Pharmacology & Therapeutics最新文献

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Molecular, metabolic, and histological subtypes of pancreatic ductal adenocarcinoma and its tumor microenvironment: Insights into tumor heterogeneity and clinical implications 胰腺导管腺癌的分子、代谢和组织学亚型及其肿瘤微环境：对肿瘤异质性和临床意义的见解

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-11-01 DOI: 10.1016/j.pharmthera.2025.108946

Yuuki Ohara , Huaitian Liu , Paloma Moreno , Seiya Suzuki , S. Perwez Hussain

Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous cancer with poor prognosis and limited therapeutic options. Bulk transcriptomic profiling has identified two major gene expression–based molecular subtypes: classical/progenitor and basal-like/squamous/quasimesenchymal. These subtypes differ in biological characteristics, differentiation status, drug sensitivity, and clinical outcomes. Advances in single-cell and spatial transcriptomics have further revealed intermediate/hybrid states, as well as distinct subtypes within the tumor microenvironment. These technologies have also uncovered intratumoral heterogeneity, tumor–stroma interactions, and spatially organized transcriptional programs that further shape subtype identity and plasticity, which can shift over time or under therapeutic pressure. In parallel, metabolomic analyses have revealed distinct metabolic subtypes that align with molecular subtypes and highlight subtype-specific metabolic rewiring and vulnerabilities. Furthermore, recent deep learning approaches applied to histopathology allow for high-resolution, morphology-based subtype prediction using Hematoxylin & Eosin-stained slides, providing practical and potentially scalable diagnostic tools. These multi-layered insights are reshaping PDAC taxonomy and enhancing our understanding of how transcriptional, metabolic, and spatial features together define tumor behavior and therapeutic response. This review discusses molecular (transcriptomic), metabolic, and histological subtyping approaches for PDAC, with the aim of enabling practical, cost-effective diagnosis and personalized medicine. By integrating data from recent experimental and clinical studies, we aim to provide a comprehensive and accessible overview of PDAC subtype heterogeneity, which may help guide future subtype-informed therapeutic strategies.

胰腺导管腺癌（PDAC）是一种高度异质性的癌症，预后差，治疗选择有限。大量转录组学分析已经确定了两种主要的基于基因表达的分子亚型：经典/祖细胞亚型和基底样/鳞状/准间质亚型。这些亚型在生物学特征、分化状态、药物敏感性和临床结果方面存在差异。单细胞和空间转录组学的进展进一步揭示了肿瘤微环境中的中间/杂交状态以及不同的亚型。这些技术还揭示了肿瘤内异质性、肿瘤-基质相互作用和空间组织的转录程序，这些程序进一步塑造了亚型的身份和可塑性，这些身份和可塑性可以随着时间或治疗压力而改变。与此同时，代谢组学分析揭示了与分子亚型一致的不同代谢亚型，并突出了亚型特异性代谢重连接和脆弱性。此外，最近应用于组织病理学的深度学习方法允许使用苏木精和伊红染色的载玻片进行高分辨率，基于形态的亚型预测，提供实用且具有潜在可扩展性的诊断工具。这些多层次的见解正在重塑PDAC分类，并增强我们对转录、代谢和空间特征如何共同定义肿瘤行为和治疗反应的理解。这篇综述讨论了PDAC的分子（转录组学）、代谢和组织学亚型方法，目的是实现实用、成本效益高的诊断和个性化医疗。通过整合最近的实验和临床研究数据，我们的目标是提供PDAC亚型异质性的全面和可访问的概述，这可能有助于指导未来的亚型知情治疗策略。

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引用次数: 0

Editorial: Beyond the opioid crisis: New targets for the management of chronic pain 社论：超越阿片类药物危机：慢性疼痛管理的新目标

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-10-28 DOI: 10.1016/j.pharmthera.2025.108942

Peter Holzer

引用次数: 0

Cannabidiol and Parkinson's disease: Investigating receptor interactions and their therapeutic implications 大麻二酚和帕金森病：研究受体相互作用及其治疗意义

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-10-27 DOI: 10.1016/j.pharmthera.2025.108943

