Biology subjects

Loza, M. I.

Publications and source records attributed to Loza, M. I..

8 recordsLinked to original sources

bioRxiv2026

A brain-penetrant P2X7R antagonist mitigates Alzheimer's disease pathology

The ATP-gated P2X7 receptor (P2X7R) activates inflammatory signaling pathways in the central nervous system. In particular, P2X7Rs drive chronic glia-mediated neuroinflammation, which is increasingly recognized as a key contributor to Alzheimers disease, a neurodegenerative disorder that lacks effective disease-modifying therapies. Here we identify a potent and selective negative allosteric modulator of P2X7Rs with therapeutic potential. We synthesize a series of small molecules based on a polycyclic scaffold and confirm blood-brain barrier penetration by testing a radiolabeled analogue using positron emission tomography imaging. Through a structure-guided medicinal chemistry campaign centered on our scaffold, we identify four promising P2X7R antagonists. Of these, UB-ALT-P2 exhibits the most favorable safety profile, high oral bioavailability and robust brain penetration. High-resolution cryo-EM structures of UB-ALT-P2 bound to human, mouse, and rat P2X7Rs reveal a conserved antagonist binding mode with steric features that favor prolonged binding to human receptors. In the 5xFAD mouse model of AD, oral UB-ALT-P2 blunts weight loss, improves short- and long-term memory, reduces amyloid-{beta} plaque burden, lowers hyperphosphorylated tau, and diminishes oxidative and inflammatory markers. These results establish UB-ALT-P2 as a potent and safe P2X7R antagonist that can mitigate core AD pathologies, providing a compelling foundation for further development.

neuroscience↗

bioRxiv2025

Exploring polycyclic scaffolds as adamantane replacements in M2 channel inhibitors of Influenza A virus

The increasing resistance of influenza A viruses to adamantane-based antivirals underscores the need for new inhibitors targeting both wild-type (WT) and mutant M2 ion channels. Here, we report the synthesis and biological evaluation of polycyclic cage amines designed to replace the adamantane scaffold as M2 inhibitors. These include ring-contracted and ring-expanded analogues, evaluated both as primary amines and as aryl-/heteroaryl-substituted derivatives. Most of the polycyclic amines inhibited the WT M2 channel as demonstrated by electrophysiological assays. Among them, compound 10, a 3,4,8,9-tetramethyltetracyclo[4.4.0.03..0.]decan-1-amine, emerged as a triple blocker active against M2 WT, M2 L27F, and M2 V27A channels. In contrast, compound 6c, a noradamantane-isoxazole derivative, showed selective inhibition of the S31N mutant. Although no antiviral activity was observed against influenza A virus in infected cell assays, both compounds 6c and 10 displayed significant antiviral activity against human coronavirus 229E. Furthermore, compound 10 demonstrated favourable pharmacokinetic properties. MD simulations show that noradamantane 6c binds inside the M2 S31N pore, with its ammonium forming H-bonds to Asn31 and the isoxazole positioned near Val27, restricting water entry. In contrast, larger polycyclic amines likely cannot access the pore due to steric hindrance.

pharmacology and toxicology↗

bioRxiv2024

Systematic standardization of organ-on-a-chip under controlled flow conditions: use case with Caki-1 and A549 cell lines

New in vitro models are an urgent need for to improve both the research data and the preclinical development of new drugs. Current standardized cellular models are mainly based in 2D cell culture, which lacks flow conditions and with complex co-culture settings. In this way, advanced cell culture models, such as organ-on-a-chip (OoC), aim to solve these limitations. OoC systems are composed by a microfluidic chip functionalized with different combinations of extracellular matrixes, coatings and cell cultures to mimic the physiological conditions of human organs. Advantages of OoC include the possibility to add 3D structures, delimited regions for co-culture and dynamic flow conditions to cell cultures. However, to perform reproducible and controlled experiments with OoC, it is necessary to systematically standardize the cell culture conditions in the microfluidic channels. For this is necessary to test both the combination of flow and extracellular matrix (ECM) coating to reliably mimic the human organ physiology. In this work, we standardized both conditions, ECM coating and the flow conditions to functionalize OoC with cell lines from kidney (Caki-1) and from lung (A549) to develop OoC systems beyond the Vessel-on-a-chip setting. In this way, the protocol detailed in this work will allow to standardize cell culture on different optimized OoC types with different cell types from different origins.

