Handbook of experimental pharmacology最新文献

{"title":"The Role of Hydrogen Sulfide-Derived Perivascular Adipose Tissue in Vascular Diseases.","authors":"Emma Mitidieri, Chiara Indolfi, Vincenzo Brancaleone, Raffaella Sorrentino, Roberta d'Emmanuele di Villa Bianca","doi":"10.1007/164_2025_755","DOIUrl":"10.1007/164_2025_755","url":null,"abstract":"<p><p>Perivascular adipose tissue (PVAT) is a metabolically active, endocrine organ that plays a crucial role in regulating blood vessel tone, endothelial function, vascular smooth muscle cell growth, and proliferation and contributes significantly to the onset and progression of cardiovascular diseases. In a healthy state, PVAT displays anticontractile, anti-inflammatory, and antioxidative properties, which are critical for maintaining vascular homeostasis. However, under certain pathophysiological conditions, PVAT exerts pro-contractile effects by decreasing the production of anticontractile and/or increasing that of pro-contractile factors. In this context, recent studies have identified hydrogen sulfide (H₂S) as a key vascular anti-contractile factor released from PVAT. The enzymes responsible for H₂S biosynthesis are differentially expressed in PVAT, depending on the vascular bed and species, and their function can be altered by metabolic and cardiovascular diseases. These alterations can influence H₂S signalling, further contributing to vascular dysfunction. PVAT-derived H₂S may have particular importance in obesity-related vascular disease, hypertension, and diabetes as it has direct paracrine effects on the vasculature. Understanding the role of PVAT-derived H₂S in both healthy and diseased states may provide new insights into preventing vascular dysfunction associated with PVAT changes. The dissection of the specific contributions of each enzyme involved in PVAT-derived H₂S biosynthesis could be relevant to fully understanding the complex role of H₂S in vascular health vs vascular disease. Further research into modulating PVAT-derived H₂S provides an exciting avenue to explore novel pharmacological targets against vascular disease pathogenesis.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"123-146"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291970","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":"Role of Innate Immune Receptors in Cardiac Damage Linked to Metabolic Disorders.","authors":"Almudena Val-Blasco, Marta Gil-Fernández, Andrea Bueno-Sen, Paula Cantolla-Pablo, María Fernández-Velasco, Patricia Prieto","doi":"10.1007/164_2026_793","DOIUrl":"10.1007/164_2026_793","url":null,"abstract":"<p><p>This chapter underscores the pivotal role of immune receptors, particularly Toll-like receptors (TLRs) and NOD-like receptors (NLRs), in the intricate interplay between metabolic diseases and their associated cardiovascular comorbidities. Their involvement extends beyond mere initiation, profoundly influencing the progression of these complex conditions. The recognition of TLRs and NLRs as promising therapeutic targets is a significant advancement, offering potential avenues for intervention in both metabolic disorders and their cardiovascular sequels.The significance of these pattern recognition receptors (PRRs) lies in their capacity to orchestrate inflammatory responses, a critical factor in the pathogenesis of metabolic diseases. Dysregulation of these pathways contributes to chronic, low-grade inflammation, a hallmark of conditions such as obesity and type 2 diabetes. This persistent inflammation, in turn, fuels the development of cardiovascular complications such as atherosclerosis, hypertension, and heart failure.Targeting TLRs and NLRs presents a strategic approach to modulate these inflammatory cascades. By selectively inhibiting or modulating the activity of these receptors, it may be possible to mitigate the detrimental effects of chronic inflammation and prevent or delay the onset of associated comorbidities. However, this approach requires a thorough understanding of the specific TLR and NLR subtypes involved in various disease processes, as well as the intricate signaling pathways they activate.Furthermore, the development of therapeutic strategies targeting PRRs must consider the potential for off-target effects and the need for personalized medicine. Given the diverse expression patterns and functional roles of TLRs and NLRs across various cell types and tissues, a tailored approach is essential to maximize efficacy and minimize adverse effects. Consequently, ongoing research is focused on identifying specific ligands and inhibitors that can selectively target these receptors, paving the way for novel therapeutic interventions.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"145-164"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316907","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":"Cardiac Cell Remodeling in Obesity and Diabetes.","authors":"Avelino-Cruz José Everardo, Yang-Bennett Daniela Sarahi, Galindo-Ramírez Fabián","doi":"10.1007/164_2026_789","DOIUrl":"10.1007/164_2026_789","url":null,"abstract":"<p><p>The contractile activity of the heart depends on the coordinated activation of cardiac muscle cells, as well as the activation of each region within these cells. The conversion of an electrical signal into a mechanical process is known as excitation-contraction coupling; this process depends on the accurate organization and functional coupling between the different participating structures. The T-tubules and the sarcoplasmic reticulum constitute the dyads, a functional structure where the activity of voltage-gated calcium channels is coupled with the type 2 ryanodine receptor to generate calcium-induced calcium release. This phenomenon increases the intracellular calcium concentration, allowing cell contraction. The relaxation process occurs at the same time as calcium extrusion or recapture into the sarcoplasmic reticulum. The formation of the T tubules, the organization of the dyad, and the distribution of the proteins that regulate the entry, reuptake, and extrusion of calcium involve different structural proteins whose expression, localization, and function can be affected in pathological processes such as heart failure. In this chapter, we give an overview of the proteins involved in cardiac cell ultrastructural organization and an insight into changes and possible causes of these changes found in diabetes, obesity, and heart failure models.