Amelioration of BPSD-like phenotype and cognitive decline in SAMP8 mice model accompanied by molecular changes after treatment with I2-imidazoline receptor ligand MCR5

Behavioural and Psychological Symptoms of Dementia (BPSD), including fear-anxiety- and depressive-like behaviour, are present in Alzheimer's disease (AD), together with memory decline. I2-imidazoline receptors (I2-IRs) have been associated with neuropsychiatric and neurodegenerative disorders, further, I2-IR ligands have demonstrated a neuroprotective role in the central nervous system (CNS). In this study, we assessed the effect of the I2-IR ligand MCR5 on both cognitive and non-cognitive symptoms in the Senescence accelerated mice prone 8 (SAMP8) mouse model. Oral administration of I2-IR ligand MCR5 (5mg/kg/day for four weeks) in 10-month SAMP8 mice ameliorated both BPSD-like phenotype and cognitive decline by attenuating depressive-like behaviour, reducing fear-anxiety-like behaviour and improving cognitive performance using different tasks. Interaction of I2-IR ligand MCR5 with serotoninergic system did not account for behavioral or cognitive improvement, although changes in molecular pathways underlying depression and anxiety phenotype were observed. MCR5 increased levels of p-AKT, phosphorylated Glycogen synthase kinase 3 β (GSK3β) at Ser9 and phosphorylated mammalian target of rapamycin complex 1 (mTORC1) levels in SAMP8 treated mice compared to SAMP8 control. Moreover, MCR5 treatment altered NMDA2B phosphorylation, and decreased the protein levels of phosphorylated Cyclin-Dependent Kinase 5 (p-CDK5) and dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa phosphorylated at Thr75 (p-DARPP32), with a parallel increase in PKA and p-CREB levels. Consistent with these changes MCR5 attenuated neuroinflammation by decreasing expression of pro-inflammatory markers such as Tumor necrosis factor-alpha (Tnf-α), Interleukin 1β (Il-1β), Interleukin 6 (Il-6), and promoted synaptic plasticity by increasing levels of Postsynaptic density protein 95 (PSD95) as well as ameliorating Tropomyosin-related kinase B (TrkB) and Nerve growth factor receptor (NGFR) signalling. Collectively, these results increase the potential of highly selective I2-IR ligands as therapeutic agents in age-related BPSD and cognitive alterations

The fossil vertebrates from Somosaguas (Pozuelo, Madrid, Spain)

[ES] Dos yacimientos de vertebrados, situados en el Campus de Somosaguas de la Universidad Complutense (Pozuelo de Alarcón, Madrid), han proporcionado unos 600 restos identificables en estados de conservación muy variados, pertenecientes a unas veinte especies de tamaños muy diversos, desde mastodontes a musarañas. Su estudio permite fechar su edad en unos 14 m.a. y reconstruir un periodo árido en la cuenca de Madrid, ocupada durante el Mioceno medio por bosques y sabanas subtropicales con fuertes avenidas y sin ríos permanentes. En estos yacimientos se puede realizar una enseñanza práctica de la Paleontología de Vertebrados, para formación de estudiantes universitarios en el estudio y la gestión del Patrimonio Paleontológico.[EN] Two vertebrate fossil sites, situated in the Universidad Complutense Campus of Somosaguas, (Pozuelo de Alarcón, Madrid, Spain) have yielded about 600 identifiable rests in different preservation states, belonging to about twenty species of highly diverse sizes, from mastodons to shrews. Their study allows dating at about 14 m.y., and reconstructing an arid climate epoch in the Madrid basin during middle Miocene times, occupied by subtropical woodlands and savannahs with strong floods and without permanent rivers. These fossil sites allow practical teaching of Vertebrate Palaeontology, and preparing university students in the Palaeontological Heritage study and management.Hemos recibido financiación y personal respaldo del Rectorado de la Universidad Complutense de Madrid, de los Decanatos de la Facultad de Ciencias Políticas y Sociología y de la Facultad de Ciencias Geológicas, y del Departamento de Paleontología de esta Facultad. El Departamento de Paleobiología del Museo Nacional de Ciencias Naturales (CSIC) realiza su investigación en el marco del Convenio de Colaboración con la Comunidad de Madrid a través de la Dirección General de Patrimonio Histórico Artístico de la Consejería de Educación.Peer reviewe

Fatty Acid Synthase Inhibitor G28 Shows Anticancer Activity in EGFR Tyrosine Kinase Inhibitor Resistant Lung Adenocarcinoma Models

