Endothelial intracellular calcium (Ca2+) signaling is a multi-scale control system that couples external stimuli (shear stress, vasoactive agonists, inflammatory mediators) to nitric oxide (NO) production, endothelium-derived hyperpolarization, barrier integrity, angiogenesis, and regulated exocytosis of prothrombotic mediators. Contemporary "endothelial Ca2+ code" frameworks emphasize that spatially restricted microdomain events, such as TRPV4 "sparklets," IP3R "pulsars/wavelets," and Piezo1-driven mechanochemical transduction, are decoded into functionally specific outputs, while organellar Ca2+ handling from the ER/SR and the mitochondria tunes amplitude, duration, and translation into redox/inflammatory responses. This framework is particularly relevant for toxicology because divalent toxicants can alter not only the magnitude but also the spatial logic of endothelial Ca2+ signaling (Moccia et al. 2023).Heavy metals and metalloids, including lead (Pb), cadmium (Cd), mercury (Hg; particularly methylmercury), and inorganic arsenic (As), are increasingly recognized as cardiovascular risk factors capable of perturbing this endothelial Ca2+ code early in exposure. Mechanistically, these toxicants (i) impersonate Ca2+ or opportunistically bind Ca2+-binding motifs, (ii) enter through or modulate Ca2+-permeable channels (notably TRP and store-operated pathways), (iii) impair pumps/exchangers or provoke ER stress, and (iv) trigger oxidative stress and inflammatory signaling that reciprocally reshapes Ca2+ dynamics and NO bioavailability. The resulting Ca2+/redox feed-forward loops can shift the endothelium toward vasoconstriction, permeability, leukocyte adhesion, dysregulated angiogenesis, and thrombosis. Experimental studies of Pb2+ cardiotoxicity and Ca2+ antagonism, together with broader exposome analyses of Pb and Hg, support the concept that divalent toxicants can act as calcium-mimetic cardiovascular stressors with direct consequences for calcium-dependent signaling (Chavarría et al. 2021; de Mattos et al. 2017; Ferreira et al. 2021a).This review synthesizes endothelial Ca2+ physiology; molecular Ca2+ handling nodes (channels, pumps, exchangers; ER/SR and mitochondria); evidence that Pb, Hg, Cd, and As disrupt Ca2+ homeostasis; downstream dysfunction phenotypes; dose-response and population vulnerability considerations; experimental models and methods; and mitigation strategies and knowledge gaps.
The advent of sodium-glucose co-transporter (SGLT) inhibitors - including selective SGLT2 and dual SGLT1/2 agents - has redefined cardiorenometabolic therapy, markedly reducing cardiovascular events, heart failure hospitalizations, and kidney disease progression in patients with and without diabetes. Despite their robust and well-documented benefits, uptake is sometimes limited in specific patient groups, often reflecting concerns about adverse effects. Traditionally reported risks - including hypoglycemia, euglycemic diabetic ketoacidosis, volume depletion, acute kidney injury, genital and urinary tract infections, bone fractures, and lower limb amputations - exhibit heterogeneous clinical relevance; some are not consistently reproduced or are of uncertain clinical significance, whereas others are rare but clinically meaningful and modulated by patient phenotype, comorbidities, and concomitant therapies. Drawing on large cardiovascular and renal outcome trials, supplemented by real-world evidence, which provide estimates of both absolute and relative risks, this chapter offers an evidence-based framework to anticipate, recognize, and mitigate complications, supporting the safe and effective integration of SGLT inhibitors across diverse clinical populations.
