bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of advanced glycation end products‐inductor glyoxal and hydrogen peroxide as oxidative stress factors on rat retinal organ cultures and neuroprotection by UK‐14,304
Authors: Knels Lilla , Worm Maximilian , Wendel Martina , Roehlecke Cora , Kniep Eva , Funk Richard H. W. 
Published: July 2008

AbstractRetinal ganglion cell degeneration is supposed to be mediated by reactive oxygen species (ROS) and advanced glycation end products (AGEs). The alpha2‐adrenergic agonist, 5‐bromo‐N‐(4,5‐dihydro‐1H‐imidazol‐2‐yl)‐6‐quinoxalinamine (brimonidine; UK‐14,304), is said to exert a neuroprotective effect. To investigate these mechanisms in detail, we exposed rat whole mounts to glyoxal or H2O2 and treated them with either UK‐14,304 alone or additionally with the phosphatidylinositide 3 kinase (PI3) kinase inhibitor, 2‐(4‐Morpholinyl)‐8‐phenyl‐4H‐1‐benzopyran‐4‐one (Ly 294002). The accumulation of Nε‐[carboxymethyl] lysine (CML) was assessed immunohistochemically and changes in intracellular pH (pHi), mitochondrial transmembrane potential (MTMP) and ROS production in cell bodies of multipolar ganglion cell layer were studied by intravital fluorescence microscopy and confocal laser scanning microscopy. Ultrastructural changes in mitochondria of multipolar ganglion cell layer cell bodies were determined by transmission electron microscopy. We found that glyoxal and H2O2 increased accumulation of CML‐modified proteins and ROS production and decreased pHi and MTMP in cell bodies of multipolar ganglion cell layer. UK‐14,304 could prevent production of ROS, accumulation of CML‐modified proteins, ameliorate acidification, preserve MTMP and attenuate ultrastructural damages of ganglion cell mitochondria. Ly 294002 reversed the UK‐14,304‐mediated attenuation of CML and ROS production. We conclude that the protective effects of UK‐14,304 seem partly to be mediated by PI3 kinase‐dependent pathways.
Neuromelanin can protect against iron‐mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease
Authors: Zecca Luigi , Casella Luigi , Albertini Alberto , Bellei Chiara , Zucca Fabio A. , Engelen Mireille , Zadlo Andrzej , Szewczyk Grzegorz , Zareba Mariusz , Sarna Tadeusz 
Published: July 2008

AbstractIn Parkinson’s disease (PD), dopamine neurons containing neuromelanin selectively degenerate. Neuromelanin binds iron and accumulates in aging. Iron accumulates in reactive form during aging, PD, and is involved in neurodegeneration. It is not clear how the interaction of neuromelanin and iron can be protective or toxic by modulating redox processes. Here, we investigated the interaction of neuromelanin from human substantia nigra with iron in the presence of ascorbic acid, dopamine, and hydrogen peroxide. We observed that neuromelanin blocks hydroxyl radical production by Fenton’s reaction, in a dose‐dependent manner. Neuromelanin also inhibited the iron‐mediated oxidation of ascorbic acid, thus sparing this major antioxidant molecule in brain. The protective effect of neuromelanin on ascorbate oxidation occurs even in conditions of iron overload into neuromelanin. The blockade of iron into a stable iron–neuromelanin complex prevents dopamine oxidation, inhibiting the formation of neurotoxic dopamine quinones. The above processes occur intraneuronally in aging and PD, thus showing that neuromelanin is neuroprotective. The iron–neuromelanin complex is completely decomposed by hydrogen peroxide and its degradation rate increases with the amount of iron bound to neuromelanin. This occurs in PD when extraneuronal iron–neuromelanin is phagocytosed by microglia and iron–neuromelanin degradation releases reactive/toxic iron.
Dietary flavonoid (−)epicatechin stimulates phosphatidylinositol 3‐kinase‐dependent anti‐oxidant response element activity and up‐regulates glutathione in cortical astrocytes
Authors: Bahia Parmvir K. , Rattray Marcus , Williams Robert J. 
Published: July 2008

