Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Olezarsen for the treatment of hypertriglyceridemia: A Bayesian reanalysis of randomized controlled trials.","authors":"Ana Carolina Covre Coan, Eric Katsuyama, Rodolfo A Lopes, Carlos Vergara Sanchez, Alonzo Armani Prata, Christian Ken Fukunaga, Armando Talavera, Michael Shapiro","doi":"10.1016/j.jpet.2026.105022","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105022","url":null,"abstract":"<p><p>Hypertriglyceridemia is associated with an increased risk of atherosclerotic cardiovascular (CV) disease. Olezarsen, an apolipoprotein C-III (APOC3) inhibitor, lowers triglyceride (TG) levels. Using a Bayesian reanalysis that incorporated prior evidence, we estimated the effects of olezarsen on TG and apolipoprotein B levels in patients with severe or moderate hypertriglyceridemia who were at high CV risk. We searched PubMed, Embase, and Cochrane data bases for randomized clinical trials comparing treatment with olezarsen versus placebo in patients with severe or moderate hypertriglyceridemia who were at CV risk. Mean differences (MDs) and 95% credible intervals (CrIs) were pooled with a Bayesian random-effects model using a vague prior for the overall effect and between-study heterogeneity. We included 4 randomized clinical trials with a total of 2678 patients, of whom 1930 (72%) received olezarsen. Most participants were men (67%) with a mean age of 60 years and a follow-up of 12 months. The baseline median TG level was 468 mg/dL (range, 239.9-838 mg/dL), and 941 (35%) patients had a history of atherosclerotic CV disease. Olezarsen was associated with reductions from baseline in TG (MD, -57.77%; 95% CrI, -66.76 to -48.45), APOC3 (MD, -66.97%; 95% CrI, -77.67 to -55.30), and apolipoprotein B (MD, -12.78%; 95% CrI, -26.76 to -0.10), as well as an increase in low-density lipoprotein cholesterol levels (MD, 25.89%; 95% CrI, 5.76-46.51) compared with placebo. In this Bayesian meta-analysis involving patients with severe hypertriglyceridemia and high CV risk, olezarsen was effective in reducing TG, APOC3, and apolipoprotein B levels. SIGNIFICANCE STATEMENT: In this Bayesian meta-analysis of randomized trials, olezarsen markedly reduced triglycerides, apolipoprotein C-III, apolipoprotein B, and non-high-density lipoprotein levels in patients with severe or moderate hypertriglyceridemia who were at high cardiovascular risk. These findings are limited to surrogate lipid biomarkers, and whether these improvements translate into reductions in cardiovascular events remains unknown.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105022"},"PeriodicalIF":4.3,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111166","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":"Calpeptin and protein kinase C inhibition suppress exosome-associated inflammatory signaling and epidermal dysregulation in a 3-dimensional psoriatic skin model.","authors":"Kamonpan Fongsodsri, Wasarat Somkaew, Pornanong Aramwit, Onrapak Reamtong, Tipparat Thiangtrongjit, Tapanee Kanjanapruthipong, Watcharamat Muangkaew, Passanesh Sukphopetch, Sumate Ampawong","doi":"10.1016/j.jpet.2026.105020","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105020","url":null,"abstract":"<p><p>Psoriasis is a chronic inflammatory skin disorder characterized by dysregulated cytokine signaling and keratinocyte hyperproliferation, in which extracellular vesicles, particularly exosomes, play key roles in mediating intercellular inflammatory communication. In this study, we evaluated the pharmacological effects of calpeptin and bisindolylmaleimide I (BIM-I), inhibitors of calpain and protein kinase C previously reported to modulate extracellular vesicle-associated pathways, in a 3-dimensional human psoriatic skin model. Both inhibitors significantly reduced the expression of proinflammatory cytokines, keratinocyte activation marker, and exosome-related marker, including interleukin (IL)-1β, tumor necrosis factor-α, IL-8, interferon gamma, IL-21, IL-20, CC chemokine ligand-20, keratin 6A, CD9, and CD63, consistent with attenuation of psoriasis-associated inflammatory signaling. BIM-I additionally suppressed IL-22 and IL-6 expression and restored epidermal ultrastructural features, including desmosome density, to levels comparable with normal skin. Integrated proteomic and immunohistochemical analyses revealed distinct downstream biological responses associated with modulation of exosome-associated markers and pathways. Calpeptin treatment was associated with enrichment of endoplasmic reticulum stress-related pathways, as indicated by increased growth arrest and DNA damage-inducible protein 153 and glucose-regulated protein 78 expression, whereas BIM-I preferentially regulated cytoskeletal organization and keratinocyte differentiation, accompanied by reduced expression of growth arrest and DNA damage-inducible protein 153, glucose-regulated protein 78, and