Characterizing the Role of Endocannabinoid Receptor Cnr1 in Mouse Ovarian Granulosa CellsRandhawa, Madogwe, McCall
et alCell Biochem Funct (2025) 43 (3), e70070
Abstract: The endocannabinoid receptors Cnr1 and Cnr2 have been found in reproductive organs such as the oviduct and uterus. These receptors bind to endocannabinoids, the arachinodoylethanolamine (AEA) and arachinodoylglycerol (2-AG), respectively. Both cannbinoid receptors have been investigated for their role in implantation and fertilization. However, not much is explored in terms of their role in ovarian granulosa cells. As these two receptors (especially Cnr1) have affinity towards the major component of Cannabis, tetrahydrocannabinol (THC), its usage raises concerns about the potential effects of THC on ovarian functions. Hence, it is important to characterize the role of endocannabinoid system in the ovarian granulosa cells. The objectives of this study were to use the mouse model to: (1) profile the expression pattern of the Cnr1 and Cnr2 and the endocannabinoid metabolizing enzymes (Faah and Mgll) in granulosa cells and (2) to determine the effect of the Cnr1 antagonist, AM251 on ovarian functions. We found that Cnr1 transcript abundance was higher (p < 0.05) at 4 h hCG than 24 h and 48 h eCG timepoints, whereas Cnr2 transcript decreased (p < 0.05) with follicular development. Conversely, Faah and Mgll transcripts were higher at 14 h hCG (p < 0.05) suggesting their upregulation after ovulation. The ovulation rate was lower in AM251 than vehicle-treated mice (p < 0.05), indicating that Cnr1 signaling may regulate ovulation. Further investigating the effect of AM251, we found that it significantly downregulated Ptgs2 and Pappa (p < 0.05). Overall, these data suggest that Cnr1, an important player in the endocannabinoid system, is important for ovulation.© 2025 The Author(s). Cell Biochemistry and Function published by John Wiley & Sons Ltd.
Fatty acid metabolism shapes immune responses in chronic lymphocytic leukemiaZhang, Ma, Li
et alBiomark Res (2025) 13 (1), 42
Abstract: Fatty acids serve as a crucial energy source for tumor cells during the progression of chronic lymphocytic leukemia (CLL). The present study aims to elucidate the characteristics of fatty acid metabolism (FAM) in CLL, construct a related prognostic score, and investigate the regulatory role and mechanisms of FAM in CLL development.Bulk RNA sequencing data from CLL patients and healthy controls were analyzed to identify differentially expressed fatty acid metabolic genes. FAM-score was constructed using Cox-LASSO regression and validated. Single-cell RNA sequencing was used to analyze the expression of key FAM genes in CLL immune cell subsets and investigate cellular communication. Functional assays, including cell viability, drug sensitivity, and oxygen consumption assays, were performed to assess the impact of fatty acid oxidation (FAO) inhibition on CLL cells.Three FAM-related genes (LPL, SOCS3, CNR1) were identified with independent prognostic significance to construct the risk score. The FAM-score demonstrated superior prognostic performance compared to the Binet stage and was associated with established clinical prognostic markers. Single-cell analysis revealed distinct expression patterns of LPL, SOCS3, and CNR1 across CLL immune cell subsets. Cellular communication analysis highlighted the regulatory role of distinct B cell and Treg subsets in the CLL microenvironment. CLL patients with high FAM-score displayed distinct immune infiltration patterns, with increased FAO pathway activity. Inhibition of FAO reduced CLL cell viability, synergistically enhanced the efficacy of the PI3K inhibitor idelalisib.The present study constructed a prognostic risk score based on FAM gene expression, revealing related immune phenotypic differences and exploring the regulatory role of FAO in CLL development. Targeting fatty acid metabolism potentially modulates the CLL immune microenvironment and synergistically enhances the efficacy of PI3K inhibitors.© 2025. The Author(s).
CB1 cannabinoid receptor agonists induce acute respiratory depression in awake miceWatkins, Aradi, Hahn
et alPharmacol Res (2025) 214, 107682
Abstract: Recreational use of synthetic cannabinoid agonists (i.e., "spice compounds") that target the cannabinoid type 1 receptor (CB1) can cause acute respiratory failure in humans. However, Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive phytocannabinoid in cannabis, is not traditionally thought to interact with the brain respiratory system, based largely upon sparse labeling of CB1 receptors in the medulla and relative safety suggested by widespread human use. Here we used whole body plethysmography and RNAscope in situ hybridization in mice to reconcile this conflict between conventional wisdom and human data. We examined the respiratory effects of the synthetic CB1 full agonist CP55,940 and Δ9-THC in male and female mice. CP55,940 and Δ9-THC potently and dose-dependently suppressed minute ventilation and tidal volume, decreasing measures of respiratory effort (i.e., peak inspiratory and expiratory flow). Both cannabinoids reduced respiratory frequency, decreasing inspiratory and expiratory time while markedly increasing inspiratory and expiratory pause. Respiratory suppressive effects were fully blocked by the CB1 antagonist AM251, were minimally impacted by the peripherally-restricted CB1 antagonist AM6545, and occurred at doses lower than those that produce cardinal behavioral signs of CB1 activation. Using RNAscope in situ hybridization, we also demonstrated extensive coexpression of Cnr1 (encoding the CB1 receptor) and Oprm1 (encoding the µ-opioid receptor) mRNA in respiratory cells in the medullary pre-Bötzinger complex, a critical nucleus of respiratory control. Our results show that mRNA for CB1 is present in respiratory cells in a medullary brain region essential for breathing and demonstrate that cannabinoids produce respiratory suppression via activation of central CB1 receptors.Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.
Spinal dorsal horn neurons involved in the alleviating effects of cannabinoid receptor agonists on neuropathic allodynia-like behaviors in ratsSueto, I, Onishi
et alJ Pharmacol Sci (2025) 157 (4), 253-260
Abstract: Mechanical allodynia, the pain caused by innocuous tactile stimuli, is a hallmark symptom of neuropathic pain that is often resistant to currently available treatments. Cannabinoids are widely used for pain management; however, their therapeutic mechanisms for neuropathic mechanical allodynia remain unclear. Using transgenic rats that enable to optogenetically stimulate touch-sensing Aβ fibers in the skin, we found that the intrathecal administration of the synthetic cannabinoid, WIN 55,212-2, alleviated the Aβ fiber-derived neuropathic allodynia. Furthermore, we injected adeno-associated virus vectors incorporating the rat cannabinoid receptor 1 (CB1 receptor) (encoded by Cnr1) promoter and tdTomato or short hairpin RNA targeting the CB1 receptor into the spinal dorsal horn (SDH) and demonstrated that the conditional knockdown of CB1 receptors in Cnr1+ SDH neurons attenuates the anti-allodynic effects of intrathecally administered WIN 55,212-2. Electrophysiological analysis revealed that Cnr1+ SDH neurons received excitatory synaptic inputs from the primary afferent Aβ fibers. Collectively, our results suggest that the CB1 receptors in Cnr1+ SDH neurons are molecular and cellular targets of intrathecal WIN 55,212-2 to alleviate neuropathic allodynia.Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.
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