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Nitric oxide (NO) plays several key roles in the functionality of an organism, and it is usually released in numerous organs and tissues. There are mainly three isoforms of the enzyme that produce NO starting from the metabolism of arginine, namely endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and neuronal nitric oxide synthase (nNOS). The expression and activity of these isoforms depends on the activation/deactivation of different signaling pathways at an intracellular level following different physiological and pathological stimuli. Compounds of natural origin such as polyphenols, which are obtainable through diet, have been widely studied in recent years in in vivo and in vitro investigations for their ability to induce or inhibit NO release, depending on the tissue. In this review, we aim to disclose the scientific evidence relating to the activity of the main dietary polyphenols in the modulation of the intracellular pathways involved in the expression and/or functionality of the NOS isoforms.

Extra virgin olive oil (EVOO) polyphenols beneficial effects have widely been debated throughout the last three decades, with greater attention to hydroxytyrosol and tyrosol, which are by far the most studied. The main concern about the evaluation of EVOO phenols activities in vitro and in vivo is that the absorption and metabolism of these compounds once ingested lead to the production of different metabolites in the human body. EVOO phenols in the ingested forms are less concentrated in human tissues than their glucuronide, sulfate and methyl metabolites; on the other hand, metabolites may undergo deconjugation before entering the cells and thus act as free forms or may be reformed inside the cells so acting as conjugated forms. In most in vitro studies the presence of methyl/sulfate/glucuronide functional groups does not seem to inhibit biological activity. Parent compounds and metabolites have been shown to reach tissue concentrations useful to exert beneficial effects others than antioxidant and scavenging properties, by modulating intracellular signaling and improving cellular response to oxidative stress and pro-inflammatory stimuli. This review aims to give an overview on the reported evidence of the positive effects exerted by the main EVOO polyphenols metabolites in comparison with the parent compounds.

The olive-oil-centered Mediterranean diet has been associated with extended life expectancy and a reduction in the risk of age-related degenerative diseases. Extra virgin olive oil (EVOO) itself has been proposed to promote a “successful aging”, being able to virtually modulate all the features of the aging process, because of its great monounsaturated fatty acids content and its minor bioactive compounds, the polyphenols above all. Polyphenols are mostly antioxidant and anti-inflammatory compounds, able to modulate abnormal cellular signaling induced by pro-inflammatory stimuli and oxidative stress, as that related to NF-E2-related factor 2 (Nrf-2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which have been identified as important modulators of age-related disorders and aging itself. This review summarizes existing literature about the interaction between EVOO polyphenols and NF-κB and Nrf-2 signaling pathways. Reported studies show the ability of EVOO phenolics, mainly hydroxytyrosol and tyrosol, to activate Nrf-2 signaling, inducing a cellular defense response and to prevent NF-κB activation, thus suppressing the induction of a pro-inflammatory phenotype. Literature data, although not exhaustive, indicate as a whole that EVOO polyphenols may significantly help to modulate the aging process, so tightly connected to oxidative stress and chronic inflammation.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells, with particularly high prevalence in Sardinia, where it is strongly associated with favism. Public awareness remains incomplete and misconceptions persist—particularly regarding symptom onset from fava bean pollen or odors. This cross-sectional survey assessed G6PD self-reported deficiency, population knowledge, and persistence of false beliefs in Sardinia. Methods: A 16-item structured questionnaire was disseminated online (May–June 2025) to adults across diverse age groups and educational backgrounds. Results: Among 536 respondents (74.25% female; 97.39% Sardinia residents), 43.47% of respondents self-reported as G6PD-deficient, a figure substantially above the expected population estimate of 8–15% and consistent with affected-network recruitment. Moreover, 49.07% self-reported as non-deficient, and 7.46% were unaware of their status. While 99.07% correctly identified fava bean ingestion as a trigger and 74.25% identified certain medications, 62.50% incorrectly attributed hazard to pollen inhalation and 25.93% to pea consumption. Only 3.92% reported a hemolytic crisis, whereas 25.93% reported feeling unwell after smelling beans or inhaling pollen. Family and friends (49.81%) and healthcare providers (42.16%) were the primary information sources; schools (25.75%) and online resources (14.55%) were underrepresented. Overall, 90.45% perceived public information as insufficient—uniformly across G6PD strata (χ2 = 0.09, p = 0.955). Exploratory analyses suggested lower perceived information adequacy among younger respondents (Cochran–Armitage Z = 2.92, p = 0.002) and, less robustly, among female respondents (χ2 = 3.90, p = 0.048; borderline significance, unadjusted). Conclusions: Although recognition of fava bean ingestion as the principal dietary trigger is nearly universal, substantial gaps persist regarding non-ingestive exposures, less-recognized dietary triggers, and pharmacological risks. Perceived information insufficiency was independent of G6PD status but associated with younger age and female sex. Integrating targeted nutritional education into school curricula, primary care, and digital platforms is warranted for these priority groups and for G6PD-endemic populations worldwide.