keratin 16. Collectively, these findings demonstrate that pharmacological inhibition of calpain and protein kinase C attenuates psoriatic inflammation and epidermal dysregulation and is associated with modulation of exosome-associated markers and pathways, together with differential regulation of endoplasmic reticulum stress and cytoskeletal networks. SIGNIFICANCE STATEMENT: This study demonstrates that pharmacological inhibition of calpain and protein kinase C attenuates inflammatory signaling and keratinocyte activation in a 3-dimensional psoriatic skin model, highlighting exosome-associated pathways as key regulators of disease pathology. Distinct mechanisms involving endoplasmic reticulum stress modulation and cytoskeletal regulation provide insight into how targeting vesicle-mediated intercellular communication may offer therapeutic potential in psoriasis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105020"},"PeriodicalIF":4.3,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955997","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":"Treating neurological diseases through epigenetic inhibition: A neuroepigenetic therapy hypothesis.","authors":"Doodipala Samba Reddy, Lauren Franklin, Victoria Golub, Hetvi Desai, Sreevidhya Ramakrishnan","doi":"10.1016/j.jpet.2026.105019","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105019","url":null,"abstract":"<p><p>Epigenetics encompasses a highly coordinated set of reversible mechanisms that regulate gene expression and function without altering the underlying DNA code. Emerging evidence indicates that dysregulation of epigenetic pathways contributes to the pathogenesis and progression of numerous central nervous system disorders. This review summarizes the major epigenetic mechanisms implicated in neurological diseases, including histone acetylation and deacetylation, DNA methylation, microRNA-mediated regulation, and bromodomain and extraterminal domain protein signaling, and highlights emerging therapeutic strategies targeting these pathways. Epigenetic modulators, including histone deacetylase inhibitors, DNA methyltransferase inhibitors, microRNA-based modulators, and bromodomain and extraterminal domain inhibitors, can broadly influence transcriptional processes involved in neuroinflammation, neuronal survival, synaptic plasticity, and tissue repair. Although many of these approaches remain in the early stages of development, preclinical studies have demonstrated considerable potential to regulate pathological immune and inflammatory responses, promote neuroprotection, and enhance functional recovery following central nervous system injury and disease. Consequently, epigenetic-based therapies have emerged as promising disease-modifying strategies for a wide range of neurological disorders, including traumatic brain injury, stroke, epilepsy, neurodegenerative diseases, and chronic pain. We propose a unifying \"neuroepigenetic therapy hypothesis\" whereby precision targeting of reversible maladaptive epigenetic states can restore transcriptional homeostasis and shift treatment of neurological disorders from symptomatic control toward disease prevention, repair, and disease modification. A deeper understanding of the complex interplay among multiple transcriptional regulatory pathways may pave the way for precision neuroepigenetic therapies capable of preventing or mitigating chronic neurological disorders with improved efficacy and safety. SIGNIFICANCE STATEMENT: Aberrant neuroepigenetic signaling is increasingly recognized as a key driver of neuroinflammation, neuronal dysfunction, and disease progression in many neurological disorders. By targeting nuclear mechanisms that regulate gene expression, epigenetic therapies have emerged as a promising class of neuroprotective and disease-modifying agents. This review highlights recent advances in epigenetic therapeutics and their potential to transform the treatment of central nervous system disorders.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105019"},"PeriodicalIF":4.3,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030371","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":"SRY-related HMG-box 5 enhances chemosensitivity in esophageal squamous cell carcinoma through toll-like receptor 4/NOD-like receptor family pyrin domain containing 3-mediated pyroptosis.","authors":"Wenbin Hu, Jiaming Zhao, Qihao Wang, Mingming Deng, Binjun He, Xiaoyan Wang","doi":"10.1016/j.jpet.2026.105018","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105018","url":null,"abstract":"<p><p>Despite established roles in multiple cancers, the specific function and molecular mechanism of SRY-related HMG-box 5 (SOX5) remain elusive in esophageal squamous cell carcinoma (ESCC). SOX5 expression in ESCC tissues, its correlation with prognosis, and its relationship with toll-like receptor 4 (TLR4) and NOD-like receptor family pyrin domain