Biology subjects

Nicholson, S. M.

Publications and source records attributed to Nicholson, S. M..

3 recordsLinked to original sources

bioRxiv2026

Proteomic and Kinetic Analyses Reveal Discordant Apolipoprotein Turnover and Support a Revised Model of Human Lipoprotein(a) Metabolism

Objective: Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease composed of apolipoprotein(a) [APO(a)] covalently linked to apolipoprotein B100 (APOB). Although plasma Lp(a) concentrations are largely genetically determined, the mechanisms governing Lp(a) metabolism after particle assembly remain poorly understood. We sought to define the Lp(a) proteome and determine the metabolic behavior of APO(a) and APOB within circulating Lp(a) particles using integrated proteomic, kinetic, and imaging approaches. Approach and Results: Sixteen healthy adults underwent stable isotope tracer studies with 2H3-L-leucine and 2H5-glycerol. Lp(a) particles were isolated by APO(a)-specific immunoprecipitation for high-resolution liquid chromatography-mass spectrometry and kinetic analyses, and extracellular vesicles (EVs) were characterized by imaging flow cytometry and super-resolution microscopy. Proteomic analysis identified 92 proteins associated with immuno-isolated Lp(a), enriched in pathways related to immunity, coagulation, and atherogenesis. Lp(a)-APO(a) exhibited a mean fractional clearance rate of 0.04 pools/day, whereas Lp(a)-APOB cleared approximately sevenfold faster (0.25 pools/day), independent of plasma Lp(a) concentration or APO(a) isoform size. Both APO(a) and APOB were detected on circulating EVs, suggesting that EVs may contribute to post-secretory Lp(a) particle remodeling. Conclusion: These integrated human studies demonstrate marked discordance between APO(a) and APOB turnover within circulating Lp(a) particles, challenging the prevailing assumption that both apolipoproteins behave as a single metabolic unit after Lp(a) assembly and supporting a revised model of human Lp(a) metabolism.

physiology↗

bioRxiv2023

Lead (Pb) Inhibits-PMA Induced Microglia Multinucleation

Multinucleated Microglia are formed in response to aging, inflammation, the presence of some pathogens, and are a histological feature of several CNS pathologies. Multinucleated microglia may be involved with increased clearance of CNS debris and whole cells. The present study has sought to determine the best model by which to study multinucleation in microglia in vitro, in order to investigate whether the known neurotoxicant metal lead (Pb) impacts the formation of multinucleated microglia. It was determined that isolated rat microglia (Sprague-Dawley), compared to murine (BV2) and human (HMC3) microglia cell-lines, when induced by Phorbol-myristate-acetate (PMA) results in the greatest amount of cell multinucleation and multinuclearity. In this model, it was shown that long-term exposure to Pb inhibited microglia cell proliferation, multinucleation, and multinuclearity in a dose-dependent manner. Pb appears to inhibit multinucleation in microglia by induction of multinuclear regression (karyolysis, pyknosis, or karyorrhexis) resulting in large mononuclear cells. The mechanism by which PMA induces multinucleation may involve p38/MAPK activity and Pb interferes with this activation.

pharmacology and toxicology↗

bioRxiv2023

Potential Immunomodulatory Role of Lead in Monocyte/Macrophage Differentiation

Lead (Pb) is a pernicious toxic metal and public health hazard, as it persists in the environment contaminating soil, food, and drinking water. Lead exerts its toxic effect on numerous organ systems, with the abundance of focus on the red blood cells and neurons of the hematopoietic and central nervous systems. However, insufficient investigation has been conducted on the effect of Pb on immune cells. In the current study, the toxic effects of Pb on immune cells of monocyte/macrophage lineage are described. Pb exerts a dose-dependent alteration in differentiation of monocyte/macrophage cells that retain some plasticity in development. Pb induces a bifurcation in differentiation of monocyte/macrophage cells, resulting in inhibition of osteoclastogenesis and induction of dendritic cells (DC). This phenomenon was demonstrated in RAW 264.7 murine monocyte/macrophage cell line and was consistent with response in rat bone-marrow derived macrophage (Sprague-Dawley). Pb primarily produced this response through induction of GM-CSF production and inhibition of p38/MAPK activity. Long-term exposure to physiologically relevant concentrations of Pb has the potential to modulate the immune system through altering the cell-lineage commitment of monocyte/macrophage lineage cells in a dose-dependent manner. Thus, Pb may function as an immunomodulator.

pharmacology and toxicology↗