Nitric oxide from inflammatory origin impairs neural stem cell proliferation by inhibiting epidermal growth factor receptor signaling

Neuroinflammation is characterized by activation of microglial cells, followed by production of nitric oxide (NO), which may have different outcomes on neurogenesis, favoring or inhibiting this process. In the present study, we investigated how the inflammatory mediator NO can affect proliferation of neural stem cells (NSCs), and explored possible mechanisms underlying this effect. We investigated which mechanisms are involved in the regulation of NSC proliferation following treatment with an inflammatory stimulus (lipopolysaccharide plus IFN-gamma), using a culture system of subventricular zone (SVZ)-derived NSCs mixed with microglia cells obtained from wild-type mice (iNOS(+/+)) or from iNOS knockout mice (iNOS(-/-)). We found an impairment of NSC cell proliferation in iNOS(+/+) mixed cultures, which was not observed in iNOS(-/-) mixed cultures. Furthermore, the increased release of NO by activated iNOS(+/+) microglial cells decreased the activation of the ERK/MAPK signaling pathway, which was concomitant with an enhanced nitration of the EGF receptor. Preventing nitrogen reactive species formation with MnTBAP, a scavenger of peroxynitrite (ONOO-), or using the ONOO- degradation catalyst FeTMPyP cell proliferation and ERK signaling were restored to basal levels in iNOS(+/+) mixed cultures. Moreover, exposure to the NO donor NOC-18 (100 mu M), for 48 h, inhibited SVZ-derived NSC proliferation. Regarding the antiproliferative effect of NO, we found that NOC-18 caused the impairment of signaling through the ERK/MAPK pathway, which may be related to increased nitration of the EGF receptor in NSC. Using MnTBAP nitration was prevented, maintaining ERK signaling, rescuing NSC proliferation. We show that NO from inflammatory origin leads to a decreased function of the EGF receptor, which compromised proliferation of NSC. We also demonstrated that NO-mediated nitration of the EGF receptor caused a decrease in its phosphorylation, thus preventing regular proliferation signaling through the ERK/MAPK pathway.Foundation for Science and Technology, (FCT, Portugal); COMPETE; FEDER [PEst-C/SAU/LA0001/2013-2014, PEst-OE/EQB/LA0023/2013-2014, PTDC/SAU-NEU/102612/2008, PTDC/NEU-OSD/0473/2012]; FCT, Portugal [SERH/BPD/78901/2011, SERH/BD/38127/2007, SFRH/BD/77903/2011, SFRH/BD/79308/2011]info:eu-repo/semantics/publishedVersio

Electrocatalytic performance of SiO2-SWCNT nanocomposites prepared by electroassisted deposition

