PPARs in the Renal Regulation of Systemic Blood Pressure

Recent research has revealed roles for the peroxisome proliferator activated receptor (PPAR) family of transcription factors in blood pressure regulation, expanding the possible therapeutic use of PPAR ligands. PPARα and PPARγ modulate the renin-angiotensin-aldosterone system (RAAS), a major regulator of systemic blood pressure and interstitial fluid volume by transcriptional control of renin, angiotensinogen, angiotensin converting enzyme (ACE) and angiotensin II receptor 1 (AT-R1). Blockade of RAAS is an important therapeutic target in hypertension management and attenuates microvascular damage, glomerular inflammation and left ventricular hypertrophy in hypertensive patients and also show antidiabetic effects. The mechanisms underlying the benefits of RAAS inhibition appear to involve PPARγ-regulated pathways. This review summarizes current knowledge on the role of PPARs in the transcriptional control of the RAAS and the possible use of PPAR ligands in the treatment of RAAS dependent hypertension

Modulación por el factor inhibidor hipotalámico-hipofisario de la actividad (Ca2+, Mg2+)ATPasa y del transporte de Ca2+ en sinaptosomas y retículo sarcoplásmico

En este trabajo se han preparado diversos 1,3-bis(trimetilsililoxi)-1,3-dienos endo-exocíclicos de manera eficiente a partir de compuestos carbonílicos cíclicos alfa-acetilados por tratamiento secuencial con LDA y TMSC1, dos veces. Estos compuestos participan en reacciones de Diels-Alder y hetero-Diels-Alder, de manera eficiente y regioselectiva bajo condiciones de reacción suaves, con p-benzoquinona, acetilenodicarboxilato de dimetilo, metil vinil cetona, benzaldehído y N-bencilidenanilina, proporcionando una interesante variedad de compuestos policíclicos de posible interés en síntesis orgánica. Mediante la reacción de Diels-Alder entre varios 1,3-bis(trimetilsililoxi)-1,3-dienos endo-exocíclicos, preparados a partir de cetonas tetrahidroaromáticas, y los dienófilos bencino y p-benzoquinona, se han preparado benzo[c]fenantrenos ([4]helicenos) y [5]helicenos funcionalizados). Se ha demostrado que los 1,3-bis(trimetilsililoxi)-1,3-dienos endo-exocíclicos son intermedios de utilidad para la síntesis del esqueleto del producto natural neomarinona. La reacción de Diels-Alder entre un 1,3-bis(trimetilsililoxi)-1,3-dieno endo-exocíclico convenientemente funcionalizado y una bromoquinona ha permitido la síntesis del esqueleto naftofuránico de neomarinona. Asimismo, se han sintetizado intermedios útiles para la síntesis de la cadena lateral de neomarinon

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease.

The heart is the first organ to acquire its physiological function during development, enabling it to supply the organism with oxygen and nutrients. Given this early commitment, cardiomyocytes were traditionally considered transcriptionally stable cells fully committed to contractile function. However, growing evidence suggests that the maintenance of cardiac function in health and disease depends on transcriptional and epigenetic regulation. Several studies have revealed that the complex transcriptional alterations underlying cardiovascular disease (CVD) manifestations such as myocardial infarction and hypertrophy is mediated by cardiac retinoid X receptors (RXR) and their partners. RXRs are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors and drive essential biological processes such as ion handling, mitochondrial biogenesis, and glucose and lipid metabolism. RXRs are thus attractive molecular targets for the development of effective pharmacological strategies for CVD treatment and prevention. In this review, we summarize current knowledge of RXR partnership biology in cardiac homeostasis and disease, providing an up-to-date view of the molecular mechanisms and cellular pathways that sustain cardiomyocyte physiology.This research was funded by the Ministerio de Ciencia, Innovacion y Universidades (MCNU) (SAF2017-90604-REDT-NurCaMeIn, RTI2018-095928-BI00) and the Comunidad de Madrid (MOIR-B2017/BMD-3684) to MR; the MCNU fellowship (BES-2016-076632) to AP; CNIC Master fellowship to RS-C. The CNIC is supported by the MCNU and the Pro CNIC Foundation.S

