Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Corrigendum to \"Rapamycin and Starvation Mitigate Indomethacin-Induced Intestinal Damage through Preservation of Lysosomal Vacuolar ATPase Integrity\": [The Journal of Pharmacology and Experimental Therapeutics 390 (2024) 108-115].","authors":"Makoto Shirakawa, Shunichi Yokoe, Takatoshi Nakagawa, Kazumasa Moriwaki, Toshihisa Takeuchi, Michio Asahi","doi":"10.1016/j.jpet.2025.103596","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103596","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103596"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958286","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":"Alzheimer disease: Amyloid peptide controversies and challenges of anti-Aβ immunotherapy.","authors":"Najlaa Hamed Almohmadi, Hayder M Al-Kuraishy, Ali K Albuhadily, Ali I Al-Gareeb, Ahmed M Abdelaziz, Athanasios Alexiou, Marios Papadakis, Gaber El-Saber Batiha","doi":"10.1016/j.jpet.2025.103639","DOIUrl":"10.1016/j.jpet.2025.103639","url":null,"abstract":"<p><p>Alzheimer disease (AD) is a progressive neurodegenerative disease marked by the accumulation of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles containing tau protein. Given the relentless deterioration in AD, strategies to slow its progression often focus on inhibiting Aβ production or aggregation. However, numerous clinical trials targeting Aβ in later disease stages have shown limited success in reversing cognitive decline, potentially due to intervening too late in the disease course. Emerging evidence suggests that addressing Aβ pathology during the earliest phases of AD, before the occurrence of neuronal damage, may be beneficial for preserving cognitive function. Thus, therapeutic approaches aimed at reducing Aβ levels, such as anti-Aβ antibodies, are likely to yield greater benefits when implemented early in the disease trajectory. Such evidence underscores the rationale for prioritizing early-stage interventions in AD drug development. However, disrupting the physiological role of Aβ, which plays a role in normal brain function, might inadvertently worsen clinical outcomes, highlighting the need for nuanced therapeutic strategies. Therefore, this review aims to explore the dual aspects of Aβ biology: its natural role in the brain and the potential of anti-Aβ immunotherapy, particularly targeting amyloid plaques, as a promising avenue for modifying AD progression when timed appropriately. SIGNIFICANCE STATEMENT: This review highlights that β-amyloid (Aβ) has a dual role in both supporting synaptic plasticity and memory via nicotinic receptor activation and driving Alzheimer disease neuropathology, emphasizing that early-stage Aβ-targeted immunotherapy may prevent cognitive decline while preserving the neuroprotective functions of Aβ, thereby refining therapeutic strategies and advancing understanding of the complex role of Aβ in neural health and disease.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103639"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659502","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":"Breaking free from opioids: A turning point in acute pain management.","authors":"Khaled S Abd-Elrahman, Cristina D Peterson, Eric R Gross, Beverley Greenwood-Van Meerveld","doi":"10.1016/j.jpet.2025.103653","DOIUrl":"10.1016/j.jpet.2025.103653","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103653"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707844","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":"Cinnamic acid enhances vinorelbine-induced cytotoxicity in MDA-MB-231 cells through modulation of PTEN and ATG5 expression.","authors":"Yassir Mustafa Kamal Al Mulla Hummadi, Wrood Salim Dawood Al-Khfajy, Meroj Ahmed Jasem","doi":"10.1016/j.jpet.2025.103654","DOIUrl":"10.1016/j.jpet.2025.103654","url":null,"abstract":"<p><p>The purpose of this study was to investigate the potential synergistic effects of cinnamic acid (CA) and vinorelbine (VNR) on cytotoxicity in triple-negative breast cancer, aiming to develop new therapeutic strategies targeting specific molecular pathways. The cytotoxic effects of VNR and CA on the human triple-negative breast cancer cell line MDA-MB-231 was investigated from January 15 to October 25, 2024, using in vitro assays and molecular techniques. Cell proliferation and viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay, while drug combination efficacy was assessed using Synergy Finder 3.0 software. Morphological changes and gene expression changes