Galanin and Neuropeptide Y Interaction Enhances Proliferation of Granule Precursor Cells and Expression of Neuroprotective Factors in the Rat Hippocampus: Role in depression and memory

Neuropeptide Y(NPY) Y1 receptor (Y1R) and galanin (GAL) receptor 2 (GALR2) interact in brain regions responsible for mood control and learning and memory processes, emphasizing the hippocampus. The current study assesses the sustained memory performance and antidepressive-like effects induced by GALR2 and NPYY1R agonists coadministration and their neurochemical hippocampal correlates. Object-in-place task and forced swimming test were conducted together with in situ proximity ligation assay (PLA) to manifest the formation of GALR2/Y1R heteroreceptor complexes. We evaluated cell proliferation through a 5-Bromo-2’-deoxyuridine (BrdU) and PCNA expression study within the hippocampus. The GalR2 agonist M1145 and GAL were demonstrated to act with the Y1R agonist to improve memory retrieval and antidepressive-like actions at 24 hours in both tasks, enhancing the cell proliferation in the DG of the hippocampus through BrdU and PCNA expression and the GALR2/Y1R heteroreceptor complexes upon agonist coactivation. Our results may provide the basis for developing heterobivalent agonist pharmacophores targeting Y1R-GALR2 heterocomplexes. It involves especially the neuronal precursor cells of the dentate gyrus in the hippocampus for the novel treatment of Alzheimer’s disease or depression.Supported by the UMA18-FEDERJA-100 and Proyecto Jovenes Investigadores (B1-2019_04) and Proyecto Puente (B4-2021) UMA , Spain to MN. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Existence of FGFR1-5-HT1AR heteroreceptor complexes in hippocampal astrocytes. Putative link to 5-HT and FGF2 modulation of hippocampal gamma oscillations

The majority of the fibroblast growth factor receptor 1-serotonin 1 A receptor (FGFR1-5-HT1AR) heterocomplexes in the hippocampus appeared to be located mainly in the neuronal networks and a relevant target for antidepressant drugs. Through a neurochemical and electrophysiological analysis it was therefore tested in the current study if astrocytic FGFR1-5-HT1AR heterocomplexes also exist in hippocampus. They may modulate the structure and function of astroglia in the hippocampus leading to possible changes in the gamma oscillations. Localization of hippocampal FGFR1-5-HT1AR heterocomplexes in astrocytes was found using in situ proximity ligation assay combined with immunohistochemistry using glial fibrillary acidic protein (GFAP) immunoreactivity as a marker for astroglia. Acute i.c.v. treatment with 8-OH-DPAT alone or together with basic fibroblast growth factor (FGF2) significantly increased FGFR1-5-HT1AR heterocomplexes in the GFAP positive cells, especially in the polymorphic layer of the dentate gyrus (PoDG) but also in the CA3 area upon combined treatment. No other hippocampal regions were studied. Also, structural plasticity changes were observed in the astrocytes, especially in the PoDG region, upon these pharmacological treatments. They may also be of relevance for enhancing the astroglial volume transmission with increased modulation of the neuronal networks in the regions studied. The effects of combined FGF2 and 5-HT agonist treatments on gamma oscillations point to a significant antagonistic interaction in astroglial FGFR1-5-HT1AR heterocomplexes that may contribute to counteraction of the 5-HT1AR-mediated decrease of gamma oscillations.The work was supported by the Swedish Medical Research Council, Sweden (62X-00715-50-3) to KF, by Parkinson Fonden, Sweden to KF, and by Hjärnfonden, Sweden (F02018-0286), Hjärnfonden, Sweden (F02019-0296) and Karolinska Institutet Forskningsstiftelser, Sweden to D.O.B-E. D.O.B-E belongs to the “Academia de Biólogos Cubanos” group, Cuba. This work was also supported by the Proyecto Puente, Spain and the UMA18-FEDERJA-100, Spain to MN. . Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Galanin and Neuropeptide Y Interaction Enhances Proliferation of Granule Precursor Cells and Expression of Neuroprotective Factors in the Rat Hippocampus with Consequent Augmented Spatial Memory

