Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Repurposing ribavirin for oncology: Integrating metabolism, signaling, and translational control.","authors":"Amrita Talukder Mohini, Chibuike Emmanuel Okafor, Joseph M Schober, Bhargav A Patel","doi":"10.1016/j.jpet.2026.105001","DOIUrl":"10.1016/j.jpet.2026.105001","url":null,"abstract":"<p><p>Repurposing of approved drugs offers a rapid and cost-effective strategy for the identification of new therapeutic applications, particularly for difficult-to-treat and therapy-resistant cancers. Ribavirin, which is a synthetic guanosine analog and used as an antiviral drug, has demonstrated promising anticancer activity. To that end, the literature has presented varied anticancer mechanisms of action for ribavirin. This review integrates the current mechanistic evidence and proposes a working hypothesis in which ribavirin may influence interconnected metabolic, signaling, and translational processes that collectively induce its anticancer activity. Ribavirin inhibits inosine monophosphate dehydrogenase and depletes GTP, which may influence small GTPase-dependent signaling such as Ras-driven pathways. More recently, modulation of metabolic signaling by ribavirin has been proposed through the inhibition of AMP-activated protein kinase-associated pathways. These upstream perturbations may propagate through oncogenic signaling networks and complement the suppression of eukaryotic translation initiation factor 4E-dependent mRNA export and protein synthesis. Further, ribavirin treatment indirectly influences epigenetic regulators, inflammatory mediators, and immune checkpoint pathways, contributing to broader reprogramming of tumor cell behavior. Ultimately, ribavirin's effects lead to cell cycle arrest, apoptosis, and enhanced chemosensitivity across diverse cancer types. Taken together, the available evidence supports the hypothesis that ribavirin may function as a multilevel modulator of cellular growth networks, although the mechanistic relationships among these pathways remain incompletely defined. SIGNIFICANCE STATEMENT: This review theorizes ribavirin as a systems-level anticancer agent by integrating its effects on guanine nucleotide metabolism, oncogenic signaling, and eukaryotic translation initiation factor 4E-dependent translation into a unified metabolic-signaling-translation axis. In addition, it identifies the disparities in the mechanistic literature, which may assist in designing future studies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"105001"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874368","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":"Aryl hydrocarbon receptor as a molecular mediator in the induction of human aldehyde oxidase gene expression.","authors":"Szu Ling Yeap, Cassandra Ching Lin Yap, Shi Han Tay, Linghua Harris Zhang, Aik Jiang Lau","doi":"10.1016/j.jpet.2026.104993","DOIUrl":"10.1016/j.jpet.2026.104993","url":null,"abstract":"<p><p>Relatively little is known about receptor-mediated regulation of aldehyde oxidase (AOX). 2,3,7,8-Tetrachlorodibenzo-p-dioxin, an aryl hydrocarbon receptor (AHR) agonist, increases mouse Aox expression. However, given the species differences in ligand-dependent AHR activation and AOX regulation, it remains to be investigated whether human AHR regulates the expression of AOX1 (the human AOX isoform). Therefore, the present study was designed to determine the effect of modulating the functionality of human AHR on AOX1 gene expression in cell culture models (HepG2 and MCF-7) known to express AHR and AOX1. Treatment of HepG2 or MCF-7 cells with a noncytotoxic concentration of a classical AHR agonist (β-naphthoflavone, benzo[a]pyrene, or 3-methylcholanthrene [3-MC]), an endogenous AHR agonist (indoxyl sulfate or 6-formylindolo[3,2-b]carbazole), or a selective AHR modulator (quercetin, 3,3'-diindolylmethane, or omeprazole) increased AOX1 and AHR-regulated CYP1A1 mRNA expression. The increases in AOX1 and CYP1A1 mRNA levels were not correlated among our panel of AHR activators. The induction of AOX1 mRNA by 3-MC was time- and concentration-dependent. It was accompanied by an increase in AOX1 protein expression and AOX1-mediated enzyme activity (O⁶-benzylguanine 8-oxidation). An AHR antagonist (3',4'-dimethoxyflavone) completely abolished the increase in AOX1 and CYP1A1 expression by an AHR agonist (3-MC). Gene knockdown by an AHR small interfering RNA substantially decreased AHR mRNA expression and attenuated AOX1 and CYP1A1 mRNA induction by 3-MC. Overall, based on the experimental approaches involving AHR activation, AHR antagonism, and AHR gene knockdown by small interfering RNA, our novel data indicate that AHR plays a role in mediating the induction of human AOX1 gene expression. SIGNIFICANCE STATEMENT: The deployment of multiple experimental approaches involving receptor activation, receptor antagonism, and gene knockdown by small interfering RNA led to the identification of the human aryl hydrocarbon receptor as a molecular mediator of aldehyde oxidase gene induction. This novel discovery expands our limited knowledge of the identity of pharmacological receptors contributing to the functionality of human aldehyde oxidase.