were evaluated post-treatment, and quantitative real-time polymerase chain reaction was used to analyze gene expression changes in response to drug exposure. The combination of VNR and CA significantly reduced cell viability, with IC₅₀ values of 142.6 nM and 4.3 mM, respectively. The combination led to a significant increase in cell death compared to either agent alone (P < .0001, VNR + CA group vs VNR or CA group) Morphological analysis showed apoptotic features in cells treated with the combination therapy. VNR treatment significantly decreased phosphatase and tensin homolog (PTEN) expression (P < .01), while CA alone significantly increased PTEN levels (P < .0001). The combination significantly maintained elevated PTEN expression by 10-fold compared with VNR alone (P < .0001). VNR and CA alone did not significantly affect autophagy-related gene 5 expression. Thus, the combination of CA and VNR appears to synergistically enhance cancer cell death by promoting PTEN-mediated apoptotic signaling and autophagy-related gene 5-associated autophagy, suggesting a dual contribution of both pathways to the observed cytotoxicity. SIGNIFICANCE STATEMENT: This study investigated the combined effects of cinnamic acid (CA) and vinorelbine (VNR) on cytotoxicity in MDA-MB-231 triple-negative breast cancer cells. The combination of VNR and CA dramatically lowered cell viability while increasing cell death. Morphological study revealed apoptotic characteristics, and the combination maintained higher PTEN expression than VNR alone. CA amplifies VNR's cytotoxic effects by altering the expression of PTEN and ATG5, likely resulting in increased apoptosis and enhanced autophagy, both contributing to cancer cell death.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103654"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718120","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 chemical flavorants on reinforcement-related behavior in an adolescent mouse model of vaping self-administration.","authors":"Sabrina M Swenson, Sean P Hill, Dami Adeshina, Gabrielle V Hammers, Sydney M McSweeney, M Kyle Sword, Matthew O Grooms, Sarah K Maddox, Hannah D Strcula, Nathan A Olszewski, Samuel Tetteh-Quarshie, Brandon J Henderson","doi":"10.1016/j.jpet.2025.103651","DOIUrl":"10.1016/j.jpet.2025.103651","url":null,"abstract":"<p><p>Electronic nicotine delivery systems (ENDSs) are a unique from combustible cigarettes due to the availability of flavor options which make these devices more attractive. Prior preclinical investigations have determined that menthol and green apple flavorants can enhance nicotine reward and reinforcement by altering dopamine transmission via nicotinic acetylcholine receptor modulation in reward-mediating brain areas. In this study, we investigated the impact of vanilla (vanillin and ethyl vanillin) and cherry (ethyl vanillin, vanillin, ethyl acetate, ethyl maltol, and maltol) flavors on reinforcement-related behavior with and without nicotine. Male and female adolescent C57BL/6J mice were used in an e-Vape self-administration assay. Four combinations were shown to increase reinforcement-related behavior: nicotine plus menthol, nicotine plus cherry, nicotine plus vanilla, and vanilla alone. We observed that zero-nicotine cherry-flavored ENDSs did not produce robust reinforcement-related behavior when compared with control vapor. We observed that zero-nicotine vanilla-flavored ENDSs did produce reinforcement-related behavior in adolescent male and female mice; the addition of nicotine did not produce a significant difference in active nose pokes or deliveries but did have increased active-to-inactive ratio. Additionally, we found that vanilla alone was able to modulate tonic and phasic release of dopamine in the nucleus accumbens core. We also looked at the physical interactions of green apple and vanilla flavors on nicotinic subunits. These data provide additional evidence that some chemical flavors promote vaping-related behaviors without the inclusion of nicotine. SIGNIFICANCE STATEMENT: The e-Vape self-administration paradigm is a translationally relevant method of investigating the impact of different flavorants on nicotine use. Because most electronic nicotine delivery system users vape flavored nicotine products, it raises questions about how chemical flavorants alter nicotine addiction and if they increase abuse liability themselves. In accordance with our prior findings on green apple, vanilla flavorants are able to cause changes in reward-related behaviors in the absence of nicotine potentially through altering dopamine release in the nucleus accumbens.