Pharmacology & Therapeutics最新文献_第3页

Pharmacological modulation of respiratory control: Ampakines as a therapeutic strategy 呼吸控制的药理调节：安非他酮作为一种治疗策略。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-08 DOI: 10.1016/j.pharmthera.2024.108744

Sabhya Rana , Anna F. Fusco , Jeffrey M. Witkin , Daniel P. Radin , Rok Cerne , Arnold Lippa , David D. Fuller

{"title":"Pharmacological modulation of respiratory control: Ampakines as a therapeutic strategy","authors":"Sabhya Rana , Anna F. Fusco , Jeffrey M. Witkin , Daniel P. Radin , Rok Cerne , Arnold Lippa , David D. Fuller","doi":"10.1016/j.pharmthera.2024.108744","DOIUrl":"10.1016/j.pharmthera.2024.108744","url":null,"abstract":"<div><div>Ampakines are a class of compounds that are positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and enhance glutamatergic neurotransmission. Glutamatergic synaptic transmission and AMPA receptor activation are fundamentally important to the genesis and propagation of the neural impulses driving breathing, including respiratory motoneuron depolarization. Ampakines therefore have the potential to modulate the neural control of breathing. In this paper, we describe the influence of ampakines on respiratory motor output in health and disease. We dissect the molecular mechanisms underlying ampakine action, delineate the diverse targets of ampakines along the respiratory neuraxis, survey the spectrum of respiratory disorders in which ampakines have been tested, and culminate with an examination of how ampakines modulate respiratory function after spinal cord injury. Collectively, the studies reviewed here indicate that ampakines may be a useful adjunctive strategy to pair with conventional respiratory rehabilitation approaches in conditions with impaired neural activation of the respiratory muscles.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"265 ","pages":"Article 108744"},"PeriodicalIF":12.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611505","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

Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase: A new approach for the treatment of Alzheimer's disease 丁酰胆碱酯酶和 p38α 丝裂原活化蛋白激酶的双重抑制：治疗阿尔茨海默病的新方法。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-07 DOI: 10.1016/j.pharmthera.2024.108748

Svit Ferjančič Benetik, Damijan Knez, Aleš Obreza, Urban Košak, Stanislav Gobec

{"title":"Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase: A new approach for the treatment of Alzheimer's disease","authors":"Svit Ferjančič Benetik, Damijan Knez, Aleš Obreza, Urban Košak, Stanislav Gobec","doi":"10.1016/j.pharmthera.2024.108748","DOIUrl":"10.1016/j.pharmthera.2024.108748","url":null,"abstract":"<div><div>The simultaneous targeting of neuroinflammation and cholinergic hypofunction, the key pathological changes in Alzheimer's disease (AD), is not addressed by drugs currently in clinical trials, highlighting a critical therapeutic gap. We propose that dual-acting small molecules that inhibit butyrylcholinesterase (BChE) and mitogen-activated protein kinase p38α (p38α MAPK) represent a novel strategy to combat AD. This hypothesis is supported by cellular and animal studies as well as <em>in silico</em> modelling showing that it is possible to act simultaneously on both enzymes. Amyloid beta (Aβ) plaques trigger a pro-inflammatory microglial response that overactivates p38α MAPK, leading to increased Aβ synthesis, tau hyperphosphorylation, and altered synaptic plasticity. Overactivated microglia exacerbate neuroinflammation and cholinergic degeneration, ultimately leading to cognitive impairment. Structural similarities between the binding sites of BChE and p38α MAPK provide a promising basis for the development of dual inhibitors that could alleviate AD symptoms and address the underlying pathology.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108748"},"PeriodicalIF":12.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611518","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

Lessons learned from 20 years of preclinical testing in pediatric cancers 从 20 年的儿科癌症临床前试验中汲取的经验教训。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-05 DOI: 10.1016/j.pharmthera.2024.108742

Malcolm A. Smith , Peter J. Houghton , Richard B. Lock , John M. Maris , Richard Gorlick , Raushan T. Kurmasheva , Xiao-Nan Li , Beverly A. Teicher , Jeffrey H. Chuang , Filemon S. Dela Cruz , Michael A. Dyer , Andrew L. Kung , Michael W. Lloyd , Yael P. Mossé , Timothy M. Stearns , Elizabeth A. Stewart , Carol J. Bult , Stephen W. Erickson