Dysregulation of hippocampal neurogenesis is linked to several neurodegenereative diseases, where boosting hippocampal neurogenesis in these patients emerges as a potential therapeutic approach. Accumulating evidence for a neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular-, cellular-, and behavioral-specific levels. The purpose of the current work was to evaluate the role of the NPY and GAL interaction in the neurogenic actions on the dorsal hippocampus. We studied the Y1R agonist and GAL effects on: hippocampal cell proliferation through the proliferating cell nuclear antigen (PCNA), the expression of neuroprotective and anti-apoptotic factors, and the survival of neurons and neurite outgrowth on hippocampal neuronal cells. The functional outcome was evaluated in the object-in-place task. We demonstrated that the Y1R agonist and GAL promote cell proliferation and the induction of neuroprotective factors. These effects were mediated by the interaction of NPYY1 (Y1R) and GAL2 (GALR2) receptors, which mediate the increased survival and neurites’ outgrowth observed on neuronal hippocampal cells. These cellular effects are linked to the improved spatial-memory effects after the Y1R agonist and GAL co-injection at 24 h in the object-in-place task. Our results suggest the development of heterobivalent agonist pharmacophores, targeting Y1R–GALR2 heterocomplexes, therefore acting on the neuronal precursor cells of the DG in the dorsal hippocampus for the novel therapy of neurodegenerative cognitive-affecting diseasesThis research was funded by the UMA18-FEDERJA-100 (Junta de Andalucía), Proyecto Jovenes Investigadores (B1-2019-04), Proyecto puente (B4-2021-06), Universidad de Málaga, Spain, to M.N. Swedish Medical Research Council, Sweden (62X-00715-50-3), to K.F., by Stiftelsen Olle Engkvist Byggmästare to K.F., and by Hjärnfonden, Sweden (F02018-0286), Hjärnfonden, Sweden (F02019-0296), and Karolinska Institutet Forskningsstiftelser, Sweden, to D.O.B.-E. D.O.B.-E. belongs to the “Academia de Biólogos Cubanos” group, Cuba. Partial funding for open access charge: Universidad de Málag

Unveiling the Synergistic Interplay of Neuropeptides for Novel Therapeutic Approaches in Neurodegenerative and Depressive Disorders.

The intricate relationship between hippocampal neurogenesis dysregulation and neurodegenerative diseases such as Alzheimer's, as well as depression, has sparked an urgent call for innovative therapeutic strategies. Our groundbreaking study delves into the interaction of Neuropeptide Y (NPY) and galanin (GAL) agonists, two neuromodulatory systems with a substantial presence in the limbic system, and their potential neurogenic impact on both the dorsal and ventral hippocampus. Through meticulous examination of the subchronic e"ects of NPY Y1 (Y1R) and GAL2 (GALR2) agonists on hippocampal cell proliferation, survival, and neuroprotective factor expression, we reveal a fascinating cascade of cellular responses. These include increased cell proliferation (PCNA), enhanced hippocampal cell survival (BrdU), and induction of neuroprotective factors (BDNF). Our functional assessment showcases the resulting improvements in spatial memory performance in the object-in-place task and antidepressant-like e"ects in the forced swimming test. These outcomes are attributed to the synergistic interaction between Y1R and GALR2 receptors, which promote neuronal survival and neurite outgrowth in hippocampal cells. This pioneering research paves the way for the development of heterobivalent agonist pharmacophores that target Y1R-GALR2 heterocomplexes. By acting on neuronal precursor cells in the dentate gyrus of the dorsal hippocampus, these novel compounds hold immense promise as transformative therapies for cognitive and a"ective impairments in neurodegenerative and depressive diseases.Supported by the Proy_Excel_2021_0613 (Junta de Andalucía) and Proyecto Puente (B4-2021) (UMA), Spain to MN. Swedish Medical Research Council, Sweden (62X-00715-50-3), to KF, by Stiftelsen Olle Engkvist Byggmästare to KF, and by Hjärnfonden, Sweden (F02018-0286), Hjärnfonden, Sweden (F02019-0296) and EMERGIA2020 (Junta de Andalucía), to DOBE. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Sudden changes in fluvial style across the Permian / Triassic boundary in the eastern Iberian Ranges, Spain: Analysis of possible causes

