RESUMO
Herbal remedies are increasing in popularity as treatments for metabolic conditions such as obesity and Type 2 Diabetes. One potential therapeutic option is fenugreek seeds (Trigonella foenum-graecum), which have been used for treating high cholesterol and Type 2 diabetes. A proposed mechanism for these benefits is through alterations in the microbiome, which impact mammalian host metabolic function. This study used untargeted metabolomics to investigate the fenugreek-induced alterations in the intestinal, liver, and serum profiles of mice fed either a 60% high-fat or low-fat control diet each with or without fenugreek supplementation (2% w/w) for 14 weeks. Metagenomic analyses of intestinal contents found significant alterations in the relative composition of the gut microbiome resulting from fenugreek supplementation. Specifically, Verrucomicrobia, a phylum containing beneficial bacteria which are correlated with health benefits, increased in relative abundance with fenugreek. Metabolomics partial least squares discriminant analysis revealed substantial fenugreek-induced changes in the large intestines. However, it was observed that while the magnitude of changes was less, significant modifications were present in the liver tissues resulting from fenugreek supplementation. Further analyses revealed metabolic processes affected by fenugreek and showed broad ranging impacts in multiple pathways, including carnitine biosynthesis, cholesterol and bile acid metabolism, and arginine biosynthesis. These pathways may play important roles in the beneficial effects of fenugreek.
Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Trigonella , Animais , Colesterol , Diabetes Mellitus Tipo 2/tratamento farmacológico , Suplementos Nutricionais , Mamíferos , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
The gut microbiota has emerged as a critical player in shaping and modulating brain function and has been shown to influence numerous behaviors, including anxiety and depression-like behaviors, sociability, and cognition. However, the effects of the gut microbiota on specific disorders associated with thalamo-cortico-basal ganglia circuits, ranging from compulsive behavior and addiction to altered sensation and motor output, are only recently being explored. Wholesale depletion and alteration of gut microbial communities in rodent models of disorders, such as Parkinson's disease, autism, and addiction, robustly affect movement and motivated behavior. A new frontier therefore lies in identifying specific microbial alterations that affect these behaviors and understanding the underlying mechanisms of action. Comparing alterations in gut microbiota across multiple basal-ganglia associated disease states allows for identification of common mechanistic pathways that may interact with distinct environmental and genetic risk factors to produce disease-specific outcomes.
Assuntos
Encéfalo/fisiopatologia , Disbiose/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Transtornos Mentais/fisiopatologia , Motivação/fisiologia , Movimento/fisiologia , Animais , Disbiose/diagnóstico , Disbiose/psicologia , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/psicologiaRESUMO
Recent clinical and laboratory evidences suggest that high fat diet (HFD) induced obesity and its associated metabolic syndrome conditions promotes neuropathology in aging and age-related neurological disorders. However, the effects of high fat diet on brain pathology are poorly understood, and the effective strategies to overcome these effects remain elusive. In the current study, we examined the effects of HFD on brain pathology and further evaluated whether donepezil, an AChE inhibitor with neuroprotective functions, could suppress the ongoing HFD induced pathological changes in the brain. Our data demonstrates that HFD induced obesity results in increased neuroinflammation and increased AChE activity in the brain when compared with the mice fed on low fat diet (LFD). HFD administration to mice activated mTOR pathway resulting in increased phosphorylation of mTOR(ser2448), AKT(thr308) and S6K proteins involved in the signaling. Interestingly, donepezil administration with HFD suppressed HFD induced increases in AChE activity, and partially reversed HFD effects on microglial reactivity and the levels of mTOR signaling proteins in the brain when compared to the mice on LFD alone. However, gross levels of synaptic proteins were not altered in the brain tissues of mice fed either diet with or without donepezil. In conclusion, these results present a new insight into the detrimental effects of HFD on brain via microglial activation and involvement of mTOR pathway, and further demonstrates the possible therapeutic role for donepezil in ameliorating the early effects of HFD that could help preserve the brain function in metabolic syndrome conditions.
