Pharmacological Reviews最新文献

{"title":"The 75-Year Anniversary of the Department of Physiology and Pharmacology at Karolinska Institutet—Examples of Recent Accomplishments and Future Perspectives","authors":"Eddie Weitzberg, Magnus Ingelman-Sundberg, Jon O. Lundberg, Göran Engberg, Gunnar Schulte, Volker M. Lauschke, Lynette Daws","doi":"10.1124/pharmrev.124.001433","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001433","url":null,"abstract":"Karolinska Institutet is a medical university encompassing 21 departments distributed across three departmental or campus groups. Pharmacological research has a long and successful tradition at the institute with a multitude of seminal findings in the areas of neuronal control of vasodilatation, cardiovascular pharmacology, neuropsychopharmacology, receptor pharmacology, and pharmacogenomics that resulted in, among many other recognitions, two Nobel prizes in Physiology and Medicine, one in 1970 to Ulf von Euler for his discovery of the processes involved in storage, release, and inactivation of neurotransmitters and the other in 1982 to Sune Bergström and Bengt Samuelsson for their work on prostaglandins and the discovery of leukotrienes. Pharmacology at Karolinska Institutet has over the last decade been ranked globally among the top 10 according to the QS World University Ranking. With the Department of Physiology and Pharmacology now celebrating its 75-year anniversary, we wanted to take this as an opportunity to showcase recent research achievements and how they paved the way for current activities at the department. We emphasize examples from preclinical and clinical research where the dpartment's integrative environment and robust infrastructure have successfully facilitated the translation of findings into clinical applications and patient benefits. The close collaboration between preclinical scientists and clinical researchers across various disciplines, along with a strong network of partnerships within the department and beyond, positions us to continue leading world-class pharmacological research at the Department of Physiology and Pharmacology for decades to come.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440529","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}

{"title":"Ironing Out the Mechanism of gp130 Signaling","authors":"Essam Eldin A. Osman, Nouri Neamati, Des Richardson","doi":"10.1124/pharmrev.124.001245","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001245","url":null,"abstract":"gp130 functions as a shared signal-transducing subunit not only for interleukin (IL)-6 but also for eight other human cytokine receptor complexes. The IL-6 signaling pathway mediated through gp130 encompasses classical, trans, or cluster signaling, intricately regulated by a diverse array of modulators affecting IL-6, its receptor, and gp130. Currently, only a limited number of small molecule antagonists and agonists for gp130 are known. This review aims to comprehensively examine the current knowledge of these modulators and provide insights into their pharmacological properties, particularly in the context of cancer and other diseases. Notably, the prominent gp130 modulators SC144, bazedoxifene, and raloxifene are discussed in detail, with a specific focus on the discovery of SC144’s iron-chelating properties. This adds a new dimension to the understanding of its pharmacological effects and therapeutic potential in conditions where iron homeostasis is significant. Our bioinformatic analysis of gp130 and genes related to iron homeostasis reveals insightful correlations, implicating the role of iron in the gp130 signaling pathway. Overall, this review contributes to the evolving understanding of gp130 modulation and its potential therapeutic applications in various disease contexts.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440483","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}

{"title":"Glatiramer Acetate for the Treatment of Multiple Sclerosis: From First-Generation Therapy to Elucidation of Immunomodulation and Repair","authors":"Rina Aharoni, Ron Milo, Ruth Arnon, Francesca Levi-Schaffer","doi":"10.1124/pharmrev.124.000927","DOIUrl":"https://doi.org/10.1124/pharmrev.124.000927","url":null,"abstract":"Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440530","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}

