Biology subjects

Galiana-Rosello, C.

Publications and source records attributed to Galiana-Rosello, C..

8 recordsLinked to original sources

bioRxiv2026

A sphingomyelin-cholesterol complex regulates TLR4 activation in microglia

Microglial activation in response to lipopolysaccharide (LPS) requires Toll-like receptor 4 (TLR4) redistribution into cholesterol- and sphingolipid-rich membrane domains, yet the lipid determinants of this process remain unclear. Here, we identify cholesterol accessibility as a key driver of TLR4-dependent microglial activation. We show that LPS increases cholesterol uptake and mobilization, whereas inhibition of intracellular cholesterol trafficking or the plasma membrane-to-ER cholesterol transporter Aster attenuates inflammatory responses. Scavenger receptor class B type 1 (SR-B1) mediates LPS-induced cholesterol uptake, and its inhibition suppresses TLR4 signaling, receptor recruitment to detergent-resistant membrane domains, and TLR4 endocytosis without altering bulk cellular cholesterol. Instead, SR-B1 inhibition remodels the sphingolipidome and expands the sphingomyelin-associated cholesterol pool, as detected by OlyA, while LPS promotes remodeling of this pool and increases accessible cholesterol detected by D4H. Manipulation of sphingomyelin-cholesterol interactions alters membrane properties and TLR4 trafficking, while stabilization of these complexes suppresses inflammatory activation. In vivo, LPS induces remodeling of sphingomyelin-associated cholesterol in microglia, whereas Alzheimer's disease-related ApoE4/Trem2R47H microglia show impaired cholesterol-pool remodeling and enhanced inflammatory responses. Together, these findings establish sphingolipid-dependent cholesterol accessibility as a key regulatory layer controlling TLR4 organization and microglial inflammatory activation, positioning SR-B1 as an upstream regulator of this lipid-signaling axis.

molecular biology↗

bioRxiv2026

Integrative multi-cohort analysis reveals consistent sex differences in gut microbiota of multiple sclerosis patients

Biological sex is a key determinant in the onset and progression of multiple diseases. In multiple sclerosis (MS), females exhibit higher disease prevalence, earlier onset, and more pronounced inflammatory activity, whereas males tend to experience a more severe neurodegenerative course, characterized by accelerated central nervous system damage and increased brain atrophy. The gut microbiome has emerged as a critical factor in MS, as its composition can either ameliorate or exacerbate disease progression. In this study, we aimed to identify reproducible sex-associated differences in gut microbial composition across independent cohorts of MS patients. Through a systematic search we identified six independent studies based on 16S rRNA gene sequencing, comprising a total of 337 samples. Despite substantial inter-study variability, sex-associated differences were more pronounced in MS patients than in healthy controls. We identified 11 microbial taxa showing significant sex-associated differences in MS, nine enriched in females and two in males. Notably, the female-enriched taxa Eggerthella and Eisenbergiella were associated with specific MS subtypes and higher disability. To facilitate the use of our findings by the scientific community, we developed a freely accessible web-based tool that provides full access to our results. Thus, in this work we identified consistent and reproducible sex differences in the gut microbiota of MS patients, highlighting the importance of incorporating sex as a critical variable in microbiome research, with potential implications for understanding disease heterogeneity in MS. IMPORTANCEMultiple sclerosis (MS) affects females and males differently, but the biological reasons behind these differences are not fully understood. One potential factor is the gut microbiome (i.e., the community of microorganisms living in our intestines) which can influence immune function and disease progression. In this study, we analyzed data from multiple independent cohorts and found consistent differences in gut microbial composition between female and male MS patients. Notably, certain bacteria were more abundant in females and were linked to more severe disease features. We also developed a freely accessible web tool where researchers can explore the complete findings in detail. Our results highlight the importance of considering sex as a key factor in microbiome research and may help guide more personalized approaches to understanding and treating MS.

neuroscience↗

bioRxiv2026

Transposable elements as new players to decipher sex differences in Parkinson Disease