Assuntos
Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Donepezila/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Serina-Treonina Quinases TOR/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Inibidores da Colinesterase/farmacologia , Donepezila/farmacologia , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/imunologia , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/imunologia , Sinapses/patologiaRESUMO
HIV protease inhibitors are key components of HIV antiretroviral therapies, which are fundamental in the treatment of HIV infection. However, the protease inhibitors are well-known to induce metabolic dysfunction which can in turn escalate the complications of HIV, including HIV associated neurocognitive disorders. As experimental and epidemiological data support a therapeutic role for adiponectin in both metabolic and neurologic homeostasis, this study was designed to determine if increased adiponectin could prevent the detrimental effects of protease inhibitors in mice. Adult male wild type (WT) and adiponectin-overexpressing (ADTg) mice were thus subjected to a 4-week regimen of lopinavir/ritonavir, followed by comprehensive metabolic, neurobehavioral, and neurochemical analyses. Data show that lopinavir/ritonavir-induced lipodystrophy, hypoadiponectinemia, hyperglycemia, hyperinsulinemia, and hypertriglyceridemia were attenuated in ADTg mice. Furthermore, cognitive function and blood-brain barrier integrity were preserved, while loss of cerebrovascular markers and white matter injury were prevented in ADTg mice. Finally, lopinavir/ritonavir caused significant increases in expression of markers of brain inflammation and decreases in synaptic markers in WT, but not in ADTg mice. Collectively, these data reinforce the pathophysiologic link from metabolic dysfunction to loss of cerebrovascular and cognitive homeostasis; and suggest that preservation and/or replacement of adiponectin could prevent these key aspects of HIV protease inhibitor-induced toxicity in clinical settings.
Assuntos
Adiponectina/metabolismo , Lesões Encefálicas/induzido quimicamente , Encéfalo/irrigação sanguínea , Inibidores da Protease de HIV/efeitos adversos , Lopinavir/efeitos adversos , Ritonavir/efeitos adversos , Adiponectina/genética , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Cognição/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Homeostase/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regulação para CimaRESUMO
Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aß levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1ß and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aß in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aß pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aß pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.
Assuntos
Doença de Alzheimer/complicações , Encéfalo/patologia , Angiopatia Amiloide Cerebral/etiologia , Dieta/efeitos adversos , Modelos Animais de Doenças , Gliose/etiologia , Obesidade/etiologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Western Blotting , Encéfalo/metabolismo , Angiopatia Amiloide Cerebral/patologia , Feminino , Gliose/patologia , Humanos , Técnicas Imunoenzimáticas , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia , Obesidade/patologia , Placa Amiloide/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, affecting an estimated 5.3million people in the United States. While many factors likely contribute to AD progression, it is widely accepted that AD is driven by the accumulation of ß-amyloid (Aß), a small, fibrillogenic peptide generated by the sequential proteolysis of the amyloid precursor protein by the ß- and γ-secretases. Though the underlying causes of Aß accumulation in sporadic AD are myriad, it is clear that lifestyle and overall health play a significant role. The adipocyte-derived hormone leptin has varied systemic affects, including neuropeptide release and neuroprotection. A recent study by Lieb et al. (2009) showed that individuals with low plasma leptin levels are at greater risk of developing AD, through unknown mechanisms. In this report, we show that plasma leptin is a strong negative predictor of Aß levels in the mouse brain, supporting a protective role for the hormone in AD onset. We also show that the inhibition of Aß accumulation is due to the downregulation of transcription of the γ-secretase components. On the other hand, ß-secretase expression is either unchanged (BACE1) or increased (BACE2). Finally, we show that only presenilin 1 (PS1) is negatively correlated with plasma leptin at the protein level (p<0.0001). These data are intriguing and may highlight a role for leptin in regulating the onset of amyloid pathology and AD.