Utilidad de Streptotest en la farmacia comunitaria para la discriminación rápida de faringitis bacteriana y vírica en pacientes adultos

INTRODUCCIÓN La faringoamigdalitis es la patología infecciosa más frecuente en consultas médicas, tanto en población infantil como adulta. Los signos y síntomas de la faringitis viral o bacteriana son inespecíficos, dificultando su diagnóstico.OBJETIVO Determinar la utilidad en la farmacia comunitaria del Streptotest para la discriminación rápida de los dos tipos de faringitis en pacientes adultos.MATERIAL Y MÉTODOS Diseño observacional no postautorización (No-EPA), prospectivo, multicéntrico y de ámbito nacional en 133 farmacias comunitarias. Criterios de selección: pacientes con edad igual o superior a 18 años, que acuden a la farmacia solicitando un remedio para un proceso de afectación faringoamigdalar agudo, que no hayan tomado antibiótico en los ultimos tres días y que hayan otorgado su consentimiento informado por escrito.RESULTADOS Se registraron un total de 1.039 casos válidos. El 33% de los pacientes solicitó un antibiótico en la farmacia para el tratamiento de la afectación faringoamigdalar. Un 54% presentó síntomas inespecíficos tanto de infección bacteriana o vírica. El resultado del test fue positivo en un 12% de los pacientes. El 93% de los pacientes con Streptotest positivo fue derivado al médico. El 97% de los pacientes con resultado positivo recibió tratamiento antibiótico, cumpliéndolo correctamente el 94%. El 96% de los pacientes tuvo una evolución positiva. El Streptotest puede ser una herramienta de gran ayuda para el farmacéutico comunitario que, en colaboración con el médico de atención primaria, puede contribuir a una reducción significativa del consumo inadecuado de antibióticos en el tratamiento de las faringoamigdalitis de origen vírico

Brain Cleanup as a Potential Target for Poststroke Recovery: The Role of RXR (Retinoic X Receptor) in Phagocytes

Background and Purpose- Phagocytic cells, such as microglia and blood-derived macrophages, are a key biological modality responsible for phagocytosis-mediated clearance of damaged, dead, or displaced cells that are compromised during senescence or pathological processes, including after stroke. This process of clearance is essential to eliminate the source of inflammation and to allow for optimal brain repair and functional recovery. Transcription factor, RXR (retinoic-X-receptor) is strongly implicated in phagocytic functions regulation, and as such could represent a novel target for brain recovery after stroke. Methods- Primary cultured microglia and bone marrow macrophages were used for phagocytic study. Mice with deleted RXR-α in myeloid phagocytes (Mac-RXR-α-/-) were subjected to transient middle cerebral artery occlusion to mimic ischemic stroke and then treated with RXR agonist bexarotene. RNA-sequencing and long-term recovery were evaluated. Results- Using cultured microglia, we demonstrated that the RXR-α promotes the phagocytic functions of microglia toward apoptotic neurons. Using mice with deleted RXR-α in myeloid phagocytes (Mac-RXR-α-/-), we have shown that despite behaving similarly to the control at early time points (up to 3 days, damage established histologically and behaviorally), these Mac-RXR-α-/- mice demonstrated worsened late functional recovery and developed brain atrophy that was larger in size than that seen in control mice. The RXR-α deficiency was associated with reduced expression of genes known to be under control of the prominent transcriptional RXR partner, PPAR (peroxisome proliferator-activated receptor)-γ, as well as genes encoding for scavenger receptors and genes that signify microglia/macrophages polarization to a reparative phenotype. Finally, we demonstrated that the RXR agonist, bexarotene, administered as late as 1 day after middle cerebral artery occlusion, improved neurological recovery, and reduced the atrophy volume as assessed 28 days after stroke. Bexarotene did not improve outcome in Mac-RXR-α-/- mice. Conclusions- Altogether, these data suggest that phagocytic cells control poststroke recovery and that RXR in these cells represents an attractive target with exceptionally long therapeutic window.This work was supported by grant from the National Institutes of Health (NINDS) 1R01NS084292 to Dr Aronowski. Additional funding from Spanish Ministerio de Ciencia, Innovación y Universidades (MCNU) (SAF2017-90604-REDT-NurCaMeln, RTI2018-095928-B-I00) to Dr Ricote permitted to study RXR (retinoic-X-receptor) deletion in the phagocytic cells. The Centro Nacional de Investigaciones Cardiovasculares is supported by the Instituto de Salud Carlos III (ISCIII), the MCNU, and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon.

