Biology subjects

Hardy, D. B.

Publications and source records attributed to Hardy, D. B..

3 recordsLinked to original sources

bioRxiv2026

Cannabidiol Impairs Glucagon Trafficking and Secretion Through the Lysosomal System in Murine αTC1-6 cells

Glucagon secretion by pancreatic cells is regulated by nutrient, paracrine, and neural inputs, and emerging evidence suggests that the islet endocannabinoid system (ECS) may also regulate -cell function. While phytocannabinoids such as cannabidiol (CBD) have been shown to interact with the ECS, and negatively regulate insulin secretion from pancreatic {beta} cells, whether CBD alters cell function in ways that disrupt glucagon trafficking and secretion remains unclear. This study investigates how acute CBD exposure affects transcriptional and secretory networks governing cell function. Using the TC1-6 glucagon-secreting cell line, we exposed the cells to 0.3 and 3 M CBD for RT-qPCR analysis, 3 M CBD for bulk RNA sequencing, and 3 M CBD or its inactive metabolite 7-COOH-CBD for imaging and secretion experiments. Transcriptomic analysis revealed that treatment with CBD did not alter the expression of ECS receptors and enzymes. However, pathways involved in cellular excitability, peptide hormone trafficking, and secretion were significantly downregulated. Using confocal microscopy, we found that CBD exposure increased the colocalization of glucagon with LAMP1 (a lysosomal marker), and that CBD rerouted peripheral glucagon, and glucagon-containing lysosomes towards the intracellular region of the cell. In conjunction with these findings, we observed reduced glucose-stimulated glucagon secretion under high glucose conditions. Overall, our data supports a model in which acute CBD exposure downregulates processes governing cellular excitability and peptide secretion and negatively regulates glucagon trafficking and secretion by rerouting peripheral glucagon into lysosome-associated intracellular compartments in TC1-6 cells.

cell biology↗

bioRxiv2020

Sex-specific Alterations in Hepatic Cholesterol Metabolism in Young Uteroplacental Insufficiency-induced Low Birth Weight Adult Guinea Pig Offspring

BackgroundIntrauterine growth restriction (IUGR) and low birth weight (LBW) have been widely reported as an independent risk factor for hypercholesterolemia and increased hepatic cholesterol underlying liver dysfunction in adulthood. However, the specific impact of uteroplacental insufficiency (UPI), a leading cause of LBW in developed world, on hepatic cholesterol metabolism in later life, is ill defined and is clinically relevant in understanding later life liver metabolic health trajectories. MethodsHepatic cholesterol metabolism pathways were studied in uterine artery ablation-induced LBW and normal birth weight (NBW) male and female guinea pig offspring at postnatal day 150. ResultsHepatic free and total cholesterol were increased in LBW versus NBW males. Transcriptome analysis of LBW versus NBW livers revealed that "Cholesterol metabolism" was an enriched pathway in LBW males but not females. Microsomal triglyceride transfer protein and cytochrome P450 7A1 protein, involved in hepatic cholesterol efflux and catabolism, respectively, and catalase activity were decreased in LBW male livers. Superoxide dismutase activity was reduced in LBW males but increased in LBW females. ConclusionsUPI environment is associated with a later life programed hepatic cholesterol accumulation via impaired cholesterol elimination, in a sex-specific manner. These programmed alterations could underlie later life cholesterol-induced hepatic lipotoxicity in LBW male offspring. Impact StatementO_LILow birth weight (LBW) is a risk factor for adult hypercholesterolemia and increased hepatic cholesterol. C_LIO_LIUteroplacental insufficiency (UPI) resulting in LBW increased hepatic cholesterol content, altered hepatic expression of cholesterol metabolism-related genes in young adult guinea pigs. C_LIO_LIUPI-induced LBW was also associated with markers of a compromised hepatic cholesterol elimination process and failing antioxidant system in young adult guinea pigs. C_LIO_LIThese changes, at the current age studied, were sex-specific, only being observed in LBW males and not LBW females. C_LIO_LIThese programmed alterations could lead to further hepatic damage and greater predisposition to liver diseases in UPI-induced LBW male offspring as they age. C_LI

physiology↗

bioRxiv2019

Exposure to the RXR agonist SR11237 in early life causes disturbed skeletal morphogenesis in a rat model

Longitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation on EO.\n\nRats given SR11237 from post-natal day 5 to 15 were harvested for micro-computed tomography scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole mount evaluation.\n\nRXR agonist-treated rats were smaller than controls, and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape corresponding with P57 immunostaining. Additionally, SOX9 positive cells were found surrounding the calcified tissue. The epiphysis of SR11237 treated bones showed increased TRAP staining, and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of treated animals. Isolated mouse long bones treated with SR11237 grew significantly less than their DMSO controls.\n\nThis study demonstrates that stimulation of the RXR receptor causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models.

developmental biology↗