Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Ranolazine inhibits invasiveness of human breast cancer cells in combination with a tyrosine kinase inhibitor: Dose-dependent synergy.","authors":"Ceren Sumer, Mustafa B A Djamgoz","doi":"10.1016/j.jpet.2026.105005","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105005","url":null,"abstract":"<p><p>Voltage-gated sodium channels (VGSCs) have emerged as important promoters of the invasive phenotype in triple-negative breast cancer (TNBC), a clinically aggressive and therapeutically challenging subtype of breast cancer. Channel activity is enhanced by hypoxia, which promotes metastatic progression. Pharmacological inhibition of VGSCs by specific channel blockers, such as ranolazine (RAN), results in antimetastatic behavior. Independently, epidermal growth factor signaling has been shown (1) to enhance VGSC activity and (2) to also promote TNBC progression. Here, we aimed to test whether cotreatment of a model TNBC cell line, MDA-MB-231, with an epidermal growth factor receptor inhibitor (AG1478 [AG]) and RAN would produce a synergistic effect on invasiveness. Two different concentrations of AG (5 and 10 μM) were used, whereas RAN was used at a clinically relevant concentration (<5 μM) under hypoxia (1% O₂). Excess 'over bliss score' was determined quantitatively to evaluate possible synergy. Indeed, both RAN and AG individually suppressed Matrigel invasion dose dependently without altering proliferative activity. Clear synergy was observed at low-concentration combinations. Specifically, combined with 5 μM AG, RAN was clearly synergistic at 1.25 μM (excess over bliss = +38.7%). In contrast, higher concentrations produced little or no synergy. We concluded that the inhibitory effect of RAN on TNBC invasiveness can be made more effective by combination with an inhibitor of epidermal growth factor receptor/tyrosine kinase inhibitor at low concentrations. Furthermore, because functional VGSCs occur in several carcinomas and receptor tyrosine kinases commonly promote their invasiveness, the results could have broader application, including via drug repurposing. SIGNIFICANCE STATEMENT: Triple-negative breast cancer is a highly aggressive malignancy with limited therapeutic options. Ranolazine, an antianginal drug and an inhibitor of the voltage-gated sodium channel persistent current, inhibited cells' invasiveness at clinically relevant concentrations. Efficacy was enhanced by combination with an epidermal growth factor receptor inhibitor (AG1478). Synergy occurred specifically at low concentrations. These findings raise the possibility of treating triple-negative breast cancer nontoxically while reducing the chance of developing drug resistance. The results are also potentially applicable to multiple carcinomas.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105005"},"PeriodicalIF":4.3,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148969424","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":"Adiponectin in cigarette smoke-induced epithelial-mesenchymal transition.","authors":"Francesca Panico, Giuseppe Spaziano, Ersilia Nigro, Davida Mirra, Renata Esposito, Eleonora Caiazzo, Aurora Daniele, Bruno D'Agostino","doi":"10.1016/j.jpet.2026.105004","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105004","url":null,"abstract":"<p><p>Cigarette smoke (CS) contributes to a wide range of chronic respiratory diseases by inducing epithelial-mesenchymal transition (EMT), which drives tissue remodeling, fibrosis, and tumor progression. In this scenario, adiponectin (Acrp30) has emerged as a potential EMT-negative regulator, inhibiting migration and invasion in non-small cell lung cancer cell lines. This study aimed to investigate ability of Acrp30 to prevent CS-induced EMT and profibrotic remodeling in normal and adenocarcinoma lung cells, through AdipoRon, a synthetic Acrp30 receptor agonist. BEAS-2B and A549 cells were used to preliminarily assess the optimal dose and timing for CS and AdipoRon exposure for subsequent evaluations by thiazolyl blue tetrazolium bromide assay. Expression of epithelial (E-cadherin), mesenchymal (vimentin), and profibrotic (α-smooth muscle actin, transforming growth factor-β, total collagen deposition, and collagen type I α1 chain) markers was examined through immunofluorescence, reverse transcription polymerase chain reaction, and Sirius Red staining. Wound-healing assay was used to assess CS and Acrp30 ability to influence cell