Biology subjects

Sanchis, P.

Publications and source records attributed to Sanchis, P..

7 recordsLinked to original sources

bioRxiv2026

IFNγ at the crossroads of systemic protection and brain vulnerability to coronavirus infection

The COVID-19 pandemic, together with previous outbreaks caused by highly pathogenic coronaviruses, highlighted the importance of understanding the host determinants that influence pathogenesis, both to improve our understanding of disease mechanisms, and to strengthen preparedness for future outbreaks. In our previous work we demonstrated dysregulation of IFN{gamma} response genes in COVID-19 patients, associated with both age and viral burden, positioning IFN{gamma} as a key mediator of host defense against SARS-CoV-2. Here, we used a preclinical murine model of coronavirus infection based on murine hepatitis virus (MHV-A59), widely validated for studying SARS-CoV-2 pathogenesis, together with IFN{gamma} knockout (IFN{gamma}-KO) mice to investigate the role of this cytokine during infection. We performed a comprehensive morphological, biochemical, hematological and proteomic characterization of infected wild-type (WT) and IFN{gamma}-deficient mice. Plasma proteomics revealed impaired inflammatory and coagulation-related responses in IFN{gamma}-KO animals compared to WT controls. We found increased viral load and infectious particles in peripheral organs, including liver, spleen, heart and muscle in IFN{gamma}-KO mice, whereas these were significantly reduced in the brain. Region-specific analysis further demonstrated decreased viral load in the prefrontal cortex and hippocampus of IFN{gamma}-KO animals. Consistently, bioinformatics analysis of transcriptomics data of IFN{gamma}-treated primary neuron cultures, together with frontal cortex from human COVID-19 patients, revealed activation of neuroinflammatory and neurological disease-associated pathways, supporting a role for IFN{gamma} in driving brain inflammatory responses during coronavirus infection. Together, these findings reveal a dual role for IFN{gamma} during coronavirus infection: it is important for controlling systemic viral dissemination and limiting peripheral tissue damage, yet it may also promote viral susceptibility and exacerbated inflammatory responses in the brain. These results support IFN{gamma} modulation as a potential therapeutic strategy to prevent or mitigate neurological complications associated with COVID-19. Author SummaryViral infections are controlled by the immune system, but the same responses that protect the body can sometimes contribute to tissue damage and disease. We investigated how a key immune molecule, called Interferon Gamma, influences the outcome of Coronavirus infection in different parts of the body. Using a mouse model of Coronavirus infection with Interferon Gamma deficiency, we found that this molecule plays two opposing roles: it helps control the spread of the virus throughout the body, but it also increases vulnerability of the brain to infection and inflammation. When this immune signal was absent, animals showed higher amounts of virus in several peripheral organs but surprisingly had lower levels of virus in specific brain regions. We further found that this immune response was associated with changes in inflammation and neurological processes in human data. Our findings reveal that antiviral immunity is not always uniformly protective and that its effects depend on the tissue involved. Understanding this balance may help guide future approaches to reduce virus-associated complications while preserving the protective functions of the immune response.

microbiology↗

bioRxiv2026

STAG2 Maintains Chromatin Compartmentalization and Represses Regulatory Element Contact to Promote Oncogenic Signaling in Muscle Invasive Bladder Cancer

Contrary to other cancer types, stromal antigen 2 (STAG2) expression is associated with shorter survival and an invasive phenotype in muscle invasive bladder cancer (MIBC). As a cohesin complex component, STAG2 regulates genome organization and cell type-specific transcription, yet its mechanistic role in MIBC remains unclear. Here, we uncover mechanisms through which STAG2 coordinates chromatin architecture and gene regulation in MIBC. Modulation of STAG2 rewired chromatin architecture, altering chromatin contacts and compartmentalization, increasing promoter-enhancer interactions, and reducing short-ranged chromatin loops. At specific gene loci, we discovered that STAG2 has context-specific activating and repressive regulatory functions. At the STAG2-activated gene ABCA1, STAG2 maintained A-compartment chromatin and high levels of promoter acetylation, indicators of active transcription. STAG2 KO resulted in loss of promoter acetylation, a shift from A to B compartment chromatin, and increased occupancy of the co-repressor TRIM28, resulting in ABCA1 downregulation and diminished invasive potential. Conversely, at the STAG2-repressed gene SPOCK3, STAG2 KO resulted in B to A compartment switching, aberrant formation of chromatin loops, and SPOCK3 upregulation. Treatment with EZH2 inhibitor tazemetostat augmented STAG2-KO induced SPOCK3 upregulation, suggesting a collaborative role of STAG2 and EZH2 in repressing Polycomb Repressive Complex 2 (PRC2) target genes. Altogether, our results indicate that STAG2 plays a multifaceted role in regulating gene expression in bladder cancer that is dictated by the epigenetic and chromatin landscape of the cells. These findings identify STAG2-dependent vulnerabilities and provide a rationale for therapeutic targeting of chromatin regulators in MIBC.