“The final publication is available at Springer via http://dx.doi.org/10.1007/s12678-013-0144-3”Composite materials made of porous SiO2 matrices filled with single-walled carbon nanotubes (SWCNTs) were deposited on electrodes by an electroassisted deposition method. The synthesized materials were characterized by several techniques, showing that porous silica prevents the aggregation of SWCNT on the electrodes, as could be observed by transmission electron microscopy and Raman spectroscopy. Different redox probes were employed to test their electrochemical sensing properties. The silica layer allows the permeation of the redox probes to the electrode surface and improves the electrochemical reversibility indicating an electrocatalytic effect by the incorporation of dispersed SWCNT into the silica films.This work was financed by the following research projects: MAT2010-15273 of the Spanish Ministerio de Economia y Competitividad and FEDER, PROMETEO/2013/038 of the GV, and CIVP16A1821 of the Fundacion Ramon Areces. Alonso Gamero-Quijano and David Salinas-Torres acknowledge Generalitat Valenciana (Santiago Grisolia Program) and Ministerio de Economia y Competitividad, respectively, for the funding of their research fellowships.Gamero-Quijano, A.; Huerta, F.; Salinas-Torres, D.; Morallón, E.; Montilla, F. (2013). Electrocatalytic performance of SiO2-SWCNT nanocomposites prepared by electroassisted deposition. Electrocatalysis. 4(4):259-266. https://doi.org/10.1007/s12678-013-0144-3S25926644P. Alivisatos, Nat. Biotechnol. 22, 47 (2004)S. Stankovich, D.A. Dikin, G.H. Dommett, K.M. Kohlhaas, E.J. Zimney, E.A. Stach, R.D. Piner, S.T. Nguyen, R.S. Ruoff, Nature 442, 282 (2006)D.W. Schaefer, R.S. Justice, Macromolecules 40, 8501 (2007)M. Endo, M.S. Strano, P.M. Ajayan, Carbon Nanotubes 111, 13 (2008)C.E. Banks, R.G. Compton, Analyst 131, 15 (2006)R.H. Baughman, A.A. Zakhidov, W.A. de Heer, Science 297, 787 (2002)Y.H. Lin, F. Lu, Y. Tu, Z.F. Ren, Nano Letters 4, 191 (2004)B.R. Azamian, J.J. Davis, K.S. Coleman, C.B. Bagshaw, M.L.H. Green, J. Am. Chem. Soc. 124, 12664 (2002)W. Yang, K. Ratinac, S. Ringer, P. Thordarson, J.G. Gooding, F. Braet, Angew. Chem. Int. Ed. 49, 2114 (2010)C.E. Banks, R.G. Compton, Analyst 130, 1232 (2005)L. Mazurenko, M. Etienne, O. Tananaiko, V. Zaitsev, A. Walcarius, Electrochim. Acta 83, 359 (2012)J.M.P. Paloma Yáñez-Sedeño, J. Riu, F.X. Rius, TrAC Trends in Analytical Chemistry 29, 939 (2010)Z.J. Wang, M. Etienne, S. Poller, W. Schuhmann, G.W. Kohring, V. Mamane, A. Walcarius, Electroanalysis 24, 376 (2012)R. Bandyopadhyaya, E. Nativ-Roth, O. Regev, R. Yerushalmi-Rozen, Nano Letters 2, 25 (2002)C. Park, Z. Ounaies, K.A. Watson, R.E. Crooks, J. Smith, S.E. Lowther, J.W. Connell, E.J. Siochi, J.S. Harrison, T.L.S. Clair, Chem. Phys. Lett. 364, 303 (2002)O. Matarredona, H. Rhoads, Z.R. Li, J.H. Harwell, L. Balzano, D.E. Resasco, Journal of Physical Chemistry B 107, 13357 (2003)L. Vaisman, H. Wagner, G. Marom, Advances in Colloid and Interface Science 128, 37 (2006)Y.C. Xing, Journal of Physical Chemistry B 108, 19255 (2004)J.J. Liang, Y. Huang, L. Zhang, Y. Wang, Y.F. Ma, T.Y. Guo, Y.S. Chen, Adv. Funct. Mater. 19, 2297 (2009)D. Salinas-Torres, F. Huerta, F. Montilla, E. Morallón, Electrochim. Acta 56, 2464 (2011)Z.F. Ren, Z.P. Huang, J.W. Xu, J.H. Wang, P. Bush, M.P. Siegal, P.N. Provencio, Science 282, 1105 (1998)W.Z. Li, S.S. Xie, L.X. Qian, B.H. Chang, B.S. Zou, W.Y. Zhou, R.A. Zhao, G. Wang, Science 274, 1701 (1996)M. Terrones, N. Grobert, J. Olivares, J.P. Zhang, H. Terrones, K. Kordatos, W.K. Hsu, J.P. Hare, P.D. Townsend, K. Prassides, A.K. Cheetham, H.W. Kroto, D.R.M. Walton, Nature 388, 52 (1997)R. Toledano, D. Mandler, Chem. Mater. 22, 3943 (2010)J.H. Rouse, Langmuir 21, 1055 (2005)X.B. Yan, B.K. Tay, Y. Yang, Journal of Physical Chemistry B 110, 25844 (2006)J. Lim, P. Malati, F. Bonet, B. Dunn, J. Electrochem. Soc. 154, A140 (2007)L.D. Zhu, C.Y. Tian, J.L. Zhai, R.L. Yang, Sensors and Actuators B-Chemical 125, 254 (2007)F. Montilla, M.A. Cotarelo, E. Morallón, J. Mater. Chem. 19, 305 (2009)D. Salinas-Torres, F. Montilla, F. Huerta, E. Morallón, Electrochim. Acta 56, 3620 (2011)T. Dobbins, R. Chevious, Y. Lvov, Polymers 3, 942 (2011)R. Esquembre, J.A. Poveda, C.R. Mateo, Journal of Physical Chemistry B 113, 7534 (2009)M.L. Ferrer, R. Esquembre, I. Ortega, C.R. Mateo, F. del Monte, Chem. Mater. 18, 554 (2006)M.J. O'Connell, S. Sivaram, S.K. Doorn, Physical Review B 69, 235415 (2004)C. Domingo, G. Santoro, Opt. Pura Apl 40, 175 (2007)M.S. Dresselhaus, G. Dresselhaus, R. Saito, A. Jorio, Physics Reports 409, 47 (2005)R.L. McCreery, Chem. Rev. 108, 2646 (2008)C.G. Zoski, in Handbook of Electrochemistry, 1st ed (Elsevier, Amsterdam, 2007