cell biology↗

bioRxiv2024

Morphological Profiling Dataset of EU-OPENSCREEN Bioactive Compounds Over Multiple Imaging Sites and Cell Lines

Morphological profiling with the Cell Painting assay has emerged as a promising method in drug discovery research. The assay captures morphological changes across various cellular compartments enabling the rapid identification of the effect of compounds. We present a comprehensive morphological profiling dataset using the carefully curated and well-annotated EU-OPENSCREEN Bioactive Compound Set. Our profiling dataset was generated across multiple imaging sites with high-throughput confocal microscopes using the Hep G2 as well as the U2 OS cell line. We employed an extensive assay optimization process to achieve high data quality across the different imaging sites. An analysis of the four replicates validates the robustness of the generated data. We compare morphological features of the different cell lines and map the profiles to activity, toxicity, and basic compound targets to further describe the dataset as well as to demonstrate the potential of this dataset to be used for mechanism of action exploration.

cell biology↗

bioRxiv2023

Elevational Range Sizes of Woody plants Increase with Climate Variability in the Tropical Andes

AimThe climate variability hypothesis proposes that species subjected to wide variation in climatic conditions will evolve wider niches, resulting in larger distributions. We test this hypothesis in tropical plants across a broad elevational gradient; specifically, we use a species-level approach to evaluate whether elevational range sizes are explained by the levels of thermal variability experienced by species. LocationCentral Andes Time periodPresent day Major taxa studiedWoody plants MethodsCombining data from 479 forest plots, we determined the elevational distributions of nearly 2300 species along an elevational gradient ([~]209 - 3800 m). For each species, we calculated the maximum annual variation in temperature experienced across its elevational distribution. We used phylogenetic generalized least square models to evaluate the effect of thermal variability on range size. Our models included additional covariates that might affect range size: body size, local abundance, mean temperature and total precipitation. We also considered interactions between thermal variability and mean temperature or precipitation. To account for geometric constraints, we repeated our analyses with a standardized measure of range size, calculated by comparing observed range sizes with values obtained from a null model. ResultsOur results supported the main prediction of the climate variability hypothesis. Thermal variability had a strong positive effect on the range size, with species exposed to higher thermal variability having broader elevational distributions. Body size and local abundance also had positive, yet weak effects, on elevational range size. Furthermore, there was a strong positive interaction between thermal variability and mean annual temperature. Main conclusionsThermal variability had an overriding importance in driving elevational range sizes of woody plants in the Central Andes. Moreover, the relationship between thermal variability and range size might be even stronger in warmer regions, underlining the potential vulnerability of tropical montane floras to the effects of global warming.

ecology↗

bioRxiv2021

Relative effects of edaphic conditions and climate on palm communities in the Central Andes