AbstractFlavonoids are plant‐derived polyphenolic compounds with neuroprotective properties. Recent work suggests that, in addition to acting as hydrogen donors, they activate protective signalling pathways. The anti‐oxidant response element (ARE) promotes the expression of protective proteins including those required for glutathione synthesis (xCT cystine antiporter, gamma‐glutamylcysteine synthetase and glutathione synthase). The use of a luciferase reporter (ARE‐luc) assay showed that the dietary flavan‐3‐ol (−)epicatechin activates this pathway in primary cortical astrocytes but not neurones. We also examined the distribution of NF‐E2‐related factor‐2 (Nrf2), a key transcription factor in ARE‐mediated gene expression. We found, using immunocytochemistry, that Nrf2 accumulated in the nuclei of astrocytes following exposure to tert‐butylhydroquinone (100 μM) and (−)epicatechin (100 nM). (−)Epicatechin signalling via Nrf2 was inhibited by wortmannin implicating a phosphatidylinositol 3‐kinase‐dependent pathway. Finally, (−)epicatechin increased glutathione levels in astrocytes consistent with an up‐regulation of ARE‐mediated gene expression. Together, this suggests that flavonoids may be cytoprotective by increasing anti‐oxidant gene expression.
Mammalian cerebral metabolism and amino acid neurotransmission during hibernation
Authors: Osborne Peter G. , Hashimoto Masaaki 
Published: July 2008

AbstractThis report demonstrates that during the torpor phase of hibernation, hamsters utilize 14C and 13C glucose in torpor‐specific brain metabolic pathways. Microdialysis of 14C glucose into the striatum rapidly induced a steady state labeling of extracellular fluid (ECF) lactate and labeling of tissue GABA, glutamate, glutamine, and alanine in ipsilateral and contralateral striata. The same tissue metabolites were labeled in cortex, hypothalamus, and brainstem after microdialysis of 14C lactate into the lateral ventricle. Serine, aspartate, glycine, taurine, tyrosine, and methionine were not synthesized from glucose or lactate during torpor. ECF levels of amino and organic acids were low and unchanging during torpor and increased late during arousal to cenothermia. Labeled intracellular 14C GABA and glutamate were not communicated to the striatal ECF or ventricular space during torpor. 13C NMR demonstrated rapid formation of lactate and functional tricarboxylic acid cycles in GABAergic and glutamatergic neurons, and enrichment of glutamine and alanine after i.v. 13C glucose. Large changes in tissue levels of amino acids occur prior to or during entrance into torpor but not during torpor. It is proposed that cerebral intracellular dehydration, the enlargement of ECF and the biochemistries associated with brain water homeostasis may have a role in regulating hibernation.
NCAM‐derived peptides function as agonists for the fibroblast growth factor receptor
Authors: Hansen Stine M. M. , Køhler Lene B. , Li Shizhong , Kiselyov Vladislav , Christensen Claus , Owczarek Sylwia , Bock Elisabeth , Berezin Vladimir 
Published: July 2008

AbstractThe neural cell adhesion molecule (NCAM) directly interacts with the fibroblast growth factor receptor (FGFR). Both fibronectin type III (FN3) modules of NCAM are involved in this interaction. One of the NCAM–FGFR contact sites has been localized recently to the upper N‐terminal part of the second NCAM FN3 module encompassing the F and G β‐strands and the interconnecting loop region. Here, we investigated whether any of the six putative strand‐loop‐strand regions in the first NCAM FN3 module are involved in FGFR interactions. Peptide sequences encompassing these regions, termed encamins, were synthesized and tested for their ability to bind and activate FGFR. Encamins localized to the N‐terminal part of the first FN3 module did not interact with FGFR, whereas encamins localized to the C‐terminal part, termed EncaminA, C and E, bound to and activated FGFR. The encamins induced FGFR‐dependent neurite outgrowth, and EncaminC and E promoted neuronal survival and enhanced pre‐synaptic function. In conclusion, the interaction between NCAM and FGFR probably involves multiple contact sites at an interface formed by the two NCAM FN3 modules and FGFR, and encamins could constitute important pharmacological tools for the study of specific functional aspects of NCAM, including neuroprotection and modulation of plasticity.
Over‐expression of Hsp27 does not influence disease in the mutant SOD1G93A mouse model of amyotrophic lateral sclerosis
Authors: Krishnan Jyothsna , Vannuvel Kayleen , Andries Maria , Waelkens Etienne , Robberecht Wim , Van Den Bosch Ludo 
Published: July 2008

AbstractAmyotrophic lateral sclerosis (ALS) is a chronic, adult‐onset neurodegenerative disorder characterized by the selective loss of upper and lower motor neurons, resulting in severe atrophy of muscles and death. Although the exact pathogenic mechanism of mutant superoxide dismutase 1 (SOD1) causing familial ALS is still elusive, toxic protein aggregation leading to insufficiency of chaperones is one of the main hypotheses. In this study, we investigated the effect of over‐expressing one of these chaperones, heat shock protein 27 (Hsp27), in ALS. Mice over‐expressing the human, mutant SOD1G93A were crossed with mice that ubiquitously over‐expressed human Hsp27. Even though the single transgenic hHsp27 mice showed protection against spinal cord ischemia, the double transgenic SOD1G93A/hHsp27 mice did not live longer, and did not show a significant delay in the onset of disease compared to their SOD1G93A littermates. There was no protective effect of hHsp27 over‐expression on the motor neurons and on the mutant SOD1 aggregates in the double transgenic SOD1G93A/hHsp27 mice. In conclusion, despite the protective action against acute motor neuron injury, Hsp27 alone is not sufficient to protect against the chronic motor neuron injury due to the presence of mutant SOD1.
Neurofilament tail phosphorylation: identity of the RT‐97 phosphoepitope and regulation in neurons by cross‐talk among proline‐directed kinases
Authors: Veeranna  , Lee Ju‐Hyun , Pareek Tej K. , Jaffee Howard , Boland Barry , Vinod K. Yaragudri , Amin Niranjana , Kulkarni Ashok B. , Pant Harish C. , Nixon Ralph A. 
Published: July 2008

AbstractAs axons myelinate, establish a stable neurofilament network, and expand in caliber, neurofilament proteins are extensively phosphorylated along their C‐terminal tails, which is recognized by the monoclonal antibody, RT‐97. Here, we demonstrate in vivo that RT‐97 immunoreactivity (IR) is generated by phosphorylation at KSPXK or KSPXXXK motifs and requires flanking lysines at specific positions. extracellular signal regulated kinase 1,2 (ERK1,2) and pERK1,2 levels increase in parallel with phosphorylation at the RT‐97 epitope during early postnatal brain development. Purified ERK1,2 generated RT‐97 on both KSP motifs on recombinant NF‐H tail domain proteins, while cdk5 phosphorylated only KSPXK motifs. RT‐97 epitope generation in primary hippocampal neurons was regulated by extensive cross‐talk among ERK1,2, c‐Jun N‐terminal kinase 1,2 (JNK1,2) and cdk5. Inhibition of both ERK1,2 and JNK1,2 completely blocked RT‐97 generation. Cdk5 influenced RT‐97 generation indirectly by modulating JNK activation. In mice, cdk5 gene deletion did not significantly alter RT‐97 IR or ERK1,2 and JNK activation. In mice lacking the cdk5 activator P35, the partial suppression of cdk5 activity increased RT‐97 IR by activating ERK1,2. Thus, cdk5 influences RT‐97 epitope generation partly by modulating ERKs and JNKs, which are the two principal kinases regulating neurofilament phosphorylation. The regulation of a single target by multiple protein kinases underscores the importance of monitoring other relevant kinases when the activity of a particular one is blocked.
Native cone photoreceptor cyclic nucleotide‐gated channel is a heterotetrameric complex comprising both CNGA3 and CNGB3: a study using the cone‐dominant retina of Nrl−/− mice
Authors: Matveev Alexander V. , Quiambao Alexander B. , Browning Fitzgerald J. , Ding Xi‐Qin 
Published: July 2008

