Handbook of experimental pharmacology最新文献

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.

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.

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.

Hydrogen sulfide (H₂S) is increasingly recognized as gaseous endogenous molecule for its significant role in various physiological processes, behind its historical association with toxicity. Recent studies have highlighted H₂S's cytoprotective properties, including antioxidant, anti-inflammatory, and antifibrotic effects, particularly in the context of skeletal muscle (SKM) health. SKM disorders, such as muscular dystrophy, human malignant hyperthermia, and sarcopenia, lead to severe structural and functional impairments that adversely affect the quality of life. Although limited literature is available on the role of H₂S in SKM physiopathology, it is gaining special interest. Emerging evidence suggests that H₂S may have a protective role in mitigating muscle damage and dysfunction. This chapter explores the dual functions of H₂S in SKM physiology and pathophysiology, emphasizing its potential therapeutic applications. We propose that H₂S-based strategies may offer promising avenues for alleviating the progression of muscle-related disorders and warrant further investigation to fully elucidate its mechanisms of action.

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.

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.

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.

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.

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.

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.