Pharmacological Reviews最新文献

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Antipsychotics and dietary interventions: Pharmacodynamics, pharmacokinetics, and synergisms in therapy. 抗精神病药物和饮食干预:药效学、药代动力学和治疗中的协同作用。
IF 17.3 1区 医学
Pharmacological Reviews Pub Date : 2025-07-01 Epub Date: 2025-04-29 DOI: 10.1016/j.pharmr.2025.100061
Cristiana Perrotta, Carla Carnovale, Marco Pozzi, Clara De Palma, Davide Cervia, Maria Nobile, Emilio Clementi
{"title":"Antipsychotics and dietary interventions: Pharmacodynamics, pharmacokinetics, and synergisms in therapy.","authors":"Cristiana Perrotta, Carla Carnovale, Marco Pozzi, Clara De Palma, Davide Cervia, Maria Nobile, Emilio Clementi","doi":"10.1016/j.pharmr.2025.100061","DOIUrl":"10.1016/j.pharmr.2025.100061","url":null,"abstract":"<p><p>Antipsychotic (AP) medications are the primary treatment for severe mental illnesses, including schizophrenia and severe mood disorders. APs are currently categorized into typical or first-generation APs and atypical or second-generation APs. Although both first-generation and second-generation APs are considered effective in treating psychotic symptoms in severe mental disorders, they differ in their mechanisms, treatment strategies, and side effect profiles. Because of their potential motor and metabolic side effects, which often compromise patient adherence and clinical outcomes, whether and how to use APs remains controversial. The use of dietary interventions in combination with APs is emerging as a viable strategy to reduce AP adverse effects while maintaining their efficacy and enhance patient adherence to treatment. In contrast to drugs that possess a well defined molecular mechanism of action, dietary interventions act in pleiotropic ways by nature. While providing a holistic approach to patient care this pleiotropy needs to be analyzed and systematized to enhance the efficacy and safety of the combination of them with APs. Guidelines for this type of treatment are still needed. In this review, we explore the pharmacological properties, therapeutic applications, and limitations of APs, and discuss the potential benefits and limitations of those dietary interventions that are employed to improve the efficacy and counteract side effects of APs discussing also their mechanisms of action. Finally, we critically discuss the main results of clinical studies combining APs and dietary interventions and provide a view on future directions in terms of research and clinical use of these combinations. SIGNIFICANCE STATEMENT: Antipsychotic drugs are useful in a variety of psychiatric conditions, yet their use is hampered by issues of efficacy and safety. An important step toward therapy optimization is their use in combination with dietary interventions (ie, dietary supplements and nutraceuticals) that have shown promising results in clinical trials.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100061"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143288","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
Antiobesity medications in adult and pediatric obesity and metabolic dysfunction-associated steatotic liver disease. 抗肥胖药物在成人和儿童肥胖和代谢功能障碍相关的脂肪变性肝病中的应用
IF 17.3 1区 医学
Pharmacological Reviews Pub Date : 2025-07-01 Epub Date: 2025-04-16 DOI: 10.1016/j.pharmr.2025.100058
Natalie Rodriguez, Phillipp Hartmann
{"title":"Antiobesity medications in adult and pediatric obesity and metabolic dysfunction-associated steatotic liver disease.","authors":"Natalie Rodriguez, Phillipp Hartmann","doi":"10.1016/j.pharmr.2025.100058","DOIUrl":"10.1016/j.pharmr.2025.100058","url":null,"abstract":"<p><p>Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are estimated to affect 13% and one-third of adults worldwide, respectively. The novel antiobesity medications achieve marked bodyweight loss and improve associated metabolic conditions, including MASLD. This review summarizes the development and mode of action and available published data on the effectiveness of approved and potential (off-label) antiobesity products in the management of adult and pediatric obesity and MASLD. Additionally, their safety is highlighted. The most effective antiobesity drugs evaluated in double-blind, randomized controlled trials include semaglutide, tirzepatide, and retatrutide with up to 10.8%, 17.8%, and 22.1% placebo-subtracted bodyweight loss, respectively, in adults after 48-72 weeks. Semaglutide also reduces placebo-subtracted body mass index mean by up to 16.7% in adolescents with obesity after 68 weeks. Moreover, these novel drugs are highly effective in treating adults with MASLD. Semaglutide and tirzepatide resolve metabolic dysfunction-associated