We present a novel integrative analysis of transposable elements (TEs) in 4 single cell RNA-seq (scRNA-seq) datasets of postmortem substantia nigra pars compacta samples of Parkinson Disease (PD) patients matched healthy controls, with the objective of building a cell-type specific trustworthy atlas of TEs that may clarify the role of TEs in sex differences in PD. We have used the soloTE tool to evaluate the TEs expression changes across all snRNA-seq studies identified in our previous systematic review, and then integrated the results using meta-analysis techniques. Finally, we evaluated the possible associations between TEs and protein coding genes by integrating our previous results in this matter with the information of TEs obtained, in order to propose the possible action mechanism by which some of the TEs contribute to PD.

bioinformatics↗

bioRxiv2025

Multi-omics integration reveals sex-based differences in the circulating extracellular vesicle lipidome and miRNome of alcohol use disorder patients

Integrated multi-omics and extracellular vesicle (EV) analysis are emerging as powerful, complementary strategies for biomarker discovery. These approaches offer promising tools to enhance early detection, diagnosis, and treatment of alcohol use disorder (AUD). Here we applied an integrated miRNomic and lipidomic approach to analyze plasma EVs from AUD patients and controls of both sexes to gain a comprehensive understanding of the underlying molecular mechanisms. We identified an AUD signature with predictive potential for diagnostic applications. Individual features (e.g., hsa-miR-99b-3p, hsa-miR-556-5p, Cer_NDS-d39:1, and PI18:0_18:2) represented important components; however, the strength of this signature lay in the combined profile rather than isolated markers. We also revealed an AUD-sex signature that provided insight into how biological responses to alcohol differ between females and males (including features such as hsa-miR-1301-3p and PC39:4), which also underscored the power of multi-omic integration. The individual miRNome approach also revealed an opposite functional alteration by sex in various alcohol related systems, such as pathways associated with immunity, oxidative stress, and autophagy. An open-access Shiny web application (https://carpercle.shinyapps.io/SexEVEthOmics/) accompanies this study, providing interactive access to the complete dataset and additional analyses for customized exploration. Together, our findings underscore the added value of multi-omics integration in identifying clinically relevant molecular signatures of disease; this sex-informed approach offers a promising path toward more personalized diagnostic tools and therapeutic strategies in AUD.

bioinformatics↗

bioRxiv2024

Uncovering sex differences in Parkinson's Disease through metaanalysis of single cell transcriptomic studies

Abundant evidence supports the significant impact of biological sex on various aspects of Parkinson Disease (PD), including incidence, progression, symptoms or response to treatment. The incidence and prevalence of the disease is higher in males, while its age of onset is earlier than in females. There are also sex differences in the symptomatology, both motor and non-motor. In female PD, tremor, pain, depression and dysphagia are predominant, whereas in male PD, freezing of gait, camptocormia, cognitive impairment and urinary dysfunction are more common. Likewise, there are sex differences in the pathophysiology of the disease, related to most of the pathological processes of PD, as is the case of the greater activation of microglia in males or the lower oxidative stress in females. All these findings support the idea that different molecular mechanisms may be involved in PD depending on the sex of the patient. Some explanations for these events are related to biological, genetic, hormonal or environmental factors, such as the possible anti-inflammatory and neuroprotective effect of estrogens. However, the underlying molecular mechanisms have not yet been fully described. Our results show sex differences in gene expression, cell-cell communication and pathway activation in all major brain cell types, highlighting the presence of greater neuroinflammation in men and greater neurodegeneration in the SNpc in men, with the latter appearing to be inverted between sexes when observed in the cortical zone. Finally, we have made all the results available in a publicly accessible webtool, in order to allow the exploration of results to other researchers and to broaden the molecular-level understanding of PD sex differences.

neuroscience↗

bioRxiv2024

Unravelling the impact of TLR4 and sex on chronic alcohol consumption-induced lipidome dysregulation in extracellular vesicles

