The intestinal microbiota, hosting trillions of microorganisms that inhabit the gastrointestinal tract, functions as a symbiotic organism that plays a crucial role in regulating health by producing biologically active molecules that can enter systemic circulation. Among them, trimethylamine-N-oxide (TMAO), an organic compound derived from dietary sources and microbial metabolism, has emerged as a critical biomarker linking diet, the gut microbiota, and the host metabolism to various pathological conditions. This comprehensive review highlights TMAO’s biosynthesis, physiological functions, and clinical significance, focusing on its mechanistic contributions to cardiovascular and neurodegenerative diseases. Notably, TMAO-mediated pathways include endothelial dysfunction, inflammation via NLRP3 inflammasome activation, and cholesterol metabolism disruption, which collectively accelerate atherosclerosis and disease progression. Nonetheless, this work underscores the innovative potential of targeting TMAO through dietary, nutraceutical, and microbiota-modulating strategies to mitigate its pathological effects, marking a transformative approach in the prevention and management of TMAO-related disorders.

Trimethylamine N-oxide (TMAO) is an endogenous osmolyte produced by enzymatic reactions starting in the human gut, where microbiota release trimethylamine (TMA) from foods, and ending in the liver, where TMA is oxidized to TMAO by flavin-containing monooxygenase 3 (FMO3). While physiological concentrations of TMAO help proteins preserve their folding, high levels of this metabolite are harmful and promote oxidative stress, inflammation, and atherosclerosis. In humans, elevated levels of circulating TMAO predispose individuals to cardiovascular diseases and chronic kidney disease and increase mortality risk, especially in the elderly. How TMAO exerts its negative effects has been only partially elucidated. In hypertensive rats, the eNOS substrate L-arginine and Taurisolo^®, a nutraceutical endowed with TMAO-reducing activity, act synergistically to reduce arterial blood pressure. Here, we investigate the molecular mechanisms underpinning this synergism and prove that TMAO, the target of Taurisolo^®, acts as direct inhibitor of endothelial nitric oxide synthase (eNOS) and competes with L-arginine at its catalytic site, ultimately inhibiting NO production and acetylcholine (Ach)-induced relaxation in murine aortas.

Background: Dysglycemia, characterized by abnormal blood glucose levels, is a critical factor in the development of type 2 diabetes mellitus (T2DM) and its related complications. Among the traditional approaches to managing glucose homeostasis, supplementation with natural antidiabetic molecules stands out. Among these, abscisic acid (ABA), a naturally occurring compound abundant in unripe fruits, has shown potential for improving insulin sensitivity and glucose uptake. This study examines the effects of AbaComplex (ABAc), a nutraceutical derived from thinned nectarines, on glycemic control in individuals with dysglycemia, both alone and in combination with trivalent chromium, known for its role in increasing insulin signal. Methods: A three-arm, randomized, placebo-controlled trial was conducted over 3 months with 120 participants assigned to one of three groups: ABAc alone, ABAc with trivalent chromium (ABAc-Cr), or a placebo. Results: The results showed significant improvements in glycemic control in both the ABAc and ABAc-Cr groups compared to the placebo. Specifically, glycated hemoglobin decreased by 6.6% in the ABAc group and 11.3% in the ABAc-Cr group, while the placebo group showed a 4.3% increase. Both treatment groups also exhibited significant reductions in fasting glucose, insulin levels, and HOMA-IR. Nonetheless, the SF-12 questionnaire revealed marked improvements in physical and mental health, with the ABAc group alone demonstrating slightly greater improvements in certain quality-of-life measures. Conclusions: Overall, these findings underscore the effectiveness of ABAc supplementation as a valuable approach for managing dysglycemic conditions and early-stage T2D.

Hypertension remains a major global health challenge, and pharmacological therapy is often constrained by tolerability issues. Adjunctive approaches targeting the nitric oxide synthase and soluble guanylate cyclase–cyclic guanosine monophosphate (sGC–cGMP) pathway may offer additional benefits. This study investigated the efficacy and safety of a nutraceutical formulation combining grape pomace extract (Taurisolo^®) and L-arginine in patients with grade 1 and grade 2 hypertension. The formulation was designed to enhance nitric oxide (NO) bioavailability and support sGC–cGMP signaling. Taurisolo^®, a polyphenol-rich extract, is known for its antioxidant and endothelial-protective properties, while L-arginine serves as the physiological substrate for endothelial NO synthase. Clinical outcomes included blood pressure changes, renal function parameters, and health-related quality of life assessed through the SF-12 questionnaire. Supplementation with Taurisolo^® plus L-arginine resulted in significant and sustained reductions in systolic and diastolic blood pressure, with renal function remaining stable throughout the study. Participants also reported meaningful improvements in perceived health, emotional well-being, vitality, and social functioning. The intervention was well tolerated, with no major adverse effects. These findings support the potential of Taurisolo^® combined with L-arginine as a safe and effective adjunctive strategy to conventional antihypertensive therapy, warranting further mechanistic investigation.

Background: Abscisic acid (ABA), a phytohormone widely distributed in nature, has recently emerged as an endogenous regulator of glucose homeostasis in humans. Specifically, scientific studies have demonstrated that exogenous ABA supplementation improves glycemic control and reduces insulin requirements, with significant advantages in prediabetic subjects. Beyond its metabolic role, growing evidence suggests that ABA is also involved in immune responses, including those associated with pulmonary diseases. Despite these promising results, the evaluation of plasma ABA levels remains largely unexplored in clinical practice. Methods: This study aimed to evaluate whether plasma ABA concentrations differ among healthy individuals, patients with type 2 diabetes, and smokers, in order to clarify the role of ABA as a potential biomarker of both metabolic imbalance and smoking-related inflammatory stress. Results: Our findings show that ABA levels were significantly higher in healthy subjects (10.9 ± 3.8 ng/mL) compared to diabetic patients (6.8 ± 4.2 ng/mL, p < 0.01 vs. healthy subjects), with the lowest levels observed in smokers (3.5 ± 2.5 ng/mL, p < 0.0001 vs. healthy subjects and p < 0.0001 vs. diabetic patients). Moreover, a significant correlation was observed between ABA plasma concentration and number of cigarettes smoked (R² = −0.6776, p = 0.0001). Conclusions: Overall, these results highlight the relevance of measuring ABA plasma levels in both metabolic and inflammatory conditions, confirming its role as a biomarker for identifying individuals who can benefit from exogenous supplementation.