Romina Uranga - Profile on Academia.edu (original) (raw)
Papers by Romina Uranga
Journal of Neurochemistry, Sep 1, 2010
Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. ... more Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are poorly understood. In the present study 20-month old male C57Bl/6 mice were fed either "Western Diet" (WD, 41% fat), very high fat lard diet (HFL, 60% fat), or corresponding control diets for 16 weeks and then assessed for changes in metabolism and brain homeostasis. Although both HFDs increased adiposity and fasting blood glucose, only the HFL diet increased age-related oxidative damage (protein carbonyls) and impaired retention in the behavioral test. This selective increase in oxidative damage and cognitive decline was also associated with a decline in Nrf2 levels and Nrf2 activity, suggesting a potential role for decreased antioxidant response. Taken together, these data suggest that while adiposity and insulin resistance following HFD consumption are linked to increased morbidity, the relationship between these factors and brain homeostasis during aging is not a linear relationship. More specifically, these data implicate impaired Nrf2 signaling and increased cerebral oxidative stress as mechanisms underlying HFD-induced declines in cognitive performance in the aged brain.
Phospholipase D and Phosphatidylinositol 3‐kinase are Activated by Oxidative Stress in Central Nervous System
The FASEB Journal, Mar 1, 2008
Effect of transition metals in synaptic damage induced by amyloid beta peptide
Neuroscience, Oct 1, 2010
The amyloid beta-peptide (Abeta), which is thought to be the major cause of Alzheimer&amp... more The amyloid beta-peptide (Abeta), which is thought to be the major cause of Alzheimer's disease (AD), is known to be capable of aggregating in different states: soluble monomers and oligomers, and insoluble aggregates. The Abeta aggregation state as well as its toxicity has been related to the interaction between the peptide and transition metals such as iron and copper. However, this relationship, as well as the effects of Abeta on the synaptic endings, is not fully understood. The aggregation states of Abeta in the presence of iron and copper, as well as their effects on synaptic viability and signaling were investigated in this work. During acute incubation treatments (5 min-4 h), Abeta/metal impaired mitochondrial function to the same extent as has been observed with the metal alone. However, in the presence of Abeta/iron (10 and 50 muM), plasma membrane integrity was disrupted to a greater extent than when generated by either iron or Abeta alone, indicating that the membrane constitutes the first target of synaptic injury. Akt activation by Abeta/iron was evident after 5 min of incubation and was higher than that observed in the presence of the metal alone. This activation was barely detected after 4 h of incubation, demonstrating that there is no correlation between the extent of synaptic damage and the activation of this kinase. Extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation profile was different from that observed for Akt. Accordingly, the presence of Abeta/metal could differentially modulate the activity of these kinases. This work shows evidence of the initial events locally triggered at the synapse by Abeta and transition metals. As synapses have been proposed as the starting point of Abeta/metal-triggered events, the characterization of early mechanisms occurring in models that mimic AD could be important for the search of unexplored therapeutics tools.
International Journal of Alzheimer's Disease, 2011
The accumulation of transition metals (e.g., copper, zinc, and iron) and the dysregulation of the... more The accumulation of transition metals (e.g., copper, zinc, and iron) and the dysregulation of their metabolism are a hallmark in the pathogenesis of several neurodegenerative diseases. This paper will be focused on the mechanism of neurotoxicity mediated by iron. This metal progressively accumulates in the brain both during normal aging and neurodegenerative processes. High iron concentrations in the brain have been consistently observed in Alzheimer's (AD) and Parkinson's (PD) diseases. In this connection, metalloneurobiology has become extremely important in establishing the role of iron in the onset and progression of neurodegenerative diseases. Neurons have developed several protective mechanisms against oxidative stress, among them, the activation of cellular signaling pathways. The final response will depend on the identity, intensity, and persistence of the oxidative insult. The characterization of the mechanisms mediating the effects of iron-induced increase in neuronal dysfunction and death is central to understanding the pathology of a number of neurodegenerative disorders.
