Glucocorticoid Nanoparticles Show Full Therapeutic Efficacy in a Mouse Model of Acute Lung Injury and Concomitantly Reduce Adverse Effects

Glucocorticoids (GCs) are widely used to treat inflammatory disorders such as acute lung injury (ALI). Here, we explored inorganic–organic hybrid nanoparticles (IOH-NPs) as a new delivery vehicle for GCs in a mouse model of ALI. Betamethasone (BMZ) encapsulated into IOH-NPs (BNPs) ameliorated the massive infiltration of neutrophils into the airways with a similar efficacy as the free drug. This was accompanied by a potent inhibition of pulmonary gene expression and secretion of pro-inflammatory mediators, whereas the alveolar–capillary barrier integrity was only restored by BMZ in its traditional form. Experiments with genetically engineered mice identified myeloid cells and alveolar type II (AT II) cells as essential targets of BNPs in ALI therapy, confirming their high cell-type specificity. Consequently, adverse effects were reduced when using IOH-NPs for GC delivery. BNPs did not alter T and B cell numbers in the blood and also prevented the induction of muscle atrophy after three days of treatment. Collectively, our data suggest that IOH-NPs target GCs to myeloid and AT II cells, resulting in full therapeutic efficacy in the treatment of ALI while being associated with reduced adverse effects

Tratamientos psicológicos empíricamente apoyados para adultos: Una revisión selectiva

Antecedentes: los tratamientos psicológicos han mostrado su eficacia, efectividad y eficiencia para el abordaje de los trastornos mentales; no obstante, considerando el conocimiento científico generado en los últimos años, no se dispone de trabajos de actualización en español sobre cuáles son los tratamientos psicológicos con respaldo empírico. El objetivo fue realizar una revisión selectiva de los principales tratamientos psicológicos empíricamente apoyados para el abordaje de trastornos mentales en personas adultas. Método: se recogen niveles de evidencia y grados de recomendación en función de los criterios propuestos por el Sistema Nacional de Salud de España (en las Guías de Práctica Clínica) para diferentes trastornos psicológicos. Resultados: los resultados sugieren que los tratamientos psicológicos disponen de apoyo empírico para el abordaje de un amplio elenco de trastornos psicológicos. El grado de apoyo empírico oscila de bajo a alto en función del trastorno psicológico analizado. La revisión sugiere que ciertos campos de intervención necesitan una mayor investigación. Conclusiones: a partir de esta revisión selectiva, los profesionales de la psicología podrán disponer de información rigurosa y actualizada que les permita tomar decisiones informadas a la hora de implementar aquellos procedimientos psicoterapéuticos empíricamente fundamentados en función de las características de las personas que demandan ayuda. Background: Psychological treatments have shown their efficacy, effectiveness, and efficiency in dealing with mental disorders. However, considering the scientific knowledge generated in recent years, in the Spanish context, there are no updating studies about empirically supported psychological treatments. The main goal was to carry out a selective review of the main empirically supported psychological treatments for mental disorders in adults. Method: Levels of evidence and degrees of recommendation were collected based on the criteria proposed by the Spanish National Health System (Clinical Practice Guidelines) for different psychological disorders. Results: The results indicate that psychological treatments have empirical support for the approach to a wide range of psychological disorders. These levels of empirical evidence gathered range from low to high depending on the psychological disorder analysed. The review indicates the existence of certain fields of intervention that need further investigation. Conclusions: Based on this selective review, psychology professionals will be able to have rigorous, up-to-date information that allows them to make informed decisions when implementing empirically based psychotherapeutic procedures based on the characteristics of the people who require help

Arabidopsis thaliana Genes Associated with Cucumber mosaic virus Virulence and Their Link to Virus Seed Transmission

Virulence, the effect of pathogen infection on progeny production, is a major determinant of host and pathogen fitness as it affects host fecundity and pathogen transmission. In plant–virus interactions, ample evidence indicates that virulence is genetically controlled by both partners. However, the host genetic determinants are poorly understood. Through a genome-wide association study (GWAS) of 154 Arabidopsis thaliana genotypes infected by Cucumber mosaic virus (CMV), we identified eight host genes associated with virulence, most of them involved in response to biotic stresses and in cell wall biogenesis in plant reproductive structures. Given that virulence is a main determinant of the efficiency of plant virus seed transmission, we explored the link between this trait and the genetic regulation of virulence. Our results suggest that the same functions that control virulence are also important for CMV transmission through seeds. In sum, this work provides evidence of a novel role for some previously known plant defense genes and for the cell wall metabolism in plant virus interactions

Inducible Knock-Down of the Mineralocorticoid Receptor in Mice Disturbs Regulation of the Renin-Angiotensin-Aldosterone System and Attenuates Heart Failure Induced by Pressure Overload

Mineralocorticoid receptor (MR) inactivation in mice results in early postnatal lethality. Therefore we generated mice in which MR expression can be silenced during adulthood by administration of doxycycline (Dox). Using a lentiviral approach, we obtained two lines of transgenic mice harboring a construct that allows for regulatable MR inactivation by RNAi and concomitant expression of eGFP. MR mRNA levels in heart and kidney of inducible MR knock-down mice were unaltered in the absence of Dox, confirming the tightness of the system. In contrast, two weeks after Dox administration MR expression was significantly diminished in a variety of tissues. In the kidney, this resulted in lower mRNA levels of selected target genes, which was accompanied by strongly increased serum aldosterone and plasma renin levels as well as by elevated sodium excretion. In the healthy heart, gene expression and the amount of collagen were unchanged despite MR levels being significantly reduced. After transverse aortic constriction, however, cardiac hypertrophy and progressive heart failure were attenuated by MR silencing, fibrosis was unaffected and mRNA levels of a subset of genes reduced. Taken together, we believe that this mouse model is a useful tool to investigate the role of the MR in pathophysiological processes