The sedimentary record of the Late Permian and Early Triassic of the eastern Iberian Ranges shows four major, sudden, or very rapid, vertical changes in fluvial style. The Late Permian sedimentary cycle starts with the Boniches Formation, of alluvial fan-braided fluvial origin, which grades vertically over within a few metres into the Alcotas Formation, deposited by low to high sinuosity, avulsion-prone rivers with extensive floodplains. The Alcotas Formation contains calcimorphic soils, plant remains and pollen and spore assemblages. However, the upper third of the unit is devoid of all organic remains and soils and is characterized by a dominant red colour, the sandstone levels were deposited by high-sinuosity, meandering rivers. This major change took place during the Late Permian and is probably coeval with the emplacement of the Emeishan basaltic Large Igneous Province (LIP) in SE China. Rocks of the Boniches and Alcotas Formations are separated by an angular unconformity from the overlying strata, which consist of the Late Permian conglomeratic Hoz del Gallo Formation, of alluvial fan–gravel braided fluvial origin and the sandy Cañizar Formation, of low-sinuosity sandy river origin. The Permian– Triassic boundary lies, probably between the upper part of the Hoz del Gallo Formation and the first metres of the Cañizar Formation. Late Permian pollen and spore assemblages have been found in the Hoz del Gallo Formation but the Cañizar Formation is barren, with the exception of an Anisian (Middle Triassic) assemblage at the top. Tectonic extensional pulses in the Iberian Basin caused the changes observed between the lower and upper parts of the Boniches Formation, at the base of the Hoz del Gallo Formation and between the lower and upper part of this Formation. The changes observed in the uppermost part of the Alcotas Formation are not easily explained by tectonic causes, nor those in the passage from the Hoz del Gallo Formation to the Cañizar Formation. Similar sedimentary characteristics of the sandy Cañizar Formation such as amalgamated sandstone bodies, erosion and reactivation surfaces, dominant trough cross-stratification, tabular geometry, absence of plant remains and pollen and spores, and absence of silts and clays to those of coeval formations in places as far away as Australia, South Africa and Brazil suggest a global rather than local cause for these abrupt changes in fluvial style. This global cause was probably die-off of plant cover over extensive areas of the catchment, related to the end of the Permian mass extinction and possibly related to the emplacement of the West Siberian basaltic Large Igneous Province (LIP), responsible for drastic atmospheric and marine changes

Polyphenol intake and mortality risk: a re-analysis of the PREDIMED trial

Background: Polyphenols may lower the risk of cardiovascular disease (CVD) and other chronic diseases due to their antioxidant and anti-inflammatory properties, as well as their beneficial effects on blood pressure, lipids and insulin resistance. However, no previous epidemiological studies have evaluated the relationship between the intake of total polyphenols intake and polyphenol subclasses with overall mortality. Our aim was to evaluate whether polyphenol intake is associated with all-cause mortality in subjects at high cardiovascular risk. Methods: We used data from the PREDIMED study, a 7,447-participant, parallel-group, randomized, multicenter, controlled five-year feeding trial aimed at assessing the effects of the Mediterranean Diet in primary prevention of cardiovascular disease. Polyphenol intake was calculated by matching food consumption data from repeated food frequency questionnaires (FFQ) with the Phenol-Explorer database on the polyphenol content of each reported food. Hazard ratios (HR) and 95% confidence intervals (CI) between polyphenol intake and mortality were estimated using time-dependent Cox proportional hazard models. Results: Over an average of 4.8 years of follow-up, we observed 327 deaths. After multivariate adjustment, we found a 37% relative reduction in all-cause mortality comparing the highest versus the lowest quintiles of total polyphenol intake (hazard ratio (HR) = 0.63; 95% CI 0.41 to 0.97; P for trend = 0.12). Among the polyphenol subclasses, stilbenes and lignans were significantly associated with reduced all-cause mortality (HR =0.48; 95% CI 0.25 to 0.91; P for trend = 0.04 and HR = 0.60; 95% CI 0.37 to 0.97; P for trend = 0.03, respectively), with no significant associations apparent in the rest (flavonoids or phenolic acids). Conclusions: Among high-risk subjects, those who reported a high polyphenol intake, especially of stilbenes and lignans, showed a reduced risk of overall mortality compared to those with lower intakes. These results may be useful to determine optimal polyphenol intake or specific food sources of polyphenols that may reduce the risk of all-cause mortality. Clinical trial registration ISRCTN35739639

