Biology subjects

Wiedrick, J.

Publications and source records attributed to Wiedrick, J..

3 recordsLinked to original sources

bioRxiv2025

Specific GPCRs Elicit Unique Extracellular Vesicle MiRNA Array Signatures: An Exploratory Study

3.All cells secrete extracellular vesicles (EVs) containing nucleic acid cargo, including microRNAs (miRNAs), that regulate the function of receiving cells. G protein-coupled receptors (GPCRs) affect intracellular function via multiple signaling cascades. However, the mechanisms of GPCR intercellular signaling through EV miRNA activity are unknown. Human U2 osteosarcoma cells expressing native GPCRs were used to selectively stimulate distinct G protein signaling cascades (Gi, Gq, G12/13, and {beta}-arrestin) by members of specific receptor subclasses including the adenosine receptor A1 (ADORA1), the histamine receptor H1 (HRH1), the frizzled class receptor 4 (FZD4), and the atypical chemokine receptor 3 (ACKR3), respectively. We hypothesized that stimulation of specific classes of GPCRs would cause the release of EVs containing miRNAs with receptor-specific up- or down-regulated expression, affecting unique pathological downstream signaling cascades. Receptor-specific agonists dose-dependently increased respective signaling cascade intermediates. We found no change in the quantity of EVs ([~]200nm diameter), but there were distinct EV miRNA signatures following stimulation of GPCRs. Network analyses of differentially expressed miRNA and their predicted targets validated the linkage between specific receptors and cell function and pathological states. The data can be used to reverse engineer mechanisms involving EV miRNAs for various physiological and pathological processes. GPCRs are major pharmacological targets, so understanding the mechanisms that stimulate or inhibit GPCR-mediated changes in extracellular miRNA signatures could improve long- and short-term therapeutic and unwanted drug effects. SummaryStimulation of specific GPCRs elicited unique EV miRNA signatures that up- and down-regulated predicted biological and pathological cellular processes. 4. Significance StatementG protein-coupled receptors (GPCR) are therapeutic targets for various human diseases. However, the mechanisms of GPCR signaling through extracellular vesicle (EV) miRNA activity are unknown. Here, we identified unique EV miRNA signatures resulting from GPCR activation. The miRNA functional analyses indicate that the downstream signaling effects and their functional networks differ by receptor. This study has important implications for developing new drugs and their long-term and "off-target" effects. 5. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/659918v2_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1a9812org.highwire.dtl.DTLVardef@1f5cbf3org.highwire.dtl.DTLVardef@20d1fdorg.highwire.dtl.DTLVardef@ba4fad_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

The CD74 inhibitor DRhQ improves cognition and mitochondrial function in 5xFAD mouse model of Aβ accumulation

Neuroinflammation and mitochondrial dysfunction are early events in Alzheimers disease (AD) and contribute to neurodegeneration and cognitive impairment. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factory (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders like AD. Our group has developed DRhQ, a novel CD74 binding construct that competitively inhibits MIF binding, blocks T-cell and macrophage activation and migration into the CNS, enhances anti-inflammatory microglia cell numbers and reduces pro-inflammatory gene expression. Here we evaluate its effects in {beta}-amyloid (A{beta}) overexpressing mice. 5xFAD mice and their wild type littermates were treated with DRhQ (100 {micro}g) or vehicle for 4 weeks. DRhQ improved cognition and cortical mitochondrial function in both male and female 5xFAD mice. A{beta} plaque burden in 5xFAD animals were not robustly impacted by DRhQ treatment nor was microglial activation, although in the hippocampus there was some evidence of a reduction in female 5xFAD mice. Future studies are needed to confirm this possible sex-dependent response on microglial activation as well as to optimize the dose, and timing of DRhQ treatment and gain a better understanding of its mechanism of action.

neuroscience↗

bioRxiv2020

Gut Microbiome Pattern Reflects Healthy Aging and Predicts Extended Survival in Humans

The gut microbiome has important effects on human health, yet its importance in human aging remains unclear. Using two independent cohorts comprising 4582 individuals across the adult lifespan we demonstrate that, starting in mid-to-late adulthood, gut microbiomes become increasingly unique with age. This uniqueness pattern is strongly associated with gut microbial amino acid derivatives circulating within the bloodstream, many of which have been previously identified as longevity biomarkers. At the latest stages of human life, two distinct patterns emerge wherein individuals in good health show continued microbial drift toward a unique compositional state, while the same drift is absent in individuals who perform worse on a number of validated health measures. The identified healthy aging pattern is characterized by an overall depletion of core genera found across most humans - primarily a depletion in the nearly ubiquitous genus Bacteroides. Consistently, retaining a high Bacteroides dominance into extreme age, or, equivalently, having a low gut microbiome uniqueness score, predicts decreased survival in a four-year follow-up. Our comprehensive analysis identifies the gut microbiome as a novel component of healthy aging, with important implications for the worlds growing older population.

systems biology↗