Journal of Pharmacology and Experimental Therapeutics最新文献

筛选
英文 中文
Mini-review: Human N-acetyltransferase genetic polymorphisms in susceptibility to aromatic amine and alkylaniline genotoxicity. 人类n -乙酰基转移酶基因多态性对芳香胺和烷基苯胺遗传毒性的易感性。
IF 3.8 3区 医学
Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-07-28 DOI: 10.1016/j.jpet.2025.103670
Mariam R Habil, David W Hein
{"title":"Mini-review: Human N-acetyltransferase genetic polymorphisms in susceptibility to aromatic amine and alkylaniline genotoxicity.","authors":"Mariam R Habil, David W Hein","doi":"10.1016/j.jpet.2025.103670","DOIUrl":"10.1016/j.jpet.2025.103670","url":null,"abstract":"<p><p>Arylamine N-acetyltransferases are xenobiotic metabolizing enzymes which play a significant role in the metabolism and detoxification of many drugs and carcinogens. Two N-acetyltransferases have been characterized in humans with similar structure but different substrate affinity. N-acetyltransferase 1 (NAT1) is found in many tissues, whereas N-acetyltransferase 2 (NAT2) is found mostly in the liver and gastrointestinal tract. Both NATs are polymorphic and catalyze both N-acetylation (usually deactivation) and O-acetylation (usually activation) of aromatic amine carcinogens. Previous studies, done in bacteria or animals, have reported that exposure to aromatic amines and alkylanilines leads to DNA damage and mutations. Mammalian models transfected with recombinant human NAT alleles have been constructed to investigate the role of NAT polymorphisms in metabolism or genotoxicity of these carcinogens. This mini-review describes biological plausibility for aromatic amine and alkylaniline carcinogenicity that further supports NAT polymorphisms as important factors for aromatic amine and alkylaniline risk assessments. SIGNIFICANCE STATEMENT: This mini-review describes biological plausibility for aromatic amine and alkylaniline carcinogenicity. N-acetyltransferase polymorphisms are important factors for aromatic amine and alkylaniline risk assessments.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103670"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958344","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}
引用次数: 0
Corrigendum to "Recent Developments in On-Demand Voiding Therapies" [The Journal of Pharmacology and Experimental Therapeutics 390 (2024) 302-317]. “按需排尿疗法的最新发展”的勘误表[药理学和实验治疗杂志390(2024)302-317]。
IF 3.8 3区 医学
Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-08-18 DOI: 10.1016/j.jpet.2025.103675
Karl B Thor, Lesley Marson, Mary A Katofiasc, Daniel J Ricca, Edward C Burgard
{"title":"Corrigendum to \"Recent Developments in On-Demand Voiding Therapies\" [The Journal of Pharmacology and Experimental Therapeutics 390 (2024) 302-317].","authors":"Karl B Thor, Lesley Marson, Mary A Katofiasc, Daniel J Ricca, Edward C Burgard","doi":"10.1016/j.jpet.2025.103675","DOIUrl":"10.1016/j.jpet.2025.103675","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103675"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958375","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}
引用次数: 0
Exploring the therapeutic potential of aloenin-loaded nanogel for imiquimod-induced psoriasis-like skin conditions: In vitro and in vivo assessment. 探索芦荟素负载纳米凝胶治疗吡喹莫德诱导的牛皮癣样皮肤病的潜力:体外和体内评估。
IF 3.8 3区 医学
Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-06-30 DOI: 10.1016/j.jpet.2025.103647
Sadaf Jamal Gilani, Ehssan Moglad, Muhammad Afzal, Misbahuddin Rafeeq, Alaa Hamed Habib, Sami I Alzarea, Nadeem Sayyed, Imran Kazmi
{"title":"Exploring the therapeutic potential of aloenin-loaded nanogel for imiquimod-induced psoriasis-like skin conditions: In vitro and in vivo assessment.","authors":"Sadaf Jamal Gilani, Ehssan Moglad, Muhammad Afzal, Misbahuddin Rafeeq, Alaa Hamed Habib, Sami I Alzarea, Nadeem Sayyed, Imran Kazmi","doi":"10.1016/j.jpet.2025.103647","DOIUrl":"10.1016/j.jpet.2025.103647","url":null,"abstract":"<p><p>The purpose of this work was to evaluate the utilization of an aloenin-containing nanogel formulation as a carrier for the treatment of skin inflammation comparable to psoriasis. Imiquimod (IMQ) was used on mice to generate inflammation mimicking psoriasis. The probe sonicator-induced homogenization method was used to