Eric A. Okrah , Claire Allan , Monika S. Doblin , Sarah J. Annesley

Cannabidiol (CBD) is one of the major active constituents among the several hundreds of compounds found in the cannabis plant. It is a non-psychoactive compound known for its anti-inflammatory, neuroprotective, antidepressant and anxiolytic effects. In preclinical studies it has shown to be effective, safe, and well-tolerated in mitigating the symptoms associated with Parkinson's disease (PD) and other neurodegenerative diseases. However, the mechanism of action is not fully characterised. CBD is postulated to exert its therapeutic effects through its interaction with the endocannabinoid system (ECS), and via interaction with a large array of non-cannabinoid receptors, neurotransmitters, and enzymes. These interactions are complex and are influenced by cell type, concentration and exposure time. The lack of specificity for a single receptor system makes CBD an intriguing therapeutic compound and enables it to influence multiple pathways. This broad interaction goes beyond its beneficial therapeutic effects and could lead to potential adverse effects. Detailed understanding of the versatility and complexity of how CBD exerts its effect is required so that the true potential as a therapeutic option can be realised.

大麻二酚（CBD）是在大麻植物中发现的数百种化合物中的主要活性成分之一。它是一种非精神活性化合物，以其抗炎、神经保护、抗抑郁和抗焦虑作用而闻名。在临床前研究中，它在减轻帕金森病（PD）和其他神经退行性疾病相关症状方面显示出有效、安全且耐受性良好。然而，其作用机制尚未完全确定。据推测，CBD通过与内源性大麻素系统（ECS）的相互作用，以及与大量非大麻素受体、神经递质和酶的相互作用来发挥其治疗作用。这些相互作用是复杂的，并受到细胞类型、浓度和暴露时间的影响。对单一受体系统缺乏特异性使得CBD成为一种有趣的治疗化合物，并使其能够影响多种途径。这种广泛的相互作用超出了其有益的治疗效果，并可能导致潜在的不良反应。需要详细了解CBD如何发挥其作用的多功能性和复杂性，以便实现其作为治疗选择的真正潜力。

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引用次数: 0

Animal models in leukotriene research: Current insights into complex pathways and therapeutic intervention 白三烯研究中的动物模型：当前对复杂途径和治疗干预的见解

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-10-27 DOI: 10.1016/j.pharmthera.2025.108944

Tarvi Teder , Olof Rådmark , Jesper Z. Haeggström , Helike Lõhelaid

Oxylipins are oxygenated bioactive lipid mediators formed from different polyunsaturated fatty acids through the bioactions of cyclooxygenases, lipoxygenases and cytochrome P450 enzymes, and participate in many physiological and pathophysiological processes. For example, oxylipins regulate vascular tone, the onset of labor, pain, inflammation, fever and contribute to diseases such as asthma, cancer, arthritis, diabetes, obesity and neurodegenerative disorders. Understanding the mechanisms and cellular components involved in oxylipin biosynthesis is crucial for developing effective therapies that minimize complications and improve disease outcomes. Thus far, various animal models have increased our understanding of oxylipin biosynthesis and regulation in complex biological environments. These models have also facilitated the discovery of novel drug targets and the evaluation of drug safety and efficacy. However, each species used as a model system has its own advantages and limitations. Here we provide an overview of the most relevant and widely used models in lipid mediator research with a focus on 5-lipoxygenase and leukotriene pathway, emphasizing the significance of animal models in advancing our understanding of the complexities of leukotriene biology and its implications for human health.

氧脂素是由不同的多不饱和脂肪酸通过环加氧酶、脂加氧酶和细胞色素P450酶的生物作用而形成的含氧生物活性脂质介质，参与许多生理和病理生理过程。例如，氧化脂素调节血管张力、分娩、疼痛、炎症、发烧的发作，并有助于哮喘、癌症、关节炎、糖尿病、肥胖和神经退行性疾病等疾病。了解参与氧化脂素生物合成的机制和细胞成分对于开发有效的治疗方法以减少并发症和改善疾病预后至关重要。到目前为止，各种动物模型增加了我们对复杂生物环境中氧化脂素的生物合成和调控的理解。这些模型也促进了新的药物靶点的发现和药物安全性和有效性的评价。然而，每个物种作为模型系统都有其自身的优点和局限性。在这里，我们概述了脂质介质研究中最相关和最广泛使用的模型，重点是5-脂氧合酶和白三烯途径，强调动物模型在促进我们对白三烯生物学复杂性及其对人类健康的影响的理解中的重要性。

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引用次数: 0

Formylpeptide receptors: A novel target to treat cardiometabolic complications 甲酰基肽受体：治疗心脏代谢并发症的新靶点。

