Pharmacology Research & Perspectives最新文献

{"title":"Using a NanoBRET-Based Ligand-Binding Assay at the β₂-Adrenoceptor for Undergraduate Pharmacology Education.","authors":"Abigail Pearce, Xianglin Huang, Theo Redfern-Nichols, Claudia M Sisk, Dewi Safitri, Michael Collins, Milena A Malcharek, Sergio Tomey García, Chiharu Nakamura, Andrzej Harris, Graham Ladds","doi":"10.1002/prp2.70275","DOIUrl":"10.1002/prp2.70275","url":null,"abstract":"<p><p>The teaching of pharmacology includes a fundamental understanding of ligand binding; how it is measured and how it is calculated. We sought to modernize the techniques by which ligand affinity is determined by undergraduate students and introduce them to parameter estimation through curve fitting. We taught a NanoBRET ligand binding assay to student cohorts completing their second year of undergraduate study in Natural Sciences (71 and 61 students in 2024 and 2025 respectively). The aim was to measure the affinity of fluorescent and unlabeled ligands for the β₂-adrenoceptor in live cells. Affinities were then calculated from their data using a custom Microsoft Excel spreadsheet. This series of practical classes was well received by students, with most students able to follow the protocol and successfully determine ligand affinities. Furthermore, students recognized the benefit of the practical class for their education, confirming they felt it improved their understanding of how ligand affinity is calculated. We also demonstrated that this protocol could be scaled up to accommodate larger class sizes (class of 367 students studying medicine and veterinary sciences).</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"14 3","pages":"e70275"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13248772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148205791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kaempferol Improves Alzheimer's Disease by Inhibiting Neuronal Ferroptosis via Activating GPX4/AKR1C3 Signaling Pathway.","authors":"Le Li, Manying Yang, Jiale Tao, Yonghong Zhao, Na Zhao, Shiguo Sun","doi":"10.1002/prp2.70255","DOIUrl":"10.1002/prp2.70255","url":null,"abstract":"<p><p>Kaempferol has been shown to be beneficial in the treatment of Alzheimer's disease (AD) in animal models. However, the action mechanism remains unclear. AKR1B1 has been identified as a target of kaempferol, initially suggested by the Therapeutic Target Database, DrugBank, and PubChem, and subsequently confirmed through experimental validation. Kaempferol treatment facilitated the expression of AKR1B1 in PC12 cells exposed to Aβ_1-42. Kaempferol treatment mitigated the Aβ_1-42-induced increases in Fe²⁺, MDA, and lipid ROS and Aβ_1-42-induced decreases in GSH synthesis and SOD activity. The reduction in ferroptosis-related proteins (GPX4, NQO1, SLC7A11, AKR1C1, and AKR1C3) and the inhibition of Nrf2 nuclear translocation and Nrf2/HO-1 signaling caused by Aβ_1-42 were also reversed by kaempferol. Overexpressing AKR1B1 led to decreased levels of Fe²⁺, MDA, and lipid ROS, along with increased GSH synthesis and SOD activity in Aβ_1-42-treated cells, although these effects were negated by Nrf2 inhibition. The upregulation of GPX4 and AKR1C3 by AKR1B1 overexpression was also reversed when Nrf2 expression was inhibited. Notably, silencing AKR1B1 counteracted the protective effects of kaempferol against Aβ_1-42-induced neuronal ferroptosis. In vivo studies revealed that kaempferol improved cognitive impairments, reduced deposition of Aβ and p-Tau, and alleviated neuronal ferroptosis in the hippocampal tissues of an AD mouse model in a dose-dependent manner, effects that were diminished by inhibiting AKR1B1 expression. Following kaempferol treatment, the levels of GPX4 and AKR1C3 in the hippocampus of AD mice were found to be reduced. Overall, our findings indicate that kaempferol treatment enhances cognitive function and mitigates pathological alterations in AD mice by inhibiting neuronal ferroptosis through the activation of the Nrf2/HO-1/GPX4/AKR1C3 signaling via upregulation of AKR1B1. This research supports the need for further investigation and clinical exploration of kaempferol.