Journal of Neurochemistry, May 6, 2010
Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable asp... more Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age-related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.
Frontiers in Neuroscience, May 24, 2019
Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the ... more Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the various organ systems of the body is only beginning to be fully appreciated. Because of the myriad of direct and indirect effects of obesity causing dysfunction of multiple tissues and organs, it is likely that there will be heterogeneity in the presentation of obesity effects in any given population. Taken together, these realities make it increasingly difficult to understand the complex interplay between obesity effects on different organs, including the brain. The focus of this review is to provide a comprehensive view of metabolic disturbances present in obesity, their direct and indirect effects on the different organ systems of the body, and to discuss the interaction of these effects in the context of brain aging and the development of neurodegenerative diseases.
Pleiotropic effects of PI3K/Akt pathway in hippocampal neurons exposed to iron‐induced oxidative stress
The FASEB Journal, Apr 1, 2013
Journal of Neuroscience Research, May 23, 2011
Amino acid analogs promote translational errors that result in aberrant protein synthesis, and ha... more Amino acid analogs promote translational errors that result in aberrant protein synthesis, and have been used to understand the effects of protein misfolding in a variety of physiological and pathological settings. TDP-43 is a protein that is linked to protein aggregation and toxicity in a variety of neurodegenerative diseases. In this study we exposed primary rat neurons and astrocyte cultures to established amino acid analogs (Canavanine and Azetidine-2-carboxylic acid), and observed both cell types undergo a dose-dependent increase in toxicity, with neurons exhibiting a greater degree of toxicity as compared to astrocytes. Neurons and astrocytes exhibited similar increases in ubiquitinated and oxidized protein following analog treatment. Analog treatment increased Heat shock protein (Hsp) levels in both neurons and astrocytes. In neurons, and to a lesser extent astrocytes, the levels of TDP-43 increased in response to analog treatment. Taken together, these data indicate that neurons exhibit preferential toxicity and alterations in TDP-43, in response to increased protein misfolding, as compared to astrocytes.
Lipid signaling events during oxidative injury in nervous system
Diversas patologías del sistema nervioso central tienen su origen en un desbalance de los mecanis... more Diversas patologías del sistema nervioso central tienen su origen en un desbalance de los mecanismos normales de oxido-reducción celular. En este aspecto, se le ha asignado al estrés oxidativo inducido por la acumulación de hierro un rol significativo en el desarrollo de enfermedades tales como la enfermedad de Parkinson (EP) y la enfermedad de Alzheimer (EA). La acumulación de hierro, sin el concomitante incremento en ferritina ocurre en el cerebro tanto en el proceso de envejecimiento neuronal como en los procesos neurodegenerativos. En este sentido la metaloneurobiología ha estado y se encuentra estudiando el rol de distintos metales de transición en los procesos de injuria neuronal y su relación con la aparición de los primeros signos de neurodegeneración. Las neuronas han desarrollado diversos mecanismos de protección contra el estrés oxidativo, entre ellos se encuentra la activación de diversas vías de señalización. La respuesta final dependerá de la identidad, la intensidad ...
