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1.
Planta ; 254(2): 32, 2021 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-34287699

RESUMEN

MAIN CONCLUSION: A ß-ketoacyl-ACP-synthase II (KAS2) like enzyme and a lysophosphatidic acid acyltransferase (LPAT2) from Consolida ajacis catalyze gondoic acid biosynthesis and incorporation into the sn-2 position of seed TAG in engineered Camelina sativa. Gondoic acid (cis-11 eicosenoic acid, 20:1∆11) is the predominant very-long-chain fatty acid (VLCFA) in camelina (Camelina sativa) seed oil accounting for 12-15% of total triacylglycerol fatty acids. To explore the feasibility of engineering increased levels of this fatty acid in camelina seed, oils from a range of plant species were analyzed to identify those producing 20-Carbon (C20) fatty acids as the only VLCFAs in their seed oil. Seeds of Consolida and Delphinium species (Ranunculaceae) were found to contain moderate levels (0.2% to 25.5%) of C20 fatty acids without accompanying longer chain fatty acids. The C20 fatty acids were abundant in both sn-2 and sn-1/3 positions of seed TAG in Consolida, but were largely absent from the sn-2 position in Delphinium seed TAG. Through generation of a developing seed transcriptome, sequences were identified and cDNAs amplified from Consolida ajacis encoding a ß-ketoacyl-ACP-synthase II like protein (CaKAS2B) that lacked a predicted chloroplast transit peptide, and two homologues of Arabidopsis thaliana lysophosphatidic acid acyltransferase 2 (CaLPAT2a and CaLPAT2b). Expression of CaKAS2B in conventional (WT) camelina and a line previously engineered for high seed oleic acid content (HO) resulted in increased seed VLCFA content. Total VLCFA levels were raised from 24 to 35% and from 7 to 23% in T3 seed from representative transformants in the WT and HO backgrounds, respectively. Gondoic acid was the predominant VLCFA in transformed HO lines with low endogenous cytoplasmic fatty acid elongation activity, suggesting limited capacity of CaKAS2B to elongate beyond C20. Expression in camelina of CaLPAT2b resulted in significantly increased C20-VLCFA esterification at the sn-2 position of seed TAG with VLCFA levels of 33.8% in this position in one transformed line compared to 0.3% at sn-2 in the corresponding control line. Only small changes in total seed VLCFA content were observed in transformed lines implying that increased VLCFA esterification capacity in camelina results in positional redistribution of VLCFAs but does not significantly enhance flux through the fatty acid elongation pathway. The full potential of CaKAS2B and CaLPAT2a for the engineering of high gondoic acid levels in camelina remains to be determined. Seed fatty acid composition of Consolida and Delphinium also provides information that may be of value in the systematics of the Ranunculaceae.


Asunto(s)
Brassicaceae , Delphinium , Brassicaceae/genética , ADN Complementario/genética , Expresión Génica Ectópica , Ácidos Grasos , Ácidos Grasos Monoinsaturados , Aceites de Plantas , Plantas Modificadas Genéticamente , Semillas/genética , Triglicéridos
2.
Cell Rep ; 25(2): 278-287.e4, 2018 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-30304668

RESUMEN

Leptin acts on hypothalamic pro-opiomelanocortin (POMC) neurons to regulate glucose homeostasis, but the precise mechanisms remain unclear. Here, we demonstrate that leptin-induced depolarization of POMC neurons is associated with the augmentation of a voltage-gated calcium (CaV) conductance with the properties of the "R-type" channel. Knockdown of the pore-forming subunit of the R-type (CaV2.3 or Cacna1e) conductance in hypothalamic POMC neurons prevented sustained leptin-induced depolarization. In vivo POMC-specific Cacna1e knockdown increased hepatic glucose production and insulin resistance, while body weight, feeding, or leptin-induced suppression of food intake were not changed. These findings link Cacna1e function to leptin-mediated POMC neuron excitability and glucose homeostasis and may provide a target for the treatment of diabetes.