migration. Reactive oxygen species levels were measured by 2',7'-dichlorofluorescin diacetate assay. Acrp30 prevents CS-induced dysregulation of E-cadherin and vimentin at both mRNA and protein levels, preserving the epithelial-mesenchymal balance in both cell lines. Furthermore, CS-induced increase in profibrotic marker expression was significantly attenuated by AdipoRon pretreatment in both BEAS-2B and A549 cells. The CS-induced increase in migratory capacity was significantly reversed by Acrp30 in both cell lines, confirming its ability to prevent EMT. Finally, Acrp30 also markedly reduced CS-induced reactive oxygen species overproduction in BEAS-2B and A549 cells, indicating a role in modulating oxidative stress-driven epithelial plasticity. Thus, Acrp30 effectively preserves epithelial markers, limits the mesenchymal shift and profibrotic remodeling, and reduces migratory capacity by mitigating oxidative stress. These results support Acrp30 as a promising therapeutic candidate for preventing airway remodeling and disease progression in smoking-related conditions. SIGNIFICANCE STATEMENT: Cigarette smoke (CS) induces epithelial-mesenchymal transition and fibrosis in both healthy and cancerous lung epithelial cells. Adiponectin pretreatment prevents CS-induced epithelial-mesenchymal transition and profibrotic remodeling in both cell lines; adiponectin can prevent airway remodeling and disease progression in CS conditions.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105004"},"PeriodicalIF":4.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956010","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":"Chemotype-dependent dissociation of binding affinity and functional potency in synthetic cannabinoids.","authors":"Laura B Kozell, Amy J Eshleman, Kamryn A Schutzer, Shelley H Bloom, Katherine M Wolfrum, Tracy L Swanson, William E Schutzer, Aaron Janowsky, Atheir I Abbas","doi":"10.1016/j.jpet.2026.105003","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105003","url":null,"abstract":"<p><p>Synthetic cannabinoids are a structurally diverse class of cannabinoid receptor 1 agonists that frequently exhibit ultrapotency and are associated with severe toxicity and mortality. To define the structural determinants underlying this ultrapotency, we performed in vitro pharmacological characterization of 74 synthetic cannabinoid receptor agonists spanning multiple chemotypes, with wide variation in headgroup, core, and N-alkyl tail chemistry, including PINACAs, BUTINACAs, PICAs, PRINACAs, and related scaffolds. Using radioligand binding and functional assays, we quantified equilibrium affinity (K_i), functional potency (EC₅₀), and efficacy (Emax) across compounds. We observed marked dissociation between affinity and potency for many compounds, with many displaying subnanomolar EC₅₀ values despite moderate nanomolar binding affinity. Comparative analysis revealed that indazole-based cores and optimal N-pentyl or 5-fluoropentyl tails primarily enhance binding stability, whereas headgroup chemistry, while also contributing to affinity, emerges as a key determinant of coupling efficiency and ultrapotent functional responses. Notably, matched headgroups across PICA and PINACA scaffolds showed similar affinity-potency dissociation but uniformly lower absolute values in PICAs, supporting a division of labor in which the core governs binding whereas the headgroup governs activation efficiency. Together, these findings provide a unifying framework for understanding the extraordinary potency of contemporary synthetic cannabinoid receptor agonists and underscore why equilibrium affinity alone is insufficient to predict their biological and toxicological impact. SIGNIFICANCE STATEMENT: Synthetic cannabinoids frequently exhibit extreme cannabinoid receptor 1 potency and are responsible for severe toxicity and fatalities. By systematically comparing 74 compounds across multiple chemotypes, we show that ultrapotency arises from dissociation between binding affinity and functional activation, with the core and tail primarily determining affinity while headgroup chemistry governs binding and activation efficiency. These findings provide a mechanistic framework for predicting the potency and toxicological risk of emerging synthetic cannabinoids.