Novel antiadipogenic effect of menadione in 3T3-L1 cells
Chemico-Biological Interactions, 2021
Inhibition of adipocyte differentiation can be used as a strategy for preventing adipose tissue e... more Inhibition of adipocyte differentiation can be used as a strategy for preventing adipose tissue expansion and, consequently, for obesity management. Since reactive oxygen species (ROS) have emerged as key modulators of adipogenesis, the effect of menadione (a synthetic form of vitamin K known to induce the increase of intracellular ROS) on 3T3-L1 preadipocyte differentiation was studied. Menadione (15 μM) increased ROS and lipid peroxidation, generating mild oxidative stress without affecting cell viability. Menadione drastically inhibited adipogenesis, accompanied by decreased intracellular lipid accumulation and diminished expression of the lipo/adipogenic markers peroxisome proliferator-activated receptor (PPAR)γ, fatty acid synthase (FAS), CCAAT/enhancer-binding protein (C/EBP) α, fatty acid binding protein (FABP) 4, and perilipin. Menadione treatment also increased lipolysis, as indicated by augmented glycerol release and reinforced by the increased expression of hormone-sensitive lipase (HSL). Additionally, menadione increased the inhibitory phosphorylation of acetyl-CoA-carboxylase (ACC), which results in the inhibition of fatty acid synthesis. As a consequence, triglyceride content was decreased. Menadione also inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Further, treatment with increased concentration of insulin, a potent physiological activator of the PI3K/Akt pathway, rescued the normal level of expression of PPARγ, the master regulator of adipogenesis, and overcame the restraining effect of menadione on the differentiation capacity of 3T3-L1 preadipocytes. Our study reveals novel antiadipogenic action for menadione, which is, at least in part, mediated by the PI3K/Akt pathway signaling and raises its potential as a therapeutic agent in the treatment or prevention of adiposity.
Phospholipase D and Phosphatidylinositol 3‐kinase are Activated by Oxidative Stress in Central Nervous System
The FASEB Journal, 2008
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Effect of transition metals in synaptic damage induced by amyloid beta peptide
Neuroscience, 2010
The amyloid beta-peptide (Abeta), which is thought to be the major cause of Alzheimer&amp... more The amyloid beta-peptide (Abeta), which is thought to be the major cause of Alzheimer's disease (AD), is known to be capable of aggregating in different states: soluble monomers and oligomers, and insoluble aggregates. The Abeta aggregation state as well as its toxicity has been related to the interaction between the peptide and transition metals such as iron and copper. However, this relationship, as well as the effects of Abeta on the synaptic endings, is not fully understood. The aggregation states of Abeta in the presence of iron and copper, as well as their effects on synaptic viability and signaling were investigated in this work. During acute incubation treatments (5 min-4 h), Abeta/metal impaired mitochondrial function to the same extent as has been observed with the metal alone. However, in the presence of Abeta/iron (10 and 50 muM), plasma membrane integrity was disrupted to a greater extent than when generated by either iron or Abeta alone, indicating that the membrane constitutes the first target of synaptic injury. Akt activation by Abeta/iron was evident after 5 min of incubation and was higher than that observed in the presence of the metal alone. This activation was barely detected after 4 h of incubation, demonstrating that there is no correlation between the extent of synaptic damage and the activation of this kinase. Extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation profile was different from that observed for Akt. Accordingly, the presence of Abeta/metal could differentially modulate the activity of these kinases. This work shows evidence of the initial events locally triggered at the synapse by Abeta and transition metals. As synapses have been proposed as the starting point of Abeta/metal-triggered events, the characterization of early mechanisms occurring in models that mimic AD could be important for the search of unexplored therapeutics tools.
Frontiers in Cellular Neuroscience, 2019
Since its discovery, the study of the biological role of α-synuclein and its pathological implica... more Since its discovery, the study of the biological role of α-synuclein and its pathological implications has been the subject of increasing interest. The propensity to adopt different conformational states governing its aggregation and fibrillation makes this small 14-kDa cytosolic protein one of the main etiologic factors associated with degenerative disorders known as synucleinopathies. The structure, function, and toxicity of α-synuclein and the possibility of different therapeutic approaches to target the protein have been extensively investigated and reviewed. One intriguing characteristic of α-synuclein is the different ways in which it interacts with lipids. Though in-depth studies have been carried out in this field, the information they have produced is puzzling and the precise role of lipids in α-synuclein biology and pathology and vice versa is still largely unknown. Here we provide an overview and discussion of the main findings relating to α-synuclein/lipid interaction and its involvement in the modulation of lipid metabolism and signaling.