{"title":"Lessons learned from 20 years of preclinical testing in pediatric cancers","authors":"Malcolm A. Smith , Peter J. Houghton , Richard B. Lock , John M. Maris , Richard Gorlick , Raushan T. Kurmasheva , Xiao-Nan Li , Beverly A. Teicher , Jeffrey H. Chuang , Filemon S. Dela Cruz , Michael A. Dyer , Andrew L. Kung , Michael W. Lloyd , Yael P. Mossé , Timothy M. Stearns , Elizabeth A. Stewart , Carol J. Bult , Stephen W. Erickson","doi":"10.1016/j.pharmthera.2024.108742","DOIUrl":"10.1016/j.pharmthera.2024.108742","url":null,"abstract":"<div><div>Programs for preclinical testing of targeted cancer agents in murine models of childhood cancers have been supported by the National Cancer Institute (NCI) since 2004. These programs were established to work collaboratively with industry partners to address the paucity of targeted agents for pediatric cancers compared with the large number of agents developed and approved for malignancies primarily affecting adults. The distinctive biology of pediatric cancers and the relatively small numbers of pediatric cancer patients are major challenges for pediatric oncology drug development. These factors are exacerbated by the division of cancers into multiple subtypes that are further sub-classified by their genomic properties. The imbalance between the large number of candidate agents and small patient populations requires careful prioritization of agents developed for adult cancers for clinical evaluation in children with cancer. The NCI-supported preclinical pediatric programs have published positive and negative results of efficacy testing for over 100 agents to aid the pediatric research community in identifying the most promising candidates to move forward for clinical testing in pediatric oncology. Here, we review and summarize lessons learned from two decades of experience with the design and execution of preclinical trials of antineoplastic agents in murine models of childhood cancers.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108742"},"PeriodicalIF":12.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602692","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

Nutraceuticals target androgen receptor-splice variants (AR-SV) to manage castration resistant prostate cancer (CRPC) 营养保健品以雄激素受体拼接变体（AR-SV）为靶点，用于治疗对阉割有抵抗力的前列腺癌（CRPC）。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-02 DOI: 10.1016/j.pharmthera.2024.108743

Ashish Tyagi , Balaji Chandrasekaran , Vaibhav Shukla , Neha Tyagi , Arun K. Sharma , Chendil Damodaran

{"title":"Nutraceuticals target androgen receptor-splice variants (AR-SV) to manage castration resistant prostate cancer (CRPC)","authors":"Ashish Tyagi , Balaji Chandrasekaran , Vaibhav Shukla , Neha Tyagi , Arun K. Sharma , Chendil Damodaran","doi":"10.1016/j.pharmthera.2024.108743","DOIUrl":"10.1016/j.pharmthera.2024.108743","url":null,"abstract":"<div><div>Every year, prostate cancer is diagnosed in millions of men. The androgen receptor's (AR) unchecked activation is crucial in causing the development and progression of prostate cancer. Second-generation anti-androgen therapies, which primarily focus on targeting the Ligand Binding Domain (LBD) of AR, are effective for most patients. However, the adverse effects pose significant challenges in managing the disease. Furthermore, genetic mutations or the emergence of AR splice variants create an even more complex tumor environment, fostering resistance to these treatments. Natural compounds and their analogs, while showing a lower toxicity profile and a potential for selective AR splice variants inhibition, are constrained by their bioavailability and therapeutic efficacy. Nonetheless, recent breakthroughs in using natural derivatives to target AR and its splice variants have shown promise in treating chemoresistant castration-resistant prostate cancer (CRPC). This review will discuss the role of AR variants, particularly androgen receptor splice variant 7 (AR-V7), in CRPC and investigate the latest findings on how natural compounds and their derivatives target AR and AR splice variants.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108743"},"PeriodicalIF":12.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566770","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

Lipoprotection in cardiovascular diseases 心血管疾病中的血脂保护。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-02 DOI: 10.1016/j.pharmthera.2024.108747

Marcel Benkhoff , Amin Polzin

引用次数: 0

The voltage sensitivity of G-protein coupled receptors: Unraveling molecular mechanisms and physiological implications G 蛋白偶联受体的电压敏感性：揭示分子机制和生理意义。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-01 DOI: 10.1016/j.pharmthera.2024.108741

Marin Boutonnet , Moritz Bünemann , Julie Perroy

{"title":"The voltage sensitivity of G-protein coupled receptors: Unraveling molecular mechanisms and physiological implications","authors":"Marin Boutonnet , Moritz Bünemann , Julie Perroy","doi":"10.1016/j.pharmthera.2024.108741","DOIUrl":"10.1016/j.pharmthera.2024.108741","url":null,"abstract":"<div><div>In the landscape of proteins controlled by membrane voltage (V<sub>m</sub>), like voltage-gated ionotropic channels, the emergence of the voltage sensitivity within the vast family of G-protein coupled receptors (GPCRs) marked a significant milestone at the onset of the 21st century. Since its discovery, extensive research has been devoted to understanding the intricate relationship between V<sub>m</sub> and GPCRs. Approximately 30 GPCRs out of a family comprising more than 800 receptors have been implicated in V<sub>m</sub>-dependent positive and negative regulation. GPCRs stand out as the quintessential regulators of synaptic transmission in neurons, where they encounter substantial variations in V<sub>m</sub>. However, the molecular mechanism underlying the V<sub>m</sub> sensor of GPCRs remains enigmatic, hindered by the scarcity of mutant GPCRs insensitive to V<sub>m</sub> yet functionally intact, impeding a comprehensive understanding of this unique property in physiology. Nevertheless, two decades of dedicated research have furnished numerous insights into the molecular aspects of GPCR V<sub>m</sub>-sensing, accompanied by recently proposed physiological roles as well as pharmacological potential, which we encapsulate in this review. The V<sub>m</sub> sensitivity of GPCRs emerges as a pivotal attribute, shedding light on previously unforeseen roles in synaptic transmission and extending beyond, underscoring its significance in cellular signaling and physiological processes.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108741"},"PeriodicalIF":12.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566772","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

