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Soriano, S.

Publications and source records attributed to Soriano, S..

12 recordsLinked to original sources
bioRxiv2025

Sex-specific effects of fecal microbiota transplantation on TBI-exacerbated Alzheimer's pathology in mice

BackgroundTraumatic brain injury (TBI) accelerates Alzheimers disease (AD) pathology and neuroinflammation, potentially via gut-brain axis disruptions. Whether restoring gut microbial homeostasis mitigates TBI-exacerbated AD features remains unclear, particularly with respect to sex differences. ObjectiveThe goal of our study was to test whether fecal microbiota transplantation (FMT) modifies amyloid pathology, neuroinflammation, gut microbial composition, metabolites, and motor outcomes in male and female 5xFAD mice subjected to TBI. MethodsMale and female 5xFAD mice received sham treatments or controlled cortical impact, followed 24 hours later by vehicle (VH) or sex-matched FMT from C57BL/6 donors. Assessments at baseline, 1, and 3 days post-injury included Thioflavin-S and 6E10 immunostaining for A{beta}, Iba-1 and GFAP for glial activation, lesion volume, rotarod performance, 16S rRNA sequencing for microbiome profiling, serum short-chain fatty acids (SCFAs), and gut histology. ResultsTBI increased cortical and dentate gyrus A{beta} burden, with females showing greater vulnerability. FMT reduced A{beta} deposition in sham animals and shifted plaque morphology but did not attenuate TBI-induced amyloid escalation. FMT differentially modulated glial responses by sex and region (reduced microgliosis in males) without altering lesion volume. Rotarod performance was better in sham females compared to males and declined in FMT-treated TBI females. Fecal microbiome alpha diversity and richness were unchanged, while beta diversity revealed marked, time-dependent community shifts after TBI that were slightly altered by FMT. Gut morphology remained broadly intact, but crypt width increased after TBI, particularly in males. ConclusionIn 5xFAD mice, TBI drives sex-dependent worsening of amyloid pathology, neuroinflammation, and dysbiosis. Acute FMT partially restores microbial composition and plaque features in sham animals but fails to reverse TBI-induced neuroinflammation or motor deficits. These findings underscore the context- and sex-dependence of microbiome interventions and support longer-term, sex-specific strategies for AD with comorbid TBI.

neuroscience↗
bioRxiv2025

Increased TGFβ /Activin-Smad2 signaling is associated with pancreatic β-cell dysfunction and glucose intolerance in gestational diabetes mellitus

BackgroundGestational diabetes mellitus (GDM) is the most common metabolic disease during pregnancy and increases the prevalence of type 2 diabetes in both mothers and offspring. GDM management provides a window of opportunity to prevent and lower the global burden of diabetes across life. Molecular mechanisms underlying GDM are poorly defined. In this study, we explore the potential involvement of transforming growth factor beta (TGF-{beta}) signaling in GDM as this pathway has been reported to affect pancreatic {beta}-cell development, proliferation and identity. MethodsWe developed a GDM animal model. Serum circulating levels of TGF{beta} family ligands were measured in mice and human GDM. Pancreatic TGF{beta} signaling was investigated at the level of gene and protein expression. ResultsOur GDM animal model recapitulates the main pathophysiological features of human GDM including glucose intolerance, decreased insulin sensitivity and pancreatic {beta}-cell malfunction. Islets from GDM mice showed impaired insulin secretion and content, altered ion channel activity, and decreased {beta}-cell replication rate. This was accompanied by increased Smad2 signaling activation. Elevated serum activin-A and inhibin levels were found in mice and human GDM, suggesting their role as upstream signaling transducers of pancreatic Smad2 activation. Pharmacological inhibition of TGF{beta}/Activin-Smad2 signaling in mouse pancreatic islets resulted in improved pancreatic {beta}-cell function and regeneration capacity of {beta}-cells. ConclusionsOur data disclose that disruption of pancreatic Smad2 pathway plays a critical role in the pathogenesis of GDM, contributing to abnormal glucose homeostasis and inadequate insulin secretion. Attenuation of this signaling pathway could represent a putative therapeutic target for GDM. HighlightsO_LIHigh fat diet just before and during pregnancy leads to gestational diabetes in mice. C_LIO_LIActivin and inhibin serum levels are increased in human and mice gestational diabetes. C_LIO_LIEnhanced pancreatic Smad2 signaling contributes to inadequate insulin secretion in gestational diabetes. C_LIO_LIInhibition of Smad2 signaling improves pancreatic {beta}-cell function and proliferation. C_LI

physiology↗
bioRxiv2024

Antibiotic treatment induces microbiome dysbiosis and reduction of neuroinflammation following traumatic brain injury in mice.

