Pharmacology & Therapeutics最新文献

Corrigendum to “Immunomodulation and targeted drug delivery with high intensity focused ultrasound (HIFU): Principles and mechanisms” [Volume 244, April 2023, 108393] “高强度聚焦超声（HIFU）的免疫调节和靶向药物递送：原理和机制”的勘误表[第244卷，2023年4月，108393]

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-05-30 DOI: 10.1016/j.pharmthera.2025.108890

Harshini Ashar, Happy Agarwal, Ashish Ranjan

引用次数: 0

Post-COVID pulmonary sequelae: Mechanisms and potential targets to reduce persistent fibrosis. covid后肺后遗症：减少持续性纤维化的机制和潜在靶点

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-05-28 DOI: 10.1016/j.pharmthera.2025.108891

Emma C A Vreeman, Janesh Pillay, Janette K Burgess

{"title":"Post-COVID pulmonary sequelae: Mechanisms and potential targets to reduce persistent fibrosis.","authors":"Emma C A Vreeman, Janesh Pillay, Janette K Burgess","doi":"10.1016/j.pharmthera.2025.108891","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2025.108891","url":null,"abstract":"<p><p>After the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) pandemic, the emergence of long-term sequelae post-infection poses a new healthcare challenge. Following initial infection with SARS-CoV-2, approximately 1 in 10 people experience post-acute sequelae of COVID-19 (PASC), also known as long COVID. PASC can affect the entire body, with the airways and lungs being a primary target of the initial viral infection. Many post-COVID symptoms have been associated with fibrotic lung lesions and diminished respiratory function. The reversibility, persistence, or progression of post-COVID-19 pulmonary fibrosis is still a topic of debate. We aimed to compare current findings and examined similar viral infections from the past, to increase understanding of prevalence, persistence and possible pharmacological targets of post-COVID-19 pulmonary fibrosis. Recent studies have documented PASC symptoms persisting up to 3 years post-recovery, and lung impairments present after 15 years after infection with the similar SARS-CoV virus in 2003. These findings suggest the potential for long-term pulmonary fibrosis following SARS-CoV-2 infection, highlighting the need for new anti-fibrotic treatments capable of reversing pulmonary fibrosis. Besides the approved anti-fibrotics, pirfenidone and nintedanib, other promising treatments include histone deacetylase inhibitors, angiotensin receptor blockers and mesenchymal stem cells. The pathophysiological mechanisms underlying post-COVID-19 pulmonary fibrosis are still incompletely understood, necessitating future research to clarify the development of persistent post-COVID-19 pulmonary fibrosis following SARS-CoV-2 infection. Given the widespread transmission of SARS-CoV-2, even a low prevalence of persistent post-COVID-19 pulmonary fibrosis would represent a significant public health concern for which therapeutic strategies are essential to identify.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108891"},"PeriodicalIF":12.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186159","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}

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Recent advances in therapeutic targeting of the KRAS pathway in cancer. KRAS通路靶向治疗肿瘤的研究进展。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-05-28 DOI: 10.1016/j.pharmthera.2025.108889

Nadia Hitchen, Sarah Williams, Jayesh Desai

{"title":"Recent advances in therapeutic targeting of the KRAS pathway in cancer.","authors":"Nadia Hitchen, Sarah Williams, Jayesh Desai","doi":"10.1016/j.pharmthera.2025.108889","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2025.108889","url":null,"abstract":"<p><p>Recent advances in cancer therapy have significantly progressed through targeted inhibition of the rat sarcoma virus (RAS) signalling pathway, particularly focusing on Kirsten rat sarcoma virus (KRAS) mutations prevalent in cancers such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). Historically deemed \"undruggable,\" KRAS mutations, especially KRASG12C and KRASG12D, are now effectively targeted by specific inhibitors that have demonstrated promising clinical results. Agents such as Sotorasib, Adagrasib, and Divarasib exhibit notable efficacy against KRASG12C mutations, particularly in NSCLC, with combination strategies significantly improving outcomes, especially in CRC. With over 50 agents currently in development, targeting KRAS has become a rapidly expanding area of cancer therapeutics. However, substantial challenges remain, including optimizing clinical trial designs, particularly in early-phase trials, and integrating pharmacodynamic tools to refine dosing and treatment schedules, thus achieving an optimal balance between efficacy and patient tolerability. This review summarizes recent therapeutic advancements, highlighting the clinical development of KRAS-specific inhibitors, and emphasizes future strategies involving a combination of mutant-specific and broader mutant-independent approaches to overcome resistance, thereby offering promise for more durable cancer control and expanded patient eligibility.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108889"},"PeriodicalIF":12.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186160","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