steatohepatitis (MASH) without worsening of fibrosis placebo-subtracted in 41% and 53% of patients, respectively, after 52-72 weeks. Semaglutide, tirzepatide, and retatrutide reduce hepatic fat on magnetic resonance imaging-proton density fat fraction placebo-subtracted by 41%, 47%, and 81%, respectively, after 48-72 weeks. Tirzepatide also decreases fibrosis without worsening of MASH placebo-subtracted in up to 25% of patients. However, no pediatric trials have been conducted to study these novel drugs in biopsy-proven MASLD. In conclusion, the novel antiobesity drugs are highly effective in obesity and MASLD. However, more biopsy-based clinical trials are required to determine the effectiveness of these medications in adult metabolic dysfunction-associated steatohepatitis-associated fibrosis and pediatric MASLD. SIGNIFICANCE STATEMENT: This work reviews the current antiobesity medications, their structure, mode of action, and effectiveness. These medications are revolutionizing the management of metabolic dysfunction-associated steatotic liver disease by significantly reducing hepatic steatosis, disease activity, and even liver fibrosis.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100058"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485478","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
Cell and tissue reprogramming: Unlocking a new era in medical drug discovery. 细胞和组织重编程:开启医学药物发现的新时代。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2025-06-26 DOI: 10.1016/j.pharmr.2025.100077
Chandan K Sen, Andrew J Friday, Sashwati Roy
{"title":"Cell and tissue reprogramming: Unlocking a new era in medical drug discovery.","authors":"Chandan K Sen, Andrew J Friday, Sashwati Roy","doi":"10.1016/j.pharmr.2025.100077","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100077","url":null,"abstract":"<p><p>Recent advancements in cell and tissue biology have fundamentally changed our understanding of cellular behavior, revealing that both stem and nonstem cells exhibit remarkable plasticity and adaptability. This discovery has paved the way for revolutionary medical drug therapies that leverage cell and tissue reprogramming to repair or regenerate damaged tissues, offering new hope for conditions that were once considered irreversible. Tissue reprogramming involves the activation of specific molecular pathways to convert the function of residual tissue to compensate for the loss of tissue function to aging, trauma, or disease processes. By targeting these pathways, emerging drugs can promote regenerative processes, enabling the restoration of tissue function lost due to aging, injury, or disease. These therapies have shown promising results in preclinical studies addressing a wide range of diseases. Unlike traditional treatments, which focus primarily on managing symptoms, tissue reprogramming therapies offer a dynamic approach that can fundamentally alter cellular states, leading to functional recovery. This review explores the current state of cell and tissue reprogramming, highlighting its potential applications in regenerative medicine and the challenges that must be addressed for successful clinical translation. As our understanding of cellular plasticity continues to evolve, these innovative therapies stand at the forefront of a new era in medicine, with the potential to transform treatment paradigms and significantly improve patient outcomes across a wide range of conditions. SIGNIFICANCE STATEMENT: Breakthrough technologies have transformed our understanding of cell and tissue biology, uncovering that cells and tissues possess remarkable adaptability and fluidity in their roles. This revelation has opened up exciting possibilities in regenerative medicine, where emerging drug therapies aim to harness and reprogram cells to repair or regenerate damaged tissues. An emerging class of medical drugs will activate the body's natural regenerative abilities, offering the potential to restore tissue function lost due to aging, injury, or disease.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100077"},"PeriodicalIF":19.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668086","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 complement system: Biology, pathology, and therapeutic interventions. 补体系统:生物学、病理学和治疗干预。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2025-06-26 DOI: 10.1016/j.pharmr.2025.100079
Xaria X Li, Trent M Woodruff
