Handbook of experimental pharmacology最新文献_第6页

The Role of Boron in the Diet and as a Dietary Supplement. 硼在饮食中的作用及其作为膳食补充剂的作用。

Handbook of experimental pharmacology Pub Date : 2026-05-26 DOI: 10.1007/164_2026_811

Rüya Kuru-Yaşar, Ayşen Yarat

引用次数: 0

Handbook of experimental pharmacology Pub Date : 2026-05-26 DOI: 10.1007/164_2026_801

Jeremy D Pearson

{"title":"Biology of the Endothelium.","authors":"Jeremy D Pearson","doi":"10.1007/164_2026_801","DOIUrl":"https://doi.org/10.1007/164_2026_801","url":null,"abstract":"Endothelial cell functions are critical for cardiovascular health, and endothelial cell dysfunction underlies the pathology of many cardiovascular diseases. This review summarises the major aspects of endothelial physiology, which together contribute importantly to vascular homeostasis. These include regulation of haemostasis and thrombosis, vascular tone and permeability, lipid transport into the vessel wall, and leukocyte traffic from blood to tissue. Key examples are presented illustrating where endothelial cell dysfunction drives pathology and disease. Signalling pathways that are targets for current or future drug treatments for cardiovascular disease are highlighted. Control of endothelial cell phenotype is described in relation to vasculogenesis, angiogenesis, and other aspects of endothelial cell plasticity. This provides an overall framework linking endothelial physiology and pathology. By virtue of its pan-organ localisation endothelial phenotype is differentiated in multiple ways between different vascular beds due to its responses to organ-specific stimuli, which can change in disease. By virtue of its exposure to blood, endothelial phenotype is further maintained or modulated by prevailing and changing physical and chemical signals.","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148015180","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}

引用次数: 0

Mitochondrial Dysfunction Contributes to Endothelial Damage in Metabolic Diseases: Role of Mitochondrial DNA in Inflammation. 线粒体功能障碍导致代谢性疾病的内皮损伤：线粒体DNA在炎症中的作用。

Handbook of experimental pharmacology Pub Date : 2026-05-23 DOI: 10.1007/164_2026_805

Mónica M Velásquez-Esparza, Rodrigo López-Velázquez, Andrés Cázares-Preciado, Hipólito O Miranda-Roblero, Perla Pérez-Treviño, Carlos Enrique Guerrero-Beltrán, Noemí García

{"title":"Mitochondrial Dysfunction Contributes to Endothelial Damage in Metabolic Diseases: Role of Mitochondrial DNA in Inflammation.","authors":"Mónica M Velásquez-Esparza, Rodrigo López-Velázquez, Andrés Cázares-Preciado, Hipólito O Miranda-Roblero, Perla Pérez-Treviño, Carlos Enrique Guerrero-Beltrán, Noemí García","doi":"10.1007/164_2026_805","DOIUrl":"https://doi.org/10.1007/164_2026_805","url":null,"abstract":"Endothelial cells (ECs) have a low mitochondrial density, around ~2-6% of cell volume, compared to cardiac cells (~32%). Consequently, ATP is generated mainly by the glycolytic pathway. The role of the mitochondrial network in ECs gains relevance as a signaling hub that modulates a wide range of endothelial functions, e.g., regulation of cell migration, proliferation, and angiogenesis, through the action of second messengers such as Ca2+ and reactive oxygen species (ROS). However, under stress conditions, such as lipotoxicity, the homeostasis of Ca2+ and ROS is disrupted due to an imbalance in the antioxidant system, leading to an oxidative stress state. In addition, the K+-channels are inhibited, causing membrane depolarization and contributing to the disruption of ionic homeostasis. This increases free Ca2+ in the cytosol and mitochondria, resulting in the opening of mitochondrial permeability transition (MPTP) and mitochondrial dysfunction. MPTP allows the escape of mitochondrial components, such as cytochrome c, ions, and even mitochondrial DNA (mtDNA) to the cytosol. Cytosolic mtDNA migrates to the endosome to interact with TLR-9 to activate the inflammation pathway. Then mtDNA is secreted by exosomes to propagate the inflammation signal to other cells.Endothelial dysfunction in obesity, metabolic syndrome, type 2 diabetes, diabesity, and cardiometabolic disease is promoted by lipotoxicity, increased oxidative stress, and inflammation. The relationship between these mechanisms likely involves the interaction of mtDNA and other mitochondrial components (e.g., HSP60) with pro-inflammatory receptors, e.g., TLR-9.","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005182","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}