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"14 3","pages":"e70255"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13132798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Evaluation of Foreign Clinical Data in the Approval Reviews of Antimicrobial Medicines in Japan: Considering Ethnic and Regional Differences in Data Extrapolations in Accordance With Regulatory Circumstances.","authors":"Rumiko Shimazawa, Masayuki Ikeda","doi":"10.1002/prp2.70267","DOIUrl":"10.1002/prp2.70267","url":null,"abstract":"<p><p>The approval requirements in new regions that do not require domestic clinical data and the clinical data evaluation of multi-regional clinical trials (MRCTs) and foreign clinical trials (FCTs) in the Japanese approval review processes for antimicrobial medicines were explored. Foreign clinical data has been used to evaluate the efficacy of more than 60% (45/70) of approved antimicrobial drugs in Japan. Two FCT extrapolations based on bridging strategies were used for antimicrobial medicine approvals in the early 2000s after the issuance of International Council for Harmonization-Efficacy Guideline 5 (ICH-E5), but 40 approvals extrapolated efficacy evaluations from outside of Japan without bridging studies. Participation in MRCTs has increased since the 2010s, following Japan's notification \"Basic Principles on Global Clinical Trials\" for global clinical trials in 2007. From the commencement of the use of FCT extrapolations, comparisons of pharmacokinetic data have been used to examine regional differences. As experience with inter-regional data interpretation increases, similarities in the drug susceptibilities of infectious agents (pharmacodynamic data) and the medical environment (extrinsic factors) are being examined. In one approval in Japan, a different dose was set compared with that approved overseas because of differences in pharmacokinetics. We demonstrated that MRCTs and FCTs of antimicrobial medicines have been accepted as confirmatory trials in Japan without the need for bridging studies, which has been enabled by examining regional differences using pharmacokinetic data and additional comparisons of pharmacodynamic data and extrinsic factors.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"14 3","pages":"e70267"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13158371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147869326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of TREK-1 and TREK-2 Two-Pore Domain Potassium Channels by the K_v4 Channel Modulator, NS5806.","authors":"E L Veale, P M Matthews, A M Rush, E B Stevens, A Mathie","doi":"10.1002/prp2.70264","DOIUrl":"10.1002/prp2.70264","url":null,"abstract":"<p><p>NS5806 is a diaryl-urea small molecule developed for the treatment of pain and neurological disorders. A potent activator of K_v4.3 potassium channels, it is widely used to study K_v4 channel physiology in excitable cells, including trigeminal neurons. Surprisingly, we found that NS5806 produced a significant, robust hyperpolarization of the resting membrane potential of all trigeminal neurons tested. Given the structural similarity of NS5806 to other negatively charged activator compounds with broad potassium channel activity, we investigated whether NS5806 might also modulate the two-pore domain potassium (K2P) TREK channels, which are abundantly expressed in sensory neurons. Here we show that NS5806 activates both TREK-1 and TREK-2 channels. While NS5806 is described as a K_v4-selective activator, our data suggest that its effects on trigeminal and other neurons may arise from concurrent activation of multiple potassium channel types, including TREK-1 and TREK-2.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"14 3","pages":"e70264"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13176460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147942369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intravenous Tolvaptan Sodium Phosphate Can Fail to Improve Fluid Overload Due to Heart Failure in Patients With Chronic Kidney Disease: A Case Report.","authors":"Takaya Uno, Ichiro Nakakura, Akari Ikeda, Atsuki Hosoda, Yutaro Mukai, Kaori Yamanishi, Naohiro Ohara, Kaori Imanishi, Yoshiko Une, Satoshi Yokoyama, Kouichi Hosomi","doi":"10.1002/prp2.70252","DOIUrl":"10.1002/prp2.70252","url":null,"abstract":"<p><p>Tolvaptan is widely used as an adjunct oral diuretic to loop and thiazide diuretics for the management of fluid overload in patients with congestive heart failure. Recently, tolvaptan sodium phosphate (TSP), a water-soluble prodrug of tolvaptan, was developed for intravenous administration and has demonstrated efficacy and safety in clinical settings. However, cases of TSP ineffectiveness have not yet been reported. Because oral tolvaptan does not work in some patients, TSP may also be ineffective in certain cases. We report the case of a 74-year-old male patient with chronic heart failure and chronic kidney disease who was unresponsive to TSP. The patient underwent off-pump coronary artery bypass grafting. Initially, intravenous furosemide and oral tolvaptan were administered to manage