The lipids that form extracellular vesicles (EVs) play critical structural and regulatory roles, and cutting-edge bioinformatics strategies have shown the ability to decipher lipid metabolism and related molecular mechanisms. We previously demonstrated that alcohol abuse induces an inflammatory immune response through Toll-like receptor 4 (TLR4), leading to structural and cognitive dysfunction. This study evaluated how TLR4 and sex as a variable (male/female) impact the lipidome of plasma-resident EVs after chronic alcohol exposure. Using a mouse model of chronic ethanol exposure in wild-type and TLR4-deficient mice, enrichment networks generated by LINEX2 highlighted significant ethanol-induced changes in the EV lipid substrate-product of enzyme reactions associated with glycerophospholipid metabolism. We also demonstrated ethanol-induced differences in Lipid Ontology enrichment analysis in EVs, focusing on terms related to lipid bilayer properties. A lipid abundance analysis revealed higher amounts of significant lipid subclasses in all experimental comparisons associated with inflammatory responses and EV biogenesis/secretion. These findings suggest that interrogating EV lipid abundance with a sensitive lipidomic-based strategy can provide deep insight into the molecular mechanisms underlying biological processes associated with sex, alcohol consumption, and TLR4 immune responses and open new avenues for biomarker identification and therapeutic development.

neuroscience↗

bioRxiv2024

Single cell landscape of sex differences in the progression of multiple sclerosis

BackgroundOne of the major challenges in addressing multiple sclerosis is to understand its progression trajectory. The pathological process transitions from acute phases predominantly driven by inflammation to progressive clinical profiles where neurodegeneration takes precedence. It is known that sex plays a crucial role in this heterogeneity; females are two to three times more likely to suffer from multiple sclerosis, while males suffer from more rapid neurodegeneration with greater severity. ResultsTo gain insight into the sex-based molecular differences, we processed single cell datasets from the central nervous system and the peripheral blood, covering the different courses of multiple sclerosis. We generated cell-type specific landscapes, including gene signatures from differentially expressed genes, functional profiling, pathway activation, and cell-cell communication networks for females, males, and their sex differential profiles. Among our findings, we revealed that female neurons may exhibit protective mechanisms against neurodegeneration. In the inflammatory-predominant forms, female immune cells present an inflammatory core driven by the AP-1 transcription factor, while male adaptive immune cells exhibit higher mitochondrial impairment. Conversely, larger differences are reported in CD8+ T cells progressive forms, with males exhibiting cytolytic profiles that may promote neurodegeneration. Complete results can be explored in the interactive webtool https://bioinfo.cipf.es/cbl-atlas-ms/. ConclusionsWe identified cell-type specific sex differences in brain and immune cells that vary in the spectrum of multiple sclerosis. We consider this molecular description a valuable resource to promote future targeted approaches considering the sex of the individual.

neuroscience↗

bioRxiv2023

Lipid network of plasma extracellular vesicles reveals sex-based differences in the lipidomic profile from patients with alcohol use disorder

Alcohol use disorder (AUD) is one of the most common psychiatric disorders, and the consumption of this substance is considered one of the main causes of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes, however little is known about the role of lipids containing extracellular vesicles (EVs), as regulatory molecules and biomarkers. In this study, a highly sensitive lipidomic strategy is employed to characterize plasma EV lipid species from individuals with AUD, to evaluate differential functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism in the alcohol consumption. Plasma EV lipids from female and male patients with AUD and healthy individuals were analyzed to obtain lipid differential abundance, as well as biological interpretation of LINEX2 lipidomics data, evaluating enzymatic dysregulation through an enrichment algorithm. Our results showed for the first time that females with AUD exhibit greater substrate-product changes in LPC and PC lipids, as well as phospholipases and acyltransferases activity, potentially linked to cancer progression and neuroinflammation. Conversely, males with AUD showed dysregulation in Cer and SM lipid, involving sphingomyelinases, sphingomyelin phosphodiesterase, and sphingomyelin synthase, which could be related with hepatotoxicity. Notably, females with AUD showed LION-terms associated with "positive intrinsic curvature", while males exhibited "negative intrinsic curvature, contributing to vesicle fusion processes. These methodological developments allow a better understanding of lipid metabolism and its regulatory mechanisms, which contributes not only to identify novel lipid targets, but also the discovery of sex-specific clinical biomarkers in the AUD.

pathology↗