Polyphenol intake and mortality risk: a re-analysis of the PREDIMED trial

Background: Polyphenols may lower the risk of cardiovascular disease (CVD) and other chronic diseases due to their antioxidant and anti-inflammatory properties, as well as their beneficial effects on blood pressure, lipids and insulin resistance. However, no previous epidemiological studies have evaluated the relationship between the intake of total polyphenols intake and polyphenol subclasses with overall mortality. Our aim was to evaluate whether polyphenol intake is associated with all-cause mortality in subjects at high cardiovascular risk. Methods: We used data from the PREDIMED study, a 7,447-participant, parallel-group, randomized, multicenter, controlled five-year feeding trial aimed at assessing the effects of the Mediterranean Diet in primary prevention of cardiovascular disease. Polyphenol intake was calculated by matching food consumption data from repeated food frequency questionnaires (FFQ) with the Phenol-Explorer database on the polyphenol content of each reported food. Hazard ratios (HR) and 95% confidence intervals (CI) between polyphenol intake and mortality were estimated using time-dependent Cox proportional hazard models. Results: Over an average of 4.8 years of follow-up, we observed 327 deaths. After multivariate adjustment, we found a 37% relative reduction in all-cause mortality comparing the highest versus the lowest quintiles of total polyphenol intake (hazard ratio (HR) = 0.63; 95% CI 0.41 to 0.97; P for trend = 0.12). Among the polyphenol subclasses, stilbenes and lignans were significantly associated with reduced all-cause mortality (HR =0.48; 95% CI 0.25 to 0.91; P for trend = 0.04 and HR = 0.60; 95% CI 0.37 to 0.97; P for trend = 0.03, respectively), with no significant associations apparent in the rest (flavonoids or phenolic acids). Conclusions: Among high-risk subjects, those who reported a high polyphenol intake, especially of stilbenes and lignans, showed a reduced risk of overall mortality compared to those with lower intakes. These results may be useful to determine optimal polyphenol intake or specific food sources of polyphenols that may reduce the risk of all-cause mortality

Interest Groups in Venezuela: Lessons from the Failure of a “Model Democracy” and the Rise of a Bolivarian Democracy

This article uses the Venezuelan case to shed light on the potential role of interest group systems in discrediting liberal democracies and to identify challenges the region’s democracies are likely to confront in constructing effective and fair interest group systems. It first analyzes the role Venezuela’s interest groups played in discrediting its forty-year two-party democracy. It argues that the discrediting of a system heralded by many as the region’s “model democracy” cannot be understood by merely assessing how the structure of the group system excluded certain groups. The study shows that the inclusion of certain business interests in visible positions of power also helped discredit the two-party democracy. The article then compares the above system with the new group system which has emerged since 1998 as part of a new democratic system inspired by Latin America’s 19th century Liberator Simón Bolívar. This comparison reveals that the current system inverts the former system of inclusion and exclusion, even as it has retained a number of the old system’s less virtuous features. The implications of the Venezuelan case for the region’s democracies are elaborated in the conclusion

Diet and food strategies in a southern al-Andalusian urban environment during Caliphal period, ecija, Sevilla