Asunto(s)
Canales de Calcio Tipo R/metabolismo , Calcio/metabolismo , Proteínas de Transporte de Catión/metabolismo , Glucosa/metabolismo , Leptina/farmacología , Hígado/metabolismo , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Animales , Canales de Calcio Tipo R/genética , Proteínas de Transporte de Catión/genética , Células Cultivadas , Homeostasis , Humanos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ratones , Ratones Transgénicos , Neuronas/efectos de los fármacos
3.
Cell Rep ; 21(12): 3559-3572, 2017 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-29262334

RESUMEN

Feeding requires the integration of homeostatic drives with emotional states relevant to food procurement in potentially hostile environments. The ventromedial hypothalamus (VMH) regulates feeding and anxiety, but how these are controlled in a concerted manner remains unclear. Using pharmacogenetic, optogenetic, and calcium imaging approaches with a battery of behavioral assays, we demonstrate that VMH steroidogenic factor 1 (SF1) neurons constitute a nutritionally sensitive switch, modulating the competing motivations of feeding and avoidance of potentially dangerous environments. Acute alteration of SF1 neuronal activity alters food intake via changes in appetite and feeding-related behaviors, including locomotion, exploration, anxiety, and valence. In turn, intrinsic SF1 neuron activity is low during feeding and increases with both feeding termination and stress. Our findings identify SF1 neurons as a key part of the neurocircuitry that controls both feeding and related affective states, giving potential insights into the relationship between disordered eating and stress-associated psychological disorders in humans.


Asunto(s)
Ansiedad/fisiopatología , Emociones , Conducta Alimentaria , Hipotálamo/fisiología , Neuronas/fisiología , Animales , Ansiedad/metabolismo , Apetito , Calcio/metabolismo , Conducta Exploratoria , Femenino , Hipotálamo/citología , Hipotálamo/metabolismo , Locomoción , Masculino , Ratones , Neuronas/metabolismo , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo
4.
Vaccine ; 35(49 Pt A): 6798-6802, 2017 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-28890194

RESUMEN

In order to avoid expensive clinical failures, better and more predictive animal models of vaccine efficacy are needed to screen Shigella and ETEC vaccine candidates for protective efficacy. The 2016 Vaccines Against Shigella and ETEC (VASE) Conference included a workshop focused on the strengths and weaknesses of current models, particularly in terms of the correlation to vaccine efficacy in human clinical trials. Workshop presenters shared information on existing preclinical animal models for assessing the immunogenicity and protective efficacy of Shigella and ETEC vaccines. The presentations were followed by a discussion about how to best utilize these models, how the models can be improved, and best practices for Shigella and ETEC vaccine developers. The workshop concluded with three major recommendations for the field: (1) develop better and more consistent reagents for animal studies and make them widely available, (2) prioritize harmonization of animal models and immunology assays, and (3) develop preclinical correlates of protection, which will be key in selecting the best vaccine candidates for further clinical development.


Asunto(s)
Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Resultado del Tratamiento , Animales , Disentería Bacilar/microbiología , Disentería Bacilar/prevención & control , Escherichia coli Enterotoxigénica/inmunología , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/prevención & control , Vacunas contra Escherichia coli/administración & dosificación , Humanos , Reproducibilidad de los Resultados , Shigella/inmunología , Vacunas contra la Shigella/administración & dosificación
5.
Cell Metab ; 23(5): 821-36, 2016 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-27133129

