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1.
Analyst ; 143(21): 5285-5294, 2018 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-30280722

RESUMEN

The development of a fluorescence method for the selective ratiometric detection of Al3+ ions in pure aqueous solutions and live cells is still a significant challenge. In the present study, we synthesized a new type of fluorescent probe using an Al3+-triggered self-assembly based on the dipeptide receptor and an aggregation-induced emission fluorophore. The fluorescent probe (1) bearing cyanostilbene with excitation by visible light detected Al3+ ions sensitively in pure aqueous buffered solution by ratiometric red-emission at 600 nm. 1 provided a highly selective ratiometric detection of Al3+ among 16 metal ions in aqueous solution. 1 exhibited sensitive ratiometric response to Al3+ in aqueous buffered solutions at pH ranging from 5 to 7.4. The detection limit (145 nM, R2 = 0.999) for Al3+ ions in pure aqueous solution was much lower than the maximum allowable level of Al3+ in drinking water demanded by the Environmental Protection Agency (EPA). The probe provided an efficient approach to detect low concentrations of Al3+ in ground water, tap water, and live cells by ratiometric red-emissions at 600 nm. The binding study using dynamic light scattering, NMR, IR, and TEM revealed that the complex between 1 and Al3+ self-assembled to form nanoparticles, resulting in the enhancement of the emission at 600 nm and a concomitant decrease in the emission at 535 nm.


Asunto(s)
Aluminio/análisis , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Benzotiazoles/química , Colorantes Fluorescentes/química , Aluminio/química , Ácido Aspártico/síntesis química , Ácido Aspártico/toxicidad , Benzotiazoles/síntesis química , Benzotiazoles/toxicidad , Línea Celular Tumoral , Fluorescencia , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/toxicidad , Agua Subterránea/análisis , Humanos , Límite de Detección , Microscopía Fluorescente/métodos , Nanopartículas/química , Tamaño de la Partícula , Espectrometría de Fluorescencia/métodos , Agua/química
2.
Biomacromolecules ; 16(4): 1276-82, 2015 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-25756603

RESUMEN

We report the synthesis and characterization of pH-responsive polysuccinimide-based nanoparticles. Polysuccinimide (PSI), a precursor to biodegradable poly(aspartic acid), was synthesized from the condensation of l-aspartic acid and subsequently functionalized with primary amines to form random amphiphilic copolymers. The copolymers formed stable nanoparticles in aqueous medium via nanoprecipitation and were subsequently loaded with a model hydrophobic molecule to demonstrate their potential as controlled-release delivery vehicles. It was found that above pH 7, the hydrophobic succinimidyl units of the PSI nanoparticles hydrolyzed to release encapsulated materials. The release rate significantly increased at elevated pH and decreased with an increasing degree of functionalization. Finally, plant toxicity studies showed that the polymer materials exhibit little to no toxic effects at biologically relevant concentrations.


Asunto(s)
Ácido Aspártico/análogos & derivados , Plásticos Biodegradables/metabolismo , Citrus/efectos de los fármacos , Nanopartículas/química , Péptidos/metabolismo , Agricultura/métodos , Ácido Aspártico/síntesis química , Ácido Aspártico/metabolismo , Ácido Aspártico/toxicidad , Plásticos Biodegradables/síntesis química , Plásticos Biodegradables/toxicidad , Citrus/metabolismo , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Péptidos/síntesis química , Péptidos/química , Péptidos/toxicidad , Semillas/efectos de los fármacos , Semillas/metabolismo
3.
Int J Cosmet Sci ; 37 Suppl 1: 28-33, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26120028

RESUMEN

BACKGROUND: Acetyl aspartic acid (A-A-A) was discovered through gene array analysis with corresponding connectivity mapping (Cmap). Using an in silico and in vitro approach, A-A-A was found increased keratinocyte regeneration, inhibited dermal expression of MMP making this compound a potential active ingredient for cosmetic application. OBJECTIVES: To determine the conditions to successfully formulate A-A-A for skin delivery investigation and in vivo clinical assessment by the systematic approach of pre-formulation testing of the active, screening of formulation type on active delivery and stability evaluations. METHODS: Analytical evaluation of A-A-A was undertaken using LC-MS ESI method. Formulation stability was evaluated using Brookfield viscometer, pH analysis, optical microscopy and organoleptic evaluations. RESULTS: Analytical evaluation of A-A-A shows that pH significantly impacts chemical stability of the molecule. A-A-A containing formulae show minimal differences to vehicle product throughout the testing. CONCLUSION: A-A-A is an active that can be successfully formulated in a cosmetic o/w emulsion within defined pH considerations.