The Iberian medieval period is unique in European history due to the widespread socio-cultural changes that took place after the arrival of Arabs, Berbers and Islam in 711 AD. Recently, isotopic research has been insightful on dietary shifts, status, resource availability and the impact of environment. However, there is no published isotopic research exploring these factors in southern Iberian populations, and as the history of this area differs to the northern regions, this leaves a significant lacuna in our knowledge. This research fills this gap via isotopic analysis of human (n = 66) and faunal (n = 13) samples from the 9th to the 13th century Écija, a town renowned for high temperatures and salinity. Stable carbon (δ13C) and nitrogen (δ15N) isotopes were assessed from rib collagen, while carbon (δ13C) values were derived from enamel apatite. Human diet is consistent with C3 plant consumption with a very minor contribution of C4 plants, an interesting feature considering the suitability of Écija to C4 cereal production. δ15N values vary among adults, which may suggest variable animal protein consumption or isotopic variation within animal species due to differences in foddering. Consideration of δ13C collagen and apatite values together may indicate sugarcane consumption, while moderate δ15N values do not suggest a strong aridity or salinity effect. Comparison with other Iberian groups shows similarities relating to time and location rather than by religion, although more multi-isotopic studies combined with zooarchaeology and botany may reveal subtle differences unobservable in carbon and nitrogen collagen studies alone.OLC is funded by Plan Galego I2C mod.B (ED481D 2017/014). The research was partially funded by the projects “Galician Paleodiet” and by Consiliencia network (ED 431D2017/08) Xunta de GaliciaS

Un examen actualizado de la percepción de las barreras para la implementación de la farmacogenómica y la utilidad de los pares fármaco/gen en América Latina y el Caribe

La farmacogenómica (PGx) se considera un campo emergente en los países en desarrollo. La investigación sobre PGx en la región de América Latina y el Caribe (ALC) sigue siendo escasa, con información limitada en algunas poblaciones. Por lo tanto, las extrapolaciones son complicadas, especialmente en poblaciones mixtas. En este trabajo, revisamos y analizamos el conocimiento farmacogenómico entre la comunidad científica y clínica de ALC y examinamos las barreras para la aplicación clínica. Realizamos una búsqueda de publicaciones y ensayos clínicos en este campo en todo el mundo y evaluamos la contribución de ALC. A continuación, realizamos una encuesta regional estructurada que evaluó una lista de 14 barreras potenciales para la aplicación clínica de biomarcadores en función de su importancia. Además, se analizó una lista emparejada de 54 genes/fármacos para determinar una asociación entre los biomarcadores y la respuesta a la medicina genómica. Esta encuesta se comparó con una encuesta anterior realizada en 2014 para evaluar el progreso en la región. Los resultados de la búsqueda indicaron que los países de América Latina y el Caribe han contribuido con el 3,44% del total de publicaciones y el 2,45% de los ensayos clínicos relacionados con PGx en todo el mundo hasta el momento. Un total de 106 profesionales de 17 países respondieron a la encuesta. Se identificaron seis grandes grupos de obstáculos. A pesar de los continuos esfuerzos de la región en la última década, la principal barrera para la implementación de PGx en ALC sigue siendo la misma, la "necesidad de directrices, procesos y protocolos para la aplicación clínica de la farmacogenética/farmacogenómica". Las cuestiones de coste-eficacia se consideran factores críticos en la región. Los puntos relacionados con la reticencia de los clínicos son actualmente menos relevantes. Según los resultados de la encuesta, los pares gen/fármaco mejor clasificados (96%-99%) y percibidos como importantes fueron CYP2D6/tamoxifeno, CYP3A5/tacrolimus, CYP2D6/opioides, DPYD/fluoropirimidinas, TMPT/tiopurinas, CYP2D6/antidepresivos tricíclicos, CYP2C19/antidepresivos tricíclicos, NUDT15/tiopurinas, CYP2B6/efavirenz y CYP2C19/clopidogrel. En conclusión, aunque la contribución global de los países de ALC sigue siendo baja en el campo del PGx, se ha observado una mejora relevante en la región. La percepción de la utilidad de las pruebas PGx en la comunidad biomédica ha cambiado drásticamente, aumentando la concienciación entre los médicos, lo que sugiere un futuro prometedor en las aplicaciones clínicas de PGx en ALC.Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region’s continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the “need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics”. Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%–99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC