The Future of Bronchodilators in COPD and Asthma / El futuro de los broncodilatadores en la EPOC y el asma

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Dexmedetomidine reduces dextran sulfate sodium (DSS)-induced NCM460 cell inflammation and barrier damage by inhibiting RhoA/ROCK signaling pathway

Objective This study investigated the role of dexmedetomidine (DEX) in dextran sulfate sodium (DSS)-induced NCM460 cells.Material and Methods The viability and apoptosis of NCM460 cells treated with DEX with or without DSS were detected by CCK-8 and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay. The level of inflammatory factors and expression of inflammation-related proteins, tight junction proteins and Ras homolog gene family, member A/Rho-associated coiled-coil containing protein kinase (RhoA/ROCK) signaling-related proteins in NCM460 cells treated with DEX and/or U46619 (RhoA/ROCK agonist) and/or DSS were detected by the respective enzyme-linked immunosorbent assay (ELISA) kits and Western blot analysis. The permeability of NCM460 monolayers was examined with transepithelial electrical resistance (TEER) assay.Results DEX had no effect on NCM460 cell viability. However, DEX improved the viability and barrier damage and suppressed the apoptosis and inflammation of DSS-induced NCM460 cells. Correspondingly, the expression of inflammation-related proteins was reduced and the expression of tight junction proteins was increased in DSS-induced NCM460 cells after treatment with DEX. In addition, RhoA/ROCK signaling was activated in NCM460 cells induced by DSS, which was suppressed by DEX. The protective effects of DEX on DSS-indued NCM460 cells were reversed by U46619 (AU)

Perspectivas futuras en el tratamiento médico del glaucoma / Future perspectives in glaucoma medical therapy

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28-Day hindlimb unweighting reduces expression of Rho kinase and inhibits its effects in femoral artery of rat

Previous studies have demonstrated inconsistent roles of Rho kinase (ROCK) in the decreased vasoconstriction of rat hindquarter vessels induced by hindlimb unweighting (HU). The present study was designed to determine the unclear role of ROCK in the mediation of HU-induced decreased femoral arterial vasoconstriction. 28-day HU rat was adopted as the animal model. With or without Y-27632, a ROCK inhibitor, isometric force of femoral artery was measured. The expression of ROCK and its effects on downstream targets were also examined. Results showed that (1) HU caused a significant decrease of the phenylephrine (PE)-evoked and potassium chloride (KCl)-evoked femoral arterial vasoconstriction (P < 0.05), confirming the functional findings by previous studies. (2) Inhibition of ROCK with Y-27632 produced an equal reduction of the vasoconstriction in CON and HU. (3) HU significantly decreased ROCK II expression and the effects of ROCK on myosin light-chain phosphatase (MLCP) and MLC (P < 0.05), but increased p65 nuclear translocation (P < 0.05) and inducible nitric oxide synthase (iNOS) expression (P < 0.05). (4) HU significantly (P < 0.05) increased NO production in femoral arteries, with Y-27632 significantly (P < 0.01) amplifying this effect. These findings have revealed that 28-day HU reduced the expression and effects of ROCK on downstream targets both directly (MLCP and MLC) and possibly indirectly (NF-κB/iNOS/NO pathway) related to vasoconstriction in femoral arteries

Novedades en el tratamiento médico del glaucoma / What´s new in the medical treatment of glaucoma

El tratamiento médico del glaucoma no puede verse sólo desde el punto de vista de las moléculas que se utilizan. Un problema que debemos resolver es lo del cumplimiento. También la toxicidad de preservantes llevó al desarrollo de formulacionescon preservantes menos agresivos o sinpreservantes, como el sistema ABAK. La mala biodisponibilidad de los fármacos de utilización tópica ocular justifica el uso de pequeños implantes sub-conjuntivales que podrán ser bien aceptados por los pacientes. En los últimos años no se han introducido nuevos principios activos para el tratamiento del glaucoma, pero hay muchos en investigación. Como hipotensores oculares hay un ARN de interferencia, que se comporta como bloqueador adrenérgico β2, y varios agonistas de los receptores de prostaglandinas, como el AR-102 o moléculas con propiedades donadoras de NO y un esqueleto de latanoprost. El aumentode flujo a través de la malla trabecular tiene un interés particular, por suactuación sobre la vía más importante. Se incluyenaquí los inhibidores de la Rho-kinasa, como el AR-12286 y fármacos que alteran la polimerización de microfilamentos de actina, como citocalasinas y latrunculinas. Otro grupo interfiere con la circulación ocular. Los antagonistas del calcio en el tratamiento del glaucoma siguen siendo controvertidos, y el uso de los antagonistas de endotelina es aún preliminar. En cuanto a los neuroprotectores, a pesar de su potencial y de resultados favorables en los animales, su utilidad humana no está demostrada. Lo mismo ocurre con los fármacos y técnicas que pretenden una acción genética o celular (AU)

