Biology subjects

Dikalov, S. I.

Publications and source records attributed to Dikalov, S. I..

3 recordsLinked to original sources

bioRxiv2026

N-aldehyde modified phosphatidylethanolamines formed by lipid peroxidation inhibit efferocytosis.

Objective: Impairments in efferocytosis, the phagocytic clearance of apoptotic cells, contribute to the development of chronic inflammation and promote the formation of large necrotic cores within atherosclerotic plaques. A better understanding of the factors that impair efferocytosis could lead to improved interventions. Many chronic inflammatory conditions feature excessive lipid peroxidation, which generates reactive lipid aldehydes that can potentially form N-aldehyde-modified phosphatidylethanolamines (NAMPs). We therefore investigated the extent to which levels of NAMPs are elevated under conditions of oxidative stress and whether exposure of macrophages to NAMPs inhibit efferocytosis. Approach and Results: The effects of synthetic NAMPs and lipid peroxidation on efferocytosis were measured using the Incucyte Live-Cell Analysis System to monitor rate of ingestion of CypHer-labeled apoptotic cells by cultured bone marrow-derived macrophages in real time. The extent of NAMP formation under various conditions was examined using liquid chromatography coupled with mass spectrometry. Several representative species of NAMPs (N-isolevuglandin-phosphatidylethanolamine, N-IsoLG-PE; N-4-hydroxynonenal-phosphatidylethanolamine, N-HNE-PE; and N-azeloyl-phosphatidylethanolamine, N-Aze-PE) inhibited efferocytosis in a concentration-dependent manner. Hydrolysis of NAMPs by recombinant N-acyl phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) abolished their inhibitory activity, whereas genetic deletion of macrophage NAPE-PLD enhanced NAMP-mediated inhibition of efferocytosis. Blocking the inhibitor of lipid peroxidation, glutathione peroxidase 4 (GPX4), increased macrophage NAMP concentrations and impaired efferocytosis. Unmodified high-density lipoprotein (HDL) promoted efferocytosis, but exposing HDL to reactive lipid aldehydes or peroxidizing agents markedly increased NAMPs and this modified HDL inhibited efferocytosis. HDL isolated from subjects with familial hypercholesterolemia had elevated levels of multiple NAMP species. NAMPs impaired macrophage cholesterol efflux, which is required for continual efferocytosis. Conclusion: NAMPs accumulate under conditions associated with lipid peroxidation and inhibit the ability of macrophages to carry out efferocytosis.

immunology↗

bioRxiv2023

Repetitive Sulfur Dioxide Exposure in Mice Models Post-Deployment Respiratory Syndrome

Soldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than non-deployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the deployers in this cohort reported exposure to sulfur dioxide (SO2), we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular disease (PVD). Although abnormalities in small airways were not sufficient to alter lung mechanics, PVD was associated with the development of pulmonary hypertension and reduced exercise tolerance in SO2 exposed mice. Further, we used pharmacologic and genetic approaches to demonstrate a critical role for oxidative stress and isolevuglandins in mediating PVD in this model. In summary, our results indicate that repetitive SO2 exposure recapitulates many aspects of PDRS and that oxidative stress may mediate PVD in this model, which may be helpful for future mechanistic studies examining the relationship between inhaled irritants, PVD, and PDRS.

pathology↗

bioRxiv2021

Metabolic properties of murine kidney mitochondria

We show that mitochondria from the kidney of mice (MKM), rat brain (RBM), and heart (RHM) oxidize long-chain fatty acids at high rates in all metabolic states only in the presence of any other mitochondrial metabolites: succinate, glutamate, or pyruvate. All supporting substrates increased several folds the respiration rates in State 4 and State 3. The stimulations of the State 3 respiration with palmitoyl-carnitine + malate oxidation (100%) were: with succinate in MKM 340%, RBM 370%, and RHM 340%; with glutamate - MKM 200%, RBM 270%, and RHM 270%; and with pyruvate - MKM 150%, RBM 260%, and RHM 280%. The increases in O2 consumption in State 4 were due to increased leakage of electrons to produce superoxide radicals (O2*). Earlier, we have shown that the brain and heart mitochondria possess a strong intrinsic inhibition of succinate oxidation to prevent the excessive O2* production at diminished functional loads. We show that kidney mitochondria lack the intrinsic inhibition of SDH. The new methodology to study {beta}-oxidation of LCFAs opens the opportunity to study energy metabolism under normal and pathological conditions, particularly in the organs that utilize LCFAs as the main energy source.

biochemistry↗