formulate nanogel particles with varying aloenin concentrations, namely 0.25% (NG1) and 0.5% (NG2). The nanogel was then assessed for appearance, size, zeta potential, spreadability, pH, in vitro diffusion, surface morphology (using scanning electron microscopy), and stability. Four groups were randomly selected among the animals: group I: normal control, group II: 1.5 mL IMQ control, group III: IMQ + 0.25% aloenin (NG1), and group IV: IMQ + 0.5% aloenin (NG2). Body weight, erythema, skin thickness scale, proinflammatory cytokine levels, oxidative stress, and histopathological examination were performed. According to the criteria used for the in vitro assessment, the nanogel formulation created had the necessary qualities. The particles had an average size of 79.1 nm, a polydispersity index of 0.200, and a surface charge of -27.7 mV. According to scanning electron microscopy examination, the nanogel was found to be spherical. The nanogel formulation effectively regulated in vivo parameters, including body weight, psoriasis area severity index, proinflammatory cytokines, and oxidative stress. According to the histopathological data, aloenin successfully healed damaged skin in IMQ-induced psoriasis-like inflammatory damage. Using this formulation, psoriatic symptoms could be effectively alleviated through the topical application of aloenin nanogel. As a potential treatment for psoriasis, the aloenin-nanogel formulation may be a beneficial and emerging trend in administering natural compounds in a more pleasant form. SIGNIFICANCE STATEMENT: This study reports the successful development of an aloenin-loaded nanogel that effectively treats imiquimod-induced psoriasis-like skin inflammation in vivo. The nanogel exhibited favorable physicochemical properties and significantly reduced inflammation, oxidative stress, and disease severity. Histopathological analysis confirmed improved skin healing. These findings demonstrate the therapeutic potential of natural compound-based nanogels as a safer and effective strategy for managing inflammatory skin disorders.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103647"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883076","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}
引用次数: 0
Network pharmacology and experimental validation reveal that betulin alleviates 5-fluorouracil-induced intestinal injury by inhibiting intestinal senescence and enhances antitumor efficacy. 网络药理学和实验验证表明,白桦脂素通过抑制肠道衰老减轻5-氟尿嘧啶诱导的肠道损伤,增强抗肿瘤作用。
IF 3.8 3区 医学
Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-07-30 DOI: 10.1016/j.jpet.2025.103666
Zhi-Wei Wang, Xiao-Jian Wu, Qian-Long Dai, Zhen-Lin Liu, Cheng-Gang Zhao, Wei Lian, Yue Zhao, Li-Hua Li, Xiao-Bo Wang
{"title":"Network pharmacology and experimental validation reveal that betulin alleviates 5-fluorouracil-induced intestinal injury by inhibiting intestinal senescence and enhances antitumor efficacy.","authors":"Zhi-Wei Wang, Xiao-Jian Wu, Qian-Long Dai, Zhen-Lin Liu, Cheng-Gang Zhao, Wei Lian, Yue Zhao, Li-Hua Li, Xiao-Bo Wang","doi":"10.1016/j.jpet.2025.103666","DOIUrl":"10.1016/j.jpet.2025.103666","url":null,"abstract":"<p><p>5-Fluorouracil (5-FU) remains the first-line chemotherapeutic agent for colorectal cancer. Although 5-FU significantly improves patient survival, its severe gastrointestinal toxicity-particularly intestinal injury and diarrhea-impairs treatment adherence and patient quality of life, often leading to therapeutic failure. Thus, effective interventions to prevent or mitigate these adverse effects are urgently needed. Betulin (BET), a natural pentacyclic triterpenoid derived primarily from birch bark, exhibits various biological activities, including anti-inflammatory, antioxidant, antiviral, and antitumor effects. Its anti-inflammatory and antioxidant properties suggest betulin (BET) as a promising candidate for alleviating chemotherapy-induced tissue damage. However, its impact on 5-FU-induced intestinal injury remains unclear. The findings of this study revealed that 5-FU led to significant intestinal injury by promoting cellular senescence and exacerbating the inflammatory response. BET mitigates these effects by decreasing senescence-associated β-galactosidase