Inhibitory Effects of LRP1-Based Immunotherapy on Cardiac Extracellular Matrix Biophysical Alterations Induced by Hypercholesterolemia

The accumulation of lipids in cardiomyocytes contributes to cardiac dysfunction. The specific blockage of cardiomyocyte cholesteryl ester (CE) loading by antibodies (Abs) against the P3 sequence (Gly-Cys) of the LRP1 receptor improves cardiac insulin sensitivity. The impact of anti-P3 Abs on high-fat diet (HFD)-induced cardiac extracellular matrix (ECM) biophysical alterations was analyzed. Both IrP (without Abs) and P3-immunized rabbits (with Abs) were randomized into groups fed either HFD or a standard chow diet. Cardiac lipids, proteins, and carbohydrates were characterized by Fourier transform infrared spectroscopy in the attenuated total reflectance mode. The hydric organization and physical structure were determined by differential scanning calorimetry. HFD increased the levels of esterified lipids, collagen, and α-helical structures and upregulated fibrosis, bound water, and ECM plasticization in the heart. The inhibitory effect of anti-P3 Abs on cardiac CE accumulation was sufficient to reduce the collagen-filled extracellular space, the level of fibrosis, and the amount of bound water but did not counteract ECM plasticization in the heart of hypercholesterolemic rabbits.The economic support to develop this project was received from Fundació MARATÓ TV3 with Grant 201521-10 (to V.L.-C.), FIS PI21/01523 (to V.L.-C.) from the Instituto de Salud Carlos III (ISCIII) and co-financed with ERDFs, and Fundación BBVA Ayudas a equipos de investigación 2019. This work was also funded by the Secretaría de Ciencia y Tecnología de la Universidad Nacional de Córdoba (SECyT-UNC) Grants PROYECTOS CONSOLIDAR 2018–2021 (to G.C.), Fondo para la Investigación Científica y Tecnológica (FONCyT), and Préstamo BID Proyecto de Investigación en Ciencia y Tecnología (PICT) Grants 2015-0807 and 2017-4497 (to G.C.). Support was received from the Albert Renold Travel Fellowship Programme 2019 from the European Foundation of the study of Diabetes (EFSD) and the Wood-Whelan fellowship Programme 2019 from the International Union of Biochemistry and Molecular Biology (IUBMB) to cover the stay of V.A.D. in Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC) and Biomedical Research Institute Sant Pau (IIB Sant Pau). V.A.D. is a postdoctoral fellow of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI). A.B.-A. is a predoctoral fellow (FI19/00205) granted by the Programme _Contratos predoctorales de formación de investigación en salud_ from the Instituto de Salud Carlos III (ISCIII) and co-financed with ERDFs. Our group is part of CIBER Enfermedades Cardiovasculares (CIBERCV; CB16/11/00276 to J.M.G. and V.L.-C.) and CIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM; CB07/08/0016 to J.C.E.-G.), projects run by the Instituto de Salud Carlos III. Our group also participates in Redes de investigación (Enfermedades Metabóloicas y Cáncer RED2018-102799-T), a project run by MINECO. The V.L.-C. group is recognized by Generalitat de Catalunya (2017 SGR 946). The authorsd thank Eva Prats and the staff from Centres Científics i Tecnològics de la Universitat de Barcelona (Campus Casanova) (CCiT/UB) for sample processing for electron microscopy. The IR-SANTPAU is a center of CERCA Programme/Generalitat de Catalunya

La inmunoterapia basada en LRP1 como estrategia eficaz para inhibir las alteraciones metabólicas en el sistema cardiovascular