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103651"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707845","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 analysis of morphine-3-glucuronide after acute morphine intravenous bolus administration to rats with traumatic brain injury.","authors":"Jonathan Birabaharan, Jeremy Henchir, Sarah Svirsky, Thomas D Nolin, Philip E Empey, Shaun W Carlson","doi":"10.1016/j.jpet.2025.103645","DOIUrl":"10.1016/j.jpet.2025.103645","url":null,"abstract":"<p><p>This study investigates the effects of traumatic brain injury (TBI) on the pharmacokinetics of morphine and its metabolite, morphine-3-glucuronide (M3G), and their influence on neuroinflammation and systemic inflammation. We hypothesized that disruptions in the blood-brain barrier (BBB) due to TBI would enhance M3G exposure to the brain, which could potentially trigger inflammatory responses. We implemented a rat model of controlled cortical impact (CCI) injury to assess systemic pharmacokinetics of morphine and M3G over 24 hours postintravenous bolus administration. To gain an understanding of relative levels in the brain, we measured the drug and metabolite concentrations in both brain tissue and plasma at the systemic maximum concentration, which occurred at 1 hour post-CCI. While this study was designed to conduct a thorough acute pharmacokinetic analysis, the design also afforded an early examination of potential pharmacodynamic effects. Markers of neuroinflammation and systemic inflammation were measured in plasma and cerebrospinal fluid at 24 hours post-CCI. Results showed a 2-fold increase in systemic M3G exposure and doubled concentrations of both morphine and M3G in the brain. Notably, only M3G demonstrated a significant increase in the brain/plasma ratio at 1 hour. Despite these pharmacokinetic changes following a single bolus, there were limited morphine-induced or M3G-induced increases in markers of neuroinflammation or systemic inflammation at 24 hour post-CCI. This study highlights that TBI significantly alters the pharmacokinetics of morphine and M3G, increasing their brain penetration without worsening acute inflammation. Future research will need to explore the implications of extended and repeated dosing on these pharmacokinetic and inflammatory outcomes after TBI. SIGNIFICANCE STATEMENT: To our knowledge, this is the first pharmacokinetic analysis of morphine and its metabolite morphine-3-glucuronide (M3G) following traumatic brain injury (TBI). This research provides the first evidence that morphine and M3G show increased systemic and brain concentrations following experimental TBI, with an acute rise in M3G's brain/plasma ratio. Although no exacerbation of acute TBI-induced inflammation was observed with either morphine or M3G, the impact of longer, more frequent dosing needs evaluation because its longer administration could exacerbate TBI's neuroinflammatory response.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103645"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742321","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":"Celebrating 50 unique Viewpoint perspectives in The Journal of Pharmacology and Experimental Therapeutics.","authors":"Daniel J Morgan, Roberto Levi, Susan K Wood, Beverley Greenwood-Van Meerveld","doi":"10.1016/j.jpet.2025.103646","DOIUrl":"10.1016/j.jpet.2025.103646","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103646"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760394","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":"Preclinical characterization of novel multi-client inhibitors of Sec61 with broad antitumor activity.","authors":"Eric Lowe, Janet L Anderl, David Bade, Cristina Delgado-Martin, Chengguo Dong, R Andrea Fan, Ying Fang, Jing Jiang, Henry W B Johnson, Aaron Kempema, Phil McGilvray, Dustin McMinn, Beatriz Millare, Tony Muchamuel, Nicole Poweleit, Yu Qian, Shahid Rehan, Giovanna Scapin, Ajia Sugahara, Dale Tranter, Brian Tuch, Jinhai Wang, Laurie Wang, Jennifer A Whang, Patricia Zuno-Mitchell, Ville O Paavilainen, Eunyong Park, Jack Taunton, Christopher J Kirk, Neel K Anand","doi":"10.1016/j.jpet.2025.103634","DOIUrl":"10.1016/j.jpet.2025.103634","url":null,"abstract":"<p><p>The Sec61 translocon mediates entry of most secreted and transmembrane proteins into the endoplasmic reticulum, providing a novel therapeutic target to block the expression of