Giulia Querio

Background: Metabolic Syndrome (MetS) is a multifactorial condition characterized by insulin resistance, dyslipidemia, hypertension, and abdominal obesity, which collectively increase the risk of type 2 diabetes mellitus and cardiovascular diseases. Lifestyle modification represents the first-line strategy in its management, whereas pharmacological interventions are complex and typically require long-term polypharmacotherapy. In this context, natural bioactive compounds with pleiotropic effects are gaining increasing attention. Among these, S-allyl cysteine (SAC), the major sulfur-containing compound derived from black garlic, has been identified as a promising candidate due to its well-documented antioxidant and anti-inflammatory properties. Methods: This narrative review examines the pathophysiological mechanisms underlying MetS and summarizes current evidence on the protective role of SAC against key pathological features of this condition, including oxidative stress, inflammation, glucose and lipid dysmetabolism, endothelial dysfunction, and gut microbiota alterations. Results: Preclinical studies indicate that SAC counteracts lipid accumulation, insulin resistance, endothelial dysfunction, and gut dysbiosis through multiple mechanisms, including hydrogen sulfide release, reactive oxygen species scavenging, inhibition of advanced glycation end products, and modulation of metabolic pathways. Conclusions: SAC emerges as a promising nutraceutical for the prevention and management of MetS and its complications. This underscores the broader relevance of nutraceuticals as promising tools in mitigating metabolic dysfunctions and reducing the burden of cardiometabolic diseases.

S -Allyl cysteine and insulin receptor activity in skeletal myotubes: ↑ Insulin signaling; ↑ GLUT4 translocation; ↑ Glucose uptake; Protection against palmitate-induced insulin resistance.

Background. Metabolic Syndrome (MetS) is a multifactorial condition characterized by insulin resistance, dyslipidemia, hypertension, and abdominal obesity, which collectively increase the risk of type 2 diabetes mellitus and cardiovascular diseases. Lifestyle modification represents the first-line strategy in its management, whereas pharmacological interventions are complex and typically require long-term polypharmacotherapy. In this context, natural bioactive compounds with pleiotropic effects are gaining increasing attention. Among these, S-allyl cysteine (SAC), the major sulfur-containing compound derived from black garlic, has been identified as a promising candidate due to its well-documented antioxidant and anti-inflammatory properties. Methods. This narrative review examines the pathophysiological mechanisms underlying MetS and summarizes current evidence on the protective role of SAC against key pathological features of this condition, including oxidative stress, inflammation, glucose and lipid dysmetabolism, endothelial dysfunction, and gut microbiota alterations. Results. Preclinical studies in-dicate that SAC counteracts lipid accumulation, insulin resistance, endothelial dysfunction, and gut dysbiosis through multiple mechanisms, including hydrogen sulfide re-lease, reactive oxygen species scavenging, inhibition of advanced glycation end products, and modulation of metabolic pathways. Conclusions. SAC emerges as a promising nutraceutical for the prevention and management of MetS and its complications. This underscores the broader relevance of nutraceuticals as promising tools in mitigating metabolic dysfunctions and reducing the burden of cardiometabolic diseases.

Human induced pluripotent stem cells (hiPSCs) are widely used in basic research because of their versatility and ability to differentiate into multiple cell types. In particular, differentiating hiPSCs into cardiac cells (hiPSC-CMs) has been an important milestone in cardiac pathophysiology studies. Although hiPSC-CMs offer a model for human cardiomyocytes, they still exhibit characteristics linked to the fetal cardiac cell phenotype. One important feature that prevents hiPSC-CMs from being identified as adult cells relates to their metabolism, which is a key factor in defining a mature phenotype capable of sustaining the workload requirements characteristic of fully differentiated cardiomyocytes. This review aims to present the most relevant strategies in terms of culture medium composition, culture times, and 3D culture methods that have been developed to promote the metabolic maturation of hiPSC-CMs, which are now widely used. Defining a standardized and universally accepted protocol would enable the creation of a cellular model for studies of cardiac pathophysiology from a patient-specific perspective and for drug screening.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a cell model now widely used to investigate pathophysiological features of cardiac tissue. Given the invaluable contribution hiPSC-CM could make for studies on cardio-metabolic disorders by defining a postnatal metabolic phenotype, our work herein focused on monitoring the insulin response in CM derived from the hiPSC line UKBi015-B. Western blot analysis on total cell lysates obtained from hiPSC-CM showed increased phosphorylation of both AKT and AS160 following insulin treatment, but failed to highlight any changes in the expression dynamics of the glucose transporter GLUT4. By contrast, the Western blot analysis of membrane fractions, rather than total lysates, revealed insulin-induced plasma membrane translocation of GLUT4, which is known to also occur in postnatal CM. Thus, these findings suggest that hiPSC-derived CMs exhibit an insulin response reminiscent to that of adult CMs regarding intracellular signaling and GLUT4 translocation to the plasma membrane, representing a suitable cellular model in the cardio-metabolic research field. Moreover, our studies also demonstrate the relevance of analyzing membrane fractions rather than total lysates in order to monitor GLUT4 dynamics in response to metabolic regulators in hiPSC-CMs.