Traumatic brain injury (TBI) induces both neuroinflammation and gut microbiome dysbiosis, yet the influence of antibiotics (ABX) on TBI-related neuropathology remains unclear. We administered a broad-spectrum oral ABX regimen to deplete the gut microbiome in single and repeated TBI mouse models. In male mice, ABX treatment significantly reduced neuroinflammation and neurodegeneration post-TBI, with no effects observed in uninjured controls. ABX also altered microbiome composition and decreased serum and fecal short-chain fatty acid levels, while intestinal damage and dysbiosis were further exacerbated by TBI severity. Notably, germ-free male mice exhibited heightened neuroinflammation and larger lesion volumes following TBI, underscoring the microbiomes essential role in recovery. Metagenomic analyses revealed Parasutterella excrementihominis and Lactobacillus johnsonii as potential ABX-resistant taxa post-injury. These findings suggest that short-term ABX treatment may attenuate TBI-induced neuroinflammation by reshaping the gut microbiome, offering directions for microbiome-targeted therapies in TBI.

neuroscience↗
bioRxiv2024

Probiotic treatment causes sex-specific neuroprotection after traumatic brain injury in mice

BackgroundRecent studies have shed light on the potential role of gut dysbiosis in shaping traumatic brain injury (TBI) outcomes. Changes in the levels and types of Lactobacillus bacteria present might impact the immune system disturbances, neuroinflammatory responses, anxiety and depressive-like behaviors, and compromised neuroprotection mechanisms triggered by TBI. ObjectiveThis study aimed to investigate the effects of a daily pan-probiotic (PP) mixture in drinking water containing strains of Lactobacillus plantarum, L. reuteri, L. helveticus, L. fermentum, L. rhamnosus, L. gasseri, and L. casei, administered for either two or seven weeks before inducing TBI on both male and female mice. MethodsMice were subjected to controlled cortical impact (CCI) injury. Short-chain fatty acids (SCFAs) analysis was performed for metabolite measurements. The taxonomic profiles of murine fecal samples were evaluated using 16S rRNA V1-V3 sequencing analysis. Histological analyses were used to assess neuroinflammation and gut changes post-TBI, while behavioral tests were conducted to evaluate sensorimotor and cognitive functions. ResultsOur findings suggest that PP administration modulates the diversity and composition of the microbiome and increases the levels of SCFAs in a sex-dependent manner. We also observed a reduction of lesion volume, cell death, and microglial and macrophage activation after PP treatment following TBI in male mice. Furthermore, PP-treated mice show motor function improvements and decreases in anxiety and depressive-like behaviors. ConclusionOur findings suggest that PP administration can mitigate neuroinflammation and ameliorate motor and anxiety and depressive-like behavior deficits following TBI. These results underscore the potential of probiotic interventions as a viable therapeutic strategy to address TBI-induced impairments, emphasizing the need for gender-specific treatment approaches.

neuroscience↗
bioRxiv2024

Counter-balancing X-linked Mecp2 hypofunction by hyperfunction ameliorates disease features in a model of Rett syndrome: implications for genetic therapies

Treating monogenic neurodevelopmental disorders remains challenging and mostly symptomatic. X-linked disorders affecting women such as the postnatal neurodevelopmental disorder Rett syndrome (caused by mutations in the gene MECP2) have additional challenges due to dosage sensitivity and to cellular mosaicism caused by random X-chromosome inactivation. An approach to augment MECP2 expression from wild-type cells in RTT may be feasible and simpler than gene replacement but has never been tested due to known toxicity of MECP2 over-expression, as evidenced by the distinct neurological condition known as MECP2 Duplication Syndrome. Here, using genetic techniques, we find that "counter-balancing" Mecp2-null cells in female Mecp2-null/+ mice by a complementary population of cells harboring an X-linked transgene associated with 3X normal levels of MECP2 leads to normalization of multiple whole animal phenotypic outcomes without noticeable toxicity. In addition, in vivo LFP recordings demonstrate that counter-balancing Mecp2 loss-of-function improves select within-region and between-region abnormalities. By comparing the counter-balance approach with an approach based on cell autonomous restoration of MeCP2 using an autosomal transgene expressing 2X normal levels of MECP2 in all cells (mimicking gene replacement), we identify neurobehavioral and electrographic features best suited for preclinical biomarkers of a therapeutic response to cell autonomous versus non-cell autonomous correction. Notably, these proof-of-concept findings demonstrate how non-cell autonomous suppression of MeCP2 deficiency by boosting overall wild-type MeCP2 levels may be a viable disease-modifying therapy for RTT, with potential implications for genetic-based therapies of monogenic X-linked disorders. One Sentence SummaryIn a mouse model of Rett syndrome, counterbalancing mosaic LOF with complementary mosaic GOF improves phenotypic outcome.

neuroscience↗
bioRxiv2023

Sex-dependent improvement in traumatic brain injury outcomes after liposomal delivery of dexamethasone in mice.

