{"title":"Pharmacology of Mammalian Na<sup>+</sup>-Dependent Transporters of Inorganic Phosphate.","authors":"Carsten A Wagner","doi":"10.1007/164_2022_633","DOIUrl":"10.1007/164_2022_633","url":null,"abstract":"<p><p>Inorganic phosphate (Pi) is an essential component of many biologically important molecules such as DNA, RNA, ATP, phospholipids, or apatite. It is required for intracellular phosphorylation signaling events and acts as pH buffer in intra- and extracellular compartments. Intestinal absorption, uptake into cells, and renal reabsorption depend on a set of different phosphate transporters from the SLC20 (PiT transporters) and SLC34 (NaPi transporters) gene families. The physiological relevance of these transporters is evident from rare monogenic disorders in humans affecting SLC20A2 (Fahr's disease, basal ganglia calcification), SLC34A1 (idiopathic infantile hypercalcemia), SLC34A2 (pulmonary alveolar microlithiasis), and SLC34A3 (hereditary hypophosphatemic rickets with hypercalciuria). SLC34 transporters are inhibited by millimolar concentrations of phosphonoformic acid or arsenate while SLC20 are relatively resistant to these compounds. More recently, a series of more specific and potent drugs have been developed to target SLC34A2 to reduce intestinal Pi absorption and to inhibit SLC34A1 and/or SLC34A3 to increase renal Pi excretion in patients with renal disease and incipient hyperphosphatemia. Also, SLC20 inhibitors have been developed with the same intention. Some of these substances are currently undergoing preclinical and clinical testing. Tenapanor, a non-absorbable Na<sup>+</sup>/H<sup>+</sup>-exchanger isoform 3 inhibitor, reduces intestinal Pi absorption likely by indirectly acting on the paracellular pathway for Pi and has been tested in several phase III trials for reducing Pi overload in patients with renal insufficiency and dialysis.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"285-317"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10461035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Iris Valtingojer, Sasha Lièvre, Philippe Bordes, Krupa Paranjpe, Winifred Thompson, Sachin Shah, Valeria Fantin, Wendy Jacquemet-Ross, Peter C Adamson
{"title":"Collaborative Innovations in Childhood Cancer Therapies.","authors":"Iris Valtingojer, Sasha Lièvre, Philippe Bordes, Krupa Paranjpe, Winifred Thompson, Sachin Shah, Valeria Fantin, Wendy Jacquemet-Ross, Peter C Adamson","doi":"10.1007/164_2024_725","DOIUrl":"10.1007/164_2024_725","url":null,"abstract":"<p><p>The outcome for children with cancer has improved significantly over the past 60 years, with more than 80% of patients today becoming 5-year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States and Europe, with significant short- and long-term toxicity of treatment continuing to impact most children. While the past 15 years have witnessed dramatic scientific innovation for certain cancers in adult patients, pediatric cancer treatment innovation lags increasingly behind. To help bridge the adult-pediatric therapeutic development gap, collaborative efforts are essential among stakeholders within and outside the pediatric oncology community. Prioritizing collaboration in areas such as cancer characterization, target identification and validation, drug discovery, and approaches to currently \"undruggable\" targets is imperative to improving the outcomes for children with cancer.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"33-50"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Progress in Ocular Drug Delivery: Challenges and Constraints.","authors":"Ilva D Rupenthal, Priyanka Agarwal","doi":"10.1007/164_2023_693","DOIUrl":"10.1007/164_2023_693","url":null,"abstract":"<p><p>The eye has several dynamic and static barriers in place to limit the entry of foreign substances including therapeutics. As such, efficient drug delivery, especially to posterior segment tissues, has been challenging. This chapter describes the anatomical and physiological challenges associated with ocular drug delivery before discussing constraints with regard to formulation parameters. Finally, it gives an overview of advanced drug delivery technologies with a specific focus on recently marketed and late-stage clinical trial products.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"267-288"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10058080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bingbing Sun, Min Li, Zhiying Yao, Ge Yu, Yubin Ma
