Biology subjects

Barbas, C.

Publications and source records attributed to Barbas, C..

11 recordsLinked to original sources

bioRxiv2026

Microglial AhR Drives Sex-Biased Amyloid Pathology

Microglia integrate local and systemic signals that can modify their response to amyloid-{beta} (A{beta}), but the molecular pathways connecting these signals to Alzheimer's disease (AD) pathology remain incompletely understood. Here, we identify the aryl hydrocarbon receptor (AhR), a sensor of microbiota- and host-derived metabolites, as a microglial regulator of amyloid pathology. Sustained administration of the AhR agonist indoxyl-3-sulfate (I3S) exacerbated cortical A{beta} deposition and plaque-associated neuritic damage in APPNL-F mice. Conversely, constitutive AhR deficiency reduced amyloid burden, promoted plaque compaction, and preserved behavioural performance, whereas inducible deletion of AhR in microglia was sufficient to reduce plaque accumulation. Single-cell RNA sequencing revealed that AhR loss reprogrammed microglia toward phagolysosomal and A{beta}-recognition states and enhanced microglial A{beta} uptake, with markedly stronger effects in females. APPNL-F mice also exhibited sex-dependent remodelling of the gut microbiota and tryptophan-derived metabolites. Circulating indole-3-aldehyde (IAld) robustly activated AhR and was associated with cortical amyloid pathology. AhR-activating bioactivity was increased in mouse serum, cortex and faecal extracts and was higher in serum from the COGNIBIO12 analytical subcohort than in independently recruited cognitively unimpaired H2H participants. Among amyloid-positive patients, higher serum AhR bioactivity was associated with lower CSF A{beta}42 concentrations. Together, these findings identify microglial AhR as a metabolically responsive regulator linking systemic ligand availability, biological sex, and microglial control of amyloid pathology.

immunology↗

bioRxiv2026

Early Lipid Remodeling During Ischemia Reperfusion Injury Is Associated with Damage- and Protection-Related Lipid Signatures in Acute Kidney Injury.

Acute kidney injury (AKI) secondary to kidney ischemia-reperfusion (IRI) is driven by profound metabolic perturbations that shape oxidative stress, inflammation, and cell death responses. Despite growing evidence of lipid dysregulation in AKI, its biological and mechanistic relevance remains unclear. To address this gap, we performed comprehensive untargeted kidney lipidomics using LC-QTOF-MS to delineate dynamic lipid changes during the acute phase of murine kidney IRI. Integration of lipidomic signatures with kidney gene-expression profiling and curated datamining revealed early activation of lipid pathways associated with injury responses. IRI induced marked lipidomic reprogramming, characterized by a marked accumulation of glycerolipids, including triacylglycerols (TGs) species detected exclusively after injury, together with increased levels of sphingolipids (ceramides, sphingomyelins, and hexosylceramides). Cardiolipins and most glycerophospholipids declined sharply following IRI, whereas specific phosphatidylcholines (PCs) exhibited opposite regulation, consistent with dynamic membrane remodeling. Datamining linked TG accumulation and altered transcriptional regulation of PC metabolism to repair-prone type 1 injured proximal tubular cells, highlighting its role in early tubular injury. Correlation analyses revealed strong associations between glycerolipids/sphingolipids and markers of renal dysfunction and inflammation, identifying TG 54:9 as a candidate for injury biomarker. Conversely, PE 40:6, PI 38:6, together with several lysophosphatidylcholines and ether-linked phospholipids, correlated positively with nephroprotective and antioxidant markers. Together, these patterns delineate two major lipid modules: a damage-associated module and a nephroprotection-associated module. These findings establish lipid remodeling as a central yet underexplored determinant of AKI pathogenesis and underscore lipidomics as a powerful discovery tool for identifying novel biomarkers and mechanistic targets in kidney disease.

pathology↗

bioRxiv2025

A lipidomic exploration of the effects of high-intensity interval exercise in healthy men after metformin intake

