopy was used to directly visualize the formation and dynamics of postsynaptic target structures (i.e., dendritic branches and spines) on pyramidal neurons within developing tissue slices. Within a 2 week period of time, pyramidal neurons in cultured slices derived from early postnatal rat (postnatal days 2-7) developed complex dendritic arbors bearing numerous postsynaptic spines. At early stages (1-2 d in vitro), many fine filopodial protrusions on dendrite shafts rapidly extended (maximum rate approximately 2.5 microM/minute) and retracted (median filopodial lifetime, 10 min), but some filopodia transformed into growth cones and nascent dendrite branches. As dendritic arbors matured, the population of fleeting lateral filopodia was replaced by spine-like structures having a low rate of turnover. This developmental progression involved a transitional stage in which dendrites were dominated by persistent (up to 22 hr) but dynamic spiny protrusions (i.e., protospines) that showed substantial changes in length and shape on a timescale of minutes. These observations reveal a highly dynamic state of postsynaptic target structures that may actively contribute to the formation and plasticity of synaptic connections during CNS development.

Animals↗