The retinoid X receptor α (RXRα), a key nuclear receptor in metabolic processes, is downregulated during host antiviral response. However, the roles of RXRα in host antiviral response are unknown. Here we show that RXRα overexpression or ligand activation increases host susceptibility to viral infections in vitro and in vivo, while Rxra-/- or antagonist treatment reduces infection by the same viruses. Consistent with these functional studies, ligand activation of RXR inhibits the expression of antiviral genes including type I interferon (IFN) and Rxra-/- macrophages produce more IFNβ than WT macrophages in response to polyI:C stimulation. Further results indicate that ligand activation of RXR suppresses the nuclear translocation of β-catenin, a co-activator of IFNβ enhanceosome. Thus, our studies have uncovered a novel RXR-dependent innate immune regulatory pathway, suggesting that the downregulation of RXR expression or RXR antagonist treatment benefits host antiviral response, whereas RXR agonist treatment may increase the risk of viral infections.We thank David Sanchez for his editorial advice and Harvey Roy Herschman for his helpful discussions. This work was funded by NIH RO1 AI078389, AI056154, AI47868, and AI069120 grants, the Tumor Immunology Training Grant (5T32CA009120), the grant from the Spanish Ministry of Economy and Competitiveness (SAF2012-31483) and the Medical Scientist Training Program.S

RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells

RARA and RXRA contribute to myeloid maturation in both mice and humans, and deletion of Rxra and Rxrb augments leukemic growth in mice. While defining the domains of RXRA that are required for anti-leukemic effects in murine KMT2A-MLLT3 leukemia cells, we unexpectedly identified RXRA DT448/9PP as a constitutively active variant capable of inducing maturation and loss of their proliferative phenotype. RXRA DT448/9PP was associated with ligand-independent activity in reporter assays, with enhanced co-activator interactions, reduced engraftment in vivo, and activation of myeloid maturation transcriptional signatures that overlapped with those of cells treated with the potent RXRA agonist bexarotene, suggestive of constitutive activity that leads to leukemic maturation. Phenotypes of RXRA DT448/9PP appear to differ from those of two other RXRA mutations with forms of constitutive activity (F318A and S427F), in that DT448/9PP activity was resistant to mutations at critical ligand-interacting amino acids (R316A/L326A) and was resistant to pharmacological antagonists, suggesting it may be ligand-independent. These data provide further evidence that activated retinoid X receptors can regulate myeloid maturation and provide a novel constitutively active variant that may be germane for broader studies of retinoid X receptors in other settings

RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells.