We have previously found that high-intensity interval exercise (HIIE) affected metformin pharmacokinetics, causing higher maximal plasma concentration compared with rest. In this scenario, changes in individual lipids could play an important role. The prolonged responses of the lipidome to HIIE have not been explored. Thus, this study aimed to explore differences in the plasma lipidomic profiles between HIIE and rest, both under metformin treatment. Nine healthy males participated in two sessions where they received 1,000 mg of metformin. In session A, they performed HIIE at an average intensity of 67% of maximum heart rate for a total duration of 76 min, whereas in session B they rested. Plasma was collected before taking metformin and during each session (in total 14 time points spanning 12 h). Samples were analysed through lipidomics using mass spectrometry. Paired Wilcoxon tests between sessions were applied for statistics. We found several variations in the lipid profiles due to HIIE, which persisted until 4 h post-exercise. The main discriminant lipid classes were fatty acids, acyl carnitines, glycerophosphocholins, sphingomyelins, and triglycerides. These changes were followed in time up to 12 h, showing the effect of the meals taken during the session. We hypothesize the changes are a synergic effect of HIIE and metformin in the lipidome with the effect of HIIE being the predominant. These findings provide important insights into the dynamic and complex physiological response of humans to intensive exercise under metformin intake.

systems biology↗

bioRxiv2023

Allergic inflammation triggers dyslipidemia via IgG signalling

BackgroundAllergic diseases begin early in life and are often chronic, thus creating an inflammatory environment that may precede or exacerbate other pathologies. In this regard, allergy has been associated to metabolic disorders and with a higher risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. MethodsWe used a murine model of allergy and atherosclerosis, different diets and sensitization methods, and cell-depleting strategies to ascertain the contribution of acute and late phase inflammation to dyslipidemia. Untargeted lipidomic analyses were applied to define the lipid fingerprint of allergic inflammation at different phases of allergic pathology. Expression of genes related to lipid metabolism was assessed in liver and adipose tissue at different times post-allergen challenge. Also, changes in serum triglycerides (TG) were evaluated in a group of 59 patients [≥]14 days after the onset of an allergic reaction. ResultsWe found that allergic inflammation induces a unique lipid signature that is characterized by increased serum TG and changes in the expression of genes related to lipid metabolism in liver and adipose tissue. Alterations in blood TGs following an allergic reaction are independent of T-cell-driven late phase inflammation. On the contrary, the IgG-mediated alternative pathway of anaphylaxis is sufficient to induce a TG increase and a unique lipid profile. Lastly, we demonstrated an increase in serum TG in 59 patients after undergoing an allergic reaction. ConclusionOverall, this study reveals that IgG-mediated allergic inflammation regulates lipid metabolism.

immunology↗

bioRxiv2023

Pentose Phosphate Pathway Inhibition activates Macrophages towards phagocytic Lymphoma Cell Clearance

Macrophages in the B-cell lymphoma microenvironment represent a functional node in progression and therapeutic response. We assessed metabolic regulation of macrophages in the context of therapeutic antibody-mediated phagocytosis. Pentose phosphate pathway (PPP) inhibition by specific compounds and shRNA targeting induced increased phagocytic lymphoma cell clearance. Moreover, macrophages provided decreased support for survival of lymphoma cells. PPP inhibition induced metabolic activation, cytoskeletal re-modelling and pro-inflammatory polarization of macrophages. A link between PPP and immune regulation was identified as mechanism of macrophage repolarization. Inhibition of the PPP causes suppression of glycogen synthesis and subsequent modulation of the immune modulatory UDPG-Stat1-Irg1-Itaconate axis. PPP inhibition rewired macrophage maturation and activation in vivo. Addition of the PPP inhibitor S3 to antibody therapy achieved significantly prolonged overall survival in an aggressive B-cell lymphoma mouse model. We hypothesize the PPP as key regulator and targetable modulator of macrophage activity in lymphoma to improve efficacy of immunotherapies. HighlightsO_LIMacrophage-mediated lymphoma cell phagocytosis is increased by pentose phosphate pathway (PPP) inhibition as an immune regulatory switch for macrophage function and polarization C_LIO_LIPPP inhibition is linked to decreased glycogen synthesis and subsequent modulation of the UDPG-Stat1-Irg1-Itaconate axis C_LIO_LIPPP inhibition is tolerable in vivo and facilitates therapeutic targeting of B-cell lymphoma C_LI

cancer biology↗

bioRxiv2022

Cross regulation between the molecular clock and kidney inflammatory, metabolic and fibrotic responses