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105003"},"PeriodicalIF":4.3,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075142","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":"PF5190457 reduces fentanyl intake and seeking with a low risk pharmacological profile in male rats.","authors":"Christina R Merritt, Leah M Salinsky, Erik J Garcia, Robert G Fox, Holly L Chapman, Jennifer J Linares, William K Russell, Frederick Gerard Moeller, Noelle C Anastasio, Kathryn A Cunningham","doi":"10.1016/j.jpet.2026.104978","DOIUrl":"10.1016/j.jpet.2026.104978","url":null,"abstract":"<p><p>The opioid epidemic remains a persistent public health challenge in the United States, leaving many people affected by or vulnerable to opioid use disorder (OUD). Although US Food and Drug Administration-approved medications for OUD improve the odds of recovery and reduce mortality, relapse rates remain high and access, adherence, and individual response variabilities limit their overall impact. The ongoing burden of OUD therefore underscores the need to develop additional therapeutics that target complementary biological mechanisms and support long-term recovery. One strategy of interest is to delineate the biological overlap between OUD and other motivated behaviors, particularly the neurobiology underlying appetitive and reward-driven processes. The orexigenic peptide hormone ghrelin, often referred to as the \"hunger hormone,\" regulates energy homeostasis, hedonic feeding, and reward sensitivity by binding to the growth hormone secretagogue receptor 1α (GHS1αR), a receptor expressed in mesolimbic circuits implicated in addiction. In the present study, we used the inverse agonist/antagonist PF5190457 to assess the impact of full GHS1αR blockade on fentanyl-mediated behaviors in preclinical models. We found that PF5190457 significantly reduced fentanyl self-administration and attenuated drug-seeking during cue tests while maintaining a favorable pharmacological and safety profile in risk assessment assays, including measures of withdrawal and respiratory depression. Collectively, these findings demonstrate a functional role for ghrelin-GHS1αR signaling in the reinforcing effects of fentanyl and positions GHS1αR inverse agonism as a promising, mechanistically novel therapeutic strategy for OUD treatment. SIGNIFICANCE STATEMENT: The present work demonstrates that the growth hormone secretagogue receptor 1α (GHS1αR) inverse agonist/antagonist PF5190457 reduces fentanyl self-administration and drug-seeking while maintaining a favorable safety profile in male rats, supporting ghrelin-GHS1αR modulation as a promising therapeutic strategy for opioid use disorder.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104978"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148685204","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":"Blocking interleukin 33 reduces joint, systemic, and lung inflammatory responses in the combined collagen-induced arthritis-inhalant endotoxin exposure model.","authors":"Jill A Poole, Jacob L Larsen, Geoffrey M Thiele, Todd A Wyatt, Amy J Nelson, Michael J Duryee, Angela M Gleason, Oliver W Schanze, Aaron D Schwab, John D Dickinson, Deanna Mosley, Michael Lush, Han-Jun Wang, E Suzanne Cohen, Bryant R England, Ted R Mikuls","doi":"10.1016/j.jpet.2026.104983","DOIUrl":"10.1016/j.jpet.2026.104983","url":null,"abstract":"<p><p>Therapies capable of resolving rheumatoid arthritis (RA)-associated lung disease, particularly in the setting of environmental exposures, are lacking. This study sought to determine whether blocking interleukin (IL)-33 in a murine model of RA-associated lung disease induced by combined collagen-induced arthritis (CIA) and repeated inhalant lipopolysaccharide (LPS) exposures could be advantageous. Arthritis prone male DBA/1J mice received CIA (vs saline) injections (days 1 and 21) plus intranasal LPS (100 ng) or saline daily for 4 weeks and were subsequently treated with 5 doses of anti-IL-33 (10 mg/kg) or isotype over 11 days. Anti-IL-33 therapy significantly (P < .05) mitigated several CIA+LPS-induced effects. Anti-IL-33 reduced arthritis inflammatory score by 76% and serum acute phase reactant pentraxin-2 by 70% and reversed weight loss induced by CIA+LPS coexposure. Anti-IL-33 reduced CIA+LPS-induced antimalondialdehyde acetaldehyde but not anticitrullinated autoantibodies in serum and reduced serum levels of inflammatory mediators. Lung cell infiltrates induced by coexposure, including neutrophils, activated lung macrophages, transitional monocytes-macrophages, monocytic-like cells, and dendritic cells, were reduced with anti-IL-33. Anti-IL-33 also reduced CIA+LPS-induced lung levels