Handbook of experimental pharmacology最新文献

{"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":"https://doi.org/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":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-28","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":"https://doi.org/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":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-27","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":"Sexual Dimorphism in the Development of Cardiometabolic Syndrome.","authors":"Myrian Velasco, Alondra Albarado-Ibañez, Carlos Larqué, Pablo Pánico, Julián Torres-Jacome, Marcia Hiriart","doi":"10.1007/164_2026_790","DOIUrl":"https://doi.org/10.1007/164_2026_790","url":null,"abstract":"<p><p>Anatomical and physiological differences between sexes explain the sexual dimorphism in the development of diseases, such as obesity and metabolic syndrome. This syndrome is a condition that increases the risk of developing cardiovascular diseases, diabetes, and certain cancer types. Cardiovascular diseases remain the leading cause of mortality in both sexes worldwide. However, CVD mortality is higher in men than women, demonstrating that the differences between women and men might have an essential role in the development of CVD.The CV system shows dimorphic variations, starting at early developmental stages. However, most studies on the CV system have been conducted predominantly in males. Understanding the differences in the CVD associated with sex is vital to improving the prevention, diagnosis, and treatment of these diseases. In this chapter, we highlight the differences found in the literature between sexes in physiological and pathological events within the cardiovascular system related to metabolic syndrome (MetS).</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146258061","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":"https://doi.org/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":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-21","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":"Physical Activity and Its Impact on Cardiometabolic Disorders.","authors":"J Gustavo Vázquez-Jiménez, Tatiana Romero-García","doi":"10.1007/164_2026_792","DOIUrl":"https://doi.org/10.1007/164_2026_792","url":null,"abstract":"<p><p>The significant concern about the incidence and prevalence of cardiometabolic disorders around the world continues to rise as this upward trend persists. As researchers intensify their search for underlying causes, there is a growing demand for effective methods of prevention and treatment. In this sense, technology dependence, high-calorie diets, and a shortage of opportunities, time, and interest in physical activity primarily drive the growth in sedentary behavior among the global population, which is strongly associated with the emergence of cardiometabolic disorders. Thus, this chapter will highlight the importance of physical activity for metabolic and cardiovascular health through the revision of the various studies carried out around the world, highlighting the benefits at a molecular and physiological level for people who suffer from obesity, metabolic syndrome and, type 2 diabetes mellitus, as well as providing a general overview regarding the particularities in the prescription of exercise for people with these conditions.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197270","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":"In Search of a Biomarker for Vasculopathy Associated with Metabolic Syndrome.","authors":"Donjuán-Loredo Guadalupe, Saavedra-Serrato Luis, Chávez-Morales Tómas, Espinosa-Tanguma Ricardo","doi":"10.1007/164_2026_791","DOIUrl":"https://doi.org/10.1007/164_2026_791","url":null,"abstract":"<p><p>Central obesity is associated with a group of metabolic and cardiovascular alterations known as metabolic syndrome (MetS). MetS affects an estimated 20-25% of the global population. The clinical diagnosis of MetS is made using different methodologies, depending on the parameter being measured; however, no established molecule or biomarker unifies these alterations and allows MetS to be identified from its inception. Fatty acid-binding proteins (FABPs) have been studied as molecules that accompany MetS abnormalities, from their role in intracellular lipid transport to their release into the circulation under pathological conditions and their elevation in various biofluids, which may be indicative of MetS. In this chapter, we will focus on adipocyte, epidermal, and intestinal FABPs as metabolic biomarkers of the early stages of MetS since they are associated with alterations such as inflammation of the tissues containing them, which allows them to be identified even in the early stages of the disease. The ability to have a molecule that combines all the parameters of MetS remains and important goal, given the existence of possible candidates. This would allow the early identification of MetS, which would represent a new approach to its clinical diagnosis.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197615","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":"Structural Basis of GPCR-Biased Modulation.","authors":"Yan Zhang","doi":"10.1007/164_2025_768","DOIUrl":"10.1007/164_2025_768","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) constitute the largest superfamily of membrane receptors in humans and serve as crucial targets for drug development. These receptors engage multiple downstream signaling pathways, including various G-proteins and arrestins, each of which can elicit distinct physiological and pathological responses. Understanding the mechanisms of biased signaling among these pathways is vital for designing more effective drugs with reduced side effects. In this chapter, we summarize the current understanding of how GPCRs selectively couple to different signaling proteins. We delve into the structural insights derived from recent studies, which reveal how ligands can stabilize specific receptor conformations, thereby favoring particular signaling pathways over others. Furthermore, we highlight various biased ligands and their mechanisms of action, emphasizing their therapeutic potential. These findings provide a critical structural foundation for future drug discovery and optimization efforts, paving the way for more targeted and safer pharmacological interventions. Through a deeper comprehension of biased signaling mechanisms, we aim to enhance the efficacy and safety profiles of new therapeutic agents.