{"title":"The complement system: Biology, pathology, and therapeutic interventions.","authors":"Xaria X Li, Trent M Woodruff","doi":"10.1016/j.pharmr.2025.100079","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100079","url":null,"abstract":"<p><p>Targeting the innate immune complement system has long been pursued as a promising strategy for treating a wide spectrum of acute and chronic immune-mediated disorders. Nearly 2 decades since the approval of the first complement inhibitor targeting C5, the field of complement therapeutics has flourished. In just the past 5 years, 8 new complement-targeting drugs have entered the market. Traditionally dominated by monoclonal antibodies, the approved drug arsenal now includes an ever-expanding selection of macrocyclic peptides, low molecular weight compounds, and aptamers. Other novel approaches in clinical development include recombinant proteins, nanobodies, oligonucleotide therapeutics, and gene therapies. Alongside this remarkable diversification of drug modalities, the complement field is advancing toward deciphering and precisely targeting all pathways of the complement network. Although current approved therapies primarily benefit patients with rare diseases, there is a nascent shift towards addressing more prevalent conditions. In line with this unprecedented expansion in the field, we aim to provide a comprehensive overview of the complement system, its activation pathways, key effector mechanisms, and regulation. We discuss the consequences of unchecked complement activation leading to disease pathologies and highlight therapeutic intervention points within the cascade. We review the discovery and molecular pharmacology of clinically approved and late-phase complement therapeutics, bridging to their clinical pharmacokinetics, safety, and regulatory status for clinical indications. We particularly focus on the diversifying modalities of complement-targeting drugs and evaluate the unique opportunities and challenges these new developments present. With this knowledge, we forecast potential short-term and long-term development trends in the field. SIGNIFICANCE STATEMENT: Therapeutic targeting of the complement system has been widely pursued for treating autoimmune and inflammatory disorders, with the field recently seeing an exponential increase in clinical approvals (8 new drugs during 2022-2024). This timely comprehensive review presents an overview of the complement cascade, its effector mechanisms, and the molecular pharmacology and clinical utility of currently approved and late-phase complement-targeting drugs. We thus provide a valuable one-stop guide for existing and upcoming researchers working in the complement field.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100079"},"PeriodicalIF":19.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668087","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 exchange proteins directly activated by cAMP signaling in vascular remodeling. cAMP信号直接激活的交换蛋白在血管重构中的作用。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2025-06-26 DOI: 10.1016/j.pharmr.2025.100078
Xiaodong Cheng, Hua Liu, Wenbo Zhang, Wenli Yang, Fang Mei
{"title":"Role of exchange proteins directly activated by cAMP signaling in vascular remodeling.","authors":"Xiaodong Cheng, Hua Liu, Wenbo Zhang, Wenli Yang, Fang Mei","doi":"10.1016/j.pharmr.2025.100078","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100078","url":null,"abstract":"<p><p>Vascular remodeling is a complex process involving the coordinated actions of multiple cellular signaling pathways in various cell types, leading to structural and functional changes in blood vessels. These changes can be adaptive, as in wound healing, or maladaptive, as seen in chronic vascular diseases such as atherosclerosis, hypertension, and retinopathy. Exchange proteins directly activated by cAMP (EPACs) are key players in cAMP-mediated cell signaling, distinct from the more traditionally studied protein kinase A pathway. EPAC proteins are guanine nucleotide exchange factors for the small G proteins Rap1 and Rap2. Recent studies have also revealed noncanonical functions of EPAC1 involving the formation of biomolecular condensates. EPAC proteins regulate various cellular processes, including cell adhesion, migration, proliferation, and differentiation. In this review, we discuss the roles of EPACs in vascular remodeling and diseases associated with the process, as well as the potential of EPACs as therapeutic targets for proliferative vascular diseases. SIGNIFICANCE STATEMENT: Vascular remodeling is associated with various human diseases, such as atherosclerosis, stroke, and retinopathy. Understanding the roles of exchange proteins directly activated by cAMP signaling in vascular remodeling provides insights into the mechanisms underlying vascular diseases and facilitates the development of targeted therapies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100078"},"PeriodicalIF":19.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708417","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
