Asunto(s)
Albinismo/tratamiento farmacológico , Enfermedades Autoinmunes/tratamiento farmacológico , Trastornos Hemorrágicos/tratamiento farmacológico , Síndrome de Hermanski-Pudlak/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Rituximab/uso terapéutico , Trombastenia/tratamiento farmacológico , Adulto , Anciano , Albinismo/sangre , Enfermedades Autoinmunes/sangre , Femenino , Trastornos Hemorrágicos/sangre , Síndrome de Hermanski-Pudlak/sangre , Humanos , Masculino , Recuento de Plaquetas , Trombastenia/sangreRESUMEN
BACKGROUND: α-Eleostearic acid and punicic acid, two typical conjugated linolenic acid (CLnA) isomers present in bitter gourd and snake gourd oil respectively, exhibit contrasting cis-trans configuration which made them biologically important. METHODS: Rats were divided into six groups. Group 1 was control and group 2 was treated control. Rats in the groups 3 and 4 were treated with mixture of α-eleostearic acid and punicic acid (1:1) (0.5% and 1.0% respectively) while rats in the groups 5 and 6 were treated with 0.5% of α-eleostearic acid and 0.5% of punicic acid respectively along with sodium arsenite by oral gavage once per day. RESULTS: Results showed that increase in nitric oxide synthase (NOS) activity, inflammatory markers expression, platelet aggregation, lipid peroxidation, protein oxidation, DNA damage and altered expression of liver X receptor-α (LXR-α) after arsenite treatment were restored with the supplementation of oils containing CLnA isomers. Altered activities of different antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and ferric reducing ability of plasma (FRAP) also restored after oil supplementation. Altered morphology and fluidity of erythrocyte membrane studied by atomic force and scanning electron microscopy, after stress induction were significantly improved due to amelioration in cholesterol/phospholipid ratio and fatty acid profile of membrane. Oils treatment also improved morphology of liver and fatty acid composition of hepatic lipid. CONCLUSIONS: Overall two isomers showed synergistic antioxidant and anti-inflammatory effect against induced perturbations and membrane disintegrity. GENERAL SIGNIFICANCE: Synergistic antioxidant and anti-inflammatory role of these CLnA isomers were established by this study.
Asunto(s)
Membrana Eritrocítica/efectos de los fármacos , Inflamación/tratamiento farmacológico , Fluidez de la Membrana/efectos de los fármacos , Modelos Animales , Estrés Oxidativo/efectos de los fármacos , Aceites de Plantas/farmacología , Ácido alfa-Linolénico/farmacología , Albinismo/tratamiento farmacológico , Albinismo/metabolismo , Animales , Antioxidantes/farmacología , Western Blotting , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Catalasa/metabolismo , Células Cultivadas , Daño del ADN/efectos de los fármacos , Sinergismo Farmacológico , Ensayo de Inmunoadsorción Enzimática , Glutatión Peroxidasa/metabolismo , Inflamación/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Lípidos/análisis , Hígado/efectos de los fármacos , Hígado/metabolismo , Receptores X del Hígado , Masculino , FN-kappa B/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Oxidación-Reducción , Aceites de Plantas/química , Agregación Plaquetaria/efectos de los fármacos , Ratas , Superóxido Dismutasa/metabolismo , Ácido alfa-Linolénico/químicaRESUMEN
Throughout our lifetime the F1Fo ATP synthase produces the majority of our biological energy, and plays central roles in the structure and organization of mitochondria, yet our understanding of its roles in human disease remain largely enigmatic. It seems logical that even intermittent impairment of this highly important enzyme could deprive the body's tissues of energy at crucial times, which may predispose or contribute to illness. Indeed, evidence is accumulating that there are dire consequences of energy depletion in acute lifethreatening conditions, such as heart attacks, as well as chronic diseases, including aging, cancer, diabetes and heart failure. Recent advances in our understanding of the expanding roles of F1Fo ATP synthase, and how it is regulated, combined with the development of novel strategies for manipulating its function, may provide renewed hope for therapeutic improvement of energy homeostasis, and mitochondrial integrity, in a host of human diseases. In this review we will highlight what is known about the molecular regulation of this amazing enzyme complex, discuss effects of physiological agonists and therapeutic drugs on its functions, and present evidence supporting its involvement in the ills of mankind. Finally, we will outline existing challenges, and promising new avenues for targeting the enzyme therapeutically.