10.1074/jbc.M113.457622 Access the most updated version of this article at doi: . JBC Affinity Si... more 10.1074/jbc.M113.457622 Access the most updated version of this article at doi: . JBC Affinity Sites Find articles, minireviews, Reflections and Classics on similar topics on the Alerts: When a correction for this article is posted • When this article is cited • to choose from all of JBC's e-mail alerts Click here http://www.jbc.org/content/288/27/19773.full.html#ref-list-1 This article cites 60 references, 15 of which can be accessed free at
Frontiers in Neuroscience, 2019
Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the ... more Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the various organ systems of the body is only beginning to be fully appreciated. Because of the myriad of direct and indirect effects of obesity causing dysfunction of multiple tissues and organs, it is likely that there will be heterogeneity in the presentation of obesity effects in any given population. Taken together, these realities make it increasingly difficult to understand the complex interplay between obesity effects on different organs, including the brain. The focus of this review is to provide a comprehensive view of metabolic disturbances present in obesity, their direct and indirect effects on the different organ systems of the body, and to discuss the interaction of these effects in the context of brain aging and the development of neurodegenerative diseases.
Current gerontology and geriatrics research, 2010
Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its num... more Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its numerous complications are believed to play a role in promoting multiple aspects of brain pathogenesis. An ever increasing number of individuals in modern Western Society are regularly consuming diets high in fat which promote the development of hypercholesterolemia. Additionally, modern societies are becoming increasingly aged, causing a collision between increased hypercholesterolemia and increased aging, which will likely lead to the development of increased pathological conditions due to hypercholesterolemia, thereby promoting deleterious neurochemical and behavioral changes in the brain. Lastly, while beneficial in controlling cholesterol levels, the long-term use of statins itself may potentially promote adverse effects on brain homeostasis, although specifics on this remain largely unknown. This review will focus on linking the current understanding of diet-induced hypercholesterolem...
Antiviral research, 2010
It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequentl... more It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequently elicit a metabolic syndrome that may include hyperlipidemia, lipodystrophy, and insulin resistance. Metabolic dysfunction in non-HIV-infected subjects has been repeatedly associated with cognitive impairment in epidemiological and experimental studies, but it is not yet understood if antiretroviral therapy-induced metabolic syndrome might contribute to HIV-associated neurologic decline. To determine if protease inhibitor-induced metabolic dysfunction in mice is accompanied by adverse neurologic effects, C57BL/6 mice were given combined lopinavir/ritonavir (50/12.5-200/50 mg/kg) daily for 3 weeks. Data show that lopinavir/ritonavir administration caused significant metabolic derangement, including alterations in body weight and fat mass, as well as dose-dependent patterns of hyperlipidemia, hypoadiponectinemia, hypoleptinemia, and hyperinsulinemia. Evaluation of neurologic function reve...
Free Radical Biology and Medicine, 2010
Maintaining protein homeostasis is vital to cell viability, with numerous studies demonstrating a... more Maintaining protein homeostasis is vital to cell viability, with numerous studies demonstrating a role for proteasome inhibition occurring during the aging of a variety of tissues, and presumably contributing to the disruption of cellular homeostasis during aging. In the present study we sought to elucidate the differences between neurons and astrocytes in regards to basal levels of protein synthesis, proteasome-mediated protein degradation, and sensitivity to cytoxicity following proteasome inhibitor treatment. In these studies we demonstrate that neurons have an increased vulnerability, as compared to astrocyte cultures, to proteasome inhibitor-induced cytotoxicity. No significant difference was observed between these two cell types in regards to the basal rates of protein synthesis, or basal rates of protein degradation, in the pool of short-lived proteins. Following proteasome inhibitor treatment neuronal crude lysates were observed to undergo greater increases in the levels of ubiquitinated and oxidized proteins, and selectively exhibited increased levels of newly synthesized proteins accumulating within the insoluble protein pool, as compared to astrocytes. Together, these data suggest a role for increased oxidized proteins and sequestration of newly synthesized proteins to the insoluble protein pool, as potential mediators of the selective neurotoxicity following proteasome inhibitor treatment. The implications for neurons exhibiting increased sensitivity to acute proteasome inhibitor exposure, and the corresponding changes in protein homeostasis observed following proteasome inhibition, are discussed in the context of both aging and age-related disorders of the nervous system.