Asunto(s)
Ácido Aspártico/toxicidad , Cosméticos , Evaluación Preclínica de Medicamentos , Concentración de Iones de Hidrógeno
4.
J Bacteriol ; 196(19): 3377-85, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25002546

RESUMEN

Peptide-nucleotide antibiotic microcin C (McC) is produced by some Escherichia coli strains. Inside a sensitive cell, McC is processed, releasing a nonhydrolyzable analog of aspartyl-adenylate, which inhibits aspartyl-tRNA synthetase. The product of mccE, a gene from the plasmid-borne McC biosynthetic cluster, acetylates processed McC, converting it into a nontoxic compound. MccE is homologous to chromosomally encoded acetyltransferases RimI, RimJ, and RimL, which acetylate, correspondingly, the N termini of ribosomal proteins S18, S5, and L12. Here, we show that E. coli RimL, but not other Rim acetyltransferases, provides a basal level of resistance to McC and various toxic nonhydrolyzable aminoacyl adenylates. RimL acts by acetylating processed McC, which along with ribosomal protein L12 should be considered a natural RimL substrate. When overproduced, RimL also makes cells resistant to albomycin, an antibiotic that upon intracellular processing gives rise to a seryl-thioribosyl pyrimidine that targets seryl-tRNA synthetase. We further show that E. coli YhhY, a protein related to Rim acetyltransferases but without a known function, is also able to detoxify several nonhydrolyzable aminoacyl adenylates but not processed McC. We propose that RimL and YhhY protect bacteria from various toxic aminoacyl nucleotides, either exogenous or those generated inside the cell during normal metabolism.


Asunto(s)
Acetiltransferasas/metabolismo , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/toxicidad , Ácido Aspártico/análogos & derivados , Bacteriocinas/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/enzimología , Iniciación de la Cadena Peptídica Traduccional , Acetiltransferasas/genética , Adenosina Monofosfato/química , Adenosina Monofosfato/metabolismo , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Ácido Aspártico/toxicidad , Bacteriocinas/química , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Iniciación de la Cadena Peptídica Traduccional/efectos de los fármacos
5.
Yao Xue Xue Bao ; 48(4): 560-5, 2013 Apr.
Artículo en Zh | MEDLINE | ID: mdl-23833946

RESUMEN

The aim of this paper is to compare the cytotoxicity and cellular uptake efficiency of three kinds of poly(b-benzyl-L-amino) block-poly(ethylene glycol) nanoparticles (PXA-PEG-NPs) using Calu-3 cells, and select one as a nasal drug delivery vector for curcumin (Cur). Poly(gamma-benzyl-L-glutamate) block-poly(ethylene glycol) nanoparticles (PBLG-PEG-NPs), poly(gamma-benzyl-L-lysine) block-poly(ethyleneglycol) nanoparticles (PZLL-PEG-NPs) and poly(gamma-benzyl-L-aspartate) block-poly(ethylene glycol) nanoparticles (PBLA-PEG-NPs) were prepared by emulsion-solvent evaporation method. MTT assays were used to evaluate the cytotoxicity of PXA-PEG-NPs against Calu-3 cells. The cellular uptake of nanoparticles was visualized by an inverted fluorescence microscope and quantified by a flow cytometer. The results indicated that even at high concentration of 2 mg x mL(-1) the three nanoparticles had no cytotoxicity on Calu-3 cells. Compared to the curcumin solution, the three curcumin-loaded PXA-PEG-NPs showed significantly higher cellular uptake efficiency on Calu-3 cells (at equal concentration of curcumin with 5 microg x mL(-1) Cur solution), PBLG-PEG-NPs group was the highest. The cellular uptake increased with incubation time, and has positive correlation with nanoparticle concentration. In brief, PXA-PEG-NPs are conducive to delivery Cur into cells, and PBLG-PEG-NPs might be provided as a good nasal drug delivery carrier.


Asunto(s)
Curcumina/administración & dosificación , Curcumina/metabolismo , Portadores de Fármacos , Polietilenglicoles/química , Ácido Poliglutámico/análogos & derivados , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Administración Intranasal , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/metabolismo , Ácido Aspártico/química , Ácido Aspártico/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Glicol de Etileno/química , Glicol de Etileno/toxicidad , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Lisina/química , Lisina/toxicidad , Nanopartículas , Tamaño de la Partícula , Polietilenglicoles/toxicidad , Ácido Poliglutámico/química , Ácido Poliglutámico/toxicidad
6.
Graefes Arch Clin Exp Ophthalmol ; 250(7): 1013-22, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22450526