RARA and RXRA contribute to myeloid maturation in both mice and humans, and deletion of Rxra and Rxrb augments leukemic growth in mice. While defining the domains of RXRA that are required for anti-leukemic effects in murine KMT2A-MLLT3 leukemia cells, we unexpectedly identified RXRA DT448/9PP as a constitutively active variant capable of inducing maturation and loss of their proliferative phenotype. RXRA DT448/9PP was associated with ligand-independent activity in reporter assays, with enhanced co-activator interactions, reduced engraftment in vivo, and activation of myeloid maturation transcriptional signatures that overlapped with those of cells treated with the potent RXRA agonist bexarotene, suggestive of constitutive activity that leads to leukemic maturation. Phenotypes of RXRA DT448/9PP appear to differ from those of two other RXRA mutations with forms of constitutive activity (F318A and S427F), in that DT448/9PP activity was resistant to mutations at critical ligand-interacting amino acids (R316A/L326A) and was resistant to pharmacological antagonists, suggesting it may be ligand-independent. These data provide further evidence that activated retinoid X receptors can regulate myeloid maturation and provide a novel constitutively active variant that may be germane for broader studies of retinoid X receptors in other settings.This work was supported by National Institutes of Health grant R01 HL128447 (JSW) , by the Siteman Investment Program (JSW) , the Washington University SPORE DRP (JSW and MAF) , the Children's Discovery Institute (JSW) , the Alex's Lemonade Stand Foundation Young Investigator Award (MAF) , the National Institutes of Health 5K12HD07622408 (MAF) , and grants from the Spanish Ministerio de Ciencia e Innovacion (MCI) (SAF2017-90604-REDT-NurCaMeIn, RTI2018-095928-BI00) (MR).S

Endogenous retinoid X receptor ligands in mouse hematopoietic cells.

The retinoid X receptor α (RXRA) has been implicated in diverse hematological processes. To identify natural ligands of RXRA that are present in hematopoietic cells, we adapted an upstream activation sequence-green fluorescent protein (UAS-GFP) reporter mouse to detect natural RXRA ligands in vivo. We observed reporter activity in diverse types of hematopoietic cells in vivo. Reporter activity increased during granulocyte colony-stimulating factor (G-CSF)-induced granulopoiesis and after phenylhydrazine (PHZ)-induced anemia, suggesting the presence of dynamically regulated natural RXRA ligands in hematopoietic cells. Mouse plasma activated Gal4-UAS reporter cells in vitro, and plasma from mice treated with G-CSF or PHZ recapitulated the patterns of reporter activation that we observed in vivo. Plasma from mice with dietary vitamin A deficiency only mildly reduced RXRA reporter activity, whereas plasma from mice on a fatty acid restriction diet reduced reporter activity, implicating fatty acids as plasma RXRA ligands. Through differential extraction coupled with mass spectrometry, we identified the long-chain fatty acid C24:5 as a natural RXRA ligand that was greatly increased in abundance in response to hematopoietic stress. Together, these data suggest that natural RXRA ligands are present and dynamically increased in abundance in mouse hematopoietic cells in vivo.We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO. for the use of the Flow Cytometry Core. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant P30 CA91842. We thank High-Throughput Screening Center at Washington University School of Medicine in St. Louis, MO. We thank Deborah Laflamme for technical assistance and Feng Gao for statistical assistance. This work was supported by NIH R01 HL128447 (JS Welch), NIH P50 CA171963 (Project 1, JS Welch), and by grants from the Spanish Ministry of Economy and Competitiveness (SAF2015-64287R, SAF2015-71878-REDT) (M Ricote). The mass spectrometry facility at Washington University is supported by NIH P30 DK020579, Daniel Ory. J.S.W., H.N. and M.R. designed experiments, performed experiments, and wrote the manuscript. H.F., O.M., G.H., M.P.M, T.E.F., G.R.B. designed and performed experiments.S

Nuclear receptors: Lipid and hormone sensors with essential roles in the control of cancer development

Nuclear receptors (NRs) are a superfamily of ligand-activated transcription factors that act as biological sensors and use a combination of mechanisms to modulate positively and negatively gene expression in a spatial and temporal manner. The highly orchestrated biological actions of several NRs influence the proliferation, differentiation, and apoptosis of many different cell types. Synthetic ligands for several NRs have been the focus of extensive drug discovery efforts for cancer intervention. This review summarizes the roles in tumour growth and metastasis of several relevant NR family members, namely androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), thyroid hormone receptor (TR), retinoic acid receptors (RARs), retinoid X receptors (RXRs), peroxisome proliferator-activated receptors (PPARs), and liver X receptors (LXRs). These studies are key to develop improved therapeutic agents based on novel modes of action with reduced side effects and overcoming resistance