{"title":"Advances in Vaccine Adjuvants: Nanomaterials and Small Molecules.","authors":"Bingbing Sun, Min Li, Zhiying Yao, Ge Yu, Yubin Ma","doi":"10.1007/164_2023_652","DOIUrl":"10.1007/164_2023_652","url":null,"abstract":"<p><p>Adjuvants have been extensively and essentially formulated in subunits and certain inactivated vaccines for enhancing and prolonging protective immunity against infections and diseases. According to the types of infectious diseases and the required immunity, adjuvants with various acting mechanisms have been designed and applied in human vaccines. In this chapter, we introduce the advances in vaccine adjuvants based on nanomaterials and small molecules. By reviewing the immune mechanisms induced by adjuvants with different characteristics, we aim to establish structure-activity relationships between the physicochemical properties of adjuvants and their immunostimulating capability for the development of adjuvants for more effective preventative and therapeutic vaccines.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"113-132"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9298841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chantel Mastos, Xiaomeng Xu, Alastair C Keen, Michelle L Halls
{"title":"Signalling of Adrenoceptors: Canonical Pathways and New Paradigms.","authors":"Chantel Mastos, Xiaomeng Xu, Alastair C Keen, Michelle L Halls","doi":"10.1007/164_2023_704","DOIUrl":"10.1007/164_2023_704","url":null,"abstract":"<p><p>The concept of G protein-coupled receptors initially arose from studies of the β-adrenoceptor, adenylyl cyclase, and cAMP signalling pathway. Since then both canonical G protein-coupled receptor signalling pathways and emerging paradigms in receptor signalling have been defined by experiments focused on adrenoceptors. Here, we discuss the evidence for G protein coupling specificity of the nine adrenoceptor subtypes. We summarise the ability of each of the adrenoceptors to activate proximal signalling mediators including cAMP, calcium, mitogen-activated protein kinases, and protein kinase C pathways. Finally, we highlight the importance of precise spatial and temporal control of adrenoceptor signalling that is controlled by the localisation of receptors at intracellular membranes and in larger protein complexes.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"147-184"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Adrenoceptors and Hypertension.","authors":"Spoorthy Kulkarni, Ian B Wilkinson","doi":"10.1007/164_2024_719","DOIUrl":"10.1007/164_2024_719","url":null,"abstract":"<p><p>Hypertension is a very prevalent condition associated with high mortality and morbidity, secondary to changes resulting in blood vessels and resultant end-organ damage. Haemodynamic changes, including an initial rise in cardiac output followed by an increase in total peripheral resistance, denote the early changes associated with borderline or stage 1 hypertension, especially in young men. Increased sodium reabsorption leading to kidney damage is another mechanism proposed as one of the initial triggers for essential hypertension. The underlying pathophysiological mechanisms include catecholamine-induced α<sub>1</sub>- and ß<sub>1</sub>-adrenoceptor stimulation, and renin-angiotensin-aldosterone system activation leading to endothelial dysfunction which is believed to lead to persistent blood pressure elevation.α<sub>1</sub> blockers, α<sub>2</sub> agonists, and ß blockers were among the first oral anti-hypertensives. They are no longer first-line therapy after outcome trials did not demonstrate any benefits over and above other agents, despite similar blood pressure reductions. Angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers), calcium channel blockers, and thiazide-like diuretics are now considered the first line of therapy, although adrenoceptor agents still have a role as second- or third-line therapy. The chapter also highlights hypertension in specific medical conditions such as pregnancy, phaeochromocytoma, hyperthyroidism, portal hypertension, pulmonary arterial hypertension, and ocular hypertension, to provide an overview for clinicians and researchers interested in the role of adrenoceptors in the pathophysiology and management of hypertension.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"297-332"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Reaching Outer Space and Enabling the mRNA Revolution: A Critical Role of Partnerships for Successful Drug and Vaccine Development.","authors":"Anita Seshire, Yukun Duan, Kahina Lang","doi":"10.1007/164_2024_723","DOIUrl":"10.1007/164_2024_723","url":null,"abstract":"<p><p>mRNA and targeted delivery of mRNA carry the promise to enable targeted treatment of undruggable diseases with high unmet medical needs. The transient nature of mRNA opens options for safe influencing of protein biology, immune responses, and complex ailments without impacting DNA heritage. Technical challenges such as mRNA stability and targeted delivery require next generation solutions, which attracted substantial funding and research interests. To build an integrated mRNA value chain and enable the development of novel therapeutics, Merck KGaA Darmstadt, Germany has initiated an internally incubated program, \"Targeted mRNA Delivery\" (TMD). This collaborative approach brings together scientists, researchers, engineers, and commercial experts from diverse backgrounds to overcome the multidimensional challenges associated with mRNA technology. In this chapter, the multiple opportunities and challenges for the development of mRNA formulations and therapeutics are described comprehensively. Specifically, the TMD program is presented as a use case to show how intrapreneurs were gathered to establish internal mRNA capabilities and foster collaborations for technology development. In the realm of targeted mRNA delivery, partnerships, encompassing internal partnership and external private, public, and hybrid collaborations, play a crucial role in driving innovation and addressing these hurdles. Within multinational pharmaceutical companies, the establishment of \"internal startups\" is an effective solution to drive innovation to the next level with support from different business sectors, where existing capabilities and positioning are seamlessly blended with the agility and speed of a startup.