bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional and molecular identification of sodium‐coupled dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons
Authors: Yodoya Etsuo , Wada Miyuki , Shimada Ayumi , Katsukawa Hiromi , Okada Naoki , Yamamoto Akira , Ganapathy Vadivel , Fujita Takuya 
Published: March 2006

AbstractNa+‐coupled carboxylate transporters (NaCs) mediate the uptake of tricarboxylic acid cycle intermediates in mammalian tissues. Of these transporters, NaC3 (formerly known as Na+‐coupled dicarboxylate transporter 3, NaDC3/SDCT2) and NaC2 (formerly known as Na+‐coupled citrate transporter, NaCT) have been shown to be expressed in brain. There is, however, little information available on the precise distribution and function of both transporters in the CNS. In the present study, we investigated the functional characteristics of Na+‐dependent succinate and citrate transport in primary cultures of astrocytes and neurons from rat cerebral cortex. Uptake of succinate was Na+ dependent, Li+ sensitive and saturable with a Michaelis constant (Kt) value of 28.4 µm in rat astrocytes. Na+ activation kinetics revealed that the Na+ to succinate stoichiometry was 3 : 1 and the concentration of Na+ necessary for half‐maximal transport was 53 mm. Although uptake of citrate in astrocytes was also Na+ dependent and saturable, its Kt value was significantly higher (∼ 1.2 mm) than that of succinate. Unlabeled succinate (2 mm) inhibited Na+‐dependent [14C]succinate (18 µm) and [14C]citrate (4.5 µm) transport completely, whereas unlabeled citrate inhibited Na+‐dependent [14C]succinate uptake more weakly. Interestingly, N‐acetyl‐l‐aspartate, which is the second most abundant amino acid in the nervous system, also completely inhibited Na+‐dependent succinate transport in rat astrocytes. The inhibition constant (Ki) for the inhibition of [14C]succinate uptake by unlabeled succinate, N‐acetyl‐l‐aspartate and citrate was 15.9, 155 and 764 µm respectively. In primary cultures of neurons, uptake of citrate was also Na+ dependent and saturable with a Kt value of 16.2 µm, which was different from that observed in astrocytes, suggesting that different Na+‐dependent citrate transport systems are expressed in neurons and astrocytes. RT–PCR and immunocytochemistry revealed that NaC3 and NaC2 are expressed in cerebrocortical astrocytes and neurons respectively. These results are in good agreement with our previous reports on the brain distribution pattern of NaC2 and NaC3 mRNA using in situ hybridization. This is the first report of the differential expression of different NaCs in astrocytes and neurons. These transporters might play important roles in the trafficking of tricarboxylic acid cycle intermediates and related metabolites between glia and neurons.
Transcranial magnetic stimulation attenuates cell loss and oxidative damage in the striatum induced in the 3‐nitropropionic model of Huntington's disease
Authors: Túnez Isaac , Drucker‐Colín René , Jimena Ignacio , Medina Francisco J. , del Carmen Muñoz Maria , Peña José , Montilla Pedro 
Published: March 2006

AbstractAn investigation was conducted on the effect of transcranial magnetic field stimulation (TMS) on the free radical production and neuronal cell loss produced by 3‐nitropropionic acid in rats. The effects of 3‐nitropropionic acid were evaluated by examining the following changes in: the quantity of hydroperoxides and total radical‐trapping antioxidant potential (TRAP), lipid peroxidation products, protein carbonyl groups, reduced glutathione (GSH) content, glutathione peroxidase (GSH‐Px), catalase and succinate dehydrogenase (SDH) activities; total nitrite and cell death [morphological changes, quantification of neuronal loss and lactate dehydrogenase (LDH) levels]. Our results reveal that 3‐nitropropionic acid induces oxidative and nitrosative stress in the striatum, prompts cell loss and also shows that TMS prevents the harmful effects induced by the acid. In conclusion, the results show the ability of TMS to modify neuronal response to 3‐nitropropionic acid.
Protective effect of a synthetic anti‐oxidant on neuronal cell apoptosis resulting from experimental hypoxia re‐oxygenation injury
Authors: Rayner Ben S. , Duong T. T. Hong , Myers Simon J. , Witting Paul K. 
Published: March 2006

