Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Using a rich-lean transition procedure to evaluate putative antianxiety medications.","authors":"Forrest Toegel, Cory Toegel, James K Rowlett, Josh A Woods, Carlos Austin Zamarripa, William S Doyle, Kevin B Freeman, Sally L Huskinson","doi":"10.1016/j.jpet.2025.103657","DOIUrl":"10.1016/j.jpet.2025.103657","url":null,"abstract":"<p><p>Potential antianxiety medications are commonly assessed by measuring their ability to increase behavior that is suppressed by aversive events like shock. These procedures have good predictive validity, but they also have practical limitations, particularly in nonhuman primates. The goal of the current experiment was to determine the feasibility of a different procedure to evaluate potential antianxiety medications without using shock. In prior research, arranging transitions from favorable to unfavorable schedules of positive reinforcement (rich-lean transitions) reliably disrupts operant behavior, and these disruptions can be ameliorated via benzodiazepine administration. We evaluated the suitability of a rich-lean transition procedure for preclinical evaluation of putative antianxiety medications. Adult rhesus monkeys' lever presses were reinforced using a 2-component multiple schedule with equivalent fixed-ratio requirements. Components were differentially signaled by colored stimulus lights. Completing a lean component produced 1 food pellet, and completing a rich component produced 4 food pellets. Sessions consisted of 41 components arranged irregularly to produce 10 iterations of 4 transition types: lean-lean, lean-rich, rich-lean, and rich-rich. As in the prior research, extended pausing was observed in rich-lean transitions. Acute administration of benzodiazepines (midazolam, alprazolam) and an imidazotriazine (TPA-023B) selectively reduced pausing in rich-lean transitions, a behavioral effect consistent with clinically effective antianxiety drugs in other preclinical anxiolysis procedures. Morphine and (+)amphetamine selectively increased rich-lean pausing, an effect consistent with an anxiogenic response in other anxiolysis procedures. Altogether, our results indicate that the rich-lean procedure has utility in the assessment putative antianxiety medications. SIGNIFICANCE STATEMENT: Transitions from favorable to unfavorable (ie, rich-lean) schedules of reinforcement reliably disrupts operant behavior, and these disruptions can be ameliorated via benzodiazepine administration. Our results indicate that the rich-lean transition procedure has utility in the assessment of putative antianxiety medications.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103657"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799455","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 evaluation and first-in-human phase 1 trial of AZD0186, a novel, oral small molecule glucagon-like peptide-1 receptor agonist.","authors":"Weier Qi, Simina M Boca, Alessandro Boianelli, Monica Fredberg, Sara Lundqvist, Graeme Davies, Joss Field, Cheryl A Brighton, Arjan Snijder, Pernilla Grundevik, Daniel Eckernäs, Annika Maria Träff, Magnus Polla, Daniel Pettersen, Sami Omar, Lars Hansen, David Janzén, Johanna Melin, Natalie van Zuydam, Jennifer Logue, Kristina Wallenius","doi":"10.1016/j.jpet.2025.103683","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103683","url":null,"abstract":"<p><p>Small molecule glucagon-like peptide-1 receptor agonist AZD0186 was developed to provide accessible and convenient treatment for a broad patient population with type 2 diabetes mellitus and/or obesity. We describe the preclinical and first-in-human single ascending dose data (NCT05694741) for this novel small molecule glucagon-like peptide-1 receptor agonist. AZD0186 was profiled in cell lines overexpressing human or cynomolgus glucagon-like peptide-1 receptor (GLP-1R) and in human-derived EndoC-βH5 cells. Glucose-stimulated insulin secretion (GSIS) was assessed following an intravenous glucose tolerance test in obese nonhuman primates and humanized GLP-1R (hGLP-1R) mice. Effects of oral repeated dosing on body weight and food intake were assessed in hGLP-1R mice. AZD0186 was evaluated at 4 oral single ascending dose levels (5, 15, 50, and 150 mg) in healthy participants. Results showed that AZD0186 is potent on the hGLP-1R and showed a concentration-dependent potentiation of GSIS in EndoC-βH5 cells (EC₅₀ = 0.6 nM). Insulin secretion was enhanced in obese nonhuman primates at all 3 dose levels evaluated following an intravenous glucose tolerance test. In hGLP-1R mice, body weight was reduced 9.9% ± 2.3% (mean ± SD) following 5 days of oral dosing (25 mg/kg per day