RESUMEN

BACKGROUND: Dyes such as brilliant blue (BBG) are used during vitreoretinal surgery to visualize anatomical structures. By adding deuterium oxide (D2O), surgeons have tried to create a dye mixture heavier than water to facilitate staining of the inner limiting membrane (ILM) without prior fluid-air exchange. This study investigated the effect of 0.4 ml BBG (Fluoron, Ulm, Germany) mixed with 0.13 ml/ml D2O and D2O on retinal function of a pseudo in vivo model using bovine and human whole mount cultures. METHODS: Bovine and human retinas were superfused, and the electroretinogram (ERG) was recorded. BBG with 0.13 ml/ml D2O and D2O were applied epiretinally, different staining periods (10, 30, 60 and 120 s) were tested, and ERG recovery was monitored. 1 mM aspartate was added to the nutrient solution to examine the photoreceptor reaction. RESULTS: Reductions of the a- and b-wave amplitudes were found directly after exposure with BBG with 0.13 ml/ml D2O and with D2O in all test series. These effects on the electroretinogram were rapidly and completely reversible within the recovery time for all exposure times. ERG amplitudes measured after dye application at the end of the washout did not differ significantly from those recorded before staining. CONCLUSIONS: The clinically used mixture of BBG/D2O seems to be safe for clinical use. Staining periods of more than 120 seconds were not tested.


Asunto(s)
Bencenosulfonatos/toxicidad , Colorantes/toxicidad , Óxido de Deuterio/toxicidad , Retina/efectos de los fármacos , Anciano de 80 o más Años , Animales , Ácido Aspártico/toxicidad , Bovinos , Electrorretinografía/efectos de los fármacos , Femenino , Humanos , Técnicas de Cultivo de Órganos , Estimulación Luminosa , Retina/fisiología , Gravedad Específica , Cirugía Vitreorretiniana
7.
Arch Toxicol ; 85(1): 43-9, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20490464

RESUMEN

(S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate, a new telluroamino acid derivative, showed remarkable glutathione peroxidase (GPx)-like activity, attesting to its antioxidant potential. However, the stability and toxicity of this compound has not yet been investigated. The present study was designed to investigate the pharmacological/toxicological properties of this compound in vitro and in vivo. In vitro, this telluroamino acid derivative significantly blocked spontaneous and Fe(II)-induced TBARS formation in rat brain homogenates, demonstrating high antioxidant activity. In addition, it exhibited GPx-like and thiol oxidase activities. However, when subcutaneously administered to mice, (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate indicated genotoxic and mutagenic effect in adult male mice. Considering the differential effects of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate in vitro and in vivo, additional experiments are needed to elucidate the mechanism(s) by which this compound displays its antioxidant/toxicological effects.


Asunto(s)
Antioxidantes/farmacología , Ácido Aspártico/análogos & derivados , Succinatos/farmacología , Administración Oral , Análisis de Varianza , Animales , Ácido Aspártico/toxicidad , Ensayo Cometa , Daño del ADN , Compuestos Ferrosos/metabolismo , Glutatión Peroxidasa/metabolismo , Dosificación Letal Mediana , Masculino , Ratones , Compuestos Organometálicos/metabolismo , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/toxicidad , Ratas , Ratas Wistar , Succinatos/toxicidad , Telurio/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo
8.
Neurochem Int ; 150: 105177, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34481039

RESUMEN

The importance of glutamate transporters in learning, memory, and emotion remains poorly understood; hence, in the present study, we investigated whether deficiency of pharmacological GLAST in neurodevelopmental processes affects cognitive and/or emotional behaviors in mice. The mice were injected with a glutamate transporter inhibitor, dl-threo-ß-benzyloxyaspartate (dl-TBOA), during the early postnatal period. At 8 weeks of age, they showed impairments in cognitive or emotional behaviors; dysfunction of glutamatergic neurotransmission (increased expressions of GLAST, GLT-1, or GFAP protein, and decreased ability of glutamate release) in the cortex or hippocampus; morphological changes (decreased cell size in the cortex and thickness of the pyramidal neuronal layer of the CA1 area in the hippocampus). Such behavioral and morphological changes were not observed in adult mice injected with dl-TBOA. These results suggest that GLAST plays an important role in the regulation of cognitive and emotional behaviors. Early postnatal glutamatergic facilitation by GLAST dysfunction leads to cognitive and emotional abnormalities due to neurodevelopmental abnormalities such as morphological changes.