Different gut microbiota-derived metabolites influence cardiovascular function, and, among all, the role of indole-3-propionic acid (IPA), from tryptophan metabolism, shows controversial effects. The aim of this study was to evaluate its role in endothelial dysfunction. IPA effects were studied on bovine aortic endothelial cells (BAE-1). First, IPA cytotoxicity was evaluated by an MTS assay. Then, the levels of intracellular reactive oxygen species (ROS) were evaluated by a microplate reader or fluorescence microscopy with the CellROX^® Green probe, and nitric oxide (NO) production was studied by fluorescence microscopy with the DAR4M-AM probe after acute or chronic treatment. Finally, immunoblotting analysis for endothelial nitric oxide synthase (eNOS) phosphorylation (p-eNOS) was performed. In BAE-1, IPA was not cytotoxic, except for the highest concentration (5 mM) after 48 h of treatment, and it showed neither oxidant nor antioxidant activity. However, the physiological concentration of IPA (1 μM) significantly reduced NO released by adenosine triphosphate (ATP)-stimulated BAE-1. These last data were confirmed by Western blot analysis, where IPA induced a significant reduction in p-eNOS in purinergic-stimulated BAE-1. Given these data, we can speculate that IPA negatively affects the physiological control of vascular tone by impairing the endothelial NO release induced by purinergic stimulation. These results represent a starting point for understanding the mechanisms underlying the relationship between gut microbiota metabolites and cardiometabolic health.

S-allyl cysteine and a black-garlic extract improve endothelial health.

Endothelial function is essential in the maintenance of systemic homeostasis, whose modulation strictly depends on the proper activity of tissue-specific angiocrine factors on the physiopathological mechanisms acting at both single and multi-organ levels. Several angiocrine factors take part in the vascular function itself by modulating vascular tone, inflammatory response, and thrombotic state. Recent evidence has outlined a strong relationship between endothelial factors and gut microbiota-derived molecules. In particular, the direct involvement of trimethylamine N-oxide (TMAO) in the development of endothelial dysfunction and its derived pathological outcomes, such as atherosclerosis, has come to light. Indeed, the role of TMAO in the modulation of factors strictly related to the development of endothelial dysfunction, such as nitric oxide, adhesion molecules (ICAM-1, VCAM-1, and selectins), and IL-6, has been widely accepted. The aim of this review is to present the latest studies that describe a direct role of TMAO in the modulation of angiocrine factors primarily involved in the development of vascular pathologies.

Trimethylamine N-oxide (TMAO) is a diet derived compound directly introduced through foodstuff, or endogenously synthesized from its precursors, primarily choline, L-carnitine, and ergothioneine. New evidence outlines high TMAO plasma concentrations in patients with overt cardiovascular disease, but its direct role in pathological development is still controversial. The purpose of the study was to evaluate the role of TMAO in affecting key intracellular factors involved in endothelial dysfunction development, such as reactive oxygen species, mitochondrial health, calcium balance, and nitric oxide release using bovine aortic endothelial cells (BAE-1). Cell viability and oxidative stress indicators were monitored after acute and prolonged TMAO treatment. The role of TMAO in interfering with the physiological purinergic vasodilatory mechanism after ATP stimulation was defined through measurements of the rise of intracellular calcium, nitric oxide release, and eNOS phosphorylation at Ser1179 (eNOS^Ser1179). TMAO was not cytotoxic for BAE-1 and it did not induce the rise of reactive oxygen species and impairment of mitochondrial membrane potential, either in the basal condition or in the presence of a stressor. In contrast, TMAO modified the purinergic response affecting intracellular ATP-induced calcium increase, nitric oxide release, and eNOS^Ser1179. Results obtained suggest a possible implication of TMAO in impairing the endothelial-dependent vasodilatory mechanism.