twice a day). In the healthy participants, AZD0186 was well tolerated, with nausea reported at 150 mg, in keeping with GLP-1RA class effects. Across the dose range, AZD0186 area under the concentration-time curve increased in an approximately dose-proportional manner. Median terminal half-life ranged from 1.95 to 7.58 hours. Findings demonstrate that AZD0186 is a potent agonist of the GLP-1R, and the first-in-human study indicates a favorable safety and tolerability profile. SIGNIFICANCE STATEMENT: AZD0186 is a novel small molecule glucagon-like peptide-1 receptor agonist that allows for oral dosing. We describe the preclinical and first-in-human single ascending dose data for AZD0186. The findings demonstrate that AZD0186 is a potent agonist of the human glucagon-like peptide-1 receptor, improves glucose control and reduces body weight in a human glucagon-like peptide-1 receptor mouse model, and has a favorable safety and tolerability profile in healthy human participants.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103683"},"PeriodicalIF":3.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182128","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":"Koningic acid reduces tumor activity in neuroendocrine prostate cancer by inhibiting glycolysis.","authors":"Haixia Xu, Liang Xiao, Lin Lin, Meixiang Li, Yunting Yang, Jiajian Lin, Lili Jiang, Yi Yang","doi":"10.1016/j.jpet.2025.103684","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103684","url":null,"abstract":"<p><p>Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer with poor prognosis and limited therapeutic options. Targeting cancer metabolism is a promising strategy for treating NEPC. This study investigated the antitumor activity and underlying mechanisms of koningic acid (KA), a selective glyceraldehyde-3-phosphate dehydrogenase inhibitor, in NEPC. NEPC cell models (PC3, LNCaP-NE, and NCI-H660) were treated with KA to assess its effects on cell viability, colony formation, glycolysis, mitochondrial function, and apoptosis. Xenograft models were used to evaluate in vivo tumor growth. Key markers and pathways were analyzed using quantitative polymerase chain reaction, western blotting, and immunohistochemistry. In this study, KA significantly inhibited cell proliferation and colony formation, with IC₅₀ values of 5.73 μM in PC3, 7.57 μM in LNCaP-NE, and 6.32 μM in NCI-H660 cells. Glycolysis was markedly suppressed, as indicated by reduced extracellular acidification rate, lactate production, and glucose uptake. KA also induced mitochondrial dysfunction, evidenced by decreased mitochondrial membrane potential, increased reactive oxygen species, and reduced ATP levels. Furthermore, KA decreased phospho (p)-Akt and p-glycogen synthase kinase-3β expression, leading to apoptosis activation. In xenograft models, KA treatment reduced tumor size, weight, and expression of Ki67, p-Akt, and of lactate dehydrogenase A, while increasing levels of apoptosis markers. In conclusion, KA exerts significant antitumor effects in NEPC by inhibiting glycolysis and inducing mitochondrial apoptosis. These findings highlight its potential as a therapeutic agent for NEPC. SIGNIFICANCE STATEMENT: Koningic acid (KA) inhibits glycolysis and suppresses proliferation in neuroendocrine prostate cancer cells by targeting glyceraldehyde-3-phosphate dehydrogenase. KA induces mitochondrial dysfunction, increases reactive oxygen species production, and activates apoptosis through downregulation of phospho-Akt and phospho-glycogen synthase kinase-3β signaling. In vivo studies demonstrate that KA reduces tumor growth and proliferation while promoting apoptosis, highlighting its potential as a therapeutic agent for neuroendocrine prostate cancer.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103684"},"PeriodicalIF":3.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113214","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":"Antithrombotic potential of lornoxicam and possible mechanistic pathways.","authors":"Waseem Khalid, Arif-Ullah Khan, Fawad Ali","doi":"10.1016/j.jpet.2025.103681","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103681","url":null,"abstract":"<p><p>Lornoxicam is traditionally used as an anti-inflammatory and analgesic drug. Recent studies suggest that nonsteroidal anti-inflammatory drugs can influence platelet and coagulation pathways. However, the antithrombotic and cardiopulmonary protective potential of lornoxicam remains unexplored. This study addressed this gap by evaluating lornoxicam's effects on thrombosis, myocardial infarction (MI), and pulmonary embolism (PE) using in silico, in vitro, and in vivo models. Docking analysis