2018 |
Herrera-Marschitz, M; Perez-Lobos, R; Lespay-Rebolledo, C; Tapia-Bustos, A; Casanova-Ortiz, E; Morales, P; Valdes, J L; Bustamante, D; Cassels, B K Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: A Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia? Artículo de revista Neurotoxicity Research, 33 (2), pp. 461-473, 2018, ISSN: 1029-8428. Resumen | Enlaces | BibTeX | Etiquetas: basal brain-damage, cell cell-death, cultures, death, delayed encephalopathy encephalopathy, factor-i, ganglia, gfap, hypoxia, hypoxic hypoxic-ischemic inducible ischaemic leukomalacia, map-2, memantine, n-acetylcysteine neonatal niacinamide, nitric-oxide nmda nnos, organotypic oxidative rat rat, receptors, stress, substantia-nigra, synthase, tunel @article{RN385, title = {Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: A Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia?}, author = { M. Herrera-Marschitz and R. Perez-Lobos and C. Lespay-Rebolledo and A. Tapia-Bustos and E. Casanova-Ortiz and P. Morales and J.L. Valdes and D. Bustamante and B.K. Cassels}, url = {/brokenurl#<Go to ISI>://WOS:000422640700020}, doi = {10.1007/s12640-017-9795-9}, issn = {1029-8428}, year = {2018}, date = {2018-01-01}, journal = {Neurotoxicity Research}, volume = {33}, number = {2}, pages = {461-473}, abstract = {Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is stabilised, associated with short- and long-term developmental disabilities, requiring inordinate care by health systems and families. Its prevalence is high (1 to 10/1000 live births) worldwide. At present, there are few therapeutic options, apart from hypothermia, that regrettably provides only limited protection if applied shortly after the insult., PA implies a primary and a secondary insult. The primary insult relates to the lack of oxygen, and the secondary one to the oxidative stress triggered by re-oxygenation, formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species, and overactivation of glutamate receptors and mitochondrial deficiencies. PA induces overactivation of a number of sentinel proteins, including hypoxia-induced factor-1 alpha (HIF-1 alpha) and the genome-protecting poly(ADP-ribose) polymerase-1 (PARP-1). Upon activation, PARP-1 consumes high amounts of ATP at a time when this metabolite is scarce, worsening in turn the energy crisis elicited by asphyxia. The energy crisis also impairs ATP-dependent transport, including glutamate re-uptake by astroglia. Nicotinamide, a PARP-1 inhibitor, protects against the metabolic cascade elicited by the primary stage, avoiding NAD(+) exhaustion and the energetic crisis. Upon re-oxygenation, however, oxidative stress leads to nuclear translocation of the NF-kappa B subunit p65, overexpression of the pro-inflammatory cytokines IL-1 beta and TNF-alpha, and glutamate-excitotoxicity, due to impairment of glial-glutamate transport, extracellular glutamate overflow, and overactivation of NMDA receptors, mainly of the extrasynaptic type. This leads to calcium influx, mitochondrial impairment, and inactivation of antioxidant enzymes, increasing further the activity of pro-oxidant enzymes, thereby making the surviving neonate vulnerable to recurrent metabolic insults whenever oxidative stress is involved. Here, we discuss evidence showing that (i) inhibition of PARP-1 overactivation by nicotinamide and (ii) inhibition of extrasynaptic NMDA receptor overactivation by memantine can prevent the short- and long-term consequences of PA. These hypotheses have been evaluated in a rat preclinical model of PA, aiming to identify the metabolic cascades responsible for the long-term consequences induced by the insult, also assessing postnatal vulnerability to recurrent oxidative insults. Thus, we present and discuss evidence demonstrating that PA induces long-term changes in metabolic pathways related to energy and oxidative stress, priming vulnerability of cells with both the neuronal and the glial phenotype. The effects induced by PA are region dependent, the substantia nigra being particularly prone to cell death. The issue of short- and long-term consequences of PA provides a framework for addressing a fundamental issue referred to plasticity of the CNS, since the perinatal insult triggers a domino-like sequence of events making the developing individual vulnerable to recurrent adverse conditions, decreasing his/her coping repertoire because of a relevant insult occurring at birth.