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Leptina/sangue , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/biossíntese , Animais , Encéfalo/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Humanos , Immunoblotting , Leptina/farmacologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Presenilina-1/genética , Presenilina-1/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The consumption of high-fat/calorie diets in modern societies is likely a major contributor to the obesity epidemic, which can increase the prevalence of cancer, cardiovascular disease, and neurological impairment. Obesity may precipitate decline via inflammatory and oxidative signaling, and one factor linking inflammation to oxidative stress is the proinflammatory, pro-oxidant enzyme NADPH oxidase. To reveal the role of NADPH oxidase in the metabolic and neurological consequences of obesity, the effects of high-fat diet were compared in wild-type C57Bl/6 (WT) mice and in mice deficient in the NAPDH oxidase subunit NOX2 (NOX2KO). While diet-induced weight gains in WT and NOX2KO mice were similar, NOX2KO mice had smaller visceral adipose deposits, attenuated visceral adipocyte hypertrophy, and diminished visceral adipose macrophage infiltration. Moreover, the detrimental effects of HFD on markers of adipocyte function and injury were attenuated in NOX2KO mice; NOX2KO mice had improved glucose regulation, and evaluation of NOX2 expression identified macrophages as the primary population of NOX2-positive cells in visceral adipose. Finally, brain injury was assessed using markers of cerebrovascular integrity, synaptic density, and reactive gliosis, and data show that high-fat diet disrupted marker expression in WT but not NOX2KO mice. Collectively, these data indicate that NOX2 is a significant contributor to the pathogenic effects of high-fat diet and reinforce a key role for visceral adipose inflammation in metabolic and neurological decline. Development of NOX-based therapies could accordingly preserve metabolic and neurological function in the context of metabolic syndrome.
Assuntos
Adiposidade , Encéfalo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glicoproteínas de Membrana/deficiência , NADPH Oxidases/deficiência , Neurônios/metabolismo , Obesidade/metabolismo , Subunidades Proteicas/deficiência , Animais , Biomarcadores/metabolismo , Encéfalo/imunologia , Encéfalo/patologia , Hipertrofia , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Síndrome Metabólica/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/imunologia , Neurônios/patologia , Obesidade/imunologia , Obesidade/patologia , Obesidade/fisiopatologia , Estresse Oxidativo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Aumento de PesoRESUMO
This study describes the effects of long-chain fatty acids on inflammatory signaling in cultured astrocytes. Data show that the saturated fatty acid palmitic acid, as well as lauric acid and stearic acid, trigger the release of TNFα and IL-6 from astrocytes. Unsaturated fatty acids were unable to induce cytokine release from cultured astrocytes. Furthermore, the effects of palmitic acid on cytokine release require Toll-like receptor 4 rather than CD36 or Toll-like receptor 2, and do not depend on palmitic acid metabolism to palmitoyl-CoA. Inhibitor studies revealed that pharmacologic inhibition of p38 or p42/44 MAPK pathways prevents the pro-inflammatory effects of palmitic acid, whereas JNK and PI3K inhibition does not affect cytokine release. Depletion of microglia from primary astrocyte cultures using the lysosomotropic agent l-leucine methyl ester revealed that the ability of palmitic acid to trigger cytokine release is not dependent on the presence of microglia. Finally, data show that the essential ω-3 fatty acid docosahexaenoic acid acts in a dose-dependent manner to prevent the actions of palmitic acid on inflammatory signaling in astrocytes. Collectively, these data demonstrate the ability of saturated fatty acids to induce astrocyte inflammation in vitro. These data thus raise the possibility that high levels of circulating saturated fatty acids could cause reactive gliosis and brain inflammation in vivo, and could potentially participate in the reported adverse neurologic consequences of obesity and metabolic syndrome.