activity and downregulating key senescence markers such as p53, p21, and p16. Moreover, BET modulates senescence-associated secretory phenotype factors, thereby reversing the proinflammatory microenvironment elicited by 5-FU. Integrating network pharmacology, Mendelian randomization, and experimental validation, we identified the mechanistic target of rapamycin/mitogen-activated protein kinase signaling pathway as a pivotal mediator of BET's protective effects against 5-FU-induced intestinal injury. In conclusion, our study reveals that 5-FU-induced intestinal damage is driven by cellular senescence, which BET effectively ameliorates through suppression of senescence and inflammation. These findings provide a novel framework for targeting antisenescence strategies to alleviate chemotherapy-associated intestinal toxicity. SIGNIFICANCE STATEMENT: This study identifies betulin as a novel agent that alleviates 5-fluorouracil-induced intestinal injury by inhibiting cellular senescence and inflammation via the mechanistic target of rapamycin/mitogen-activated protein kinase pathways. These findings highlight antisenescence as a promising therapeutic strategy to mitigate chemotherapy-induced gastrointestinal toxicity.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103666"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957896","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}
引用次数: 0
miR-146b disrupts the epidermal growth factor receptor/transforming growth factor β receptor profibrotic feedforward loop to inhibit lung fibroblast proliferation and differentiation. miR-146b破坏表皮生长因子受体/转化生长因子β受体前纤维化前馈回路,抑制肺成纤维细胞增殖和分化。
IF 3.8 3区 医学
Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-08-05 DOI: 10.1016/j.jpet.2025.103672
Yan Xie, Yapei Huang, Venkatlaxmi Chettiar, Tianzhou Xing, Steven K Huang, Bethany B Moore, Hiroshi Asahara, Peter W Abel, Yaping Tu
{"title":"miR-146b disrupts the epidermal growth factor receptor/transforming growth factor β receptor profibrotic feedforward loop to inhibit lung fibroblast proliferation and differentiation.","authors":"Yan Xie, Yapei Huang, Venkatlaxmi Chettiar, Tianzhou Xing, Steven K Huang, Bethany B Moore, Hiroshi Asahara, Peter W Abel, Yaping Tu","doi":"10.1016/j.jpet.2025.103672","DOIUrl":"10.1016/j.jpet.2025.103672","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease. Despite recent treatment advancements, survival rates for IPF patients remain low, reflecting the urgent need for a deeper understanding of disease mechanisms. A key feature of IPF progression is the excessive growth of fibroblasts and their transformation into myofibroblasts, driven by a profibrotic feedforward loop involving mediators like transforming growth factor (TGF) α and β1. These factors activate the epidermal growth factor receptor (EGFR) and TGFβ1 receptor (TGFβR1), perpetuating fibrosis. MicroRNAs play a vital role in regulating gene expression, and many are disrupted in IPF. Through RNA sequencing and quantitative reverse-transcription polymerase chain reaction, we identified miR-146b as one of the most significantly reduced miRNAs in human lung fibroblasts (HLF) following TGFβ1 treatment, with a confirmed 70% decrease in expression. Although miR-146b is normally abundant in lung fibroblasts, its levels are significantly lower in lung fibroblasts from IPF patients (HLF-F) and in mice with experimental pulmonary fibrosis. HLF-F exhibited greater responses to profibrotic signals compared with nonfibrotic fibroblasts. Elevating miR-146b levels in HLF-F reduced TGFα-induced proliferation and inhibited TGFβ1-induced myofibroblast differentiation by 60%-90%. Conversely, deletion of the miR-146b gene enhanced fibrotic responses in mouse lung fibroblasts. Additionally, miR-146b directly targets critical signaling pathways, including EGFR, Jun, TGFβR1, and SMAD3, thereby suppressing fibroblast proliferative and fibrogenic activities. Thus, targeting miR-146b presents a promising therapeutic strategy to inhibit lung fibroblast proliferation and differentiation by modulating the profibrotic feedforward loop of EGFR and TGFβR signaling pathways. SIGNIFICANCE STATEMENT: Excess fibroblast proliferation and differentiation into myofibroblasts in response to profibrotic mediators are considered key steps in idiopathic pulmonary fibrosis progression. This study identified miR-146b as an important endogenous antifibrotic factor via inhibition of both lung fibroblast proliferation and differentiation. The repression of miR-146b by transforming growth factor β1 also uncovers a new mechanism linking the factors that drive fibrosis and excessive cell growth in idiopathic pulmonary fibrosis, opening up new avenues for slowing disease progression and improving patient outcomes via restoration of miR-146b expression.