Journal of Neurochemistry, Sep 1, 2010
Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. ... more Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are poorly understood. In the present study 20-month old male C57Bl/6 mice were fed either "Western Diet" (WD, 41% fat), very high fat lard diet (HFL, 60% fat), or corresponding control diets for 16 weeks and then assessed for changes in metabolism and brain homeostasis. Although both HFDs increased adiposity and fasting blood glucose, only the HFL diet increased age-related oxidative damage (protein carbonyls) and impaired retention in the behavioral test. This selective increase in oxidative damage and cognitive decline was also associated with a decline in Nrf2 levels and Nrf2 activity, suggesting a potential role for decreased antioxidant response. Taken together, these data suggest that while adiposity and insulin resistance following HFD consumption are linked to increased morbidity, the relationship between these factors and brain homeostasis during aging is not a linear relationship. More specifically, these data implicate impaired Nrf2 signaling and increased cerebral oxidative stress as mechanisms underlying HFD-induced declines in cognitive performance in the aged brain.
Phospholipase D and Phosphatidylinositol 3‐kinase are Activated by Oxidative Stress in Central Nervous System
The FASEB Journal, Mar 1, 2008
Effect of transition metals in synaptic damage induced by amyloid beta peptide
Neuroscience, Oct 1, 2010
The amyloid beta-peptide (Abeta), which is thought to be the major cause of Alzheimer&amp... more The amyloid beta-peptide (Abeta), which is thought to be the major cause of Alzheimer's disease (AD), is known to be capable of aggregating in different states: soluble monomers and oligomers, and insoluble aggregates. The Abeta aggregation state as well as its toxicity has been related to the interaction between the peptide and transition metals such as iron and copper. However, this relationship, as well as the effects of Abeta on the synaptic endings, is not fully understood. The aggregation states of Abeta in the presence of iron and copper, as well as their effects on synaptic viability and signaling were investigated in this work. During acute incubation treatments (5 min-4 h), Abeta/metal impaired mitochondrial function to the same extent as has been observed with the metal alone. However, in the presence of Abeta/iron (10 and 50 muM), plasma membrane integrity was disrupted to a greater extent than when generated by either iron or Abeta alone, indicating that the membrane constitutes the first target of synaptic injury. Akt activation by Abeta/iron was evident after 5 min of incubation and was higher than that observed in the presence of the metal alone. This activation was barely detected after 4 h of incubation, demonstrating that there is no correlation between the extent of synaptic damage and the activation of this kinase. Extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation profile was different from that observed for Akt. Accordingly, the presence of Abeta/metal could differentially modulate the activity of these kinases. This work shows evidence of the initial events locally triggered at the synapse by Abeta and transition metals. As synapses have been proposed as the starting point of Abeta/metal-triggered events, the characterization of early mechanisms occurring in models that mimic AD could be important for the search of unexplored therapeutics tools.
International Journal of Alzheimer's Disease, 2011
The accumulation of transition metals (e.g., copper, zinc, and iron) and the dysregulation of the... more The accumulation of transition metals (e.g., copper, zinc, and iron) and the dysregulation of their metabolism are a hallmark in the pathogenesis of several neurodegenerative diseases. This paper will be focused on the mechanism of neurotoxicity mediated by iron. This metal progressively accumulates in the brain both during normal aging and neurodegenerative processes. High iron concentrations in the brain have been consistently observed in Alzheimer's (AD) and Parkinson's (PD) diseases. In this connection, metalloneurobiology has become extremely important in establishing the role of iron in the onset and progression of neurodegenerative diseases. Neurons have developed several protective mechanisms against oxidative stress, among them, the activation of cellular signaling pathways. The final response will depend on the identity, intensity, and persistence of the oxidative insult. The characterization of the mechanisms mediating the effects of iron-induced increase in neuronal dysfunction and death is central to understanding the pathology of a number of neurodegenerative disorders.
Journal of Neurochemistry, May 6, 2010
Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable asp... more Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age-related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.