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"104993"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13688995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"US postmarketed drug removals: Analysis of discontinued and withdrawn drugs.","authors":"Lilly Josephine Bindel, Roland Seifert","doi":"10.1016/j.jpet.2026.104996","DOIUrl":"10.1016/j.jpet.2026.104996","url":null,"abstract":"<p><p>Drugs removed from the US market after approval can be either discontinued by the manufacturer or withdrawn by the US Food and Drug Administration (FDA). However, a systematic overview is currently lacking. This minireview provides a comprehensive analysis of removed drugs, identifies patterns regarding drug classes, indications, adverse effects, and scientific interest, and compares US removals with the European Union and FDA boxed warnings. A total of 166 drugs were removed between 1955 and 2026, including 88 discontinued and 78 withdrawn drugs. Removed drugs represented a wide range of therapeutic fields, with certain drug classes occurring repeatedly, particularly cyclooxygenase inhibitors and fluoroquinolones. Market removals were frequently associated with serious adverse effects such as hepatotoxicity, cardiotoxicity, and hematologic toxicity. The prominent drug classes and adverse effect categories also occurred frequently among drugs carrying boxed warnings. While withdrawn drugs were typically banned by the FDA because of severe safety concerns, discontinued drugs were often removed because of commercial decisions or obsolescence, sometimes in combination with safety considerations. The analysis of publication peaks showed that for most drugs, scientific interest peaked before market removal, while in other cases, publication peaks occurred around or after withdrawal, indicating renewed scientific interest. Drug removals from the US market represent a heterogeneous group of drugs, indications, and underlying causes. While withdrawals and discontinuations differ in their regulatory implications, they share overlapping characteristics and safety considerations. Integration of European Union availability and FDA boxed warning comparisons highlights international differences and patterns requiring precautionary attention, with recurring drug classes and adverse effects. SIGNIFICANCE STATEMENT: This minireview provides a comprehensive overview of US postmarketing drug removals, covering drugs and causes, as well as evaluating and comparing their characteristics. Patterns and characteristics are identified and compared between discontinued and withdrawn drugs. The analysis of publication peaks and the derived patterns allow an evaluation of changes in scientific interest. This analysis provides information on past drug safety decisions and guides future risk-benefit assessments, while identifying prevalent drug classes and adverse effects that require precaution.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"104996"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13688983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modafinil ameliorates sleep deprivation-induced memory impairment under acute hypobaric hypoxia via biphasic Cyp3a11 regulation and altered pharmacokinetics.","authors":"Gang Zhao, Limin Meng, Yajuan Li, Hui Shen, Xiao Liu, Gang Wang, Qun Wan, Di Zhu, Junhui Xue, Fengzhou Liu","doi":"10.1016/j.jpet.2026.105007","DOIUrl":"10.1016/j.jpet.2026.105007","url":null,"abstract":"<p><p>This study aimed to elucidate the dynamic impact of acute hypobaric hypoxia (HH) on the pharmacokinetics of modafinil (MOD) and its association with liver injury and regulation of the key metabolizing enzyme Cyp3a11. A mouse model combining acute HH (simulating 5000 m) with 24 hours sleep deprivation was established. MOD was administered by gavage. Assessments included the Morris water maze test, high-performance liquid chromatography pharmacokinetic analysis, serum alanine aminotransferase/aspartate aminotransferase measurement, hepatic H&E staining, and analysis of Cyp3a11 expression via quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry assays. HH exacerbated cognitive deficits, which were ameliorated by MOD. It induced biphasic