RESUMEN

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Células Secretoras de Insulina/enzimología , Células Secretoras de Insulina/patología , Obesidad/enzimología , Adiposidad/genética , Adulto , Envejecimiento/patología , Proteína Relacionada con Agouti/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Metabolismo Energético/genética , Activación Enzimática , Conducta Alimentaria , Femenino , Heterocigoto , Humanos , Hiperfagia/complicaciones , Hiperfagia/enzimología , Hiperfagia/genética , Hiperfagia/patología , Hipotálamo/metabolismo , Insulina/metabolismo , Masculino , Ratones , Mitocondrias/metabolismo , Mutación/genética , Neuronas/metabolismo , Obesidad/sangre , Obesidad/complicaciones , Obesidad/patología , Fosforilación Oxidativa , Receptores de Ghrelina/metabolismo , Ribosomas/metabolismo , Transducción de Señal/genética , Transcriptoma/genética , Regulación hacia Arriba/genética
6.
Sci Rep ; 6: 22181, 2016 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-26916792

RESUMEN

Feedstocks for industrial applications ranging from polymers to lubricants are largely derived from petroleum, a non-renewable resource. Vegetable oils with fatty acid structures and storage forms tailored for specific industrial uses offer renewable and potentially sustainable sources of petrochemical-type functionalities. A wide array of industrial vegetable oils can be generated through biotechnology, but will likely require non-commodity oilseed platforms dedicated to specialty oil production for commercial acceptance. Here we show the feasibility of three Brassicaceae oilseeds crambe, camelina, and carinata, none of which are widely cultivated for food use, as hosts for complex metabolic engineering of wax esters for lubricant applications. Lines producing wax esters >20% of total seed oil were generated for each crop and further improved for high temperature oxidative stability by down-regulation of fatty acid polyunsaturation. Field cultivation of optimized wax ester-producing crambe demonstrated commercial utility of these engineered crops and a path for sustainable production of other industrial oils in dedicated specialty oilseeds.


Asunto(s)
Reactores Biológicos , Brassicaceae/metabolismo , Productos Agrícolas/metabolismo , Ingeniería Metabólica , Aceites de Plantas/metabolismo , Plantas Modificadas Genéticamente/metabolismo , Ceras/metabolismo , Brassicaceae/genética , Productos Agrícolas/genética , Plantas Modificadas Genéticamente/genética
7.
Zhong Yao Cai ; 38(3): 514-7, 2015 Mar.
Artículo en Chino | MEDLINE | ID: mdl-26495651

RESUMEN

OBJECTIVE: To investigate the chemical constituents in the ethanol extract from the whole plant of Euphorbia lunulata. METHODS: The whole plant of Euphorbia lunulata was extracted by 95% ethanol, then partitioned by system solvents with different polarity. The ethyl acetate and n-butyl alcohol extracts were separated on silica gel, Sephadex LH-20,and MCI columns. The isolated compounds were determined by detailed analysis of their spectral data. RESULTS: Twelve compounds were isolated and identified from the ethyl acetate and n-butyl alcohol extracts of Euphorbia lunulata and the structures were identified as 7ß-methoxy-stigmast-5-ene-3ß-ol (1), 7ß-methoxy-stigmast-5-ene-3ß,22ß-diol(2), asperglaucide(3), moscatin (4), p-hydroxybenzoic acid (5),3-methoxy-4-hydroxy benzoic acid(6), erigeside C(7),5,7,4'-trihydroxy flavanone(8), kaempferol(9), quercetin(10), corosolic acid(11) and acacetin (12). CONCLUSION: All compounds except for 9 and 10 are reported from this plant for the first time.


Asunto(s)
Euphorbia/química , Fitoquímicos/química , Extractos Vegetales/química , Quempferoles , Fitoquímicos/aislamiento & purificación , Quercetina
8.
Theor Appl Genet ; 128(9): 1865-79, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26105686

