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Emerging approaches for antagonizing the aryl hydrocarbon receptor. 拮抗芳烃受体的新方法。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-05 DOI: 10.1016/j.tips.2025.05.003
Zdeněk Dvořák, Sridhar Mani, Jan Vondráček
{"title":"Emerging approaches for antagonizing the aryl hydrocarbon receptor.","authors":"Zdeněk Dvořák, Sridhar Mani, Jan Vondráček","doi":"10.1016/j.tips.2025.05.003","DOIUrl":"https://doi.org/10.1016/j.tips.2025.05.003","url":null,"abstract":"<p><p>Antagonizing the aryl hydrocarbon receptor (AhR) is a highly pertinent pharmacotherapeutic strategy. To overcome the drawbacks of existing AhR antagonists, novel molecules that can selectively target canonical and noncanonical AhR pathways are urgently needed. Recent reports on the structures and functions of cytosolic and nuclear AhR-protein complexes have allowed for understanding structural determinants for intrinsic activity and functional selectivity of AhR ligands. This new information regarding AhR surface interactions has opened new avenues for the development of novel AhR antagonists. Achievable strategies include the negative allosteric modulation of AhR and the disruption of AhR-protein and AhR-DNA interfaces using peptidomimetics or small molecules. Here, we discuss such novel approaches that may lead to new AhR-targeted therapeutics.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
The ASO drug olezarsen targets familial chylomicronemia syndrome. ASO药物olezarsen针对家族性乳糜微粒血症综合征。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-05 DOI: 10.1016/j.tips.2025.05.007
Jing Jin, Le Tra Giang Nguyen, Sherouk M Tawfik, Beshoy Armanios, Xiao-Bo Zhong
{"title":"The ASO drug olezarsen targets familial chylomicronemia syndrome.","authors":"Jing Jin, Le Tra Giang Nguyen, Sherouk M Tawfik, Beshoy Armanios, Xiao-Bo Zhong","doi":"10.1016/j.tips.2025.05.007","DOIUrl":"https://doi.org/10.1016/j.tips.2025.05.007","url":null,"abstract":"","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Limiting TDP-43 aggregation by induced recruitment to PML-NB. 通过诱导募集PML-NB限制TDP-43聚集。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-05 DOI: 10.1016/j.tips.2025.05.012
Chien-Han Kao, Ruey-Hwa Chen
{"title":"Limiting TDP-43 aggregation by induced recruitment to PML-NB.","authors":"Chien-Han Kao, Ruey-Hwa Chen","doi":"10.1016/j.tips.2025.05.012","DOIUrl":"https://doi.org/10.1016/j.tips.2025.05.012","url":null,"abstract":"<p><p>TAR DNA binding protein 43 kD (TDP-43) aggregation is associated with several neurodegenerative diseases and limiting TDP-43 aggregates could offer therapeutic benefit. Recently, Wagner et al. utilized the induced proximity to PML for enhancing TDP-43 solubility under stress. Mechanistically, this strategy triggers a SUMOylation-ubiquitylation cascade on TDP-43 and the compartmentalization of TDP-43 to the promyelocytic leukemia-nuclear bodies (PML-NBs).</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
PSA inhibitors for contraception: insights from prostate cancer. PSA抑制剂用于避孕：来自前列腺癌的见解。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-04 DOI: 10.1016/j.tips.2025.05.005
Wipawee Winuthayanon
{"title":"PSA inhibitors for contraception: insights from prostate cancer.","authors":"Wipawee Winuthayanon","doi":"10.1016/j.tips.2025.05.005","DOIUrl":"https://doi.org/10.1016/j.tips.2025.05.005","url":null,"abstract":"<p><p>Despite the availability of effective hormonal contraceptive methods, nearly half of pregnancies worldwide remain unintended, highlighting the urgent need for innovative, nonhormonal options. Prostate-specific antigen (PSA) is a biomarker for prostate cancer and is well established for its role in liquefying semen by hydrolyzing gel-forming proteins. Liquefaction is essential for sperm motility and fertilization, making PSA inhibition a prime candidate for novel contraceptive strategies. Advances in prostate cancer research have led to the development of PSA inhibitors for cancer therapeutic purposes, including drugs that suppress PSA activity or selectively kill PSA-expressing cells. PSA presents a unique target as it is produced in men and acts in women, making it a promising contraceptive strategy for both sexes. This opinion explores the potential adaptation of existing PSA inhibitors from the oncology field for contraceptive applications. It also highlights emerging strategies to identify effective PSA-targeted contraceptive candidates, opening new avenues for next-generation nonhormonal contraception for men and women.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Targeting AMPK as a potential treatment for hepatic fibrosis in MASLD. 靶向AMPK作为MASLD肝纤维化的潜在治疗方法。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-01 Epub Date: 2025-04-28 DOI: 10.1016/j.tips.2025.03.008
