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.

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.

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.

Platelets are a crucial component in the maintenance of normal haemostasis. In response to vascular damage, activated platelets adhere to the damaged endothelium leading to both aggregation and coagulation. Under healthy conditions, these processes prevent excessive vascular haemorrhage and promote vascular repair and regeneration. However, in cardiovascular diseases, hyperactive platelet activation leads to acute coronary syndrome characterised by occlusive thrombus formation, myocardial infarction and stroke. Targeted platelet therapy has been used extensively in the inhibition of inappropriate platelet activation for the treatment of cardiovascular diseases including cyclooxygenase inhibitors, purinergic antagonists, thrombin inhibitors, PAR receptor antagonists, and phosphodiesterase inhibitors. In this review, we discuss the current clinical portfolio of antiplatelet therapies whilst also discussing promising new antiplatelet targets for the treatment of cardiovascular disorders.

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.

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.

Hydrogen sulfide (H2S) is an endogenous gasotransmitter able to exert a pivotal role in different organs and systems, strongly influencing cardiovascular health. It is an endowed antioxidant, a vasorelaxant, and has cardioprotective properties, thanks to the activation of different classes of potassium channels and the interaction with several pathways including those involving sirtuins, nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), and nitric oxide (NO) production. Alterations in the homeostasis of H2S represent an etiopathogenetic factor in the onset and progression of cardiovascular diseases, such as hypertension, atherosclerosis, and vascular diabetic complications, highlighting the therapeutic potential of exogeneous H2S-donors in H2S-poor diseases. Several natural H2S-donor compounds, or their precursors, derive from plants belonging to the Alliaceae (e.g., garlic and onion), Brassicaceae (e.g., broccoli and rocket salad), or Moringaceae (e.g., moringa) families. Preclinical studies demonstrated the antioxidant, vasoprotective, and anti-hypertensive properties of both plant extracts and isolated polysulfides or isothiocyanates (ITCs). In fact, polysulfides and ITCs are able to exert vascular effects superimposable to those induced by H2S. Preclinical and clinical studies successfully demonstrated that garlic extracts decrease systolic and diastolic blood pressure and contrast endothelial dysfunction and atherosclerosis. Similarly, preclinical studies highlighted the anti-inflammatory, anti-hypertensive, and vasoprotective properties of ITCs. However, clinical studies only demonstrated the improvement of the lipid profile in healthy patients, with no effects on systolic or diastolic blood pressure. Taken together, these findings suggest that natural H2S-donors could restore H2S homeostasis, therefore preventing and/or contrasting cardiovascular diseases.

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.

G protein-coupled receptors (GPCRs) engage multiple transducers to regulate distinct physiological processes. These transducers include various G proteins subtypes, GPCR kinases (GRKs), and β-arrestins. In addition to promoting receptor desensitization, β-arrestins serve as scaffolds for signaling via non-G protein pathways. Biased signaling enables GPCRs to selectively engage specific transducers, typically through different conformational states of GPCRs. While significant focus has been placed on developing biased ligands that preferentially activate specific G proteins or β-arrestins, the strategy focused on modulating particular G protein subunits (Gα versus βγ) remains underexplored. Recently, members of the KCTD (potassium channel tetramerization domain-containing) family have emerged as critical regulators of GPCR signaling, particularly through their roles in mediating Gβγ degradation or uncoupling Gβγ from downstream effectors. This ability positions the KCTD family as potential targets for selectively modulating Gβγ signaling with minimal impact on Gα-mediated pathways. In this chapter, we introduce the KCTD family, summarize current knowledge of their role in GPCR signaling regulation, and highlight unsolved questions in existing models, along with directions for future research.

Immunoglobulin G (IgG) antibodies are an essential component of humoral immunity protecting the host from recurrent infections. Among all antibody isotypes, IgG antibodies have a uniquely long half-life, can basically reach any tissue in the body, and have the ability to kill opsonized target cells, which has made them the molecule of choice for therapeutic interventions in cancer and autoimmunity. Moreover, IgG antibodies in the form of pooled serum IgG preparations from healthy donors are used to treat chronic inflammatory and autoimmune diseases, providing evidence that serum IgG antibodies can have an active immunomodulatory activity. Research over the last two decades has established that the single sugar moiety attached to each IgG heavy chain plays a very important role in modulating the pro- and anti-inflammatory activities of IgG. Moreover, specific sugar moieties such as sialic acid and galactose residues can serve as highly specific biomarkers for ongoing inflammatory processes. This chapter will summarize how different sugar residues in the IgG sugar moiety change upon inflammation and how such changes may translate to altered IgG function and hence maybe useful for optimizing or modulating the function of therapeutic antibodies.