Asunto(s)
Ácido Aspártico/toxicidad , Transportador 1 de Aminoácidos Excitadores/antagonistas & inhibidores , Transportador 1 de Aminoácidos Excitadores/metabolismo , Trastornos Mentales/inducido químicamente , Trastornos Mentales/metabolismo , Neuronas/metabolismo , Animales , Animales Recién Nacidos , Ácido Aspártico/administración & dosificación , Femenino , Inyecciones Intraventriculares , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Trastornos Mentales/patología , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/patología , Embarazo
9.
Transl Neurodegener ; 10(1): 34, 2021 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-34496956

RESUMEN

BACKGROUND: ß Amyloid (Aß)-mediated neuronal hyperactivity, a key feature of the early stage of Alzheimer's disease (AD), is recently proposed to be initiated by the suppression of glutamate reuptake. Nevertheless, the underlying mechanism by which the impaired glutamate reuptake causes neuronal hyperactivity remains unclear. Chronic suppression of the glutamate reuptake causes accumulation of ambient glutamate that could diffuse from synaptic sites at the dendrites to the soma to elevate the tonic activation of somatic N-methyl-D-aspartate receptors (NMDARs). However, less attention has been paid to the potential role of tonic activity change in extrasynaptic glutamate receptors (GluRs) located at the neuronal soma on generation of neuronal hyperactivity. METHODS: Whole-cell patch-clamp recordings were performed on CA1 pyramidal neurons in acute hippocampal slices exposed to TFB-threo-ß-benzyloxyaspartic acid (TBOA) or human Aß1-42 peptide oligomer. A series of dendritic patch-clamp recordings were made at different distances from the soma to identify the location of the changes in synaptic inputs. Moreover, single-channel recording in the cell-attached mode was performed to investigate the activity changes of single NMDARs at the soma. RESULTS: Blocking glutamate uptake with either TBOA or the human Aß1-42 peptide oligomer elicited potentiation of synaptic inputs in CA1 hippocampal neurons. Strikingly, this potentiation  specifically occurred at the soma, depending on the activation of somatic GluN2B-containing NMDARs (GluN2B-NMDARs) and accompanied by a substantial and persistent increment in the open probability of somatic NMDARs. Blocking the activity of GluN2B-NMDARs at the soma completely reversed both the TBOA-induced or the Aß1-42-induced somatic potentiation and neuronal hyperactivity. CONCLUSIONS: The somatic potentiation of synaptic inputs may represent a novel amplification mechanism that elevates cell excitability and thus contributes to neuronal hyperactivity initiated by impaired glutamate reuptake in AD.


Asunto(s)
Péptidos beta-Amiloides/toxicidad , Cuerpo Celular/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Neuronas/fisiología , Fragmentos de Péptidos/toxicidad , Receptores de N-Metil-D-Aspartato/fisiología , Sinapsis/fisiología , Animales , Ácido Aspártico/toxicidad , Cuerpo Celular/efectos de los fármacos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Humanos , Masculino , Neuronas/efectos de los fármacos , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-Dawley , Sinapsis/efectos de los fármacos
10.
Amino Acids ; 38(3): 817-27, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19381779

RESUMEN

Previously we demonstrated the potential of D-aspartic acid (D-Asp), an acidic amino acid to induce oxidative response in prepubertal rat testis in vitro. In the present study, we determined the extent of oxidative stress in the testis of prepubertal rats that were administered D-Asp (100 and 500 mg/kg bw/d, i.p. 7 days). D-Asp treatment significantly elevated the levels of reactive oxygen species, malondialdehyde and hydroperoxide in cytosol and mitochondria of testis, which were accompanied by enhanced glutathione levels, elevated activities of glutathione-dependent enzymes and catalase suggesting a state of oxidative stress. Further, the activities of D-aspartate oxidase and 3beta-hydroxy steroid dehydrogenase were elevated in the testis. The testis mitochondria of D-Asp-treated rats showed altered citric acid and complex enzyme activities, reduction in membrane potential, increased permeability and intracellular Ca(2+) levels. Collectively, these findings suggest the potential of D-Asp to induce oxidative perturbations in the testis of prepubertal rats and this mechanism may in part be responsible for the observed physiological effects.


Asunto(s)
Ácido Aspártico/toxicidad , Enfermedades Mitocondriales/inducido químicamente , Enfermedades Mitocondriales/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Maduración Sexual , Testículo/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Señalización del Calcio/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Peroxidación de Lípido/efectos de los fármacos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Membranas Mitocondriales/efectos de los fármacos , Membranas Mitocondriales/enzimología , Membranas Mitocondriales/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Distribución Aleatoria , Ratas , Ratas Wistar , Estereoisomerismo , Fracciones Subcelulares/enzimología , Fracciones Subcelulares/metabolismo , Testículo/metabolismo , Testículo/patología , Factores de Tiempo
11.
Mol Cell Biochem ; 344(1-2): 231-9, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20686917

