Vittorio Calabrese

Anthocyanins exhibit various health benefits despite their low bioavailability. This study investigated the underlying mechanisms of this paradox, focusing on how the B-ring substitution patterns of pelargonidin-3-glucoside (P3G), cyanidin-3-glucoside (C3G), and delphinidin-3-glucoside (D3G) influence their redox stability and subsequent autonomic modulation. Under acidic conditions (pH 2.8), only D3G underwent degradation, while P3G and C3G remained stable. Under simulated gastrointestinal conditions at pH 7.0, all three anthocyanins degraded with the degradation velocity following the order of D3G > C3G = P3G. Furthermore, under neutral conditions and at low concentrations, the capacity to generate superoxide radicals (O2• −) followed the order C3G > D3G > P3G. In the open-field test, C3G elicited a significant increase in spontaneous locomotor activity in mice. In rats, anthocyanins except P3G induced a significant increase in cremasteric arterial blood flow. For the cumulative endocrine response, C3G administration induced the most prominent elevation in urinary catecholamine levels in mice. In biological evaluations, the activity of these anthocyanins followed the order C3G > D3G > P3G, consistent with their O2• −-producing capacity. Although D3G possesses a high theoretical redox potential, its physiological efficacy was limited due to excessive reactivity and near-instantaneous auto-oxidation. Conversely, C3G maintained an optimal temporal window of action, and its degradation products consistently sustained pro-oxidant signaling. These findings demonstrate that the persistence of structure-dependent local pro-oxidant signaling in the gut is the primary determinant of anthocyanin-induced central and sympathetic nervous system activation, redefining poorly absorbed polyphenols as interoceptive functional modulators via the gut-brain axis.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of some anticancer treatments, often persisting beyond therapy and severely affecting patient quality of life. Mitochondrial dysfunction has emerged as a key contributor to CIPN pathogenesis, yet the underlying molecular mechanisms remain incompletely understood. Paclitaxel (PTX) is a widely used chemotherapeutic agent whose neurotoxicity is linked to oxidative stress, mitochondrial dysfunction, and apoptosis. Here, we investigated whether the polyphenols hydroxytyrosol (HT) and resveratrol (RSV) mitigate PTX-induced damage in SH-SY5Y neuroblastoma cells. PTX induced robust apoptotic responses, including increased DAPI staining, reduced cell viability and increased late apoptotic cells. HT significantly attenuated these effects, whereas RSV did not provide detectable cytoprotection. Both compounds counteracted the PTX-dependent increase of ROS, but only HT preserved mitochondrial morphology, preventing the hyperfused phenotype and normalizing mitochondrial form factor and branch length by modulating DRP1 protein level and its phosphorylation at serine 637. Bioenergetic analysis showed that PTX impaired oxidative phosphorylation and glycolysis. HT partially restored mitochondrial respiration, improving coupled and maximal respiratory capacities. Mechanistically, PTX reduced cAMP levels and CREB phosphorylation. Although HT did not restore total cAMP, it rescued CREB phosphorylation. The protective effect of HT was abolished by the PKA inhibitor H89 and mimicked by 8-Br-cAMP indicating a PKA-dependent mechanism. Overall, these findings indicate HT as a protective modulator of mitochondrial homeostasis against PTX-induced neurotoxicity, acting through preservation of mitochondrial dynamics, and reactivation of cAMP/PKA signaling.

The low bioavailability of polyphenols including flavonoids often contradicts their observed metabolic benefits. We hypothesized that these flavnoids function as luminal signaling molecules via gastrointestinal bitter taste receptors (T2Rs). Using an integrated approach of human sensory tests, intraperitoneal glucose tolerance test in Skn-1a-/- (taste-deficient) mice, and molecular dynamics (MD) simulations, we investigated the structural basis of this mechanism. Only bitter substances, such as naringin (NGR), improved glucose tolerance in wild-type mice and not in Skn-1a-/- mice, confirming T2R-mediated regulation. MD simulations revealed that NGR exhibits superior binding stability with T2R46, characterized by a critical "anchor" interaction with the conserved W883.32. Notably, the glycosyl moiety of NGR enhances receptor affinity through peripheral interactions, allowing the unabsorbed glycoside to trigger prolonged signaling. Our results demonstrate that bitterness serves as a functional proxy for the metabolic utility of flavonoids, which act as potent luminal ligands rather than systemic precursors.

