Molecular Pharmacology最新文献

{"title":"Corrigendum to \"Functional Interaction between Transient Receptor Potential V4 Channel and Neuronal Calcium Sensor 1 and the Effects of Paclitaxel\".","authors":"","doi":"10.1016/j.molpha.2025.100051","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100051","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 7","pages":"100051"},"PeriodicalIF":3.2,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275348","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":"Upregulating vascular endothelial K_Ca2.3 channels alleviates pulmonary hypertension in mice.","authors":"Meng-Zhuan Han, Yan Wang, Ke-Xin Sun, Yong-Jian Zhang, Ru-Yue Bai, Lin-Hong Wu, Xia-Xia Hai, Bao-Chang Lai, Jing-Jing Li, Gang She, Yi Zhang, Xiao-Jun Du, Zheng-Da Pang, Xiu-Ling Deng","doi":"10.1016/j.molpha.2025.100048","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100048","url":null,"abstract":"<p><p>Endothelial dysfunction of pulmonary arteries is important in the initiation of pulmonary hypertension (PH). Pulmonary vascular tone is regulated by endothelium-dependent hyperpolarization (EDH) that induces vasodilation. Although K_Ca2.3 channels are involved as a key initiator of EDH response, therapeutic potential of endothelial K_Ca2.3 channels in PH remains unclear. Bioinformatic and biochemical analyses were used to explore K_Ca2.3 expression in patients with PH. Two mouse PH models were created by injection of Sugen 5416 plus hypoxia or injection with monocrotaline. Endothelial-specific K_Ca2.3 adeno-associated virus (AAV-Kcnn3) was constructed, and the efficacy in both PH models was tested using immunohistochemistry, myograph system, and echocardiography. Expression of K_Ca2.3 was decreased in pulmonary arterial endothelial cells or lung tissues from patients with PH and both experimental PH models. AAV-Kcnn3 treatment increased K_Ca2.3 expression in pulmonary endothelium and ameliorated K_Ca2.3-medieated vasodilation of small pulmonary arteries and pulmonary vascular endothelial dysfunction in both PH models. The key PH phenotypes, including elevated right ventricular pressure, Fulton index, pulmonary artery wall thickness, and the free wall thickness of the right ventricle, were remarkably alleviated by AAV-Kcnn3 treatment in both PH models. In conclusion, augmented expression of endothelium-specific K_Ca2.3 channels markedly inhibits the development of PH by improving endothelium-dependent relaxation. SIGNIFICANCE STATEMENT: This study demonstrated downregulated expression of K_Ca2.3 channels in lung tissues, specifically in pulmonary artery endothelial cells from patients or mice with pulmonary hypertension. Upregulation of endothelial K_Ca2.3 might serve as a therapeutic strategy in the early-stage pulmonary hypertension.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 7","pages":"100048"},"PeriodicalIF":3.2,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326227","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":"Fenofibrate promotes erucic acid metabolism by peroxisome enzyme EHHADH activation alleviating high-fat diet-induced steatotic liver disease.","authors":"Ming Jin, Rongmi Zhang, Wenwen Xin, Li Sun, Xue Fan, Qian Lu, Luyong Zhang, Zhenzhou Jiang, Qinwei Yu","doi":"10.1016/j.molpha.2025.100047","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100047","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. Fatty-acid metabolism disorders, especially long-chain fatty acids (LCFA) accumulation, is the main pathological feature of high fat diet-induced MASLD. Fenofibrate is mainly used for the treatment of hyperlipidemia and metabolic disorders in clinical settings. In recent years, its therapeutic effect on MASLD has also been reported, but the mechanism is still unclear. Here, we aimed to investigate the effect and mechanism of fenofibrate on hepatic steatosis via fatty-acid metabolism regulation. It was found that fenofibrate strongly reduced hepatic LCFA accumulation, especially decreased the content of erucic acid (EA). In AML-12 cells treated with EA, fenofibrate improved hepatic lipid accumulation by accelerating EA metabolism. In vivo and in vitro experiments have proven that peroxidase enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase is the key enzyme of fenofibrate in promoting LCFA metabolism. This study confirmed that fenofibrate upregulated peroxisome enzyme enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase expression to promote LCFA oxidation, which provided a novel strategy for the treatment of high-fat diet-induced steatotic liver disease in clinical settings. SIGNIFICANCE STATEMENT: We found that long-chain fatty acid overload was a characteristic of high-fat diet-induced fatty liver, and fenofibrate ameliorated high-fat diet-induced fatty liver by upregulating enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase to promote the oxidation of long-chain fatty acids, especially erucic acid. This study may contribute to the use of fenofibrate in the treatment of fatty liver disease.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 7","pages":"100047"},"PeriodicalIF":3.2,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294120","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":"Corrigendum to \"The Natural Compound Withaferin A Covalently Binds to Cys239 of β-Tubulin to Promote Tubulin Degradation\".","authors":"","doi":"10.1016/j.molpha.2025.100045","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100045","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100045"},"PeriodicalIF":3.