Handbook of experimental pharmacology最新文献

{"title":"GPCR Biased Signaling in Metabolism.","authors":"Zhaoyu Zhang, Zijian Li","doi":"10.1007/164_2025_774","DOIUrl":"10.1007/164_2025_774","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and the most prominent drug targets. GPCR-biased signaling exerts different functions through distinct downstream signaling pathways of receptor to maintain body homeostasis. Metabolism is the series of biochemical processes that occur within a living organism to maintain life. GPCR-biased signaling and metabolism exhibit bidirectional interplay. On the one hand, metabolites including short-chain fatty acids (SCFAs) and long-chain fatty acids (LCFAs) act as ligands inducing biased GPCRs signaling. On the other hand, activated GPCRs regulate diverse metabolic functions by biased signal sorting (G protein or β-arrestin-mediated). G protein signaling mainly mediates rapid metabolic reaction, and β-arrestin signaling mainly mediates sustained metabolic effects. In clinical drug applications, GPCR-biased drugs can revolutionize metabolic disease therapeutics by enabling pathway-selective drug design to enhance efficacy while reducing side effects. Thus, delving deeper into the relationship between GPCR-biased signaling and metabolism is of great importance in physiology, pathology, and pharmacology. A systematic exploration of biased signaling will enhance insights into GPCRs-metabolism interactions, aiding disease mechanism studies, drug discovery, and clinical treatment strategies.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"319-341"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058262","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":"Hydrogen Sulfide Consumption and Cell Bioenergetics in Human (Patho)physiology.","authors":"Maria Petrosino, Karim Zuhra","doi":"10.1007/164_2025_776","DOIUrl":"10.1007/164_2025_776","url":null,"abstract":"<p><p>Hydrogen sulfide (H₂S), once considered merely a toxic gas, is now recognized as a key endogenous signaling molecule with profound effects on vascular tone, inflammation, and cytoprotection. Central to its physiological roles is a tightly regulated balance between synthesis and degradation. While much attention has been given to H₂S biosynthesis and its signaling functions, its catabolism - particularly through the mitochondrial sulfide oxidizing pathway - has received comparatively less pharmacological exploration. This pathway not only serves as a critical detoxification mechanism but also links H₂S oxidation directly to cellular bioenergetics by contributing to mitochondrial ATP production. Such coupling underscores a unique intersection between gasotransmitter regulation and energy metabolism. This chapter highlights the bioenergetic significance of H₂S degradation, emphasizing how modulation of its mitochondrial catabolic machinery could serve as a novel therapeutic strategy. By modulating H₂S clearance, especially in pathologies marked by disrupted sulfur homeostasis and mitochondrial dysfunction, targeted pharmacological intervention may restore metabolic balance and cellular energy efficiency.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"19-40"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762649","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":"Crosstalk Between H₂S and Hormones: The Bilateral Relationship and Molecular Mechanisms.","authors":"Guangdong Yang","doi":"10.1007/164_2025_756","DOIUrl":"10.1007/164_2025_756","url":null,"abstract":"<p><p>Hydrogen sulfide (H₂S) is increasingly recognized as a key gasotransmitter with diverse physiological roles across a range of organisms. Accumulating evidence has clearly shown that disruptions in H₂S homeostasis are linked to various endocrine disorders. Hormones are crucial in regulating H₂S metabolism and signaling, while H₂S influences hormones by modulating their biosynthesis, secretion, transport, and signaling pathways. H₂S and hormones function cooperatively to regulate cell survival, metabolism, reproduction, development, and stress responses, etc. The interaction between H₂S and hormones exhibits a certain degree of complexity due to the fact that they interact dynamically and through multiple signaling pathways. This book chapter summarizes the current state of knowledge on the bilateral relationship of H₂S and several important hormones, detailing the molecular mechanisms of H₂S-mediated hormone release and signal pathways, hormone-modulated H₂S synthesis and metabolism, and the related pathological implications. Insights into the reciprocal interactions between H₂S and various hormones can facilitate the development of therapeutic strategies for hormone-related disorders.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"173-205"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762651","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":"Comparison of the Biologic Activity of Different Species of Heparin.","authors":"Walter Jeske","doi":"10.1007/164_2025_781","DOIUrl":"10.1007/164_2025_781","url":null,"abstract":"<p><p>Heparin and related low molecular weight heparin derivatives remain critical drugs for the prevention and treatment of thrombotic conditions. Concerns relating to the stability and sufficiency of the porcine intestinal mucosa supplies from which most heparin is currently derived have spurred an interest in identifying other sources for heparin. Commercial quantities of heparin may be obtained from cow and sheep intestine, and heparin or heparin-like material has been identified in a number of other species. Being biologic in nature, these heparins exhibit unique structural and functional profiles. This chapter summarizes our current understanding of these heparins.