Frontiers in Neuroscience, May 24, 2019
Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the ... more Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the various organ systems of the body is only beginning to be fully appreciated. Because of the myriad of direct and indirect effects of obesity causing dysfunction of multiple tissues and organs, it is likely that there will be heterogeneity in the presentation of obesity effects in any given population. Taken together, these realities make it increasingly difficult to understand the complex interplay between obesity effects on different organs, including the brain. The focus of this review is to provide a comprehensive view of metabolic disturbances present in obesity, their direct and indirect effects on the different organ systems of the body, and to discuss the interaction of these effects in the context of brain aging and the development of neurodegenerative diseases.
Pleiotropic effects of PI3K/Akt pathway in hippocampal neurons exposed to iron‐induced oxidative stress
The FASEB Journal, Apr 1, 2013
Journal of Neuroscience Research, May 23, 2011
Amino acid analogs promote translational errors that result in aberrant protein synthesis, and ha... more Amino acid analogs promote translational errors that result in aberrant protein synthesis, and have been used to understand the effects of protein misfolding in a variety of physiological and pathological settings. TDP-43 is a protein that is linked to protein aggregation and toxicity in a variety of neurodegenerative diseases. In this study we exposed primary rat neurons and astrocyte cultures to established amino acid analogs (Canavanine and Azetidine-2-carboxylic acid), and observed both cell types undergo a dose-dependent increase in toxicity, with neurons exhibiting a greater degree of toxicity as compared to astrocytes. Neurons and astrocytes exhibited similar increases in ubiquitinated and oxidized protein following analog treatment. Analog treatment increased Heat shock protein (Hsp) levels in both neurons and astrocytes. In neurons, and to a lesser extent astrocytes, the levels of TDP-43 increased in response to analog treatment. Taken together, these data indicate that neurons exhibit preferential toxicity and alterations in TDP-43, in response to increased protein misfolding, as compared to astrocytes.
Lipid signaling events during oxidative injury in nervous system
Diversas patologías del sistema nervioso central tienen su origen en un desbalance de los mecanis... more Diversas patologías del sistema nervioso central tienen su origen en un desbalance de los mecanismos normales de oxido-reducción celular. En este aspecto, se le ha asignado al estrés oxidativo inducido por la acumulación de hierro un rol significativo en el desarrollo de enfermedades tales como la enfermedad de Parkinson (EP) y la enfermedad de Alzheimer (EA). La acumulación de hierro, sin el concomitante incremento en ferritina ocurre en el cerebro tanto en el proceso de envejecimiento neuronal como en los procesos neurodegenerativos. En este sentido la metaloneurobiología ha estado y se encuentra estudiando el rol de distintos metales de transición en los procesos de injuria neuronal y su relación con la aparición de los primeros signos de neurodegeneración. Las neuronas han desarrollado diversos mecanismos de protección contra el estrés oxidativo, entre ellos se encuentra la activación de diversas vías de señalización. La respuesta final dependerá de la identidad, la intensidad ...
Novel antiadipogenic effect of menadione in 3T3-L1 cells
Chemico-Biological Interactions, 2021
Inhibition of adipocyte differentiation can be used as a strategy for preventing adipose tissue e... more Inhibition of adipocyte differentiation can be used as a strategy for preventing adipose tissue expansion and, consequently, for obesity management. Since reactive oxygen species (ROS) have emerged as key modulators of adipogenesis, the effect of menadione (a synthetic form of vitamin K known to induce the increase of intracellular ROS) on 3T3-L1 preadipocyte differentiation was studied. Menadione (15 μM) increased ROS and lipid peroxidation, generating mild oxidative stress without affecting cell viability. Menadione drastically inhibited adipogenesis, accompanied by decreased intracellular lipid accumulation and diminished expression of the lipo/adipogenic markers peroxisome proliferator-activated receptor (PPAR)γ, fatty acid synthase (FAS), CCAAT/enhancer-binding protein (C/EBP) α, fatty acid binding protein (FABP) 4, and perilipin. Menadione treatment also increased lipolysis, as indicated by augmented glycerol release and reinforced by the increased expression of hormone-sensitive lipase (HSL). Additionally, menadione increased the inhibitory phosphorylation of acetyl-CoA-carboxylase (ACC), which results in the inhibition of fatty acid synthesis. As a consequence, triglyceride content was decreased. Menadione also inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Further, treatment with increased concentration of insulin, a potent physiological activator of the PI3K/Akt pathway, rescued the normal level of expression of PPARγ, the master regulator of adipogenesis, and overcame the restraining effect of menadione on the differentiation capacity of 3T3-L1 preadipocytes. Our study reveals novel antiadipogenic action for menadione, which is, at least in part, mediated by the PI3K/Akt pathway signaling and raises its potential as a therapeutic agent in the treatment or prevention of adiposity.