Epidermal growth factor receptor (EGFR) tyrosine kinases inhibitors (TKIs) are effectivetherapies for non-small cell lung cancer (NSCLC) patients whose tumors harbor an EGFR activatingmutation. However, this treatment is not curative due to primary and secondary resistance suchas T790M mutation in exon 20. Recently, activation of transducer and activator of transcription 3(STAT3) in NSCLC appeared as an alternative resistance mechanism allowing cancer cells to elude theEGFR signaling. Overexpression of fatty acid synthase (FASN), a multifunctional enzyme essentialfor endogenous lipogenesis, has been related to resistance and the regulation of the EGFR/Jak2/STATsignaling pathways. Using EGFR mutated (EGFRm) NSCLC sensitive and EGFR TKIs' resistantmodels (Gefitinib Resistant, GR) we studied the role of the natural polyphenolic anti-FASN compound(−)-epigallocatechin-3-gallate (EGCG), and its derivative G28 to overcome EGFR TKIs' resistance.We show that G28's cytotoxicity is independent of TKIs' resistance mechanisms displaying synergisticeffects in combination with gefitinib and osimertinib in the resistant T790M negative (T790M−)model and showing a reduction of activated EGFR and STAT3 in T790M positive (T790M+) models.Our results provide the bases for further investigation of G28 in combination with TKIs to overcomethe EGFR TKI resistance in NSCLC

An Imidazoline 2 Receptor Ligand Relaxes Mouse Aorta via Off-Target Mechanisms Resistant to Aging

Imidazoline receptors (IR) are classified into three receptor subtypes (I1R, I2R, and I3R) and previous studies showed that regulation of I2R signaling has neuroprotective potential. In order to know if I2R has a role in modulating vascular tone in health and disease, we evaluated the putative vasoactive effects of two recently synthesized I2R ligands, diethyl (1RS,3aSR,6aSR)-5- (3-chloro-4-fluorophenyl)-4,6-dioxo-1-phenyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrrole -1- phosphonate (B06) and diethyl [(1-(3-chloro-4-fluorobenzyl)-5,5-dimethyl-4-phenyl-4,5-dihydro- 1H-imidazol-4-yl]phosphonate] (MCR5). Thoracic aortas from Oncins France 1 (3- to 4-monthsold) and C57BL/6 (3- to 4- and 16- to 17-months-old mice) were mounted in tissue baths to measure isometric tension. In young mice of both strains, MCR5 induced greater relaxations than either B06 or the high-affinity I2R selective ligand 2-(2-benzofuranyl)-2-imidazoline (2-BFI), which evokedmarginal responses.MCR5 relaxations were independent of I2R, as IR ligands did not significantly affect them, involved activation of smoothmuscle KATP channels and inhibition of L-type voltage-gated Ca2+ channels, and were only slightly modulated by endothelium-derived nitric oxide (negatively) and prostacyclin (positively). Notably, despite the presence of endothelial dysfunction in old mice, MCR5 relaxations were preserved. In conclusion, the present study provides evidence against a functional contribution of I2R in the modulation of vascular tone in the mouse aorta. Moreover, the I2R ligand MCR5 is an endothelium-independent vasodilator that acts largely via I2R-independent pathways and is resistant to aging. We propose MCR5 as a candidate drug for the management of vascular disease in the elderly

Els espais altimontans pirenaics orientals a l'Antiguitat : 10 anys d'estudis en arqueologia del paisatge del GIAP-ICAC

En aquest treball s'ofereix una panoràmica dels estudis realitzats pel Grup d'Investigació en Arqueologia del Paisatge (GIAP) als espais altimontans pirenaics orientals en els darrers 10 anys. Des d'un enfocament multidisciplinari en el marc de l'arqueologia del paisatge, els resultats obtinguts permeten trencar amb la visió tradicional d'aquestes àrees muntanyenques a l'Antiguitat, mostrant la seva intensa explotació i una forta antropització que ja comença en el període Neolític.This work offers an overview about the studies conducted by the Grup d'Investigació en Arqueologia del Paisatge (GIAP) in the Eastern Pyrenees high mountain areas during the last ten years. From a multidisciplinary approach within the framework of landscape archaeology, the results obtained make it possible to break with the traditional vision of these mountainous areas in antiquity, showing their intense exploitation and strong anthropization, already beginning in the Neolithic period

Textural and mineral-chemistry constraints on columbite group minerals in the Penouta deposit: evidence from magmatic and fluid-related processes.