of chemokines involved in monocyte-macrophage recruitment and fibrotic/repair mediators collagen deposition, IL-33 expression, inflammatory CC motif chemokine receptor 2⁺ monocytes/macrophages, and airway Muc5b immunostaining induced by CIA+LPS were reduced with anti-IL-33. CIA+LPS-induced lung expression of post-translational modified autoantigens including citrullinated and malondialdehyde acetaldehyde and its common substrate, vimentin, was reduced with anti-IL-33 treatment. Blocking IL-33 was beneficial in hastening lung recovery after establishment of disease by coexposure to CIA+LPS and potentially represents a novel therapeutic approach in RA-associated lung disease. SIGNIFICANCE STATEMENT: Blocking the interleukin (IL)-33 signaling pathway after the establishment of, but not during the induction of, rheumatoid arthritis (RA)-associated lung disease, as modeled by coexposure of collagen-induced arthritis with repetitive inhalant endotoxin, demonstrated beneficial consequences in reducing inflammatory joint, systemic, and lung disease. Treatment with anti-IL-33 agents, particularly in men with a history of environmental exposures, may represent a novel approach to reduce disease burden in humans with established RA-lung disease, underscoring an important role for the IL-33 pathway.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104983"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148603895","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":"Safety, pharmacodynamics, and pharmacokinetics of oral cannabigerol in healthy adults.","authors":"David Wolinsky, Dhathri Srungaram, Alec Zhang, Catherine F Moore, Zachary J Pierce-Messick, C Austin Zamarripa, Tory R Spindle, Justin C Strickland, Cristina Sempio, Jost Klawitter, Jorge Campos Palomino, Uwe Christians, Matthew T Feldner, Ryan Vandrey, Marcel O Bonn-Miller, Elise M Weerts, Cecilia L Bergeria","doi":"10.1016/j.jpet.2026.104984","DOIUrl":"10.1016/j.jpet.2026.104984","url":null,"abstract":"<p><p>Cannabigerol (CBG) is a minor cannabinoid that has been considered as a potential therapeutic, yet basic acute pharmacodynamics and pharmacokinetics across commercially available doses have not been examined. To complete this critical step, healthy adults (n = 12) were enrolled in a single ascending dose human laboratory study where they consumed 0, 25, 50, 100, and 200 mg of CBG isolate suspended in medium-chain triglyceride oil. The placebo administration occurred randomly within the dosing sequence. Standardizing flavor and solution volume facilitated blinding. Adverse events were recorded throughout to characterize safety and tolerability. Pharmacodynamic outcomes (ie, subjective, cognitive, and physiological responses) and plasma samples were collected at baseline and regular intervals after drug administration (0.5-, 1-, 1.5-, 2-, 3-, 4- , 5-, 6-, and 8-hours). Pharmacokinetic parameters (eg, peak plasma CBG concentration) were also measured. Liver function tests were characterized at baseline and after acute administration of the 2 highest doses. No drug-related adverse events occurred. Subjective effects associated with CBG administration were minimal with the exception of significant decreases in self-reported ratings of Jittery and Active associated with 50 mg, significant decreases in Calm associated with 100 mg, and increases in Appetite associated with 200 mg of CBG. Pharmacokinetics were dose-orderly, but significant individual variability was observed. Liver function tests never exceeded the upper limit of normal following acute administration of the highest doses. Overall CBG was well-tolerated with no robust pharmacodynamic effects; chronic dosing studies are needed to more fully characterize the safety and pharmacodynamic profile of oral CBG. SIGNIFICANCE STATEMENT: Cannabigerol has garnered attention as a potential therapeutic for many diagnoses before the fundamental studies investigating its pharmacokinetics and pharmacodynamics have been completed. We aimed to provide this information through a single ascending dose study, finding that cannabigerol is well-tolerated while yielding few pharmacodynamic or psychoactive effects.