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103672"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958386","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}
引用次数: 0
Network pharmacology and experimental validation reveal clotrimazole alleviates dextran sulfate sodium-induced ulcerative colitis by inhibiting intestinal senescence. 网络药理学和实验验证表明,克霉唑可通过抑制肠道衰老来缓解葡聚糖硫酸钠诱导的溃疡性结肠炎。
IF 3.8 3区 医学
Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-07-18 DOI: 10.1016/j.jpet.2025.103664
Cui Chen, Zhi-Wei Wang, Zhen-Lin Liu, Wei Lian, Shu-Jia Song, Ya-Xing Xu, Li-Hua Li, Min Zhou, Xiao-Bo Wang
{"title":"Network pharmacology and experimental validation reveal clotrimazole alleviates dextran sulfate sodium-induced ulcerative colitis by inhibiting intestinal senescence.","authors":"Cui Chen, Zhi-Wei Wang, Zhen-Lin Liu, Wei Lian, Shu-Jia Song, Ya-Xing Xu, Li-Hua Li, Min Zhou, Xiao-Bo Wang","doi":"10.1016/j.jpet.2025.103664","DOIUrl":"10.1016/j.jpet.2025.103664","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is one of the spontaneous inflammatory bowel disease, which is characterized by chronic and relapsing intestinal mucosal inflammation that principally affects the colon. Chronic inflammation is a hallmark of senescent tissues, and intestinal tissue gradually appears injured with the occurrence of senescence. Therefore, senescence may aggravate the severity of UC. However, little is known about the relationship between UC and senescence. Clotrimazole (CTZ) is a synthetic azole broad-spectrum antifungal drug that has been also reported to have anti-inflammatory and anticarcinogenic effects. However, little research is available about CTZ therapeutic role and underlying mechanisms on UC and senescence. In this study, we identified that dextran sulfate sodium (DSS), a widely recognized inducer of UC, promotes senescence in normal human colon epithelial normal colon mucosa cell line 460 cells and murine colonic tissues. Furthermore, CTZ, identified from a compound library, exhibited potent antisenescence activity in DSS-treated normal colon mucosa cell line 460 cells. Our study revealed that CTZ, as an antisenescence agent, demonstrated significant efficacy in alleviating DSS-induced UC and mitigating colonic senescence. Through network pharmacology analysis, Mendelian randomization, and experimental validation, we identified the potential signaling pathways (AMP-activated protein kinase [AMPK]/ mitogen-activated protein kinase [MAPK]) underlying CTZ's therapeutic effects in UC. We discovered that DSS disrupts the AMPK signaling pathway while excessively activating the MAPK pathway, leading to cellular senescence. However, CTZ treatment significantly restored AMPK activity and inhibited MAPK activation, ultimately reducing cellular senescence. In conclusion, our findings suggest that DSS-induced UC can stimulate senescence in colonic tissues, while CTZ effectively alleviates DSS-induced colonic damage. Our results highlight the potential therapeutic value of CTZ in targeting intestinal senescence for UC treatment, laying a foundation for future antisenescence strategies in colitis therapy. SIGNIFICANCE STATEMENT: This study integrates network pharmacology and Mendelian randomization to identify clotrimazole as a potent inhibitor of intestinal senescence, revealing its therapeutic potential for colitis. Experimental validation confirms that clotrimazole alleviates dextran sulfate sodium-induced colitis by targeting cellular senescence, highlighting antisenescence as a promising strategy for colitis treatment.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103664"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958413","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}