Cracking the EGFR code: Cancer biology, resistance mechanisms, and future therapeutic frontiers. 破解EGFR密码:癌症生物学、耐药机制和未来治疗前沿。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2025-06-25 DOI: 10.1016/j.pharmr.2025.100076
Yafei Du, Feride Karatekin, Wendy Kehan Wang, Wanjin Hong, Gandhi T K Boopathy
{"title":"Cracking the EGFR code: Cancer biology, resistance mechanisms, and future therapeutic frontiers.","authors":"Yafei Du, Feride Karatekin, Wendy Kehan Wang, Wanjin Hong, Gandhi T K Boopathy","doi":"10.1016/j.pharmr.2025.100076","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100076","url":null,"abstract":"<p><p>Epidermal growth factor receptor (EGFR) plays a crucial role in tumorigenesis across multiple cancer types. EGFR mutations, overexpression, amplifications, dysregulated signaling, and impaired receptor downregulation drive cancer progression, particularly in non-small cell lung cancer, glioblastoma, colorectal cancer, gastric cancer, and head and neck cancers. Over the past decades, EGFR-targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, have significantly improved patient outcomes. However, drug resistance inevitably arises through on-target mutations, activation of bypass signaling pathways, and disruptions in receptor trafficking and degradation. To overcome resistance, novel therapeutic strategies such as new generation of tyrosine kinase inhibitors, antibody-drug conjugates, and targeted protein degradation approaches like proteolysis-targeting chimeras are being actively explored. Additionally, combination therapies targeting parallel or compensatory pathways are being explored in mitigating drug resistance. Advances in genomic profiling and liquid biopsy technologies further enable personalized treatment strategies tailored to individual genetic backgrounds. In this review, we provide an overview of EGFR signaling and examine the landscape of EGFR mutations and currently available targeted therapies, while highlighting key resistance mechanisms. Furthermore, emerging strategies designed to overcome resistance are discussed, offering insights into future directions for EGFR-targeted cancer treatment. SIGNIFICANCE STATEMENT: Epidermal growth factor receptor (EGFR) is a key driver of tumorigenesis across multiple cancers, with overexpression, mutations, and amplifications promoting disease progression and therapeutic resistance. Despite the success of EGFR-targeted therapies, resistance remains a significant barrier to sustainable efficacy. This review provides an overview of EGFR biology and therapy, resistance mechanisms, and emerging new therapeutic strategies. A deeper understanding of these aspects is crucial for overcoming resistance and guiding the development of more effective and personalized cancer treatments.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100076"},"PeriodicalIF":19.3,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659795","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
Microbial-induced trained immunity for cancer immunotherapy. 微生物诱导的训练免疫用于癌症免疫治疗。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2025-06-12 DOI: 10.1016/j.pharmr.2025.100074
Patricia Vuscan, Brenda Kischkel, Leo A B Joosten, Mihai G Netea
{"title":"Microbial-induced trained immunity for cancer immunotherapy.","authors":"Patricia Vuscan, Brenda Kischkel, Leo A B Joosten, Mihai G Netea","doi":"10.1016/j.pharmr.2025.100074","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100074","url":null,"abstract":"<p><p>Myeloid innate immune cells, including macrophages, neutrophils, myeloid-derived suppressor cells, and dendritic cells, represent major components of the tumor microenvironment (TME), exhibiting remarkable plasticity and dual roles in cancer progression and immune regulation. In recent years, microbial-induced innate immune memory, also termed \"trained immunity\" (TRIM), has emerged as a novel strategy to reprogram myeloid cells into an immunostimulatory, antitumor state. In this review, we explore the intricate landscape of myeloid cells in cancer and examine how microbial ligands, such as the Bacillus Calmette-Guérin vaccine and β-glucan, reprogram both bone marrow progenitors and tissue-resident myeloid cells to enhance inflammatory and antitumor responses. Notable findings include the hematopoietic stem and progenitor cell reprogramming by Bacillus Calmette-Guérin for sustained anticancer immunity, and the enhanced granulopoiesis and neutrophil-mediated tumor killing mediated by β-glucan-induced TRIM. These