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"51-81"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RNA Delivery to Mitochondria.","authors":"Yuma Yamada, Hideyoshi Harashima","doi":"10.1007/164_2023_650","DOIUrl":"10.1007/164_2023_650","url":null,"abstract":"<p><p>The approval of mRNA-containing lipid nanoparticles (LNPs) for use in a vaccine against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the clinical utility of RNA-loaded nanocapsules has stimulated a rapid acceleration in research in this area. The development of mRNA-containing LNP vaccines has been rapid, not only because of regulatory adjustments, but also to the advances made in nucleic acid delivery as the result of efforts by many basic researchers. RNA functions, not only in the nucleus and cytoplasm, but also in mitochondria, which have their own genomic apparatus. Mitochondrial diseases caused by mutations or defects in the mitochondrial genome, mitochondrial DNA (mtDNA) are intractable and are mainly treated symptomatically, but gene therapy as a fundamental treatment is expected to soon be a reality. To realize this therapy, a drug delivery system (DDS) that delivers nucleic acids including RNA to mitochondria is required, but efforts in this area have been limited compared to research targeting the nucleus and cytoplasm. This contribution provides an overview of mitochondria-targeted gene therapy strategies and discusses studies that have attempted to validate mitochondria-targeted RNA delivery therapies. We also present the results of 'RNA delivery to mitochondria' based on the use of our mitochondria-targeted DDS (MITO-Porter) that was developed in our laboratory.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"329-339"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9302621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Introduction: A Short History of Adrenoceptor Research.","authors":"Martin C Michel","doi":"10.1007/164_2024_718","DOIUrl":"10.1007/164_2024_718","url":null,"abstract":"<p><p>This chapter provides a short history of adrenoceptor research starting from the initial discovery of adrenaline. It covers the evolving classification of adrenoceptor subtypes, the cloning of these subtypes from multiple species, and factors such as adrenoceptor regulation, inverse agonism and biased agonism. More details on many of these aspects are provided in other chapters of this volume of Handbook of Experimental Pharmacology.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141155175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Genetic Variants of Adrenoceptors.","authors":"Andrea Ahles, Stefan Engelhardt","doi":"10.1007/164_2023_676","DOIUrl":"10.1007/164_2023_676","url":null,"abstract":"<p><p>Adrenoceptors are class A G-protein-coupled receptors grouped into three families (α<sub>1</sub>-, α<sub>2</sub>-, and β-adrenoceptors), each one including three members. All nine corresponding adrenoceptor genes display genetic variation in their coding and adjacent non-coding genomic region. Coding variants, i.e., nucleotide exchanges within the transcribed and translated receptor sequence, may result in a difference in amino acid sequence thus altering receptor function and signaling. Such variants have been intensely studied in vitro in overexpression systems and addressed in candidate-gene studies for distinct clinical parameters. In recent years, large cohorts were analyzed in genome-wide association studies (GWAS), where variants are detected as significant in context with specific traits. These studies identified two of the in-depth characterized 18 coding variants in adrenoceptors as repeatedly statistically significant genetic risk factors - p.Arg389Gly in the β<sub>1</sub>- and p.Thr164Ile in the β<sub>2</sub>-adrenoceptor, along with 56 variants in the non-coding regions adjacent to the adrenoceptor gene loci, the functional role of which is largely unknown at present. This chapter summarizes current knowledge on the two coding variants in adrenoceptors that have been consistently validated in GWAS and provides a prospective overview on the numerous non-coding variants more recently attributed to adrenoceptor gene loci.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"27-54"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9991700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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