Chronic kidney disease is a highly prevalent condition that remains a major clinical and biomedical challenge. Tubulo-interstitial fibrosis is the common pathological substrate for many causes that lead to chronic kidney disease. It is characterized by profound derangements in metabolic and inflammatory responses, whereby functional tissue is replaced with extracellular matrix, leading to the suppression of renal function. Perturbations in the circadian rhythm have been associated with many human pathologies, including renal disease. However, the role of the molecular clock in the instauration of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (UUO, FAN and adenine toxicity), employing genetically-modified mice with selective deficiencies of the clock components Bmal1, Clock and Cry. We found that UUO induced a marked increase in the expression of Bmal1. In human tubular epithelial cells, the pro-fibrotic mediator, TGF-{beta}, significantly altered the expression of core clock components. We further observed that the absence of Cry drastically aggravated kidney fibrosis, while both Cry and Clock played a role in the neutrophil and macrophage mediated inflammatory response, respectively. Suppression of Cry1/2 was associated with a major shift in the expression of metabolism-related genes, underscoring the importance of metabolic dysfunction in fibrosis. These results support a reciprocal interaction between the circadian clock and the response to kidney injury. Translational statementChronic kidney disease (CKD) is a highly prevalent clinical syndrome that still poses major clinical challenges. Kidney fibrosis underlies many cases of CKD and therapies against it are of very limited efficacy. Alterations in circadian rhythms (CR) are relevant in patients with CKD, but very little is known about the relationship between CKD and CR. Our study shows that disruption of the molecular clock can impact kidney inflammation and fibrosis and that, reciprocally, kidney fibrosis can alter the expression of clock components. A better understanding of this crosstalk could open new therapeutic avenues for the prevention and treatment of CR-related CKD.

physiology↗

bioRxiv2021

Metabolic snapshot of plasma samples reveals new pathways implicated in SARS-CoV-2 pathogenesis

Despite of the scientific and human efforts to understand COVID-19, there are questions still unanswered. Variations in the metabolic reaction to SARS-CoV-2 infection could explain the striking differences in the susceptibility to infection and the risk of severe disease. Here, we used untargeted metabolomics to examine novel metabolic pathways related to SARS-CoV-2 susceptibility and COVID-19 clinical severity using capillary electrophoresis coupled to a time-of-flight mass spectrometer (CE-TOF-MS) in plasma samples. We included 27 patients with confirmed COVID-19 early after symptom onset who were prospectively followed and 29 healthcare workers heavily exposed to SARS-CoV-2 but with low susceptibility to infection ( nonsusceptible). We found that the metabolite profile was predictive of the study group. We identified a total of 55 metabolites as biomarkers of SARS-CoV-2 susceptibility or COVID-19 clinical severity. We report the discovery of new plasma biomarkers for COVID-19 that provide mechanistic explanations for the clinical consequences of SARS-CoV-2, including mitochondrial and liver dysfunction as a consequence of hypoxemia (citrulline, citrate, and BAIBA), energy production and amino acid catabolism (L-glycine, L-alanine, L-serine, L-proline, L-aspartic acid and L-histidine), endothelial dysfunction and thrombosis (citrulline, L-ADMA, 2-AB, and Neu5Ac), and we found interconnections between these pathways. In summary, in this first report of the metabolomic profile of individuals with severe COVID-19 and SARS-CoV-2 susceptibility by CE-MS, we define several metabolic pathways implicated in SARS-CoV-2 susceptibility and COVID-19 clinical progression that could be developed as biomarkers of COVID-19.

biochemistry↗

bioRxiv2021

An evolutionarily ancient Fatty Acid Desaturase is required for the synthesis of hexadecatrienoic acid, which is the main source of the bioactive jasmonate in Marchantia polymorpha

