The Bile Acid Sensor FXR Protects against Dyslipidemia and Aortic Plaques Development Induced by the HIV Protease Inhibitor Ritonavir in Mice

Although human immunodeficiency virus (HIV)–related morbidity and mortality rates in patients treated with a combination of high active antiretroviral therapy (HAART) have declined, significant metabolic/vascular adverse effects associated with the long term use of HIV protease inhibitors (PIs) have emerged as a significant side effect. Here we illustrate that targeting the bile acid sensor farnesoid X receptor (FXR) protects against dyslipidemia and vascular injury induced HIV-PIs in rodents. mice with gemfibrozil, a PPARα agonist. FXR activation counter-regulated induction of expression/activity of CD36 caused by HIV-PIs in circulating monocytes and aortic plaques. In macrophages cell lines, CDCA attenuated CD36 induction and uptake of acetylated LDL caused by ritonavir. Natural and synthetic FXR ligands reduced the nuclear translocation of SREBP1c caused by ritonavir.Activation of the bile acid sensor FXR protects against dyslipidemia and atherosclerotic caused by ritonavir, a widely used HIV PI. From a mechanistic stand point it appears that besides reducing the liver expression of genes involved in fatty acid synthesis, FXR activation counter-regulates the expression/activity of CD36 on monocytes. FXR ligands might hold promise in the treatment dyslipidemia induced by ritonavir

Probiotics Modulate Intestinal Expression of Nuclear Receptor and Provide Counter-Regulatory Signals to Inflammation-Driven Adipose Tissue Activation

BACKGROUND: Adipocytes from mesenteric white adipose tissue amplify the inflammatory response and participate in inflammation-driven immune dysfunction in Crohn's disease by releasing proinflammatory mediators. Peroxisome proliferator-activated receptors (PPAR)-α and -γ, pregnane x receptor (PXR), farnesoid x receptor (FXR) and liver x-receptor (LXR) are ligand-activated nuclear receptor that provide counter-regulatory signals to dysregulated immunity and modulates adipose tissue. AIMS: To investigate the expression and function of nuclear receptors in intestinal and adipose tissues in a rodent model of colitis and mesenteric fat from Crohn's patients and to investigate their modulation by probiotics. METHODS: Colitis was induced by TNBS administration. Mice were administered vehicle or VSL#3, daily for 10 days. Abdominal fat explants obtained at surgery from five Crohn's disease patients and five patients with colon cancer were cultured with VSL#3 medium. RESULTS: Probiotic administration attenuated development of signs and symptoms of colitis, reduced colonic expression of TNFα, IL-6 and IFNγ and reserved colonic downregulation of PPARγ, PXR and FXR caused by TNBS. Mesenteric fat depots isolated from TNBS-treated animals had increased expression of inflammatory mediators along with PPARγ, FXR, leptin and adiponectin. These changes were prevented by VSL#3. Creeping fat and mesenteric adipose tissue from Crohn's patients showed a differential expression of PPARγ and FXR with both tissue expressing high levels of leptin. Exposure of these tissues to VSL#3 medium abrogates leptin release. CONCLUSIONS: Mesenteric adipose tissue from rodent colitis and Crohn's disease is metabolically active and shows inflammation-driven regulation of PPARγ, FXR and leptin. Probiotics correct the inflammation-driven metabolic dysfunction

Políticas espaciales y espacialidad de la política. Reflexiones y avances de investigación

Fil: Aichino, Gina Lucía. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Ávila, Emanuel. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Llorens, Santiago. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Palladino, Lucas. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Pedrazzani, Carla Eleonora. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.En este trabajo se presenta el recorrido realizado hasta el momento por miembros del grupo de investigación “Políticas espaciales y espacialidad de la política: vinculaciones y co-implicancias” radicado en el Departamento de Geografía de la Universidad Nacional de Córdoba. Dicho proyecto surge como continuidad de dos proyectos de investigación anteriores “Lugar y Políticas de lugar. Aportes para su discusión teórico epistemológica” (2010-2011), y “Políticas de Lugar: convergencias de discusiones e intervenciones académicas, sociales y políticas” (2012-2013), ambos avalados y subsidiados por Secyt-UNC; y se presenta como un intento de abordar problemáticas planteadas y buscar respuestas a nuevos interrogantes que surgieron de los avances en las investigaciones mencionadas. En este sentido, el interés ha sido el de indagarla co-producción de espacio y política haciendo foco en las convergencias y divergencias entre las perspectivas teórico-conceptuales que abordan la temática, las prácticas políticas que re-producen en la cotidianeidad grupos y movimientos sociales subalternizados y las espacialidades que se co-constituyen en sus procesos de reivindicación colectiva.Fil: Aichino, Gina Lucía. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Ávila, Emanuel. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Llorens, Santiago. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Palladino, Lucas. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Pedrazzani, Carla Eleonora. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Geografía Cultural y Económic

Una lucha por recuperar la vida urbana : políticas de lugar y la experiencia de la multisectorial "Defendamos Alberdi"

Las propuestas de lugar y políticas de lugar, han sido y son actualmente- abordadas desde distintos enfoques tanto en Ciencias Sociales como en Geografía. Existen convergencias y divergencias en las significaciones desarrolladas por los distintos autores; por lo cual, se vuelve fundamental, a la hora de una reflexión sobre éstos, aproximarse y precisar los aspectos ontológicos, epistemológicos, sociales y políticos presentes en las distintas propuestas. El objetivo de este artículo, es analizar la experiencia del Barrio Alberdi de la Ciudad de Córdoba, Argentina y de la Multisectorial "Defendamos Alberdi" buscando realizar un primer diálogo con abordajes constructivistas y post-constructivistas en lo referente al análisis de lugar y políticas de lugar. Este barrio posee una amplia y rica historia de reivindicaciones en las cuales han convergido y convergen actualmente una heterogeneidad de grupos: sectores populares, comunidades originarias, trabajadores, estudiantes, comunidades de inmigrantes peruanos y bolivianos. La Multisectorial representa parte de esta compleja pluralidad de formas, vivencias, saberes y experiencias de la propia vida del barrio y, se sintetiza en un colectivo que encara la lucha/defensa del patrimonio, de la identidad y de la vida barrial frente al avance de los grupos inmobiliarios y desarrollistas que atentan sobre el barrio y su historia. En este sentido, se afirma que en el ámbito de lo espacial los lugares contribuyen a hacer políticas más allá del plano de la representación al enredar en dicha política entidades e identidades en una negociación que implica como indica Massey "un acabar juntos, el inevitable desafío de negociar un aquí-y-ahora" y la negociación que debe acontecer dentro y entre ambos, lo humano y lo no humano (Massey, 2008:203). Desde la cátedra de Epistemología de la Geografía y como geógrafos intentamos aportar la generación de herramientas para la organización del territorio que incluyan y comprendan esos valores y esos proyectos que quedan afuera de la lógica mercantil y que son reivindicados por los vecinos. En base a ello, se comenzaron a realizar diversas actividades desde metodologías participativas que a través del diálogo de saberes y experiencias compartidas pretenden iniciar un camino de construcción conjunta de conocimiento práctico y teórico sobre la problemática y que exprese los antagonismos presentes y las disputas espaciales existentes. Para este trabajo, no sólo existe una revisión bibliográfica sino también la articulación de diversas técnicas en un trabajo de campo conjunto con la Multisectorial.Fil: Aichino, Gina Lucía. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Ávila, Emanuel. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Haidar Martínez, José. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Llorens, Santiago. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Palladino, Lucas. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Pedrazzani, Carla Eleonora. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Fil: Reynoso, Nicolás. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Departamento de Geografía; Argentina.Ciencias Sociales Interdisciplinaria

Serum Resistin, Cardiovascular Disease and All-Cause Mortality in Patients with Type 2 Diabetes