Trabajo presentado en el Congreso SEC de la Salud Cardiovascular, celebrado en Mallorca (España), del 20 al 22 de octubre de 2022Background: Antibodies against the P3 sequence (Gly1127-Cys1140) of LRP1 (anti-P3 Abs) specifically block cholesteryl ester (CE) accumulation in vascular cells. LRP1 is a key regulator of insulin receptor (InsR) trafficking in different cell types. The link between CE accumulation and the insulin response are largely unknown. Here, the effects of P3 peptide immunization on the alterations induced by a high-fat diet (HFD) in cardiac insulin response were evaluated. Methods: Irrelevant (IrP)- or P3 peptide-immunized rabbits were randomized into groups fed either HFD or normal chow. Cardiac lipid content was characterized by thin-layer chromatography, confocal microscopy, and electron microscopy. LRP1, InsR and glucose transporter type 4 (GLUT4) levels were determined in membranes and total lysates from rabbit heart. The interaction between InsR and LRP1 was analyzed by immunoprecipitation and confocal microscopy. Insulin signaling activity and glucose uptake were evaluated in HL-1 cells exposed to rabbit serum from the different groups. Findings: HFD reduces cardiac InsR and GLUT4 membrane levels and the interactions between LRP1/InsR. Targeting the P3 sequence on LRP1 through anti-P3 Abs specifically reduces CE accumulation in the heart independently of changes in the circulating lipid profile. This restores InsR and GLUT4 levels in cardiac membranes as well as the LRP1/InsR interactions of HFD-fed rabbits. In addition, anti-P3 Abs restores the insulin signaling cascade and glucose uptake in HL-1 cells exposed to hypercholesterolemic rabbit serum

Emphysematous Pyelonephritis with Septic Shock and Disseminated Intravascular Coagulation: Case Report and Literature Review

Introducción: La pielonefritis enfisematosa es una presentación grave de las infecciones del tracto urinario secundaria a microorganismos productores de gas, considerada una entidad rara, de difícil diagnóstico y asociada a una alta mortalidad sin tratamiento oportuno. Metodología: Se realizó revisión de la literatura relacionada, identificando el impacto de esta entidad en la sobrevida de los pacientes, así como recomendaciones actuales sobre el correcto abordaje diagnóstico y terapéutico. Caso Clínico: Se trata de paciente femenina con antecedente médico de diabetes mellitus tipo 2, con mal apego terapéutico, en la cual se estableció el diagnóstico de pielonefritis enfisematosa unilateral izquierda complicada con cetoacidosis diabética moderada, coagulación intravascular diseminada y choque séptico, la cual posterior a tratamiento médico y quirúrgico es egresada deambulando por medios propios. Conclusión: La presentación clínica inespecífica de pielonefritis enfisematosa acompañada a su rápida evolución al estado de choque lleva a retraso en el diagnóstico y tratamiento, el cual está asociado en gran medida a desenlaces adversos, destacando el caso presentado, que requirió nefrectomía de urgencia e ingresar a unidad de cuidados intensivos para sobrevivir a esta entidad. Introduction: Emphysematous pyelonephritis is a serious presentation of urinary tract infections secondary to gas-producing microorganisms, considered a rare entity, difficult to diagnose and associated with high mortality without timely treatment. Methodology: A review of the related literature was carried out, identifying the impact of this entity on patient survival, as well as current recommendations on the correct diagnostic and therapeutic approach. Clinical Case: This is a female patient with a medical history of type 2 diabetes mellitus, with poor therapeutic adherence, in which the diagnosis of left unilateral emphysematous pyelonephritis complicated with moderate diabetic ketoacidosis, disseminated intravascular coagulation and severe septic shock was established, which after medical and surgical treatment, she is discharged walking on her own. Conclusion: The nonspecific clinical presentation of emphysematous pyelonephritis accompanied by its rapid evolution to a state of shock leads to a delay in diagnosis and treatment, which is largely associated with adverse outcomes, highlighting the case presented, which required emergency nephrectomy and hospitalization to the intensive care unit to survive this entity

Examining the role of foreign assistance in security sector reforms : the Indonesian case

Indonesian and the donor community are agreed that security sector reforms are needed to restore investor confidence and sustain the pace of economic recovery. However, donor-assisted programmes have had only a limited success so far and the army's post-Suharto reforms appeared to have ground to a halt. This paper offers some suggestions on how to restore the momentum for reform in the light of donor limitations, the military's historical circumstances and the current mood of intense nationalism. Donors should initiate a quiet track II (non-official) dialogue with the military, the police, the civilian authorities and civil society to scope out a doable programme of cooperation. The issue of civilian supremacy should be dealt with pragmatically, allowing for a process of negotiation to find an effective working relationship between civilian and military authorities. The dialogue sould frame the reform process as a burden for the entire society, reminding civilian leaders that they too have responsibility to improve their performance and demonstrate their ability to oversee military affairs capably and fairly. Since U.S. assistance to the Indonesian military is likely to remain constrained, the paper proposed a "military donors club" that can expand the donor base and work informally with the World Bank-led Consultative Group on Indonesia. the dialogue should deal creatively and patiently with two of the most vexing issues relating to the army - restructuring its network of territorial commands and phasing out its controversial tradition of self-financing. This could be difficult learning process for both sides of the civilian-military divide that could last a decade or more

