Biology subjects

de Haan, J. B.

Publications and source records attributed to de Haan, J. B..

3 recordsLinked to original sources

bioRxiv2026

Inhibition of Gasdermin D by Disulfiram Attenuates Cardiac Inflammation and Fibrosis following Ischaemia Reperfusion Injury

IntroductionInadequately controlled inflammation is a key driver of adverse cardiac remodelling after acute myocardial infarction (AMI). Central to this process is activation of the NLRP3 inflammasome-gasdermin D (GSDMD) pathway, which promotes pyroptosis and the release of the pro-inflammatory cytokine interleukin-1{beta} (IL-1{beta}), a mediator strongly associated with infarct severity and poor clinical outcomes. This study investigates whether repurposing the FDA-approved therapeutic Disulfiram, recently shown to inhibit GSDMD pore formation, could reduce inflammation and thus improve cardiac injury after AMI. Methods and ResultsCardiac ischemia-reperfusion (I/R) injury was induced in C57BL/6 mice by 60-minute ligation of the left coronary artery followed by reperfusion. Disulfiram (25 or 50 mg/kg) was administered at reperfusion and daily thereafter. Cardiac function was assessed by echocardiography, while fibrosis and inflammation were evaluated by histology, RT-PCR, immunohistochemistry and immunoblotting. Leukocyte populations in blood, spleen, bone marrow and heart were analysed by flow cytometry. In vitro, mouse bone marrow-derived macrophages (BMDMs) and PMA-differentiated THP-1 cells were treated with Disulfiram. Cytokine secretion, inflammatory gene expression and changes in cell viability (propidium iodide (PI) staining and lactate dehydrogenase (LDH) release) were measured. Disulfiram (50 mg/kg) significantly improved cardiac function 7 days post-I/R. This was accompanied by a significant reduction in cardiac fibrosis and inflammation, as reflected by a lower abundance of inflammatory cells in circulation and cardiac tissue. In LPS- and ATP/Nigericin-stimulated BMDMs and THP-1 cells, Disulfiram dose-dependently (0.1-50 {micro}M) reduced IL-1{beta} and IL-6 secretion and attenuated membrane permeability and cell lysis. ConclusionsThis study demonstrates that Disulfiram improves cardiac function post-AMI by ameliorating inflammation and fibrosis, which was associated with reductions in cytokine release from inflammatory cells in vitro. Therefore, targeting GSDMD by "repurposing" the FDA-approved drug, Disulfiram, may represent a novel way to provide cardio-protection post-AMI. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/710794v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@7fd82eorg.highwire.dtl.DTLVardef@149de52org.highwire.dtl.DTLVardef@a2fe0eorg.highwire.dtl.DTLVardef@d56b4f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Dimethyl fumarate modulates the Duchenne muscular dystrophy disease program following short-term treatment in mdx mice

New medicines are urgently required to treat the fatal neuromuscular disease, Duchenne muscular dystrophy (DMD). DMD involves progressive muscle damage and weakness, which are preceded by oxidative stress, inflammation, and mitochondrial dysfunction. Dimethyl fumarate (DMF) is a potent small molecule nuclear erythroid 2-related factor 2 (Nrf2) activator with current clinical utility in the treatment of multiple sclerosis and psoriasis. Pharmaceutical targeting of Nrf2 by DMF has strong translational potential for DMD, given it: (1) promotes antioxidant defence systems; (2) has a potent immuno-modulatory profile; and (3) can be rapidly re-purposed into clinical care strategies for DMD patients. Here, we tested two weeks of daily 100mg/kg DMF versus 5mg/kg standard care prednisone (PRED) treatment during the peak muscle degeneration period in juvenile mdx mice, the gold standard murine DMD model. Both drugs modulated seed genes driving the DMD disease program and improved muscle force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects that protected contracting muscles from fatigue, improved histopathology and augmented clinically compatible muscle function tests. In contrast, PRED treatment stunted mouse growth, worsened histopathology and modulated many normally expressed inflammatory and extracellular matrix (ECM) genes consistent with pan immunosuppression. These findings suggest DMF could be a more selective modulator of the DMD disease program with better efficacy and fewer side effects than standard care PRED therapy warranting follow-up studies to progress clinical translation.

pathology↗

bioRxiv2021

SOD2 in Skeletal Muscle: New Insights from an Inducible Deletion Model

Metabolic conditions such as obesity, insulin resistance and glucose intolerance are frequently associated with impairments in skeletal muscle function and metabolism. This is often linked to dysregulation of homeostatic pathways including an increase in reactive oxygen species (ROS) and oxidative stress. One of the main sites of ROS production is the mitochondria, where the flux of substrates through the electron transport chain (ETC) can result in the generation of oxygen free radicals. Fortunately, several mechanisms exist to buffer bursts of intracellular ROS and peroxide production, including the enzymes Catalase, Glutathione Peroxidase and Superoxide Dismutase (SOD). Of the latter there are two intracellular isoforms; SOD1 which is mostly cytoplasmic, and SOD2 which is found exclusively in the mitochondria. Developmental and chronic loss of these enzymes has been linked to disease in several studies, however the temporal effects of these disturbances remain largely unexplored. Here, we induced a post-developmental (8-week old mice) deletion of SOD2 in skeletal muscle (SOD2-iMKO) and demonstrate that 16 weeks of SOD2 deletion leads to no major impairment in whole body metabolism, despite these mice displaying alterations in aspects of mitochondrial abundance and voluntary ambulatory movement. Furthermore, we demonstrated that SOD2 deletion impacts on specific aspects of muscle lipid metabolism, including the abundance of phospholipids and phosphatidic acid (PA), the latter being a key intermediate in several cellular signaling pathways. Thus, our findings suggest that post-developmental deletion of SOD2 induces a more subtle phenotype than previous embryonic models have shown, allowing us to highlight a previously unrecognized link between SOD2, mitochondrial function and bioactive lipid species including PA.

physiology↗