Palms (family Arecaceae) are conspicuous and structural elements in forests ecosystems of tropical regions and mountain forests in South America. Additionally, many species of palms are culturally and economically important to human populations. Because of their ecological and ethnobotanical significance, understanding the drivers of palm distribution and diversity is critical. However, most past research has focused in tropical lowland palm communities, while our understanding of montane tropical palm ecology and biogeography is comparatively lacking. We investigate the environmental factors that influence patterns of richness, composition, and abundance of palms in the Central Andes. In particular, we are interested in the relative effects that soil edaphic conditions and climate have on palm community structure. For these analyses, we used a network of 88 forest plots distributed along a broad elevational gradient (1,000 - 3,200 meters), which are part of the Madidi Project in north-western Bolivia. We carried out palm community-level analysis, as well as species-specific analyses for each of the 16 most common species. We found that soils and climate contribute differentially to shaping Andean palm diversity and distributions. We found that soils explain more variation in species composition (14.4%) than climate (3.45%), but that climate explains more variation in species richness (13%) than soils (6.1%). Moreover, species-specific analyses reveal that there is great variation in how different common species respond to their abiotic environment. Our results contribute to understanding the drivers of biodiversity for a highly important group of plants in one of the most important hotspots for biodiversity. RESUMENEn el neotropico, las palmeras (Arecaceae) son un grupo diverso y abundante de plantas que constituyen elementos estructurales en bosques tropicales tanto de tierras bajas como de montana. Ademas, muchas especies de palmeras son culturalmente y economicamente importantes para muchas poblaciones humanas. Debido a su importancia ecologica y etnobotanica, entender los mecanismos que controlan la diversidad y la distribucion de las palmeras es extremadamente importante. Sin embargo, la mayoria de la investigacion hasta el momento se ha enfocado en comunidades de palmeras de tierras bajas, mientras que la ecologia y biogeografia de las palmeras de montanas es relativamente poco entendida. En este estudio, nosotros investigamos los factores ambientales que influencian la riqueza, composicion y abundancia de palmeras en los Andes Centrales. En particular, estamos interesados en entender los efectos relativos de las condiciones edaficas del suelo y el clima en la estructura de comunidades de palmeras. Para nuestros analisis, usamos una red de 88 parcelas de arboles distribuidas a lo largo de un gradiente elevacional (1,000 - 3,200 metros), la misma que es parte del Proyecto Madidi en Bolivia. Encontramos que el suelo y el clima tienen efectos diferentes. El suelo explica mas variacion en la composicion de especies (14.4%) que el clima (3.45%), pero el clima explica mas variacion en la riqueza de especies (13%) que los suelos (6.1%). Ademas, analisis independientes para las 16 especies mas comunes demuestran gran variacion en como cada especie responde a las condiciones ambientales. Nuestros resultados contribuyen a entender los factores que controlan la diversidad de un grupo importante de plantas en una de las regiones mas diversas del planeta.

ecology↗

bioRxiv2020

The evolutionary assembly of forest communities along environmental gradients: recent diversification or sorting of pre-adapted clades?

O_LIBiogeographic events occurring in the deep past can contribute to the structure of modern ecological communities. However, little is known about how the emergence of environmental gradients shape the evolution of species that underlie community assembly. In this study, we address how the creation of novel environments lead to community assembly via two non-mutually exclusive processes: 1) the immigration and ecological sorting of pre-adapted clades (ISPC), and 2) recent adaptive diversification (RAD). We study these processes in the context of the elevational gradient created by the uplift of the Central Andes. C_LIO_LIWe develop a novel approach and method based on the decomposition of species turnover into within- and among-clade components, where clades correspond to lineages that originated before mountain uplift. Effects of ISPC and RAD can be inferred from how components of turnover change with elevation. We test our approach using data from over 500 Andean forest plots. C_LIO_LIWe found that species turnover between communities at different elevations is dominated by the replacement of clades that originated before the uplift of the Central Andes. C_LIO_LIOur results suggest that immigration and sorting of clades pre-adapted to montane habitats is the primary mechanism shaping communities across elevations. C_LI

ecology↗

bioRxiv2019

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 two compounds that have entered 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 Alzheimers Disease (AD). Of interest, we have found that sEH is upregulated in brains from AD patients. We have evaluated the cognitive impairment and the pathological hallmarks in two models of age-related cognitive decline and AD using three structurally different and potent sEH inhibitors as chemical probes. Our findings supported our expectations on the beneficial effects of central sEH inhibition, regarding of reducing cognitive impairment, tau hyperphosphorylation pathology and the number of amyloid plaques. Interestingly, our results suggest that reduction of inflammation in the brain is a relevant therapeutic strategy for all stages of AD.

pharmacology and toxicology↗