AbstractCone vision mediated by photoreceptor cyclic nucleotide‐gated (CNG) channel activation is essential for central and color vision and visual acuity. Mutations in genes encoding the cone CNG channel subunits, CNGA3 and CNGB3, have been linked to various forms of achromatopsia and progressive cone dystrophy in humans. This study investigates the biochemical components of native cone CNG channels, using the cone‐dominant retina in mice deficient in the transcription factor neural retina leucine zipper (Nrl). Abundant expression of CNGA3 and CNGB3 but no rod CNG channel expression was detected in Nrl−/− retina by western blotting and immunolabeling. Localization of cone CNG channel in both blue (S)‐ and red/green (M)‐cones was shown by double immunolabeling using antibodies against the channel subunits and against the S‐ and M‐opsins. Immunolabeling also showed co‐localization of CNGA3 and CNGB3 in the mouse retina. Co‐immunoprecipitation demonstrated the direct interaction between CNGA3 and CNGB3. Chemical cross‐linking readily generated products at sizes consistent with oligomers of the channel complexes ranging from dimeric to tetrameric complexes, in a concentration‐ and time‐dependent pattern. Thus this work provides the first biochemical evidence showing the inter‐subunit interaction between CNGA3 and CNGB3 and the presence of heterotetrameric complexes of the native cone CNG channel in retina. No association between CNGA3 and the cone Na+/Ca2+‐K+ exchanger (NCKX2) was shown by co‐immunoprecipitation and chemical cross‐linking. This may implicate a distinct modulatory mechanism for Ca2+ homeostasis in cones compared to rods.
NFκB in the mechanism of ammonia‐induced astrocyte swelling in culture
Authors: Sinke Anne P. , Jayakumar Arumugam R. , Panickar Kiran S. , Moriyama Mitsuaki , Reddy Pichili V. B. , Norenberg Michael D. 
Published: July 2008

AbstractAstrocyte swelling and brain edema are major neuropathological findings in the acute form of hepatic encephalopathy (fulminant hepatic failure), and substantial evidence supports the view that elevated brain ammonia level is an important etiological factor in this condition. Although the mechanism by which ammonia brings about astrocyte swelling remains to be determined, oxidative/nitrosative stress and mitogen‐activated protein kinases (MAPKs) have been considered as important elements in this process. One factor known to be activated by both oxidative stress and MAPKs is nuclear factor κB (NFκB), a transcription factor that activates many genes, including inducible nitric oxide synthase (iNOS). As the product of iNOS, nitric oxide (NO), is known to cause astrocyte swelling, we examined the potential involvement of NFκB in ammonia‐induced astrocyte swelling. Western blot analysis of cultured astrocytes showed a significant increase in NFκB nuclear translocation (a measure of NFκB activation) from 12 h to 2 days after treatment with NH4Cl (5 mM). Cultures treated with anti‐oxidants, including superoxide dismutase, catalase, and vitamin E as well as the MAPKs inhibitors, SB239063 (an inhibitor of p38‐MAPK) and SP600125 (an inhibitor of c‐Jun N‐terminal kinase), significantly diminished NFκB activation by ammonia, supporting a role of oxidative stress and MAPKs in NFκB activation. The activation of NFκB was associated with increased iNOS protein expression and NO generation, and these changes were blocked by BAY 11–7082, an inhibitor of NFκB. Additionally, ammonia‐induced astrocyte swelling was inhibited by the NFκB inhibitors, BAY 11–7082 and SN‐50, thereby implicating NFκB in the mechanism of astrocyte swelling. Our studies indicate that cultured astrocytes exposed to ammonia display NFκB activation, which is likely to be a consequence of oxidative stress and activation of MAPKs. NFκB activation appears to contribute to the mechanism of ammonia‐induced astrocyte swelling, apparently through its up‐regulation of iNOS protein expression and the subsequent generation of NO.
Cisplatin‐mediated activation of extracellular signal‐regulated kinases 1/2 (ERK1/2) by inhibition of ERK1/2 phosphatases
Authors: Gozdz Agata , Vashishta Aruna , Kalita Katarzyna , Szatmari Erzsebet , Zheng Jing‐Juan , Tamiya Shigeo , Delamere Nicholas A. , Hetman Michal 
Published: July 2008