residual fluid overload; however, intravenous furosemide was discontinued owing to a decline in serum potassium levels. Oral loop and thiazide diuretics in combination with TSP were then added to ongoing oral tolvaptan therapy, but this regimen did not achieve sufficient weight reduction. Subsequently, high-dose intravenous furosemide was reintroduced in place of oral loop diuretics, with careful monitoring for hypokalaemia. Although high-dose intravenous furosemide worsened renal dysfunction, it successfully improved fluid overload and reduced plasma B-type natriuretic peptide levels, effects that persisted even after discontinuation of TSP. This case suggests that in patients with chronic kidney disease who are unresponsive to TSP, high-dose intravenous furosemide may provide more effective management of fluid retention in heart failure, though renal function must be closely monitored.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"14 3","pages":"e70252"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13087111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147699527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined Inhibition of TRPM4/NMDA Receptor Complex and Extrasynaptic NMDA Receptors Is Candidate Therapeutic Target for Suppression of Epileptic Seizures and Improvement of Cognitive Impairments.","authors":"Motohiro Okada, Ruri Okubo, Tomoka Oka, Eishi Motomura","doi":"10.1002/prp2.70256","DOIUrl":"10.1002/prp2.70256","url":null,"abstract":"<p><p>Cognitive impairments are important therapeutic targets in epilepsy medication; however, effective pharmacological treatments for epilepsy patients with comorbid cognitive impairment have not been established. Effects of chronic administration of MK-801 (noncompetitive NMDA receptor inhibitor), memantine (low-affinity extrasynaptic-NMDA receptor preferential inhibitor), FP802 (TwinF interface inhibitor), and probenecid (pannexin1 containing hemichannel inhibitor) for 14 days on epileptic seizure frequency, sucrose preference, extracellular levels of L-glutamate and D-serine, expression of GluN2A and GluN2B, and phosphorylated CREB levels in the frontal cortex (epileptic focus region) were investigated using a genetic rat model of epilepsy with cognitive impairment (S286L-TG rats). Seizure frequency of S286L-TG was reduced by chronic administration of probenecid, MK-801, and memantine + FP802, but not by memantine or FP802 alone. Decreased sucrose preference of S286L-TG relative to wild-type littermate rats was restored by memantine and memantine + FP802, but aggravated by MK-801 without being affected by probenecid or FP802. Downregulated GluN2A/GluN2B expression in S286L-TG relative to wild-type was restored by probenecid, memantine, and memantine + FP802, but further decreased by MK-801, and was unaffected by FP802. Upregulated basal extracellular L-glutamate/D-serine levels in S286L-TG were restored by probenecid and memantine + FP802, further increased by MK-801, and unaffected by FP802. In contrast, chronic memantine alone restored the basal D-serine increasing but did not affect basal L-glutamate. These results suggest the possibility that a combination of suppressing TRPM4/NMDA receptor complex and extrasynaptic NMDA receptor may contribute to reducing epileptic seizures and ameliorating dysfunction/bias of preference regulation, providing a potential therapeutic strategy for epilepsy patients comorbid with cognitive impairments.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"14 3","pages":"e70256"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147778112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin as a Multifaceted Therapeutic Agent for Gastrointestinal Diseases: Mechanisms, Clinical Efficacy, and Future Directions.","authors":"Sayedeh Azimeh Hosseini, Hassan Valadbeigi, Seyedeh Mahdieh Khoshnazar, Saeed Khoshnood, Shahab Falahi, Delsuz Rezaee, Ali Hematian, Mohammad Hossein Haddadi","doi":"10.1002/prp2.70257","DOIUrl":"10.1002/prp2.70257","url":null,"abstract":"<p><p>The high prevalence of gastrointestinal (GI) diseases and their significant impact on the quality of life require new therapeutic strategies. The development of novel therapeutic strategies should prioritize targeting the fundamental pathophysiological mechanisms underlying these diseases, including inflammation, cellular proliferation, and gut microbiota dysregulation. Metformin, a first-line antidiabetic agent, exhibits pleiotropic pharmacological properties beyond its glucose-lowering effects, such as anti-inflammatory, antiproliferative, and microbiota-modulating activities. These multifaceted mechanisms position metformin as a promising therapeutic candidate for a spectrum of disorders, from IBS to liver disorders. This review synthesizes preclinical and clinical evidence supporting the therapeutic potential of metformin across GI pathologies-such as Helicobacter pylori infection, inflammatory bowel disease, colorectal cancer, and hepatocellular carcinoma-while elucidating its molecular mechanisms, such as AMPK/mTOR modulation, NF-κB inhibition, and gut barrier stabilization. We critically evaluate combination therapies, ongoing clinical trials, and challenges, including lactic acidosis risk and GI intolerance to position metformin as a repurposed agent for GI disease management.