Assuntos
Astrócitos/efeitos dos fármacos , Citocinas/metabolismo , Ácidos Graxos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Encéfalo/citologia , Células Cultivadas , Relação Dose-Resposta a Droga , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Ácidos Graxos/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ácido Oleico/farmacologia , Ácido Palmítico/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
As a part of aging there are known to be numerous alterations which occur in multiple tissues of the body, and the focus of this study was to determine the extent to which oxidative stress and hypoxia occur during adipose tissue aging. In our studies we demonstrate for the first time that aging is associated with both hypoxia (38% reduction in oxygen levels, Po(2) 21.7 mmHg) and increases reactive oxygen species in visceral fat depots of aging male C57Bl/6 mice. Interestingly, aging visceral fat depots were observed to have significantly less change in the expression of genes involved in redox regulation compared with aging subcutaneous fat tissue. Exposure of 3T3-L1 adipocytes to the levels of hypoxia observed in aging adipose tissue was sufficient to alter multiple aspects of adipose biology inducing increased levels of in insulin-stimulated glucose uptake and decreased lipid content. Taken together, these data demonstrate that hypoxia and increased levels of reactive oxygen species occur in aging adipose tissue, highlighting the potential for these two stressors as potential modulators of adipose dysfunction during aging.
Assuntos
Tecido Adiposo/metabolismo , Envelhecimento/metabolismo , Hipóxia/metabolismo , Estresse Oxidativo/fisiologia , Tecido Adiposo/fisiopatologia , Envelhecimento/genética , Animais , Expressão Gênica , Hipóxia/genética , Hipóxia/fisiopatologia , Masculino , Camundongos , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cognitive impairment in Alzheimer's disease (AD) is strongly associated with both extensive deposition of amyloid ß peptides and oxidative stress, but the exact role of these indices in the development of dementia is not clear. This study was designed to determine the relationship between cognitive impairment, activation of the free radical producing enzyme NADPH oxidase (NOX), and progressive changes in Aß deposition and solubility in humanized APP×PS1 knock-in mice of increasing age. Data show that cognitive performance and expression of key synaptic proteins were progressively decreased in aging APP×PS1 mice. Likewise, NOX activity and expression of the specific NOX subunit NOX4 were significantly increased in APP×PS1 mice in an age-dependent manner, and NOX activity and cognitive impairment shared a significant linear relationship. Data further show that age-dependent increases in Aß(1-42) had a significant linear relationship with both NOX activity and cognitive performance in APP×PS1 knock-in mice. Collectively, these data show that NOX expression and activity are significantly upregulated with age in this humanized model of Aß pathogenesis, and suggest that NOX-associated redox pathways are intimately linked to both the loss of cognitive function and the deposition of Aß(1-42).
Assuntos
Peptídeos beta-Amiloides/metabolismo , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Regulação da Expressão Gênica/genética , NADPH Oxidases/metabolismo , Fragmentos de Peptídeos/metabolismo , Fatores Etários , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Transtornos Cognitivos/etiologia , Proteína 1 Homóloga a Discs-Large , Modelos Animais de Doenças , Guanilato Quinases/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Sinapsinas/metabolismo , Tubulina (Proteína)/metabolismoRESUMO
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. This study exposed primary rat neurons and astrocyte cultures to established amino acid analogs (canavanine and azetidine-2-carboxylic acid) and showed that both cell types undergo a dose-dependent increase in toxicity, with neurons exhibiting a greater degree of toxicity compared with 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 compared with astrocytes.