AbstractThe mechanism(s) underlying neurodegeneration‐associated activation of ERK1/2 remain poorly understood. We report that in cultured rat cortical neurons, whose basal ERK1/2 phosphorylation required NMDA receptors (NMDAR), the neurotoxic DNA intercalating drug cisplatin increased ERK1/2 phosphorylation via NMDAR despite reducing their activity. The rate of ERK1/2 dephosphorylation was lowered by cisplatin. Cisplatin‐treated neurons showed general transcription inhibition likely accounting for the reduced expression of the ERK1/2‐selective phosphatases including the dual specificity phosphatase‐6 (DUSP6) and the DUSP3 activator vaccinia‐related kinase‐3 (VRK3). Hence, cisplatin effects on ERK1/2 may be due to the deficient ERK1/2 inhibition by the transcription‐regulated phosphatases. Indeed, the transcription inhibitor actinomycin D reduced expression of DUSP6 and VRK3 while inducing the NMDAR‐dependent activation of ERK1/2 and the impairment of ERK1/2 dephosphorylation. Thus, cisplatin‐mediated transcriptional inhibition of ERK1/2 phosphatases contributed to delayed and long lasting accumulation of phospho‐ERK1/2 that was driven by the basal NMDAR activity. Our results provide the first direct evidence for transcriptionally‐regulated inactivation of neuronal ERK1/2. Its disruption likely contributes to neurodegeneration‐associated activation of ERK1/2.
The Notch signaling inhibitor DAPT down‐regulates cdk5 activity and modulates the distribution of neuronal cytoskeletal proteins
Authors: Kanungo Jyotshnabala , Zheng Ya‐Li , Amin Niranjana D. , Pant Harish C. 
Published: July 2008

AbstractNotch signaling is critical for the development of the nervous system. Cyclin‐dependent kinase 5 (cdk5) is a neuronal kinase involved in neuronal development and phosphorylates a number of neuronal cytoskeletal proteins. To determine the relationship between Notch and cdk5 signaling, we tested the effects of the Notch inhibitor, N‐[N‐(3,5‐difluorophenacetyl)‐1‐alanyl]‐S‐phenylglycine t‐butyl ester (DAPT) on cdk5 expression, activity and cytoskeletal protein distribution in the rat cortical neurons in primary cultures. Neurons treated with 10 μM DAPT showed attenuated cdk5 activity in spite of an up‐regulation of cdk5 protein level, consistent with a phenomenon reported in the cdk5 transgenic mice. Immunoblot and immunofluorescence analyses showed an increased level of cdk5, but not p35. Phospho‐tau and phospho‐neurofilament showed a shift from axons to cell bodies in DAPT‐treated cells. DAPT‐induced attenuation of cdk5 activity was restored by over‐expression of p35 indicating that it interacted with cdk5 and up‐regulated nascent cdk5 activity. p35 over‐expression also rescued DAPT‐induced translocation of phospho‐tau and phospho‐neurofilament. Immunoprecipitation followed by immunoblotting demonstrated that DAPT does not disrupt cdk5 and p35 interaction. Moreover, DAPT up‐regulated neurogenin that is negatively regulated by Notch, and down‐regulated Hes1, a downstream target of Notch, suggesting that Notch signaling in the cortical neurons was disrupted. Semi‐quantitative and quantitative RT‐PCR analyses confirmed that DAPT up‐regulated cdk5 expression at the transcriptional level. These results establish a link between Notch signaling and cdk5 expression regulating neuronal cytoskeletal protein dynamics.
The heme precursor delta‐aminolevulinate blocks peripheral myelin formation
Authors: Felitsyn Natalia , McLeod Colin , Shroads Albert L. , Stacpoole Peter W. , Notterpek Lucia 
Published: July 2008

