Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Modulating hormonally upregulated neu-associated kinase (HUNK) activity in breast cancer: The development of HUNK inhibitors.","authors":"Alexander E Kritikos, Anslyn C Freije, Elizabeth S Yeh","doi":"10.1016/j.jpet.2025.103604","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103604","url":null,"abstract":"<p><p>Hormonally upregulated neu-associated kinase (HUNK) is a serine/threonine protein kinase in the sucrose non-fermenting 1/AMP-activated protein kinase family that promotes cell survival and plays an important role in breast cancer growth and metastasis. Robust methods to alter HUNK expression and activity are currently in use to advance our understanding of this kinase and its function. However, despite its role in the aggressive triple-negative cancer and human epidermal growth factor receptor 2 (HER2)+ breast cancer subtypes, targeted pharmacological inhibition of HUNK is still in its infancy. There are 2 goals of this review: first, to summarize the work done to modulate HUNK activity and advance scientific understanding of the kinase, and second, to describe the current work toward HUNK's pharmacological inhibition and the application of HUNK inhibitors. Clinically, HER2+ breast cancer often develops resistance to the HER2-targeted standard of care therapy, and experimental studies have shown that this can occur via a HUNK-dependent mechanism. In triple-negative breast cancer, where targeted treatments are lacking, HUNK has been shown to promote cancer progression to metastasis. Thus, further research on HUNK and its pharmacology may lead to novel therapeutics for patients with breast cancer and improved treatment outcomes. SIGNIFICANCE STATEMENT: Having recently been identified to promote aggressive breast cancers, hormonally upregulated neu-associated kinase is showing promise as a potential therapeutic target, yet drug discovery in this area is still at an early stage. This review aims to highlight recent efforts and methods to study the kinase and to identify novel inhibitors that may prove useful in continued basic science and translational research.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103604"},"PeriodicalIF":3.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181604","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":"Better together? Individual and synergistic effects of noneuphorigenic cannabinoids on visceral sensation.","authors":"Matthew D Coates, Wesley M Raup-Konsavage, Kent E Vrana","doi":"10.1016/j.jpet.2025.103593","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103593","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103593"},"PeriodicalIF":3.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127925","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":"Death receptor 5 agonists mitigate cardiac pathology in a chronic isoproterenol-induced cardiac remodeling and dysfunction.","authors":"Miles A Tanner, Katrina Dougherty, Laurel A Grisanti","doi":"10.1016/j.jpet.2025.103600","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103600","url":null,"abstract":"<p><p>Heart failure is a leading cause of death. Despite the economic and health burden, few recent therapeutic advances have been made and current therapies alleviate the symptoms, but minimally impact mortality, highlighting the need for identifying novel therapeutic targets. Death receptor 5 (DR5) has been studied extensively in cancer for its role in inducing apoptosis in transformed cells. However, DR5 is ubiquitously expressed, including in the heart, where its function is poorly understood. Clinical studies have associated DR5 and its ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), with heart failure due to multiple etiologies. Previous studies in cardiac cells and mouse models have demonstrated that DR5 promotes eccentric cardiac hypertrophy through ERK1/2-dependent mechanisms and the apoptosis of myofibroblasts. ERK1/2 signaling has been associated with prosurvival mechanisms in cardiomyocytes suggesting DR5 agonism may be a novel therapeutic approach to outcomes in heart failure. We hypothesized that activation of DR5 will be protective in heart failure. Using a chronic isoproterenol administration model, mice were administered a DR5 agonist and progression of cardiac dysfunction was monitored by echocardiography. Cardiac remodeling was assessed by histology and prohypertrophic and profibrotic marker expression. Specificity of these responses was confirmed with DR5 knockout and the involvement of ERK1/2 signaling was confirmed using pharmacological inhibitors. DR5 agonists decreased cardiac remodeling and improved contractility in response to isoproterenol, which was prevented by ERK1/2 inhibition. These findings demonstrate that activation of DR5 reduces the progression of cardiac remodeling and dysfunction and may be a novel therapeutic target for heart failure treatment. SIGNIFICANCE STATEMENT: Death receptor 5 (DR5) is expressed in cardiomyocytes where its function is poorly defined and clinically, DR5 has been associated with heart failure development and severity. Previous studies show in healthy cardiomyocytes, DR5 activates ERK1/2 signaling, causing eccentric hypertrophy, which are associated with cardioprotection during heart failure. This study investigates the therapeutic potential of targeting DR5 and demonstrates that, in a chronic isoproterenol-infusion model of cardiac dysfunction, DR5 activation reduces maladaptive cardiac remodeling and preserves function through ERK1/2-dependent mechanisms.