Biology subjects

Garcia-Garcia, F.

Publications and source records attributed to Garcia-Garcia, F..

At least 19 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

Urinary extracellular vesicles reveal a sex-specific miRNome profile in alcohol use disorder patients

miRNA-based transcriptomic analysis of extracellular vesicles (EVs) provide a promising strategy for identifying non-invasive biomarkers and understanding complex pathological mechanisms. Recently, however, urinary extracellular vesicles (uEVs) have emerged as a valuable window into molecular alterations. Despite the high morbidity and mortality associated with alcohol use disorder (AUD), the molecular mechanisms underlying its sex-specific differences remain poorly understood. To address this, we characterize for the first time the uEV miRNome in AUD, revealing its sexually dimorphic profile. We employed uEVs from actively drinking AUD patients of both sexes who did not have advanced liver disease, alongside matched controls. Deep sequencing revealed 14 differentially expressed miRNAs in females (e.g., hsa-miR-197-3p, hsa-miR-19b-3p, hsa-miR-505-3p, hsa-miR-625-5p, and hsa-miR-27a-5p) and 6 in males (e.g., hsa-miR-1290, hsa-miR-1246, hsa-miR-450a-5p, and miR-590-5p). Notably, whereas hsa-miR-4787-5p was consistently overexpressed in uEVs from both sexes, it was absent in plasma-derived EVs, highlighting the specificity of the urinary compartment. Remarkably, the miRNA signatures we uncovered reflect the multiorgan impact of AUD. For instance, hsa-miR-1290 and hsa-miR-197-3p point to alcohol-related liver injury and systemic inflammation, whereas hsa-miR-19b-3p and hsa-miR-1246 signal neuroinflammation and neuronal stress. A subset--including hsa-miR-1290, hsa-miR-1246, and hsa-miR-27a-5p--has been implicated in cancer contexts. Collectively, these findings support the uEV miRNome as a promising sex-informed molecular signature of AUD with biomarker and mechanistic relevance.

cell 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↗

bioRxiv2026

MetaOmixTools: an interactive web suite for meta-analysis of ranked features and functional enrichment

The growing number of omics datasets in public repositories provides an opportunity to enhance data reusability through data integration; however, complex statistical barriers often hinder the effective combination of independent studies. To address this problem, we present MetaOmixTools, an interactive web-based suite that streamlines the meta-analysis of ranked feature lists and functional enrichment profiles. The platform integrates two primary modules - MetaRank and MetaEnrich within a code-free environment. MetaRank generates robust consensus rankings from multiple lists by implementing weighted (e.g., Rank Product) and unweighted (e.g., Robust Rank Aggregation) strategies, while MetaEnrich performs functional meta-analyses by combining probability values from individual over-representation analyses using established statistical techniques. Using case studies, we established consensus rankings for acute spinal cord injury across heterogeneous platforms, identifying conserved inflammatory marker genes in the upregulated gene list (e.g., Slpi, Ccl2, Msr1) and synaptic loss genes in the downregulated gene list (e.g., Kcna2, Dao, Ppp1r1b), and also characterized inverse functional intersections between melanoma brain metastasis and neurodegenerative diseases. By providing intuitive, real-time visualization and reproducible workflows, MetaOmixTools empowers the research community to extract consistent biological insights from multi-study data. We have made MetaOmixTools freely available at https://bioinfo.cipf.es/metaomixtools/. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=163 HEIGHT=200 SRC="FIGDIR/small/707748v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@c1974org.highwire.dtl.DTLVardef@5b4b38org.highwire.dtl.DTLVardef@1a753f8org.highwire.dtl.DTLVardef@79fb20_HPS_FORMAT_FIGEXP M_FIG C_FIG

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↗

bioRxiv2025

Deciphering lipidomics landscape of urine extracellular vesicles in alcohol use disorder patients

Urine extracellular vesicles (EVs) have garnered increasing interest in recent years as, in combination with their lipid content, they represent a potential source of non-invasive biomarkers. Alcohol use disorder (AUD) is one of the most common psychiatric disorders and a significant contributor to morbimortality. Thus, there is growing interest in assessing previous alcohol consumption and evaluating the severity of liver or brain injury, particularly via non-invasive methods. Here, we employed a novel approach based on urine EVs and a highly sensitive lipidomics strategy to characterize lipid species in male AUD patients, as well as to evaluate the differential functional roles and enzymatic activity networks of urine EV lipids. Our results show, for the first time, that the lipidomic profiling of urine EVs in AUD males is characterized by an enrichment of fatty acyls and glycerophospholipids, with FA 22:0 emerging as a potential biomarker. Notably, increased acyl chain saturation and elevated long-chain fatty acids (22-24 carbons) suggest links to AUD-associated inflammation, cancer, and metabolic dysfunction. These findings support an improved understanding of the urine EV lipidome, which could contribute to the identification of novel lipid targets and the discovery of non-invasive biomarkers in AUD.