Assuntos
Astrócitos/efeitos dos fármacos , Ácido Azetidinocarboxílico/toxicidade , Canavanina/toxicidade , Proteínas de Ligação a DNA/metabolismo , Neurônios/efeitos dos fármacos , Dobramento de Proteína/efeitos dos fármacos , Aminoácidos/agonistas , Aminoácidos/toxicidade , Animais , Astrócitos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Proteínas de Ligação a DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico/efeitos dos fármacos , Proteínas de Choque Térmico/metabolismo , Neurônios/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
The incidence of obesity is increasing worldwide, and is especially pronounced in developed western countries. While the consequences of obesity on metabolic and cardiovascular physiology are well established, epidemiological and experimental data are beginning to establish that the central nervous system (CNS) may also be detrimentally affected by obesity and obesity-induced metabolic dysfunction. In particular, data show that obesity in human populations is associated with cognitive decline and enhanced vulnerability to brain injury, while experimental studies in animal models confirm a profile of heightened vulnerability and decreased cognitive function. This review will describe findings from human and animal studies to summarize current understanding of how obesity affects the brain. Furthermore, studies aimed at identifying key elements of body-brain dialog will be discussed to assess how various metabolic and adipose-related signals could adversely affect the CNS. Overall, data suggest that obesity-induced alterations in metabolism may significantly synergize with age to impair brain function and accelerate age-related diseases of the nervous system. Thus, enhanced understanding of the effects of obesity and obesity-related metabolic dysfunction on the brain are especially critical as increasing numbers of obese individuals approach advanced age.
Assuntos
Encéfalo/fisiopatologia , Obesidade/fisiopatologia , Envelhecimento/fisiologia , Animais , Metabolismo Energético/fisiologia , Humanos , Obesidade/metabolismo , Transdução de Sinais/fisiologiaRESUMO
A number of metabolic disturbances occur in response to the consumption of a high fat western diet. Such metabolic disturbances can include the progressive development of hyperglycemia, hyperinsulemia, obesity, metabolic syndrome, and diabetes. Cumulatively, diet-induced disturbances in metabolism are known to promote increased morbidity and negatively impact life expectancy through a variety of mechanisms. While the impact of metabolic disturbances on the hepatic, endocrine, and cardiovascular systems is well established there remains a noticeable void in understanding the basis by which the central nervous system (CNS) becomes altered in response to diet-induced metabolic dysfunction. In particular, it remains to be fully elucidated which established features of diet-induced pathogenesis (observed in non-CNS tissues) are recapitulated in the brain, and identification as to whether the observed changes in the brain are a direct or indirect effect of peripheral metabolic disturbances. This review will focus on each of these key issues and identify some critical experimental questions which remain to be elucidated experimentally, as well as provide an outline of our current understanding for how diet-induced alterations in metabolism may impact the brain during aging and age-related diseases of the nervous system.
Assuntos
Encéfalo/metabolismo , Gorduras na Dieta/metabolismo , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Demência/metabolismo , Demência/patologia , Demência/fisiopatologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Homeostase , Humanos , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Estresse Oxidativo/fisiologiaRESUMO
Inhibition of the proteasome proteolytic pathway occurs as the result of normal aging, as well as in a variety of neurodegenerative conditions, and is believed to promote cellular toxicity in each of these conditions through diverse mechanisms. In the present study, we examined whether proteasome inhibition alters the protein kinase receptor-like endoplasmic reticulum kinase (PERK). Our studies demonstrate that proteasome inhibitors induce the transient activation of PERK in both primary rat neurons as well as the N2a neural cell line. Experiments with siRNA to PERK demonstrated that the modulation of PERK was not significant involved in regulating toxicity, ubiquitinated protein levels, or ribosome perturbations in response to proteasome inhibitor treatment. Surprisingly, PERK was observed to be involved in the up-regulation of p38 kinase following proteasome inhibitor treatment. Taken together, these data demonstrate the ability of proteasome inhibition to activate PERK and demonstrate evidence for novel cross-talk between PERK and the activation of p38 kinase in neural cells following proteasome inhibition. Taken together, these data have implications for understanding the basis by which proteasome inhibition alters neural homeostasis, and the basis by which cell signaling cascades are regulated by proteasome inhibition.
