Pharmacology & Therapeutics最新文献

Treatment strategies for leptomeningeal disease in patients with breast cancer. 乳腺癌患者轻脑膜疾病的治疗策略。

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-10-08 DOI: 10.1016/j.pharmthera.2025.108933

Lennard Spanehl,Thomas Grinda,Rishab Ramapriyan,Himanshu Soni,Sarah Blitz,Philip Heesen,Rohan Jha,Chibueze D Nwagwu,Florian A Gessler,Pablo Valdes,Sarah L Sammons,Wenya Linda Bi,Gregory K Friedman,Ayal A Aizer,E Antonio Chiocca,Nancy U Lin,Joshua D Bernstock

{"title":"Treatment strategies for leptomeningeal disease in patients with breast cancer.","authors":"Lennard Spanehl,Thomas Grinda,Rishab Ramapriyan,Himanshu Soni,Sarah Blitz,Philip Heesen,Rohan Jha,Chibueze D Nwagwu,Florian A Gessler,Pablo Valdes,Sarah L Sammons,Wenya Linda Bi,Gregory K Friedman,Ayal A Aizer,E Antonio Chiocca,Nancy U Lin,Joshua D Bernstock","doi":"10.1016/j.pharmthera.2025.108933","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2025.108933","url":null,"abstract":"Leptomeningeal disease (LMD) associated with breast cancer (BC), characterized by the invasion of metastatic BC cells into the leptomeninges and cerebrospinal fluid, poses a significant clinical challenge. Current management strategies are not curative but rather aim to slow the rapid clinical decline associated with LMD, each with its own set of limitations. For instance, systemic chemotherapy faces delivery barriers while intrathecal administration directly targets the site of disease but struggles with uneven drug distribution, toxicity, and limited efficacy. Radiation therapy, including whole brain radiation, stereotactic radiosurgery, and proton craniospinal irradiation, offer palliative relief, though with varying levels of toxicity. The prognosis for patients with BC-associated LMD remains poor under existing treatment paradigms, highlighting an urgent need for innovative therapeutic strategies and delivery systems. Emerging approaches under investigation include advanced radiation techniques, targeted therapies, and novel immunotherapeutic modalities such as oncolytic viruses. Herein, we examine (1) contemporary treatment approaches for LMD in BC and (2) promising novel therapies that may reshape the management of this devastating condition.","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"19 1","pages":"108933"},"PeriodicalIF":13.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261160","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

Crosstalk between anti-angiogenic and pro-angiogenic pathways in disease: Mechanisms and therapeutic strategies. 疾病中抗血管生成和促血管生成途径之间的串扰：机制和治疗策略。

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-10-08 DOI: 10.1016/j.pharmthera.2025.108934

Runa Wang,Renshuai Zhang,Jun Zhou,Jie Ran

{"title":"Crosstalk between anti-angiogenic and pro-angiogenic pathways in disease: Mechanisms and therapeutic strategies.","authors":"Runa Wang,Renshuai Zhang,Jun Zhou,Jie Ran","doi":"10.1016/j.pharmthera.2025.108934","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2025.108934","url":null,"abstract":"Angiogenesis, which entails the sprouting of new blood vessels from existing ones, is a critical process in normal development and tissue repair. However, when dysregulated, it contributes to a variety of diseases, including cancer, ischemic disorders, and chronic inflammation. Central to these processes are key factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). Recent research has focused on therapeutic modulation of angiogenesis, employing both anti-angiogenic and pro-angiogenic strategies to regulate these pathways. Anti-angiogenic therapies primarily target the VEGF pathway to inhibit vessel formation, thereby reducing tumor vascularization in cancer and preventing abnormal blood vessel growth in neovascular ocular diseases such as age-related macular degeneration and diabetic retinopathy. Conversely, pro-angiogenic therapies stimulate vessel growth to improve vascularization in conditions like coronary artery disease and Alzheimer's disease, enhancing tissue perfusion and promoting regeneration. In this review, we summarize current knowledge on targeted modulation of angiogenesis, detailing therapeutic strategies, the mechanisms that regulate vascular homeostasis, and their implications for disease management.","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"38 1","pages":"108934"},"PeriodicalIF":13.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261460","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 cell cycle checkpoints for glioma therapy 靶向细胞周期检查点治疗胶质瘤。

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-10-01 DOI: 10.1016/j.pharmthera.2025.108932

Fengchao Lang, Chunzhang Yang

引用次数: 0

Towards directed therapy for fusion-positive rhabdomyosarcoma. 融合阳性横纹肌肉瘤的定向治疗。

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-09-30 DOI: 10.1016/j.pharmthera.2025.108931

George M Turco,Sapna Oberoi,Brian Ladle, Raavi,Lars Wagner,Angela N Koehler,Corinne M Linardic