RESUMEN

A simple Weibull distribution based empirical model that predicts pollen-parent fecundity distributions based on polycross size alone has been developed in outbred forage legume species for incorporation into quantitative genetic theory. Random mating or panmixis is a fundamental assumption in quantitative genetic theory. Random mating is sometimes thought to occur in actual fact, although a large body of empirical work shows that this is often not the case in nature. Models have been developed to explain many non-random mating phenomena. This paper measured pollen-parent fecundity distributions among outbred perennial forage legume species [autotetraploid alfalfa (Medicago sativa L.), autohexaploid kura clover (Trifolium ambiguum M. Bieb.), and diploid red clover (Trifolium pratense L.)] in ten polycrosses ranging in size (N) from 9 to 94 pollinated with bee pollinators [Bumble Bees (Bombus impatiens Cr.) and leafcutter bees (Megachile rotundata F.)]. A Weibull distribution best fit the observed pollen-parent fecundity distributions. After standardizing data among the 10 polycrosses, a single Weibull distribution-based model was obtained with an R (2) of 0.978. The model is able to predict pollen-parent fecundity distributions based on polycross size alone. The model predicts that the effective polycross size will be approximately 9 % smaller than under random mating (i.e., N e/N ~ 0.91). The model is simple and can easily be incorporated into other models or simulations requiring a pollen-parent fecundity distribution. Further work is needed to determine how widely applicable the model is.


Asunto(s)
Cruzamientos Genéticos , Fertilidad/genética , Medicago sativa/genética , Polen/genética , Trifolium/genética , Animales , Abejas , ADN de Plantas/genética , Modelos Biológicos , Fitomejoramiento , Polinización , Análisis de Secuencia de ADN
9.
Cell Rep ; 11(3): 335-43, 2015 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-25865886

RESUMEN

Hypothalamic ribosomal S6K1 has been suggested as a point of convergence for hormonal and nutrient signals in the regulation of feeding behavior, bodyweight, and glucose metabolism. However, the long-term effects of manipulating hypothalamic S6K1 signaling on energy homeostasis and the cellular mechanisms underlying these roles are unclear. We therefore inactivated S6K1 in pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, but in contrast to the current view, we found no evidence that S6K1 regulates food intake and bodyweight. In contrast, S6K1 signaling in POMC neurons regulated hepatic glucose production and peripheral lipid metabolism and modulated neuronal excitability. S6K1 signaling in AgRP neurons regulated skeletal muscle insulin sensitivity and was required for glucose sensing by these neurons. Our findings suggest that S6K1 signaling is not a general integrator of energy homeostasis in the mediobasal hypothalamus but has distinct roles in the regulation of glucose homeostasis by POMC and AgRP neurons.


Asunto(s)
Metabolismo Energético/fisiología , Conducta Alimentaria/fisiología , Glucosa/metabolismo , Hipotálamo/metabolismo , Neuronas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Proteína Relacionada con Agouti/metabolismo , Animales , Peso Corporal/fisiología , Homeostasis/fisiología , Resistencia a la Insulina/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proopiomelanocortina/metabolismo , Transducción de Señal/fisiología
10.
Lipids ; 48(1): 75-85, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23054551

RESUMEN

Triacylglycerol estolides have been reported as components of the seed oil of a number of plant species and are generally associated with the presence of fatty acids containing hydroxyl groups. We have used MALDI-TOF MS to examine the intact acylglycerol species present in the seed oils of two plants that produce kamlolenic acid (18-hydroxy-Δ9cis,11trans,13trans-octadecatrienoic acid). Mallotus philippensis and Trewia nudiflora were both shown to produce seed oil rich in TAG-estolides. Analysis by MALDI-TOF MS/MS demonstrated that the TAG-estolides had a structure different to that previously proposed after enzymatic digestion of the oil. Acylglycerols containing up to 14 fatty acids were detected but fatty acid estolides were only present in a single position on the glycerol backbone, with predominantly non-hydroxyl fatty acids in the remaining two positions. Increased numbers of fatty acids per glycerol backbone were accounted for by the presence of fatty acid estolides containing a correspondingly greater number of fatty acids. For example, acylglycerols containing seven fatty acids had a fatty acid estolide of five fatty acids at one position on the glycerol backbone. Both capped and uncapped fatty acid estolides, with a free hydroxyl group, were present, with capped fatty acid estolides being more abundant in T. nudiflora and uncapped fatty acid estolides in M. philippensis.