引用次数: 0
Pharmacological insights into gut microbiota modulation in systemic lupus erythematosus: Mechanisms, treatment strategies, and clinical implications. 系统性红斑狼疮中肠道菌群调节的药理学见解:机制、治疗策略和临床意义。
IF 3.8 3区 医学
Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-07-15 DOI: 10.1016/j.jpet.2025.103659
Kantrol Kumar Sahu, Krishna Yadav, Madhulika Pradhan, Mukesh Sharma, Akhilesh Dubey, Sucheta, J John Kirubakaran
{"title":"Pharmacological insights into gut microbiota modulation in systemic lupus erythematosus: Mechanisms, treatment strategies, and clinical implications.","authors":"Kantrol Kumar Sahu, Krishna Yadav, Madhulika Pradhan, Mukesh Sharma, Akhilesh Dubey, Sucheta, J John Kirubakaran","doi":"10.1016/j.jpet.2025.103659","DOIUrl":"10.1016/j.jpet.2025.103659","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by widespread inflammation and immune system dysregulation. Recent research suggests that the gut microbiota may play a role in the development of SLE by modulating immune system responses, affecting cytokine production, and altering the activity of T and B cells lymphocytes. As a result, there is a growing interest in microbiota-targeted therapies, including probiotics, dietary changes, and fecal microbiota transplantation. These methods may help restore the balance of microbes and reduce disease activity, but there are still a number of problems to solve. For example, microbiota composition varies greatly from person to person, and it is not clear how dysbiosis causes disease onset. There are also safety concerns about fecal microbiota transplantation. Experimental and clinical studies have started to shed light on the complicated ways in which microbial communities and immune function affect each other in SLE. These studies provide useful information, but their results are often inconsistent. As research continues, integrative methods like metagenomics and metabolomics may help find microbial signatures linked to disease, helping create more accurate and personalized treatments. The gut microbiome is a promising yet still developing area of research that could help us learn more about autoimmune diseases and their treatment, such as SLE. SIGNIFICANCE STATEMENT: Grasping the complex interplay between gut microbiota and systemic lupus erythematosus (SLE) has provided an avenue for therapeutic intervention. This study emphasizes the importance of gut dysbiosis in immune dysregulation, with connections between microbial translocation, molecular mimicry, and inflammatory pathways as contributing factors to the progression of SLE. This work sets the stage for novel and targeted approaches to treating SLE and improving patient outcomes by investigating microbiota-centric treatment options, such as probiotics, dietary interventions, and fecal microbiota transplantation.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103659"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030133","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}
引用次数: 0
Brain exposure of the mesenchymal-epithelial transition inhibitor savolitinib in nonhuman primates: A positron emission tomography study. 非人灵长类动物间充质上皮过渡抑制剂savolitinib的脑暴露:正电子发射断层扫描研究。
IF 3.8 3区 医学
Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-06-18 DOI: 10.1016/j.jpet.2025.103638
Peter Johnström, Zsolt Cselényi, Kowser Miah, Aurelija Jucaite, Graeme Scarfe, Miguel A Cortés González, Lars Farde, Christer Halldin, Karthick Vishwanathan, Magnus Schou
{"title":"Brain exposure of the mesenchymal-epithelial transition inhibitor savolitinib in nonhuman primates: A positron emission tomography study.","authors":"Peter Johnström, Zsolt Cselényi, Kowser Miah, Aurelija Jucaite, Graeme Scarfe, Miguel A Cortés González, Lars Farde, Christer Halldin, Karthick Vishwanathan, Magnus Schou","doi":"10.1016/j.jpet.2025.103638","DOIUrl":"10.1016/j.jpet.2025.103638","url":null,"abstract":"<p><p>The receptor tyrosine kinase mesenchymal-epithelial transition factor inhibitor savolitinib is currently being evaluated as a treatment in non-small cell lung cancer (NSCLC) in combination with osimertinib. NSCLC patients with epidermal growth factor receptor/anaplastic