Alternative splicing in aging and aging-related diseases: From pathogenesis to therapy 衰老和衰老相关疾病的选择性剪接：从发病机制到治疗。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-05-23 DOI: 10.1016/j.pharmthera.2025.108887

Mingrui Han , Peiru Han , Zihui Wang , Lingdong Kong , Qiang Xu , Qianqian Liu , Yang Sun

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N-methyl-d-aspartate receptors (NMDARs): a glutamate-activated cation channel with biased signaling and therapeutic potential in brain disorders. n -甲基-d-天冬氨酸受体（NMDARs）：一种谷氨酸激活的阳离子通道，具有偏倚信号传导和治疗脑疾病的潜力。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-05-22 DOI: 10.1016/j.pharmthera.2025.108888

Xuan Zhang, Wensheng Cai, Chao Wang, Jing Tian

{"title":"N-methyl-d-aspartate receptors (NMDARs): a glutamate-activated cation channel with biased signaling and therapeutic potential in brain disorders.","authors":"Xuan Zhang, Wensheng Cai, Chao Wang, Jing Tian","doi":"10.1016/j.pharmthera.2025.108888","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2025.108888","url":null,"abstract":"<p><p>N-methyl-d-aspartate receptors (NMDARs) are a type of calcium-permeable ion channel receptors that are extensively distributed throughout the body, composed of various subunits. The presence of diverse ligands and subcellular localizations of the receptors confer biased signaling and distinct functional roles. Activation of the NMDARs induces calcium influx, which plays a pivotal role in neurotransmitter release, synaptic plasticity, and intracellular signaling. Differential localization of NMDARs at synaptic and extrasynaptic sites results in divergent physiological effects; excessive or insufficient activation of NMDARs disrupts calcium homeostasis, leading to neuronal damage and subsequent neurological dysfunction as well as related diseases. Therefore, it is crucial to develop drugs targeting NMDAR with high efficacy with low toxicity for treating disorders associated with NMDARs abnormalities. In this review, we summarize both fundamental and clinical studies on NMDARs while discussing potential therapeutic targets aimed at modulating ion channel activity through regulating mechanisms, subunit rearrangement, membrane expression, and the specific targeting of synaptic versus extrasynaptic NMDARs. Our goal is to provide new insights for innovative drug development.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108888"},"PeriodicalIF":12.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140959","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}

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Editorial: Pharmacological targets for the control of tissue remodelling and fibrosis 编辑：控制组织重塑和纤维化的药理学靶点。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-05-20 DOI: 10.1016/j.pharmthera.2025.108880

Peter Holzer

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Human intestinal enteroids: Nonclinical applications for predicting oral drug disposition, toxicity, and efficacy. 人类肠道类肠：预测口服药物处置、毒性和疗效的非临床应用。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-05-19 DOI: 10.1016/j.pharmthera.2025.108879

Eimear T O'Mahony, Christopher M Arian, Kayenat S Aryeh, Kai Wang, Kenneth E Thummel, Edward J Kelly

{"title":"Human intestinal enteroids: Nonclinical applications for predicting oral drug disposition, toxicity, and efficacy.","authors":"Eimear T O'Mahony, Christopher M Arian, Kayenat S Aryeh, Kai Wang, Kenneth E Thummel, Edward J Kelly","doi":"10.1016/j.pharmthera.2025.108879","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2025.108879","url":null,"abstract":"<p><p>The application of human enteroid systems presents a significant opportunity within the drug development pipeline, highlighting considerable potential for advancements in the characterization and evaluation of new molecular entities. Derived from LGR5<sup>+</sup> crypt-based columnar cells, enteroid systems more accurately recapitulate the microanatomy and physiological processes of the human intestinal mucosa compared to traditionally used systems. They contain the complement of major mucosal epithelial cell types, maintain the genetic identity of the donor and intestinal segment they were derived from, and exhibit biological functions and specific activities that are seen in vivo. In this review, we examine the applications of human enteroid systems in nonclinical drug development and compare findings to existing and emerging in vitro models of the small intestine. Specifically, we explore enteroid systems in the context of predicting oral drug disposition, focusing on apparent permeability, intestinal first-pass metabolism, and drug interactions, as well as their utility in assessing drug-induced gastrointestinal toxicity and screening therapeutic efficacy against enteric diseases. Additionally, we highlight aspects of enteroid systems that warrant further study.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108879"},"PeriodicalIF":12.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118466","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 many facets of biased signaling: Mechanisms and possible therapeutic implications 偏倚信号的许多方面：机制和可能的治疗意义。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-05-16 DOI: 10.1016/j.pharmthera.2025.108877