引用次数: 0

Are There Common Mechanisms and Consequences of Placental Endothelial Dysfunction in Women with Gestational Diabetes Mellitus and Pre-eclampsia? 妊娠期糖尿病和子痫前期妇女胎盘内皮功能障碍是否存在共同的机制和后果？

Handbook of experimental pharmacology Pub Date : 2026-05-19 DOI: 10.1007/164_2026_803

Katherin Silva, Paola Valero, Fernanda Espinoza, José Carlos Rivas, Dilcia Sauceda-Acosta, Luis Sobrevia

{"title":"Are There Common Mechanisms and Consequences of Placental Endothelial Dysfunction in Women with Gestational Diabetes Mellitus and Pre-eclampsia?","authors":"Katherin Silva, Paola Valero, Fernanda Espinoza, José Carlos Rivas, Dilcia Sauceda-Acosta, Luis Sobrevia","doi":"10.1007/164_2026_803","DOIUrl":"https://doi.org/10.1007/164_2026_803","url":null,"abstract":"Placental endothelial dysfunction represents a unifying pathophysiological interface in gestational diabetes mellitus (GDM) and pre-eclampsia (PE), linking abnormal placentation with metabolic stress and impaired foetoplacental vascular regulation. In GDM, maternal hyperglycaemia, insulin resistance, and inflammation reprogramme the endothelial phenotype by disrupting vasomotor homeostasis and remodelling the adenosine/L-arginine/nitric oxide (ALANO) axis. This disturbance is closely associated with impaired equilibrative nucleoside transporter-dependent adenosine transport, intracellular alkalinization, oxidative stress, and downstream cytoskeletal and epigenetic changes that together compromise placental angiogenesis, barrier integrity, and endothelial signalling. In PE, defective trophoblast invasion and incomplete spiral artery remodelling give rise to placental hypoxia and ischaemia, favouring the release of anti-angiogenic mediators. The resulting loss of NO bioavailability and endothelial repair capacity is amplified by inflammatory and vasoactive signalling, establishing a vasoconstrictor, pro-oxidant, and pro-inflammatory vascular environment. GDM and PE arise from distinct initiating insults, but they meet at the level of endothelial injury through interrelated disturbances in redox balance, inflammatory tone, angiogenic control, and NO-dependent regulation. When both disorders coexist, these derangements are likely to interact in ways that intensify placental hypoperfusion, endothelial dysfunction, and adverse maternal and foetal outcomes. An integrated mechanistic outline centred on endothelial signalling and vascular adaptation may provide stronger basis for biological stratification, biomarker development, and precision therapeutic targeting.","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147972128","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}

引用次数: 0

Microvasculature of the Pancreatic Islets of Langerhans in Health and Diabetes. 朗格汉斯健康与糖尿病患者胰岛微血管的研究。

Handbook of experimental pharmacology Pub Date : 2026-04-24 DOI: 10.1007/164_2026_804

