Handbook of experimental pharmacology最新文献

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.

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.

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.

In the late 1990s, the antiplatelet agent clopidogrel, a P2Y12 inhibitor, was introduced into clinical practice. Concurrently, several new methods for assessing platelet function emerged, such as the PFA-100 in 1995, marking the beginning of a sustained expansion in platelet function testing. It soon became apparent that patient responses to clopidogrel varied significantly, with some individuals exhibiting high on-treatment platelet reactivity. This variability prompted discussions around the utility of platelet function testing to tailor antiplatelet therapy. Additionally, such testing was proposed for patients preparing for cardiac surgery to better manage the balance between thrombotic risk before surgery and bleeding risk during the perioperative period. This chapter explores widely used platelet function tests in these contexts, particularly those considered point-of-care (POC) or requiring minimal laboratory processing. It also reviews recent guidelines and clinical trial evidence, building on a previously published chapter, regarding the role and effectiveness of platelet function testing in these clinical scenarios.

Hydrogen sulfide (H₂S) is a gasotransmitter that contributes to the regulation of peripheral nervous system (PNS) function. H₂S is produced by several enzymes whose expression changes under different physiological and pathological conditions, influencing how peripheral neurons respond to environmental and internal signals. H₂S modulates neuronal excitability through its actions on ion channels and through interactions with other gasotransmitters, shaping sensory, autonomic, and pain-related pathways. In autonomic circuits, H₂S adjusts sympathetic and parasympathetic activity. Through these actions, it affects cardiovascular control, gastrointestinal motility, and respiratory rhythm. In pain pathways, H₂S can modulate nociception in either direction, with its effectsshaped by the physiological or pathological state. H₂S participates in multiple pain conditions and contributes to changes in peripheral and spinal processing that influence pain sensitivity. Overall, H₂S influences several components of peripheral neurobiology and represents a potential target for strategies aimed at treating autonomic dysfunction and chronic pain.