Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"The phosphodiesterase 4B inhibitor A33 blocks locomotor stimulation by low doses of ethanol and diazepam.","authors":"Yuri A Blednov, Sonia Mason, Jody Mayfield, Sindhu Sriramoji-Virdi, Miriam E Bocarsly, Robert O Messing","doi":"10.1016/j.jpet.2026.105040","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105040","url":null,"abstract":"<p><p>Nonselective phosphodiesterase type 4 (PDE4) inhibitors (subtypes A-D) such as apremilast significantly reduce voluntary ethanol consumption. The PDE4B inhibitor A33 does not alter apremilast-mediated reductions in drinking but does alter recovery from intoxicating doses of ethanol in C57BL/6J mice. Here, we used A33 to test the hypothesis that PDE4B modulates the effects of low doses of ethanol. A33 (1 mg/kg, i.p.) prevented locomotor stimulation induced by 1.25 and 1.5 g/kg ethanol during the daytime, when mouse activity is normally low, and blocked stimulation by 1.25 g/kg ethanol in the open field. In other behavioral tests, A33 prevented the motivation to escape a stressful situation (hole-board test) and exploratory activity by 1.25 g/kg ethanol (spontaneous alternation test). However, A33 did not alter the anxiolytic effect of 1.25 g/kg ethanol in the elevated plus maze or working memory in the spontaneous alternation test. Similarly, A33 prevented locomotor stimulation by low-dose diazepam (1 mg/kg, i.p.) without altering its anxiolytic effect. Neurochemically, A33 blocked ethanol-evoked dopamine release in the nucleus accumbens, consistent with the behavioral finding that it blocks ethanol-induced locomotor stimulation. Together with evidence that A33 accelerates recovery from intoxication without altering acute tolerance or metabolism, these findings suggest that A33 specifically blocks the stimulant-like properties of low-dose ethanol. SIGNIFICANCE STATEMENT: Apremilast nonselectively inhibits phosphodiesterase type 4 (PDE4) subtypes A-D and reduces alcohol drinking in preclinical and human studies. We use subtype-selective inhibitors to identify the subtype(s) driving anti-drinking effects. The PDE4B inhibitor A33 blocked motor stimulation by low-dose alcohol, which may explain its ability to shorten intoxication. A33 also blocked alcohol-induced dopamine release in a central area of the brain's reward system. A33 may prevent stimulatory behaviors associated with alcohol-induced euphoria in humans, which may reduce drinking.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 11","pages":"105040"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149269450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Locomotor stimulant and methamphetamine-like interoceptive effects of putative impurity N-ethyl-methamphetamine in rodents: Role of Phase I metabolism.","authors":"Brenda M Gannon, Justin M Pressley, Andriy Fomin, Sierra Rowe, Hannah E Shaw, Melinda G Gunnell, Isabel L Ritter, Marina Avram, Cassandra Prioleau, Jeffery H Moran, William E Fantegrossi","doi":"10.1016/j.jpet.2026.105039","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105039","url":null,"abstract":"<p><p>Over the past 20 years, N-ethyl-methamphetamine (NEM) has been identified in seized methamphetamine (METH) samples. Often considered a byproduct or impurity of illicit METH synthesis, its structural similarity to METH suggests that it may have pharmacological actions of its own or be metabolically converted to METH or amphetamine (AMPH) in vivo. These studies assessed the potency and effectiveness of NEM as a locomotor stimulant compared to METH in NIH Swiss mice, and probed the role of cytochrome P450 (CYP) vs non-CYP metabolism in these locomotor effects using pretreatments with the broad spectrum CYP inhibitor 1-aminobenzotriazole (1-ABT) or the selective CYP2D6 inhibitor quinidine. Blood samples taken from mice treated with NEM, with and without pretreatments of 1-ABT or quinidine, were quantitively analyzed for NEM, METH, and AMPH using Quadrupole Time-of-Flight. Additionally, the discriminative stimulus effects of NEM were assayed in Sprague-Dawley rats trained to discriminate METH from saline. NEM produced dose-dependent locomotor stimulant and METH-like interoceptive effects, but with a slower onset and less potently than METH. Locomotor stimulant effects of NEM were abolished by pretreatment with 1-ABT or quinidine, and both pretreatments also decreased conversion of NEM to METH and AMPH in mouse blood. These data demonstrate METH-like biological effects of NEM and suggest that the likely mechanism for these effects is metabolic conversion of NEM to METH and AMPH via CYP2D6. NEM thus functions as a prodrug for METH and AMPH, and would be expected to have METH-like abuse liability in humans. SIGNIFICANCE STATEMENT: N-ethyl-methamphetamine (NEM) has been identified in seized methamphetamine (METH) samples, and is typically considered a byproduct or impurity of illicit METH synthesis. These studies demonstrate METH-like biological effects of NEM and suggest that the likely mechanism for these effects is metabolic conversion of NEM to METH and AMPH via CYP2D6. NEM thus functions as a prodrug for METH and AMPH, and would be expected to have METH-like abuse liability in humans.