with 16 target proteins revealed novel interactions with lornoxicam, suggesting potential antithrombotic and cardiopulmonary benefits of beyond its cyclooxygenase (COX)-mediated actions. AutoDock (version 4.2.6) was used with default parameters and empirical force field (Exhaustiveness: 8). High binding affinities (E-value > -9.0 kcal/mol) were observed for COX-1, glycoprotein IIb/IIIa, antithrombin III, COX-2, and nuclear factor kappa light chain enhancer of activated B cells (NFκB), and molecular dynamics simulations confirmed stable ligand-protein complexes. In arachidonic acid-induced platelet aggregation, lornoxicam showed concentration-dependent inhibition (77.8% at 10 μM, IC₅₀ = 0.61 μM) compared with 94.81% inhibition by aspirin (10 μM). In ADP-induced aggregation assays, inhibition was less pronounced (23.21% at 10 μM, IC₅₀ = 20.6 μM). Lornoxicam significantly prolonged prothrombin time, activated partial thromboplastin time, thrombin time, and clot lysis at 1, 3, and 10 μM concentrations (P < .001 vs saline). The cardioprotective potential of lornoxicam was confirmed via an isoprenaline (ISO)-induced MI model in rats, while its protective effect on PE was assessed using a self-embolus-induced PE rat model. Lornoxicam protected the heart and lung tissues of rats against histological damage and infarction by decreasing oxidative stress and inflammatory responses. This effect was due to reduced expression of NFκB, tumor necrosis factor alpha, COX-2, NOD-like receptor family, pyrin domain containing 3, and platelet-derived growth factor beta (in the lungs), as confirmed via immunohistochemical analysis, ELISA, and reverse-transcription polymerase chain reaction. This study opens a new avenue for the repurposing and prophylactic use of lornoxicam in patients more prone to thrombotic disorders. SIGNIFICANCE STATEMENT: The in silico, in vitro, and in vivo experiments in this study revealed the excellent antithrombotic potential and protective effect of lornoxicam on myocardial infarction and pulmonary embolism, even at lower doses. This study proposes that lornoxicam treatment, just like aspirin, at lower doses could be an appropriate prophylactic option in patients who are more prone to myocardial infarction and pulmonary embolism.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103681"},"PeriodicalIF":3.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086320","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 loncastuximab-based cucurmosin immunotoxin with high potency in vitro against lymphoma.","authors":"Jiayi Wang, Jingyi Xia, Mengping Lin, Yunrong Fu, Xiuhua You, Chengyan Wang, Cailing Yan, Jieming Xie","doi":"10.1016/j.jpet.2025.103680","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103680","url":null,"abstract":"<p><p>Loncastuximab is a humanized monoclonal antibody targeting CD19 for the treatment of diffuse large B-cell lymphoma. Chemoimmunotherapies still leave many patients unresponsive to treatment or retreatment following relapse, with complete remission rates being low. The main purpose of this study was to broaden the therapeutic window of loncastuximab by conjugating it with recombinant cucurmosin to form an immunotoxin called L-CUS_245C. L-CUS_245C was chemically conjugated, and the purification of L-CUS_245C was evaluated by SDS-PAGE. Thiazolyl blue tetrazolium bromide assay showed remarkable cytotoxicity of L-CUS_245C, with IC₅₀ values in the picomolar range, against CD19-positive cancer cells, while it exhibited no significant inhibitory effect on the proliferation of CD19-negative cells (P < .01). Mechanistic studies demonstrated that L-CUS_245C induces apoptosis in positive cancer cells via mitochondrial membrane potential disruption. Synergistic effects were observed when L-CUS_245C was combined with I-CUS_245C, enhancing proliferation inhibition in CD19-positive cells. These results indicate the therapeutic potential of L-CUS_245C for CD19-targeted therapy, offering a promising strategy to improve treatment efficacy and patient prognosis. SIGNIFICANCE STATEMENT: We propose applying CUS_245C, conjugating with loncastuximab, to prepare L-CUS_245C. At the same time, we hope that L-CUS_245C can play an objective therapeutic role in diffuse large B-cell lymphoma, achieving the effect of reducing the recurrence rate of the disease and thereby improving prognosis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103680"},"PeriodicalIF":3.8,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102991","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":"Store-operated calcium entry-based targets for novel cancer therapeutic development.","authors":"Moana E Hala'ufia, David