}, keywords = {basal brain-damage, cell cell-death, cultures, death, delayed encephalopathy encephalopathy, factor-i, ganglia, gfap, hypoxia, hypoxic hypoxic-ischemic inducible ischaemic leukomalacia, map-2, memantine, n-acetylcysteine neonatal niacinamide, nitric-oxide nmda nnos, organotypic oxidative rat rat, receptors, stress, substantia-nigra, synthase, tunel}, pubstate = {published}, tppubtype = {article} } Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is stabilised, associated with short- and long-term developmental disabilities, requiring inordinate care by health systems and families. Its prevalence is high (1 to 10/1000 live births) worldwide. At present, there are few therapeutic options, apart from hypothermia, that regrettably provides only limited protection if applied shortly after the insult., PA implies a primary and a secondary insult. The primary insult relates to the lack of oxygen, and the secondary one to the oxidative stress triggered by re-oxygenation, formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species, and overactivation of glutamate receptors and mitochondrial deficiencies. PA induces overactivation of a number of sentinel proteins, including hypoxia-induced factor-1 alpha (HIF-1 alpha) and the genome-protecting poly(ADP-ribose) polymerase-1 (PARP-1). Upon activation, PARP-1 consumes high amounts of ATP at a time when this metabolite is scarce, worsening in turn the energy crisis elicited by asphyxia. The energy crisis also impairs ATP-dependent transport, including glutamate re-uptake by astroglia. Nicotinamide, a PARP-1 inhibitor, protects against the metabolic cascade elicited by the primary stage, avoiding NAD(+) exhaustion and the energetic crisis. Upon re-oxygenation, however, oxidative stress leads to nuclear translocation of the NF-kappa B subunit p65, overexpression of the pro-inflammatory cytokines IL-1 beta and TNF-alpha, and glutamate-excitotoxicity, due to impairment of glial-glutamate transport, extracellular glutamate overflow, and overactivation of NMDA receptors, mainly of the extrasynaptic type. This leads to calcium influx, mitochondrial impairment, and inactivation of antioxidant enzymes, increasing further the activity of pro-oxidant enzymes, thereby making the surviving neonate vulnerable to recurrent metabolic insults whenever oxidative stress is involved. Here, we discuss evidence showing that (i) inhibition of PARP-1 overactivation by nicotinamide and (ii) inhibition of extrasynaptic NMDA receptor overactivation by memantine can prevent the short- and long-term consequences of PA. These hypotheses have been evaluated in a rat preclinical model of PA, aiming to identify the metabolic cascades responsible for the long-term consequences induced by the insult, also assessing postnatal vulnerability to recurrent oxidative insults. Thus, we present and discuss evidence demonstrating that PA induces long-term changes in metabolic pathways related to energy and oxidative stress, priming vulnerability of cells with both the neuronal and the glial phenotype. The effects induced by PA are region dependent, the substantia nigra being particularly prone to cell death. The issue of short- and long-term consequences of PA provides a framework for addressing a fundamental issue referred to plasticity of the CNS, since the perinatal insult triggers a domino-like sequence of events making the developing individual vulnerable to recurrent adverse conditions, decreasing his/her coping repertoire because of a relevant insult occurring at birth. |
2017 |
Almodovar, I; Rezende, M C; Cassels, B K; Garcia-Arriagada, M Theoretical Insights into the Regioselectivity of a Pictet-Spengler Reaction: Transition State Structures Leading to Salsolinol and Isosalsolinol Artículo de revista Journal of Physical Organic Chemistry, 30 (8), 2017, ISSN: 0894-3230. Resumen | Enlaces | BibTeX | Etiquetas: borylation, calculations, catalyzed condensation, density-functional-approach, derivatives dft dopamine, frontier-electron isosalsolinol, mechanism, norcoclaurine of pictet-spengler regioselectivity, salsolinol, synthase, tautomerism, theory @article{RN343, title = {Theoretical Insights into the Regioselectivity of a Pictet-Spengler Reaction: Transition State Structures Leading to Salsolinol and Isosalsolinol}, author = { I. Almodovar and M.C. Rezende and B.K. Cassels and M. Garcia-Arriagada}, url = {/brokenurl#<Go to ISI>://WOS:000406979900005}, doi = {10.1002/poc.3666}, issn = {0894-3230}, year = {2017}, date = {2017-01-01}, journal = {Journal of Physical Organic Chemistry}, volume = {30}, number = {8}, abstract = {The mechanism of the cyclization step of the Pictet-Spengler reaction between acetaldehyde and dopamine to give salsolinol and isosalsolinol was studied computationally, using density functional theory. The preferential formation in acidic media of salsolinol, the product of para-cyclization, and the requirement of a neutral pH for the formation of the ortho-cyclized isosalsolinol are explained in terms of 2 different mechanistic routes with an iminium ion or a phenolate-iminium zwitterion as starting reactants.}, keywords = {borylation, calculations, catalyzed condensation, density-functional-approach, derivatives dft dopamine, frontier-electron isosalsolinol, mechanism, norcoclaurine of pictet-spengler regioselectivity, salsolinol, synthase, tautomerism, theory}, pubstate = {published}, tppubtype = {article} } The mechanism of the cyclization step of the Pictet-Spengler reaction between acetaldehyde and dopamine to give salsolinol and isosalsolinol was studied computationally, using density functional theory. The preferential formation in acidic media of salsolinol, the product of para-cyclization, and the requirement of a neutral pH for the formation of the ortho-cyclized isosalsolinol are explained in terms of 2 different mechanistic routes with an iminium ion or a phenolate-iminium zwitterion as starting reactants. |