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"65-87"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147305076","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":"Correction to: 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_2026_795","DOIUrl":"10.1007/164_2026_795","url":null,"abstract":"","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"273-274"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627676","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 Adipose Tissue Biology.","authors":"Antonia Katsouda, Andreas Papapetropoulos","doi":"10.1007/164_2025_759","DOIUrl":"10.1007/164_2025_759","url":null,"abstract":"<p><p>Over the past several decades, sulfide has emerged as an important signaling molecule, playing diverse physiological and pathological roles across a broad spectrum of human health conditions. Among its recently recognized systemic effects, sulfide has been identified as a key regulator of adipose tissue (AT) homeostasis; its critical involvement in numerous adipose tissue functions, including adipogenesis, lipogenesis, and lipid and glucose metabolism, has been reported. Growing evidence indicates that dysregulation of H₂S signaling within the adipose tissue contributes to the development and progression of obesity and related metabolic disorders. The pharmacological modulation of endogenous sulfide levels is being actively explored as a promising therapeutic strategy for improving metabolic health. Herein, we provide a comprehensive and critical review of the current literature on the role of sulfide in adipose tissue biology and physiology. Particular emphasis is placed on the broader implications of sulfide signaling in the prevention and treatment of obesity.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"207-232"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145855515","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":"GPCR Phospho-Barcodes and Biased Signaling.","authors":"Qingtao He, Jinpeng Sun, Shenming Huang","doi":"10.1007/164_2025_761","DOIUrl":"10.1007/164_2025_761","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs), the largest family of membrane receptors in humans, primarily regulate diverse physiological and pathological processes through G protein- and arrestin-mediated signaling pathways, making them important drug targets. Notably, arrestins not only mediate GPCR desensitization and internalization but also regulate G protein-independent signal transduction. However, the mechanisms underlying arrestin-mediated biased signaling remain incompletely understood, posing significant challenges for developing targeted GPCR drugs with signaling bias. To address this knowledge gap, researchers have conducted systematic investigations and proposed innovative models, including the flute model, the polyproline sorting dock model, and the time order effects of GPCR phospho-barcodes to elucidate the dynamic processes driving biased signaling in arrestin activations. These key findings not only refine the theoretical framework of GPCR phosphorylation in biased signaling but also provide a solid foundation for developing biased drugs targeting the GPCR-arrestin pathway, offering new opportunities for precision therapeutics in diverse diseases.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"3-11"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185460","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 and Point of Care Monitoring of Vitamin K Antagonist Treatment.","authors":"Ian Jennings, Dianne Kitchen","doi":"10.1007/164_2025_782","DOIUrl":"10.1007/164_2025_782","url":null,"abstract":"<p><p>Vitamin K antagonist (VKA) therapy is given to patients either after a thrombosis or prophylactically to prevent a thrombotic event. VKAs block the action of vitamin K reductase which converts inactive forms of Factors II, FVII, FIX, FX, protein C, S and Z to their functional enzyme zymogens. In this way the levels of functional clotting factors in the circulation are reduced and thus the potential of the blood to clot is lowered. VKA therapy requires careful monitoring as pharmacological responses vary significantly between individuals; too much anticoagulation can increase bleeding risks, but too little increases the risk of a new or extended thrombosis. The effects of VKA therapy are monitored using the International Normalised Ratio (INR). This is a standardised test based on the prothrombin time (PT), developed in the 1980s to allow comparability between all different methods and reagents. This then means that a patient can be tested anywhere in the world and the same INR results would be obtained. The INR tests can be performed in a laboratory setting but also since the late 1990s as a Point of Care test (POCt). Although this test has been standardised, there is still potential to see differences between methods in particular samples or in certain patient conditions. An understanding of the factors affecting this straightforward test, and constant quality control, is required to ensure results are valid and reliable, and patient treatment is optimised. Comparability between different test systems for INR monitoring is greatest in over-anticoagulated patients, and strategies for treatment of these patients, for example, with reversal agents such as Vitamin K either orally or by injection need to be in place.