引用次数: 0

Lipid metabolism in AKI and AKI-CKD transition: Dysregulation, lipotoxicity and therapeutic potential AKI和AKI- ckd转变中的脂质代谢：失调、脂毒性和治疗潜力。

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-09-25 DOI: 10.1016/j.pharmthera.2025.108930

Shuangshuang Wei , Ying Fu , Yuqing Zeng , Wenwen Wu , Juan Cai , Zheng Dong

引用次数: 0

Mass spectrometry-based absolute quantitative proteomics of drug-metabolizing enzymes in human liver 基于质谱的人肝脏药物代谢酶绝对定量蛋白质组学研究。

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-09-12 DOI: 10.1016/j.pharmthera.2025.108929

Zachary McCalla, Xinwen Wang

{"title":"Mass spectrometry-based absolute quantitative proteomics of drug-metabolizing enzymes in human liver","authors":"Zachary McCalla, Xinwen Wang","doi":"10.1016/j.pharmthera.2025.108929","DOIUrl":"10.1016/j.pharmthera.2025.108929","url":null,"abstract":"<div><div>Mass spectrometry-based absolute quantitative proteomics has emerged as a powerful method for accurately quantifying hepatic drug-metabolizing enzymes, which play a crucial role in drug disposition and therapeutic outcomes. Understanding the absolute drug-metabolizing enzyme protein concentrations and the associated interindividual variability in the liver, a primary organ for drug metabolism, is essential for developing predictive models for personalized pharmacotherapy. Over the past few decades, the rapid advancement of mass spectrometry-based proteomics has enabled the application of various techniques to study drug-metabolizing enzymes, significantly enhancing our understanding of their isoform composition in the liver. However, a focused review on mass spectrometry-based absolute protein quantification of human hepatic drug-metabolizing enzymes remains lacking. This review introduces commonly used strategies in mass spectrometry-based absolute protein quantification and summarizes the absolute quantities of Phase I and Phase II hepatic drug-metabolizing enzymes. It also updates the isoform compositions of cytochrome P450s and uridine diphosphate glucuronosyltransferases and explores factors contributing to variability in quantifications across studies. Additionally, we discuss the genetic and non-genetic regulations of hepatic enzyme protein expressions, as revealed by mass-spectrometry based-proteomics. Despite its potential for clinical applications, MS-based proteomics faces challenges, such as sensitivity limitation, significant inter-study varibility, cellular heterogeneity, and a lack of integration with other omics data. Future advancements in mass spectrometry-based quantitative proteomics, including single-cell proteomics, multi-omics integration, and artificial intelligence-driven data analysis, hold promise for better understanding of drug metabolizing enzymes, improving predictions of drug responses, and optimizing therapeutic outcomes for patients.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"275 ","pages":"Article 108929"},"PeriodicalIF":12.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058937","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

Cerebrovascular protective functions of amyloid precursor protein: Progress and therapeutic prospects 淀粉样前体蛋白的脑血管保护功能：研究进展及治疗前景。

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-09-05 DOI: 10.1016/j.pharmthera.2025.108921

Zvonimir S. Katusic , Livius V. d'Uscio , Tongrong He

{"title":"Cerebrovascular protective functions of amyloid precursor protein: Progress and therapeutic prospects","authors":"Zvonimir S. Katusic , Livius V. d'Uscio , Tongrong He","doi":"10.1016/j.pharmthera.2025.108921","DOIUrl":"10.1016/j.pharmthera.2025.108921","url":null,"abstract":"<div><div>Under physiological conditions, amyloid precursor protein (APP) is critically important for normal brain development, neurogenesis, neuronal survival, and synaptic signaling. Dyshomeostasis of APP increases deposition and accumulation of amyloid β (Aβ) in the brain parenchyma and cerebral blood vessels thereby leading to development of Alzheimer's disease and cerebral amyloid angiopathy. In this review, we critically examine existing literature supporting the concept that endothelial APP performs important vascular protective functions in the brain. Studies in cultured human brain microvascular endothelium and cerebral arteries derived from genetically modified mice indicate that loss of APP impairs expression and function of Krüppel-like Factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS) thereby causing endothelial dysfunction. Congruency between the findings obtained in murine and human cerebrovascular endothelium is consistent with strong evolutionary conservation of APP, and reinforces the concept that APP is an important vascular protective protein. Furthermore, we highlight vascular protective effects of APP during aging. We also address the roles of endothelial prostacyclin and nitric oxide in control of expression and proteolytic cleavage of APP. Finally, we outline potential translational opportunities emerging from recent advances in understanding of cerebrovascular function of APP. Several pharmacologically active domains of APP have been identified thus providing templates for creation of novel peptides with therapeutic properties.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"275 ","pages":"Article 108921"},"PeriodicalIF":12.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008693","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