Assuntos
Neurônios/enzimologia , Inibidores de Proteases/farmacologia , Inibidores de Proteassoma , eIF-2 Quinase/metabolismo , Animais , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Leupeptinas/farmacologia , Neurônios/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Gorduras na Dieta , Resistência à Insulina , Obesidade/metabolismo , Adiposidade , Envelhecimento/patologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Humanos , Estresse OxidativoRESUMO
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' (41% fat), very high fat lard diet (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 high fat lard 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 NF-E2-related factor 2 (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.
Assuntos
Envelhecimento/metabolismo , Transtornos Cognitivos/metabolismo , Gorduras na Dieta/administração & dosagem , Hipocampo/metabolismo , Fator 2 Relacionado a NF-E2/fisiologia , Estresse Oxidativo , Adiposidade , Envelhecimento/psicologia , Animais , Glicemia/metabolismo , Peso Corporal , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Insulina/sangue , Leptina/sangue , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Carbonilação Proteica , Transdução de SinaisRESUMO
Fenugreek (Trigonella foenum-graecum) is an annual herbaceous plant and a staple of traditional health remedies for metabolic conditions including high cholesterol and diabetes. While the mechanisms of the beneficial actions of fenugreek remain unknown, a role for intestinal microbiota in metabolic homeostasis is likely. To determine if fenugreek utilizes intestinal bacteria to offset the adverse effects of high fat diets, C57BL/6J mice were fed control/low fat (CD) or high fat (HFD) diets each supplemented with or without 2% (w/w) fenugreek for 16 weeks. The effects of fenugreek and HFD on gut microbiota were comprehensively mapped and then statistically assessed in relation to effects on metrics of body weight, hyperlipidemia, and glucose tolerance. 16S metagenomic analyses revealed robust and significant effects of fenugreek on gut microbiota, with alterations in both alpha and beta diversity as well as taxonomic redistribution under both CD and HFD conditions. As previously reported, fenugreek attenuated HFD-induced hyperlipidemia and stabilized glucose tolerance without affecting body weight. Finally, fenugreek specifically reversed the dysbiotic effects of HFD on numerous taxa in a manner tightly correlated with overall metabolic function. Collectively, these data reinforce the essential link between gut microbiota and metabolic syndrome and suggest that the preservation of healthy populations of gut microbiota participates in the beneficial properties of fenugreek in the context of modern Western-style diets.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Bactérias/genética , Glicemia , Peso Corporal/efeitos dos fármacos , Suplementos Nutricionais , Modelos Animais de Doenças , Dislipidemias/prevenção & controle , Glucose/metabolismo , Intolerância à Glucose/prevenção & controle , Hiperlipidemias/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/microbiologia , Extratos Vegetais/metabolismo , RNA Ribossômico 16S/genética , Trigonella/metabolismoRESUMO
Human immunodeficiency virus (HIV)-infected individuals who abuse opiates show faster progression to AIDS, and enhanced incidence of HIV-1 encephalitis. Most opiates with abuse liability are preferential agonists for mu-opioid receptors (MORs), and MORs are expressed on both neurons and glia, including oligodendrocytes (OLs). Tat, gp120, and other viral toxins, cause neurotoxicity in vitro and/or when injected into brain, and co-exposure to opiates can augment HIV-1 protein-induced insults to both glial and neuronal populations. We examined the effects of HIV-1 Tat +/- opiate exposure on OL survival and differentiation. In vivo studies utilized transgenic mice expressing Tat(1-86) regulated by an inducible glial fibrillary acidic protein promoter. Although MBP levels were unchanged on immunoblots, certain structural and apoptotic indices were abnormal. After only 2 days of Tat induction, OLs showed an upregulation of active caspase-3 that was enhanced by morphine exposure. Tat also upregulated TUNEL staining, but only in the presence of morphine. Tat significantly reduced the length of processes in Golgi-Kopsch impregnated OLs. A greater proportion of cells exhibited diminished or aberrant cytoplasmic processes, especially when mice expressing Tat were co-exposed to morphine. Collectively, our data show that OLs in situ are extremely sensitive to effects of Tat +/- morphine, although it is not clear if immature OLs as well as differentiated OLs are targeted equally. Significant elevations in caspase-3 activity and TUNEL labeling, and evidence of increased degeneration/regeneration of OLs exposed to Tat +/- morphine suggest that toxicity toward OLs may be accompanied by heightened OL turnover.