The introduction of the sodium-glucose cotransporter-2 inhibitors (SGLT2i) was a landmark moment in the treatment of diabetes. Their unique insulin independent mechanism of action, results in decreased reabsorption of glucose at the renal tubular level and increased glucosuria, which lowers blood glucose along with modest weight reduction due to caloric loss in the urine. Today, the SGLT2i are approved not only for their glycemic benefits, but also to reduce the risk of heart failure (HF) hospitalization and progression to chronic kidney disease (CKD) in patients with type 2 diabetes (T2DM) and CKD/HF. Notably, the SGLT2i are also approved for cardiorenal benefits in those without diabetes. However, SGLT2i are not approved for use in those with type 1 diabetes (T1DM) due to the increased risk for diabetic ketoacidosis (DKA) and euglycemic ketoacidosis. This review provides an overview of the various metabolic effects seen with the use of SGLT2i and dual SGLT1/2 inhibitors in patients with T1DM, including beneficial effects on glycemia despite a paradoxical increase in endogenous glucose production (EGP), changes in insulin sensitivity, hyperglucagonemia and changes in substrate oxidation. We also discuss mechanisms leading to increased ketogenesis and a higher risk of DKA in those with T1DM and potential measures to mitigate this risk, so that patients with T1DM can safely avail the robust glycemic and cardiorenal benefits of these agents.
Carboranes are boron-rich polyhedral clusters with unique physicochemical properties, including high hydrophobicity, three-dimensional structure, and the ability to act as bioisosteres of aromatic groups. These features make them attractive building blocks in medicinal chemistry. This chapter summarizes recent advances in the design of carborane-containing derivatives of biologically active scaffolds, including 1,8-naphthalimides, acridines, penicillin G, and isoniazid.The incorporation of carborane clusters significantly influenced the biological activity of parent compounds by modulating DNA interactions, anticancer mechanisms, antibacterial activity, lipophilicity, and membrane permeability. In anticancer conjugates, carborane modification affected DNA binding, reactive oxygen species generation, apoptosis induction, and cellular localization. In antibacterial agents, carborane incorporation improved the activity of selected penicillin G and isoniazid derivatives, including activity against resistant bacterial strains.These examples demonstrate that carboranes are versatile pharmacophores capable of enhancing the biological properties of established drug scaffolds and represent promising tools for the development of novel anticancer and antimicrobial agents.
Boron has emerged as a versatile element in medicinal chemistry because its empty p-orbital enables reversible covalent interactions with biologically important nucleophiles while supporting diverse, tunable molecular architectures. Following approval of bortezomib in 2003, boron-containing therapeutics have expanded beyond proteasome inhibition to infectious disease, inflammation, thrombosis, metabolic and cardiovascular disease, cancer immunotherapy, and boron neutron capture therapy (BNCT). This chapter critically surveys boron-containing candidates that have entered clinical trials, organizing them by scaffold class: boronic acids, borinic acids, benzoxaboroles, cyclic boron heterocycles, and boron clusters. The agents reviewed include borofalan, delanzomib, flovagatran, dutogliptin, talabostat, numidargistat, OATD-02, AN0128, epetraborole, ganfeborole, acoziborole, taniborbactam, xeruborbactam, and sodium borocaptate, as well as the five FDA-approved boroncontaining drugs (bortezomib, ixazomib, crisaborole, tavaborole, vaborbactam). Their mechanisms, pharmacokinetics, clinical efficacy, safety, regulatory status, and development trajectories are compared. Collectively, the clinical evidence illustrates how boron chemistry enables selective target engagement through reversible covalent inhibition, tRNA trapping, β-lactamase blockade, arginase modulation, and isotope-mediated cellular destruction. Particularly notable advances include borofalan-based BNCT for head and neck cancer, single-dose acoziborole for gambiense human African trypanosomiasis, ganfeborole-containing regimens for tuberculosis, and broad-spectrum cyclic boronate β-lactamase inhibitors designed to restore antibiotic activity against multidrug-resistant Gram-negative pathogens. Across programs, most candidates were generally well tolerated, whereas discontinuations frequently reflected inadequate comparative efficacy, commercial competition, funding limitations, or manufacturing requirements rather than intrinsic boron toxicity. The histories of dutogliptin and talabostat further demonstrate that mechanistically distinctive boron compounds may be successfully repositioned after setbacks in their original indications. Together, these findings show that boron's structural versatility, low inherent toxicity, and capacity for precise, often reversible target binding continue to support productive clinical translation. The review also highlights how clinical success depends on matching pharmacology with unmet need, feasible administration, competitive differentiation, and durable development partnerships. Ongoing advances in scaffold design, delivery, combination therapy, and indication selection are expected to broaden the therapeutic impact of boron-containing medicines.