Per- and polyfluoroalkyl substances (PFAS) are persistent contaminants that require very strict performance criteria from the methods that want to analyze them in food for research or regulatory purposes. This systematic literature review tried to evaluate Quick, Easy, Cheap, Effective, Rugged, Safe (QuEChERS) extraction methodologies coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-resolution mass spectrometry (HRMS) for PFAS determination in food. Peer-reviewed articles (2010–2025) were eligible if they analyzed PFAS in food matrices using QuEChERS extraction protocols with LC-MS/MS or HRMS and reported performance and/or validation data. Scopus, WoS and Google Scholar were searched up to 18 December 2025. Due to heterogeneity in matrices, PFAS panels and reported validation metrics, no meta-analysis was performed, and the results were synthesized narratively. Twenty-four studies met the inclusion criteria. Most methods used acidified acetonitrile (ACN)-based QuEChERS workflows and achieved limits of quantification (LOQ) reported to be compatible with EU Regulation 2023/915 and Commission Implementing Regulation 2022/1428. Analytical scope expanded from 9 to 15 legacy PFAS to >40 analytes. Short-chain PFAS analyses in vegetable matrices and methods from developing countries are underrepresented. QuEChERS-based LC-MS/MS and HRMS methods support regulatory PFAS monitoring and PFAS research. The main limitation of this review is the heterogeneity of included studies and the absence of formal meta-analysis.

The B-ring hydroxyl groups of flavanols significantly influence their redox properties; however, their behavior in the gastrointestinal environment remains poorly understood. This study evaluated the stability and O2• − reactivity of (+)-catechin (CA), (-)-epicatechin (EC), which possess a catechol skeleton, epigallocatechin (EGC), which has a pyrogallol structure, and dimethylepicatechin (MeEC) under neutral pH conditions mimicking the oral and intestinal environments. Molecular dynamics (MD) simulations were employed to estimate the molecular fluctuations associated with these reactions. Stability at pH 7 followed the order: MeEC >> CA > EC > EGC. While CA inhibited O2• − production, EC and EGC significantly enhanced it at low concentrations, acting as pro-oxidants, whereas MeEC remained inactive. MD analysis revealed a marked increase in Root Mean Square Deviation (RMSD) for EC, indicating higher structural instability compared to MeEC. Furthermore, a single administration to mice showed that EC and EGC significantly increased sympathetic-dependent urinary catecholamine excretion, an effect absent in CA and MeEC groups. The present results suggest that EC and EGC act as gut-level pro-oxidants that trigger hyperactivation of the sympathetic nerve system as a stress response, driven by their specific B-ring structures. These findings pave the way for innovative nutritional strategies leveraging polyphenol pro-oxidant potential to regulate autonomic and metabolic homeostasis.

Polyphenols are plant metabolites with potent physiological activities. Despite their known bitterness and astringency, their specific sensory characteristics remain poorly understood. To clarify the relationship between polyphenol chemical structures and sensory profiles, we developed a sensory evaluation protocol for a young-adult panel. Following four days of intensive monthly training, the panel achieved proficiency in distinguishing bitterness, astringency, and acidity. Four polyphenols with distinct structures—gallic acid, quercetin hydrate, epigallocatechin gallate (EGCG), and a procyanidin-rich fraction (PRF)—were evaluated using flavor profile analysis (FPA) and 3-Alternative Forced Choice (3-AFC) tests for their qualitative properties, and quantitative descriptive analysis (QDA) for their quantitative properties. The results showed that gallic acid was acidic, and EGCG was bitter and astringent, with the intensity being concentration-dependent. In contrast, quercetin hydrate did not show any significant sensory properties. This methodology facilitates the elucidation of the relationship between polyphenol structures, and their organoleptic properties and subsequent findings help to further clarify the role of polyphenol–taste receptor interactions in health benefits.