pharmacokinetic alterations: accelerated absorption (higher early plasma concentration) but impeded elimination (increased area under the plasma concentration-time curve, prolonged mean residence time, and decreased apparent clearance). These changes correlated with time-dependent liver responses: after 1 hour HH, alanine aminotransferase/aspartate aminotransferase transiently decreased with compensatory Cyp3a11 upregulation but no significant histopathological damage; after 24 hours HH, progressive liver injury (inflammation, vacuolation, and necrosis) developed alongside significant suppression of Cyp3a11 expression. While MOD retains cognitive-enhancing efficacy under HH, its pharmacokinetics are markedly altered. The shift from accelerated absorption to delayed elimination is closely associated with HH-induced biphasic regulation of hepatic Cyp3a11 and progressive liver injury, indicating a need for optimized dosing strategies in HH scenarios. SIGNIFICANCE STATEMENT: This study reveals how high-altitude hypoxia alters modafinil's pharmacokinetics and efficacy via hepatic Cyp3a11 regulation, offering critical insights for optimizing drug use in hypobaric hypoxia environments.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"105007"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891848","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":"CircDOPEY2 promotes prostate cancer metastasis via inhibiting heterogeneous nuclear ribonucleoprotein M ubiquitination to stabilize intercellular adhesion molecule 2 mRNA.","authors":"Dingchang Shao, Yufeng Song, Jinke Liu, Mingkun Zhao, Xuefeng Xie, Ziwei Wei, Dunsheng Han, Xiaoming Song, Huan Xu, Guoxiong Xu, Gang Chen, Shiyu Wang","doi":"10.1016/j.jpet.2026.104995","DOIUrl":"10.1016/j.jpet.2026.104995","url":null,"abstract":"<p><p>Prostate cancer (PCa) ranks among the most prevalent malignancies affecting the male population worldwide, and metastatic PCa (mPCa) carries a poor prognosis. Circular RNAs (circRNAs), a distinct class of RNAs, have been implicated in the progression of various tumors. However, their specific biological functions and underlying mechanisms in PCa, particularly in mPCa, remain largely undefined. In this study, we identified a novel circRNA derived from the back-splicing of exons 20-21 of the Dopey Family Member 2 (DOPEY2) gene. This circRNA, which we named circDOPEY2, was highly expressed in PCa. The circDOPEY2 expression was significantly correlated with multiple clinicopathological indicators associated with PCa severity and prognosis, including Gleason score, clinical M stage, and D'Amico risk classification. Functional assays demonstrated that circDOPEY2 significantly promoted PCa cell metastasis both in vitro and in vivo. Mechanistically, circDOPEY2 directly bound to heterogeneous nuclear ribonucleoprotein M and inhibited its degradation via the ubiquitin-proteasome pathway. The resulting stabilization of heterogeneous nuclear ribonucleoprotein M upregulated the intercellular adhesion molecule 2 expression by enhancing the stability of its mRNA, ultimately promoting PCa metastasis. Moreover, serine/arginine-rich splicing factor 1 mediates circDOPEY2 biogenesis through specific interactions with AluSx1 and AluSx elements. In summary, our findings identify circDOPEY2 as a key promoter of PCa metastasis, highlighting its potential as both a clinical biomarker and therapeutic target for mPCa. SIGNIFICANCE STATEMENT: This study identifies circDOPEY2 as a driver of prostate cancer (PCa) metastasis. Mechanistically, circDOPEY2 inhibits heterogeneous nuclear ribonucleoprotein M ubiquitin-proteasome degradation, stabilizing it to upregulate intercellular adhesion molecule 2 and promote PCa metastasis. This study also provides the first evidence that serine/arginine-rich splicing factor 1 interacts with Alu sequences to regulate circDOPEY2 biogenesis. These findings highlight circDOPEY2 as a novel clinical biomarker and therapeutic target for metastatic PCa.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"104995"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850965","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":"Prior Toll-like receptor 3 stimulation abolishes the ability of a MAPK/ERK kinase inhibitor to increase lipopolysaccharide-induced nitric oxide production concomitant with tumor necrosis factor-α suppression.","authors":"Ryota Hashimoto, Yaojia Wu, Kaily Fujimoto, Haruto Shintani, Hiroshi Koide, Youichi Katoh","doi":"10.1016/j.jpet.2026.105013","DOIUrl":"10.1016/j.jpet.2026.105013","url":null,"abstract":"<p><p>Lipopolysaccharide (LPS) is an endotoxin that can trigger multiple types of acute organ failure by increasing the production of nitric