Xavier Palomer, Jue-Rui Wang, Claudia Escalona, Siyuan Wu, Walter Wahli, Manuel Vázquez-Carrera
{"title":"Targeting AMPK as a potential treatment for hepatic fibrosis in MASLD.","authors":"Xavier Palomer, Jue-Rui Wang, Claudia Escalona, Siyuan Wu, Walter Wahli, Manuel Vázquez-Carrera","doi":"10.1016/j.tips.2025.03.008","DOIUrl":"10.1016/j.tips.2025.03.008","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, and often progresses to hepatic fibrosis, cirrhosis, and liver failure. Despite its increasing prevalence, effective pharmacological treatments for MASLD-related fibrosis remain limited. Recent research has highlighted AMP-activated protein kinase (AMPK) as a key regulator of the processes that promote fibrogenesis, and AMPK activation shows potential in mitigating fibrosis. Advances in AMPK activators and deeper insights into their role in fibrotic pathways have recently revitalized interest in targeting AMPK for fibrosis treatment. This review discusses the molecular mechanisms linking AMPK to hepatic fibrosis and evaluates emerging AMPK-directed therapies. Furthermore, it addresses challenges in clinical translation. Importantly, we combine the latest mechanistic discoveries with recent therapeutic developments to provide a comprehensive perspective on AMPK as a target for hepatic fibrosis treatment.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"551-566"},"PeriodicalIF":13.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Developmental toxicity: artificial intelligence-powered assessments. 发育毒性：人工智能驱动的评估。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-01 Epub Date: 2025-05-15 DOI: 10.1016/j.tips.2025.04.005
Tong Wang, Xuelian Jia, Lauren M Aleksunes, Hui Shen, Hong-Wen Deng, Hao Zhu
{"title":"Developmental toxicity: artificial intelligence-powered assessments.","authors":"Tong Wang, Xuelian Jia, Lauren M Aleksunes, Hui Shen, Hong-Wen Deng, Hao Zhu","doi":"10.1016/j.tips.2025.04.005","DOIUrl":"10.1016/j.tips.2025.04.005","url":null,"abstract":"<p><p>Regulatory agencies require comprehensive toxicity testing for prenatal drug exposure, including new drugs in development, to reduce concerns about developmental toxicity, that is, drug-induced toxicity and adverse effects in pregnant women and fetuses. However, defining developmental toxicity endpoints and optimal analysis of associated public big data remain challenging. Recently, artificial intelligence (AI) approaches have had a critical role in analyzing complex, high-dimensional data, uncovering subtle relationships between chemical exposures and associated developmental risks. Here, we present an overview of major big data resources and data-driven models that focus on predicting various toxicity endpoints. We also highlight emerging, interpretable AI models that integrate multimodal data and domain knowledge to reveal toxic mechanisms underlying complex endpoints, and outline a potential framework that leverages multiple interpretable models to comprehensively evaluate chemical-induced developmental toxicity.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"486-502"},"PeriodicalIF":13.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Phylogeny-guided discovery of new antifungals. 系统发育引导下发现新的抗真菌药物。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-01 Epub Date: 2025-05-14 DOI: 10.1016/j.tips.2025.04.004
Nicolas Papon, Vincent Courdavault, Vishnu Chaturvedi
{"title":"Phylogeny-guided discovery of new antifungals.","authors":"Nicolas Papon, Vincent Courdavault, Vishnu Chaturvedi","doi":"10.1016/j.tips.2025.04.004","DOIUrl":"10.1016/j.tips.2025.04.004","url":null,"abstract":"<p><p>Fungal infections are increasing globally, with limited antifungal classes, drug toxicity issues, and the rapid emergence of multidrug resistance (MDR). By using a glycosyltransferase phylogeny-guided strategy, Deng and colleagues recently identified a new broad-spectrum polyene macrolide active against many fungal pathogens, with a novel mechanism of action and excellent safety profile.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"483-485"},"PeriodicalIF":13.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Molecular glue meets antibody: next-generation antibody-drug conjugates. 分子胶与抗体结合：新一代抗体-药物偶联物。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-01 Epub Date: 2025-05-08 DOI: 10.1016/j.tips.2025.04.002
Yiran Tao, Ying Lu, Bin Yu, Yuxi Wang