AbstractOxidative stress is associated with the pathology of acute and chronic neurodegenerative disease. Cultured neuronal cells exposed to hypoxia‐reoxygenation (H/R) injury, as a model for stroke, yield a burst of reactive oxygen species (ROS) as measured with electron paramagnetic resonance (EPR) spectroscopy in combination with spin trapping. Added superoxide dismutase inhibited spin‐adduct formation verifying that superoxide radical anion was formed in neuronal cells following H/R injury. The intracellular ADP/ATP ratio increased rapidly over the first 5 h following injury and this was due primarily to the decreased cellular pools of ATP, consistent with the notion that H/R promotes mitochondrial dysfunction leading to decreased ATP reserve and increased ROS formation. As an early response to the enhanced oxidative stress, genes encoding for hypoxia‐inducible factor 1‐α (HIF1‐α), inducible haemoxygenase‐1 (HO‐1), and the oxygen‐sensor neuroglobin increased significantly. Up‐regulation of the HO‐1 gene was paralleled by increased HO protein expression and activity. Despite this cellular response, apoptosis increased significantly following H/R injury indicating that the endogenous anti‐oxidant defenses were unable to protect the cells. In contrast, addition of a phenolic anti‐oxidant, bisphenol (BP), prior to H/R injury, inhibited ROS production and gene regulation and significantly decreased neuronal cell apoptosis. Added BP was converted stoichiometrically to the corresponding diphenoquinone indicating the synthetic anti‐oxidant effectively decreased oxidative stress through a radical scavenging mechanism. Together, these data indicate that BP has the potential to act as a neuro‐protective drug.
Capacitative Ca2+ entry is involved in regulating soluble amyloid precursor protein (sAPPα) release mediated by muscarinic acetylcholine receptor activation in neuroblastoma SH‐SY5Y cells
Authors: Kim Jin Hyoung , Choi Sinkyu , Jung Ji‐Eun , Roh Eun‐Jihn , Kim Hwa‐Jung 
Published: March 2006

AbstractPrevious studies have demonstrated that stimulation of phospholipase C‐linked G‐protein‐coupled receptors, including muscarinic M1 and M3 receptors, increases the release of the soluble form of amyloid precursor protein (sAPPα) by α‐secretase cleavage. In this study, we examined the involvement of capacitative Ca2+ entry (CCE) in the regulation of muscarinic acetylcholine receptor (mAChR)‐dependent sAPPα release in neuroblastoma SH‐SY5Y cells expressing abundant M3 mAChRs. The sAPPα release stimulated by mAChR activation was abolished by EGTA, an extracellular Ca2+ chelator, which abolished mAChR‐mediated Ca2+ influx without affecting Ca2+ mobilization from intracellular stores. However, mAChR‐mediated sAPPα release was not inhibited by thapsigargin, which increases basal [Ca2+]i by depletion of Ca2+ from intracellular stores. While these results indicate that the mAChR‐mediated increase in sAPPα release is regulated largely by Ca2+ influx rather than by Ca2+ mobilization from intracellular stores, we further investigated the Ca2+ entry mechanisms regulating this phenomenon. CCE inhibitors such as Gd3+, SKF96365, and 2‐aminoethoxydiphenyl borane (2‐APB), dose dependently reduced both Ca2+ influx and sAPPα release stimulated by mAChR activation, whereas inhibition of voltage‐dependent Ca2+ channels, Na+/Ca2+ exchangers, or Na+‐pumps was without effect. These results indicate that CCE plays an important role in the mAChR‐mediated release of sAPPα.
Interactions between β‐neuregulin and neurotrophins in motor neuron apoptosis
Authors: Ricart Karina , J. Pearson Richard , Viera Liliana , Cassina Patricia , Kamaid Andrés , Carroll Steven L. , Estévez Alvaro G. 
Published: March 2006

AbstractNeuregulins play a major role in the formation and stabilization of neuromuscular junctions, and are produced by both motor neurons and muscle. Although the effects and mechanism of neuregulins on skeletal muscle (e.g. regulation of acetylcholine receptor expression) have been studied extensively, the effects of neuregulins on motor neurons remain unknown. We report that neuregulin‐1β (NRGβ1) inhibited apoptosis of rat motor neurons for up to 7 days in culture by a phosphatidylinositol 3 kinase‐dependent pathway and synergistically enhanced motor neuron survival promoted by glial‐derived neurotrophic factor (GDNF). However, binding of neurotrophins, including brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF), to the p75 neurotrophin receptor (p75NTR) abolished the neuregulin anti‐apoptotic effect on motor neurons. Inhibitors of the c‐Jun N‐terminal kinase (JNK) mitogen‐activated protein kinase prevented motor neuron death caused by co‐incubation of NRGβ1 and BDNF or NGF, as well as by trophic factor deprivation. Motor neuron apoptosis resulting from both trophic factor deprivation and exposure to NRGβ1 plus neurotrophins required the induction of neuronal nitric oxide synthase and peroxynitrite formation. Because motor neurons express both p75NTR and neuregulin erbB receptors during the period of embryonic programmed cell death, motor neuron survival may be the result of complex interactions between trophic and death factors, which may be the same molecules acting in different combinations.
Spatial and temporal relationship between monocyte chemoattractant protein‐1 expression and spinal glial activation following peripheral nerve injury
Authors: Zhang Ji , De Koninck Yves 
Published: March 2006