containing 3 (NLRP3) were assessed with bioinformatic methods. Expression of SOX5 and TLR4 in ESCC cells was detected by quantitative reverse transcription polymerase chain reaction. In SOX5-overexpressing or TLR4-knockdown ESCC cells, cell death was evaluated by propidium iodide staining, migration and invasion were detected using Transwell assays, cell proliferation was assessed by colony formation assay, pyroptosis was observed using an optical microscope and confirmed using Annexin V/7-aminoactinomycin D staining, the binding of SOX5 to the TLR4 promoter was confirmed by chromatin immunoprecipitation assay, and the expression of key pyroptosis pathway proteins (Gasdermin D, Gasdermin D-N, cleaved Caspase-1 (c-CASP1), and NLRP3) was analyzed by Western blot. SOX5 downregulation in ESCC tissues and cells was observed and correlated with shorter survival in patients with ESCC. SOX5 expression positively correlated with the key pyroptosis pathway genes TLR4 and NLRP3. SOX5 overexpression promoted ESCC cell pyroptosis and enhanced sensitivity to cisplatin (DDP). Mechanistically, SOX5 interacted with the TLR4 promoter and upregulated key pyroptosis pathway proteins; TLR4 knockdown reduced the enhanced pyroptosis and DDP sensitivity observed in SOX5-overexpressing cells. SOX5 enhances DDP sensitivity in ESCC by mediating TLR4/NLRP3 expression to promote cell pyroptosis, providing novel insights for ESCC treatment. SIGNIFICANCE STATEMENT: SRY-related HMG-box 5 function in esophageal squamous cell carcinoma was uncovered. SRY-related HMG-box 5 regulated toll-like receptor 4/NOD-like receptor family pyrin domain containing 3 to mediate pyroptosis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105018"},"PeriodicalIF":4.3,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111118","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":"Shiheleucel, an allogeneic natural killer cell product expanded under chemically defined conditions, in combination with rituximab-based chemotherapy in relapsed/refractory diffuse large B-cell lymphoma: An exploratory clinical study.","authors":"Yunhong Huang, Yuan Yang, Yunfei Hu, Jingling Tang, Kai Liao, Liyun Wu, Haiyan Jiang, Honglin Liu, Jindan Shen, Xiaoyang Li, Yang Xue, Yuan Wang, Kunqiao Yang, Rongjie Gu, Yuan Cheng","doi":"10.1016/j.jpet.2026.105012","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105012","url":null,"abstract":"<p><p>Natural killer (NK) cell dysfunction contributes to tumor resistance, particularly in antibody-dependent cell-mediated cytotoxicity. This study evaluated a fully chemically defined system for expanding high-purity NK (hpNK) cells and their clinical application. In preclinical studies, hpNK demonstrated strong antibody-dependent cell-mediated cytotoxicity activity in combination with rituximab. An exploratory clinical trial involving 19 patients with relapsed/refractory diffuse large B-cell lymphoma assessed the safety and preliminary clinical efficacy of combining allogeneic hpNK (shiheleucel) with anti-CD20 antibody and chemotherapy. Among 17 patients treated, no dose-limiting toxicity was observed. Among the 12 patients who underwent at least 1 postbaseline positron emission tomography and computed tomography efficacy assessment, the investigator-assessed objective response rate was 75.0% (9/12), including 7 complete responses and 2 partial responses. Median progression-free survival was 24 weeks, with median overall survival not reached at the time of analysis. Shiheleucel demonstrated a manageable safety profile and preliminary clinical activity, warranting further evaluation in larger controlled studies. SIGNIFICANCE STATEMENT: This study demonstrates that a fully chemically defined expansion system can generate high-purity natural killer (NK) cells with potent antibody-dependent cell-mediated cytotoxicity activity in preclinical settings. In an exploratory clinical trial combining allogeneic NK cell therapy with anti-CD20 antibody and chemotherapy to treat relapsed/refractory diffuse large B-cell lymphoma provided a manageable safety profile and evidence of clinical activity. These findings support further investigation of antibody-dependent cell-mediated cytotoxicity-driven NK cell-based allogeneic cell therapy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105012"},"PeriodicalIF":4.3,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955252","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":"Δ⁹-Tetrahydrocannabinol treatment impairs CD8⁺ T cell differentiation into interferon gamma-competent CD45RO⁺ cells.","authors":"Joel R Marty, Robert B Crawford, Lance K Blevins, Peter Gulick, Norbert E Kaminski","doi":"10.1016/j.jpet.2026.105010","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105010","url":null,"abstract":"<p><p>Chronic human immunodeficiency virus (HIV) infection results in a persistent state of neuroinflammation, even with combined