RESUMEN

N-Acetylaspartic acid (NAA) accumulates in Canavan disease, a severe inherited neurometabolic disorder clinically characterized by mental retardation, hypotonia, macrocephaly, and seizures. The mechanisms of brain damage in this disease remain poorly understood. Recent studies developed by our research group showed that NAA induces oxidative stress in vitro and in vivo in cerebral cortex of rats. Lipoic acid is considered as an efficient antioxidant which can easily cross the blood-brain barrier. Considering the absence of specific treatment to Canavan disease, this study evaluates the possible prevention of the oxidative stress promoted by NAA in vivo by the antioxidant lipoic acid to preliminarily evaluate lipoic acid efficacy against pro-oxidative effects of NAA. Fourteen-day-old Wistar rats received an acute administration of 0.6 mmol NAA/g body weight with or without lipoic acid (40 mg/kg body weight). Catalase (CAT), glutathione peroxidase (GPx), and glucose 6-phosphate dehydrogenase activities, hydrogen peroxide content, thiobarbituric acid-reactive substances (TBA-RS), spontaneous chemiluminescence, protein carbonyl content, total antioxidant potential, and DNA-protein cross-links were assayed in the cerebral cortex of rats. CAT, GPx activities, and total antioxidant potential were significantly reduced, while hydrogen peroxide content, TBA-RS, spontaneous chemiluminescence, and protein carbonyl content were significantly enhanced by acute administration of NAA. Those effects were all prevented by lipoic acid pretreatment. Our results clearly show that lipoic acid may protect against the oxidative stress promoted by NAA. This could represent a new therapeutic approach to the patients affected by Canavan disease.


Asunto(s)
Ácido Aspártico/análogos & derivados , Fármacos Neuroprotectores/farmacología , Ácido Tióctico/farmacología , Animales , Ácido Aspártico/toxicidad , Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo
12.
Metab Brain Dis ; 25(2): 251-9, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20437087

RESUMEN

N-Acetylaspartic acid accumulates in Canavan Disease, a severe inherited neurometabolic disease clinically characterized by severe mental retardation, hypotonia, macrocephaly and generalized tonic and clonic type seizures. Considering that the mechanisms of brain damage in this disease remain poorly understood, in the present study we investigated the in vitro and in vivo effects of N-acetylaspartic acid on the activities of catalase, superoxide dismutase and glutathione peroxidase, as well as on hydrogen peroxide concentration in cerebral cortex of 14-day-old rats. Catalase and glutathione peroxidase activities were significantly inhibited, while hydrogen peroxide concentration was significantly enhanced by N-acetylaspartic acid both in vitro and in vivo. In contrast, superoxide dismutase activity was not altered by N-acetylaspartic acid. Our results clearly show that N-acetylaspartic acid impairs the enzymatic antioxidant defenses in rat brain. This could be involved in the pathophysiological mechanisms responsible for the brain damage observed in patients affected by Canavan Disease.


Asunto(s)
Antioxidantes/metabolismo , Ácido Aspártico/análogos & derivados , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Peróxido de Hidrógeno/metabolismo , Superóxido Dismutasa/metabolismo , Animales , Ácido Aspártico/metabolismo , Ácido Aspártico/toxicidad , Ácido Aspártico/orina , Encéfalo/enzimología , Enfermedad de Canavan/metabolismo , Enfermedad de Canavan/fisiopatología , Catalasa/efectos de los fármacos , Esquema de Medicación , Femenino , Glutatión Peroxidasa/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Ratas Wistar , Superóxido Dismutasa/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología
13.
Science ; 247(4949 Pt 1): 1474-7, 1990 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-2157282

RESUMEN

High concentrations of potent N-methyl-D-aspartate (NMDA) agonists can trigger degeneration of cultured mouse cortical neurons after an exposure of only a few minutes; in contrast, selective non-NMDA agonists or low levels of NMDA agonists require exposures of several hours to induce comparable damage. The dihydropyridine calcium channel antagonist nifedipine was used to test whether this slow neurotoxicity is mediated by a calcium influx through voltage-gated channels. Nifedipine had little effect on the widespread neuronal degeneration induced by brief exposure to high concentrations of NMDA but substantially attenuated the neurotoxicity produced by 24-hour exposure to submaximal concentrations of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate, kainate, or quinolinate. Calcium ion influx through dihydropyridine-sensitive, voltage-dependent calcium channels may be an important step in the neuronal injury induced by the prolonged activation of NMDA or non-NMDA glutamate receptors.