Anales de Edafología y Agrobiología Tomo 21 Número 5-6

Magnetita secundaria en un dique de dolerita de la formación arvoniense (N. de Gales), por J. Benayas y D. Ball.-- Contribución al estudio de homogeneizados celulares de tejidos foliares mediante técnicas micrográficas y electroforéticas, por A. Ortuño Martínez y S. Navarro Blaya.-- Abonado en habas. Efecto de la adición de boro, por E. Esteban Velasco y M. Lachica Garrido.-- Composición mineralógica de las arcillas de algunos suelos del Pirineo de Huesca, por Julia Mª Gonzáles Peña.-- Control químico del magnesio y manganeso, por Gerardo Dios, Ramón Dios y Benito Sánchéz.-- El papel de la vegetación en la . evolución de· los suelos, por. Ph. Duchaufour.—Notas II. Reunión Plenaria del Instituto de Edafología y Agrobiología-- Colegio Internacional de Ciencias de la Naturaleza.-- XXVI Congreso Iuso-Español para el Progreso de las Ciencias. II Coloquiosobre las Asociaciones de Investigación.—Rectificación. Bibliografía.-- Japanese Pofassium Symposium. Mine papers read at the third Japanese Potassium CongressPeer reviewe

Anales de Edafología y Agrobiología Tomo 33 Número 5-6

Consideraciones generales sobre la formación de minerales secundarios en los andosoles. Esquema de una secuencia de meteorización de las cenizas volcánicas, por E. Besoain M.-- Distribución y características de los suelos canarios. II. Isla del Hierro, por E. Fernández Caldas, F. Monturiol y F. Gutiérrez.-- Nutrición del chirimoyo: ciclo anual, por C. González O. y E. Esteban.-- Acción deí nitrógeno y tactores externos en el trigo cultivado en el campo, por L. Sánchez de la Puente y R. Martínez-Carrasco.-- Determinación de elementos-traza y distribución en las distintas fracciones del suelo. I. Suelo pardo rojizo mediterráneo, por C. Maqueda, M. Lachica, M. Delgado y J. L. Pérez Rodríguez.-- Influencia de la acidez o alcalinidad del medio de cultivo sobre la planta de «Brassican, por M.o. P. Sánchez Conde y C. Azuara del Molino .-- Nematodes associes a la culture des agrumes en Espagne, por A. Bello, E. Laborda et P. Alvira.-- Estudio de diversos métodos de determinación de la capacidad de cambio catiónica dependiente e independiente del pH y su aplicación a suelos calizos, por E. Díaz Barrientos y P. de Arambarri.-- Efecto de la localización del fertilizante fosfatado sobre su asimilación por olivos, por P. de Arambarri y L. Madrid.-- Humic matter from vertisols. II. Fulvic acids, by F. Martín, C. Saiz-Jiménez and F. J. González Vila.-- Estudios recapitulativos.-- La ultraestructura de los líquenes, por M.o. C. Ascaso.—Notas.-- Fallecimiento del Prof. Baade, Consejero de Honor del C. S. l. C.-- Nombramiento de Consejero de Honor.-- Reunión Plenaria de la División de Ciencias y de sus Patronatos.-- Cambios en el l. N. C. M. A.-- Renuncia del Sr. García Gutiérrez como Vocal de la Junta de Gobierno del Patronato Alonso de Herrera.-- Nombramiento en el Instituto de Alimentación y Productividad Animal.-- Cambio de Vocales técnicos de la Estación Experimental La Mayoral.-- Creación de la Sección de Geoquímica y Génesis Mineral.-- Próxima reunión de la Comisión de Climatología.-- II Jornadas Técnicas sobre «Los plaguicidas y el medio ambiente.-- Seminario sobre «Tipos diferentes de costras calizas y su distribución regional.—Congresos y reuniones.-- DistincionesPeer reviewe