Introduction: Despite the impressive progress carried out in the field of biomedical sciences in recent decades, the incidence of emerging and neglected lethal viral infections mainly belonging to the Coronaviridae, Filoviridae, Arenaviridae, Bunyaviridae, and Paramyxoviridae families has considerably impaired human health. The worldwide vaccination campaign at the end of the 1970s determined the eradication of smallpox. However, the growing number of cases of diseases linked to orthopoxvirus diseases, such as the recent epidemic of monkeypox zoonosis in various countries around the world, has increased the need for knowledge of these viral pathogens. To date, there is no specific treatement for Monkeypox virus (MPXV) infection. However, several antiviral drugs used to treat Smallpox and other viral infections could also be beneficial for Monkeypox disease. In this study we report the design and synthesis of new, variously substituted benzimidazole derivatives and the evaluation of their cytotoxicity and antiviral activity against representatives of the Orthopoxvirus genus, Vaccinia Virus (VV), closely related to variola virus and MPXV. Methods: A combination of cell-based assays and experimental techniques was used to investigate the cytotoxicity, antiviral activity, and mechanisms of action of the most interesting compound. Results: In our study, new, variously substituted benzimidazoles showed interesting EC50 values against vaccinia and MPXV and a cytotoxic profile in the high micromolar range. Conclusions: Our work shows that the new tested benzimidazole derivatives possess appealing activity and selectivity, accompanied by low cytotoxicity. These results set a valid foundation with which to identify potent and selective anti-Poxvirus agents.

Nitric oxide (NO) is an important signaling molecule involved in many pathophysiological processes. NO mediates vasodilation and blood flow in the arteries, and its action contributes to maintaining vascular homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. Dietary antioxidants and their metabolites have been found to be directly and/or indirectly involved in the modulation of the intracellular signals that lead to the production of NO. The purpose of this study was to investigate the contribution of conjugated metabolites of hydroxytyrosol (HT) and tyrosol (TYR) to the release of NO at the vascular level, and the related mechanism of action, in comparison to their parental forms. Experiments were performed in human aortic endothelial cells (HAEC) to evaluate the superoxide production, the release of NO and production of cyclic guanosine monophosphate (cGMP), the activation of serine/threonine-protein kinase 1 (Akt1), and the activation state of endothelial nitric oxide synthase (eNOS). It was observed that the tested phenolic compounds enhanced NO and cGMP concentration, inhibiting its depletion caused by superoxide overproduction. Moreover, some of them enhanced the activation of Akt (TYR, HT metabolites) and eNOS (HT, HVA, TYR-S, HT-3S). Overall, the obtained data showed that these compounds promote NO production and availability, suggesting that HT and TYR conjugated metabolites may contribute to the effects of parental extra virgin olive oil (EVOO) phenolics in the prevention of cardiovascular diseases.

Ferulic acid (FA) is a polyphenol pertaining to the class of hydroxycinnamic acids present in numerous foods of a plant origin. Its dietary consumption leads to the formation of several phase I and II metabolites in vivo, which represent the largest amount of ferulates in the circulation and in the intestine in comparison with FA itself. In this work, we evaluated their efficacy against the proinflammatory effects induced by lipopolysaccharide (LPS) in intestinal Caco-2 cell monolayers, as well as the mechanisms underlying their protective action. LPS-induced overexpression of proinflammatory enzymes such as inducible nitric oxide synthase (iNOS) and the consequent hyperproduction of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) were limited by physiological relevant concentrations (1 µM) of FA, its derivatives isoferulic acid (IFA) and dihydroferulic acid (DHFA), and their glucuronidated and sulfated metabolites, which acted upstream by limiting the activation of MAPK p38 and ERK and of Akt kinase, thus decreasing the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) translocation into the nucleus. Furthermore, the compounds were found to promote the expression of Nrf2, which may have contributed to the downregulation of NF-ĸB activity. The overall data show that phase I/II metabolites retain the efficacy of their dietary free form in contrasting inflammatory response.

