Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06

Abstract: The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I2 receptors (I2‐IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I2‐IR by developing structurally new molecules, in particular, a family of bicyclic α‐iminophosphonates, endowed with high affinity and selectivity to these receptors. Treatment of two murine models, one for age‐related cognitive decline and the other for Alzheimer's disease (AD), with representative compound B06 ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, B06 revealed beneficial in vitro ADME‐Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de‐risk B06 for progressing in the preclinical development. To further characterize the pharmacological properties of B06, we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson's disease (PD). B06 rescued the human dopaminergic cell line SH‐SY5Y from death after treatment with 6‐hydroxydopamine (6‐OHDA) and showed a crucial anti‐inflammatory effect in a cellular model of neuroinflammation. This research reveals B06 as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I2‐IR as a fresh approach for the therapy of ND

Association between ribs shape and pulmonary function in patients with Osteogenesis Imperfecta

The aim of the present study was to test the hypothesis that ribs shape changes in patients with OI are more relevant for respiratory function than thoracic spine shape. We used 3D geometric morphometrics to quantify rib cage morphology in OI patients and controls, and to investigate its relationship with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), expressed as absolute value and as percentage of predicted value (% pred). Regression analyses on the full sample showed a significant relation between rib shape and FEV1, FVC and FVC % pred whereas thoracic spine shape was not related to any parameter. Subsequent regression analyses on OI patients confirmed significant relations between dynamic lung volumes and rib shape changes. Lower FVC and FEV1 values are identified in OI patients that present more horizontally aligned ribs, a greater antero-posterior depth due to extreme transverse curve at rib angles and a strong spine invagination, greater asymmetry, and a vertically short, thoracolumbar spine, which is relatively straight in at levels 1–8 and shows a marked kyphosis in the thoraco-lumbar transition. Our research seems to support that ribs shape is more relevant for ventilator mechanics in OI patients than the spine shapeThis project was funded by grants of the Fundacion Eresa (grant number: BF14_005), the Ministry of Economy, Industry and Competitiveness (grant number: CGL2015-63648-P), the Care4Brittlebones Foundation (grant number: OTR2016-15543INVES), and the University of Valencia (grant number: UV-INV_AE18-773873)

A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration

I2 receptors (I2-IR) are widely distributed in the central nervous system. I2-IR ligands are associated with a neuroprotective effect but, as I2-IR structure remains unknown, the discovery of better and more selective ligands is necessary to understand the pharmacological and molecular implications of I2-IR. Recently, we described a new imidazoline-structure family which showed high affinity and selectivity for I2-IR. In vivo studies in mice indicated a neuroprotective role and revealed beneficial effects in behaviour and cognition with a murine model of neurodegeneration, senescence-accelerated prone mouse (SAMP8). Herein, we report a novel non-imidazoline-structure of bicyclic α-iminophosphonates family with high affinities for I2-IR. In vivo studies in 5X-FAD mice (a transgenic representative model of AD) and SAMP8 mice (a model of neurodegeneration linked to aging) showed an improvement in behaviour and cognition, a reduction of AD hallmarks and of neuroinflammation markers for the mice treated with the lead compound B06. After evaluating several pathways associated with neurodegeneration, we demonstrated that CaN pathway plays a critical role on the neuroprotective effects of I2-IR ligands on SAMP8 mice model. To rule out warnings of the novel family, we calculated DMPK and physicochemical properties for the novel bicyclic α-iminophosphonates. As well, we carried out drug metabolism, safety studies and in vivo pharmacokinetics for lead compound B06. In summary, we present a novel family of I2-IR ligands, its effectiveness in in vivo models and the possible neuroprotective molecular mechanism mediated by them. This highlights that the modulation of I2-IR by bicyclic α-iminophosphonates may open a new therapeutic venue for unmet neurodegenerative conditions

Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M

Background: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued. Methods: A compound embodying a 3-alkyl-1,8-dibenzylxanthine nucleus (iPEPCK-2), was synthesized and successfully probed in silico on a PEPCK-M structural model. Potency and target engagement in vitro and in vivo were evaluated by kinetic and cellular thermal shift assays (CETSA). The compound and its target were validated in tumor growth models in vitro and in murine xenografts. Results: Cross-inhibitory capacity and increased potency as compared to 3-MPA were confirmed in vitro and in vivo. Treatment with iPEPCK-2 inhibited cell growth and survival, especially in poor-nutrient environment, consistent with an impact on colony formation in soft agar. Finally, daily administration of the PEPCK-M inhibitor successfully inhibited tumor growth in two murine xenograft models as compared to vehicle, without weight loss, or any sign of apparent toxicity. Conclusion: We conclude that iPEPCK-2 is a compelling anticancer drug targeting PEPCK-M, a hallmark gene product involved in metabolic adaptations of the tumor

Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer's Disease

The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with three compounds in clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's Disease (AD). Evaluation of cognitive impairment and pathological hallmarks were used in two models of age-related cognitive decline and AD using three structurally different and potent sEH inhibitors as chemical probes. sEH is upregulated in brains from AD patients. Our findings supported the beneficial effects of central sEH inhibition, regarding reducing cognitive impairment, neuroinflammation, tau hyperphosphorylation pathology and the number of amyloid plaques. This study suggests that inhibition of inflammation in the brain by targeting sEH is a relevant therapeutic strategy for AD

Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's disease

Imidazoline I2 receptors (I2-IR), widely distributed in the CNS and altered in patients that suffered from neurodegenerative disorders, are orphan from the structural point of view and new I2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and 3D-QSAR studies of a new family of bicyclic α-iminophosphonates endowed with relevant affinities for human brain I2-IR. Acute treatment in mice with a selected compound significantly decreased the FADD protein in the hippocampus, a key marker in neuroprotective actions. Additionally, in vivo studies in the familial Alzheimer's disease 5xFAD murine model revealed beneficial effects in behavior and cognition. These results are supported by changes in molecular pathways related to cognitive decline and Alzheimer's disease. Therefore bicyclic α-iminophosphonates are tools that may open new therapeutic avenues for I2-IR, particularly for unmet neurodegenerative conditions

COVID-19 Severity and Survival over Time in Patients with Hematologic Malignancies: A Population-Based Registry Study

Mortality rates for COVID-19 have declined over time in the general population, but data in patients with hematologic malignancies are contradictory. We identified independent prognostic factors for COVID-19 severity and survival in unvaccinated patients with hematologic malignancies, compared mortality rates over time and versus non-cancer inpatients, and investigated post COVID-19 condition. Data were analyzed from 1166 consecutive, eligible patients with hematologic malignancies from the population-based HEMATO-MADRID registry, Spain, with COVID-19 prior to vaccination roll-out, stratified into early (February–June 2020; n = 769 (66%)) and later (July 2020–February 2021; n = 397 (34%)) cohorts. Propensity-score matched non-cancer patients were identified from the SEMI-COVID registry. A lower proportion of patients were hospitalized in the later waves (54.2%) compared to the earlier (88.6%), OR 0.15, 95%CI 0.11–0.20. The proportion of hospitalized patients admitted to the ICU was higher in the later cohort (103/215, 47.9%) compared with the early cohort (170/681, 25.0%, 2.77; 2.01–3.82). The reduced 30-day mortality between early and later cohorts of non-cancer inpatients (29.6% vs. 12.6%, OR 0.34; 0.22–0.53) was not paralleled in inpatients with hematologic malignancies (32.3% vs. 34.8%, OR 1.12; 0.81–1.5). Among evaluable patients, 27.3% had post COVID-19 condition. These findings will help inform evidence-based preventive and therapeutic strategies for patients with hematologic malignancies and COVID-19 diagnosis.Depto. de MedicinaFac. de MedicinaTRUEFundación Madrileña de Hematología y HemoterapiaFundación Leucemia y LinfomaAsociación Madrileña de Hematología y Hemoterapiapu

Desde y para la biblioteca

La finalidad principal de este proyecto es el diseño de un plan de actuación para el fomento de la lectura y el desarrollo de la comprensión lectora. Los objetivos son impulsar el papel de la biblioteca escolar para que se convierta en un recurso imprescindible en el centro; instaurar un programa estable de actividades que contribuya al desarrollo de las áreas de conocimiento del currículo; fomentar la lectura y la escritura como actividades a realizar en momentos de ocio; y potenciar la relación con la biblioteca pública de la localidad. Entre las actividades se encuentran la elaboración de marca páginas; la implantación del préstamo de libros durante quince días; la realización de actividades en colaboración con la biblioteca municipal; la lectura pública de libros y textos breves; la celebración del Día del Libro; la creación de un club de lectores; la formación de usuarios; la realización de exposiciones en el centro escolar y la visita a otras organizadas por la biblioteca municipal; la elaboración de guías de lectura; la edición de una revista; y la informatización de los libros de la biblioteca. Se incluyen en anexos los materiales elaborados: el horario de la biblioteca; un marca páginas; una ficha de préstamo; guías de lectura; documentos utilizados en las lecturas públicas; anuncios promocionales del club de lectores; folletos de exposiciones; material para la formación de usuarios; un ejemplar de la revista editada por el colegio; cuestionarios para la evaluación de las actividades; fotografías de la experiencia; y un CD con imágenes, vídeos y presentaciones en Power Point.Madrid (Comunidad Autónoma). Consejería de Educación. Dirección General de Ordenación AcadémicaMadridMadrid (Comunidad Autónoma). Subdirección General de Formación del Profesorado. CRIF Las Acacias; General Ricardos 179 - 28025 Madrid; Tel. + 34915250893ES

De libro en libro descubriendo el mundo

Esta experiencia consiste, básicamente, en recoger investigaciones realizadas por los alumnos, producciones literarias, recopilaciones de aportaciones de las familias o ilustraciones de textos y se realizan libros que posteriormente pasan a formar parte de los fondos de la biblioteca del centro. Se pretende sistematizar la producción de libros y permitir aprovechar al máximo las posibilidades educativas que ofrecen los diferentes tipos de textos así como las diferentes técnicas de ilustración. Los objetivos son fomentar la lectura y la escritura, hacer más significativas las actividades de lectoescritura, desarrollar la capacidad creadora en el alumnado y motivarles para que suman un papel activo en la producción de cultura. Con motivo de una salida para recoger moras y hacer mermelada, se realiza el libro Las Moras; también se recogen canciones dibujos y adivinanzas sobre el otoño; se hace una recopilación de recetas; uno sobre el carnaval; y sobre diferentes obras de teatro que se representan en el centro. Adjunta CD-ROM con los materiales elaborados por los alumnos.Madrid (Comunidad Autónoma). Consejería de Educación. Dirección General de Ordenación AcadémicaMadridMadrid (Comunidad Autónoma). Subdirección General de Formación del Profesorado. CRIF Las Acacias; General Ricardos 179 - 28025 Madrid; Tel. + 34915250893ES