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103600"},"PeriodicalIF":3.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142825","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":"Investigation of dose-exposure-response relationship for adeno-associated virus-mediated delivery of antibody genes.","authors":"Aneesh Rajwade, Shufang Liu, Mokshada Kumar, Avanobe Ghobrial, Sara Hahn, Dhaval K Shah","doi":"10.1016/j.jpet.2025.103601","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103601","url":null,"abstract":"<p><p>Adeno-associated virus (AAV)-based gene therapies have advanced significantly, yet the pharmacology of these therapies, particularly the relationship between dose and transgene expression, remains incompletely understood. Here, we investigated the dose-response dynamics of AAV8 vectors encoding an antibody (trastuzumab) gene in C57BL/6 mice to assess virus pharmacokinetics, transgene expression, liver toxicity, and immunogenicity across a broad dose range (1E8-1E13 vector genomes/mouse). Whole-body viral pharmacokinetics data revealed dose nonproportionality, with higher doses leading to less than proportional increases in AAV exposure across most tissues, except for the spleen, which exhibited a more than proportional increase. Plasma transgene concentrations demonstrated a sigmoidal dose-response relationship, with Emax of ∼ 8000 nM and EC50 of ∼8E9 vector genomes, indicating saturation at higher doses. Immune responses to AAV8 were dose-dependent, with IgM titers peaking on day 2 and IgG titers appearing by day 21, both escalating with increasing doses. Elevated aspartate aminotransferase and alanine aminotransferase levels at higher doses indicate a hepatotoxic effect. These findings suggest that the nonlinear dose-exposure relationship stems from saturable tissue distribution, nonlinear transgene production, or heightened immune activation at higher doses. Importantly, the nonlinearity in translational efficiency and an increased risk for immunogenicity and hepatotoxicity at higher dose levels underscore the critical need to optimize AAV dosing to balance efficacy and safety. These data provide valuable insights into the pharmacology of AAV gene therapies and offer a framework for determining optimal dosing strategies that maximize therapeutic benefit while minimizing toxicity and immunogenicity. SIGNIFICANCE STATEMENT: The research presented here demonstrates that there is an optimal dose for adeno-associated virus-based therapies and exceeding this dose might lead to more immunogenicity, more toxicity, and reduced transgene expression.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103601"},"PeriodicalIF":3.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159668","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":"More than just a prime: Cocaine gives monkeys the munchies.","authors":"Lydia Gordon-Fennell, Paul E M Phillips","doi":"10.1016/j.jpet.2025.103580","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103580","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103580"},"PeriodicalIF":3.1,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022859","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 gut response: Application of human enteroid monolayers to probe the mechanism of the goldenseal-mediated inhibition of metformin intestinal absorption.","authors":"Christopher M Arian, Eimear T O'Mahony, Preston K Manwill, Tyler N Graf, Nicholas H Oberlies, Nadja B Cech, John D Clarke, Jason G Smith, Mary F Paine, Edward J Kelly, Kenneth E Thummel","doi":"10.1016/j.jpet.2025.103597","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103597","url":null,"abstract":"<p><p>Continued growth in global sales of natural products has led to an increased risk of natural product-drug interactions that can compromise drug efficacy and safety. One such natural product, goldenseal, was shown to decrease systemic exposure to a subtherapeutic dose of oral metformin in healthy adults. A follow-up study involving therapeutic metformin doses and adults with type II diabetes demonstrated a metformin dose-dependent pharmacokinetic interaction with goldenseal. These results, along with no change in metformin half-life or renal clearance in both studies, suggested that the goldenseal-metformin interaction occurred in the gut via inhibition of an unidentified saturable intestinal transport process. We used enteroid monolayers derived from the duodenum of 4 healthy human adult donors to recapitulate