pathology↗

bioRxiv2025

Transcriptomic meta-analysis in plaque psoriasis: an integrative bioinformatic approach to deciphering the genetic landscape and molecular pathways

Psoriasis is a chronic inflammatory skin disease influenced by both genetic and environmental factors. Despite extensive research, its precise etiology remains unclear, posing significant challenges to understanding and treatment. The disease pathogenesis involves self-reactive T cells and immune-related cytokines. Genome-wide association studies have identified various susceptibility loci for immune-related diseases, but the underlying mechanisms remain only partially understood. Recent discoveries of critical signaling pathways, biological processes, and immune cell involvement have expanded our knowledge and offer hope for improved therapeutic strategies. This study aimed to enhance our understanding of psoriasis and proposes novel therapeutic approaches by employing integrated bioinformatics to identify signaling pathways and biological processes as potential disease markers. Presenting a systematic review and taking a meta-analytical approach to transcriptomic profiles, this investigation examined differential gene expression patterns across 44 studies involving 975 samples comparing lesional psoriasis, non-lesional psoriasis, and healthy controls. Consensus transcriptome signatures revealed a significant association between immune-related genes and psoriasis pathogenesis. Functional enrichment analysis identified several enriched pathways related to immunity and immune system processes. Comparison of these findings with the existing literature indicated that some immune-related genes were already known, while others are novel in the context of psoriasis. Additionally, novel gene analysis demonstrated psoriasis involvement in pathways such as gluconeogenesis, the FoxO signaling pathway, and mitophagy. This integrative approach confirmed classic genetic associations while uncovering novel gene expression patterns and pathways relevant to psoriasis. Notably, the disruption of the gluconeogenesis pathway emerged as a critical finding. These insights enhance our understanding of psoriasis pathophysiology and pave the way for targeted therapies, offering improved management options for affected individuals.

molecular biology↗

bioRxiv2025

Monocarboxylate transporter 2 is required for the maintenance of myelin and axonal integrity by oligodendrocytes

Neurodegenerative pathologies including multiple sclerosis (MS) are consistently associated with energy deficit in the central nervous system (CNS). This might directly impact myelinating oligodendrocytes as these are particularly vulnerable to metabolic insults. Importantly, oligodendroglial dysfunction and myelin alterations occur in most, if not all neurodegenerative diseases, and are associated with axonal pathology/loss. Thus, elucidating metabolic mechanisms required for oligodendroglial myelin maintenance and axonal support might be crucial to identify therapeutic targets to achieve neuroprotection. While monocarboxylates are important energy fuels for the CNS, their role in myelinating oligodendrocyte function remains unclear. Here we show that, just like neurons, myelinating oligodendrocytes express high affinity monocarboxylate transporter 2 (MCT2) both in mice and humans, which is downregulated in progressive MS. While deletion of MCT2 in mouse oligodendrocytes did not affect the survival of these cells, it resulted in downregulation of lipid synthesis-associated enzymes and failure of myelin maintenance. Moreover, axonal upregulation of lactate dehydrogenase A concomitant with axonal damage was observed but could be alleviated by ketogenic diet. We conclude that oligodendroglial MCT2 is required for myelin maintenance and axonal support, which becomes altered in progressive MS, but may be compensated for by specific metabolic therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/632306v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@2b7b22org.highwire.dtl.DTLVardef@a111fdorg.highwire.dtl.DTLVardef@a410f5org.highwire.dtl.DTLVardef@1556e2f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

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

Unveiling the role of miRNAs from MSC-EVs in neuroinflammation and behavioral impairments induced by chronic alcohol consumption