Cancer Biology↗

bioRxiv2026

The intestinal immune response is influenced by nutritional-status and increased physical activity level

Beyond its role in digestion and barrier function, the intestine is an energy-responsive organ that actively regulates molecular metabolism. Whether and how lifestyle interventions regulate intestinal metabolism at both tissue and molecular levels remain unclear. Here, we show that both chronic exercise and dietary energy density drive robust, segment-specific intestinal remodeling. Voluntary wheel running in ad-libitum chow fed mice, induced elongation of the small intestine and colon, alongside pronounced, region-specific, transcriptional changes in the proximal, mid, and distal small intestine, particularly within immune and stress-related pathways. Caloric dilution diet also increased intestinal length in mice but elicited transcriptional adaptations, prominently in the proximal small intestine, directly linking energy density and intake to structural and molecular plasticity. In contrast, voluntary wheel running in control-fed and caloric-diluted-fed mice subtly modulated immune-associated gene expression, highlighting that diet and physical activity induce complementary and mechanistically distinct effects on the gut. We further identified an exercise-induced state of intestinal preconditioning. Upon refeeding, sedentary mice mounted robust, segment-specific activation of apoptotic, proliferative, and immune pathways. Similarly, acute treadmill exercise acted as a transient intestinal stressor in sedentary animals by shortening the length of the small intestine and rapidly activating epithelial stress, apoptosis, proliferation, and immune signaling. However, these responses were attenuated in chronically active mice despite higher basal expression of key genes, consistent with adaptive epithelial remodeling. The results suggest that habitual physical activity buffers acute nutritional stress and restrains excessive intestinal immune activation. Finally, translational plasma analyses in humans demonstrate that acute moderate-intensity exercise increases circulating markers of monocyte activation and epithelial stress, including CD14, IL-32, Reg-3-alpha and I-FABP, in both lean and obese individuals. Collectively, these findings suggest that the intestine plays a role as a metabolic organ that integrates energy-sensing signals from diet composition and physical activity.

immunology↗

bioRxiv2026

Regular parental exercise before mating influences offspring lower adiposity associated to hypothalamic neurodevelopmental changes

Physical inactivity is highly prevalent worldwide and affects not only individual health but also the health of future generations. However, the impact of parental physical activity, limited to the pre-mating period, on offspring body weight and composition remains poorly understood. Using a voluntary wheel running approach in mice, we uncovered that post-weaning offspring body weight and composition changes are modulated by the combined effects of pre-mating parental exercise and parental age. Notably, during lactation, pre-mating parental exercise reduced offspring visceral and subcutaneous adiposity, shortened tibia length in female offspring, and influenced offspring transcriptomic profiles of the hypothalamus, the central region regulating body weight and energy balance. These results highlight that regular pre-mating parental exercise may induce offspring neurodevelopmental changes. Although pre-mating exercise minimally impacted the expression of lactation-related genes in maternal subcutaneous fat, as well as breastmilk nutritional composition and miRNA content, these modest miRNA changes may nonetheless influence offspring hypothalamic regulation. Together, these data provide a comprehensive understanding of how parental age and pre-mating exercise impact post-weaning offspring body weight and composition and offer deeper insights into how regular pre-mating parental exercise influences offspring physiology during lactation.

neuroscience↗

bioRxiv2025

The metabolic and molecular mechanisms underlying running-induced energy compensation