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 11","pages":"105039"},"PeriodicalIF":4.3,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From stress cytokine to drug target: The translational landscape of growth differentiation factor 15.","authors":"Nicholas R Najjar, Bart C De Jonghe, Matthew R Hayes, Robert P Doyle","doi":"10.1016/j.jpet.2026.105036","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105036","url":null,"abstract":"<p><p>Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine that translates cellular injury, metabolic imbalance, and disease burden into systemic physiological responses. Discovery of its hindbrain-restricted receptor, glial cell line-derived neurotrophic factor family receptor α-like (GFRAL) and cosignaling partner rearranged during transfection (RET), established a dedicated neuroendocrine axis (GDF15-GFRAL-RET) linking stress to appetite suppression, nausea, and autonomic effects on energy expenditure. Initially regarded as a passive disease biomarker, GDF15 is now recognized as an active mediator in cancer-related anorexia-cachexia syndrome, chemotherapy-induced nausea and vomiting, obesity, aging, cardiovascular disease, hepatic, renal, gastrointestinal diseases, neurodegeneration, eating disorders, and hyperemesis gravidarum. This expanding biology has driven parallel development of GFRAL agonists and antagonists, as well as approaches to bind and eliminate circulating GDF15 in the treatment of illness behaviors associated with these numerous disease states. Here we review GDF15 biology and signaling from a medicinal chemistry perspective, examining reported structure-activity relationship-guided drug discovery across biologics and small molecules, including patents and ongoing clinical trials targeting the GDF15-GFRAL-RET axis. SIGNIFICANCE STATEMENT: Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that signals through the hindbrain-restricted GFRAL-RET receptor complex to regulate appetite, nausea, and energy balance. This review highlights advances in understanding GDF15 biology, its role in disease, and synthesizes medicinal chemistry efforts targeting this pathway. By integrating structure-activity relationships, biologics, and small molecule approaches, this study outlines therapeutic strategies and translational challenges in modulating the GDF15-GFRAL-RET axis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 11","pages":"105036"},"PeriodicalIF":4.3,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of monosodium iodoacetate, medial meniscal transection, and partial medial meniscectomy in vivo rat models of osteoarthritis from the pain and industrial perspective.","authors":"Paula Lehtinen, Liisa Ailanen, Johanna Kela, Sami Virtanen, Carina Stenfors, Andrii Domanskyi","doi":"10.1016/j.jpet.2026.105038","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105038","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a major global health burden marked by progressive cartilage degeneration and chronic pain with intertwined inflammatory and neuropathic mechanisms. This study compared three rat OA models, monosodium iodoacetate (MIA), medial meniscal transection (MMT), and partial medial meniscectomy (MNX), to assess their translational value, suitability for pharmaceutical research, and identify the most robust and reproducible model for preclinical OA pain research. OA was induced in male Wistar (MIA) or Sprague Dawley (MMT, MNX) rats, and pain progression was evaluated by testing mechanical sensitivity and dynamic weight-bearing. A single oral dose of pregabalin (30 mg/kg) was used for pharmacological validation. The MIA model produced a rapid, robust pain phenotype, with pronounced mechanical hypersensitivity and consistent weight-bearing deficits by day 21. Surgical models progressed more slowly and variably: hypersensitivity emerged by day 21 in MNX rats and by day 49 in MMT rats. Neither surgical model generated stable dynamic weight-bearing deficits, indicating limited sensitivity of current gait-analysis methods for detecting their subtler impairments. Pregabalin reduced mechanical hypersensitivity across all 3 models, confirming their pharmacological validity and utility for analgesic screening. Overall, the MIA model remains the most efficient and reliable for industrial research due to its strong behavioral window, whereas the MNX model offers greater translational relevance if paired with more sensitive and objective behavioral measures. SIGNIFICANCE STATEMENT: By systematically comparing chemical and surgical rat models of osteoarthritis, this study clarifies their strengths and limitations for modeling chronic pain. The results demonstrate that, although the monosodium iodoacetate model delivers robust, reproducible behavioral outcomes, surgical models more accurately reflect disease progression but lack sensitive behavioral readouts. This work informs translational model selection and underscores the need for more objective pain assessment tools.