The Penouta Sn-Ta deposit, in the northwest of Spain, is a greisenized granitic cupola where Ta minerals occur mainly as disseminations in a leucogranite body intruded in Precambrian-Lower Cambrian gneises and mica-schists. This leucogranite is a medium- to fine-grained inequigranular rock consisting mainly of quartz, albite, K-feldspar and muscovite. Accessory minerals are mainly of spessartine, zircon, cassiterite, Nb-Ta oxides, monazite, xenotime, native bismuth and pyrite. The alteration processes were mainly albitization, muscovitization and kaolinitization. This leucogranite is peraluminous and P-poor, with 0.03-0.07 wt.% P2O5, 900-1500 ppm Rb, 30-65 ppm Cs, 120-533 ppm Li, 80-140 ppm Ta, 51-81 ppm Nb and up to 569 ppm of Sn. Mineralogical characterization of Nb-Ta oxide minerals was determined by X-ray diffraction, scanning electron microscopy, electron microprobe analysis and mineral liberation analysis. Mn-rich members of the columbite-group minerals (CGM) are the most common Ta-bearing phases, but microlite, wodginite, tapiolite and Ta-rich cassiterite occur also. CGM crystals are commonly zoned concentrically, with a Nb-rich core surrounded by a Ta-rich rim, with a sharp boundary between them. Convoluted zoning occurs also. Dissolution textures resulting from the corrosion of columbite and tantalite rims, in particular, are common. TheMn/(Mn + Fe) ratio varies between 0.33 and 0.97 and the Ta/(Ta + Nb) ratio between 0.07 and 0.93. Wodginite and microlite formed as late replacements of CGM and occur associated with tantalite and cassiterite. Subhedral to anhedral cassiterite crystals, usually up to 200 μmacross, occur in two generations: the earlier one is Nb,Ta-poor whereas in the later generation, the Ta content can reach >9 wt.%of Ta2O5 and 1.7 wt.%of Nb. The presence of a fluid phase in the apical zone of the granite, probably related to the separation of a fluid/vapour of the melt, could explain the sponge-like textures, the Ta enrichment associated with these textures, the occurrence of Taenriched mineral phases (microlite and wodginite) and their common interstitial character

I2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway

Brain aging and dementia are current problems that must be solved. The levels of imidazoline 2 receptors (I2-IRs) are increased in the brain in Alzheimer's disease (AD) and other neurodegenerative diseases. We tested the action of the specific and selective I2-IR ligand B06 in a mouse model of accelerated aging and AD, the senescence-accelerated mouse prone 8 (SAMP8) model. Oral administration of B06 for 4 weeks improved SAMP8 mouse behavior and cognition and reduced AD hallmarks, oxidative stress, and apoptotic and neuroinflammation markers. Likewise, B06 regulated glial excitatory amino acid transporter 2 and N-methyl-D aspartate 2A and 2B receptor subunit protein levels. Calcineurin (CaN) is a phosphatase that controls the phosphorylation levels of cAMP response element-binding (CREB), apoptotic mediator BCL-2-associated agonist of cell death (BAD) and GSK3β, among other molecules. Interestingly, B06 was able to reduce the levels of the CaN active form (CaN A). Likewise, CREB phosphorylation, BAD gene expression, and other factors were modified after B06 treatment. Moreover, phosphorylation of a target of CaN, nuclear factor of activated Tcells, cytoplasmic 1 (NFATC1), was increased in B06- treated mice, impeding the transcription of genes related to neuroinflammation and neural plasticity. In summary, this I2 imidazoline ligand can exert its beneficial effects on age-related conditions by modulating CaN pathway action and affecting several molecular pathways, playing a neuroprotective role in SAMP

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

Long-term outcomes of high-risk HR-positive and HER2-negative early breast cancer patients from GEICAM adjuvant studies and El Álamo IV registry

Purpose The monarchE trial showed that the addition of abemaciclib improves efficacy in patients with high-risk early breast cancer (EBC). We analyzed the long-term outcomes of a population similar to the monarchE trial to put into context the potential benefit of abemaciclib. Methods HR-positive/HER2-negative EBC patients eligible for the monarchE study were selected from 3 adjuvant clinical trials and a breast cancer registry. Patients with ≥ 4 positive axillary lymph nodes (N +) or 1–3 N + with tumor size ≥ 5 cm and/or histologic grade 3 and/or Ki67 ≥ 20%, who had undergone surgery with curative intent and had received anthracyclines ± taxanes and endocrine therapy in the neoadjuvant and /or adjuvant setting were included. We performed analysis of Invasive Disease-Free Survival (iDFS), Distant Disease-Free Survival (dDFS) and Overall Survival (OS) at 5 and 10 years, as well as yearly (up to 10) of Invasive Relapse Rate (IRR), Distant Relapse Rate (DRR) and Death Rate (DR). Results A total of 1,617 patients were analyzed from the GEICAM-9906 (312), GEICAM-2003–10 (210), and GEICAM-2006–10 (160) trials plus 935 from El Álamo IV. With a median follow-up of 10.1 years, the 5 and 10 years iDFS rates were 75.2% and 57.0%, respectively. The dDFS and OS rates at 5 years were 77.4% and 88.8% and the respective figures at 10 years were 59.7% and 70.9%. Conclusions This data points out the need for new therapies for those patients. A longer follow-up of the monarchE study to see the real final benefit with abemaciclib is warranted

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