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"83-96"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762692","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":"Direct Oral Anticoagulant Inhibitors: Mode of Action, Clinical Aspects.","authors":"Eman Hassan, Will Lester","doi":"10.1007/164_2025_786","DOIUrl":"10.1007/164_2025_786","url":null,"abstract":"<p><p>This chapter provides a comprehensive overview of direct oral anticoagulants (DOACs), focusing on their mechanisms of action, clinical utility, and practical considerations in anticoagulation management. DOACs have revolutionised anticoagulation by selectively targeting thrombin and activated factor X (FXa), offering improved safety, predictable pharmacokinetics, and reduced need for monitoring. The chapter covers their indications, contraindications, dosing, perioperative management, reversal, and use in special populations, including those with renal or hepatic impairment, cancer-associated thrombosis, and extreme body weights. It provides clinicians with practical guidance for the effective application of DOACs in various clinical settings.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"99-121"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145855477","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":"The Role of H2S in Atherosclerosis and Associated Cardiometabolic Comorbidities.","authors":"Odysseia Savvoulidou, Turtushikh Damba, Daniel F J Ketelhuth, Maria Peleli","doi":"10.1007/164_2025_760","DOIUrl":"10.1007/164_2025_760","url":null,"abstract":"<p><p>Hydrogen sulfide (H₂S) is an important gasotransmitter with multiple roles and is involved in several pathophysiological processes, including atherosclerosis and associated cardiometabolic comorbidities. This chapter examines the molecular mechanisms by which H₂S can influence the development and progression of atherosclerosis, including its effects on vascular tone, angiogenesis, oxidative stress, and inflammation, which can also affect atherosclerotic plaque stability. Moreover, we describe how H₂S affects the outcomes of cardiometabolic comorbidities associated with atherosclerosis, such as diabetes, hypertension, cardiac ischemia-reperfusion injury (IRI), stroke, metabolic-associated fatty liver disease (MAFLD), and kidney disease. Finally, we discuss how H₂S levels could potentially serve as biomarkers and the potential of increasing H₂S levels (both donors and metabolic pathway modulators) as promising therapeutic agents for improving vascular function, reducing plaque formation, and mitigating cardiovascular disease risk.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"95-121"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145855453","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":"Hydrogen Sulfide in Experimental Organ Transplantation: From Bench to Bedside.","authors":"George J Dugbartey, Alp Sener","doi":"10.1007/164_2025_778","DOIUrl":"10.1007/164_2025_778","url":null,"abstract":"<p><p>Organ transplantation is the treatment of choice for patients with organ failure. However, the long-term success of this complex life-saving procedure is severely challenged by several inherent factors such as ischemia-reperfusion injury (IRI), an unavoidable pathological condition which occurs due to temporary cessation of blood supply to the donor organ during procurement and cold preservation, and subsequent blood restoration upon engraftment. IRI decreases organ graft quality and function and increases the incidence of post-transplant complications. While the transplant community has adopted the use of sub-optimal organ grafts from extended criteria donors and deceased donors in addition to viable organs from healthy living donors to expand the pool of transplantable organs with the aim to overcome the global organ shortage crisis, the sub-optimal organs are more susceptible to IRI. Also worrying is the fact that organ preservation techniques have not changed for over the last 50 years, suggesting the need to optimize existing preservation techniques or develop effective alternative preservation solutions to limit ischemic injury during organ graft preservation. Among several pharmacological agents being tested in preservation solutions in the pretext of improving transplantation outcomes, hydrogen sulfide (H₂S), the third established member of a family of gaseous signaling molecules, is emerging as an excellent candidate, with therapeutic properties such as antioxidant, anti-inflammatory, anti-apoptotic, and vasodilating properties. In this chapter, we discussed the therapeutic benefits of H₂S and its donor compounds against IRI in various experimental models of organ transplantation. In fact, one of the H₂S donor compounds, sodium thiosulfate, which our research team is currently investigating in experimental kidney transplantation, is already in clinical use. Therefore, it is a question of repositioning it for clinical organ transplantation after substantial evidence of its protective effects in experimental organ transplantation.