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"39-56"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145855465","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":"Oxidative Modifications in Cardiac Mitochondrial and Ca²⁺ Handling Proteins in Obesity and Metabolic Syndrome: Antioxidant Alternatives.","authors":"Karla Carvajal, David Julian Arias-Chávez, Patrick Mailloux-Salinas, Guadalupe Bravo, Norma Leticia Gómez-Viquez","doi":"10.1007/164_2026_794","DOIUrl":"10.1007/164_2026_794","url":null,"abstract":"<p><p>Obesity and its related comorbidities, collectively defined as metabolic syndrome (MetS), represent a major health concern due to their strong association with increased cardiometabolic risk. A defining feature of obesity and MetS is the excessive production of reactive oxygen species and reactive nitrogen species, resulting in systemic oxidative stress (OS) and nitrosative stress (NS). In the heart, OS and NS induce structural and conformational alterations in proteins, referred to as oxidative post-translational modifications (oxPTMs). These modifications disrupt protein function, thereby impairing essential cellular processes and ultimately contributing to diastolic and systolic dysfunction. Several proteins critical for cardiac function have been identified as targets of oxPTMs in the context of obesity and MetS. Among the most studied are mitochondrial proteins such as dynamin-related protein 1 (Drp1), respiratory chain complexes I, II, and IV, and creatine kinase, as well as Ca²⁺-handling proteins including sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a) and ryanodine receptors (RyR2). This chapter summarizes current knowledge on the mechanisms underlying cardiac dysfunction in obesity and MetS, with a particular emphasis on OS and its damaging effects on mitochondrial metabolism and Ca²⁺ handling. Finally, we provide an update on recent findings regarding natural antioxidants and mitochondria-targeted antioxidant therapies, highlighting their potential as treatment strategies for cardiovascular diseases associated with obesity and MetS.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"127-143"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146258089","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":"Cardiovascular Dysfunction in Type 2 Diabetes: The Role of MicroRNAs.","authors":"Gizem Kayki-Mutlu, Ebru Arioglu-Inan","doi":"10.1007/164_2026_799","DOIUrl":"10.1007/164_2026_799","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) is a major health concern that leads to multiple chronic complications. Among these, cardiovascular dysfunction is a prominent contributor to the morbidity and mortality associated with T2D. MicroRNAs (miRNAs) are non-coding RNAs that regulate protein synthesis by activating or suppressing target genes. Recently, their role in the cardiovascular complications of T2D has attracted significant attention. Several miRNAs have emerged as key regulators. In diabetic hearts, miRNAs such as miR-133, miR-1, miR-34a, and miR-21 influence critical processes, including hypertrophy, fibrosis, oxidative stress, and cell death. miR-126, in particular, is one of the most studied miRNAs in the context of vascular function in T2D, playing a crucial role in endothelial function, vascular integrity, and angiogenesis. Evidence to date suggests that altered levels of specific miRNAs contribute to cardiovascular dysfunction in T2D, making them potential therapeutic targets for preventing or treating these complications. In this chapter, we aim to discuss the impact of miRNAs on the cardiovascular system in T2D.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"165-195"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147868087","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":"Mechanisms of Location Bias in G Protein-Coupled Receptors.","authors":"Uyen Pham, Anand Chundi, Sudarshan Rajagopal","doi":"10.1007/164_2025_764","DOIUrl":"10.1007/164_2025_764","url":null,"abstract":"<p><p>GPCRs are known for their versatile signaling roles at the plasma membrane; however, recent studies have revealed that these receptors also function within various intracellular compartments, such as endosomes, the Golgi apparatus, and the endoplasmic reticulum. This spatially distinct signaling, termed location bias, allows GPCRs to initiate unique signaling cascades and influence cellular processes-including cAMP production, calcium mobilization, and protein phosphorylation-in a compartment-specific manner. By mapping the impact of GPCR signaling from these subcellular locations, this chapter emphasizes the mechanisms underlying signaling from intracellular receptor pools in diversifying receptor functionality. Such mechanistic insights into location-biased signaling open up novel therapeutic strategies aimed at targeting GPCRs within specific organelles, promising new levels of precision in therapeutic modulation and potential improvements in treatment efficacy and specificity.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"87-119"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029793","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}