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104984"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706797","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":"Keeping it acid ceramidase: How adiponectin protects in the glomerulus.","authors":"Noelle I Frambes, Erin B Taylor, Jennifer C Sullivan, Michael J Ryan","doi":"10.1016/j.jpet.2026.104979","DOIUrl":"10.1016/j.jpet.2026.104979","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104979"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148603932","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":"Cardiac homing peptide-decorated epigallocatechin gallate-loaded poly(lactic-co-glycolic acid) nanoparticles alleviate acute myocardial infarction.","authors":"Haiqi Li, Ruohui Huang, Jinhong Zhang, Dongli Jiang, Jie Jian","doi":"10.1016/j.jpet.2026.104985","DOIUrl":"10.1016/j.jpet.2026.104985","url":null,"abstract":"<p><p>Epigallocatechin gallate (EGCG) exerts cardioprotective effects on acute myocardial infarction through multiple pathways. However, the clinical application of EGCG is limited because of its instability under physiological conditions and low bioavailability. In this study, poly(lactic-co-glycolic acid) was used as a drug carrier to prepare EGCG nanoparticles (NPs), then an EGCG targeting drug delivery system was designed by modifying with cardiac homing peptide. We constructed a preparation route combining the double-emulsion solvent evaporation method and the carbodiimide method. By optimizing the preparation process, the particle size of the EGCG NP was reduced, and the dispersibility was improved. In addition, the established preparation procedure uses safe and low-toxicity reagents, requires no strict temperature control or specialized instrumentation, and therefore significantly reduces the technical difficulty of large-scale industrial production. EGCG-poly(lactic-co-glycolic acid)-cardiac homing peptide had myocardial targeting and good safety in the 3‑(4,5‑dimethyl‑2‑thiazolyl)‑2,5‑diphenyl‑2H‑tetrazolium bromide (MTT) cytotoxicity test, and alleviated acute myocardial infarction by regulating apoptosis-related protein expression in a dose-dependent manner. Compared with EGCG monomer, EGCG-poly(lactic-co-glycolic acid)-cardiac homing peptide achieved a better therapeutic effect. This study provides a new strategy for promoting the application of EGCG in the clinical treatment of acute myocardial infarction. SIGNIFICANCE STATEMENT: This study develops cardiac homing peptide-modified poly(lactic-co-glycolic acid) nanoparticles to enable targeted delivery of epigallocatechin gallate for acute myocardial infarction therapy. By overcoming the inherent instability and poor bioavailability of epigallocatechin gallate, this scalable nanoplatform achieves superior cardioprotection through regulated apoptosis and exhibits excellent safety in the MTT cytotoxicity test. These findings establish a clinically translatable strategy for targeted drug delivery in the treatment of cardiovascular disease.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104985"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679083","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":"Bronchorelaxant and anti-inflammatory profile of ensifentrine alone and combined with inhaled medications in lipopolysaccharide-challenged human airways from chronic obstructive pulmonary disease donors.","authors":"Luigino Calzetta, Tara Rheault, Shima Gholamalishahi, Francesco Facciolo, Giuseppe Cardillo, Paola Rogliani","doi":"10.1016/j.jpet.2026.104976","DOIUrl":"10.1016/j.jpet.2026.104976","url":null,"abstract":"<p><p>The ENHANCE trials demonstrated that ensifentrine (CAS Number 1884461-72-6), an inhaled dual phosphodiesterase (PDE) 3/4 inhibitor, offers additional benefits in chronic obstructive pulmonary disease (COPD). Its bifunctional activity warrants pharmacological investigation to elucidate mechanisms behind lung function improvements and exacerbation reduction. Human bronchial tissues from COPD donors were examined after lipopolysaccharide challenge. The effects of ensifentrine on bronchial relaxation were evaluated in response to carbachol and electrical field stimulation (EFS), also in combination with long-acting muscarinic antagonist (LAMA), long-acting β₂-adrenoceptor agonists (LABA), and inhaled corticosteroids (ICS). Anti-inflammatory effects were assessed by profiling cytokines, alarmins, and growth factors. Drug interactions were analyzed using the Bliss-Loewe Uncertainty Range (BLUR) model. Ensifentrine induced concentration-dependent relaxation to carbachol in both epithelium-intact and epithelium-denuded tissues (E_max 81.97 ± 6.17%, pEC₅₀ 4.86 ± 0.17) and inhibited EFS-induced contractility from 0.1 μM, with maximum reduction of 29.01% ± 2.50%. When combined with