Asunto(s)
Ácido Aspártico/análogos & derivados , Canales de Calcio/efectos de los fármacos , Neuronas/efectos de los fármacos , Nifedipino/farmacología , Receptores de Neurotransmisores/efectos de los fármacos , Animales , Ácido Aspártico/toxicidad , Antagonismo de Drogas , Ácido Iboténico/análogos & derivados , Ácido Iboténico/toxicidad , Técnicas In Vitro , Activación del Canal Iónico , Ácido Kaínico/toxicidad , Ratones , N-Metilaspartato , Neuronas/metabolismo , Ácido Quinolínico , Ácidos Quinolínicos/toxicidad , Receptores de Glutamato , Receptores de N-Metil-D-Aspartato , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico
14.
Neurosci Lett ; 454(2): 165-9, 2009 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-19429077

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons. Although organotypic spinal slice cultures (OSCs) exposed to inhibitors of glutamate uptake have been used as a model of ALS for screening of potentially therapeutic drugs, little development of such drugs has been achieved. In the present study we attempted to establish OSCs from G93A SOD1 transgenic mice (G93A) and to characterize the specific cell death pathway in motoneurons using glial cell line-derived neurotrophic factor (GDNF) in these mice. In the presence of GDNF, the number of surviving neurons in the OSCs was dramatically increased in both G93A and control mice. Exposure to threo-hydroxyaspartate (THA), a glutamate transport inhibitor, for 14 days induced loss of motoneurons in OSCs in G93A and control mice. In OSCs cultured with GDNF, THA-induced motoneuronal death was significantly inhibited in G93A mice, whereas that in control mice was not significantly affected. Moreover, the cleaved form of caspase-12 was increased after THA in the OSCs in G93A but not in control mice, and the activation of caspase-12 was attenuated by OSCs cultured with GDNF. These results suggest that the pathway responsible for motoneuronal death induced by THA in OSCs in G93A mice involves not only in excitotoxicity but also other mechanisms, and that the caspase-12-dependent ER stress pathway plays a role in spinal neuronal death in G93A mice. Moreover, OSCs prepared from the G93A mouse model of ALS may provide a suitable in vitro drug screening model for ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/fisiopatología , Ácido Glutámico/toxicidad , Neuronas Motoras/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Esclerosis Amiotrófica Lateral/patología , Animales , Ácido Aspártico/análogos & derivados , Ácido Aspártico/toxicidad , Caspasa 12/metabolismo , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Ratones , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Médula Espinal/fisiopatología , Superóxido Dismutasa/genética
15.
Metab Brain Dis ; 24(2): 283-98, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19294497

RESUMEN

N-acetylaspartic acid (NAA) is the biochemical hallmark of Canavan Disease, an inherited metabolic disease caused by deficiency of aspartoacylase activity. NAA is an immediate precursor for the enzyme-mediated biosynthesis of N-acetylaspartylglutamic acid (NAAG), whose concentration is also increased in urine and cerebrospinal fluid of patients affected by CD. This neurodegenerative disorder is clinically characterized by severe mental retardation, hypotonia and macrocephaly, and generalized tonic and clonic type seizures. Considering that the mechanisms of brain damage in this disease remain not fully understood, in the present study we investigated whether intracerebroventricular administration of NAA or NAAG elicits oxidative stress in cerebral cortex of 30-day-old rats. NAA significantly reduced total radical-trapping antioxidant potential, catalase and glucose 6-phosphate dehydrogenase activities, whereas protein carbonyl content and superoxide dismutase activity were significantly enhanced. Lipid peroxidation indices and glutathione peroxidase activity were not affected by NAA. In contrast, NAAG did not alter any of the oxidative stress parameters tested. Our results indicate that intracerebroventricular administration of NAA impairs antioxidant defenses and induces oxidative damage to proteins, which could be involved in the neurotoxicity of NAA accumulation in CD patients.


Asunto(s)
Ácido Aspártico/análogos & derivados , Enfermedad de Canavan/metabolismo , Corteza Cerebral/metabolismo , Neurotoxinas/toxicidad , Estrés Oxidativo/fisiología , Animales , Antioxidantes/metabolismo , Ácido Aspártico/administración & dosificación , Ácido Aspártico/metabolismo , Ácido Aspártico/toxicidad , Daño Encefálico Crónico/etiología , Daño Encefálico Crónico/metabolismo , Enfermedad de Canavan/complicaciones , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Corteza Cerebral/efectos de los fármacos , Dipéptidos/administración & dosificación , Dipéptidos/metabolismo , Dipéptidos/toxicidad , Modelos Animales de Enfermedad , Glucosafosfato Deshidrogenasa/efectos de los fármacos , Glucosafosfato Deshidrogenasa/metabolismo , Glutatión Peroxidasa/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Inyecciones Intraventriculares , Peroxidación de Lípido , Masculino , Neuropéptidos/administración & dosificación , Neuropéptidos/metabolismo , Neuropéptidos/toxicidad , Neurotoxinas/administración & dosificación , Neurotoxinas/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar
16.
Neurotox Res ; 13(1): 49-61, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18367440