The medical treatment of glaucoma cannot be seen only from the point of view of the molecules used. A problem that must solved is the patient compliance. The toxicity of the preservatives has led to new formulations, with less aggressive preservatives or withoutthem, such as the ABAK system. The poor bioavailability of topical ocular drugs justifies the use of small subconjunctival implants which may be well accepted by patients. In recent years no new molecules have been introduced for the treatment of glaucoma, although many are in development. Among the hypotensive agentsthere isan interferenceRNA, which behaves like β2 adrenergic receptor blocker, and several agonists of prostaglandins receptors, such as AR-102 or molecules comprising a nitric oxide donor associated to a latanoprost skeleton. Drugs that increase the flow through the trabecular meshwork have a particular interest, as this is the most important pathway. These include among others the Rho-kinase inhibitors, such as AR-12286, and drugs that alter the polymerization of actin microfilaments, as cytochalasins and latrunculins. A second group includes drugs that interfere with the ocular circulation. The use of calcium channel blockers in the treatment of glaucoma remains controversial, and the use of antagonists of endothelin is still preliminary. As for neuroprotective drugs, despite the various possible ways of intervention and the favorable results in animals, their usefulness in human beings is not yet proven. The same could be said in relation to drugs and techniques aimed at a cellular or genetic intervention (AU)

Nuevos desarrollos en el tratamiento médico del glaucoma / New developments in glaucoma medical treatment

El tratamiento médico del glaucoma ha presentadouna gran evolución en los últimos años. Las investigacionesque se están desarrollando en este campose basan en el perfeccionamiento de productos activospreexistentes y en el descubrimiento de nuevosprincipios activos. En productos activos comercializadosse busca obtener una mejor tolerancia local,utilizando conservantes menos tóxicos, como es elcaso del preservante sofZia que se ha asociado altravoprost, y la eliminación del uso de conservantes,como sucede con el tafluprost. También el desarrollode nuevas combinaciones fijas de fármacoscomercializados podría facilitar su administración yel cumplimiento terapéutico.Por otro lado, se están investigando nuevas moléculasque puedan ser de utilidad en el tratamientomédico del glaucoma. Entre estos podemos destacarlas investigaciones sobre antagonistas del calciocomo la lomerizina, que parece no producir hipotensiónsistémica, y productos que se están investigandopara uso tópico ocular como la flunarizina yla iganidipina. También se están investigando inhibidoresde la endotelina 1, como el sulfisoxazol y labunazosina. Dentro del sistema renina-angiotensinase están evaluando la Angiotensina (1-7) y el olmesartan.La investigación de drogas trabeculares,como los inhibidores de la Rho-kinasa, podríanactuar sobre el mecanismo patogénico del glaucoma primario de ángulo abierto. Finalmente, se estáevaluando la mifepristona tópica, antagonista dereceptores glucocorticoides, en la elevación de lapresión ocular secundaria al uso de esteroides(AU)

The medical treatment of glaucoma has undergonesignificant development in recent years. Researchin this field is focused on improving pre-existingdrugs and on the development of new molecules. Inrelation to commercial drugs, there is a trend toimprove local tolerance, using less toxic preservativesas in the case of sofZIA in travoprost, and eliminatingthe preservatives as in tafluprost. Thedevelopment of new, fixed combinations of commercialdrugs could also enhance their administrationand therapeutic compliance.There is also intense research activity in the searchfor new therapeutic groups for glaucoma treatment.Calcium channel-blockers such as lomerizine donot seem to affect systemic hypotension, while topicalcalcium-blockers like flunarizine and iganidipineare also under research. Endothelin 1 antagonistssuch as sulfisoxazole and bunazosine could be alsouseful in the treatment of glaucoma. In the reninangiotensin system, angiotensin (1-7) and olmesartanare under investigation for use in glaucomapatients. Trabecular drugs such as Rho-kinase inhibitorscould be effective on the pathogenic mechanismof primary open angle glaucoma.Finally, topical mifepristone, an antagonist of glucocorticoidreceptors, is under evaluation for corticosteroid-induced elevated intraocular pressure(AU)

Identification of the Rock-dependent transcriptome in rodent fibroblasts

Rock proteins are Rho GTPase-dependent serine/ threonine kinases with crucial roles in F-actin dynamics and cell transformation. By analogy with other protein kinase families, it can be assumed that Rock proteins act, at least in part, through the regulation of gene expression events. However, with the exception of some singular transcriptional targets recently identified, the actual impact of these kinases on the overall cell transcriptome remains unknown. To address this issue, we have used a microarray approach to compare the transcriptomes of exponentially growing NIH3T3 cells that had been untreated or treated with Y27632, a well known specific inhibitor for Rock kinase activity. We show here that the Rock pathway promotes a weak impact on the fibroblast transcriptome, since its inhibition only results in changes in the expression of 2.3% of all the genes surveyed in the microarrays. Most Y27632-dependent genes are downregulated at moderate levels, indicating that the Rock pathway predominantly induces the upregulation of transcriptionally active genes. Although functionally diverse, a common functional leitmotiv of Y27632-dependent genes is the implication of their protein products in cytoskeletal-dependent processes. Taken together, these results indicate that Rock proteins can modify cytoskeletal dynamics by acting at post-transcriptional and transcriptional levels. In addition, they suggest that the main target of these serine/threonine kinases is the phosphoproteome and not the transcriptome (AU)

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