Human Glucocorticoid Receptor β Regulates Gluconeogenesis and Inflammation in Mouse Liver

Whilein vitrostudies have demonstrated that a glucocorticoid receptor (GR) splice isoform, β-isoform of human GR (hGRβ), acts as a dominant-negative inhibitor of the classic hGRα and confers glucocorticoid resistance, thein vivofunction of hGRβ is poorly understood. To this end, we created an adeno-associated virus (AAV) to express hGRβ in the mouse liver under the control of the hepatocyte-specific promoter. Genome-wide expression analysis of mouse livers showed that hGRβ significantly increased the expression of numerous genes, many of which are involved in endocrine system disorders and the inflammatory response. Physiologically, hGRβ antagonized GRα's function and attenuated hepatic gluconeogenesis through downregulation of phosphoenolpyruvate carboxykinase (PEPCK) in wild-type (WT) mouse liver. Interestingly, however, hGRβ did not repress PEPCK in GR liver knockout (GRLKO) mice. In contrast, hGRβ regulates the expression of STAT1 in the livers of both WT and GRLKO mice. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that hGRβ binds to the intergenic glucocorticoid response element (GRE) of the STAT1 gene. Furthermore, treatment with RU486 inhibited the upregulation of STAT1 mediated by hGRβ. Finally, our array data demonstrate that hGRβ regulates unique components of liver gene expressionin vivoby both GRα-dependent and GRα-independent mechanisms

Effect of sterilization on drugs and lenses for ophthalmic applications

Poster presented at the 10th World Biomaterials Congress. Montreal, Canada, 17-22 May 2016N/

Corticosteroids Are Essential for Maintaining Cardiovascular Function in Male Mice

Activation of the hypothalamic-pituitary-adrenal axis results in the release of hormones from the adrenal glands, including glucocorticoids and mineralocorticoids. The physiological association between corticosteroids and cardiac disease is becoming increasingly recognized; however, the mechanisms underlying this association are not well understood. To determine the biological effects of corticosteroids on the heart, we investigated the impact of adrenalectomy in C57BL/6 male mice. Animals were adrenalectomized (ADX) at 1 month of age and maintained for 3–6 months after surgery to evaluate the effects of long-term adrenalectomy on cardiac function. Morphological evaluation suggested that ADX mice showed significantly enlarged hearts compared with age-matched intact controls. These changes in morphology correlated with deficits in left ventricular (LV) function and electrocardiogram (ECG) abnormalities in ADX mice. Correlating with these functional defects, gene expression analysis of ADX hearts revealed aberrant expression of a large cohort of genes associated with cardiac hypertrophy and arrhythmia. Combined corticosterone and aldosterone replacement treatment prevented the emergence of cardiac abnormalities in ADX mice, whereas corticosterone replacement prevented the effects of adrenalectomy on LV function but did not block the emergence of ECG alterations. Aldosterone replacement did not preserve the LV function but prevented ECG abnormalities. Together, the data indicate that adrenal glucocorticoids and mineralocorticoids either directly or indirectly have selective effects in the heart and their signaling pathways are essential in maintaining normal cardiac function

The effects of addition of functional monomers and molecular imprinting on dual drug release from intraocular lens material

Although cataract surgery is considered a safe procedure, post-surgery complications such as endophthalmitis and ocular inflammation, may occur. To prevent this, antibiotics and anti-inflammatories are prescribed in the form of eye drops during the post-operatory period, but they lead to a low drug bioavailability in target tissues. The objective of this work is to develop an intraocular lens (IOL) material to deliver simultaneously one antibiotic, moxifloxacin (MXF), and one anti-inflammatory, diclofenac (DFN), in therapeutic concentrations to prevent both complications. The IOL material was modified through the incorporation of functional monomers, as well as molecular imprinting with both drugs using the same functional monomers, namely acrylic acid (AA), methacrylic acid (MAA), 4-vinylpiridine (4-VP) and a combination of MAA + 4-VP. The best results were obtained with MAA. Molecular imprinting did not influence the drug release, except with AA. Application of a mathematical model predicted that the released MXF and DFN concentrations would stay above the pre-determined MIC of S. aureus and S. epidermidis and the minimum values of IC50 of COX-1 and COX-2, for 9 and 14 days, respectively. Antibacterial tests showed that the released antibiotic remained active. The physical properties of the drug-loaded MAA-hydrogel remained adequate. The developed system proved to be non-irritant and non-cytotoxic.publishe