antiretroviral therapy. Neuroinflammation contributes to pathology termed HIV-associated neurocognitive disorder, which is exacerbated by interferon gamma (IFNγ)-producing CD8⁺ T cells in the central nervous system. Many people living with HIV self-report using Cannabis sativa to mitigate symptoms of chronic infection and side effects of treatment. C. sativa is composed of various phytocannabinoids, including Δ⁹-tetrahydrocannbinol (THC), which possesses immune-modulating properties. This study aims to determine whether C. sativa use by people living with HIV, and specifically THC, affects IFNγ secretion by CD8⁺ T cells. We found that HIV status does not influence T cell IFNγ responses, and C sativa use modestly reduces the average secretion of IFNγ by CD8⁺ T cells from HIV+ donors. Treatment of CD8⁺ T cells with THC and the selective cannabinoid receptor 2 agonist, JWH-015, reduced T-cell cytokine secretion, with THC eliciting greater suppression than cannabidiol. These results suggest that THC treatment does not directly impair IFNγ gene expression or protein production, as determined by polymerase chain reaction and flow cytometry. However, THC treatment impaired CD8⁺ T cell differentiation into IFNγ-competent CD45RO⁺ cells. These studies are of clinical relevance because reduction of CD8⁺ T-cell-derived IFNγ in the central nervous system may improve cognitive outcomes during HIV infection. Furthermore, these findings may be generalizable to other inflammatory diseases in which IFNγ-producing CD8⁺ T cells have been implicated. SIGNIFICANCE STATEMENT: Δ⁹-Tetrahydrocannbinol (THC) treatment reduces CD8⁺ T cell interferon gamma (IFNγ) secretion isolated from HIV- and HIV+ individuals. THC and the selective cannabinoid receptor 2 agonist, JWH-015, both reduced CD8⁺ T cell secretion of IFNγ, interleukin 2, and tumor necrosis factor α, suggesting the involvement of cannabinoid receptor 2. Although THC treatment does not suppress IFNγ mRNA or protein levels, it reduces the number of IFNγ-secreting cells by impairing CD8⁺ T-cell differentiation into IFNγ-competent CD45RO⁺ cells.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105010"},"PeriodicalIF":4.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982301","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 drug sequestrant-based therapeutic candidate reverses methamphetamine-induced hyperthermia and hypermetabolism and abates multiorgan toxicity in rats.","authors":"Joseph F Cotten, John J Marota, Elie Adam","doi":"10.1016/j.jpet.2026.105006","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105006","url":null,"abstract":"<p><p>Methamphetamine (meth) is a central nervous system stimulant associated with many fatalities. Meth can cause agitation and psychosis, hyperthermia, and multiple organ damage. Medical treatment of meth toxicity is challenged because of meth's prolonged clinical duration of action and the lack of targeted therapy. CS-1103 is an acyclic cucurbit[n]uril-type sequestrant that binds meth with high affinity, and sequestration is a pharmacologic method of reversing a target drug effect through binding, inactivation, and elimination. We hypothesized that high-dose meth would cause multiple toxicities and that CS-1103 would reduce meth-induced toxicities. We administered (+)-methamphetamine [(+)-meth; 10 mg/kg, i.v.] followed by saline or CS-1103 (400 mg/kg, i.v.) after 15 minutes to conscious, restrained rats. (+)-Meth effects were quantified for 60 minutes by continuous physiologic monitoring and by premeth (-5 minutes) and postmeth (+60 minutes) blood analysis. (+)-Meth administration caused transient agitation and death or the need for euthanasia; however, with CS-1103, agitation resolved, and obtundation and death were prevented. Select (+)-meth toxicities with saline and CS-1103 posttreatments, respectively, were as follows (mean ± SEM; P < .02 for each): hyperthermia (peak Δtemperature: 4.0 ± 0.6 vs 2.0 ± 0.5 °C), acidemia (ΔpH: -0.2 ± 0.1 vs 0.0 ± 0.0), hypoxia (Δoxygen: -35 ± 7 vs -6 ± 4 mm Hg), nephrotoxicity (Δcreatinine: 0.5 ± 0.1 vs 0.0 ± 0.1 mg/dL), hyperkalemia (Δpotassium: 2.5 ± 0.6 vs -0.4 ± 0.1 mM), and rhabdomyolysis (Δcreatine kinase: 2353 ± 624 vs 1210 ± 492 U/L). CS-1103 is a viable therapy to abort (+)-meth toxicities and to promote survival in this novel rat model of (+)-meth toxicity. SIGNIFICANCE STATEMENT: Methamphetamine is a common drug of abuse associated with broad toxicity and fatality in humans. An animal model that replicates many of these toxicities was developed and this model was used to demonstrate that CS-1103, a methamphetamine-binding sequestrant, has efficacy in preventing toxicity and death.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105006"},"PeriodicalIF":4.3,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956012","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":"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}