a LAMA, dual LABA/LAMA, or triple ICS/LABA/LAMA combinations, ensifentrine showed synergistic bronchorelaxant effect (overall increase in relaxation 20.47% ± 0.39%), leading to near-complete relaxation (>90%) at higher concentrations. At lower concentrations, ensifentrine reduced inflammation by 84.34% ± 8.69% in medium bronchi and 64.75% ± 8.96% in small airways; at the higher concentrations, inflammation was almost abolished (>90%), comparable to roflumilast. Drug combinations showed synergistic anti-inflammatory interactions in 31.43% of cases, mainly affecting interleukin 10, interleukin 25, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-α. This study supports ensifentrine as an adjunct in COPD therapy, because of its dual bronchodilator and anti-inflammatory actions. Further research is warranted to optimize combination strategies to maximize clinical benefits and to identify additional activities in the target tissue. SIGNIFICANCE STATEMENT: The inhaled dual PDE 3/4 inhibitor ensifentrine emerges as a potent therapeutic option for COPD, showing remarkable bronchodilator and anti-inflammatory effects within human airways, the primary target tissue. It exhibits synergistic interactions with existing inhaler therapies, enhancing their efficacy. By demonstrating anti-inflammatory efficacy comparable to the established PDE4 inhibitor, roflumilast, our findings emphasize ensifentrine's capacity to significantly improve treatment outcomes and guide the development of optimized future combination strategies for COPD management.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104976"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148603878","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":"Apatinib inhibits gastric cancer progression by inducing ferroptosis through cysteine dioxygenase 1/phosphoinositide 3-kinase/Akt axis.","authors":"Li-Bin Li, Wen-Ji Xu","doi":"10.1016/j.jpet.2026.104968","DOIUrl":"10.1016/j.jpet.2026.104968","url":null,"abstract":"<p><p>Although the clinical efficacy of apatinib in advanced gastric cancer has been widely confirmed, its anticancer mechanism still needs to be further studied. This study found that apatinib significantly inhibited gastric cancer cell viability by inducing the expression of cysteine dioxygenase 1 (CDO1; a key ferroptosis regulatory gene) and then enhancing ferroptosis, and CDO1 knockdown reduced ferroptosis. Apatinib and CDO1 significantly downregulated the expression of glutathione peroxidase 4 and solute carrier family 7 member 11, reduced cell viability and glutathione production, promoted acyl-CoA synthetase long chain family member 4 expression, and increased the accumulation of reactive oxygen species, Fe²⁺, and malondialdehyde; when knocking down CDO1 expression or activating phosphoinositide 3-kinase (PI3K)/Akt pathway, the expression of key ferroptosis regulatory genes and the contents of ferroptosis markers were significantly restored, indicating that apatinib-induced ferroptosis is associated with CDO1/PI3K/Akt axis. Meanwhile, both apatinib and CDO1 significantly inhibited the expression and secretion of metalloproteinase (MMP)-2 and MMP-9, and reduced cell invasion and migration; the ferroptosis inhibitor Fer-1, CDO1 small interfering RNA, and PI3K/Akt pathway activator 740 Y-P all weakened the regulation of apatinib and CDO1 on MMP expression, cell invasion and migration. Further in vivo nude mouse tumorigenesis experiments showed that apatinib significantly inhibited tumor growth and the expression of glutathione peroxidase 4 and solute carrier family 7 member 11, promoted CDO1 and acyl-CoA synthetase long chain family member 4 expression, increased reactive oxygen species, Fe²⁺, and malondialdehyde contents, and reduced glutathione production; after knocking down CDO1 expression, all these ferroptosis indicators were significantly restored. Therefore, apatinib inactivates PI3K/Akt pathway by promoting CDO1 expression, thereby enhancing ferroptosis and then inhibiting tumor growth. SIGNIFICANCE STATEMENT: Apatinib is a small-molecule tyrosine kinase inhibitor and can inhibit tumor cell growth through various mechanisms other than antiangiogenesis. Therefore, understanding the anticancer mechanism of apatinib is of great significance for its clinical application.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 8","pages":"104968"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436914","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}