Background: High serum resistin has been associated with increased risk of cardiovascular disease in the general population, Only sparse and conflicting results, limited to Asian individuals, have been reported, so far, in type 2 diabetes. We studied the role of serum resistin on coronary artery disease, major cardiovascular events and all-cause mortality in type 2 diabetes. Methods: We tested the association of circulating resistin concentrations with coronary artery disease, major cardiovascular events (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and all-cause mortality in 2,313 diabetic patients of European ancestry from two cross-sectional and two prospective studies. In addition, the expression of resistin gene (RETN) was measured in blood cells of 68 diabetic patients and correlated with their serum resistin levels. Results: In a model comprising age, sex, smoking habits, BMI, HbA1c, and insulin, antihypertensive and antidyslipidemic therapies, serum resistin was associated with coronary artery disease in both cross-sectional studies: OR (95%CI) per SD increment = 1.35 (1.10–1.64) and 1.99 (1.55–2.55). Additionally, serum resistin predicted incident major cardiovascular events (HR per SD increment = 1.31; 1.10–1.56) and all-cause mortality (HR per SD increment = 1.16; 1.06–1.26). Adjusting also for fibrinogen levels affected the association with coronary artery disease and incident cardiovascular events, but not that with all cause-mortality. Finally, serum resistin was positively correlated with RETN mRNA expression (rho = 0.343). Conclusions: This is the first study showing that high serum resistin (a likely consequence, at least partly, of increased RETN expression) is a risk factor for cardiovascular disease and all-cause mortality in diabetic patients of European ancestry

Sonic Hedgehog Therapy in a Mouse Model of Age-Associated Impairment of Skeletal Muscle Regeneration

Sonic hedgehog (Shh) is a morphogen regulating muscle development during embryogenesis. We have shown that the Shh pathway is postnatally recapitulated after injury and during regeneration of the adult skeletal muscle and regulates angiogenesis and myogenesis after muscle injury. Here, we demonstrate that in 18-month-old mice, there is a significant impairment of the upregulation of the Shh pathway that physiologically occurs in the young skeletal muscle after injury. Such impairment is even more pronounced in 24-month-old mice. In old animals, intramuscular therapy with a plasmid encoding the human Shh gene increases the regenerative capacities of the injured muscle, in terms of Myf5-positive cells, regenerating myofibers, and fibrosis. At the molecular level, Shh treatment increases the upregulation of the prototypical growth factors, insulin-like growth factor-1 and vascular endothelial growth factor. These data demonstrate that Shh increases regeneration after injury in the muscle of 24-month-old mice and suggest that the manipulation of the Shh pathway may be useful for the treatment of muscular diseases associated with aging

Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells

International audienceThe pregnane-X-receptor (PXR) is master gene overseeing detoxification of wide number of xenobiotics and is critical for maintenance of intestinal integrity. The intestinal expression of genes involved in cellular detoxification is down-regulated in patients with inflammatory bowel diseases (IBD). Rifaximin, is a non absorbable antibiotic endowed with a PXR agonistic activity. In the present study we have investigated whether rifaximin activates PXR in primary human colon epithelial cells and human colon biopsies and assessed whether this antibiotic antagonizes the effect of Tumor necrosis factor (TNF)-α on expression of PXR and PXR-related genes. Present results demonstrate that primary colon epithelial cells express PXR and that their exposure to rifaximin induces the expression of genes involved in cellular detoxification. Exposure to TNFα reduces the expression of PXR mRNA as well as expression of its target genes. This inhibitory effect was prevented by that co-treatment with rifaximin. Knocking down the expression of PXR in colon epithelial cells by an anti-PXR siRNA, abrogated the counter-regulatory effects exerted by rifaximin on cell exposed to TNFα. Finally, exposure of colon biopsies obtained from ulcerative colitis patients to rifaximin increased the expression of genes involved in xenobiotics metabolism. In aggregate, these data illustrate that rifaximin increases the expression of PXR and PXR-regulated genes involved in the metabolism and excretion of xenobiotics and antagonized the effects of TNFα in intertsinal epithelial cells and colon biopsies. These non-antibiotic effects of rifaximin could contribute to the maintenance of the intestinal barrier integrity against xenobiotics and products generated by luminal bacteria

Measurement of proton, deuteron, triton, and α particle emission after nuclear muon capture on Al, Si, and Ti with the AlCap experiment

Heavy charged particles after nuclear muon capture are an important nuclear physics background to the muon-to-electron conversion experiments Mu2e and COMET, which will search for charged lepton flavor violation at an unprecedented level of sensitivity. The AlCap experiment measured the yield and energy spectra of protons, deuterons, tritons, and alpha particles emitted after the nuclear capture of muons stopped in Al, Si, and Ti in the low energy range relevant for the muon-to-electron conversion experiments. Individual charged particle types were identified in layered silicon detector packages and their initial energy distributions were unfolded from the observed energy spectra. Detailed information on yields and energy spectra for all observed nuclei are presented in the paper.Comment: 24 pages, 19 figure