Asunto(s)
Euphorbiaceae/química , Mallotus (Planta)/química , Aceites de Plantas/química , Semillas/química , Triglicéridos/análisis , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
11.
CNS Neurol Disord Drug Targets ; 11(1): 81-5, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22229318

RESUMEN

The pathological lesions typical of Alzheimer disease (AD) are sites of significant and abnormal metal accumulation. Metal chelation therapy, therefore, provides a very attractive therapeutic measure for the neuronal deterioration of AD, though its institution suffers fundamental deficiencies. Namely, chelating agents, which bind to and remove excess transition metals from the body, must penetrate the blood-brain barrier to instill any real effect on the oxidative damages caused by the presence of the metals in the brain. Despite many advances in chelation administration, however, this vital requirement remains therapeutically out of reach: the most effective chelators-i.e., those that have high affinity and specificity for transition metals like iron and copper-are bulky and hydrophilic, making it difficult to reach their physiological place of action. Moreover, small, lipophilic chelators, which can pass through the brain's defensive wall, essentially suffer from their over-effectiveness. That is, they induce toxicity on proliferating cells by removing transition metals from vital RNA enzymes. Fortunately, research has provided a loophole. Nanoparticles, tiny, artificial or natural organic polymers, are capable of transporting metal chelating agents across the blood-brain barrier regardless of their size and hydrophilicity. The compounds can thereby sufficiently ameliorate the oxidative toxicity of excess metals in an AD brain without inducing any such toxicity themselves. We here discuss the current status of nanoparticle delivery systems as they relate to AD chelation therapy and elaborate on their mechanism of action. An exciting future for AD treatment lies ahead.


Asunto(s)
Encéfalo/efectos de los fármacos , Quelantes/administración & dosificación , Terapia por Quelación , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Estrés Oxidativo/efectos de los fármacos , Elementos de Transición , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Quelantes/farmacocinética , Humanos , Permeabilidad/efectos de los fármacos , Receptores de LDL/metabolismo
12.
Neurobiol Aging ; 33(9): 2062-71, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21982274

RESUMEN

Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer's disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD. Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1 (SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression. Taken together our findings indicate that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene.


Asunto(s)
Envejecimiento/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Neurotransmisores/administración & dosificación , Estilbenos/administración & dosificación , Envejecimiento/sangre , Envejecimiento/genética , Enfermedad de Alzheimer/genética , Análisis de Varianza , Animales , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Suplementos Dietéticos , Modelos Animales de Enfermedad , Femenino , Cromatografía de Gases y Espectrometría de Masas , Regulación de la Expresión Génica/efectos de los fármacos , MAP Quinasa Quinasa 4/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Neurotransmisores/sangre , PPAR alfa/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Resveratrol , Transducción de Señal/efectos de los fármacos , Sirtuina 1/genética , Sirtuina 1/metabolismo , Estilbenos/sangre , Proteínas tau/metabolismo
13.
Diabetes ; 60(3): 735-45, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21266325

RESUMEN

OBJECTIVE: AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca(2+)-calmodulin-dependent protein kinase kinase ß (CaMKKß) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation. RESEARCH DESIGN AND METHODS: Mice lacking either Camkkß or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed. RESULTS: Deletion of Camkkß in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased α-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice. CONCLUSIONS: Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons.