L Roman","doi":"10.1016/j.jpet.2025.103682","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103682","url":null,"abstract":"<p><p>Store-operated calcium entry (SOCE) is the major mechanism for cellular calcium homeostasis that is ubiquitous across cell types and is responsible for replenishing Ca²⁺ in the endoplasmic reticulum. The major calcium channel that facilitates this role is Orai1. Orai1 is regulated by proteins that interact with either its N- or C-terminus. Stromal interaction molecule 1 (STIM1) is an activator of Orai1 that binds to Orai1's C-terminus, causing the channel to open and allow for Ca²⁺ influx. Together, Orai1 and STIM1 constitute a calcium release-activated calcium channel that is critical for SOCE. Alternatively, adenylyl cyclase type 8 (AC8) binds to Orai1's N-terminus, causing the Orai1 channel to close after phosphorylation by protein kinase A. Other proteins also interact with Orai1 to elicit modulatory effects and influence the gating properties of this channel. As SOCE is critical for cellular Ca²⁺ balance and calcium-sensitive cellular functions, impairment of Orai1 function by restricting its ability to form normal protein-protein interactions (PPIs) can be deleterious and lead to pathologies. It has been discovered that overexpression of Orai1 and AC8 leads to proliferation of triple negative breast cancer cells through mechanisms dependent on Ca²⁺ signaling. Thus, PPIs involving Orai1 can be approached as therapeutic targets in diseases that arise from aberrant Ca²⁺ signaling. Orai1 PPIs can serve as targets for diseases that currently lack targeted therapies, such as triple negative breast cancer. This review examines Orai1 PPIs with STIM1 and AC8, discusses the relevance of these PPIs in cancer, and reviews the landscape of Orai1 inhibitors. SIGNIFICANCE STATEMENT: The study of proteins that are involved in cancer progression is important for developing targeted cancer therapies. Store-operated calcium entry-based proteins have been proposed as therapeutic cancer targets because inhibition of these proteins disrupts Ca²⁺ influx, thereby decreasing cell proliferation in certain cancers. Additionally, store-operated calcium entry-based proteins are implicated in many other disease states such as Stormorken syndrome, tubular aggregate myopathy, and immunodeficiency, highlighting the therapeutic relevance of these proteins.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103682"},"PeriodicalIF":3.8,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206691","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":"Pharmacodynamic effects of highly selective aldosterone synthase inhibitor vicadrostat in cynomolgus monkeys: Contrasting effects of once versus twice daily dosing.","authors":"Steven M Weldon, Derek A Cogan, Matthew A Cerny, Kosea S Frederick, Kristina K Gueneva-Boucheva, Holly E Clifford, Stanley Kugler, Daniel Marshall, Jeremy G Richman, Nicholas F Brown","doi":"10.1016/j.jpet.2025.103649","DOIUrl":"10.1016/j.jpet.2025.103649","url":null,"abstract":"<p><p>Novel inhibitors of aldosterone synthase (CYP11B2) hold promise as treatments for cardiorenal conditions including chronic kidney disease, heart failure, and hypertension. The inadequacy of rodent models and the failure of recombinant systems to reliably recapitulate the properties of the native human enzyme have hindered research in this area. Thus, we developed in vitro and in vivo models based on nonhuman primates. This approach led to the discovery of vicadrostat (BI 690517), an inhibitor with an in vitro IC₅₀ of 19 nM against human aldosterone synthase, 250-fold selective against the highly homologous cortisol synthase (CYP11B1), and with drug-like chemical and pharmacokinetic properties. In an acute in vivo model in cynomolgus monkeys, vicadrostat displayed an IC₅₀ against aldosterone production of 25 nM, with >2000-fold selectivity against synthesis of cortisol. The pharmacodynamic effects of repeated administration were determined in cynomolgus using doses estimated to mimic a likely therapeutic intervention in humans. Vicadrostat significantly lowered plasma aldosterone, with no effect on cortisol. Effects on precursor steroids were observed, with little effect on electrolytes. Importantly, a clear difference between dosing regimens emerged, indicating that once daily dosing (partial-day coverage) resulted in a sustained effect, whereas dosing twice daily (full-day coverage) induced a counteractive increase in aldosterone synthesis that resulted in a loss of effect on overall daily aldosterone levels. These studies were key to the design of early clinical trials with vicadrostat and illustrate the value of establishing a physiologically relevant pharmacodynamic model in reducing the scope of necessary human investigation. SIGNIFICANCE STATEMENT: The standard of care for chronic kidney disease is inadequate to prevent gradual loss of renal function in many patients. Here, the study describes key preclinical studies with the novel aldosterone synthase inhibitor vicadrostat that were instrumental in the design of early clinical studies and provide insight into predicted and unpredicted pharmacodynamic effects. These observations will inform further development of vicadrostat and related drugs for the treatment of kidney disease and other metabolic disease-related morbidities.