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"253-272"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145819055","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":"S-Nitrosylation of GPCR Regulatory Machinery as a Mechanism to Bias Signaling.","authors":"Mingda Chen, Zachary W Grimmett, Richard T Premont, Jonathan S Stamler","doi":"10.1007/164_2025_765","DOIUrl":"10.1007/164_2025_765","url":null,"abstract":"<p><p>Upon stimulation by endogenous ligands, G protein-coupled receptors (GPCRs) activate downstream signaling pathways through multiple mechanisms, including G protein subtypes, β-arrestins, and receptor-specific partners. Synthetic ligands may activate only a subset of these pathways, resulting in functional selectivity or signaling bias. Since not all signaling outputs are therapeutically desirable, there is pharmaceutical interest in exploiting biased signaling. Although much effort is focused on designing ligands to induce receptor conformations that result in signal bias, it is also true that cellular systems adapt dynamically in ways that tune receptor signaling, termed system bias. In this chapter, we provide evidence that posttranslational modification of receptor machinery by S-nitrosylation is an important regulator of system bias in GPCR signaling. S-nitrosylation has been reported to affect the function of multiple classes of GPCR signaling pathway components, including receptors, G proteins, G protein-coupled receptor kinases, β-arrestins, and others. Further, untargeted proteomic studies of S-nitrosylated proteins have identified over 60 GPCRs, most heterotrimeric G proteins, and numerous GPCR signaling components, hinting at a class effect and unifying mechanism to bias the functional repertoires of GPCRs in vivo. Thus, protein S-nitrosylation provides prototypic examples for how post-translational regulatory mechanisms bias GPCRs endogenously.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"121-142"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199152","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":"Laboratory Testing of Direct Oral Anticoagulants.","authors":"Christopher Reilly-Stitt","doi":"10.1007/164_2025_783","DOIUrl":"10.1007/164_2025_783","url":null,"abstract":"<p><p>Direct oral anticoagulants (DOACs), also referred to as non-vitamin K oral anticoagulants (NOACs), have revolutionised anticoagulant therapy since their introduction in the late 2000s. These agents - dabigatran (a direct thrombin inhibitor) and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban - offer more predictable pharmacokinetics, fewer food and drug interactions, and do not typically require routine laboratory monitoring, unlike traditional anticoagulants such as warfarin and heparin. Despite these advantages, laboratory assessment of DOAC activity remains clinically important in specific circumstances, including bleeding, thrombosis during therapy, emergency surgery, renal or hepatic impairment, and suspected non-compliance.This chapter reviews the pharmacology, clinical applications, and laboratory evaluation of DOACs, outlining available assays and their principles. The gold standard for quantification is liquid chromatography-tandem mass spectrometry (LC-MS/MS), though chromogenic anti-Xa and dilute thrombin time (DTT) or ecarin-based assays are more commonly used in clinical laboratories. The impact of DOACs on routine coagulation tests such as PT, APTT, and TT is variable and reagent dependent, underscoring the need for drug-specific calibrators and assay validation.Quality assurance through both internal quality control (IQC) and external quality assessment (EQA) is essential to maintain assay accuracy and reproducibility, in accordance with ISO 15189:2022 standards. Furthermore, DOACs can interfere with other haemostasis assays - including factor assays, antithrombin, and lupus anticoagulant testing - leading to potential diagnostic errors. Recent studies demonstrate that activated charcoal-based reagents, such as DOAC Remove™ and DOAC Stop™, can effectively neutralise DOAC interference in such assays.In conclusion, while DOACs have largely supplanted warfarin in the management of non-valvular atrial fibrillation and venous thromboembolism due to their safety and convenience, laboratory testing retains a critical role in ensuring safe and effective patient management under specific clinical scenarios.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"123-133"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762646","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":"Heparin: Over 100 Years of Anticoagulation.","authors":"John Hogwood, Elaine Gray","doi":"10.1007/164_2025_780","DOIUrl":"10.1007/164_2025_780","url":null,"abstract":"<p><p>This chapter provides an overview of heparin, including discovery, structure, mechanism of action, and principal use for anticoagulation. For over 100 years, heparin has a central role in prophylaxis and treatment of prothrombotic states, be it used in the event of pulmonary embolism or maintaining blood fluidity during dialysis. Indeed, heparin had a role in enabling the development of cardiopulmonary bypass for the surgical treatment of cardiopulmonary diseases. The development of heparin depolymerization which produced low molecular weight heparin further enhanced the usefulness of this anticoagulant, where this type of heparin can be self-administered. There has been much written about heparin over the last century, and this chapter provides a concise overview.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"59-81"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145855510","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}