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"181-199"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199133","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":"Structural Perspectives on Biased Allostery of GPCR Signaling.","authors":"Chang Zhao, Siyuan Shen, Chao Wu, Renxuan Luo, Wei Yan, Zhenhua Shao","doi":"10.1007/164_2025_767","DOIUrl":"10.1007/164_2025_767","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are highly dynamic membrane receptors with numerous subtypes and complex signal transduction pathways. Precise regulation of GPCR signaling is closely related to disease treatment but presents significant challenges with classical orthosteric ligands. Allosteric modulators, a class of emerging drug candidates, can selectively bind to the allosteric sites located outside the conserved orthosteric pocket. In particular, biased allosteric modulators (BAMs) can stabilize specific conformations of GPCRs to harness signal transduction with high selectivity and specificity, offering a novel approach to modulate GPCR pharmacology and develop safer therapeutic agents. In recent years, significant progress has been made in the study of GPCR allosteric modulation due to advancements in structural biology. However, knowledge about GPCR-biased allostery is still in its infancy. In this chapter, we present the most recent breakthroughs in the discovery of BAM binding site in GPCRs and provide structural insights into biased allostery of GPCR signaling.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"161-179"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199101","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 Signaling in Neurodegenerative Movement Disorders.","authors":"Andrew A Pieper, Bindu D Paul","doi":"10.1007/164_2025_757","DOIUrl":"10.1007/164_2025_757","url":null,"abstract":"<p><p>Hydrogen sulfide (H₂S) is a gaseous signaling molecule, also known as a gasotransmitter, present in nearly all mammalian organs. It plays crucial roles in regulating various physiological processes in both the brain and peripheral systems. The body maintains tight control over H₂S levels, as both excessive and deficient levels can disrupt normal physiological functions and lead to disease. H₂S has a significant impact on cognitive and motor functions, which are often compromised in neurodegenerative disorders. It modulates signaling and metabolism primarily by post-translationally modifying reactive cysteine residues on proteins through sulfhydration, also known as persulfidation. This chapter reviews the signaling mechanisms regulated by H₂S in neurodegenerative diseases that significantly affect motor function, specifically focusing on Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), and Leigh syndrome (LS), as well as other mitochondrial disorders. While PD, HD, and SCA are linked to decreased levels of H₂S, elevated levels of H₂S are associated with ALS, DS, and LS. We also explore potential therapeutic applications of modulating H₂S levels in the brain.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"65-93"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12988654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet Membrane Receptors and Signalling Pathways.","authors":"Alice Y Pollitt, Craig E Hughes, Chris I Jones","doi":"10.1007/164_2025_787","DOIUrl":"10.1007/164_2025_787","url":null,"abstract":"<p><p>Platelets are central mediators of haemostasis, responding rapidly to vascular injury through tightly regulated activation and inhibitory mechanisms. This response is mediated by a range of agonists, membrane receptors, and associated signalling pathways, enabling platelets to respond rapidly and specifically to stimuli. This chapter outlines the processes of platelet activation following vascular damage, highlighting the roles of collagen, von Willebrand factor, and secondary agonists such as ADP, thromboxane A₂, and thrombin, alongside endothelial-derived inhibitory signals that restrain excessive activation. It focuses on tyrosine kinase-linked receptors, detailing immunoreceptor tyrosine-based activatory (ITAM and hemITAM) and inhibitory (ITIM/ITSM) pathways, with emphasis on key kinases including Src family kinases, Syk, and Tec family members, and receptors such as GPVI, FcγRIIA, CLEC-2, PECAM-1, and G6b-B. Adhesion receptors, particularly integrins αIIbβ3 and α2β1 and the GPIb- IX-V complex, are examined with respect to inside-out and outside-in signalling and mechanotransduction. Finally, the G-protein-coupled receptors that amplify or inhibit platelet responses are discussed, including PARs, purinergic receptors, thromboxane, and prostaglandin receptors, along with emerging concepts in the regulation of platelets by GPCRs and in therapeutic targeting. The activatory and inhibitory pathways outlined here work together to maintain a balance between haemostasis and thrombosis. This enables a rapid and coordinated platelet response to vascular damage while preventing inappropriate and excessive activation. This maintains vascular integrity while preventing excessive bleeding and pathological thrombosis.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"137-175"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145855543","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}