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-10-26 DOI: 10.1016/j.pharmthera.2025.108941

Chen Huei Leo , Elizabeth A. Vecchio , Ting Fu , Xiangyan Yi , Cheng Peng , Peishen Zhao , Owen L. Woodman , Jonathan Baell , Rebecca H. Ritchie , Cheng Xue Qin

The formylpeptide receptor (FPR) family, particularly FPR2, has emerged as a master regulator of inflammation and its resolution. Given that both cardiovascular diseases and metabolic disorders are characterised by pro-inflammatory scenarios, often with resultant impairment of the healing response to (i.e. resolution of) inflammation, therapeutic targeting of the FPR family with judicious agonist selection provides new promise for tackling cardiometabolic disease. Here, we consider the pharmacology of this intriguing receptor family, the potential for novel biased signalling at its receptor subtypes and the current status of both endogenous and synthetic agonists (including peptides/proteins, small molecules and lipids) reported to be active at FPRs. A detailed review of the therapeutic potential of published FPR ligands involved in regulating and resolving inflammation in cardiometabolic disease is also provided. We anticipate that a broader understanding of, and greater appreciation for, the translational potential of pro-resolution FPR-based therapies may offer new effective means of targeting a range of cardiometabolic disorders and their resultant complications.

甲酰基肽受体（FPR）家族，特别是FPR2，已经成为炎症及其解决的主要调节因子。鉴于心血管疾病和代谢紊乱都以促炎情景为特征，通常会导致炎症愈合反应（即消退）的损害，明智地选择激动剂治疗FPR家族为治疗心脏代谢疾病提供了新的希望。在这里，我们考虑了这个有趣的受体家族的药理学，其受体亚型的新偏态信号的潜力，以及内源性和合成激动剂（包括肽/蛋白，小分子和脂质）的现状，这些激动剂被报道在fpr中有活性。详细回顾了已发表的FPR配体参与调节和解决心脏代谢疾病炎症的治疗潜力。我们预计，更广泛的理解和更大的赞赏，以促解决fpr为基础的治疗的转化潜力可能提供针对一系列心脏代谢疾病及其并发症的新的有效手段。

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引用次数: 0

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 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

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

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, offers 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.

轻脑膜病（LMD）与乳腺癌（BC）相关，其特征是转移性BC细胞侵入轻脑膜和脑脊液，这是一个重大的临床挑战。目前的管理策略不是治愈性的，而是旨在减缓与LMD相关的快速临床衰退，每种策略都有其自身的局限性。例如，全身化疗面临递送障碍，而鞘内给药直接针对疾病部位，但药物分布不均匀、毒性和疗效有限。放射治疗，包括全脑放射、立体定向放射外科和质子颅脊髓照射，虽然具有不同程度的毒性，但可提供姑息性缓解。在现有的治疗模式下，bc相关性LMD患者的预后仍然很差，因此迫切需要创新的治疗策略和给药系统。正在研究的新方法包括先进的放射技术、靶向治疗和新的免疫治疗方式，如溶瘤病毒。在此，我们研究了(1)不列颠哥伦比亚省LMD的当代治疗方法和(2)可能重塑这种破坏性疾病管理的有希望的新疗法。

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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 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

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

Runa Wang , Renshuai Zhang , Jun Zhou , Jie Ran

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.

血管生成是指从现有血管中冒出新的血管，是正常发育和组织修复的关键过程。然而，当失调时，它会导致多种疾病，包括癌症、缺血性疾病和慢性炎症。这些过程的核心是关键因子，如血管内皮生长因子（VEGF）、成纤维细胞生长因子（FGF）和血小板衍生生长因子（PDGF）。最近的研究主要集中在血管生成的治疗性调节，采用抗血管生成和促血管生成策略来调节这些途径。抗血管生成疗法主要针对VEGF途径抑制血管形成，从而减少癌症中肿瘤的血管化，防止年龄相关性黄斑变性、糖尿病性视网膜病变等新生血管性眼病的血管异常生长。相反，促血管生成疗法刺激血管生长以改善冠状动脉疾病和阿尔茨海默病等疾病的血管化，增强组织灌注并促进再生。在这篇综述中，我们总结了目前关于血管生成靶向调节的知识，详细介绍了治疗策略，调节血管稳态的机制，以及它们对疾病管理的意义。

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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 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

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

Fengchao Lang, Chunzhang Yang

Glioma is a devastating disease associated with unfavorable clinical outcomes. Current standard treatments, including surgery, radiotherapy, and chemotherapy, are largely palliative and offer limited improvements in survival rates. Glioma is characterized by high proliferative capacity, which is primarily through exploiting the dysregulated cell cycle mechanisms for disease progression. Over the past few decades, targeting the glioma cell cycle—particularly key molecules involved in cell cycle checkpoints—has been a promising direction for future glioma therapeutics. In this review, we summarize the distinctive molecular patterns of cell cycle in glioma, and discuss emerging targeted therapies designed for glioma cell cycle regulators.