{"title":"Molecular glue meets antibody: next-generation antibody-drug conjugates.","authors":"Yiran Tao, Ying Lu, Bin Yu, Yuxi Wang","doi":"10.1016/j.tips.2025.04.002","DOIUrl":"10.1016/j.tips.2025.04.002","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) have revolutionized oncology by enabling the delivery of cytotoxic agents. However, persistent limitations in payload diversity and emerging drug-resistance mechanisms have spurred investigations into innovative payload modalities. Molecular glue-antibody conjugates (MACs), which utilize molecular glues as payloads, represent a groundbreaking advance in this field. By leveraging the catalytic, event-driven nature of molecular glues, MACs offer enhanced efficacy, reduced off-target effects, and an improved therapeutic index. Two MACs are now in clinical trials. This review explores MAC mechanisms, advances, and potential to surpass traditional ADCs and molecular glues, while addressing development challenges and future directions.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"520-534"},"PeriodicalIF":13.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Efferocytosis in inflammatory bone disorders. 炎性骨疾病中的Efferocytosis。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-01 Epub Date: 2025-05-09 DOI: 10.1016/j.tips.2025.04.001
Linlin Wen, Rongrong Ye, Wenhao Zhai, Daowei Li, Hongchen Sun
{"title":"Efferocytosis in inflammatory bone disorders.","authors":"Linlin Wen, Rongrong Ye, Wenhao Zhai, Daowei Li, Hongchen Sun","doi":"10.1016/j.tips.2025.04.001","DOIUrl":"10.1016/j.tips.2025.04.001","url":null,"abstract":"<p><p>Efferocytosis, the clearance of apoptotic cells (ACs) by phagocytes, is crucial for bone homeostasis and immune balance. This tightly regulated process depends on molecular markers such as phosphatidylserine on ACs and MERTK on phagocytes. In the bone microenvironment, multiple cell types participate in efferocytosis, including osteal macrophages, mesenchymal stem cells, osteoblasts, and osteoclasts, directly influencing bone remodeling and immune responses. Impaired efferocytosis disrupts bone turnover, exacerbates inflammation, and contributes to inflammatory bone diseases. Despite its recognized importance, the precise mechanisms regulating efferocytosis in osteoimmunology remain underexplored, including specific signaling pathways, cell-specific interactions, and therapeutic applications. Recent advances highlight the therapeutic potential of targeting efferocytosis using modalities and biomaterial-based strategies. This review systematically examines the role of efferocytosis in osteoimmunology, discusses key challenges in its therapeutic translation, and explores emerging strategies to optimize efferocytosis-based interventions for inflammatory bone disorders.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"567-583"},"PeriodicalIF":13.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Targeting the NLRP3 inflammasome for inflammatory disease therapy. 靶向NLRP3炎性小体用于炎性疾病治疗。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-01 Epub Date: 2025-05-15 DOI: 10.1016/j.tips.2025.04.007
Julia Elise Cabral, Anna Wu, Haitian Zhou, Minh Anh Pham, Sophia Lin, Reginald McNulty
{"title":"Targeting the NLRP3 inflammasome for inflammatory disease therapy.","authors":"Julia Elise Cabral, Anna Wu, Haitian Zhou, Minh Anh Pham, Sophia Lin, Reginald McNulty","doi":"10.1016/j.tips.2025.04.007","DOIUrl":"10.1016/j.tips.2025.04.007","url":null,"abstract":"<p><p>The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a megadalton complex implicated in numerous inflammation-driven diseases including COVID-19, Alzheimer's disease, and gout. Although past efforts have focused on inhibiting IL-1β downstream of NLRP3 activation using drugs such as canakinumab, no FDA-approved NLRP3-targeted inhibitors are currently available. MCC950, a direct NLRP3 inhibitor, showed promise but exhibited off-target effects. Recent research has focused on optimizing the sulfonylurea-based MCC950 scaffold by leveraging recent structural and medicinal chemistry insights into the NLRP3 nucleotide-binding and oligomerization (NACHT) domain to improve solubility and clinical efficacy. In addition, oxidized DNA (oxDNA) has emerged as a key inflammasome trigger, and molecules targeting the pyrin domain have shown promise in inhibiting NLRP3 activation. This review discusses the role of NLRP3 in inflammation-related diseases, the status of ongoing clinical trials, and emerging small-molecule therapeutics targeting NLRP3.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"503-519"},"PeriodicalIF":13.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
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