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 11","pages":"105038"},"PeriodicalIF":4.3,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antinociceptive interaction of Δ⁹-tetrahydrocannabinol and cannabidiol in a humanized mouse model of sickle cell disease.","authors":"Alex Mabou Tagne, Olufunke Florence Ajeigbe, Heidi C Avalos, Francesca Galvani, Saeed Al Masri, Carolina Mireles, Kalpna Gupta, Daniele Piomelli","doi":"10.1016/j.jpet.2026.105037","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105037","url":null,"abstract":"<p><p>Sickle cell disease (SCD) is characterized by recurrent, debilitating pain. Opioid analgesics are routinely used in its management, but limited efficacy and pervasive side effects prompt many patients with SCD to seek alternatives, including cannabis. Prior work has shown that 2 major cannabis constituents, Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD), exert antinociceptive effects in HbSS-BERK mice, a model of SCD. The present study investigated the pharmacological interaction between these 2 agents and characterized the effects associated with repeated coadministration. Fixed-ratio isobolographic analyses demonstrated that Δ⁹-THC and CBD produced dose-dependent antinociception following acute coadministration. Fixed-ratio isobolographic analyses showed that the experimentally determined median effective dose of the mixture was lower than the theoretical additive dose, but the difference was not statistically significant, supporting an additive antinociceptive interaction. Repeated coadministration maintained antinociceptive efficacy over 14 days and reduced SCD-evoked anxiety-like behavior in one cohort but did not improve recognition-memory deficits. Liquid chromatography-tandem mass spectrometry analyses revealed that repeated coadministration increased plasma CBD concentrations, produced a modest increase in Δ⁹-THC exposure, and markedly elevated circulating levels of the endocannabinoid 2-arachidonoyl-sn-glycerol. Molecular analyses of spinal cord tissue showed that HbSS-BERK mice exhibited increased oxidative stress (malondialdehyde, MDA) and proinflammatory signaling (interleukin [IL]-1β mRNA), with no change in anti-inflammatory signaling (IL-10 mRNA). Following 14 days of treatment, CBD reduced MDA and IL-1β transcription, whereas Δ⁹-THC reduced MDA and increased IL-10. Notably, the combination treatment simultaneously reduced oxidative stress, suppressed IL-1β, and enhanced IL-10. Together, these findings demonstrate an additive antinociceptive interaction between Δ⁹-THC and CBD and sustained efficacy during repeated administration in SCD mice. SIGNIFICANCE STATEMENT: Chronic pain in sickle cell disease remains difficult to treat, and many patients use cannabis despite limited understanding of how its constituents interact to produce analgesia. This study demonstrates that the 2 major phytocannabinoids in cannabis, Δ⁹-tetrahydrocannabinol and cannabidiol, produce additive antinociceptive effects in a humanized mouse model of sickle cell disease, and their combined efficacy is maintained during repeated administration without detectable tolerance.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 11","pages":"105037"},"PeriodicalIF":4.3,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leucine-rich repeat kinase 2 is involved in the microtubule-mediated regulation of intraocular pressure.","authors":"Yuji Takahashi, Masaki Ito, Reijiro Arakawa","doi":"10.1016/j.jpet.2026.105035","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105035","url":null,"abstract":"<p><p>Leucine-rich repeat kinase 2 (LRRK2) is known as the most common gene responsible for familial Parkinson disease (PD). This protein plays a key role in the neurodegenerative pathways associated with PD. LRRK2 also plays critical roles in actin dynamics and microtubule cytoskeletal assembly in the cells. In addition to PD, actin and microtubule cytoskeletons are associated with the onset and development of glaucoma by regulating the intraocular pressure (IOP) in humans and animals. However, the role of LRRK2 in regulating IOP remains unclear. Hence, this study investigated the contribution of LRRK2 to cytoskeleton-mediated regulation of IOP. LRRK2 was detected in primary human trabecular meshwork cells by immunofluorescence and western blotting analysis. Inhibition of the function and the expression of LRRK2 by LRRK2 inhibitors and LRRK2 siRNA, induced a significant reduction of TEER in these cells. TEER reduction by an LRRK2 inhibitor was attenuated by paclitaxel, a-tubulin polymerization inducer, but not by jasplakinolide, an actin polymerization inducer, suggesting that inhibition of LRRK2 induced depolymerization of microtubules, resulting in decreased TEER. Finally, LRRK2 gene knockout and LRRK2 inhibition led