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103649"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742320","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":"Transforming growth factor β receptor 1 and mitogen-activated protein 4 kinase 4 dual inhibitor, TK-850, reduces renal fibrosis in unilateral ureteral-obstructed mice.","authors":"Henry A Palfrey, Samaneh Goorani, Abhishek Mishra, Md Abdul Hye Khan, Baku Acharya, Brendan Frett, John D Imig","doi":"10.1016/j.jpet.2025.103644","DOIUrl":"10.1016/j.jpet.2025.103644","url":null,"abstract":"<p><p>Renal fibrosis is a common progression from chronic kidney disease to end-stage renal disease, and its causes are multifactorial. Effective treatment for renal fibrosis requires strategies that address various molecular mechanisms simultaneously. In this study, we investigated the preventive and interventional anti-fibrotic effects of TK-850, a novel dual inhibitor of transforming growth factor-β receptor (TGF-βR)1 and mitogen-activated protein 4 kinase (MAP4K)4. The antifibrotic potential of TK-850 was evaluated using 8-10-week-old male and female C57Bl/6 mice that were subjected to unilateral ureteral obstruction (UUO) surgery to induce renal fibrosis. Rodents were subjected to UUO and were administered TK-850 (20 mg/kg per day intraperitoneally) 7 days before or 3 days following UUO. The contralateral kidneys served as the control. Kidneys and blood were collected 10 days post-UUO for histopathologic and biochemical analyses. Kidney hydroxyproline levels, a marker for collagen content and fibrosis, increased by UUO in all groups; however, TK-850 preventive and interventional administration effectively reduced these levels, indicating its potential to mitigate renal fibrosis. Gene array data demonstrated upregulation of several profibrotic genes, notably Timp1, which promote extracellular matrix accumulation. Preventive or interventional TK-850 administration reduced Timp1 expression in UUO mice. Renal interstitial collagen increased in UUO mice, and it was reduced by preventive and interventional TK-850. Notably, neither preventive nor interventional administration of TK-850 affected the terminal body weight or caused any mortality. Overall, these data provide proof of concept that the novel dual-acting TGF-βR1/MAP4K4 inhibitor, TK-850, is a renal antifibrotic agent. SIGNIFICANCE STATEMENT: TK-850, a novel dual transforming growth factor-β receptor 1/ mitogen-activated protein 4 kinase 4 inhibitor, reduces renal fibrosis in a unilateral ureteral obstruction mouse model by lowering hydroxyproline and tissue inhibitor of metalloproteinase 1 levels without impacting body weight or mortality, supporting its therapeutic potential.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103644"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707847","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":"Behavioral mechanisms of oxycodone's effects in female and male rats: Rate-dependent effects on impulsive choice.","authors":"Ryan C Blejewski, Justin T Van Heukelom, Pedro Vidal, Christine E Hughes, Raymond C Pitts","doi":"10.1016/j.jpet.2025.103648","DOIUrl":"10.1016/j.jpet.2025.103648","url":null,"abstract":"<p><p>Impulsive choice may be empirically defined as a preference for a smaller-sooner reinforcer over a larger-later reinforcer with choices involving different reinforcement magnitudes and delays. Opioid agonists increase impulsive choice; however, opioids other than morphine have not been examined extensively. The aim of the current study was to examine the acute effects of the prescription opioid oxycodone on impulsive choice by characterizing its effects on the relative impact of reinforcement magnitude and delay in female (n = 6) and male (n = 8) rats. It was hypothesized that oxycodone would decrease sensitivity to both magnitude and delay. Rats responded under a concurrent-chains procedure in which combinations of magnitude and delay were manipulated within sessions. The