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079133","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":"Research approaches for exploring the hidden conversations of G protein-coupled receptor transactivation.","authors":"Janbolat Ashim, Min Jae Seo, Sangho Ji, Joongyu Heo, Wookyung Yu","doi":"10.1016/j.molpha.2025.100043","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100043","url":null,"abstract":"<p><p>G protein-coupled receptor (GPCR) signaling is a crucial physiological mechanism that encompasses a wide range of signaling phenomena. Although traditional GPCR signaling involves G protein or arrestin-related activation, other modes such as biphasic activation, dimer or oligomeric activation, and transactivation have also been observed. Herein, we focus on the increasingly recognized process of GPCR-transactivation. Transactivation refers to the ability of GPCRs to activate other receptor types, especially receptor tyrosine kinases, without engaging their own specific ligands. This cross-talk between GPCRs and other receptors facilitates the integration of multiple signaling pathways, thereby regulating diverse cellular responses, which underscores its physiological significance. In this review, we provide a comprehensive overview of the role of GPCR-transactivation in physiology. We also discuss the growing interest in this field and examine the various tools available for studying transactivation. Additionally, we highlight recent advancements in emerging tools and their application to GPCR-transactivation research. Finally, we propose future research directions and consider the potential impact of new technologies in this rapidly evolving field. SIGNIFICANCE STATEMENT: G protein-coupled receptor transactivation plays a key role in integrating multiple signaling pathways by activating other proteins, like receptor tyrosine kinases, without binding their specific ligands. Here, we focus on the significance of transactivation and the various approaches used to study this phenomenon.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100043"},"PeriodicalIF":3.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191973","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":"Special section: William A. Catterall Memorial Issue - Mechanisms of Electrical Excitability.","authors":"Lori L Isom","doi":"10.1016/j.molpha.2025.100044","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100044","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100044"},"PeriodicalIF":3.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094171","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":"Corrigendum to \"Targeting the Metastasis Suppressor, N-Myc Downstream Regulated Gene-1, with Novel Di-2- Pyridylketone Thiosemicarbazones: Suppression of Tumor Cell Migration and Cell-Collagen Adhesion by Inhibiting Focal Adhesion Kinase/Paxillin Signaling\".","authors":"","doi":"10.1016/j.molpha.2025.100038","DOIUrl":"10.1016/j.molpha.2025.100038","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 5","pages":"100038"},"PeriodicalIF":3.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971671","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":"Discovery of RGS2-FBXO44 interaction inhibitors using a cell-based NanoBit assay.","authors":"Sadikshya Aryal, Cindy Shi Yee Wong, Harrison J McNabb, Ahmad Junaid, Ryan A Altman, Benita Sjögren","doi":"10.1016/j.molpha.2025.100030","DOIUrl":"10.1016/j.molpha.2025.100030","url":null,"abstract":"<p><p>Regulators of G protein signaling (RGS) proteins negatively regulate signaling through G protein-coupled receptors, and reduced RGS protein function is involved in numerous pathologies. However, therapeutic intervention is challenging, as RGS proteins lack druggable binding pockets and enzymatic activity. Instead, targeting mechanisms that control RGS protein expression show promise as an alternative. Pharmacological stabilization of RGS2 would be a feasible therapeutic strategy in pathologies associated with reduced RGS2 protein levels, such as hypertension, heart failure, and asthma. RGS2 is rapidly degraded through the ubiquitin-proteasomal system, and we recently identified the E3 ligase that recognizes RGS2. F-box Only Protein 44 (FBXO44) acts as the substrate recognition site for RGS2 in this E3 ligase complex, and we hypothesize that inhibiting the RGS2-FBXO44 interaction will lead to enhanced RGS2 levels. Here, we developed a NanoLuc Binary Technology (NanoBiT) assay that detects the interaction between RGS2 and FBXO44. This assay was used to screen 1600 compounds from the Life Chemicals protein-protein interaction fragment library. We identified a promising hit, denoted compound 10, that inhibits the RGS2-FBXO44 interaction with a potency of 19.6 μM, through direct binding to RGS2. The resulting increase in RGS2 protein levels is dependent on FBXO44, as siRNA-mediated FBXO44 knockdown attenuates the effect of compound 10. Altogether, compound 10 represents the first example of a small-molecule inhibitor of the RGS2-FBXO44 interaction and a first step toward the development of molecular probes with a defined mechanism to stabilize RGS2 protein levels. SIGNIFICANCE STATEMENT: This study provides a strategy to identify molecules that selectively inhibit RGS2 protein degradation as well as the first example of a compound with the ability to inhibit RGS2 interaction with the E3 ligase component FBXO44. This study provides proof of concept that a small-molecule RGS2-FBXO44 interaction inhibitor will increase RGS2 protein levels. Future development of compounds with this mechanism of action would be clinically useful in pathologies associated with low RGS2 protein levels, including hypertension, heart failure, and asthma.