Colorectal cancer (CRC) cells are ‘addicted’ to glutamine to satisfy energy and biosynthetic needs. Inhibiting glutamine metabolism enzymes, like glutaminase, is a potential cancer therapy strategy. Although the GLS inhibitor CB-839 is being evaluated in clinical trials, a comprehensive assessment of its antitumor activity in CRC cells is crucial. The present study aimed to evaluate the impact of CB-839 treatment on different CRC cell lines in terms of survival and proliferation. Furthermore, metabolic adaptations resulting from CB-839 treatment, particularly in energetic pathways, were investigated. Three CRC cell lines (HCT116, HT29, and SW480) were treated with different CB-839 concentrations. Cytotoxicity was assessed via MTT assay, proliferation capacity by flow cytometry, and ATP production rates by Seahorse XF analysis. Moreover, metabolomic profile was explored with untargeted GC-MS and 1 H-NMR, and targeted analysis of the Krebs cycle was conducted using GC-MS/MS. HT29 cells exhibited the highest sensitivity to CB-839. Subsequent experiments focused on HT29 and SW480 cells. CB-839 treatment altered cell cycle progression and increased glycolytic ATP production in HT29 cells. Metabolomic analysis revealed changes in Krebs cycle and glutaminolysis in both cell lines, along with alterations in amino acids, sugars, antioxidants, and organic acid levels. This study highlighted glutamine’s key role in CRC cells and provided a foundation for elucidating the mechanisms of response and resistance to CB-839.

Perovskia atriplicifolia Benth., a perennial aromatic plant widespread in Iran’s Sistan and Baluchestan region, is known for its essential oil composition, rich in aromatic and non-aromatic sesquiterpenes. To the best of our knowledge, limited information exists on the composition of its non-volatile extracts. Herein, the phytochemical investigation of the EtOH extract of P. atriplicifolia aerial parts was performed, guided by an analytical approach based on LC-(-)ESI/QExactive/MS/MS. This led to the identification of phenolics, flavonoids, diterpenes (mainly carnosic acid derivatives), and triterpenes. Structural elucidation was performed via NMR and HRMSMS analysis. Furthermore, considering the occurrence of diterpenes closely related to carnosic acid and carnosol, known for their antioxidant properties, the antioxidant activity of the extract (0.5–5.0 μg/mL) and selected pure compounds (0.5–25 μM; compounds 5, 7, 9, 10, 12, 16) was evaluated in Caco-2 intestinal cells, showing significant reduction in free radical levels. The quantitative results highlighted that the above cited compounds occurred in concentrations ranging from 1.73 to 520.21 mg/100 g aerial parts, with carnosol (12) exhibiting the highest concentration (520.21 mg/100 g aerial parts), followed by 1α-hydroxydemethylsalvicanol (9) (91.73 mg/100 g aerial parts) and carnosic acid (16) (88.16 mg/100 g aerial parts).

In this study, water residue obtained from Salvia desoleana Atzei et Picci steam distillation was evaluated for its antioxidant activity in vitro using different experimental models. In particular, the study evaluated the antiradical and antioxidant activity of Salvia desoleana extracts using CUPRAC, FRAP, DPPH•, and ABTS•+ assays; and tested ROS scavenging activity in Caco-2 cell cultures. Phenolic compounds were identified by (HR) LC-ESI-QTOF MS/MS and quantified with HPLC-PDA. Furthermore, Keap1-Nrf2, iNOS, and NOX enzymes involved in oxidative stress and antioxidant defences were the targets of molecular docking on key polyphenols. Hydroxycinnamic acids and flavonoids are the most important classes of compounds detected in the extracts. Among these compounds, the most significant was rosmarinic acid, followed by caffeic acid, luteolin glucuronide, and methyl rosmarinate. Although all extracts have shown encouraging results, the ethanolic extract solubilised with water (SEtOHA) was the one with the highest hydroxycinnamic acid content and total phenol content (518.64 ± 5.82 mg/g dw and 106.02 ± 6.02 mg GAE/g dw), as well as the highest antioxidant and antiradical activity. The extracts have shown anti-inflammatory activity by inhibiting NO release in LPS-stimulated Caco-2 cells. Finally, the in silico evaluation against the three selected enzymes showed interesting results for both numerical affinity ranking and predicted ligand binding models. The outcome of this study suggests this by-product as a possible ally in counteracting oxidative stress, as established by its favourable antioxidant compound profile, thus suggesting an interesting future application as a nutraceutical.