AbstractPeripheral nerve injury can induce spinal microglial/astrocyte activation. Substances released by activated glial cells excite spinal nociceptive neurons. Pharmacological disruption of glial activation or antagonism of substances released by activated glia prevent or reverse pain hypersensitivity. It is not known, however, what causes spinal cord glia to shift from a resting to an activated state. In an attempt to understand the potential role of monocyte chemoattractant protein‐1 (MCP‐1) in triggering spinal glial activation and its contribution to the development of neuropathic pain, we investigated the effect of peripheral nerve injury on MCP‐1 expression in dorsal root ganglia (DRG) and the spinal cord, and established its temporal relationship with activation of spinal microglia and astrocytes. We observed that MCP‐1 was induced by chronic constriction of the sciatic nerve in DRG sensory neurons, spinal cord motor neurons and in the superficial dorsal horn, ipsilateral to the injury. Neuronal MCP‐1 induction was followed by surrounding microglial activation. After peaking at day 7 after injury, MCP‐1 levels began to decline rapidly and had returned to baseline by day 150. In contrast, microglial activation peaked by day 14 and declined afterwards to reach a lower, yet significantly raised level beyond day 22 and remained increased until the end of the test period. Astrocyte activation became detectable later, progressed more slowly and also remained increased until the end of the test period, in parallel with a decreased nociceptive threshold. Our results suggest that neuronal MCP‐1 may serve as a trigger for spinal microglial activation, which participates in the initiation of neuropathic pain. Delayed, sustained astrocyte activation may participate with microglia in the persistent phase of pain hypersensitivity.
APPε, the ε‐secretase‐derived N‐terminal product of the β‐amyloid precursor protein, behaves as a type I protein and undergoes α‐, β‐, and γ‐secretase cleavages
Authors: Lefranc‐Jullien Solveig , Sunyach Claire , Checler Frédéric 
Published: March 2006

Abstractβ‐Amyloid peptide accumulates in the brain of patients affected by sporadic or familial forms of Alzheimer's disease. It derives from the proteolytic attacks of the β‐amyloid precursor protein (βAPP) by β‐ and γ‐secretase activities. An additional ε cleavage taking place a few residues C‐terminal to the γ‐site has been reported, leading to the formation of an intracellular fragment referred to as APP intracellular domain C50. This ε cleavage received particular attention because it resembles the S3 Notch cleavage generating Notch intracellular domain. Indeed, APP intracellular domain, like its Notch counterpart, appears to mediate important physiological functions. γ and ε cleavages on βAPP appear spatio‐temporally linked but pharmacologically distinct and discriminable by mutagenesis approaches. As these cleavages could be seen as either deleterious (γ‐site) or beneficial (ε‐site), it appears of most interest to set up models aimed at studying these activities separately, particularly to design specific and bioavailable inhibitors. On the other hand, it is important to respect the topology of the substrates in order to examine physiologically relevant cleavages. Here we describe the obtention of cells overexpressing APPε, the ε‐secretase‐derived N‐terminal fragment of βAPP. Interestingly, this N‐terminal fragment of βAPP was shown by biochemical and immunohistochemical approaches to behave as a genuine membrane‐bound protein. APPε undergoes constitutive and protein kinase C‐regulated α‐secretase cleavages. Furthermore, APPε is targeted by the β‐secretase β‐site APP‐cleaving enzyme and is subsequently cleaved by γ‐secretase. The resulting β‐amyloid peptide production is fully prevented by various γ‐secretase inhibitors. Altogether, our study shows that APPε is a relevant βAPP derivative to study γ‐secretase activities and to design specific inhibitors without facing any rate‐limiting effect of ε‐secretase‐derived cleavage.
Fibroblast growth factor receptor signaling affects development and function of dopamine neurons – inhibition results in a schizophrenia‐like syndrome in transgenic mice
Authors: Klejbor Ilona , Myers Jason M. , Hausknecht Kathy , Corso Thomas D. , Gambino Angelo S. , Morys Janusz , Maher Pamela A. , Hard Robert , Richards Jerry , Stachowiak Ewa K. , Stachowiak Michal K. 
Published: March 2006