2013 |
Contreras, G; Barahona, S; Rojas, M C; Baeza, M; Cifuentes, V; Alcaino, J Increase in the Astaxanthin Synthase Gene (Crts) Dose by in Vivo DNA Fragment Assembly in Xanthophyllomyces Dendrorhous Artículo de revista Bmc Biotechnology, 13 , 2013, ISSN: 1472-6750. Resumen | Enlaces | BibTeX | Etiquetas: astaxanthin beta-carotene, biosynthetic-pathway, carotenoid cloning, dendrorhous, DNA assembler, expression, growth mutants, overproducing oxygen, phaffia-rhodozyma, selection, strains, synthase, xanthophyllomyces @article{RN132, title = {Increase in the Astaxanthin Synthase Gene (Crts) Dose by in Vivo DNA Fragment Assembly in Xanthophyllomyces Dendrorhous}, author = { G. Contreras and S. Barahona and M.C. Rojas and M. Baeza and V. Cifuentes and J. Alcaino}, url = {/brokenurl#<Go to ISI>://WOS:000327426600001}, doi = {Unsp 84, 10.1186/1472-6750-13-84}, issn = {1472-6750}, year = {2013}, date = {2013-01-01}, journal = {Bmc Biotechnology}, volume = {13}, abstract = {Background: Xanthophyllomyces dendrorhous is a basidiomycetous yeast that is relevant to biotechnology, as it can synthesize the carotenoid astaxanthin. However, the astaxanthin levels produced by wild-type strains are low. Although different approaches for promoting increased astaxanthin production have been attempted, no commercially competitive results have been obtained thus far. A promising alternative to facilitate the production of carotenoids in this yeast involves the use of genetic modification. However, a major limitation is the few available molecular tools to manipulate X. dendrorhous., Results: In this work, the DNA assembler methodology that was previously described in Saccharomyces cerevisiae was successfully applied to assemble DNA fragments in vivo and integrate these fragments into the genome of X. dendrorhous by homologous recombination in only one transformation event. Using this method, the gene encoding astaxanthin synthase (crtS) was overexpressed in X. dendrorhous and a higher level of astaxanthin was produced., Conclusions: This methodology could be used to easily and rapidly overexpress individual genes or combinations of genes simultaneously in X. dendrorhous, eliminating numerous steps involved in conventional cloning methods.}, keywords = {astaxanthin beta-carotene, biosynthetic-pathway, carotenoid cloning, dendrorhous, DNA assembler, expression, growth mutants, overproducing oxygen, phaffia-rhodozyma, selection, strains, synthase, xanthophyllomyces}, pubstate = {published}, tppubtype = {article} } Background: Xanthophyllomyces dendrorhous is a basidiomycetous yeast that is relevant to biotechnology, as it can synthesize the carotenoid astaxanthin. However, the astaxanthin levels produced by wild-type strains are low. Although different approaches for promoting increased astaxanthin production have been attempted, no commercially competitive results have been obtained thus far. A promising alternative to facilitate the production of carotenoids in this yeast involves the use of genetic modification. However, a major limitation is the few available molecular tools to manipulate X. dendrorhous., Results: In this work, the DNA assembler methodology that was previously described in Saccharomyces cerevisiae was successfully applied to assemble DNA fragments in vivo and integrate these fragments into the genome of X. dendrorhous by homologous recombination in only one transformation event. Using this method, the gene encoding astaxanthin synthase (crtS) was overexpressed in X. dendrorhous and a higher level of astaxanthin was produced., Conclusions: This methodology could be used to easily and rapidly overexpress individual genes or combinations of genes simultaneously in X. dendrorhous, eliminating numerous steps involved in conventional cloning methods. |
2018 |
Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: A Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia? Artículo de revista Neurotoxicity Research, 33 (2), pp. 461-473, 2018, ISSN: 1029-8428. |
2017 |
Theoretical Insights into the Regioselectivity of a Pictet-Spengler Reaction: Transition State Structures Leading to Salsolinol and Isosalsolinol Artículo de revista Journal of Physical Organic Chemistry, 30 (8), 2017, ISSN: 0894-3230. |
2013 |
Increase in the Astaxanthin Synthase Gene (Crts) Dose by in Vivo DNA Fragment Assembly in Xanthophyllomyces Dendrorhous Artículo de revista Bmc Biotechnology, 13 , 2013, ISSN: 1472-6750. |