mechanisms synergize with immunotherapies, such as immune checkpoint inhibitors, by reshaping the immunosuppressive TME and enhancing adaptive immunity. However, challenges remain, including the structural complexity of microbial products, the lack of predictive biomarkers, and the need for optimized dosing and delivery strategies. Addressing these gaps by introducing precise characterization of microbial-derived ligands, biomarker-driven patient selection through large-scale clinical trials, as well as the development of novel approaches for targeted therapy will be essential to harness the full potential of microbial-induced TRIM, ultimately paving the way for more effective and durable cancer immunotherapies. SIGNIFICANCE STATEMENT: Tumor-promoting myeloid cells within the tumor microenvironment remain a major barrier to effective cancer immunotherapy. Microbial-induced trained immunity offers a novel strategy to reprogram myeloid cells into an antitumor state. This review provides a comprehensive overview of myeloid cell populations in cancer and the mechanisms underlying microbial-induced trained immunity. It also highlights preclinical and clinical evidence demonstrating the efficacy of microbial-based strategies in overcoming immunosuppression and synergizing with existing immunotherapies, offering a promising approach to improve cancer treatment outcomes.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100074"},"PeriodicalIF":19.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567721","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
Pathological and therapeutic roles of bile acid metabolism and signaling in hepatocellular carcinoma: Insights from human and mouse studies. 胆汁酸代谢和信号传导在肝细胞癌中的病理和治疗作用:来自人和小鼠研究的见解。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2025-06-06 DOI: 10.1016/j.pharmr.2025.100073
Xue Wang, Curtis D Klaassen, Xin Chen, Youcai Zhang
{"title":"Pathological and therapeutic roles of bile acid metabolism and signaling in hepatocellular carcinoma: Insights from human and mouse studies.","authors":"Xue Wang, Curtis D Klaassen, Xin Chen, Youcai Zhang","doi":"10.1016/j.pharmr.2025.100073","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100073","url":null,"abstract":"<p><p>Bile acids (BAs), the end products of cholesterol catabolism, play a crucial role in various physiological and pathological processes. Defects in BA synthetic enzymes and transporters cause rare monogenic diseases. Dysregulation of BA homeostasis contributes to the pathogenesis and progression of various liver diseases, including hepatocellular carcinoma (HCC), the most common form of liver cancer. BA profiles are altered in patients with HCC and in mouse models of HCC, and their diagnostic potential is currently under clinical investigation. Growing evidence suggests that BA metabolism and signaling regulate key processes involved in HCC development. Recent advances in understanding the complex interactions between the gut microbiota and BAs have provided new insights into HCC. In this review, we summarize the current literature on BA quantification, detoxification, synthesis, transport, signaling functions, and the interplay between BAs and bacteria in the pathogenesis and progression of HCC, particularly in patients with HCC and mouse models. Furthermore, we discuss potential therapeutic strategies targeting BA metabolism and signaling as promising approaches for HCC treatment. SIGNIFICANCE STATEMENT: Bile acids hold promise as potential biomarkers for the diagnosis and prognosis of hepatocellular carcinoma. Modulating bile acid metabolism and signaling pathways represents a promising novel strategy for hepatocellular carcinoma treatment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100073"},"PeriodicalIF":19.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554132","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 serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges. 靶向血清素能系统治疗神经退行性疾病-新兴疗法和未满足的挑战。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2025-05-28 DOI: 10.1016/j.pharmr.2025.100071
Alina Brüge, Evgeni Ponimaskin, Josephine Labus