the goldenseal-metformin interaction in vitro and identify the transporters involved in the observed in vivo interaction. Our results implicate thiamine transporter (ThTr) 2 as the predominant transporter involved in metformin uptake through the apical membrane, accounting for approximately 45% of total metformin intracellular accumulation. Additionally, goldenseal inhibited ThTr-2, but only under subsaturating metformin dosing concentrations. The goldenseal-metformin interaction mediated under therapeutic metformin dose conditions involves a low-affinity basolateral transporter, ThTr-1, which accounts for approximately 50% of inhibitable metformin apical to basolateral flux. However, a substantial fraction of metformin flux appears to involve paracellular transport. These results further elucidate the mechanism underlying the goldenseal-metformin interaction and suggest that enteroid monolayers are a promising model to study intestinal natural product-drug interactions. SIGNIFICANCE STATEMENT: The research presented in this article demonstrates the utility of enteroid monolayers to predict and ascertain the mechanisms of drug-drug and natural product-drug interactions. Using this model, the study was able to identify the transporters (thiamine transporter-1 and thiamine transporter-2) involved in metformin absorption that are inhibited by the natural product, goldenseal, which were previously unidentified.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103597"},"PeriodicalIF":3.1,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127924","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":"Enhanced negative modulation of urotensin II on cardiac function and [Ca²⁺]_i regulation in a diabetic rat model: Insights into molecular and cellular mechanisms.","authors":"Xiaowei Zhang, Zhe Chen, Jing Cao, Peng Zhou, Zhi Zhang, Xiaoqiang Sun, Yixi Liu, Tiankai Li, Heng-Jie Cheng, Che Ping Cheng","doi":"10.1016/j.jpet.2025.103594","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103594","url":null,"abstract":"<p><p>The direct cardiac effects of urotensin II (UII) in normal and diabetic subjects remain controversial. The alteration and functional significance of cardiac UII/UII receptor (UT) in diabetes are still unclear. We assessed the hypothesis that in diabetes, the cardiomyocyte UII/UT system is increased. This augmentation is proposed to exacerbate the dysfunctional [Ca²⁺]_i regulation, enhance inhibitions of left ventricle (LV) and myocyte contraction and relaxation, leading to worsening cardiac dysfunction. We compared LV myocyte UII and UT expression, LV and myocyte contractile, [Ca²⁺]_i transient ([Ca²⁺]_iT) and calcium current (I_Ca,L) responses to UII stimulation in male Sprague-Dawley rats (12/group) with streptozotocin-induced diabetes mellitus and controls. We found that UII and UT protein levels were significantly greater in diabetic myocytes than in control myocytes. Compared with control rats, UII (400 pmol/kg, i.p.) administration produced greater decreases in LV contractility of E_ES (diabetes mellitus: 32% vs C: 13%) and M_SW with significantly increased LV time constant relaxation in diabetes. In response to UII (10^-5 M) superfusion, diabetic myocytes had much greater decreases in the velocity of shortening and relengthening accompanied by significantly larger decreases in the peak systolic [Ca²⁺]_iT and I_Ca,L (29% vs 15%). These responses were abolished by pretreatment of diabetic myocytes with urantide, pertussis toxin, or dibutyryl-cAMP, respectively. We conclude that UII has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. In diabetes, cardiac UII/UT is upregulated, enhancing UII-caused negative modulation on cardiac function and [Ca²⁺]_i regulation. This may contribute to the progression of cardiac dysfunction in diabetes and diabetic cardiomyopathy. SIGNIFICANCE STATEMENT: Urotensin II (UII) has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. Compared with normal rats, cardiac UII/UII receptors (UT) were upregulated in diabetic rats, resulting in significantly greater decreases in [Ca²⁺]_iT and I_Ca,L and increased inhibitions of left ventricle and myocyte contraction and relaxation. These effects are coupled with UT and mediated by G_i proteins. These data provide new insights and evidence that upregulation of cardiomyocyte UII/UT may promote the progressive cardiac dysfunction in diabetes and diabetic cardiomyopathy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103594"},"PeriodicalIF":3.