Extracellular vesicles derived from mesenchymal stromal cells (MSC-EVs) have emerged as a promising form of regenerative and immunomodulatory therapy; indeed, micro (mi)RNAs contained within MSC-EVs modulate target gene expression and impact disease-associated pathways. Chronic alcohol consumption results in neuroinflammation, brain damage, and impaired cognition; in this study, we asked whether the repeated intravenous administration of MSC-EVs could ameliorate neuroinflammation and behavioral impairment induced by chronic alcohol consumption in mice. MSC-EVs diminished the increased binding of a micro-positron emission tomography tracer (18F-FDG) when analyzing whole-brain 3D images and brain coronal sections of ethanol-treated mice. MSC-EV administration protected against ethanol-induced proinflammatory gene upregulation, cognitive dysfunction, and addictive-like behavior. miRNA sequencing data from MSC-EVs helped to reveal the elevated expression of EV-derived miR-483-5p and miR-140-3p in the brains of ethanol-treated mice following MSC-EV administration. In addition, MSC-EVs modulated the expression of pro-inflammatory-related miRNA target genes (e.g., Socs3, Tnf, Mtor, Atf6) in the brains of ethanol-treated mice. These results suggest that MSC-EVs could function as a neuroprotective therapy to ameliorate the neuroinflammation, cognitive dysfunction, and addictive-like behavior associated with chronic alcohol consumption.

neuroscience↗

bioRxiv2024

Transcriptomic landscape of sex differences in obesity and type 2 diabetes in subcutaneous adipose tissue

Obesity represents a significant risk factor in the development of type 2 diabetes (T2D), a chronic metabolic disorder characterized by elevated blood glucose levels. Significant sex differences have been identified in the prevalence, development, and pathophysiology of obesity and T2D; however, the underlying molecular mechanisms remain unclear. This study aims to identify sex-specific biomarkers in obesity and T2D and enhance our understanding of the underlying mechanisms associated with sex differences by integrating expression data. A systematic review, individual transcriptomic analysis, gene-level meta-analysis, and functional characterization were performed to achieve this aim. Eight studies and 236 subcutaneous adipose tissue samples were analyzed, identifying common and sex-specific biomarkers, many of which were previously associated with obesity or T2D. The obesity meta-analysis yielded nineteen differentially-expressed biomarkers from a sex-specific perspective (e.g., SPATA18, KREMEN1, NPY4R, and PRM3), while a comparison of the expression profiles between sexes in T2D prompted the identification and validation of specific transcriptomic signatures in males (SAMD9, NBPF3, LDHD, and EHD3) and females (RETN, HEY1, PLPP2, and PM20D2). At the functional level, we highlighted the fundamental role of the Wnt pathway in the development of obesity and T2D in females and the roles of more significant mitochondrial damage and free fatty acids in males. Overall, our sex-specific meta-analyses supported the detection of differentially expressed genes in males and females associated with the development of obesity and T2D, emphasizing the relevance of sex-based information in biomedical data and opening new avenues for research. HighlightsO_LIFirst meta-analysis on WAT with sex as a central perspective in obesity and T2D C_LIO_LIThis study identifies 19 sex-differential biomarkers in obesity, highlighting NPY4 C_LIO_LISex specific transcriptional signatures in SAT in the development of T2D C_LIO_LIWnt pathway genes show sex-specific roles in obesity and T2D, notably in females C_LIO_LIObesity increases mitogenesis in male, mediated by SPATA18, with an increased role of free fatty acids in T2D C_LI

molecular biology↗

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↗

bioRxiv2024

A spinal cord injury time and severity consensus transcriptomic reference suite in rat reveals translationally-relevant biomarker genes

Spinal cord injury (SCI) is a devastating condition that leads to motor, sensory, and autonomic dysfunction. Current therapeutic options remain limited, emphasizing the need for a comprehensive understanding of the underlying SCI-associated molecular mechanisms. This study characterized distinct SCI phases and severities at the gene and functional levels, focusing on biomarker gene identification. Our approach involved a systematic review, individual transcriptomic analysis, gene meta-analysis, and functional characterization. We compiled a total of fourteen studies with 273 samples, leading to the identification of severity-specific biomarker genes for injury prognosis (e.g., Srpx2, Hoxb8, Acap1, Snai1, and Aadat) and phase-specific genes for the precise classification of the injury profile (e.g., Il6, Fosl1, Cfp, C1qc, Cp). We investigated the potential transferability of severity-associated biomarkers and identified a twelve-gene signature that predicted injury prognosis from human blood samples. We also report the development of MetaSCI-app - an interactive web application designed for researchers - that allows the exploration and visualization of all generated results (https://metasci-cbl.shinyapps.io/metaSCI). Overall, we present a transcriptomic reference and provide a comprehensive framework for assessing SCI considering severity and time perspectives. TeaserA transcriptomic meta-analysis of spinal cord injury provides a consensus reference and biomarker genes for injury phase/severity.