Exercise not only regulates energy expenditure but also appetite, yet the underpinnings remain unclear. We describe that increased energy intake is a defense against energy loss that depends on initial running distance and operates independently of diet and age. Running caused a rapid circadian-dependent fat remodeling leading to a decline in circulating leptin accompanied by the activation of hypothalamic neurons. We discovered that the activation of the {beta}3-adrenergic receptor drives running-induced fat loss and the lower leptin triggers energy compensation by upregulating Neuropeptide Y. Once energy compensation is achieved, running is associated with molecular changes in hypothalamic signaling related to appetite and functional adaptations, such as enhanced sensitivity to hunger and satiety signals and increased responsiveness to appetite suppression induced by -Melanocyte-Stimulating Hormone. The increased food intake persisted without fat rebound beyond running in both lean and obese young mice, uncovering a new homeostatic balance in young mice.

physiology↗

bioRxiv2025

Physical activity promotes gut adaptation, responses to nutrients, and sensitivity to gut peptides

Physical activity is essential for body weight maintenance after body weight-loss, partly by promoting the coupling between energy intake and expenditure. However, the underlying mechanisms remain largely unknown. Here we demonstrate that running induces small intestine growth independently of GLP-2. In addition, exercise increases L-cell density in the small intestine and glucose-stimulated GLP-1 secretion, and improves the sensitivity both to the gut-derived hormones PYY, CCK and ghrelin, and to treatment with GLP-1 receptor agonist. Moreover, increased physical activity enhances satiation and satiety post-fasting, regulates the gene expression of appetite signals in the intestine, nodose ganglia and brainstem, and induces a greater feeding-response in the activation of hypothalamic and brainstem neurons. This improves overall appetite regulation, and in turn, promotes body weight maintenance. In summary, the present data suggest that increased physical activity improves body weight maintenance by inducing adaptations in the gut and in gut- to-brain communication that control appetite. HIGHLIGHTSO_LIIncreased physical activity promotes intestinal growth C_LIO_LISensitivity to gut-derived hormones PYY, CCK and ghrelin is improved in active mice C_LIO_LIIncreased physical activity enhances glucose-stimulated GLP-1 secretion from the small intestine C_LIO_LIIncreased physical activity regulates effectively satiation and satiety post-fasting C_LI

physiology↗

bioRxiv2025

Effects of Interleukin-6 dysregulation in a mouse model of Alzheimer's disease: unraveling the complexity beyond amyloidosis

Interleukin-6 (IL-6) is a cytokine detected in the brains and peripheral fluids of both Alzheimers disease (AD) patients and mouse models, where it colocalizes with amyloid-beta (A{beta}) levels and amyloid plaques. Interestingly, IL-6 deficiency ameliorates cognitive deficits and attenuates hippocampal neuroinflammation, whereas astrocyte-targeted IL-6 signaling via its soluble receptor accentuates pathological features in AD mouse models. This finding suggests that central IL-6 overexpression may actively drive disease manifestations. However, because IL-6 also signals through its classical membrane-bound receptor pathway, the overall impact of central IL-6 on Alzheimers disease pathophysiology is still not fully elucidated. To explore the contribution of central IL-6 overexpression in modulating AD-related mortality, metabolic, behavioral and neuroinflammatory changes in the hippocampus and cortex, we crossed a transgenic mouse model (Tg2576) of A{beta}-driven amyloidosis with mice expressing IL-6 under the Glial Fibrillary Acidic Protein (GFAP) promoter, which predominantly targets astrocytes. Chronic IL-6 overexpression reduced inguinal white adiposity in both males and females and decreased body weight in females. Early behavioral alterations were also observed, along with increased cortical and hippocampal A{beta}42/A{beta}40 ratios and gliosis in aged Tg2576 female and male mice. Interestingly, chronic IL-6 overexpression also decreased cortical and hippocampal periplaque astrocytosis and microgliosis, suggesting a heterogeneous response of astrocytes and microglia to IL-6 overexpression within the primary regions affected by this pathology. Finally, cortical transcriptomic profiling in Tg2576 mice revealed widespread changes in immune, synaptic, and stress response pathways in response to chronic IL-6 overexpression, with cortical neuroinflammatory and neurotransmission-associated gene networks showing sex-dependent differences. Our findings emphasize that chronic central-targeted IL-6 overexpression shapes the cortical and hippocampal molecular landscape underlying amyloidosis in both male and female Tg2576 mice. Thereby, we propose IL-6 as a potential target for future AD therapeutic strategies.

neuroscience↗