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127975","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":"Predicting kinase target inhibition level for efficacy in rheumatoid arthritis: A translational approach based on collagen-induced arthritis rodent studies.","authors":"Rui Li, Roger Gifford, Peter Symanowicz, Cara M M Williams, Martin Hegen","doi":"10.1016/j.jpet.2025.103589","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103589","url":null,"abstract":"<p><p>Setting a clinically efficacious dose in the preclinical stage is an important but challenging task in developing new therapies, including small-molecule kinase inhibitors for rheumatoid arthritis (RA). Besides pharmacokinetics and potency, another key component in determining the efficacious dose of a small molecule targeted therapy is the target inhibition level required for efficacy, which few established approaches can predict based on preclinical data. Using collagen-induced arthritis rodent data, we aimed to establish a translational approach in predicting the lowest efficacious target inhibition level in patients with RA, assuming that similar levels of target inhibition are required for efficacy in both patients and animal models. Target inhibition levels of tofacitinib, zimlovisertib, and 3 literature kinase inhibitors at efficacious and inefficacious doses were compared between patients and rodents using a new approach based on average inhibition level (I_AVG). For comparison purposes, classic approaches based on average, maximal, and minimal exposures and durations with exposure above IC₃₀, IC₅₀, IC₇₀, and IC₉₀ are also included in our analysis. We found that the lowest I_AVG required for efficacy was generally consistent between humans and rodents. Overall, the I_AVG-based approach led to a better alignment between rodent and human efficacy and is more universally applicable than other approaches. For future kinase inhibitors in discovery or development, I_AVG-based rodent-to-human translation can be used to identify the target inhibition level required for efficacy and corresponding efficacious dose in patients with RA. SIGNIFICANCE STATEMENT: Identifying the target inhibition level required for clinical efficacy in the preclinical stage is important in developing new therapies. However, there are few established approaches aiming to predict this level based on preclinical data. Using data from kinase inhibitors for rheumatoid arthritis, this study proposed a rodent-to-human translation approach. The established translation helps to predict the efficacious inhibition level and corresponding efficacious dose for future kinase inhibitors for rheumatoid arthritis. The approach may also be applicable to other small-molecule targeted therapies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103589"},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094129","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":"Next-generation of antithrombotic therapies: Beyond conventional drugs.","authors":"Wei Li, Hong Yue","doi":"10.1016/j.jpet.2025.103574","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103574","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 5","pages":"103574"},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024348","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":"Bioactive phytoconstituent millettone as a potential inhibitor of catechol O-methyltransferase: Implications for neuroprotective therapy in Parkinson's disease.","authors":"Mohammad Khalid, Mohammed H Alqarni, Ahmed I Foudah","doi":"10.1016/j.jpet.2025.103592","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103592","url":null,"abstract":"<p><p>Catechol O-methyltransferase (COMT) is a cation-dependent enzyme essential for the metabolism of catechols, including dopamine, norepinephrine, caffeine, and estrogens. COMT is highly expressed in tissues such as the brain, liver, and erythrocytes, and its elevated levels in dopaminergic neurons are implicated in Parkinson's disease. Considering it as a promising target for drug development against Parkinson's disease, this study employed in silico screening of plant-derived compounds from the IMPPAT 2.0 data base to identify potential COMT inhibitors. Compounds were initially filtered out based on their pharmacokinetic properties and binding affinities. Further screening included ligand-receptor interaction calculations, pan-assay interface compounds filtering, ADMET analysis, and biological activity prediction, followed by stability assessments to select the most promising phytochemicals. Millettone emerged as a top candidate, demonstrating high affinity and specific binding interactions with COMT. Comprehensive evaluations, including all-atom molecular dynamics simulations and essential dynamics analysis, further supported millettone's stability and effectiveness as a potential COMT inhibitor. These findings suggest that millettone is a strong candidate for further experimental studies, with potential application as an anti-Parkinson's therapeutic targeting COMT. SIGNIFICANCE STATEMENT: This study identified a plant-based natural compound, millettone, as a potential catechol O-methyltransferase inhibitor through in silico screening and molecular dynamics simulations. Its strong binding and stability suggest therapeutic potential for Parkinson's disease, warranting further experimental validation.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103592"},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086389","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}