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1.
J Avian Med Surg ; 32(4): 314-321, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31112645

RESUMEN

Unusual ocular abnormalities were documented in 3 wild eastern screech owls (Megascops asio) presented to a wildlife rehabilitation hospital after vehicular strike-induced trauma to the head. All 3 had anterior uveitis and free air bubbles in the anterior chamber, but none of the cases had any discernable corneal damage, either grossly or with fluorescein stain technique. Perforation of the globe at the level of the scleral ossicle was considered a possible cause. All 3 cases recovered with standard treatment for anterior uveitis, and the free air was absorbed within 10-14 days and did not appear to cause any lingering complications. The owls were later released back into the wild after demonstrating the ability to navigate obstacles in a flight cage and capture live prey.


Asunto(s)
Cámara Anterior/patología , Enfermedades de las Aves/etiología , Traumatismos Craneocerebrales/veterinaria , Estrigiformes , Uveítis/veterinaria , Accidentes de Tránsito , Animales , Enfermedades de las Aves/patología , Traumatismos Craneocerebrales/complicaciones , Traumatismos Craneocerebrales/patología , Presión Intraocular , Estrigiformes/lesiones , Uveítis/etiología , Uveítis/terapia
2.
J Biol Chem ; 291(9): 4356-73, 2016 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-26679998

RESUMEN

The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.


Asunto(s)
Corteza Cerebral/efectos de los fármacos , Ciclofilinas/antagonistas & inhibidores , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Esclerosis Múltiple/prevención & control , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Compuestos de Quinolinio/uso terapéutico , Sustitución de Aminoácidos , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/inmunología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Peptidil-Prolil Isomerasa F , Ciclofilinas/genética , Ciclofilinas/metabolismo , Ciclosporinas/efectos adversos , Ciclosporinas/síntesis química , Ciclosporinas/farmacología , Ciclosporinas/uso terapéutico , Células Hep G2 , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos , Ratones Noqueados , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Mutación , Neuronas/inmunología , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacología , Péptidos Cíclicos/efectos adversos , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/uso terapéutico , Compuestos de Quinolinio/efectos adversos , Compuestos de Quinolinio/síntesis química , Compuestos de Quinolinio/farmacología , Distribución Aleatoria , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/patología
3.
Nat Commun ; 8(1): 1804, 2017 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-29180704

RESUMEN

Vps34 PI3K is thought to be the main producer of phosphatidylinositol-3-monophosphate, a lipid that controls intracellular vesicular trafficking. The organismal impact of systemic inhibition of Vps34 kinase activity is not completely understood. Here we show that heterozygous Vps34 kinase-dead mice are healthy and display a robustly enhanced insulin sensitivity and glucose tolerance, phenotypes mimicked by a selective Vps34 inhibitor in wild-type mice. The underlying mechanism of insulin sensitization is multifactorial and not through the canonical insulin/Akt pathway. Vps34 inhibition alters cellular energy metabolism, activating the AMPK pathway in liver and muscle. In liver, Vps34 inactivation mildly dampens autophagy, limiting substrate availability for mitochondrial respiration and reducing gluconeogenesis. In muscle, Vps34 inactivation triggers a metabolic switch from oxidative phosphorylation towards glycolysis and enhanced glucose uptake. Our study identifies Vps34 as a new drug target for insulin resistance in Type-2 diabetes, in which the unmet therapeutic need remains substantial.


Asunto(s)
Resistencia a la Insulina , Mitocondrias/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/fisiología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Autofagia/fisiología , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasas Clase III , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Técnicas de Sustitución del Gen , Glucosa/análisis , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Glucólisis/fisiología , Hepatocitos , Heterocigoto , Humanos , Insulina/metabolismo , Hígado/citología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Animales , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Mioblastos , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Cultivo Primario de Células
4.
Methods Enzymol ; 543: 47-72, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24924127

RESUMEN

Intracellular Ca(2+) signaling is involved in a series of physiological and pathological processes. In particular, an intimate crosstalk between bioenergetic metabolism and Ca(2+) homeostasis has been shown to determine cell fate in resting conditions as well as in response to stress. The endoplasmic reticulum and mitochondria represent key hubs of cellular metabolism and Ca(2+) signaling. However, it has been challenging to specifically detect highly localized Ca(2+) fluxes such as those bridging these two organelles. To circumvent this issue, various recombinant Ca(2+) indicators that can be targeted to specific subcellular compartments have been developed over the past two decades. While the use of these probes for measuring agonist-induced Ca(2+) signals in various organelles has been extensively described, the assessment of basal Ca(2+) concentrations within specific organelles is often disregarded, in spite of the fact that this parameter is vital for several metabolic functions, including the enzymatic activity of mitochondrial dehydrogenases of the Krebs cycle and protein folding in the endoplasmic reticulum. Here, we provide an overview on genetically engineered, organelle-targeted fluorescent Ca(2+) probes and outline their evolution. Moreover, we describe recently developed protocols to quantify baseline Ca(2+) concentrations in specific subcellular compartments. Among several applications, this method is suitable for assessing how changes in basal Ca(2+) levels affect the metabolic profile of cancer cells.


Asunto(s)
Calcio/metabolismo , Colorantes Fluorescentes/metabolismo , Fracciones Subcelulares/metabolismo , Compartimento Celular , Ingeniería Genética , Sondas Moleculares
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