Phospholipase D and Phosphatidylinositol 3‐kinase are Activated by Oxidative Stress in Central Nervous System
The FASEB Journal, 2008
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Effect of transition metals in synaptic damage induced by amyloid beta peptide
Neuroscience, 2010
The amyloid beta-peptide (Abeta), which is thought to be the major cause of Alzheimer&amp... more The amyloid beta-peptide (Abeta), which is thought to be the major cause of Alzheimer's disease (AD), is known to be capable of aggregating in different states: soluble monomers and oligomers, and insoluble aggregates. The Abeta aggregation state as well as its toxicity has been related to the interaction between the peptide and transition metals such as iron and copper. However, this relationship, as well as the effects of Abeta on the synaptic endings, is not fully understood. The aggregation states of Abeta in the presence of iron and copper, as well as their effects on synaptic viability and signaling were investigated in this work. During acute incubation treatments (5 min-4 h), Abeta/metal impaired mitochondrial function to the same extent as has been observed with the metal alone. However, in the presence of Abeta/iron (10 and 50 muM), plasma membrane integrity was disrupted to a greater extent than when generated by either iron or Abeta alone, indicating that the membrane constitutes the first target of synaptic injury. Akt activation by Abeta/iron was evident after 5 min of incubation and was higher than that observed in the presence of the metal alone. This activation was barely detected after 4 h of incubation, demonstrating that there is no correlation between the extent of synaptic damage and the activation of this kinase. Extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation profile was different from that observed for Akt. Accordingly, the presence of Abeta/metal could differentially modulate the activity of these kinases. This work shows evidence of the initial events locally triggered at the synapse by Abeta and transition metals. As synapses have been proposed as the starting point of Abeta/metal-triggered events, the characterization of early mechanisms occurring in models that mimic AD could be important for the search of unexplored therapeutics tools.
Frontiers in Cellular Neuroscience, 2019
Since its discovery, the study of the biological role of α-synuclein and its pathological implica... more Since its discovery, the study of the biological role of α-synuclein and its pathological implications has been the subject of increasing interest. The propensity to adopt different conformational states governing its aggregation and fibrillation makes this small 14-kDa cytosolic protein one of the main etiologic factors associated with degenerative disorders known as synucleinopathies. The structure, function, and toxicity of α-synuclein and the possibility of different therapeutic approaches to target the protein have been extensively investigated and reviewed. One intriguing characteristic of α-synuclein is the different ways in which it interacts with lipids. Though in-depth studies have been carried out in this field, the information they have produced is puzzling and the precise role of lipids in α-synuclein biology and pathology and vice versa is still largely unknown. Here we provide an overview and discussion of the main findings relating to α-synuclein/lipid interaction and its involvement in the modulation of lipid metabolism and signaling.