K. Helivier Solís, M. Teresa Romero-Ávila, Rocío Alcántara-Hernández, J. Adolfo García-Sáinz

{"title":"The many facets of biased signaling: Mechanisms and possible therapeutic implications","authors":"K. Helivier Solís, M. Teresa Romero-Ávila, Rocío Alcántara-Hernández, J. Adolfo García-Sáinz","doi":"10.1016/j.pharmthera.2025.108877","DOIUrl":"10.1016/j.pharmthera.2025.108877","url":null,"abstract":"<div><div>Receptor-mediated cell activation frequently results in a plethora of effects, and interestingly, not all agonists that act on a given receptor activate all of those actions to the same extent. Biased agonism refers to this fact, i.e., the possibility to activate only a part of the receptor's signaling capabilities. It is worth mentioning that Biased Signaling is an integral concept that includes the system (organisms, isolated tissues, or cells), the individual receptor studied, and the ligands. It should be remembered that the system's genetic expression profile defines the type, abundance, and cellular localization of proteins that participate in signaling. This short review will be focused on G protein receptors, but biased signaling occurs in many other receptor types.</div><div>Biased signaling can be related to the G proteins and β-arrestins available. Similarly, enzymes that catalyze receptor posttranslational modifications, such as phosphorylation, acylation, or ubiquitination, can play a role. G protein-coupled receptor signaling occurs at the plasma membrane, but it is well-established that endosomal signaling is a functional reality. Therefore, paying attention to cellular elements that participate in receptor endosomal traffic and destination (recycling to the plasma membrane/ degradation) is pertinent. There is still much to be known about these bias mechanisms, which are essential for basic knowledge of receptor drug action and for treating many pathological entities.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108877"},"PeriodicalIF":12.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092365","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 free fatty acid receptor 2 (FFA2): Mechanisms of action, biased signaling, and clinical prospects 游离脂肪酸受体2 (FFA2)：作用机制、偏倚信号和临床前景

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-05-16 DOI: 10.1016/j.pharmthera.2025.108878

Yang Li , Qiao Liu , Chuan-Ying Pan , Xian-Yong Lan

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Neuromuscular and cardiac organoids and assembloids: Advanced platforms for drug testing 神经肌肉和心脏类器官和组合体：先进的药物测试平台。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-05-14 DOI: 10.1016/j.pharmthera.2025.108876

Lorenzo Fontanelli , Noemi Nisini , Sergio Pirola , Fabio A. Recchia

{"title":"Neuromuscular and cardiac organoids and assembloids: Advanced platforms for drug testing","authors":"Lorenzo Fontanelli , Noemi Nisini , Sergio Pirola , Fabio A. Recchia","doi":"10.1016/j.pharmthera.2025.108876","DOIUrl":"10.1016/j.pharmthera.2025.108876","url":null,"abstract":"<div><div>The inherent technical difficulties, ethical/regulatory issues and costs of experimental studies in animal models is prompting investigators to replace as much as possible living organisms with <em>in vitro</em> physiological models named organoids and assembloids. Generated from induced pluripotent stem cells, these three-dimensional structures approximate the complexity of tissues and their interactions, enabling personalized disease modelling and drug testing. The integration of multiple components in assembloids further enhances their predictive value for multi-system interactions and toxicities. This review describes how neuromuscular organoids, incorporating functional neuromuscular junctions and contractile muscle tissue, have been used to replicate, <em>in vitro</em>, complex neuromuscular morpho-functional structures, offering very valuable platforms to study molecular mechanisms and drug effects in models of incurable diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. In the cardiological field, cardiac organoids and assembloids are proving reliable models for testing drug effects at molecular, morphological, electrophysiological and mechanical level. Recently, the integration of neuronal components into cardiac organoids has provided a potential approach to investigate autonomic function, a fundamental aspect of many neurological, neuromuscular and cardiac diseases. Challenges and limitations still remain, including the non-uniform differentiation protocols across studies, the incomplete maturation of cell phenotypes, and the lack of integrated pharmacokinetic modelling. We discussed some future developments aimed at overcoming such hurdles. Despite their current limitations, organoids and assembloids clearly hold great promises and will help advancing many fields of biomedicine.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108876"},"PeriodicalIF":12.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085592","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