Ensiling Alfalfa (Medicago sativa L.) and Orchard Grass (Dactylis glomerata L.) Forage Harvested at 08:00 or 14:00, without Wilting or 1 or 2 h Wilting and with or without Use of Bacterial Inoculant

Alfalfa forage is difficult to ensile due to low water-soluble carbohydrate content and high buffering capacity. The objective was to assess at Chapingo, Mexico, during the rainy season effects of combinations of harvest hours (08:00, 14:00), wilting time (0, 1, 2 h) and bacterial inoculants on the quality of silage made of alfalfa and orchard grass forage, made in 200-L containers. The experiment was conducted in three phases with two replicates per phase. Variables measured in freshly cut forage and silages were dry matter content (DM), buffer capacity, pH, and alcohol soluble carbohydrates (ASC). Silos remained sealed during 60 d, and additional variables measured in silage were aerobic stability, NH3 -N and in vitro disappearance of DM. In forage harvested at 14:00 h, DM and ASC contents were higher; pH and buffering capacity were not affected by harvest hour; in silages made of that forage, NH3-N levels were lower, while ASC contents and in vitro disappearance of MS were unaffected by harvest hour. Treatments with inoculants were less aerobic stable for 5 days when made of forage harvested at 08:00 h but more stable when made of forage harvested at 14:00 h. Harvesting at 14:00 h was advantageous as silage presented higher DM and ASC contents

Dual drug delivery from hydrophobic and hydrophilic intraocular lenses: in-vitro and in-vivo studies

Posterior capsule opacification (PCO) still remains the most frequent long term complication after cataract surgery, while endophthalmitis is rare but severe and should be prevented at all cost. Intraocular lenses (IOLs) with different designs (eg. edge and body-haptics angle) and materials (acrylic hydrophobic and acrylic hydrophilic surfaces) have been studied to reduce PCO. For the prevention of endophthalmitis, intracameral injection followed or not by topical treatment with antibiotics and anti-inflammatories are usually prescribed. The objective of this work was to investigate the use of IOLs as controlled release platforms of two drugs, the antibiotic moxifloxacin (MXF) and the anti-inflammatory ketorolac (KTL) that could advantageously substitute the usual treatment. Two types of IOLs were chosen, hydrophobic and hydrophilic. Hydrophobic IOLs have shown better results in the prevention of PCO because they adhere better to the posterior capsular bag, while hydrophilic IOLs are advised in the case of patients with uveitis, glaucoma or diabetes. The IOLs were loaded with MXF + KTL and sterilized by high hydrostatic pressure. Both IOLs reduced the tendency for adhesion of LECs. In vivo tests were done to compare the concentration of the drugs in the aqueous humor obtained after eye drops administration and drug-loaded IOLs implantation. The developed IOLs were able to release MXF and KTL at therapeutic levels, in a sustained way, which contrasts with the eye drops prophylaxis. No PCO signs were detected and histological analyses demonstrated biocompatibility of these devices.publishe

Inhibiting HER3 Hyperphosphorylation in HER2‐Overexpressing Breast Cancer through Multimodal Therapy with Branched Gold Nanoshells

Treatment failure in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2) is associated mainly to the upregulation of human epidermal growth factor receptor 3 (HER3) oncoprotein linked to chemoresitence. Therefore, to increase patient survival, here a multimodal theranostic nanoplatform targeting both HER2 and HER3 is developed. This consists of doxorubicin-loaded branched gold nanoshells functionalized with the near-infrared (NIR) fluorescent dye indocyanine green, a small interfering RNA (siRNA) against HER3, and the HER2-specific antibody Transtuzumab, able to provide a combined therapeutic outcome (chemo- and photothermal activities, RNA silencing, and immune response). In vitro assays in HER2+/HER3+ SKBR-3 breast cancer cells have shown an effective silencing of HER3 by the released siRNA and an inhibition of HER2 oncoproteins provided by Trastuzumab, along with a decrease of the serine/threonine protein kinase Akt (p-AKT) typically associated with cell survival and proliferation, which helps to overcome doxorubicin chemoresistance. Conversely, adding the NIR light therapy, an increment in p-AKT concentration is observed, although HER2/HER3 inhibitions are maintained for 72 h. Finally, in vivo studies in a tumor-bearing mice model display a significant progressively decrease of the tumor volume after nanoparticle administration and subsequent NIR light irradiation, confirming the potential efficacy of the hybrid nanocarrierE.V.-A. and I.G.-C. contributed equally to this work. This work was sup ported by the Agencia Estatal de Investigación (AEI) through Project No. PID2019-109517RB-I00) and from the Xunta de Galicia, Project No. ED431C2022/18. European Regional Development Funds are also ac knowledged. A.A.-M. and P.T. also thank the International Scientific Part nership Program ISSP at King Saud University for additional funding of this research through Grant No. ISPP-144. This work also received fi nancial support from the ISCIII, Ministerio de Economía y Competitivi dad (Grant No. PI15/01129; J.A.C.), and the AEI (Grant No. PID2020- 113501RB-I00; J.A.C.). I.-G.C. thanks for financial support through Grant No. PRE/2011/131, and the Centro Singular de Investigación de Galicia accreditation Grant No. 2016–2019 ED431G/05)S