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 5","pages":"100030"},"PeriodicalIF":3.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811903","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":"Multiwalled carbon nanotubes activate the NLRP3 inflammasome-dependent pyroptosis in macrophages.","authors":"Chol Seung Lim, Ja Kook Gu, Qiang Ma","doi":"10.1016/j.molpha.2025.100031","DOIUrl":"10.1016/j.molpha.2025.100031","url":null,"abstract":"<p><p>Macrophages are major innate immune cells for the clearance of inhaled nanoparticles but may undergo cell death upon phagocytosis of certain nanoparticles due to their resistance to lysosomal degradation and high toxicity to the cell. Here we investigated the pyroptotic effect of exposure to fibrogenic multiwalled carbon nanotubes (MWCNTs) on macrophages, an inflammatory form of cell death. We first evaluated MWCNT-induced cell death in M1 and M2 macrophages that mediate the temporal inflammatory response to MWCNTs in mammalian lungs. Macrophages were differentiated from human monocytic THP-1 cells, followed by polarization to M1 or M2 cells. MWCNTs caused concentration- and time-dependent cytotoxicity in M1 and, to a lesser extent, M2 cells. Carbon black, an amorphous carbonous material control for CNTs, did not cause apparent toxicity in the cells. MWCNTs increased the production and secretion of IL-1β, accompanied by activation of caspase-1, in M1, but not M2, cells. Moreover, MWCNTs induced the formation of apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain specks and the release of cathepsin B in M1 cells, revealing activation of the nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome via lysosomal damage. MWCNTs induced the cleavage of gasdermin D (GSDMD) to form the 31 kDa N-terminal fragment (GSDMD-N), the pore-forming peptide causing pyroptotic cell death. Increased IL-1β release was completely suppressed by AC-YVAD-CMK (a caspase-1 inhibitor), MCC-950 (an NLRP3 inflammasome inhibitor), or CA-074 Me (a cathepsin B inhibitor), alongside the blockage of MWCNT-induced cleavage of GSDMD. The study demonstrates that MWCNTs trigger pyroptosis in M1 macrophages and boost sterile inflammation by activating the NLRP3 inflammasome pathway. SIGNIFICANCE STATEMENT: The nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 inflammasome mediates the inflammatory response to fibrogenic nanoparticles in the lung via multiple means. The current study uncovers the induction of pyroptotic death of macrophages as a major means of nanotoxicity and sterile inflammation via the nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 pathway by nanoparticles.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 5","pages":"100031"},"PeriodicalIF":3.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010182","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":"Non-nutritive sweeteners in food-drug interactions: An overview of current evidence.","authors":"Laura Danner, Kale Kroenke, Stephanie Olivier-Van Stichelen","doi":"10.1016/j.molpha.2025.100035","DOIUrl":"10.1016/j.molpha.2025.100035","url":null,"abstract":"<p><p>Food-drug interactions occur when the presence of foods interferes with the absorption, distribution, metabolism, or excretion of pharmaceuticals. Specific compounds within foods, like certain phytochemicals from grapefruit, have been known to precipitate food-drug interactions for decades, leading to guidance from physicians and pharmacists about patients' dietary restrictions while taking certain drugs. Although approved by the Food and Drug Administration, high-intensity non-nutritive sweeteners (NNS) share qualities with drugs that suggest the potential for similar interactions. In this minireview, we have reviewed 5 of the most popular NNS, including saccharin, aspartame, acesulfame potassium, sucralose, and stevia, and detail their drug-like qualities, regulatory status, pharmacokinetics, and primary research articles containing evidence of NNS interacting with drug absorption, distribution, metabolism, and excretion. Although studies varied widely in concentration ranges for NNS, model systems, and methods, all NNS included in this review were found to have known interactions with mediators of absorption, distribution, metabolism, and excretion from studies conducted after their Food and Drug Administration approval or generally recognized as safe designation. We have highlighted essential gaps in the literature and recommend the scientific community actively research NNS as food additives that may interact with drugs. SIGNIFICANCE STATEMENT: Food-drug interactions are a growing concern in Western societies where polypharmacy and ultraprocessed foods and beverages are increasingly common. High-intensity non-nutritive sweeteners bear structural similarities to pharmaceuticals, and evidence suggests they interact with mediators of drug pharmacokinetics. This minireview highlights the interactions uncovered thus far and serves as a call to action for the scientific community to establish rigorous, consistent testing that will enable updated safety guidelines for consumers.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 5","pages":"100035"},"PeriodicalIF":3.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972015","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}