Assuntos
Complexo AIDS Demência/metabolismo , Doenças Desmielinizantes/virologia , Morfina/toxicidade , Oligodendroglia/virologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Complexo AIDS Demência/induzido quimicamente , Complexo AIDS Demência/virologia , Analgésicos Opioides/toxicidade , Animais , Apoptose/genética , Caspase 3/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Forma Celular/efeitos dos fármacos , Forma Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/fisiopatologia , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Transgênicos , Bainha de Mielina/metabolismo , Bainha de Mielina/virologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Coloração pela Prata , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismoRESUMO
A chronic high fat Western diet (WD) promotes a variety of morbidity factors although experimental evidence for short-term WD mediating brain dysfunction remains to be elucidated. The amyloid precursor protein and presenilin-1 (APP x PS1) knock-in mouse model has been demonstrated to recapitulate some key features of Alzheimer's disease pathology, including amyloid-beta (Abeta) pathogenesis. In this study, we placed 1-month-old APP x PS1 mice and non-transgenic littermates on a WD for 4 weeks. The WD resulted in a significant elevation in protein oxidation and lipid peroxidation in the brain of APP x PS1 mice relative to non-transgenic littermates, which occurred in the absence of increased Abeta levels. Altered adipokine levels were also observed in APP x PS1 mice placed on a short-term WD, relative to non-transgenic littermates. Taken together, these data indicate that short-term WD is sufficient to selectively promote cerebral oxidative stress and metabolic disturbances in APP x PS1 knock-in mice, with increased oxidative stress preceding alterations in Abeta. These data have important implications for understanding how WD may potentially contribute to brain dysfunction and the development of neurodegenerative disorders such as Alzheimer's disease.
Assuntos
Doença de Alzheimer/metabolismo , Córtex Cerebral/metabolismo , Complicações do Diabetes/metabolismo , Gorduras na Dieta/efeitos adversos , Alimentos Formulados/efeitos adversos , Estresse Oxidativo/fisiologia , Adipocinas/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Química Encefálica/genética , Córtex Cerebral/fisiopatologia , Complicações do Diabetes/etiologia , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Feminino , Técnicas de Introdução de Genes , Humanos , Peroxidação de Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Presenilina-1/genéticaRESUMO
Opiate abuse alters the progression of human immunodeficiency virus and may increase the risk of neuroAIDS. As neuroAIDS is associated with altered microglial reactivity, the combined effects of human immunodeficiency virus-Tat and morphine were determined in cultured microglia. Specifically, experiments determined the effects of Tat and morphine on microglial-free radical production and oxidative stress, and on cytokine release. Data show that combined Tat and morphine cause early and synergistic increases in reactive oxygen species, with concomitant increases in protein oxidation. Furthermore, combined Tat and morphine, but not Tat or morphine alone, cause reversible decreases in proteasome activity. The effects of morphine on free radical production and oxidative stress are prevented by pre-treatment with naloxone, illustrating the important role of opioid receptor activation in these phenomena. While Tat is well known to induce cytokine release from cultured microglia, morphine decreases Tat-induced release of the cytokines tumor necrosis factor-alpha and interleukin-6, as well as the chemokine monocyte chemoattractant protein-1 (MCP-1). Finally, experiments using the reversible proteasome inhibitor MG115 show that temporary, non-cytotoxic decreases in proteasome activity increase protein oxidation and decrease tumor necrosis factor-alpha, interleukin-6, and MCP-1 release from microglia. Taken together, these data suggest that oxidative stress and proteasome inhibition may be involved in the immunomodulatory properties of opioid receptor activation in microglia.