AbstractDeveloping and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor‐1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK–)] from the catecholaminergic, neuron‐specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk–)/th(tk–) mice, significant reductions in the size of TH‐immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360. Newborn th(tk–)/th(tk–) mice had a reduced density of DA neurons in both SNc and VTA, and the changes in SNc were maintained into adulthood. The reduced density of DA transporter in the striatum further demonstrated an impaired development of the nigro‐striatal DA system. Paradoxically, the th(tk–)/th(tk–) mice had increased levels of DA, homovanilic acid and 3‐methoxytyramine in the striatum, indicative of excessive DA transmission. These structural and biochemical changes in DA neurons are similar to those reported in human patients with schizophrenia and, furthermore, these th(tk–)/th(tk–) mice displayed an impaired prepulse inhibition that was reversed by a DA receptor antagonist. Thus, this study establishes a new developmental model for a schizophrenia‐like disorder in which the inhibition of FGF signaling leads to alterations in DA neurons and DA‐mediated behavior.
Amyloid beta peptide increases DP5 expression via activation of neutral sphingomyelinase and JNK in oligodendrocytes
Authors: Chen Shawei , Lee Jin‐Moo , Zeng Chenbo , Chen Hong , Hsu Chung Y. , Xu Jan 
Published: March 2006

AbstractThere is growing recognition that white matter pathology is a common feature in Alzheimer's disease. We have previously reported that the amyloid beta peptide (Aβ) induces apoptosis in oligodendrocytes (OLG), via activation of neutral sphingomyelinase (nSMase) and resultant generation of ceramide. In the current study, we report that both Aβ and ceramide increased expression of the proapoptotic protein DP5/Hrk (DP5), and release of cytochrome C from mitochondria to cytoplasm in OLGs. We provide evidence that the Jun N‐terminal kinase (JNK) signaling pathway mediates Aβ‐ and ceramide‐induced apoptosis: Both Aβ and ceramide activated JNK phosphorylation, and subsequent AP‐1 DNA binding activity; JNK siRNA decreased AP‐1 DNA binding, DP5 expression and reduced cell death. Furthermore, inhibition of nSMase attenuated Aβ‐induced JNK phosphorylation, AP‐1 DNA binding activity, DP5 expression, and cytochrome C release. Collectively, these results suggest that Aβ‐induced apoptosis involves the sequential activation of nSMase with ceramide generation, JNK activation, AP‐1 DNA binding, and DP5 expression.
Problem of Distinguishing False‐Positive Tests from Acute or Transient Helicobacter pylori Infections
Authors: Nugalieva Zhannat Z. , Opekun Antone R. , Graham David Y. 
Published: March 2006

AbstractBackground:  Reliable detection of acute Helicobacter pylori infections remains problematic. The high prevalence of false‐positive non‐invasive tests in low H. pylori prevalence populations makes identification of acute and transient infections difficult.Methods:  We explored the use of serum pepsinogens (PG) for diagnosis of acute infection in patients following H. pylori challenge such that the onset of the infection was known. We then compared those findings to a group of children with presumed acute infections defined as a positive urea breath test (UBT) and negative IgG serology.Results:  We examined the pattern and calculated cut‐off values of PG levels in 18 adult volunteers with known acute H. pylori infection. We then compared the results with sera from nine symptomatic children with presumed acute H. pylori infection and a matched control group of nine children who did not meet criteria for acute H. pylori infection. In acute infection, both PGI and II levels increased following H. pylori infection reaching a peak by 2 weeks post‐infection. The frequency of a positive test defined as a value > mean +2 SD was 17, 71, and 94% at week 1, 2, and 4 post‐infection, respectively. Only one child with presumed acute H. pylori infection had an elevated serum PGI and one had an elevated PGII. Five of the children had follow‐up UBTs and four were negative consistent with the diagnosis of false‐positive UBT. H. pylori infection was confirmed in the child with an elevated PGI level.Conclusions:  These data suggest that a single positive noninvasive test in populations of low prevalence is most likely a false‐positive result. This suggests that a single positive test requires confirmation preferably using a test that measures a different parameter (e.g., UBT confirmed by stool antigen test). It appears that most “transient”H. pylori infections are diagnosed on the basis of false‐positive tests. PG levels are possible candidates as the confirmatory test.
Comparison of Localized Gastric Mucosa‐Associated Lymphoid Tissue (MALT) Lymphoma with and without Helicobacter pylori Infection
Authors: Akamatsu Taiji , Mochizuki Taro , Okiyama Yoko , Matsumoto Akihiro , Miyabayashi Hideharu , Ota Hiroyoshi 
Published: March 2006