Oxytocin in neurodevelopmental disorders: Autism spectrum disorder and Prader-Willi syndrome 神经发育障碍中的催产素：自闭症谱系障碍和普拉德-威利综合征。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-10-23 DOI: 10.1016/j.pharmthera.2024.108734

Alyssa Josselsohn , Yin Zhao , Danielle Espinoza , Eric Hollander

引用次数: 0

New drug discovery and development from natural products 从天然产品中发现和开发新药物。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-10-23 DOI: 10.1016/j.pharmthera.2024.108733

Michael J. Curtis

引用次数: 0

Natural products that alleviate depression: The putative role of autophagy 缓解抑郁症的天然产品：自噬的潜在作用

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-10-18 DOI: 10.1016/j.pharmthera.2024.108731

Yunfeng Zhou , Fengwei Nan , Qianwen Zhang , Wangjun Xu , Shaojie Fang , Ke Liu , Bingxin Zhao , Hao Han , Xinmei Xie , Changjiang Qin , Xiaobin Pang

{"title":"Natural products that alleviate depression: The putative role of autophagy","authors":"Yunfeng Zhou , Fengwei Nan , Qianwen Zhang , Wangjun Xu , Shaojie Fang , Ke Liu , Bingxin Zhao , Hao Han , Xinmei Xie , Changjiang Qin , Xiaobin Pang","doi":"10.1016/j.pharmthera.2024.108731","DOIUrl":"10.1016/j.pharmthera.2024.108731","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a common mental disorder that severely disrupts psychosocial function and decreases the quality of life. Although the pathophysiological mechanism underlying MDD is complex and remains unclear, emerging evidence suggests that autophagy dysfunction plays a role in MDD occurrence and progression. Natural products serve as a major source of drug discovery and exert tremendous potential in developing antidepressants. Recently published reports are paying more attention on the autophagy regulatory effect of antidepressant natural products. In this review, we comprehensively discuss the abnormal changes occurred in multiple autophagy stages in MDD patients, and animal and cell models of depression. Importantly, we emphasize the regulatory mechanism of antidepressant natural products on disturbed autophagy, including monomeric compounds, bioactive components, crude extracts, and traditional Chinese medicine formulae. Our comprehensive review suggests that enhancing autophagy might be a novel approach for MDD treatment, and natural products restore autophagy homeostasis to facilitate the renovation of mitochondria, impede neuroinflammation, and enhance neuroplasticity, thereby alleviating depression.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108731"},"PeriodicalIF":12.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455010","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

Role of epigenetic mechanisms in the pathogenesis of chronic respiratory diseases and response to inhaled exposures: From basic concepts to clinical applications 表观遗传机制在慢性呼吸系统疾病发病机制和吸入暴露反应中的作用：从基本概念到临床应用。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-10-18 DOI: 10.1016/j.pharmthera.2024.108732

Renata Z. Jurkowska

{"title":"Role of epigenetic mechanisms in the pathogenesis of chronic respiratory diseases and response to inhaled exposures: From basic concepts to clinical applications","authors":"Renata Z. Jurkowska","doi":"10.1016/j.pharmthera.2024.108732","DOIUrl":"10.1016/j.pharmthera.2024.108732","url":null,"abstract":"<div><div>Epigenetic modifications are chemical groups in our DNA (and chromatin) that determine which genes are active and which are shut off. Importantly, they integrate environmental signals to direct cellular function. Upon chronic environmental exposures, the epigenetic signature of lung cells gets altered, triggering aberrant gene expression programs that can lead to the development of chronic lung diseases. In addition to driving disease, epigenetic marks can serve as attractive lung disease biomarkers, due to early onset, disease specificity, and stability, warranting the need for more epigenetic research in the lung field.</div><div>Despite substantial progress in mapping epigenetic alterations (mostly DNA methylation) in chronic lung diseases, the molecular mechanisms leading to their establishment are largely unknown. This review is meant as a guide for clinicians and lung researchers interested in epigenetic regulation with a focus on DNA methylation. It provides a short introduction to the main epigenetic mechanisms (DNA methylation, histone modifications and non-coding RNA) and the machinery responsible for their establishment and removal. It presents examples of epigenetic dysregulation across a spectrum of chronic lung diseases and discusses the current state of epigenetic therapies. Finally, it introduces the concept of epigenetic editing, an exciting novel approach to dissecting the functional role of epigenetic modifications. The promise of this emerging technology for the functional study of epigenetic mechanisms in cells and its potential future use in the clinic is further discussed.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108732"},"PeriodicalIF":12.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455011","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