lymphoma kinase mutations appear to have a high incidence (50%-60%) of brain metastasis; hence, cancer drugs that can efficiently access the brain hold a critical advantage. In this study, savolitinib blood-brain barrier penetration properties were investigated in nonhuman primates using positron emission tomography and intravenous administration of microdoses of [<sup>11</sup>C]savolitinib either as a bolus or a bolus-constant infusion. Following a bolus, rapid distribution of radioactivity to the brain was observed reaching a maximum radioactivity concentration (C<sub>max</sub>) of 0.33% of injected radioactivity. An estimated value of the concentration ratio of the total brain-to-plasma ratio (K<sub>p</sub>) of 0.35 was derived using kinetic positron emission tomography data analysis. Intriguingly, notwithstanding the low C<sub>max</sub>, the estimated unbound brain-to-plasma ratio using predetermined in vitro values for free fractions in brain and plasma showed a favorable brain-to-plasma partition with a K<sub>p,uu</sub> of 0.65. This apparent contrast could be explained by the high free fraction of savolitinib in brain tissue. To further build confidence in the estimated K<sub>p,uu</sub>, a bolus-constant infusion protocol successfully established a brain-to-plasma concentration steady-state yielding values for K<sub>p</sub> and K<sub>p,uu</sub> of 0.32 and 0.60, respectively, in good agreement with the bolus study. Our findings confirm blood-brain barrier penetrance and exposure of savolitinib in the nonhuman primate brain. If a similar penetrance in humans is observed, it may help to prevent and/or treat brain metastasis in NSCLC patients. SIGNIFICANCE STATEMENT: Patients with brain malignancies are challenging to treat due to the blood-brain barrier limiting the exposure of therapeutics to the central nervous system. This study demonstrates blood-brain barrier penetrance and exposure of the mesenchymal-epithelial transition inhibitor savolitinib in the nonhuman primate brain. If a similar penetrance in humans is observed, it may help to prevent and/or treat brain metastasis in non-small cell lung cancer patients.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103638"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958359","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}
引用次数: 0
Experimental and computational approaches for evaluating molecule interactions with equilibrative nucleoside transporters 1 and 2. 评估分子与平衡核苷转运体1和2相互作用的实验和计算方法。
IF 3.8 3区 医学
Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-07-15 DOI: 10.1016/j.jpet.2025.103660
Lucy J Martinez-Guerrero, Patricia A Vignaux, Dominique O Farrera, Joshua S Harris, Renuka Raman, Thomas R Lane, Stephen H Wright, Sean Ekins, Nathan J Cherrington
{"title":"Experimental and computational approaches for evaluating molecule interactions with equilibrative nucleoside transporters 1 and 2.","authors":"Lucy J Martinez-Guerrero, Patricia A Vignaux, Dominique O Farrera, Joshua S Harris, Renuka Raman, Thomas R Lane, Stephen H Wright, Sean Ekins, Nathan J Cherrington","doi":"10.1016/j.jpet.2025.103660","DOIUrl":"10.1016/j.jpet.2025.103660","url":null,"abstract":"<p><p>Equilibrative nucleoside transporters (ENTs) facilitate the equilibrative movement of nucleosides and nucleobases across cell membranes in a sodium-independent manner. ENT1 (SLC29A1) and ENT2 (SLC29A2) also transport nucleoside analogs and can affect the pharmacokinetics and pharmacodynamics of drugs used in cancer, viral infections, and inflammatory disorders. ENT1 and ENT2 may be differentiated functionally by their sensitivity to inhibition by nitrobenzylthioinosine (NBMPR), and we used this difference in NBMPR sensitivity to create a HeLa-based ENT2 inhibition assay. We then screened a library of 1600 diverse compounds composed of drugs and natural products for inhibition against ENT1 and ENT2, selecting a subset of compounds for side-by-side comparison of dose-response studies. We used these screening data to build machine learning models for ENT1 and ENT2 inhibition, employing dataset balancing and conformal prediction to adjust for the asymmetrical nature of the data. A random forest model predicted a prospective test set