Biology subjects

Vary, C.

Publications and source records attributed to Vary, C..

3 recordsLinked to original sources

bioRxiv2024

Lipidomic and Proteomic Insights from Extracellular Vesicles in Postmortem Dorsolateral Prefrontal Cortex Reveal Substance Use Disorder-Induced Brain Changes

Substance use disorder (SUD) significantly increases the risk of neurotoxicity, inflammation, oxidative stress, and impaired neuroplasticity. The activation of inflammatory pathways by substances may lead to glial activation and chronic neuroinflammation, potentially mediated by the release of extracellular particles (EPs), such as extracellular condensates (ECs) and extracellular vesicles (EVs). These particles, which reflect the physiological, pathophysiological, and metabolic states of their cells of origin, might carry molecular signatures indicative of SUD. In particular, our study investigated neuroinflammatory signatures in SUD by isolating EVs from the dorsolateral prefrontal cortex (dlPFC) Brodmanns area 9 (BA9) in postmortem subjects. We isolated BA9-derived EVs from postmortem brain tissues of eight individuals (controls: n=4, SUD: n=4). The EVs were analyzed for physical properties (concentration, size, zeta potential, morphology) and subjected to integrative multi-omics analysis to profile the lipidomic and proteomic characteristics. We assessed the interactions and bioactivity of EVs by evaluating their uptake by glial cells. We further assessed the effects of EVs on complement mRNA expression in glial cells as well as their effects on microglial migration. No significant differences in EV concentration, size, zeta potential, or surface markers were observed between SUD and control groups. However, lipidomic analysis revealed significant enrichment of glycerophosphoinositol bisphosphate (PIP2) in SUD EVs. Proteomic analysis indicates downregulation of SERPINB12, ACYP2, CAMK1D, DSC1, and FLNB, and upregulation of C4A, C3, and ALB in SUD EVs. Gene ontology and protein-protein interactome analyses highlight functions such as cell motility, focal adhesion, and acute phase response signaling that is associated with the identified proteins. Both control and SUD EVs increased C3 and C4 mRNA expression in microglia, but only SUD EVs upregulated these genes in astrocytes. SUD EVs also significantly enhanced microglial migration in a wound healing assay.This study successfully isolated EVs from postmortem brains and used a multi-omics approach to identify EV-associated lipids and proteins in SUD. Elevated C3 and C4 in SUD EVs and the distinct effects of EVs on glial cells suggest a crucial role in acute phase response signaling and neuroinflammation.

neuroscience↗

bioRxiv2022

The Fatty Acid Binding Protein Family Represents a Novel Target in Multiple Myeloma

BackgroundMultiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate, highlighting a critical need for new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. MethodsMyeloma cells treated with FABP inhibitors (BMS3094013 and SBFI-26) were examined in vivo and in vitro for cell cycle, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation. Myeloma cell responses to BMS309403 and/or SBFI-26 were assessed with RNA-sequencing and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using DepMap. Finally, MM patient datasets (CoMMpass and GEO) were mined for FABP expression correlations with clinical outcomes. ResultsMyeloma cells treated with FABPi or with FABP5 knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation in vitro. FABPi had potent anti- tumor effects both in vitro and in vivo in two pre-clinical MM mouse models where increased mouse survival was observed. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells. Clinical data demonstrated worse overall and progression-free survival in patients with high FABP5. ConclusionsThis study establishes the FABP family as a therapeutically actionable dependency in multiple myeloma with a multitude of actions and cellular roles that result in the support of myeloma progression. Statement of translational relevanceMultiple myeloma (MM) is an incurable disease of the plasma cell and MM patients require better treatments as soon as possible. The fatty acid binding protein (FABP) family plays a number of roles in cells, including supporting fatty acid oxidation, lipid shuttling and signal transduction. Here, we demonstrate with CoMMpass and other clinical data that FABPs represent a biomarker for aggressive disease in MM, and are a novel, targetable protein family expressed by myeloma cells. Pharmacologically inhibiting FABPs kills tumor cells and induces cell cycle arrest in vitro and in pre-clinical models. Mechanisms of action are multitudinous, as we discovered with RNA-sequencing, proteomic analysis, and phenotyping assays. Cell metabolism, cell signaling, cell stress, and epigenetic signatures were altered in MM cells when FABPs were inhibited. In summary, targeting FABP5 holds great therapeutic potential for killing diseased cells, with few negative off-target effects on healthy cells.

cancer biology↗

bioRxiv2020

PHOSPHO1, a novel skeletal regulator of insulin resistance and obesity

The skeleton is recognised as a key endocrine regulator of metabolism. Here we show that mice lacking the bone mineralization enzyme PHOSPHO1 (Phospho1-/-) exhibited improved basal glucose homeostasis and resisted high-fat-diet induced weight gain and diabetes. The metabolic protection in Phospho1-/- mice was manifested in the absence of altered levels of osteocalcin. Osteoblasts isolated from Phospho1-/- mice were enriched for genes associated with energy metabolism and diabetes; Phospho1 both directly and indirectly interacted with genes associated with glucose transport and insulin receptor signalling. Canonical thermogenesis via brown adipose tissue did not underlie the metabolic protection observed in adult Phospho1-/- mice. However, the decreased serum choline levels in Phospho1-/- mice were normalized by feeding a 2% choline rich diet resulting in a normalization in insulin sensitivity and fat mass. This study identifies PHOSPHO1 as a potential therapeutic target for the treatment of obesity and diabetes.

physiology↗