While the number of publications on wine and health is steadily increasing, ranging from a molecular level to epidemiological studies, often with contradictory results, little attention has been given to a holistic approach to research, starting from the molecular level to arrive at pharmacological and medical conclusions. In this review, some unusual concepts are considered, such as the phytocomplex, the vehicle, and the Matrix effect. The concept of the phytocomplex is discussed, specifically the biological activities of Tyrosol, Hydroxytyrosol, and Resveratrol; indeed, the interactions among different molecules in herbal matrices provide a specific response. This is often markedly different from the response evoked by single constituents in the modulation of microbial populations in the gut, in intestinal stability and bioaccessibility, and, obviously, in inducing biological responses. Among the many alcoholic beverages which contain these molecules, wine has the most peculiar Matrix effect, which can heavily influence the bioavailability of the phytocomplex obtained by the fermentation processes that produce this beverage. Wine’s Matrix effect plays an instrumental role in improving the beneficial compounds’ bioavailability and/or in inhibiting alcohol metabolites’ carcinogenicity. Underestimation of the wine Matrix effect could lead to deceiving results, as in the case of dealcoholized wine or wine-compound-based nutritional supplements; alternatively, this can occur in the emphasis of a single component’s toxic activity, in this case, alcohol, ignoring the specific molecular-level protective action of other compounds (polyphenols) that are present in the same matrix. The dark side of the Matrix effect is also discussed. This review confirms the research recommendations made by the WHO Scientific Group, which suggests it is important “to investigate the possible protective effects of ingredients other than alcohol in alcoholic beverages”, considering that most recent studies seem not only relevant but also capable of directing future research towards innovative points of view that have so far been too neglected.

Berberine (BER) is an alkaloid found, together with other protoberberinoids (PROTBERs), in several species used in medicines and food supplements. While some herbal preparations containing BER and PROTBERs, such as Berberis aristata DC. bark extracts, have shown promising potential for human health, their safety has not been fully assessed. Recently, the EFSA issued a call for data to deepen the pharmacokinetic and pharmacodynamic understanding of products containing BER and PROTBERs and to comprehensively assess their safety, especially when used in food supplements. In this context, new data were collected in this work by assessing: (i) the phytochemical profile of 16 different commercial B. aristata dry extracts, which are among the most widely used preparations containing BER and PROTBERs in Europe; (ii) the In Vitro and In Silico investigation of the pharmacokinetic properties of BER and PROTBERs; (iii) the In Vitro cytotoxicity of selected extracts in different human cell lines, including tests on hepatic cells in the presence of CYP450 substrates; (iv) the effects of the extracts on cancer cell migration; and (v) the In Vitro molecular effects of extracts in non-cancer human cells. Results showed that commercial B. aristata extracts contain BER as the main constituent, with jatrorrhizine as main secondary PROTBER. BER and jatrorrhizine were found to have a good bioaccessibility rate, but they interact with P-gp. B. aristata extracts showed limited cytotoxicity and minimal interaction with CYP450 substrates. Furthermore, tested extracts demonstrated inhibition of cancer cell migration and were devoid of any pro-tumoral effects in normal cells. Overall, our work provides a valuable overview to better elucidate important concerns regarding botanicals containing BER and PROTBERs.

Objectives: The objective of this study is to evaluate the wound healing potential of Eurasian propolis by analyzing the phytochemical profile and the biological effects of three representative propolis samples. Methods: Specific colorimetric assays were used to estimate the total phenolic and flavonoid contents and the triterpenoids content. Some of the main components of Eurasian propolis (pinocembrin, pinobanksin, CAPE, chrysin and galangin) were analyzed using HPLC-DAD. Scavenging activity and total antioxidant capacity were assessed through DPPH and ORAC assays, respectively. Human keratinocyte, fibroblast, and monocytic cell lines were used for the biological in vitro analyses. The direct wound healing properties were tested through scratching assays and ELISA kits for the assessment of the production of growth factors (FGF-7, Latency Associated Peptide-LAP), while the indirect effects were evaluated through the estimation of the levels of MMP9, IL-1β, IL-8, and TNF-α using ELISA kits together with a cell-free test on the inhibition capacity on collagenases. Network Pharmacology analysis was employed to further explore possible mechanisms of the action of propolis on the healing process. Results: The analyses confirmed the high phenolic content of Eurasian propolis (142.50–211.30 mg GAE/g), dominated by flavonoids (95.50–196.80 mg Galangin Equivalents/g), and terpenes (431.50–650.00 mg β-sitosterol Equivalents/g), while also verifying the significant antioxidant (4.9–8.9 mM/g Trolox Equivalents) and antiradical (DPPH IC₅₀ 26.1–54.4 μg/mL) activities. The samples showed indirect wound healing properties by mitigating inflammation and remodeling (reduced IL-1β and MMP9) and potentially modulating the immune response (upregulated IL-8). In vitro studies confirmed these effects, demonstrating decreased MMP9 production and collagenase inhibition when cells were co-treated with propolis and a stressor. Propolis also suppressed IL-1β release in fibroblasts, although its impact on TNF-α was inconclusive. Notably, co-treatment upregulated IL-8 in monocytes, suggesting a potential immunomodulatory role. Conclusions: Eurasian propolis may not directly stimulate cell proliferation during wound healing. Its anti-inflammatory and immunomodulatory properties could indicate an indirect contribution in helping the process.