Jasmonates are fatty acid derived hormones that regulate multiple aspects of plant development, growth and stress responses. Bioactive jasmonates, defined as the ligands of the conserved COI1 receptor, differ between vascular plants and bryophytes (using jasmonoyl-L-isoleucine; JA-Ile and dinor-12-oxo-10,15(Z)-phytodienoic acid; dn-OPDA, respectively). Whilst the biosynthetic pathways of JA-Ile in the model vascular plant Arabidopsis thaliana have been elucidated, the details of dn-OPDA biosynthesis in bryophytes are still unclear. Here, we identify an ortholog of Arabidopsis Fatty Acid Desaturase 5 (AtFAD5) in the model liverwort Marchantia polymorpha and show that FAD5 function is ancient and conserved between species separated by more than 450 million years of independent evolution. Similar to AtFAD5, MpFAD5 is required for the synthesis of 7Z-hexadecenoic acid. Consequently, in Mpfad5 mutants the hexadecanoid pathway is blocked, dn-OPDA levels almost completely depleted and normal chloroplast development is impaired. Our results demonstrate that the main source of dn-OPDA in Marchantia is the hexadecanoid pathway and the contribution of the octadecanoid pathway, i.e. from OPDA, is minimal. Remarkably, despite extremely low levels of dn-OPDA, MpCOI1-mediated responses to wounding and insect feeding can still be activated in Mpfad5, suggesting that dn-OPDA is not the only bioactive jasmonate and COI1 ligand in Marchantia.

plant biology↗

bioRxiv2021

A novel α/β T-cell subpopulation defined by recognition of EPCR

T-cell self-recognition of antigen presenting molecules is led by antigen-dependent or independent mechanisms. The endothelial protein C receptor (EPCR) shares remarkable similarity with CD1d, including a lipid binding cavity. We have identified EPCR-specific /{beta} T-cells in the peripheral blood of healthy donors. The average frequency in the CD3+ leukocyte pool is comparable to other autoreactive T-cell subsets that specifically bind MHC-like receptors. Alteration of the EPCR lipid cargo, revealed by X-ray diffraction studies, points to a prevalent, yet not exclusive, lipid-independent self-recognition. In addition, we solve the EPCR lipidome, and detect species not yet described as EPCR ligands. These studies report, for the first time, novel recognition by circulating /{beta} T-cells and provide grounds for EPCR and lipid mediated T-cell restriction.

immunology↗

bioRxiv2020

Metabolic changes in brain slices over time: a multiplatform metabolomics approach

Brain slice preparations are widely used for research in neuroscience. However, a high-quality preparation is essential and there is no consensus regarding stable parameters that can be used to define the status of the brain slice preparation after its collection at different time points. Thus, it is critical to establish the best experimental conditions for ex-vivo studies using brain slices for electrophysiological recording. In this study, we used a multiplatform (LC-MS and GC-MS) untargeted metabolomics-based approach to shed light on the metabolome and lipidome changes induced by the brain slice preparation process. We have found significant modifications in the levels of 300 compounds, including several lipid classes and their derivatives, as well as metabolites involved in the GABAergic pathway and the TCA cycle. All these preparation-dependent changes in the brain biochemistry should be taken into consideration for future studies to facilitate non-biased interpretations of the experimental results.

neuroscience↗

bioRxiv2020

Renal tubule Cpt1a overexpression mitigates kidney fibrosis by restoring mitochondrial homeostasis

Chronic kidney disease (CKD) remains a major epidemiological, clinical and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) suffer a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine if FAO gain-of-function (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1 A (CPT1A) in TECs. Cpt1a knock-in (CPT1A KI) mice subjected to three different models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy-FAN and adenine induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted pro-inflammatory response and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restituted oxidative metabolism and mitochondrial number and enhanced bioenergetics increasing palmitate oxidation and ATP levels, changes also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients evidenced decreased CPT1 levels and increased accumulation of short and middle chain acyl-carnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD. Graphical abstractOverexpression of CPT1A impedes tubular epithelial renal cell dedifferentiation and a pro-fibrotic phenotype by restoring mitochondrial metabolic bioenergetics. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biochemistry↗