neuroscience↗

bioRxiv2024

Unveiling common transcriptomic features between melanoma brain metastases and neurodegenerative diseases

Melanoma represents a critical clinical challenge due to its high incidence rates and unfavorable clinical outcomes. This type of skin cancer presents unique adaptability to the brain microenvironment, but its underlying molecular mechanisms are poorly understood. To further characterize its tumor neurobiology, we explore the relation between the transcriptional profiles of melanoma brain metastasis (MBM) and the neurodegenerative diseases Alzheimers disease, Parkinsons disease, and multiple sclerosis. Through an in silico approach, we unveiled the neurodegenerative signature of MBM when compared to melanoma non-brain metastasis (53 dysregulated genes enriched in 11 functional terms) and to non tumor-bearing brain controls (195 dysregulated genes, mostly involved in development and cell differentiation, chromatin remodeling and nucleosome organization, and translation). Two genes, ITGA10 and DNAJC6, emerged as key potential markers, as they are dysregulated in both scenarios. Lastly, we developed a user-friendly web tool (https://bioinfo.cipf.es/metafun-mbm/) as an open source, so that any user can interactively delve into the results.

cancer biology↗

bioRxiv2023

Emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

NOD-like receptors are innate immunity sensors that provide an early and effective response to pathogenic or injury conditions. However, abnormalities in these receptors may cause excessive inflammation. Our studies have reported that an activation of the NLRP3-inflammasome complex in ethanol-treated astrocytes and in chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Considering the therapeutic role of the molecules contained in the extracellular vesicles (EVs) derived by mesenchymal stem cells (MSC-EVs), the present study aims to evaluate whether the intravenous administration of MSC-EVs from adipose tissue, through inhibiting the NLRP3 inflammasome activation, is capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrate that MSC-EVs ameliorate the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., NLRP1, NLRC4 and AIM2), as well as the alterations of inflammatory genes (IL-1{beta}, IL-18, iNOS, NF-{kappa}B, MCP-1 and CX3CL1) and miRNAs (miR-21a-5p, miR-146a-5p and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice. Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways. Taken together, these findings provide, for the first time, evidence of the therapeutic potential of MSC-derived EVs to restore the hippocampal neuroinflammatory response through the NLRP3 inflammasome activation induced by binge drinking in adolescence.

neuroscience↗

bioRxiv2023

Novel diagnosis and progression microRNA signatures in melanoma

Melanoma incidence is rising, and accurate risk stratification remains challenging because of the molecular heterogeneity underlying disease progression. Specifically, the transition from benign nevi to malignant melanoma and the acquisition of the aggressive ulcerated phenotype represent critical barriers in clinical management that require novel biomarkers. In addition, there is a critical need for novel biomarkers to identify patients with primary melanoma who, despite complete surgical resection, remain at high risk of recurrence and would benefit from adjuvant therapy. We applied an integrative systems biology approach to decipher the miRNA-dependent regulatory architecture of melanoma. Following PRISMA guidelines, we conducted a robust meta-analysis of six independent transcriptomic studies, overcoming inter-study heterogeneity. This was coupled with network inference algorithms to construct validated miRNA-mRNA interactomes and identify dynamic functional modules. In the diagnostic scenario, we identified a consensus signature of 24 miRNAs. Network topology analysis revealed hsa-miR-142-5p as a master regulator that orchestrates the dismantling of the Oncogene-Induced Senescence (OIS) barriers by targeting CDK6, SIRT1, and TGFBR2. In the prognostic scenario (ulceration), we identified a specific "stress-adaptive" signature of 23 miRNAs. Notably, the upregulation of hsa-miR-223-3p emerged as a key driver of invasiveness by suppressing the motility-limiting tumor suppressor RHOB, while the concurrent loss of hsa-miR-200c and hsa-miR-489-3p may unleash Epithelial-Mesenchymal Transition (EMT) and EGFR-driven survival pathways. Our study supports a double-switch mechanism where specific miRNA alterations first drive senescence escape and subsequently promote survival in the hypoxic ulcerated niche. These signatures offer robust biomarkers for diagnosis and highlight the miR-142-5p/CDK6 and miR-223-3p/RHOB axes as potential therapeutic targets for precise intervention.

cancer biology↗