of 44 additional molecules (from the MedChem Express Drug Repurposing Library [2700 compounds]) as potential ENT1 inhibitors with 59% accuracy. This resulted in the identification of the Food and Drug Administration-approved drugs isradipine, avanafil, and istradefylline as inhibitors of ENT1. These new experimental and computational methods and models for these clinically relevant transporters can be used to evaluate drug-transporter interactions early in drug discovery, before testing in vivo. SIGNIFICANCE STATEMENT: Recent regulatory guidance have suggest the inclusion of the equilibrative nucleoside transporters (eg, ENT1 and ENT2) as transporters with emerging clinical relevance for in vitro and in vivo assessment. We have screened over 1600 diverse molecules, allowing us to build machine learning models that in turn were further used to make predictions to validate the models. Our combined experimental and machine learning approach resulted in the identification of multiple Food and Drug Administration-approved medications as inhibitors of ENT1 or ENT2.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103660"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804362","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}
引用次数: 0
The enduring legacy of Peter B. Dews: Rate-dependency and impulsive choice. Peter B. Dews的不朽遗产:利率依赖和冲动选择。
IF 3.8 3区 医学
Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-07-16 DOI: 10.1016/j.jpet.2025.103656
Raymond C Pitts, Christine E Hughes
{"title":"The enduring legacy of Peter B. Dews: Rate-dependency and impulsive choice.","authors":"Raymond C Pitts, Christine E Hughes","doi":"10.1016/j.jpet.2025.103656","DOIUrl":"10.1016/j.jpet.2025.103656","url":null,"abstract":"<p><p>Substantial progress has been made in characterizing effects of a variety of drugs on impulsive behavior and elucidating some of the relevant neurobiological mechanisms. Nevertheless, there are still considerable discrepancies in the literature, both within and across studies. Recent evidence suggests that effects of drugs and other manipulations on impulsive choice can depend upon baseline levels. In this paper, we briefly summarize some of the discrepant effects of acutely administered stimulants and opioids in preclinical studies of impulsive choice and then explore the possibility that some of these discrepancies result from behavioral processes related to a principle in behavioral pharmacology first articulated by Peter B. Dews: rate-dependency. As an example of the law of initial value, rate-dependent effects occur when a drug or other treatment increases relatively low rates and decreases relatively high rates. We then summarize some of our data aimed at identifying potential behavioral mechanisms involved in these effects. In our behavioral procedures, both of these drug classes mainly decrease sensitivity to the reinforcement dimensions typically controlling impulsive choice (reinforcement magnitude and reinforcement delay), effects that can be characterized as rate-dependent. We suggest that these effects might be better described as rate-convergent and, further, that they result from a disruption/destruction of control over choice by reinforcement magnitude and delay. Nevertheless, together with previous reports of rate-dependent effects with impulsive choice, our analyses indicate that rate-dependency remains a useful framework within which to characterize effects of drugs and, thus, illustrate the enduring legacy of Peter B. Dews. SIGNIFICANCE STATEMENT: Although stimulants and opioids tend to increase and decrease impulsive choice, respectively, there is substantial variation in these effects both within and across studies. Further analyses of selected experimental results have revealed that these discrepancies may be related to behavioral processes captured by the principle of rate-dependency. It is suggested that these data illustrate the enduring contributions of Peter B. Dews to behavioral pharmacology.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103656"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794776","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}
引用次数: 0
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信