Traumatic Brain Injury (TBI) can have long-lasting physical, emotional, and cognitive consequences due to the neurodegeneration caused by its robust inflammatory response. Despite advances in rehabilitation care, effective neuroprotective treatments for TBI patients are lacking. Furthermore, current drug delivery methods for TBI treatment are inefficient in targeting inflamed brain areas. To address this issue, we have developed a liposomal nanocarrier (Lipo) encapsulating dexamethasone (Dex), an agonist for the glucocorticoid receptor utilized to alleviate inflammation and swelling in various conditions. In vitro studies show that Lipo-Dex were well tolerated in human and murine neural cells. Lipo-Dex showed significant suppression of inflammatory cytokines, IL-6 and TNF-, release after induction of neural inflammation with lipopolysaccharide. Further, the Lipo-Dex were administered to young adult male and female C57BL/6 mice immediately after a controlled cortical impact injury. Our findings demonstrate that Lipo-Dex can selectively target the injured brain, thereby reducing lesion volume, cell death, astrogliosis, the release of proinflammatory cytokines, and microglial activation compared to Lipo-treated mice in a sex-dependent manner, showing a major impact only in male mice. This highlights the importance of considering sex as a crucial variable in developing and evaluating new nano-therapies for brain injury. These results suggest that Lipo-Dex administration may effectively treat acute TBI.

neuroscience↗
bioRxiv2022

EXPLORING THE EFFECTS OF METABOLISM-DISRUPTING CHEMICALS ON PANCREATIC alpha-CELL BIOLOGY: A SCREENING TESTING APPROACH

Humans are constantly exposed to many environmental pollutants, some of which have been largely acknowledged as key factors in the development of metabolic disorders such as diabetes and obesity. These chemicals have been classified as endocrine-disrupting chemicals (EDCs) and, more recently, since they can interfere with metabolic functions, they have been renamed as metabolism-disrupting chemicals (MDCs). MDCs are present in many consumer products, including food packaging, personal care products, plastic bottles and containers, and detergents. The scientific literature has ever-increasingly focused on insulin-releasing pancreatic {beta}-cells as one of the main targets for MDCs. Evidence highlights that these substances may disrupt glucose homeostasis, altering pancreatic {beta}-cell physiology. However, their potential impact on glucagon-secreting pancreatic -cells remains poorly known despite the essential role that this cellular type plays in controlling glucose metabolism. In the present study, we have selected seven paradigmatic EDCs representing major toxic classes, including bisphenols, phthalates, perfluorinated compounds, metals, and pesticides. By using an in vitro cell-based model, the pancreatic -cell line TC1-9, we have explored the effects of these compounds on pancreatic -cell viability, gene expression, and secretion. Our results indicated that most of the selected chemicals studied caused functional alterations in pancreatic -cells. Moreover, we revealed, for the first time, their direct effects on key molecular aspects of pancreatic -cell biology.

pharmacology and toxicology↗
bioRxiv2022

SCREENING OF RELEVANT METABOLISM-DISRUPTING CHEMICALS ON PANCREATIC β-CELLS: EVALUATION OF MURINE AND HUMAN IN VITRO MODELS

Endocrine-disrupting chemicals (EDCs) are chemical substances that can interfere with the normal function of the endocrine system. EDCs are ubiquitous and can be found in a variety of consumer products such as food packaging materials, personal care and household products, plastic additives, and flame retardants. Over the last decade, the impact of EDCs on human health has been widely acknowledged as they have been associated with different endocrine diseases. Among them, a subset called metabolism-disrupting chemicals (MDCs) are able to promote metabolic changes that can lead to the development of metabolic disorders such as diabetes, obesity, hepatic steatosis, and metabolic syndrome, among others. Despite this, today, there are still no definitive and standardized in vitro tools to support the metabolic risk assessment of existing and emerging MDCs for regulatory purposes. Here, we evaluated two different pancreatic cell-based in vitro systems, the murine pancreatic {beta}-cell line MIN6 as well as the human pancreatic {beta}-cell line EndoC- {beta}H1. Both were challenged with a range of relevant concentrations of seven well-known EDCs (bisphenol-A (BPA), bisphenol-S (BPS), bisphenol-F (BPF), perfluorooctanesulfonic acid (PFOS), di(2-ethylhexyl) phthalate (DEHP), cadmium chloride (CdCl2) and dichlorodiphenyldichloroethylene (DDE)). The screening revealed that most of the tested chemicals have detectable deleterious effects on glucose-stimulated insulin release, insulin content, electrical activity, gene expression, and/or viability. Our data provide new molecular information on the direct effects of the selected chemicals on key aspects of pancreatic {beta}-cell function such as the stimulus-secretion coupling and ion channel activity. In addition, we found that, in general, the sensitivity and responses were comparable to those from other in vivo studies reported in the literature. Overall, our results suggest that both systems can serve as effective tools for rapid screening of potential MDC effects on pancreatic {beta}-cell physiology as well for deciphering and better understanding the molecular mechanisms that underlie their action.