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"14 3","pages":"e70257"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Trials to Clinics: Considerations for Implementing Psychedelic-Assisted Therapy Into Clinical Practice.","authors":"Jessie Kim, Liam Lochhead, Cory R Weissman","doi":"10.1002/prp2.70262","DOIUrl":"10.1002/prp2.70262","url":null,"abstract":"","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"14 3","pages":"e70262"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13158267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147869280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of FCGR2A and FCGR3A Gene Variants on the Response to Rituximab in Patients With Glomerular Diseases.","authors":"María Larrosa-García, Irene Agraz Pamplona, Susana Rojo Tolosa, Alberto Jiménez Morales, María Teresa Sanz Martínez, Mónica Martínez Gallo, Roger Colobran, Helena Genestal Vicente, Nerea Moreno Pena, Roxana Paola Bury Macías, José Bruno Montoro Ronsano","doi":"10.1002/prp2.70261","DOIUrl":"10.1002/prp2.70261","url":null,"abstract":"<p><p>Rituximab is an anti-CD20 monoclonal antibody used in autoimmune diseases, including glomerular diseases. The FCGR2A (rs1801274) and FCGR3A (rs396991) variants have been suggested to affect rituximab efficacy; this study evaluates their impact on rituximab efficacy in glomerular diseases. A clinical trial was performed including adults with glomerular diseases who required rituximab (NEFRTX; EudraCT: 2020-000484-23). Patients received 1.0 g or 0.5 g of rituximab on day 1 (± day 14); biochemical parameters and rituximab concentration were measured, and FCGR2A and FCGR3A variants were characterized. Clinical outcome was evaluated at 6 and 12 months. 30 patients were included. FCGR2A (rs1801274) and FCGR3A (rs396991) variants did not show an effect on clinical response to rituximab. When the effect of the variant was corrected by rituximab exposure, the expression of the FCGR2A rs1801274-A allele vs. no expression was related to a poorer response at month 6 (odds ratio 0.034; 95% confidence interval 0.002-0.725; p = 0.030); this effect was not seen for FCGR3A. Additional studies involving larger cohorts are warranted to validate these findings.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"14 3","pages":"e70261"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13240126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147988611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implementation of an Integrated Pharmacology Curriculum in a Flipped, Small-Group, Case-Based, Pre-Clerkship Medical Curriculum Improved Student Performance.","authors":"Brinda Desai Bradaric, Eric Van Rite, Lalita Prasad-Reddy, Michael Bradaric","doi":"10.1002/prp2.70258","DOIUrl":"10.1002/prp2.70258","url":null,"abstract":"<p><p>Rush Medical College implemented a new, integrated pre-clerkship curriculum. Pharmacology was integrated with other basic sciences into a flipped, small-group, case-based structure. This report describes the main features of the pharmacology curriculum for pharmacology directors to have a template. When pharmacology assessment items were compared from before and after the curriculum change, both the degree of difficulty and the point biserial correlation increased for the items created during the new curriculum. Furthermore, student satisfaction, as reported by the Graduate Questionnaire (GQ), steadily increased. Therefore, student performance and perception of pharmacology content were positively affected by the integrated curriculum. This paper describes a framework for directors of pharmacology to use for integration of novel curricular strategies and provides examples of how to achieve successful integration.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"14 3","pages":"e70258"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13130840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147778071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}