Asunto(s)
Glucosa/metabolismo , Homeostasis/genética , Hipotálamo/metabolismo , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Análisis de Varianza , Animales , Área Bajo la Curva , Peso Corporal/genética , Recuento de Células , Ingestión de Alimentos/genética , Electrofisiología , Metabolismo Energético/genética , Femenino , Glucosa/genética , Técnica de Clampeo de la Glucosa , Inmunohistoquímica , Resistencia a la Insulina/genética , Masculino , Ratones , Ratones Transgénicos , Proopiomelanocortina/genética , Proteínas Serina-Treonina Quinasas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Estadísticas no Paramétricas
15.
Expert Rev Neurother ; 10(7): 1201-8, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20586698

RESUMEN

Oxidative stress is an important factor, and one that acts in the earliest stages, of Alzheimer's disease (AD) pathogenesis. The reduction of oxidative stress has been tested as a therapy for AD. While the trial of vitamin E supplementation in moderately severe AD is the most promising so far, it also reveals the limitations of general antioxidant therapies that simply lower oxidative stress and, therefore, the complexity of the redox system. The multiple contributing factors that foster the clinical manifestations of AD should be considered when designing antioxidative stress therapy. In this article, we discuss the multiple pathogenic mechanisms of oxidative stress in AD and the potential targeting approaches.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antioxidantes/uso terapéutico , Estrés Oxidativo/fisiología , Enfermedad de Alzheimer/fisiopatología , Animales , Ensayos Clínicos como Asunto , Humanos , Estrés Oxidativo/efectos de los fármacos
16.
Biochem J ; 429(2): 323-33, 2010 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-20465544

RESUMEN

AMPK (AMP-activated protein kinase) signalling plays a key role in whole-body energy homoeostasis, although its precise role in pancreatic beta-cell function remains unclear. In the present study, we therefore investigated whether AMPK plays a critical function in beta-cell glucose sensing and is required for the maintenance of normal glucose homoeostasis. Mice lacking AMPK alpha2 in beta-cells and a population of hypothalamic neurons (RIPCre alpha2KO mice) and RIPCre alpha2KO mice lacking AMPK alpha1 (alpha1KORIPCre alpha2KO) globally were assessed for whole-body glucose homoeostasis and insulin secretion. Isolated pancreatic islets from these mice were assessed for glucose-stimulated insulin secretion and gene expression changes. Cultured beta-cells were examined electrophysiologically for their electrical responsiveness to hypoglycaemia. RIPCre alpha2KO mice exhibited glucose intolerance and impaired GSIS (glucose-stimulated insulin secretion) and this was exacerbated in alpha1KORIPCre alpha2KO mice. Reduced glucose concentrations failed to completely suppress insulin secretion in islets from RIPCre alpha2KO and alpha1KORIPCre alpha2KO mice, and conversely GSIS was impaired. Beta-cells lacking AMPK alpha2 or expressing a kinase-dead AMPK alpha2 failed to hyperpolarize in response to low glucose, although KATP (ATP-sensitive potassium) channel function was intact. We could detect no alteration of GLUT2 (glucose transporter 2), glucose uptake or glucokinase that could explain this glucose insensitivity. UCP2 (uncoupling protein 2) expression was reduced in RIPCre alpha2KO islets and the UCP2 inhibitor genipin suppressed low-glucose-mediated wild-type mouse beta-cell hyperpolarization, mimicking the effect of AMPK alpha2 loss. These results show that AMPK alpha2 activity is necessary to maintain normal pancreatic beta-cell glucose sensing, possibly by maintaining high beta-cell levels of UCP2.


Asunto(s)
Proteínas Quinasas Activadas por AMP/deficiencia , Células Secretoras de Insulina/fisiología , Insulina/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Glucoquinasa/metabolismo , Glucosa/metabolismo , Glucosa/farmacología , Transportador de Glucosa de Tipo 2/metabolismo , Homeostasis , Hipoglucemia/fisiopatología , Hipotálamo/fisiología , Técnicas In Vitro , Secreción de Insulina , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/efectos de los fármacos , Canales Iónicos/antagonistas & inhibidores , Canales Iónicos/metabolismo , Potenciales de la Membrana , Ratones , Ratones Noqueados , Proteínas Mitocondriales/antagonistas & inhibidores , Proteínas Mitocondriales/metabolismo , Ratas , Transducción de Señal , Proteína Desacopladora 2
17.
Methods Mol Biol ; 610: 123-44, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20013176