pharmacology and toxicology↗
bioRxiv2021

Fecal microbiota transplantation derived from Alzheimer's disease mice worsens brain trauma outcomes in young C57BL/6 mice

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration, both which increase the risk and accelerate the progression of Alzheimers disease (AD). The gut microbiome is an essential modulator of the immune system, impacting in the brain. AD has been related with reduced diversity and alterations in the community composition of the gut microbiota. This study aimed to determine whether the gut microbiota from AD mice exacerbates neurological deficits after TBI in control mice. We prepared fecal microbiota transplants from 18-24 months old 3xTg-AD (FMT-AD) and from healthy controls (FMT-young) mice. FMTs were administered orally to young control C57BL/6 (wild-type, WT) mice after they underwent controlled cortical impact (CCI) injury, as a model of TBI. Then, we characterized the microbiota composition of the fecal samples by full-length 16S rRNA gene sequencing analysis. We collected the blood, brain, and gut tissues for protein and immunohistochemical analysis. Our results showed that FMT-AD administration stimulates a higher relative abundance of the genus Muribaculum and a decrease in Lactobacillus johnsonii compared to FMT-young in WT mice. Furthermore, WT mice exhibited larger lesion, increased activated microglia/macrophages, and reduced motor recovery after FMT-AD compared to FMT-young one day after TBI. In summary, we observed gut microbiota from AD mice to have a detrimental effect and aggravate the neuroinflammatory response and neurological outcomes after TBI in young WT mice.

neuroscience↗
bioRxiv2021

Emu: Species-Level Microbial Community Profiling for Full-Length Nanopore 16S Reads

16S rRNA based analysis is the established standard for elucidating microbial community composition. While short read 16S analyses are largely confined to genus-level resolution at best since only a portion of the gene is sequenced, full-length 16S sequences have the potential to provide species-level accuracy. However, existing taxonomic identification algorithms are not optimized for the increased read length and error rate of long-read data. Here we present Emu, a novel approach that employs an expectation-maximization (EM) algorithm to generate taxonomic abundance profiles from full-length 16S rRNA reads. Results produced from one simulated data set and two mock communities prove Emu capable of accurate microbial community profiling while obtaining fewer false positives and false negatives than alternative methods. Additionally, we illustrate a real-world application of our new software by comparing clinical sample composition estimates generated by an established whole-genome shotgun sequencing workflow to those returned by full-length 16S sequences processed with Emu.

bioinformatics↗
bioRxiv2020

Bisphenol-S and Bisphenol-F alter mouse pancreatic β-cell ion channel expression and activity and insulin release through an estrogen receptor ERβ mediated pathway

Bisphenol-S (BPS) and Bisphenol-F (BPF) are current Bisphenol-A (BPA) substitutes. Here we used pancreatic {beta}-cells from wild type (WT) and estrogen receptor {beta} (ER{beta}) knockout (BERKO) mice to investigate the effects of BPS and BPF on insulin secretion, and the expression and activity of ion channels involved in {beta}-cell function. BPS or BPF rapidly increased insulin release and diminished ATP-sensitive K+ (KATP) channel activity. Similarly, 48 h treatment with BPS or BPF enhanced insulin release and decreased the expression of several ion channel subunits in {beta}-cells from WT mice, yet no effects were observed in cells from BERKO mice. PaPE-1, a ligand designed to preferentially trigger extranuclear-initiated ER pathways, mimicked the effects of bisphenols, suggesting the involvement of extranuclear-initiated ER{beta} pathways. Molecular dynamics simulations indicated differences in ER{beta} ligand-binding domain dimer stabilization and solvation free energy among different bisphenols and PaPE-1. Our data suggest a mode of action involving ER{beta} whose activation alters three key cellular events in {beta}-cell, namely ion channel expression and activity, and insulin release. These results may help to improve the hazard identification of bisphenols.

pharmacology and toxicology↗