to a significant reduction of IOP in C57BL6J mice and Japanese white rabbits, respectively. These results suggested that LRRK2 is associated with catalysis of a-tubulin in trabecular meshwork cells and regulates IOP in mice and rabbits. Hence, there is a possibility that an LRRK2 inhibitor contributes to glaucoma therapeutics. Further evaluation to clarify the role of LRRK2 in IOP regulation is needed. SIGNIFICANCE STATEMENT: In this study, a significant contribution of LRRK2 to the regulation of intraocular pressure (IOP) was shown. Inhibition of LRRK2 results in a decrease in TEER of the trabecular meshwork cells, associated with the depolymerization of microtubules. Furthermore, both LRRK2 knockout and administration of the LRRK2 inhibitor induced a significant decrease in the IOP in animals. These results clearly indicate the role of LRRK2 in the regulation of IOP and the possibility of a novel therapeutic approach to glaucoma.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 11","pages":"105035"},"PeriodicalIF":4.3,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sirtuin 1-microRNA regulatory networks in liver diseases: Mechanistic convergence, cellular senescence, and translational implications.","authors":"Amr Ali Mohamed Abdelgawwad El-Sehrawy, Safa H Radhie, Mirza R Baig, Djaloliddin Mansurov, Rekha M M, Priya Priyadarshini Nayak, Neeraj Bainsal, Divya Singhal, Aseel Smerat, Mohammed Almajar","doi":"10.1016/j.jpet.2026.105031","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105031","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease, hepatotoxicity, liver fibrosis, and hepatocellular carcinoma are stages of chronic liver injury that occur in the setting of complex interactions of the various factors, including metabolic dysregulation, inflammation, oxidative stress, and cellular senescence. Recent studies propose that microRNAs (miRNAs), regulators of these processes, act through modulation of sirtuin 1 (SIRT1), a key metabolic and stress-response sensor recognizing the organism's needs under various physiological and pathological conditions. Abnormalities in the SIRT1-miRNA network function are implicated in processes of lipid accumulation, mitochondrial dysfunction, immune-cell activation, stellate-cell transdifferentiation, fibrogenesis, and tumor development. In the present review, we make an attempt to carry out joint analysis of SIRT1-miRNA interaction throughout the history of liver diseases. In contrast to the previously existing reviews focusing on independent miRNAs and diseases independently, we focus on the idea of mechanistic convergence and the specificity of how SIRT1 works in different disease stages. We also consider novel ideas, including the concept of cellular senescence, immunometabolic switch, communication through exosomes, and the role of SIRT1 in hepatocellular carcinoma development. We analyze the way the regulation of SIRT1 by miRNA affects metabolic adaptation and fibrogenesis. Although experimental studies consistently support the biological significance of the SIRT1-miRNA axis, important translational challenges remain, including disease heterogeneity, cell-specific targeting, delivery limitations, and insufficient clinical validation. Future integration of multiomics technologies, circulating miRNA biomarkers, and precision-medicine approaches may improve understanding of SIRT1-centered regulatory networks and facilitate the development of more effective therapeutic strategies for liver diseases. SIGNIFICANCE STATEMENT: By investigating the intricacies of sirtuin 1-microRNA (SIRT1-miRNA) regulatory mechanisms, valuable knowledge is gained regarding the role of SIRT1 post-transcriptional regulation in causing metabolic disorders, inflammation, fibrosis, and progression of hepatocellular carcinoma. The article also highlights serious pharmacological challenges in this area, such as specificity of treatment, possible influence of drugs on other mechanisms of the body, and ability to separate the beneficial effects of SIRT1 activation in the case of metabolic liver disease from its harmful effects in more advanced cases of hepatocellular carcinoma.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 11","pages":"105031"},"PeriodicalIF":4.3,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic and pharmacodynamic profile of high-dose D⁹-tetrahydrocannabinol in male and female rats.","authors":"Olufunke Florence Ajeigbe, Adren Tran, Rodrigo Klein, Alex Mabou Tagne, Heidi C Avalos, Faizy Ahmed, Daniele Piomelli","doi":"10.1016/j.jpet.2026.105033","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105033","url":null,"abstract":"<p><p>Cannabis products with elevated Δ⁹-tetrahydrocannabinol (THC) content are prevalent in parts of North America, yet their pharmacokinetic (PK) and pharmacodynamic (PD) properties remain incompletely characterized. We investigated the effects of a single administration of high-dose THC (10 and 30 mg/kg, intraperitoneal, IP) compared with a lower dose (3 