胶质瘤是一种具有破坏性的疾病，其临床结果往往不佳。目前的标准治疗，包括手术、放疗和化疗，在很大程度上是姑息性的，对生存率的改善有限。胶质瘤的特点是高增殖能力，这主要是通过利用失调的细胞周期机制来实现疾病进展。在过去的几十年里，靶向胶质瘤细胞周期——特别是参与细胞周期检查点的关键分子——已经成为未来胶质瘤治疗的一个有希望的方向。在这篇综述中，我们总结了胶质瘤细胞周期的独特分子模式，并讨论了针对胶质瘤细胞周期调节剂的新兴靶向治疗方法。

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 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

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

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. The fusion-positive variant of rhabdomyosarcoma has the dubious distinction of being one of the most difficult to cure childhood cancers. Although the gene fusions PAX3::FOXO1 and PAX7::FOXO1 were discovered in the early 1990s, and since that time shown to be the molecular drivers of the disease, the best treatment to date still remains VAC (vincristine, actinomycin D, cyclophosphamide) combination therapy, first instituted as standard of care in the 1970s. Here we review the history, contemporary application, clinical evaluation, and future of fusion positive rhabdomyosarcoma systemic therapy. It is hoped that a better understanding of the underlying biology and the effective leverage of new strategies for targeting RNA, proteins, and the immune system will result in meaningful advances for treating this aggressive childhood cancer.

横纹肌肉瘤是儿童最常见的软组织肉瘤。横纹肌肉瘤的融合阳性变体具有最难以治愈的儿童癌症之一的可疑区别。虽然基因融合PAX3::FOXO1和PAX7::FOXO1在20世纪90年代初被发现，并且从那时起被证明是该疾病的分子驱动因素，但迄今为止最好的治疗方法仍然是VAC （vincristine，放线菌素D，环磷酰胺）联合疗法，该疗法于20世纪70年代首次作为标准护理制定。在此，我们回顾融合阳性横纹肌肉瘤全身治疗的历史、当代应用、临床评价和未来。希望对潜在生物学的更好理解和针对RNA、蛋白质和免疫系统的新策略的有效利用将导致治疗这种侵袭性儿童癌症的有意义的进展。

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 Q1 PHARMACOLOGY & PHARMACY

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

Acute kidney injury (AKI) is a prevalent clinical syndrome characterized by a rapid loss of renal function with high rates of morbidity and mortality. After AKI, the kidney may repair but the repair is often incomplete or maladaptive resulting in chronic pathologies for the development of chronic kidney disease (CKD). Emerging evidence highlights significant alterations in renal lipid profiles in both AKI and CKD models and human patients. The disturbances in lipid metabolism, characterized by lipid accumulation, lipid peroxidation, and subsequent development of a lipotoxic inflammatory milieu, are intricately linked to both the initiation of AKI and its transition or progression to CKD. Current research has focused on unraveling the changes in lipid metabolism and pinpoint the role of lipid dysregulation in AKI and AKI-CKD transition. In addition, pharmacological interventions targeting lipid metabolism have shown therapeutic promise in these disease models.

急性肾损伤（AKI）是一种常见的临床综合征，其特点是肾功能迅速丧失，发病率和死亡率高。AKI后，肾脏可以修复，但修复往往不完全或不适应，导致慢性病理发展为慢性肾脏疾病（CKD）。新出现的证据强调了AKI和CKD模型和人类患者肾脂质谱的显著改变。脂质代谢紊乱，以脂质积累、脂质过氧化和随后脂毒性炎症环境的发展为特征，与AKI的发生及其向CKD的转变或进展有着复杂的联系。目前的研究主要集中在揭示脂质代谢的变化，明确脂质失调在AKI和AKI- ckd转变中的作用。此外，针对脂质代谢的药物干预在这些疾病模型中显示出治疗前景。

引用次数: 0

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