protumorigenic factors. Sec61 inhibitors with antitumor activity, mostly derived from natural products, have been reported. However, poor tolerability and suboptimal pharmaceutical properties have precluded their further development. We report here the discovery and characterization of KZR-834 and KZR-261, related small molecule analogs that directly bind to the Sec61 channel to potently inhibit the biogenesis of a subset of Sec61 client proteins. This client inhibition profile includes several tumorigenic factors, results in the activation of an endoplasmic reticulum stress response, and leads to broad anticancer effects in vitro. In vivo, KZR-261 was well tolerated and exhibits antitumor effects across multiple models, both as a single agent and in combination with anti-PD-1 immunotherapy. Based on the strength of this preclinical data, KZR-261 progressed into a phase I clinical trial (NCT05047536) in patients with malignant disease, where it was found to be well tolerated at doses that achieved durable stable disease. These results highlight the potential of Sec61 inhibition as a novel therapeutic target. SIGNIFICANCE STATEMENT: KZR-834 and KZR-261 are novel Sec61 inhibitors with the ability to block multiple Sec61 client proteins, leading to well-tolerated efficacy in in vivo cancer models. This represents a novel mechanism for blocking expression of oncogenic factors, including those not amenable to targeting through conventional methods.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103634"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649800","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":"Whole-body physiologically based pharmacokinetic modeling of the nonlinear pharmacokinetics of prednisolone and its reversible metabolite prednisone in rats.","authors":"Xiaonan Li, William J Jusko","doi":"10.1016/j.jpet.2025.103637","DOIUrl":"10.1016/j.jpet.2025.103637","url":null,"abstract":"<p><p>The pharmacokinetics (PK) and interconversion of prednisolone (PNL) and prednisone (PN) were assessed in the rat following single doses and intravenous infusions of PNL and PN. Their concentrations in blood and 11 tissues were determined by liquid chromatography-tandem mass spectrometry, and unbound drug by ultrafiltration. The PK of both steroids were nonlinear, featuring dose/concentration-dependent decreases in apparent steady-state plasma clearance and volume of distribution, with interconversion exhibiting continual rapid equilibria. The plasma and tissue profiles of PNL and PN were assessed with a comprehensive dual physiologically based pharmacokinetic model incorporating saturable plasma and tissue binding of PNL linked by their interconversion in liver and kidneys. All PK data were fitted jointly using Adapt software. Nonlinear tissue binding of PNL exhibited a range of equilibrium dissociation rate constants with highest in lung and 5 groups of binding capacity values. PN showed linear binding in most tissues, with a wide range of tissue-to-plasma partition coefficients with lowest in kidney to highest in lung. Conversion clearances of PN to PNL were found highest in liver and lesser in kidneys, whereas PNL to PN conversion occurred only in kidneys. Further irreversible elimination of PNL from venous plasma was nonlinear, whereas PN elimination was linear. The established physiologically based pharmacokinetic model well described the nonlinear whole-body disposition and interconversion of PNL and PN with relevance to humans and providing important insights into local steroid concentrations that drive diverse pharmacodynamic responses. SIGNIFICANCE STATEMENT: This work provides a detailed quantitative characterization of whole-body disposition of prednisolone and prednisone using a comprehensive dual physiologically based pharmacokinetic model that incorporates various complexities. This offers an instructive quantitative framework for other drugs that exhibit or affect metabolic interconversion and/or nonlinear disposition kinetics.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103637"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618687","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":"A novel model system to predict efficacy and safety of dexamethasone.","authors":"Lawrence H Lash","doi":"10.1016/j.jpet.2025.103633","DOIUrl":"10.1016/j.jpet.2025.103633","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103633"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567584","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}