{"title":"Pharmacological therapies for male infertility.","authors":"Amarnath Rambhatla, Rupin Shah, Germar M Pinggera, Taymour Mostafa, Widi Atmoko, Ramadan Saleh, Eric Chung, Taha Hamoda, Selahittin Cayan, Hyun Jun Park, Ates Kadioglu, Logan Hubbard, Ashok Agarwal","doi":"10.1124/pharmrev.124.001085","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001085","url":null,"abstract":"<p><p>Male factor infertility is a multifaceted problem that affects approximately 50% of couples suffering from infertility. Causes of male infertility include endocrine disturbances, gonadotoxins, genetic abnormalities, varicocele, malignancies, infections, congenital or acquired urogenital abnormalities, iatrogenic factors, immunological factors, and idiopathic reasons. There are a variety of treatment options for male infertility, depending on the underlying cause(s). These can include surgical treatments, medical/hormonal therapies, and assisted reproductive techniques (ART), which can be combined with surgical sperm retrieval (SSR) if necessary. In this review article, the pharmacological therapies for male infertility are grouped by their underlying causes. Some of these therapies are targeted and specific, while others are used empirically to treat idiopathic male infertility. This will include treatments to optimize infertility in patients who have hypogonadism, ejaculatory dysfunction, infections, or idiopathic male infertility. Finally, we will provide an overview of the future directions of pharmacological therapies for male infertility. <b>Significance Statement</b> Male infertility is a significant worldwide problem. Detailed knowledge of the pharmacological therapies available will ensure the prescription of appropriate therapy and avoid the use of unnecessary or harmful treatments.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471881","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}

{"title":"How to drug a cloud? Targeting intrinsically disordered proteins.","authors":"Vladimir N Uversky","doi":"10.1124/pharmrev.124.001113","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001113","url":null,"abstract":"<p><p>Biologically active proteins/regions without stable structure (i.e., intrinsically disordered proteins and regions (IDPs and IDRs)) are commonly found in all proteomes. They have a unique functional repertoire that complements the functionalities of ordered proteins and domains. IDPs/IDRs are multifunctional promiscuous binders capable of folding at interaction with specific binding partners on a template- or context-dependent manner, many of which undergo liquid-liquid phase separation, leading to the formation of membrane-less organelles and biomolecular condensates. Many of them are frequently related to the pathogenesis of various human diseases. All this defines IDPs/IDRs as attractive targets for the development of novel drugs. However, their lack of unique structures, multifunctionality, binding promiscuity, and involvement in unusual modes of action preclude direct use of traditional structure-based drug design approaches for targeting IDPs/IDRs, and make disorder-based drug discovery for these \"protein clouds\" challenging. Despite all these complexities there is continuing progress in the design of small molecules affecting IDPs/IDRs. This article describes the major structural features of IDPs/IDRs and the peculiarities of the disorder-based functionality. It also discusses the roles of IDPs/IDRs in various pathologies, and shows why the approaches elaborated for finding drugs targeting ordered proteins cannot be directly used for the intrinsic disorder-based drug design, and introduces some novel methodologies suitable for these purposes. Finally, it emphasizes that regardless of their multifunctionality, binding promiscuity, lack of unique structures, and highly dynamic nature, \"protein clouds\" are principally druggable. <b>Significance Statement</b> <b>Intrinsically disordered proteins and regions are highly abundant in nature, have multiple important biological functions, are commonly involved in the pathogenesis of a multitude of human diseases, and are therefore considered as very attractive drug targets. Although dealing with these unstructured multifunctional protein/regions is a challenging task, multiple innovative approaches have been designed to target them by small molecules.</b></p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471880","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}