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from the progressive loss of motor neurons in the spinal cord and brain. To date, clinically effective neuroprotective agents have not been available. The current study demonstrates for the first time that huperzine A, a potential neuroprotective agent, has the ability to protect a motor neuron-like cell line and motor neurons in spinal cord organotypic cultures from toxin-induced cell death. The neuroblastoma-spinal motor neuron fusion cell line, NSC34 and rat spinal cord organotypic cultures (OTC) were exposed to cell death inducers for 24 h or 14 d, respectively, with and without pre-treatment with huperzine A. The inducers used here include: staurosporine, thapsigargin, hydrogen peroxide (H2O2), carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and L-(-)-threo-3-hydroxyaspartic acid (THA). These agents were selected as they induce apoptosis/necrosis via mechanisms implicated in patients with generalized motor neuron disease. Cell death was determined in NSC34 cells by metabolic activity, caspase activity/expression and by nuclear morphology and in the OTCs, using immunohistochemistry and Western blot analysis. Nuclear staining of NSC34 cells revealed cell death induced by staurosporine, thapsigargin, H2O2 and CCCP. This induction was significantly reduced with 2 h pre-treatment with 10 microM huperzine A (maximum, 35% rescue; p 0.05) following exposure to staurosporine, thapsigargin and H2O2 but not with CCCP. These data were supported by the metabolic assays and caspase activity. In addition, pre-treatment with huperzine A dramatically improved motor neuron survival, based on choline acetyltransferase (ChAT) expression analysis in OTCs following exposure to THA, and compared to THA-treated control cultures. These studies are currently being extended to include other inducers and with additional compounds as potential drug therapies that could be used in combination for the treatment of patients with ALS.


Asunto(s)
Apoptosis/efectos de los fármacos , Neuronas Motoras/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Sesquiterpenos/farmacología , Médula Espinal/efectos de los fármacos , Alcaloides , Animales , Ácido Aspártico/análogos & derivados , Ácido Aspártico/toxicidad , Carbonil Cianuro m-Clorofenil Hidrazona/toxicidad , Línea Celular , Interacciones Farmacológicas , Inhibidores Enzimáticos/toxicidad , Peróxido de Hidrógeno/toxicidad , Ionóforos/toxicidad , Neuronas Motoras/citología , Técnicas de Cultivo de Órganos , Oxidantes/toxicidad , Ratas , Ratas Sprague-Dawley , Médula Espinal/patología , Estaurosporina/toxicidad , Tapsigargina/toxicidad
17.
Food Chem Toxicol ; 46(8): 2789-95, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18583012

RESUMEN

A subchronic oral toxicity study of l-aspartic acid (l-Asp) was conducted with groups of 10 male and 10 female Fischer 344 rats fed a powder diet containing 0%, 0.05%, 1.25%, 2.5% and 5.0% concentrations for 90 days. Serum biochemistry showed treatment-related decreases of blood urea nitrogen, creatinine and uric acid levels in both sexes. In addition, incidences of urinary ketone and protein were significantly increased in treated both sexes, while relative kidney weight was significantly increased in the 5.0% male rat, and regenerative renal tubules with tubular dilation were histopathologically observed in male rats of the 2.5% or greater groups. The observed renal injury was confirmed not to be due to accumulation of alpha2u-globulin. Acinar cell hypertrophy of salivary glands was histopathologically evident in male and female rats of the 2.5% or greater groups. The present results indicate that l-Asp causes toxic effects on kidneys and possibly salivary glands at high dose levels in male and female Fischer 344 rats. Such toxic effects were observed only in animals given 2.5% and/or higher doses of l-Asp. In conclusion, the no-observed-adverse-effect-level (NOAEL) for l-Asp is 1.25% (696.6 mg/kg body weight/day for males and 715.2 mg/kg body weight/day for females) under the present experimental conditions.


Asunto(s)
Ácido Aspártico/toxicidad , Enfermedades Renales/inducido químicamente , Enfermedades de las Glándulas Salivales/inducido químicamente , Animales , Recuento de Células Sanguíneas , Análisis Químico de la Sangre , Peso Corporal/efectos de los fármacos , Dieta , Ingestión de Líquidos , Ingestión de Alimentos , Femenino , Riñón/patología , Enfermedades Renales/patología , Masculino , Nivel sin Efectos Adversos Observados , Ratas , Ratas Endogámicas F344 , Enfermedades de las Glándulas Salivales/patología , Glándulas Salivales/patología , Urinálisis
18.
Food Chem Toxicol ; 46(6): 2023-34, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18329151