RESUMEN

Current therapies for Alzheimer disease (AD) such as the acetylcholinesterase inhibitors and the latest NMDA receptor inhibitor, Namenda, provide moderate symptomatic delay at various stages of the disease, but do not arrest the disease progression or bring in meaningful remission. New approaches to the disease management are urgently needed. Although the etiology of AD is largely unknown, oxidative damage mediated by metals is likely a significant contributor since metals such as iron, aluminum, zinc, and copper are dysregulated and/or increased in AD brain tissue and create a pro-oxidative environment. This role of metal ion-induced free radical formation in AD makes chelation therapy an attractive means of dampening the oxidative stress burden in neurons. The chelator desferrioxamine, FDA approved for iron overload, has shown some benefit in AD, but like many chelators, it has a host of adverse effects and substantial obstacles for tissue-specific targeting. Other chelators are under development and have shown various strengths and weaknesses. Here, we propose a novel system of chelation therapy through the use of nanoparticles. Nanoparticles conjugated to chelators show unique ability to cross the blood-brain barrier (BBB), chelate metals, and exit through the BBB with their corresponding complexed metal ions. This method may provide a safer and more effective means of reducing the metal load in neural tissue, thus attenuating the harmful effects of oxidative damage and its sequelae. Experimental procedures are presented in this chapter.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Terapia por Quelación/métodos , Quelantes del Hierro/uso terapéutico , Nanopartículas , Anciano , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Benzoatos/química , Benzoatos/farmacología , Benzoatos/uso terapéutico , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Deferasirox , Deferoxamina/química , Deferoxamina/farmacología , Deferoxamina/uso terapéutico , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Portadores de Fármacos/uso terapéutico , Ferritinas/química , Humanos , Hierro/química , Quelantes del Hierro/síntesis química , Quelantes del Hierro/química , Quelantes del Hierro/farmacología , Metales/química , Metales/metabolismo , Estructura Molecular , Nanopartículas/química , Nanopartículas/uso terapéutico , Triazoles/química , Triazoles/farmacología , Triazoles/uso terapéutico
19.
Cell Metab ; 10(5): 343-54, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19883613

RESUMEN

PI3K signaling is thought to mediate leptin and insulin action in hypothalamic pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, through largely unknown mechanisms. We inactivated either p110alpha or p110beta PI3K catalytic subunits in these neurons and demonstrate a dominant role for the latter in energy homeostasis regulation. In POMC neurons, p110beta inactivation prevented insulin- and leptin-stimulated electrophysiological responses. POMCp110beta null mice exhibited central leptin resistance, increased adiposity, and diet-induced obesity. In contrast, the response to leptin was not blocked in p110alpha-deficient POMC neurons. Accordingly, POMCp110alpha null mice displayed minimal energy homeostasis abnormalities. Similarly, in AgRP neurons, p110beta had a more important role than p110alpha. AgRPp110alpha null mice displayed normal energy homeostasis regulation, whereas AgRPp110beta null mice were lean, with increased leptin sensitivity and resistance to diet-induced obesity. These results demonstrate distinct metabolic roles for the p110alpha and p110beta isoforms of PI3K in hypothalamic energy regulation.


Asunto(s)
Proteína Relacionada con Agouti/metabolismo , Metabolismo Energético/fisiología , Isoenzimas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proopiomelanocortina/metabolismo , Adiposidad/genética , Animales , Fosfatidilinositol 3-Quinasa Clase I , Dieta , Fenómenos Electrofisiológicos , Hipotálamo/metabolismo , Insulina/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Leptina/metabolismo , Ratones , Ratones Noqueados , Células Neuroendocrinas/enzimología , Obesidad/genética , Obesidad/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Transducción de Señal
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