D J Hill

{"title":"Microvasculature of the Pancreatic Islets of Langerhans in Health and Diabetes.","authors":"D J Hill","doi":"10.1007/164_2026_804","DOIUrl":"https://doi.org/10.1007/164_2026_804","url":null,"abstract":"Insulin and glucagon secreted by beta- and alpha-cells of the islets of Langerhans, respectively, regulate tissue glucose uptake, metabolism, and glycolysis. Islets represent around 2% of pancreatic mass but receive around 20% of the arterial blood flow; arteriolar blood entering the islet giving rise to a dense, fenestrated capillary bed enabling rapid glucose sensing and prompt hormone excretion. Local regulation of blood flow within each islet is achieved by contractile pericytes lining the capillaries. Endothelial cells and pericytes contribute to the lineage commitment and maturation of islet endocrine cells in utero, which can be disrupted by maternal under- or over-nutrition. Vascular cells generate the basement membranes juxtaposing endocrine cells and ensure optimal endocrine function. In type 2 diabetes, the intra-islet capillary density is increased but capillary walls are thickened with loss of fenestration and dysregulated hormone release. De-differentiation of pericytes to myofibroblasts causes islet fibrosis. In type 1 diabetes, this pathology is exacerbated by inflammatory cell-derived cytokine action on vascular cells. Pancreatic cancer-associated diabetes (type 3c), as seen with ductal adenocarcinoma, involves fibrotic thickening of the peri-islet basement membrane caused by tumor-derived growth factors. Conversely, insulin secretion may contribute to cancer growth. Therapeutic options to prevent or delay diabetes include maintaining islet vascular function through limiting cellular oxidative stress and inflammation.","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270771","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}

引用次数: 0

Structural Basis of GPCR-Biased Modulation. gpcr偏置调制的结构基础。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2025_768

Yan Zhang

{"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":"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.","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}

引用次数: 0

Structural Perspectives on Biased Allostery of GPCR Signaling. GPCR信号偏置变构的结构视角。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2025_767

Chang Zhao, Siyuan Shen, Chao Wu, Renxuan Luo, Wei Yan, Zhenhua Shao

引用次数: 0

Platelet Membrane Receptors and Signalling Pathways. 血小板膜受体和信号通路。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2025_787

Alice Y Pollitt, Craig E Hughes, Chris I Jones

{"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":"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.","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}

引用次数: 0

Calcium Signaling Dysregulation in Diabetic Cardiomyopathy: Roles of STIM and Orai Channels. 钙信号在糖尿病心肌病中的失调：STIM和Orai通道的作用。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2026_797

Tarik Smani, Beltzane Dominguez-Liste, Marta de Jesús Gutiérrez-Barranco, Carlos Aspron-Martin, Celia Cordero-Sánchez, Eva M Calderón-Sánchez, Juan Antonio Rosado, Abdelkrim Hmadcha

{"title":"Calcium Signaling Dysregulation in Diabetic Cardiomyopathy: Roles of STIM and Orai Channels.","authors":"Tarik Smani, Beltzane Dominguez-Liste, Marta de Jesús Gutiérrez-Barranco, Carlos Aspron-Martin, Celia Cordero-Sánchez, Eva M Calderón-Sánchez, Juan Antonio Rosado, Abdelkrim Hmadcha","doi":"10.1007/164_2026_797","DOIUrl":"10.1007/164_2026_797","url":null,"abstract":"Diabetes mellitus is a major metabolic disorder that significantly increases the risk of cardiovascular disease. Altered calcium (Ca2+) homeostasis, particularly through store-operated calcium entry (SOCE), has emerged as a critical pathway linking diabetes with cardiac dysfunction. Evidence indicates that SOCE is dysregulated in diabetes, but findings remain controversial. Some studies report reduced SOCE due to downregulation or impaired coupling of STIM1 and Orai1, leading to altered Ca2+ homeostasis and cardiac dysfunction. Others demonstrate enhanced SOCE linked to Orai and STIM isoforms upregulation, contributing to mitochondrial dysfunction, maladaptive hypertrophy, and metabolic remodeling in diabetic cardiomyopathy. Recent work also highlighted an unexpected role of STIM1 in fatty acid metabolism, linking Ca2+ signaling with energy substrate preference in the diabetic heart. This chapter synthesizes current evidence on the molecular mechanisms of STIM and Orai proteins in the regulation of SOCE under diabetic conditions, highlighting their roles in heart dysfunction.","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"89-104"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147868040","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}

引用次数: 0

Hydrogen Sulfide Signaling in Neurodegenerative Movement Disorders. 神经退行性运动障碍中的硫化氢信号。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2025_757

Andrew A Pieper, Bindu D Paul

{"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":"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.","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}

引用次数: 0