oxide (NO), which is synthesized by inducible NO synthase (iNOS) in macrophages through increased production of tumor necrosis factor (TNF)-α, interferon gamma, and interleukin-12. We have reported that an inhibitor of MAPK/ERK kinase (MEK), which is activated by LPS, increased the mortality rate in LPS-treated mice through enhanced NO production. However, a strategy to prevent lethal NO production by MEK inhibitors, which are used as anticancer agents, remains unclear. In the present study, we examined whether prestimulation of Toll-like receptors (TLRs) influences NO production by a MEK inhibitor in the presence of LPS because LPS is a ligand of TLR4 and macrophages acquire tolerance through repeated TLR stimulation. The MEK inhibitor increased iNOS expression and NO production in LPS-stimulated mouse macrophages. While pretreatment with TLR3, TLR7/8, or TLR9 agonists abolished the increase in iNOS expression, the subsequent increase in NO production was confirmed to be suppressed by TLR3 stimulation. The MEK inhibitor also suppressed the serum levels of both NO and TNF-α in mice pretreated with the TLR3 agonist poly I:C followed by LPS administration. Both iNOS expression and NO production depended on the TNF-α concentration in mouse macrophages treated with interferon gamma and interleukin-12. These results suggest that the ability of MEK inhibitors to increase NO production in mice treated with LPS is abolished by prior TLR3 stimulation, which is associated with the suppression of TNF-α production. SIGNIFICANCE STATEMENT: A MAPK/ERK kinase inhibitor increased nitric oxide production in lipopolysaccharide-treated mice; however, prior Toll-like receptor 3 stimulation abolished this effect, accompanied by a reduction in tumor necrosis factor-α production. Prior Toll-like receptor 3 stimulation may contribute to a potential strategy to prevent lethal nitric oxide production by MAPK/ERK kinase inhibitors in mice treated with lipopolysaccharide.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"105013"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148897398","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":"BE2012 a novel, REV-ERB antagonist that promotes regenerative myogenesis in vivo with substantially improved pharmacokinetics relative to SR8278.","authors":"Isabelle Cote, Aurore C Valfort, Ryan K Sanders, Sheryl L Burris, Matthew E Hayes, Rhea Arya, Lingaiah Maram, Bahaa Elgendy, Feng Yue, Thomas P Burris","doi":"10.1016/j.jpet.2026.105011","DOIUrl":"10.1016/j.jpet.2026.105011","url":null,"abstract":"<p><p>Pharmacological inhibition of REV-ERBs has emerged as a potential therapeutic strategy for several diseases with unmet medical needs. Indeed, chronic treatment with SR8278, a synthetic REV-ERB antagonist, has mitigated pathology in various preclinical models of human musculoskeletal and neurological diseases, including Duchenne muscular dystrophy, epilepsy, Alzheimer disease, Parkinson disease, and frontotemporal dementia. However, SR8278, the first and most widely used REV-ERB antagonist, has poor pharmacokinetic properties, which limits its utility. The REV-ERBs (α and β) are widely expressed nuclear receptors that function as ligand-dependent transcriptional repressors, and the therapeutic potential for inhibition of these receptors remains unclear because of the lack of adequate pharmacological tools. Here, we report BE2012, a significantly improved REV-ERB antagonist with >22-fold longer half-life than SR8278. In a cell-based reporter assay, BE2012 exhibited greater potency toward REV-ERBα (EC₅₀ = 0.38 μM) and REV-ERBβ (EC₅₀ = 0.57 μM) compared with SR8278. Notably, in primary myoblast differentiation assays, BE2012 outperformed SR8278 in increasing the proportion of MyoG⁺ cells as well as differentiation and fusion indices. In a cardiotoxin-induced muscle injury model, both BE2012 and SR8278 led to increased myofiber cross-sectional area (22%-34% higher than controls). Lastly, transcriptomic profiling revealed remarkable overlap of differentially expressed genes between the 2 compounds, with oxidative phosphorylation and mitochondrial protein complex emerging as the most significantly enriched pathways for both ligands, which have been shown to accelerate regenerative myogenesis. These results establish BE2012 as a refined REV-ERB antagonist for in vivo applications and a valuable tool for deeper exploration of the therapeutic potential of inhibiting REV-ERB activity. SIGNIFICANCE STATEMENT: This study establishes BE2012 as a novel REV-ERBα/β antagonist with a 22-fold longer half-life and improved potency compared with SR8278, the only available REV-ERB antagonist whose poor bioavailability has limited its utility for in vivo use. In an acute muscle injury model in mice, BE2012 promoted regenerative myogenesis and induced a broad transcriptomic reprogramming that was highly concordant with that of SR8278, suggesting it could serve as a new gold-standard REV-ERB antagonist tool compound in the field.