RESUMEN

N-acetyl-l-aspartic acid (NAA) is a constituent of the mammalian central nervous system (CNS) that has been identified in a number of commonly consumed foods. The current study reports the outcome of acute and repeated dose oral toxicology studies conducted with NAA in Sprague-Dawley (SD) rats. No mortalities or evidence of adverse effects were observed in SD rats following acute oral administration of 2000mg/kg NAA. In a separate study, NAA was added to the diets of SD rats (n=10/sex group) at concentrations corresponding to daily doses of 10, 100, or 1000mg/kg/day for 14 consecutive days and 100, 500, and 1000mg/kg/day for another 14 days. All rats survived until scheduled sacrifice and no differences in body weights, feed consumption values, or clinical signs were observed in any of the treatment groups. No biologically significant differences were observed in functional observational battery (FOB), motor activity evaluations, ophthalmologic examinations, hematology, coagulation, clinical chemistry, or organ weights of any of the NAA treatment groups. Further, no test substance-related gross or microscopic changes were observed in NAA exposure groups. Based on these results, NAA was not considered acutely toxic following oral exposure to 2000mg/kg and the no-observed-adverse-effect-level (NOAEL) for systemic toxicity from repeated dose dietary exposure to NAA is 1000mg/kg/day.


Asunto(s)
Ácido Aspártico/análogos & derivados , Administración Oral , Animales , Ácido Aspártico/análisis , Ácido Aspártico/toxicidad , Conducta Animal/efectos de los fármacos , Recuento de Células Sanguíneas , Análisis Químico de la Sangre , Coagulación Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Dieta , Ingestión de Alimentos/efectos de los fármacos , Ojo/patología , Femenino , Análisis de los Alimentos , Masculino , Actividad Motora/efectos de los fármacos , Embarazo , Ratas , Ratas Sprague-Dawley
19.
Drug Res (Stuttg) ; 68(5): 280-285, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29036735

RESUMEN

Natural L-aspartic acid coated iron oxide magnetic nanoparticles (Asp@IONPs) were prepared by a one pot, in-situ and green co-precipitation method in an aqueous medium. Functionalized iron oxide magnetic nanoparticles (IONPs) were characterized by Vibrating Sample Magnetometer (VSM), X-ray diffraction (XRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM) techniques. Cellular toxicity of IONPs was also investigated on HEK-293 cell lines. The results showed that the zeta potential of Asp@IONPs was about -21.1 mV and the average size was 17.80±3.09 nm. Cell toxicity results show that as prepared IONPs are biocompatible. Asp@IONPs show the possibility of using these nanoparticles in the development of in vitro and in vivo biomedical fields due to do not possess a toxic effect, good ζ-potential and related small and narrow size distribution.


Asunto(s)
Ácido Aspártico/química , Compuestos Férricos/química , Nanopartículas de Magnetita/química , Ácido Aspártico/toxicidad , Supervivencia Celular/efectos de los fármacos , Estabilidad de Medicamentos , Compuestos Férricos/toxicidad , Células HEK293 , Humanos , Nanopartículas de Magnetita/toxicidad , Nanopartículas de Magnetita/ultraestructura , Tamaño de la Partícula , Propiedades de Superficie
20.
Mol Cell Biol ; 16(5): 2214-25, 1996 May.
Artículo en Inglés | MEDLINE | ID: mdl-8628288

RESUMEN

Chemotherapeutic treatment of tumor cells leads either to tumor cell death (usually by apoptosis) or to the formation of drug-resistant subpopulations. Known mechanisms of cancer cell drug resistance include gene amplification and increased expression of drug transporters. On the other hand, normal cells survive many forms of chemotherapy with minimal damage probably because of their capacity for growth arrest and stringent control of apoptosis. Microcell hybrids between B78 (murine melanoma) and HSF5 (normal human fibroblasts) were analyzed to identify a new human chromosomal region involved in the promotion of drug-induced growth arrest and suppression of apoptosis. In these hybrids, the presence of human chromosome 3 was strongly associated with suppression of apoptosis via G1 and G2 growth arrest during exposure to the antimetabolite N-phosphonoacetyl-L-aspartate (PALA), suggesting that a gene(s) on chromosome 3 serves an antiproliferative role in a drug-responsive growth arrest pathway.


Asunto(s)
Apoptosis/genética , Ciclo Celular/genética , Cromosomas Humanos Par 3 , Animales , Antimetabolitos Antineoplásicos , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Ácido Aspártico/análogos & derivados , Ácido Aspártico/toxicidad , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Radioisótopos de Cesio , Mapeo Cromosómico , Fibroblastos , Citometría de Flujo , Fase G1 , Fase G2 , Rayos gamma , Marcadores Genéticos , Humanos , Células Híbridas , Hibridación Fluorescente in Situ , Melanoma Experimental , Ratones , Ácido Fosfonoacético/análogos & derivados , Ácido Fosfonoacético/toxicidad , Células Tumorales Cultivadas
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