Quid: observatorio de medios

Informe organizado en cinco capítulos. En "El sistema de comunicación en Guadalajara" se incluyen trabajos sobre la transformación de algunos medios de comunicación, nuevos medios de comunicación en línea, periodismo religioso, la falta de institucionalidad en el Sistema Jalisciense de Radio y Televisión, y el sistema legal de radiodifusión y telecomunicaciones. En "Libertad de expresión en Jalisco", se presentan trabajos sobre la inseguridad laboral en los medios de comunicación, el desinformado cuarto de guerra del gobernador Aristóteles Sandoval, y sobre los periodistas escritores. En el apartado "Derecho a la información en Jalisco", se presenta un trabajo sobre la mucha administración y dosificada transparencia del Instituto de Trasparencia e Información Pública de Jalisco. El quinto apartado es una semblanza sobre “Rudy”, Rodolfo Rosales López, fotoperiodista tapatío. En el último apartado, “La investigación del observatorio de medios”, se presenta un trabajo sobre la cobertura en temas de medio ambiente y cambio climático en el periódico El Informador.ITESO, A.C

Glucocorticoid receptor alters isovolumetric contraction and restrains cardiac fibrosis

Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with that of littermate controls. Doppler measurements of blood flow across the mitral valve showed an elongated isovolumetric contraction time in surviving adult SMGRKO mice, indicating impairment of the initial left ventricular contractile phase. Although heart weight was elevated in both genders, only male SMGRKO mice showed evidence of pathological cardiomyocyte hypertrophy, associated with increased myosin heavy chain-β expression. Left ventricular fibrosis, evident in both genders, was associated with elevated levels of mRNA encoding MR as well as proteins involved in cardiac remodelling and fibrosis. However, MR antagonism with spironolactone from birth only modestly attenuated the increase in pro-fibrotic gene expression in SMGRKO mice, suggesting that elevated MR signalling is not the primary driver of cardiac fibrosis in SMGRKO mice, and cardiac fibrosis can be dissociated from MR activation. Thus, GR contributes to systolic function and restrains normal cardiac growth, the latter through gender-specific mechanisms. Our findings suggest the GR:MR balance is critical in corticosteroid signalling in specific cardiac cell types

Q ITESO: Análisis Crítico de Medios

En esta séptima entrega de Q ITESO: Análisis Crítico de Medios se examina un 2014 colmado de acontecimientos sobre la reconfiguración de los medios de Jalisco y del país, y sus relaciones con el estado, los empresarios y el público. Destaca la aprobación de la Ley Federal de Telecomunicaciones y Radiocomunicación y los nuevos equilibrios de poder que esto supone. También, se analizan las alianzas de algunos diarios nacionales y del estado con medios extranjeros, para compensar algunas carencias y ampliar su oferta editorial e informativa. Otras cuestiones no menos relevantes tienen que ver con la libertad de expresión y la inseguridad laboral en la que viven muchos trabajadores de los medios de comunicación jaliscienses, sobre todo los impresos, y el caso emblemático del llamado “cuarto de guerra” al servicio del gobernador del estado, Aristóteles Sandoval, para espiar -y en ocasiones hasta coaccionar- a directivos y reporteros de medios para atenuar la crítica al gobierno. El derecho a la información, la transparencia, la situación de los nuevos medios en línea, los periodistas que publican libros, el cambio climático y los periodistas que ya no están con nosotros merecen también una mirada atenta en este informe.ITESO, A.C