combination of magnitude and delay for one option was constant across the experiment, whereas the combination for the other option was varied within the session. For both sexes, choice was controlled by the combined effects of magnitude and delay; on average, sensitivity to magnitude was higher than to delay. Oxycodone decreased sensitivity to magnitude and delay in both sexes, with a greater reduction in sensitivity to magnitude relative to delay, suggesting oxycodone may increase impulsive choice by decreasing sensitivity to magnitude more than sensitivity to delay. These effects, however, varied across rats. Additional analyses indicated that oxycodone's effects on sensitivity to both magnitude and delay were an outcome of rate-dependent effects on responding on the individual levers. These data illustrate the enduring contributions of Peter Dews to the understanding of behavioral effects of drugs. SIGNIFICANCE STATEMENT: Opioid use disorder is associated with an increased likelihood of impulsive and risky behaviors. This study investigated the behavioral mechanisms of the effects of the prescription opioid, oxycodone, in a preclinical rodent model of impulsive choice. Effects of oxycodone under this procedure were rate-dependent, a finding that may have important implications for the treatment of impulsive disorders, including opioid use, and one that illustrates the enduring contributions of Peter Dews to behavioral pharmacology.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103648"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765037","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":"Crosstalk between inflammation, voiding dysfunction, and psychiatric symptoms: novel hypothesis and therapeutics for urinary incontinence.","authors":"Yutaka Nakagawa, Shizuo Yamada","doi":"10.1016/j.jpet.2025.103640","DOIUrl":"10.1016/j.jpet.2025.103640","url":null,"abstract":"<p><p>The lower urinary tract, composed of the urinary bladder and urethra, is responsible for urine storage and excretion, which are regulated by the peripheral nervous system, spinal cord, and brain. Whereas micturition is a voluntary behavior depending on executive control and social cognition, it is unclear how brain neural network disruption causes urinary incontinence. Data suggest that when bladder volume increases, healthy individuals experience dorsolateral prefrontal cortex activation with executive control to preserve continence, and this brain region regulates the cingulate cortex and emotional system to modulate urinary urgency and emotions. In patients with urge urinary incontinence, proinflammatory diets can induce inflammation in the lower urinary tract with voiding dysfunction and resultant increases in blood proinflammatory cytokine levels. The proinflammatory cytokines likely cause blood-cerebrospinal fluid barrier disruption, presumably accompanied by an elevation of proinflammatory cytokine concentrations in the cerebrospinal fluid, resulting in glial cell aberration-related hyperactivation of the cingulate cortex and emotional system as well as deactivation of the dorsolateral prefrontal cortex. The impaired dorsolateral prefrontal cortex regulation of these brain regions can contribute to executive control impairment with incontinence, uncontrollable urinary urgency, involuntary urination-associated anxiety, depressed mood caused by anticipatory anxiety, and catastrophizing about bladder fullness with urinary urgency due to cognitive distortion or catastrophic thinking, leading to a vicious spiral along with dysfunctional voiding. These symptoms suggest that while diet-related inflammation presumably initiates lower urinary tract dysfunction, neuroinflammation-induced brain neural network disturbance may promote the progression of urge urinary incontinence. Our model could predict novel medications for this condition. SIGNIFICANCE STATEMENT: Our hypothesis suggests that promoting anti-inflammation and/or resolution of inflammation in the brain as well as lower urinary tract may have therapeutic potential in the management of urinary incontinence with uncontrollable urinary urgency. Nonsteroidal anti-inflammatory drugs prevent cyclooxygenase activity and prostaglandin production, and prostaglandin E₂ is responsible for resolution of inflammation as well as inflammatory responses; therefore, we propose novel medications for this condition that can prompt anti-inflammatory and proresolution properties without inhibition of prostaglandin production.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103640"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618684","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}