Biology subjects

Orr, S.

Publications and source records attributed to Orr, S..

3 recordsLinked to original sources

bioRxiv2026

Novel Cardiometabolic Factors Regulate Neurite Outgrowth in Cancer Chemotherapy-Induced Cardiotoxicity

BackgroundCardiovascular diseases and cancer are the leading causes of death in the United States and worldwide. Although various therapies against cancer improve patient survival, cardiotoxicity remains a life-threatening adverse outcome, with emerging evidence of downstream effects, including neural dysfunction. While autonomic regulation of the cardiovascular system is well-studied, regulation of the nervous system by the heart is not fully clear. We hypothesized that cardiac cells secrete non-canonical paracrine metabolic factors that support neuronal growth and function, and chemotherapy disrupts this signaling. MethodsWe employed co- culture models of the well-established H9C2 cardiac and PC12 neuronal cell lines and human induced pluripotent stem cells (hiPSCs), and assessed them with molecular, omic, biochemical, morphological, physiological, and pharmacological assays. ResultsHealthy H9C2 cells robustly induced PC12 neurite outgrowth (neurite length and number of neurite-bearing cells) both directly (with cellular contact) and indirectly (only conditioned media), whereas doxorubicin-exposed H9C2 cells failed to produce this effect. Recently approved anti-cancer agents (2020 or later) also reduced or attenuated cardiac cell-induced outgrowth. Untargeted metabolomic analysis of conditioned media revealed multiple novel potential neurite-promoting factors, and pharmacologically inhibiting them significantly reduced PC12 neurite outgrowth. The analysis also identified distinct metabolites that were differentially regulated following doxorubicin exposure. These findings were further supported in a hiPSC-based model, in which conditioned media from doxorubicin-injured hiPSC cardiomyocytes reduced {beta}III-tubulin intensity and norepinephrine secretion in hiPSC-derived sympathetic neurons. ConclusionTogether, these findings unravel a new line of research on cardio-neuronal communication and reveal novel metabolic targets that may inform future strategies to mitigate neurotoxicity induced by chemotherapy-associated cardiac injury.

Cell Biology↗

bioRxiv2025

Mgl2+ cDC2 triggering of fungal allergic inflammation depends on a spore induced glycolytic shift fuelled by local availability of glucose

Fungal spores are a major cause of severe asthmatic disease. However, the precise events that cause individuals to become sensitised to spores are poorly understood. Mgl2+ type 2 conventional dendritic cells (Mgl2+ cDC2s) are critical in coordinating allergic airway inflammation in mice following repeated exposure to inhaled spores. Yet, whether these DCs are directly acquiring spores from the airway, and the downstream mechanism(s) upon fungal uptake causing DCs to trigger allergic inflammation are unknown. Here we find that spores are acquired by lung DCs after inhalation although these events are rare ([~] 0.5% of the cDC2 population). Transcriptomics on isolated spore+ Mgl2+ cDC2s, compared to spore- Mgl2+ cDC2s from the same environment, revealed that a major consequence of fungal uptake was a boost in metabolic activity. Single-cell metabolic profiling revealed this increase in Mgl2+ cDC2 metabolism upon spore acquisition was fuelled by a glycolytic shift. To pinpoint if nutrient availability and acquisition is an important determinant of this response, mass spectrometry-based metabolomics revealed that, during fungal allergic inflammation, the local airway nutrient environment is altered. To ascertain which of these could be fuelling DC responses, we identified which substrates that feed into glycolysis were crucial. Of these, we found that glucose availability acts as a key rheostat in shaping cDC2 responses to spores. These data highlight a crucial role for glycolytic metabolism in driving cDC2 responses to spores, which is governed by glucose availability, defining novel targets for future therapeutic development of fungal allergic inflammation.

immunology↗

bioRxiv2023

Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury

Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Seizures and cortical spreading depolarization (CSD) are metabolically demanding processes that may worsen secondary brain injury. Metabolic stress has been associated with mitochondrial dysfunction, including impaired calcium homeostasis, reduced ATP production, and elevated ROS production. However, the association between mitochondrial impairment and vascular function after TBI is poorly understood. Here, we explored this association using a rodent closed head injury model. CSD resulted in neurobehavioral decline after TBI. Craniotomy was performed to elicit CSD via electrical stimulation or to induce seizures via 4-aminopyridine application. We measured vascular dysfunction following CSDs and seizures in TBI animals using laser doppler flowmetry. We observed a more profound reduction in local cortical blood flow in TBI animals compared to healthy controls. Following TBI, CSD resulted in mitochondrial dysfunction and pathological signs of increased oxidative stress adjacent to the vasculature. We explored these findings further using electron microscopy and found that TBI and CSDs resulted in vascular morphological changes and mitochondrial cristae damage in astrocytes, pericytes and endothelial cells. Overall, we provide evidence that CSDs induce mitochondrial dysfunction, impaired cortical blood flow, and neurobehavioral deficits in the setting of TBI. HighlightsCortical spreading depolarization after TBI causes behavioral decline in rats. Vasoconstriction and oligemia after cortical spreading depolarization is worse in TBI brains. Spreading depolarization causes impaired mitochondrial function. TBI and spreading depolarization result in constricted vessels and increased pericyte size. TBI and spreading depolarization result in mitochondrial damage in vascular cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/549872v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@176a9a6org.highwire.dtl.DTLVardef@17bfc19org.highwire.dtl.DTLVardef@e3d74dorg.highwire.dtl.DTLVardef@4c194e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