AbstractDelta‐aminolevulinic acid (δ‐ALA) is a heme precursor implicated in neurological complications associated with porphyria and tyrosinemia type I. Delta‐ALA is also elevated in the urine of animals and patients treated with the investigational drug dichloroacetate (DCA). We postulated that δ‐ALA may be responsible, in part, for the peripheral neuropathy observed in subjects receiving DCA. To test this hypothesis, myelinating cocultures of Schwann cells and sensory neurons were exposed to δ‐ALA (0.1–1 mM) and analyzed for the expression of neural proteins and lipids and markers of oxidative stress. Exposure of myelinating samples to δ‐ALA is associated with a pronounced reduction in the levels of myelin‐associated lipids and proteins, including myelin protein zero and peripheral myelin protein 22. We also observed an increase in protein carbonylation and the formation of hydroxynonenal and malondialdehyde after treatment with δ‐ALA. Studies of isolated Schwann cells and neurons indicate that glial cells are more vulnerable to this pro‐oxidant than neurons, based on a selective decrease in the expression of mitochondrial respiratory chain proteins in glial, but not in neuronal, cells. These results suggest that the neuropathic effects of δ‐ALA are attributable, at least in part, to its pro‐oxidant properties which damage myelinating Schwann cells.
Anticipating Tax Changes: Evidence from the Finnish Corporate Income Tax Reform of 2005*
Authors: Kari Seppo , Karikallio Hanna , Pirttilä Jukka 
Published: July 2008

AbstractUsing register‐based panel data covering all Finnish firms from 1999 to 2004, we examine how corporations anticipated the 2005 dividend tax increase via changes in their dividend and investment policies. The Finnish capital and corporate income tax reform of 2005 creates a useful opportunity to measure this behaviour, since it involves exogenous variation in the tax treatment of different types of firms. The estimation results reveal that those firms that anticipated a dividend tax hike increased their dividend payouts in a statistically significant way. This increase was not accompanied by a reduction in investment activities, but rather was associated with increased indebtedness in non‐listed firms. The results also suggest that the timing of dividend distributions probably offsets much of the potential for increased dividend tax revenue following the reform.
How Did the Elimination of the US Earnings Test above the Normal Retirement Age Affect Labour Supply Expectations?*
Authors: Michaud Pierre‐Carl , Van Soest Arthur 
Published: July 2008

AbstractWe look at the effect of the 2000 repeal of the earnings test above the normal retirement age (NRA) on the self‐reported probabilities of working full‐time after ages 65 and 62 of male workers in the US Health and Retirement Study (HRS). Using administrative records on social security benefit entitlements linked to the HRS survey data, we can distinguish groups of respondents according to the predicted effect of the earnings test before its repeal on their marginal wage rate after the NRA. We use panel data models with fixed and random effects to investigate the effect of the repeal. We find that male workers whose predicted marginal wage rate increased because the earnings test was repealed had the largest increase in the subjective probability of working full‐time after age 65. We find no significant effects of the repeal on the subjective probability of working full‐time past age 62.