Air pollution and diseases: signaling, G protein-coupled and Toll like receptors 空气污染与疾病：信号、G蛋白偶联和Toll样受体。

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-09-04 DOI: 10.1016/j.pharmthera.2025.108920

Isabella Cattani-Cavalieri , Katrina F. Ostrom , Jordyn Margolis , Rennolds S. Ostrom , Martina Schmidt

{"title":"Air pollution and diseases: signaling, G protein-coupled and Toll like receptors","authors":"Isabella Cattani-Cavalieri , Katrina F. Ostrom , Jordyn Margolis , Rennolds S. Ostrom , Martina Schmidt","doi":"10.1016/j.pharmthera.2025.108920","DOIUrl":"10.1016/j.pharmthera.2025.108920","url":null,"abstract":"<div><div>Air pollution is a significant public health issue that impacts lung health, particularly in vulnerable populations such as children, the elderly, and individuals with pre-existing respiratory conditions. Both natural and anthropogenic sources of air pollution give rise to a variety of toxic compounds, including particulate matter (PM), ozone (O₃), sulfur dioxide (SO₂), nitrogen dioxide (NO₂), carbon monoxide (CO), and polycyclic aromatic hydrocarbons (PAHs). Exposure to these pollutants is strongly associated with the development and exacerbation of respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF). Notably, early life exposure to pollutants such as PM, NO₂, and O₃ is linked to an increased risk of childhood asthma. Air pollution can mediate adverse effects through effects on receptor signaling pathways, particularly those involving G-protein coupled receptors (GPCRs) and Toll-like receptors (TLRs). Both of these receptor families play key roles in regulating pulmonary function and immune responses. GPCRs are involved in mediating cellular responses via cyclic AMP (cAMP), calcium and other second messengers, while TLRs initiate immune responses. Understanding how air pollutants and cigarette smoke alter GPCR and TLR function to contribute to lung disease is a critical area of study, as these receptors play central roles in regulating inflammation, immune responses, oxidative stress, airway remodeling and airway tone. Disruption of their signaling by pollutants can exacerbate respiratory conditions such as asthma and COPD. This review explores what is known about how air pollution impacts GPCR and TLR signaling, offers insights into the mechanisms underlying respiratory disease development and highlights potential therapeutic strategies aimed at mitigating the impact of air pollution on lung health.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"275 ","pages":"Article 108920"},"PeriodicalIF":12.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007087","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

Suppressor tRNAs as personalized therapy for nonsense mutation-associated pathologies 抑制trna作为无义突变相关病理的个性化治疗

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-08-22 DOI: 10.1016/j.pharmthera.2025.108919

Zoya Ignatova, Suki Albers

引用次数: 0

Therapeutic exploration of biased ligands at class A G protein-coupled receptors over the past 20 years 在过去的20年中，对A类G蛋白偶联受体的偏配体的治疗探索

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-08-21 DOI: 10.1016/j.pharmthera.2025.108918

Jixia Wang , Fangfang Xu , Yanfang Liu , Han Zhou , Wenjie Yuan , Fan Liu , Ye Fang , Xinmiao Liang

{"title":"Therapeutic exploration of biased ligands at class A G protein-coupled receptors over the past 20 years","authors":"Jixia Wang , Fangfang Xu , Yanfang Liu , Han Zhou , Wenjie Yuan , Fan Liu , Ye Fang , Xinmiao Liang","doi":"10.1016/j.pharmthera.2025.108918","DOIUrl":"10.1016/j.pharmthera.2025.108918","url":null,"abstract":"<div><div>Recent decades have witnessed significant advances in the development of biased ligands for G protein-coupled receptors (GPCRs) as potential therapeutic agents with enhanced efficacy and reduced on-target side effects. This is largely attributed to the unique capability of biased ligands to activate pathway-selective signaling, which can effectively modulate in vivo pharmacology. This review presents a comprehensive analysis of biased ligands targeting class A GPCRs over the past 20 years, encompassing discovery strategies, assays, biological effects and therapeutic applications. The analysis covers approximately 383 biased ligands acting on 60 different GPCRs, among which opioid, 5-hydroxytryptamine, dopamine, adrenergic and cannabinoid receptors are the five subfamilies with the highest number of reported biased ligands. The biological effects of these biased ligands are primarily investigated in the area of pain, cardiovascular, neurological, respiratory, metabolic and inflammatory diseases. The regulatory approval of the opioid biased agonist TRV130 for pain management, along with the growing number of biased drugs tested in clinical trials, heralds a new era in GPCR drug development. Additionally, various natural product biased ligands have been identified. A deeper understanding of the biological functions and pharmacological effects of biased ligands will support future advancements in GPCR drug development.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"274 ","pages":"Article 108918"},"PeriodicalIF":12.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144891968","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