Berberine (BER) is a natural alkaloid found in various Berberis species, used traditionally in herbal medicine and dietary supplements. BER exhibited various biological activities, including anti-inflammatory, antioxidant, antidiabetic, and anti-tumour properties by modulating cellular pathways and influencing gene expression. While BER shows promise in various health applications, its possible toxicity raises concerns. In 2023, EFSA issued a call for data on BER- and protoberberine (PROTBER)-containing products, to comprehensively assess its safety and potential health claims. With these premises, new data was collected by assessing: i) the phytochemical profile of BER- and PROTBER-containing preparations by newly developed HPLC-DAD method; ii) in silico and in vitro investigation of pharmacokinetics properties of BER; iii) in vitro cytotoxicity in different human cell lines and, iv) biological and molecular activities of extracts containing BER and PROTBER in in vitro human non-cancer cells. By testing 16 commercial Berberis extracts, the evidence collected showed a good qualitative reliability in terms of phytochemical profile and limited relapses on cytotoxicity even at 200 µg/ml after a 24h of exposure, while evidencing a good cellular bioavailability and cell migration inhibition. The potential for plant-drug interactions affecting CYP450 proved to be minimal. Overall, our work provides a useful overview to better elucidate potential concerns on botanicals containing BER and minor PROTBER commonly used in food supplement.

While the number of publications on wine and health is steadily increasing, ranging from molecular level to epidemiological studies, often with contradictory results, little attention has been given to an holistic approach. In this review some unusual concepts are considered, such as phytocomplex, vehicle and the Matrix effect. As an example, three mono/polyphenols present in wine, Tyrosol, Hydroxytyrosol and Resveratrol, have been selected and the consequences of respecting, disregarding or ignoring the Matrix effect are shown. Underestimation of the wine Matrix effect could lead to deceiving results, as in the case of de-alcoholized wine or wine-compound-based nutritional supplements,or in emphasizing a single component toxic activity, in this case alcohol, ignoring the specific protective action at molecular level of other compounds (polyphenols) present in the same Matrix. The dark side of Matrix effect is also discussed. It is suggested that specificity of wine should be always taken in consideration by public health Authorities.

Objectives: This study aimed to evaluate the potential of poplar-type propolis for wound healing by analyzing its phytochemical profile and biological effects. Methods: The phytochemical characterization included specific colorimetric assays to estimate the total phenolic and flavonoid contents and the triterpenoids content. Some of the main components of poplar propolis (pinocembrin, pinobanksin, CAPE, chrysin, galangin) were analyzed using HPLC-DAD. Scavenging activity and total antioxidant capacity were assessed through DPPH and ORAC assays, respectively. Biological in vitro assays used keratinocyte, fibroblast, and monocytic cell lines. The direct wound healing properties were tested through scratching assays and ELISA kits for the assessment of the production of growth factors (FGF-7, Latency Associated Peptide - LAP), while the indirect effects were evaluated through the estimation of the levels of MMP9, IL-1β, IL-8 and TNF-α using ELISA kits together with a cell-free test on the inhibition capacity on collagenases. During the study, the Network Pharmacology analysis was employed to further explore possible mechanisms of action of propolis on the healing process. Results: The analyses confirmed the high phenolic content of poplar propolis, dominated by flavonoids, and terpenes. Propolis exhibited significant antioxidant activity and interestingly, propolis showed indirect wound-healing properties by mitigating inflammation and remodeling (reduced IL-1β and MMP9) and potentially modulating the immune response (upregulated IL-8). In vitro studies confirmed these effects, demonstrating decreased MMP9 production and collagenase inhibition when cells were co-treated with propolis and a stressor. Propolis also suppressed IL-1β release in fibroblasts, although its impact on TNF-α was inconclusive. Notably, co-treatment upregulated IL-8 in monocytes, suggesting a potential immunomodulatory role. Conclusion: poplar propolis may not directly stimulate cell proliferation during wound healing, while its anti-inflammatory and immunomodulatory properties could suggest an indirect contribution to the process.