Biology subjects

Baron, L.

Publications and source records attributed to Baron, L..

5 recordsLinked to original sources

bioRxiv2026

Platelet C5aR1 mediates sex-specific ischemia-driven revascularization through estradiol-dependent CXCL4 release

BackgroundSex-specific differences in cardiovascular diseases remain incompletely understood at the molecular level. ObjectivesHere, we investigated the role of the platelet complement receptor C5aR1 as a sex-specific critical mediator of revascularization following hindlimb ischemia. MethodsIschemia-driven revascularization was analyzed in the hind limb ischemia (HLI) model using wild type (WT) and complement receptor-deficient male and female mice, and involved mechanisms were analyzed in platelets and megakaryocyte-shed platelets ex vivo. ResultsIn WT mice, ischemic tissue exhibited robust complement activation with C3b and C5a accumulation that correlated strongly with deposition of the anti-angiogenic factor CXCL4 (PF4). Mechanistically, C5a stimulation of platelets triggered CXCL4 secretion, and female animals with a platelet-specific deletion of C5aR1 (using PF4-Cre-C5aR1fl/fl mice) showed a significantly delayed revascularization. Female mice exhibited substantially lower platelet C5aR1 expression, and C5a-induced CXCL4 secretion was virtually abolished compared to male animals. The sex-specific difference in tissue CXCL4 deposition was not present any more in the absence of C5aR1 from platelets. We observed that megakaryocytes, which give rise to platelets, express estradiol receptors. Importantly, estradiol stimulation of megakaryocytes suppressed C5aR1 expression during pro-platelet formation, uncovering a hormone-dependent regulatory mechanism. ConclusionsThe here described estradiol-C5aR1-CXCL4 axis provides a molecular explanation for sex-specific differences in ischemic revascularization known from patient studies. Our findings establish a novel and unexpected mechanistic link between sex hormones, a complement-platelet crosstalk and the angiogenic response to ischemia with potential clinical implications for sex-specific personalized therapeutic strategies.

immunology↗

bioRxiv2025

Importance of Apparatus Scaling in Novel Object Recognition for Juvenile and Adult Rats.

The growing interest in ontogenetic studies of learning and memory, along with early-life perturbations, has led to the use of younger rodents as a key biological variable in many investigations. This development prompts an important question about whether procedures and apparatuses designed for studying learning and memory in adults should be simply adapted for use with younger and smaller rodents. The current study examined how arena size affects novel object recognition (NOR) performance in juvenile and adult rats. A commonly used larger arena reliably detected novel object preference in adults but not in juveniles. Adjusting the arena size based on average weight differences between age groups improved the consistency of NOR performance in juvenile rats. Sex differences were observed: adult males performed reliably across all arena sizes, whereas adult females required larger arenas to demonstrate effective NOR performance. These findings highlight the importance of tailoring arena dimensions to developmental stage and sex for accurate cognitive assessment. Specifically, they support the use of weight-based arena scaling as a methodological approach in developmental neurobehavioral research and emphasize the importance of careful design when studying female rodents. Future studies should explore similar environmental adjustments for other behavioral tests in juvenile and female populations.

animal behavior and cognition↗

bioRxiv2024

Melanin concentrating hormone projections to the nucleus accumbens enhance the reward value of food consumption and do not induce feeding or REM sleep

Regulation of food intake and energy balance is critical to survival. Hunger develops as a response to energy deficit and drives food-seeking and consumption. However, motivations to eat are varied in nature, and promoted by factors other than energy deficit. When dysregulated, non-homeostatic drives to consume can contribute to disorders of food intake, adding to the increasing prevalence of restrictive eating disorders and obesity. Melanin-concentrating hormone (MCH) neurons have been implicated in the regulation of feeding behavior, in addition to a number of other fundamental behaviors including sleep, anxiety, and maternal behavior. Several studies suggest that MCH peptide increases food consumption, while studies of MCH neurons show effects only on cued feeding, and others show no effect of MCH neuron manipulation on feeding. MCH neurons have widespread projections to diverse downstream brain regions yet few studies have investigated the function of specific projections or differentiated the behaviors they regulate. Here we use optogenetics, in combination with different behavioral paradigms, to elucidate the role of MCH projections to the nucleus accumbens (NAc) in sleep and feeding behavior. We show that MCH neurons projecting to the NAc do not induce changes in baseline feeding or REM sleep, but do enhance the preference for a food paired with optogenetic stimulation. Furthermore, this effect is diminished in female mice relative to males, in line with previous results suggesting sex differences in the functional role of MCH neurons. These results suggest that MCH projections to the NAc can enhance the rewarding value of consumed food. Significance StatementWhile feeding is often driven by hunger, there are non-homeostatic reasons why animals consume food. Melanin-concentrating hormone (MCH) neurons have been implicated in the regulation of many fundamental behaviors, including feeding, sleep and reward. They project broadly throughout the brain, suggesting that they may mediate this diverse set of behaviors independently via specific projections to downstream regions. We used optogenetic activation of MCH neurons and their projections to the nucleus accumbens (NAc) in combination with complex behavioral paradigms to demonstrate that MCH projections to the NAc do not induce baseline feeding or increases in REM sleep but do enhance the value of a paired food. These results suggest that MCH neurons contribute to non-homeostatic consumption via projections to the NAc.

neuroscience↗

bioRxiv2022

Discovery of a druggable copper-signaling pathway that drives cell plasticity and inflammation

Inflammation is a complex physiological process triggered in response to harmful stimuli. It involves specialized cells of the immune system able to clear sources of cell injury and damaged tissues to promote repair. Excessive inflammation can occur as a result of infections and is a hallmark of several diseases. The molecular basis underlying inflammatory responses are not fully understood. Here, we show that the cell surface marker CD44, which characterizes activated immune cells, acts as a metal transporter that promotes copper uptake. We identified a chemically reactive pool of copper(II) in mitochondria of inflammatory macrophages that catalyzes NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with a rationally-designed dimer of metformin triggers distinct metabolic and epigenetic states that oppose macrophage activation. This drug reduces inflammation in mouse models of bacterial and viral (SARS-CoV-2) infections, improves well-being and increases survival. Identifying mechanisms that regulate the plasticity of immune cells provides the means to develop next-generation medicine. Our work illuminates the central role of copper as a regulator of cell plasticity and unveils a new therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

cell biology↗

bioRxiv2021

The Sec61 translocon is a therapeutic vulnerability in Multiple Myeloma

Multiple Myeloma (MM) is an incurable malignancy characterized by the uncontrolled expansion of plasma cells in the bone marrow. While proteasome inhibitors like bortezomib efficiently halt MM progression, drug resistance or toxicity inevitably develop. Here, we used a recently discovered inhibitor, mycolactone, to assess the interest of targeting the Sec61 translocon in MM. In human cell lines and tumors from MM patients, mycolactone triggered pro-apoptotic endoplasmic reticulum stress responses synergizing with bortezomib for induction of MM cell death, irrespective of their resistance to proteasome inhibition. Notably, this synergy was selective of cancer cells and extended to B cell acute lymphoblastic leukemia. Sec61 blockade also caused collateral defects in MM secretion of immunoglobulins and expression of pro-survival interleukin (IL)-6 receptor and CD40, whose activation stimulates IL-6 production. Further, the mycolactone-bortezomib combination demonstrated superior therapeutic efficacy over single drug treatments in immunodeficient mice engrafted with MM cells, without inducing toxic side effects. Collectively, these findings establish Sec61 blockers as novel anti-MM agents and reveal the interest of targeting both the translocon and the proteasome in proteostasis-addicted tumors.

cancer biology↗