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"105011"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148897361","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":"Impact of Δ⁹-tetrahydrocannabinol and oxycodone coadministration on measures of antinociception, dependence, circadian activity, and reward in mice.","authors":"Richard A Slivicki, Justin G Wang, Kayla V Kucz, Jakayla Folarin Hines, Vy Trinh Tran Nhat, Alexxai V Kravitz, Meaghan C Creed, Robert W Gereau","doi":"10.1016/j.jpet.2026.105008","DOIUrl":"10.1016/j.jpet.2026.105008","url":null,"abstract":"<p><p>Oxycodone is commonly prescribed for moderate-to-severe pain. While efficacious, long-term use can result in tolerance, physical dependence, and opioid use disorder. Cannabis and Δ⁹-tetrahydrocannabinol (Δ⁹-THC) have been reported to potentiate oxycodone-induced antinociception in animals and humans. Whether Δ⁹-THC also facilitates unwanted aspects of oxycodone intake, such as tolerance, dependence, and reward at antinociceptive doses, remains unclear. We evaluated the coadministration of Δ⁹-THC and oxycodone on antinociception, dependence, circadian activity, and reward in male and female mice. Oxycodone and Δ⁹-THC produced dose-dependent antinociception in the hotplate assay, with oxycodone showing lower potency in females. Repeated treatment (twice daily for 5 days) produced antinociceptive tolerance. Δ⁹-THC produced a potentiation-like effect on oxycodone-induced antinociception and delayed antinociceptive tolerance. Repeated oxycodone produced physical dependence and alterations in circadian activity, neither of which was exacerbated by cotreatment with Δ⁹-THC. Combination treatment of oxycodone and Δ⁹-THC produced conditioned place preference at doses that did not produce preference when administered alone. Fiber photometry recordings of nucleus accumbens dopamine release showed that Δ⁹-THC potentiated oxycodone-evoked dopamine release at subeffective oxycodone doses, a candidate mechanism for the behavioral reward potentiation. These data indicate that Δ⁹-THC may facilitate oxycodone-induced antinociception without augmenting certain unwanted features of opioid intake (eg, dependence and circadian rhythm alterations). However, Δ⁹-THC also recruited the rewarding properties of oxycodone at therapeutically relevant doses. These reward-related findings indicate that Δ⁹-THC and oxycodone combinations may carry increased abuse liability, a primary consideration for their therapeutic evaluation. SIGNIFICANCE STATEMENT: In mice, Δ⁹-tetrahydrocannabinol (Δ⁹-THC) produced a potentiation-like effect on oxycodone-induced antinociception and delayed antinociceptive tolerance without exacerbating opioid dependence or circadian disruption, but Δ⁹-THC also produced conditioned place preference and potentiated nucleus accumbens dopamine release at subeffective oxycodone doses. These findings indicate that Δ⁹-THC may enhance oxycodone-induced antinociception, but also that Δ⁹-THC recruits the rewarding properties of oxycodone at doses that are otherwise subeffective. The increased abuse liability of such combinations is a primary consideration for their therapeutic evaluation.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"105008"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13688984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Profiles of nonsteroidal anti-inflammatory drug-induced gastric antral ulcers: A comprehensive review of the preclinical data.","authors":"Hiroshi Satoh, Yasutada Akiba, Jonathan D Kaunitz","doi":"10.1016/j.jpet.2026.105024","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105024","url":null,"abstract":"<p><p>Nonsteroidal anti-inflammatory drugs (NSAIDs) frequently induce gastric ulcers in the prepyloric antrum in humans; however, the mechanisms underlying this antral specificity remain unclear. Moreover, although gastric antral ulcers (AUs) exhibit poor responsiveness to histamine H₂ receptor antagonists, AUs respond favorably to proton pump inhibitors (PPIs). To clarify these issues, we examined the characteristics of NSAID-induced gastric ulcers in mice. The location of gastrointestinal lesions caused by NSAIDs was entirely dependent on feeding conditions: under fasted conditions, indomethacin produced lesions selectively in the gastric corpus; under refed conditions, indomethacin induced ulcers specifically in the gastric antrum; under fed