Asunto(s)
Mitocondrias/enzimología , ATPasas de Translocación de Protón Mitocondriales/fisiología , Adenosina Trifosfato/biosíntesis , Corticoesteroides/farmacología , Envejecimiento/fisiología , Albinismo/tratamiento farmacológico , Alcoholismo/fisiopatología , Animales , Enfermedades Autoinmunes/fisiopatología , Infecciones Bacterianas/fisiopatología , Restricción Calórica , Enfermedades Cardiovasculares/fisiopatología , Diabetes Mellitus/fisiopatología , Humanos , Potencial de la Membrana Mitocondrial/fisiología , Translocasas Mitocondriales de ADP y ATP/fisiología , ATPasas de Translocación de Protón Mitocondriales/química , ATPasas de Translocación de Protón Mitocondriales/efectos de los fármacos , Modelos Moleculares , Neoplasias/fisiopatología , Fosforilación Oxidativa , Subunidades de Proteína/químicaRESUMEN
BACKGROUND: During development the switch from a depolarizing to a hyperpolarizing action of GABA is a consequence of a decrease of the Na+-K+-2Cl- co-transporter (NKCC1, Cl--uptake) and increase of the K+-Cl- co-transporter (KCC2, Cl--extrusion) expression. However albino visual cortex neurons don't show a corresponding decrease in intracellular chloride concentration during development of the visual system as compared to pigmented animals. RESULTS: Our study revealed that more cells express NKCC1 in albinos compared to pigmented rat visual cortex neurons whereas KCC2 is expressed in all cells in both strains. We determined a positive relationship between the presence of NKCC1 and an inhibitory deficit in single neurons of the albino visual cortex. After pharmacological blockade of NKCC1 function with its specific inhibitor, bumetanide, the reversal potential of electrically evoked GABAA receptor-mediated postsynaptic currents and, as a consequence, [Cl-]i in albino visual cortex neurons shifted to the pigmented rat brain value. In conclusion, our pharmacological experiments and subsequent single cell real time PCR analysis of the co-transporter mRNA demonstrated that the inhibitory deficit present in the albino visual cortical network is almost exclusively mediated by NKCC1. CONCLUSION: Our findings suggest that blocking of NKCC1 in albino visual cortex neurons could improve processing in visual cortex and therefore might be beneficial for vision in albinos.
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Cloruros/metabolismo , Células Piramidales/fisiología , Simportadores de Cloruro de Sodio-Potasio/fisiología , Corteza Visual/citología , Albinismo/tratamiento farmacológico , Albinismo/genética , Albinismo/fisiopatología , Animales , Bumetanida/farmacología , Cloruros/análisis , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Long-Evans , Ratas Wistar , Receptores de GABA-A/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Simportadores de Cloruro de Sodio-Potasio/genética , Especificidad de la Especie , Corteza Visual/fisiología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Certain drugs and chemicals, such as chloroquine, chlorpromazine, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), are bound to melanin and retained in pigment cells for long periods. This specific retention in pigmented tissues can cause adverse effects in the skin, eye, inner ear, and pigmented nerve cells of the substantia nigra of the brain. To date, all studies have been focused on eu- and neuromelanin. In the present study, we show that chloroquine, chlorpromazine, chlomipramine, paraquat, acridine orange, and nickel, which are bound to eumelanin, also bind to synthetic pheomelanin, but the binding to pheomelanin is lower. The binding varied with the cysteine content and pH, and the results indicate that the binding is complex and includes ionic interactions. In addition, we have shown that these substances also bind to synthetic thiourea-containing melanin, but to quite a low extent. We also present a microautoradiographic study on the binding of 14C-chloroquine to natural pheomelanin in vivo in yellow mice C57BL (Ay/a). Black (C57/BL) and albino (NMRI) mice were used as controls. The autoradiography demonstrated a pronounced uptake of chloroquine in the hair follicles and the dermal melanocytes in the ear of yellow mice, which was comparable to the corresponding accumulation of label in black mice. In the albino mouse, the uptake was lower and more homogeneously distributed in the skin. These results suggest that the toxicological risks of melanin-related adverse effects are applicable to persons with a high content of pheomelanin in the skin and hair.
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Cloroquina/metabolismo , Melaninas/metabolismo , Piel/efectos de los fármacos , Albinismo/tratamiento farmacológico , Albinismo/metabolismo , Animales , Autorradiografía , Sitios de Unión , Radioisótopos de Carbono , Cloroquina/farmacocinética , Clorpromazina/metabolismo , Clomipramina/metabolismo , Cisteína/química , Color del Cabello , Melaninas/síntesis química , Melaninas/química , Ratones , Ratones Endogámicos C57BL , Piel/metabolismo , Tiourea/química , Tiourea/metabolismoAsunto(s)
Albinismo/tratamiento farmacológico , Clobetasol/análogos & derivados , Epidermólisis Ampollosa Distrófica/tratamiento farmacológico , Fluocinonida/uso terapéutico , Enfermedades Cutáneas Papuloescamosas/tratamiento farmacológico , Triamcinolona/uso terapéutico , Administración Cutánea , Adulto , Albinismo/complicaciones , Clobetasol/uso terapéutico , Epidermólisis Ampollosa Distrófica/complicaciones , Humanos , Masculino , Pomadas , Enfermedades Cutáneas Papuloescamosas/complicaciones , Resultado del TratamientoRESUMEN
The effect of the synthetic vasopressin derivative 1-desamino-8D-arginine vasopressin (DDAVP = desmopressin) on bleeding time was studied in three patients with Hermansky Pudlak syndrome. A good response was observed in this type of storage pool disease. DDAVP might be useful in managing the bleeding disorder found in patients with the Hermansky-Pudlak syndrome.