Activation of mGlu3 Receptors Stimulates the Production of GDNF in Striatal Neurons

Metabotropic glutamate (mGlu) receptors have been considered potential targets for the therapy of experimental parkinsonism. One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by ionotropic glutamate receptor antagonists, such as sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25–3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. We speculate that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF

Nos2 Inactivation Promotes the Development of Medulloblastoma in Ptch1+/− Mice by Deregulation of Gap43–Dependent Granule Cell Precursor Migration

Medulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs) of the developing cerebellum and demonstrates aberrant hedgehog signaling, typically due to inactivating mutations in the receptor PTCH1, a pathomechanism recapitulated in Ptch1+/− mice. As nitric oxide may regulate GCP proliferation and differentiation, we crossed Ptch1+/− mice with mice lacking inducible nitric oxide synthase (Nos2) to investigate a possible influence on tumorigenesis. We observed a two-fold higher medulloblastoma rate in Ptch1+/− Nos2−/− mice compared to Ptch1+/− Nos2+/+ mice. To identify the molecular mechanisms underlying this finding, we performed gene expression profiling of medulloblastomas from both genotypes, as well as normal cerebellar tissue samples of different developmental stages and genotypes. Downregulation of hedgehog target genes was observed in postnatal cerebellum from Ptch1+/+ Nos2−/− mice but not from Ptch1+/− Nos2−/− mice. The most consistent effect of Nos2 deficiency was downregulation of growth-associated protein 43 (Gap43). Functional studies in neuronal progenitor cells demonstrated nitric oxide dependence of Gap43 expression and impaired migration upon Gap43 knock-down. Both effects were confirmed in situ by immunofluorescence analyses on tissue sections of the developing cerebellum. Finally, the number of proliferating GCPs at the cerebellar periphery was decreased in Ptch1+/+ Nos2−/− mice but increased in Ptch1+/− Nos2−/− mice relative to Ptch1+/− Nos2+/+ mice. Taken together, these results indicate that Nos2 deficiency promotes medulloblastoma development in Ptch1+/− mice through retention of proliferating GCPs in the external granular layer due to reduced Gap43 expression. This study illustrates a new role of nitric oxide signaling in cerebellar development and demonstrates that the localization of pre-neoplastic cells during morphogenesis is crucial for their malignant progression

Análisis del uso de la ciencia recreativa en la enseñanza de materias científicas y técnicas en educación secundaria

Numerosas investigaciones constatan la desmotivación y la falta de interés de los alumnos por el estudio de las materias científicas. Una causa potencial de dicho desinterés es la percepción que los estudiantes tienen de las asignaturas científicas como materias "aburridas". Para ello, se analiza el uso de actividades de ciencia recreativa (ACR) en la E.S.O., en los libros de texto y se recogen las opiniones del profesorado al respecto. Por último, se analizan las consecuencias de esto en el alumnado