Biology subjects

Woodward, T.

Publications and source records attributed to Woodward, T..

4 recordsLinked to original sources

bioRxiv2026

Integrated lipidomic and transcriptomic analyses reveal novel endogenous lipid signaling system regulation in skin and plasma during psoriasiform inflammation

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and immune dysregulation. Emerging clinical and experimental evidence suggests that endogenous lipid (endolipid) signaling systems, including the endocannabinoid system (ECS), represent a promising therapeutic target to treat psoriasis; however, comprehensive characterization of small-molecule endolipids and related proteins in psoriatic skin and their relationship to systemic changes remains limited. Here, we used the imiquimod (IMQ)-induced mouse model of psoriasis to perform combined lipidomic and transcriptional profiling of endolipid signaling in both skin and plasma. Targeted lipidomics revealed a striking divergence between tissues: most endolipids increased in inflamed skin but decreased in plasma, including the canonical ECS lipids anandamide and 2-arachidonoylglycerol. In contrast, selected lipid species, including taurine-conjugated metabolites (both N-acyl taurines and bile acids), were elevated in both tissues, indicating pathway-specific regulation. Targeted transcriptional analysis of whole skin showed reduced expression of key endolipid biosynthetic enzymes (Napepld, Dagla, Daglb) and the cannabinoid receptor Cnr1, while Cnr2 and ECS-related metabolic enzymes remained unchanged. Additional alterations were observed in transcripts involved in related endolipid signaling (Trpv1, Trpv4, Ppara, Pparg, Gpr55), bile acid metabolism (Fxr, Bsep, Fabp4, Fabp5, Cyp27a1, Cyp8b1), and inflammatory pathways (Cox-2). To resolve this apparent discrepancy between lipid levels and gene expression, we performed compartment-specific analyses of epidermal and dermal layers. These revealed a predominantly suppressive epidermal response across multiple ECS-related proteins, contrasted by a more variable dermal profile with selective preservation or upregulation, particularly of Cnr2. Together, these findings demonstrate that psoriasiform inflammation is associated with compartment-specific remodeling of endolipid signaling across skin and systemic compartments, underscoring the functional heterogeneity of epidermal and dermal layers. This dataset provides novel insights into the dysregulation of endolipid signaling systems in psoriasis and provides a foundation for the development of spatially informed, lipid-based therapeutic strategies.

molecular biology↗

bioRxiv2025

Sex Differences in Plasma Levels of Endocannabinoids and Related Lipids Before and After acute and repeated mTBI: an exploratory study for plasma biomarkers for mTBI

Mild traumatic brain injury (mTBI) is common diagnosis across all age groups and while most symptoms resolve within a few weeks; between 10 and 25 percent of mTBI patients suffer long-term problems. Known as post-concussion syndrome (PCS), symptoms include headache, a range of cognitive deficits, and depression. Currently, there are no established treatments for PCS and no clear predictive biometrics to determine which patients are at increased risk. Previous studies have identified some protein-derived plasma biomarkers for mTBI, however, the effects of mTBI on lipid signaling molecules and metabolites in blood is largely unknown. Endogenous lipids (endolipids) such as the endocannabinoids (eCBs) and their congeners are lipid signaling molecules that are associated with promoting neuroprotective responses after head trauma in animal models. Here, we examine the plasma lipidome using a rat model of acute and repeated mTBI that we previously demonstrated had a sex dependent change in neuroinflammation wherein females showed a higher degree of neurodegeneration after repeated head-injury than males. Key results of this exploratory lipidomics screen here demonstrates that acute head injury drives significantly more changes in plasma endolipids in males (32%) than females (8%), whereas, on the second day of head injury, only 11% change in males but 15% in females. Some key endolipids were modified in both males are precursors for resolving molecules and this was lacking in females. Given that females with repeated mTBI in this model demonstrated aspects of PCS, this could be an important component in evaluating clinical cases. Endolipids in the screen were measurable in plasma using only 100{micro}L, a volume necessary to be able to perform multiple blood draws on these rodent subjects. This threshold provides evidence that the levels of these endolipids could be readily measured throughout a patients recovery. Therefore, this family of endolipids has the potential to provide data on the progression of the injury and could be another crucial aspect in predicting mTBI outcomes.

neuroscience↗

bioRxiv2025

Acetaminophen inhibits diacylglycerol lipase synthesis of 2-arachidonoyl glycerol: implications for nociception

SUMMARYThough acetaminophen is a ubiquitous analgesic, its mechanism of action remains unknown. Thus, even though acetaminophen causes ∼500 deaths each year in the US it has not been possible to design safer alternatives. Because endocannabinoids may have a role in acetaminophen action, we examined interactions between the two. We now report that acetaminophen inhibits the activity of diacylglycerol lipase α (DAGLα), but not DAGLβ, decreasing production of the endocannabinoid 2-arachidonoyl glycerol. This gave rise to the counterintuitive hypothesis that decreasing endocannabinoid production by DAGLαinhibitionmay be antinociceptive in certain settings. Supporting this hypothesis, we find that DAGL inhibition by RHC80267 is antinociceptive in wildtype but not CB1 knockout mice in the hotplate test. We propose 1) that activation of DAGLα may exacerbate some forms of nociception and 2) a novel mechanism for the antinociceptive actions of acetaminophen whereby acetaminophen inhibits a DAGLα/CB1-based circuit that plays a permissive role in at least one form of nociception.

neuroscience↗

bioRxiv2025

Dose-dependent changes in global brain activity and functional connectivity following exposure to psilocybin: a BOLD MRI study in awake rats.

Psilocybin is a hallucinogen with complex neurobiological and behavioral effects. This is the first study to use MRI to follow functional changes in brain activity in response to different doses of psilocybin in fully awake, drug naive rats. Female and male rats were given IP injections of vehicle or psilocybin in doses of 0.03 mg/kg, 0.3 mg/kg, and 3.0 mg/kg while fully awake during the imaging session. Changes in BOLD signal were recorded over a 20 min window. Data for resting state functional connectivity were collected approximately 35 min post injection All data were registered to rat 3D MRI atlas with 173 brain regions providing site-specific changes in global brain activity and changes in functional connectivity. Treatment with psilocybin resulted in a significant dose-dependent increase in positive BOLD signal. The areas most affected by the acute presentation of psilocybin were the somatosensory cortex, basal ganglia and thalamus. Females were significantly more sensitive to the 0.3 mg/kg dose of psilocybin than males. There was a significant dose-dependent global increase in functional connectivity, highlighted by hyperconnectivity to the cerebellum. Brain areas hypothesized to be involved in loss of sensory filtering and organization of sensory motor stimuli such as the claustrum and the cortico-basal ganglia-thalamic-cortical loop were all affected by psilocybin in a dose-dependent manner. Indeed, the general neuroanatomical circuitry associated with the psychedelic experience was affected but the direction of the BOLD signal and pattern of activity between neural networks was inconsistent with the human literature.

neuroscience↗