conditions, indomethacin caused ulcers only in the small intestine. Histamine H₂ receptor antagonists inhibited indomethacin-induced corpus lesions in fasted mice but did not affect AUs in refed mice. In contrast, PPIs markedly inhibited the formation of both AUs and corpus lesions. The protective effects of PPIs against AUs were mediated by increasing gastric mucosal blood flow regulated via capsaicin-sensitive afferent nerves, activation of the vanilloid receptor transient receptor potential vanilloid 1, and nitric oxide synthesis. Furthermore, gastroparesis induced by restraint stress, corticotropin-releasing factor, atropine, or dopamine enhanced duodenogastric bile reflux and exacerbated indomethacin-induced AUs via 5-hydroxytryptamine-3, dopamine D₂, and cholecystokinin 1 receptors. Dietary supplementation with taurocholate aggravated indomethacin-induced AUs, whereas cholestyramine, a bile acid sequestrant, attenuated them. Insoluble dietary fibers, such as cellulose, accelerated AU formation, whereas soluble fibers, such as pectin, prevented it. These findings provide new insights into the pathogenesis of NSAID-induced foregut mucosal injury and may contribute to novel and effective strategies for ulcer prevention. SIGNIFICANCE STATEMENT: Nonsteroidal anti-inflammatory drug-induced gastric ulcers are induced dependently on feeding conditions, dietary fibers, intragastric bile acids, gastric motility, and stress. This review summarizes the recent advances and provides new insights into the pathogenesis of nonsteroidal anti-inflammatory drug-induced foregut mucosal injury and may contribute to novel and effective pharmacological approaches for ulcer prevention in humans.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105024"},"PeriodicalIF":4.3,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990365","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":"Capsaicin and cinnamaldehyde as topical transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 agonists in humans: Formulation, stability, and pharmacodynamic evaluation.","authors":"Luigi Francesco Iannone, Erika Maria Mancuso, Benedetta Pasquini, Eva Lombardo, Marina Romozzi, Romina Nassini, Pierangelo Geppetti, Felice Petraglia, Francesco De Cesaris, Silvia Fiani, Natascia Mennini, Viola Seravalli","doi":"10.1016/j.jpet.2026.105023","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105023","url":null,"abstract":"<p><p>Transient receptor potential (TRP) vanilloid 1 and TRP ankyrin 1 channels mediate nociceptive and neurovascular signaling and can be activated experimentally by capsaicin and cinnamaldehyde, respectively. We characterized the physicochemical stability, in vitro permeation, and human pharmacodynamic effects of topical capsaicin and cinnamaldehyde formulations. Solutions underwent six-month stability testing at 4 °C and permeation studies in Franz diffusion cells using Strat-M and lauryl alcohol-impregnated cellulose nitrate membranes. The formulations were then applied to the forearm skin of 15 women with migraine, and dermal blood flow was measured for 90 minutes using laser speckle contrast imaging. Both formulations remained stable for 6 months. No active compound was detected in the receptor chamber with Strat-M, whereas low but pharmacologically relevant permeation occurred across the cellulose nitrate membrane. Capsaicin produced a robust and sustained vasodilatory response, with dermal blood flow increasing by 264.7% at 30 minutes and peaking at 291.0% at 45 minutes; the response remained elevated at 90 minutes. Cinnamaldehyde produced a rapid but transient response, increasing dermal blood flow by 231.6% at 30 minutes and progressively returning toward baseline by 90 minutes. No local or systemic adverse events were reported. These findings support topical capsaicin and cinnamaldehyde as complementary experimental probes for studying TRP vanilloid 1- and TRP ankyrin 1-mediated cutaneous neurovascular responses in humans. SIGNIFICANCE STATEMENT: This study establishes a reproducible human model integrating physicochemical validation and in vivo pharmacodynamic assessment of transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 agonists, demonstrating that minimal topical permeation is sufficient to elicit robust, receptor-specific vascular responses without systemic exposure. The distinct temporal profiles of capsaicin and cinnamaldehyde provide a translational framework for probing neurogenic inflammation and for early-phase evaluation of targeted therapies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105023"},"PeriodicalIF":4.3,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025188","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}