10.1074/jbc.M113.457622 Access the most updated version of this article at doi: . JBC Affinity Si... more 10.1074/jbc.M113.457622 Access the most updated version of this article at doi: . JBC Affinity Sites Find articles, minireviews, Reflections and Classics on similar topics on the Alerts: When a correction for this article is posted • When this article is cited • to choose from all of JBC's e-mail alerts Click here http://www.jbc.org/content/288/27/19773.full.html#ref-list-1 This article cites 60 references, 15 of which can be accessed free at
Frontiers in Neuroscience, 2019
Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the ... more Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the various organ systems of the body is only beginning to be fully appreciated. Because of the myriad of direct and indirect effects of obesity causing dysfunction of multiple tissues and organs, it is likely that there will be heterogeneity in the presentation of obesity effects in any given population. Taken together, these realities make it increasingly difficult to understand the complex interplay between obesity effects on different organs, including the brain. The focus of this review is to provide a comprehensive view of metabolic disturbances present in obesity, their direct and indirect effects on the different organ systems of the body, and to discuss the interaction of these effects in the context of brain aging and the development of neurodegenerative diseases.
Current gerontology and geriatrics research, 2010
Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its num... more Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its numerous complications are believed to play a role in promoting multiple aspects of brain pathogenesis. An ever increasing number of individuals in modern Western Society are regularly consuming diets high in fat which promote the development of hypercholesterolemia. Additionally, modern societies are becoming increasingly aged, causing a collision between increased hypercholesterolemia and increased aging, which will likely lead to the development of increased pathological conditions due to hypercholesterolemia, thereby promoting deleterious neurochemical and behavioral changes in the brain. Lastly, while beneficial in controlling cholesterol levels, the long-term use of statins itself may potentially promote adverse effects on brain homeostasis, although specifics on this remain largely unknown. This review will focus on linking the current understanding of diet-induced hypercholesterolem...
Antiviral research, 2010
It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequentl... more It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequently elicit a metabolic syndrome that may include hyperlipidemia, lipodystrophy, and insulin resistance. Metabolic dysfunction in non-HIV-infected subjects has been repeatedly associated with cognitive impairment in epidemiological and experimental studies, but it is not yet understood if antiretroviral therapy-induced metabolic syndrome might contribute to HIV-associated neurologic decline. To determine if protease inhibitor-induced metabolic dysfunction in mice is accompanied by adverse neurologic effects, C57BL/6 mice were given combined lopinavir/ritonavir (50/12.5-200/50 mg/kg) daily for 3 weeks. Data show that lopinavir/ritonavir administration caused significant metabolic derangement, including alterations in body weight and fat mass, as well as dose-dependent patterns of hyperlipidemia, hypoadiponectinemia, hypoleptinemia, and hyperinsulinemia. Evaluation of neurologic function reve...
Free Radical Biology and Medicine, 2010
Maintaining protein homeostasis is vital to cell viability, with numerous studies demonstrating a... more Maintaining protein homeostasis is vital to cell viability, with numerous studies demonstrating a role for proteasome inhibition occurring during the aging of a variety of tissues, and presumably contributing to the disruption of cellular homeostasis during aging. In the present study we sought to elucidate the differences between neurons and astrocytes in regards to basal levels of protein synthesis, proteasome-mediated protein degradation, and sensitivity to cytoxicity following proteasome inhibitor treatment. In these studies we demonstrate that neurons have an increased vulnerability, as compared to astrocyte cultures, to proteasome inhibitor-induced cytotoxicity. No significant difference was observed between these two cell types in regards to the basal rates of protein synthesis, or basal rates of protein degradation, in the pool of short-lived proteins. Following proteasome inhibitor treatment neuronal crude lysates were observed to undergo greater increases in the levels of ubiquitinated and oxidized proteins, and selectively exhibited increased levels of newly synthesized proteins accumulating within the insoluble protein pool, as compared to astrocytes. Together, these data suggest a role for increased oxidized proteins and sequestration of newly synthesized proteins to the insoluble protein pool, as potential mediators of the selective neurotoxicity following proteasome inhibitor treatment. The implications for neurons exhibiting increased sensitivity to acute proteasome inhibitor exposure, and the corresponding changes in protein homeostasis observed following proteasome inhibition, are discussed in the context of both aging and age-related disorders of the nervous system.