mg/kg, IP) in male and female Long Evans rats. Plasma, brain, and white adipose tissue concentrations of THC and its metabolites 11-hydroxy-THC and 11-carboxy-THC were quantified over acute (up to 24 h) and prolonged (14 days) periods. Behavioral endpoints included ingestive behavior, pica, locomotor activity, anxiety-like and stress-coping responses, and nociception. Plasma concentrations of multiple cytokines were also assessed. PK results showed nonlinear disposition with disproportionate increases in maximal concentration at higher doses, greater systemic and tissue exposure in females, and extensive sequestration in adipose tissue. PD effects were also dose- and sex-dependent: suppression of food/water intake and body weight, transient locomotor stimulation in females at low dose and suppression at high doses, increased pica in females at 30 mg/kg, modest anxiety-like shifts, bidirectional stress-coping changes in males, and antinociception primarily in males at 1 hour and 24 hours postdosing. No meaningful changes in proinflammatory or anti-inflammatory cytokines were observed in either sex. The findings indicate that high-dose THC produces nonlinear sex-dependent PK with prolonged central and peripheral retention, alongside distinct acute PD profiles compared with lower doses. SIGNIFICANCE STATEMENT: High-potency cannabis products are common, yet their impact on health remains poorly understood. This study shows that high-dose THC produces nonlinear, sex-dependent distribution and metabolism in rats, with females showing markedly greater systemic exposure, prolonged brain retention, and extensive adipose sequestration, alongside distinct acute pharmacological profiles. These findings show that high-dose THC generates disproportionate systemic and central exposure and distinct acute pharmacological profiles compared with lower doses.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 11","pages":"105033"},"PeriodicalIF":4.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-37 overexpression enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells in atopic dermatitis by activating autophagy and improving skin barrier dysfunction.","authors":"Wenjing Chen, Shuyan Li, Xiaoping Guo, Fengxia Hu, Qian Wang, Xiaoyu Zhang, Fuyang Xiao, Jinying Zhang, Junqin Liang","doi":"10.1016/j.jpet.2026.105032","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105032","url":null,"abstract":"<p><p>Adipose-derived mesenchymal stem cells (ADSCs) have emerged as a promising therapeutic option because of their immunomodulatory and tissue-repair capabilities in the treatment of Atopic dermatitis (AD). However, their efficacy is limited by cellular senescence and functional decline. Interleukin-37 (IL-37), an anti-inflammatory cytokine, has shown potential in mitigating inflammation and enhancing skin barrier function. This study investigated whether IL-37 overexpression in ADSCs could augment their therapeutic effects in AD and the underlying mechanism. Lentiviral-mediated IL-37 overexpression in ADSCs enhanced proliferation, reduced senescence (evidenced by decreased β-galactosidase activity), and activated autophagy, as shown by elevated LC3B-II/I and Beclin-1 levels, reduced p62, and increased LC3B puncta formation. These effects were reversed by the autophagy inhibitor 3-MA. In an IL-4/IL-13-induced HaCaT cell model of AD, coculture with IL-37-overexpressing ADSCs promoted keratinocyte proliferation, reduced apoptosis, suppressed proinflammatory cytokines (IL-1β, IL-6, tumor necrosis factor-α, thymus and activation-regulated chemokine), and restored the expression of skin barrier proteins (Filaggrin, Involucrin). In vivo, local injection of IL-37-overexpressing ADSCs into lesional skin in a 2,4-dinitrochlorobenzene-induced AD mouse model attenuated skin lesions, reduced inflammation, and improved barrier protein expression. These results demonstrate that IL-37 overexpression enhances the therapeutic efficacy of ADSCs in AD through autophagy activation and restoration of skin barrier function, providing a novel genetically engineered stem cell-based strategy for the treatment of AD. SIGNIFICANCE STATEMENT: IL-37-engineered adipose-derived mesenchymal stem cells improve atopic dermatitis treatment by activating autophagy to reduce senescence and enhance proliferation. These cells suppress inflammation while restoring skin barrier proteins, providing a novel therapy for refractory skin diseases.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 11","pages":"105032"},"PeriodicalIF":4.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabigerol on the brain: Rethinking anxiety, metabolites, and mechanism.","authors":"Patrick Glassman, Michael Ippolito, Sara Jane Ward","doi":"10.1016/j.jpet.2026.105014","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105014","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105014"},"PeriodicalIF":4.3,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148969491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}