Deletion of the Mineralocorticoid Receptor in Myeloid Cells Attenuates Central Nervous System Autoimmunity

Myeloid cells play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Monocytes, macrophages, and microglia can adopt two distinct phenotypes, with M1-polarized cells being more related to inflammation and autoimmunity while M2-polarized cells contribute to tissue repair and anti-inflammatory processes. Here, we show that deletion of the mineralocorticoid receptor (MR) in bone marrow-derived macrophages and peritoneal macrophages caused their polarization toward the M2 phenotype with its distinct gene expression, altered phagocytic and migratory properties, and dampened NO production. After induction of EAE, mice that are selectively devoid of the MR in their myeloid cells (MRlysM mice) showed diminished clinical symptoms and ameliorated histological hallmarks of neuroinflammation. T cells in peripheral lymphoid organs of these mice produced less pro-inflammatory cytokines while their proliferation and the abundance of regulatory T cells were unaltered. The numbers of inflammatory monocytes and reactive microglia in the central nervous system (CNS) in MRlysM mice were significantly lower and they adopted an M2-polarized phenotype based on their gene expression profile, presumably explaining the ameliorated neuroinflammation. Our results indicate that the MR in myeloid cells plays a critical role for CNS autoimmunity, providing a rational to interfere with diseases such as MS by pharmacologically targeting this receptor

Nueva ruta para la obtención de multiferroicos magnetoeléctricos monofásicos

Se describe una nueva estrategia para la síntesis de multiferroicos monofásicos mediante el diseño asistido por computadora. Hoy en día existe un gran interés científico en el logro de tales compuestos, debido a sus potenciales aplicaciones dentro de la nanotecnología. Se aborda el tema de la dificultad de obtención de materiales magnetoeléctricos monofásicos a temperatura ambiente. Se enumeran los requisitos para que un material cumpla con esta propiedad desde el punto de vista químico, estructural y eléctrico. Se presentan algunos ejemplos de cerámicos multiferroicos y sus rasgos principales. Se propone la búsqueda de magnetoeléctricos multiferroicos dentro de la familia de las cerámicas de Aurivillius. Se plantea una estrategia novedosa, basada en la modelación teórica, para el logro de compuestos con características superiores dentro de dicha familia. DOI: https://doi.org/10.54167/tecnociencia.v1i2.4

Physiological changes in inducible MR knock-down mice after TAC.

<p>(A) Control (con) and transgenic (tg) mice of line B received Dox via food pellets throughout the entire duration of the experiment. Two weeks after the beginning of Dox treatment TAC surgery was performed and another four weeks later the mice were sacrificed. MR mRNA levels in the heart were determined by RT-QPCR at the end of the experiment, renin plasma levels were analyzed by ELISA. The ventricular weight was measured for each animal and is depicted relative to the respective tibia lengths. The collagen staining area was determined after incubating paraffin sections from heart with picrosirius red followed by computer-aided quantification. (B) Analysis by echocardiography was performed one week before TAC (pre) as well as one (1w) and four weeks after TAC (4w). The diagrams show alterations of four parameters over time, namely the end-diastolic anterior wall thickness (AWThd), the left ventricular weight relative to the body weight (LVW/BW), the fractional area shortening (FAS) and the ejection fraction (EF). Values in all panels are depicted as mean ± SEM; N = 5/7. Statistical analysis was performed by unpaired two-tailed Student’s t test. n.s.: non-significant; *: p <0.05; **: p <0.01; ***: p <0.001.</p

Generation and characterization of inducible MR knock-down mice.

<p>(A) Operating principle of the lentiviral system used for inducible MR knock-down. The vector comprises one cassette consisting of the H1 promoter with tetracycline resistance operator sequences (tetO) and a MR-specific shRNA, and a second one encompassing the tet repressor (TetR) linked to eGFP by a T2A element under the control of the ubiquitin C promoter (Ub-p). In the absence of doxycycline (Dox), the TetR binds to tetO and blocks shRNA expression. After addition of Dox, the TetR is released thus enabling shRNA transcription. Under both conditions, eGFP is expressed constitutively. (B) Peripheral blood leukocytes of one control (con) and one transgenic (tg) mouse were analyzed for eGFP expression by flow cytometry. (C) Kidney, heart, colon, hippocampus, liver, lung, stomach and muscle samples obtained from control (con) and transgenic (tg) mice of line B and D were analyzed for eGFP mRNA expression by RT-QPCR. N = 3–7 (line B), N = 3–5 (line D). Gene expression was normalized to HPRT and is depicted in arbitrary units as mean ± SEM. (D) Kidney sections from one control (con) and one transgenic (tg) mouse of line B were analyzed by immunohistochemistry for eGFP expression. One representative example out of three is shown for each genotype. Size bar: 50 μm.</p