AbstractBackground:  The clinical features and clinical course of Helicobacter pylori‐negative gastric mucosa‐associated lymphoid tissue (MALT) lymphoma are unclear and a treatment strategy has not yet been established.Aim:  To clarify the clinical differences between H. pylori‐positive and H. pylori‐negative gastric MALT lymphoma, we compared these two types of gastric MALT lymphoma.Materials and Methods:  Fifty‐seven patients with localized gastric MALT lymphoma were studied. H. pylori infection was present in 41 and absent in 16. Treatment consisted of antibiotic therapy and/or 30 Gy radiation therapy. Response assessment was performed every 3–6 months by esophagogastroduodenoscopy including gathering biopsy samples, endoscopic ultrasonography, clinical examination, and various imaging procedures. The median follow‐up period was 37 months.Results:  There were no significant differences between H. pylori‐positive and H. pylori‐negative gastric MALT lymphoma patients in terms of sex, age, stage, gross phenotype, affected area of the stomach, or the presence of monoclonality. Complete regression was achieved with antibiotic therapy against H. pylori‐negative gastric MALT lymphoma in one of nine patients (11.1%), compared to 28 of 38 patients (73.7%) with H. pylori‐positive gastric MALT lymphoma (p < .001). Radiation therapy showed high effectiveness for the local control of H. pylori‐negative or antibiotic‐resistant gastric MALT lymphoma (92.9%), although distant recurrence was recognized in three of 14 patients (21.4%). Two of 16 patients (12.5%) with H. pylori‐negative gastric MALT lymphoma died because of the transformation of the disease into diffuse large B‐cell lymphoma. There was a significant difference in both the overall and cause‐specific survival rate between the two groups (p = .038).Conclusion:  Radiation therapy is the effective treatment for H. pylori‐negative or antibiotic‐resistant localized gastric MALT lymphoma. However, careful systemic follow‐up for distant involvement should be required. Transformation into diffuse large B‐cell lymphoma is thought to be the important cause of death in patients with gastric MALT lymphoma.
Dating metamorphic reactions and fluid flow: application to exhumation of high‐P granulites in a crustal‐scale shear zone, western Canadian Shield
Authors: MAHAN K. H. , GONCALVES P. , WILLIAMS M. L. , JERCINOVIC M. J. 
Published: March 2006

AbstractThe Legs Lake shear zone is a crustal‐scale thrust fault system in the western Canadian Shield that juxtaposes high‐pressure (1.0+ GPa) granulite facies rocks against shallow crustal (< 0.5 GPa) amphibolite facies rocks. Hangingwall decompression is characterized by breakdown of the peak assemblage Grt + Sil + Kfs + Pl + Qtz into the assemblage Grt + Crd + Bt ± Sil + Pl + Qtz. Similar felsic granulite occurs throughout the region, but retrograde cordierite is restricted to the immediate hangingwall of the shear zone. Textural observations, petrological analysis using P–T/P–MH2O phase diagram sections, and in situ electron microprobe monazite geochronology suggest that decompression from peak conditions of 1.1 GPa, c. 800 °C involved several distinct stages under first dry and then hydrated conditions. Retrograde re‐equilibration occurred at 0.5–0.4 GPa, 550–650 °C. Morphology, X‐ray maps, and microprobe dates indicate several distinct monazite generations. Populations 1 and 2 are relatively high yttrium (Y) monazite that grew at 2.55–2.50 Ga and correspond to an early granulite facies event. Population 3 represents episodic growth of low Y monazite between 2.50 and 2.15 Ga whose general significance is still unclear. Population 4 reflects low Y monazite growth at 1.9 Ga, which corresponds to the youngest period of high‐pressure metamorphism. Finally, population 5 is restricted to the hydrous retrograded granulite and represents high Y monazite growth at 1.85 Ga that is linked directly to the synkinematic garnet‐consuming hydration reaction (KFMASH): Grt + Kfs + H2O = Bt + Sil + Qtz. Two samples yield weighted mean microprobe dates for this population of 1853 ± 15 and 1851 ± 9 Ma, respectively. Subsequent xenotime growth correlates with the reaction: Grt + Sil + Qtz + H2O = Crd. We suggest that the shear zone acted as a channel for fluid produced by dehydration of metasediments in the underthrust domain.