{"title":"Intestinal Lymphatic Biology, Drug Delivery, and Therapeutics: Current Status and Future Directions.","authors":"Sanjeevini Babu Reddiar, Yining Xie, Mohammad Abdallah, Sifei Han, Luojuan Hu, Orlagh M Feeney, Gracia Gracia, Abel Anshabo, Zijun Lu, Muhammad Asim Farooq, Ian K Styles, Anthony R J Phillips, John A Windsor, Christopher J H Porter, Enyuan Cao, Natalie L Trevaskis","doi":"10.1124/pharmrev.123.001159","DOIUrl":"10.1124/pharmrev.123.001159","url":null,"abstract":"<p><p>Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins, and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focused primarily on the drugs' physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic, and tissue-specific players in a range of biological and pathological processes, including within the intestine. These findings have, in turn, inspired exploration of lymph-specific therapies for a range of diseases, as well as the development of more sophisticated strategies to actively deliver drugs or vaccines to the intestinal lymph, including a range of nanotechnologies, lipid prodrugs, and lipid-conjugated materials that \"hitchhike\" onto lymphatic transport pathways. With the increasing development of novel therapeutics such as biologics, there has been interest in whether these therapeutics are absorbed and transported through intestinal lymph after oral administration. Here we review the current state of understanding of the anatomy and physiology of the gastrointestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. We summarize the current state-of-the-art approaches to deliver drugs and quantify their uptake into the intestinal lymphatic system. Finally, and excitingly, we discuss recent examples of significant pharmacokinetic and therapeutic benefits achieved via intestinal lymphatic drug delivery. We also propose approaches to advance the development and clinical application of intestinal lymphatic delivery strategies in the future. SIGNIFICANCE STATEMENT: This comprehensive review details the understanding of the anatomy and physiology of the intestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. It highlights current state-of-the-art approaches to deliver drugs to the intestinal lymphatics and the shift toward the use of these strategies to achieve pharmacokinetic and therapeutic benefits for patients.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047017","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}

{"title":"Cytochrome P450 Enzymes: The Old Pandora's Box with an Ever-Growing Hope for Therapy Optimization and Drug Development-Editorial.","authors":"Ahmed F El-Yazbi,Ali H Eid","doi":"10.1124/pharmrev.124.001432","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001432","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447959","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}

{"title":"Summing Up Pharmacological Reviews' 75th Anniversary Year and a Look to the Future.","authors":"Lynette C Daws","doi":"10.1124/pharmrev.124.000992","DOIUrl":"https://doi.org/10.1124/pharmrev.124.000992","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447960","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}

{"title":"Seventy-Five Years of Interactions: The Department of Physiology and Pharmacology at Karolinska Institutet and Pharmacological Reviews.","authors":"Gunnar Schulte","doi":"10.1124/pharmrev.124.001403","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001403","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447961","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}

{"title":"Nitric Oxide Signaling and Regulation in the Cardiovascular System: Recent Advances.","authors":"Mattias Carlström, Eddie Weitzberg, Jon O Lundberg","doi":"10.1124/pharmrev.124.001060","DOIUrl":"10.1124/pharmrev.124.001060","url":null,"abstract":"<p><p>Nitric oxide (NO) from endothelial NO synthase importantly contributes to vascular homeostasis. Reduced NO production or increased scavenging during disease conditions with oxidative stress contribute to endothelial dysfunction and NO deficiency. In addition to the classical enzymatic NO synthases (NOS) system, NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches aimed at increasing NO bioactivity, especially in the cardiovascular system, have been the focus of much research since the discovery of this small gaseous signaling molecule. Despite wide appreciation of the biological role of NOS/NO signaling, questions still remain about the chemical nature of NOS-derived bioactivity. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase, and directly activate the soluble guanylyl cyclase-cGMP-protein kinase G pathway without intermediacy of free NO. Moreover, interaction between red blood cells and the endothelium in the regulation of vascular NO homeostasis have gained much attention, especially in conditions with cardiometabolic disease. In this review we discuss both classical and nonclassical pathways for NO generation in the cardiovascular system and how these can be modulated for therapeutic purposes. SIGNIFICANCE STATEMENT: After four decades of intensive research, questions persist about the transduction and control of nitric oxide (NO) synthase bioactivity. Here we discuss NO signaling in cardiovascular health and disease, highlighting new findings, such as the important role of red blood cells in cardiovascular NO homeostasis. Nonclassical signaling modes, like the nitrate-nitrite-NO pathway, and therapeutic opportunities related to the NO system are discussed. Existing and potential pharmacological treatments/strategies, as well as dietary components influencing NO generation and signaling are covered.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311273","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}