{"title":"Targeting the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges.","authors":"Alina Brüge, Evgeni Ponimaskin, Josephine Labus","doi":"10.1016/j.pharmr.2025.100071","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100071","url":null,"abstract":"<p><p>More than 65 million people worldwide experience neurodegenerative diseases, such as Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis. As the risk of developing these diseases increases with age, increasing life expectancy will further accelerate their prevalence. Despite major advances in the understanding of the molecular mechanisms of neurodegeneration, no curative therapy is available to date. Neurodegenerative diseases are known to be associated with alterations in serotonergic neurotransmission, which might critically contribute to the pathogenesis of these diseases. Therefore, targeting the serotonergic system appears to be a promising therapeutic approach. In this review, we provide a comprehensive overview of pathological changes in serotonergic neurotransmission in different neurodegenerative diseases and discuss novel treatment strategies based on targeted modulation of the serotonergic system. We primarily focus on the therapeutic approaches modulating serotonin homeostasis, its biosynthesis, and the modulation of defined serotonin receptors. SIGNIFICANCE STATEMENT: A common feature of multiple neurodegenerative diseases is dysregulation of the serotonergic system at the cellular, molecular, and genetic levels that strongly contributes to specific pathological phenotypes. Targeting these alterations represents a suitable therapeutic strategy to combat disease-relevant pathomechanisms, slow down disease progression, and overcome pathological consequences.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100071"},"PeriodicalIF":19.3,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626813","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
Cryoelectron microscopy as a tool for illuminating activation mechanisms of human class A orphan G protein-coupled receptors. 低温电子显微镜作为阐明人类a类孤儿G蛋白偶联受体激活机制的工具。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2025-05-01 Epub Date: 2025-04-02 DOI: 10.1016/j.pharmr.2025.100056
Isabella C Russell, Dongju Lee, Denise Wootten, Patrick M Sexton, Fabian Bumbak
{"title":"Cryoelectron microscopy as a tool for illuminating activation mechanisms of human class A orphan G protein-coupled receptors.","authors":"Isabella C Russell, Dongju Lee, Denise Wootten, Patrick M Sexton, Fabian Bumbak","doi":"10.1016/j.pharmr.2025.100056","DOIUrl":"10.1016/j.pharmr.2025.100056","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are critically important medicinal targets, and the cryogenic electron microscopy (cryo-EM) revolution is providing novel high-resolution GPCR structures at a rapid pace. Orphan G protein-coupled receptors (oGPCRs) are a group of approximately 100 nonolfactory GPCRs for which endogenous ligands are unknown or not validated. The absence of modulating ligands adds difficulties to understanding the physiologic significance of oGPCRs and in the determination of high-resolution structures of isolated receptors that could facilitate drug discovery. Despite the challenges, cryo-EM structures of oGPCR-G protein complexes are emerging. This is being facilitated by numerous developments to stabilize GPCR-G protein complexes such as the use of dominant-negative G proteins, mini-G proteins, complex-stabilizing nanobodies or antibody fragments, and protein tethering methods. Moreover, many oGPCRs are constitutively active, which can facilitate complex formation in the absence of a known activating ligand. Consequently, in addition to providing templates for drug discovery, active oGPCR structures shed light on constitutive GPCR activation mechanisms. These comprise self-activation, whereby mobile extracellular portions of the receptor act as tethered agonists by occupying a canonical orthosteric-binding site in the transmembrane core, constitutive activity due to alterations to conserved molecular switches that stabilize inactive states of GPCRs, as well as receptors activated by cryptic ligands that are copurified with the receptor. Cryo-EM structures of oGPCRs are now being determined at a rapid pace and are expected to be invaluable tools for oGPCR drug discovery. SIGNIFICANCE STATEMENT: Orphan G protein-coupled receptors (GPCRs) provide large untapped potential for development of new medicines. Many of these receptors display constitutive activity, enabling structure determination and insights into observed GPCR constitutive activity including (1) self-activation by mobile receptor extracellular portions that function as tethered agonists, (2) modification of conserved motifs canonically involved in receptor quiescence and/or activation, and (3) activation by cryptic lipid ligands. Collectively, these studies advance fundamental understanding of GPCR function and provide opportunities for novel drug discovery.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100056"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036362","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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