Reproductive toxicity assessment of cellulose nanofibers, citric acid, and branched polyethylenimine in sea urchins: Eco-design of nanostructured cellulose sponge framework (Part B).

In the framework of a safe-by-design approach, we previously assessed the eco-safety of nanostructured cellulose sponge (CNS) leachate on sea urchin reproduction. It impaired gamete quality, gamete fertilization competence, and embryo development possibly due to the leaching of chemical additives used during the CNS synthesis process. To extend this observation and identify the component(s) that contribute to CNS ecotoxicity, in the present study, we individually screened the cytotoxic effects on sea urchin Arbacia lixula and Paracentrotus lividus gametes and embryos of the three main constituents of CNS, namely cellulose nanofibers, citric acid, and branched polyethylenimine. The study aimed to minimize any potential safety risk of these components and to obtain an eco-safe CNS. Among the three CNS constituents, branched polyethylenimine resulted in the most toxic agent. Indeed, it affected the physiology and fertilization competence of male and female gametes as well as embryo development in both sea urchin species. These results are consistent with those previously reported for CNS leachate. Moreover, the characterisation of CNS leachate confirmed the presence of detectable branched polyethylenimine in the conditioned seawater even though in a very limited amount. Altogether, these data indicate that the presence of branched polyethylenimine is a cause-effect associated with a significant risk in CNS formulations due to its leaching upon contact with seawater. Nevertheless, the suggested safety protocol consisting of consecutive leaching treatments and conditioning of CNS in seawater can successfully ameliorate the CNS ecotoxicity while maintaining the efficacy of its sorbent properties supporting potential environmental applications.

Reassessing the role of phytochemicals in cancer chemoprevention.

In this comprehensive review we tried to reassess the role of phytochemicals in cancer chemoprevention. The exploration of the "synergistic effect" concept, advocating combined chemopreventive agents, faces challenges like low bioavailability. The review incorporates personal, occasionally controversial, viewpoints on natural compounds' cancer preventive capabilities, delving into mechanisms. Prioritizing significant contributions within the vast research domain, we aim stimulating discussion to provide a comprehensive insight into the evolving role of phytochemicals in cancer prevention. While early years downplayed the role of phytochemicals, the late nineties witnessed a shift, with leaders exploring their potential alongside synthetic compounds. Challenges faced by chemoprevention, such as limited pharmaceutical interest and cost-effectiveness issues, persist despite successful drugs. Recent studies, including the EPIC study, provide nuanced insights, indicating a modest risk reduction for increased fruit and vegetable intake. Phytochemicals, once attributed to antioxidant effects, face scrutiny due to low bioavailability and conflicting evidence. The Nrf2-EpRE signaling pathway and microbiota-mediated metabolism emerge as potential mechanisms, highlighting the complexity of understanding phytochemical mechanisms in cancer chemoprevention.

An organic extract from ascidian Ciona robusta induces cytotoxic autophagy in human malignant cell lines.

The last decades have seen an increase in the isolation and characterization of anticancer compounds derived from marine organisms, especially invertebrates, and their use in clinical trials. In this regard, ascidians, which are included in the subphylum Tunicata, represent successful examples with two drugs, Aplidine© and Yondelis© that reached the market as orphan drugs against several malignancies. Here, we report that an organic extract prepared from homogenized tissues of the Mediterranean ascidian Ciona robusta inhibited cell proliferation in HT-29, HepG2, and U2OS human cells with the former being the most sensitive to the extract (EC50 = 250 µg/mL). We demonstrated that the ascidian organic extract was not cytotoxic on HT-29 cells that were induced to differentiate with sodium butyrate, suggesting a preference for the mixture for the malignant phenotype. Finally, we report that cell death induced by the organic extract was mediated by the activation of a process of cytotoxic autophagy as a result of the increased expression of the LC3-II marker and number of autophagic vacuoles, which almost doubled in the treated HT-29 cells. In summary, although the detailed chemical composition of the Ciona robusta extract is still undetermined, our data suggest the presence of bioactive compounds possessing anticancer activity.

A Comparative Study between Microwave Hydrodiffusion and Gravity (MHG) and Ultrasound-Assisted Extraction (UAE): Chemical and Biological Characterization of Polyphenol-Enriched Extracts from Aglianico Grape Pomace.

The wine industry produces large amounts of grape pomace (GP), a waste that needs to be disposed of properly. Bioactive compounds with high added value can be recovered from GP as an interesting strategy to reduce the environmental impact. Here, two different technologies were employed to recover polyphenol compounds from GP: microwave hydrodiffusion and gravity (MHG) and ultrasound-assisted extraction (UAE). The further purification of UAE and MHG extracts was carried out through solid-phase extraction (SPE) to obtain three fractions, F1, F2 and F3. ATR-FTIR analysis confirmed the presence of sugar and polysaccharide components in F1, as well as non-anthocyanin and anthocyanin compounds in F2 and F3, respectively. Also, the chemical profile was determined by HPLC-UV-DAD, identifying the presence of catechin in F2, and malvidin-3-O-glucoside chloride and cyanidin chloride derivative as the main anthocyanin compounds in F3. The fractions and their parental extracts were characterized for total phenolic content (TPC) and scavenger activity by in vitro assays. We found that F2-MHG and F3-MHG contained phenol contents 6.5 and 8.5 times higher than those of the parental non-fractionated extracts. Finally, F3-MHG (100 µg/mL, w/v) was shown to reduce the proliferation of HT-29 cells.

Nanostructured cellulose sponge engineered for marine environmental remediation: Eco-safety assessment of its leachate on sea urchin reproduction (Part A).

Nanostructured cellulose sponges (CNS) have been developed as eco-friendly and sustainable engineered materials for marine environmental remediation. Despite their functionality, sensitivity, efficiency and specificity have been proved, CNS application is still limited since their environmental safety (eco-safety) has not been completely assessed. In this study, CNS were allowed to leach in natural seawater simulating the remediation process condition and the eco-safety of CNS leachate on sea urchin reproduction has been assessed by carrying out a multi-response integrated approach, combining standardized ecotoxicity tests, innovative bioassays and gamete quality assessment. Overall, the ecotoxicity data indicate that CNS leachate affects gamete quality, gamete fertilisation competence, and embryo development probably associated with the release of chemical additives used during the synthesis process. However, in the framework of the eco-design approach, consecutive leaching treatments and conditioning of CNS in seawater open the route for a new safety protocol successfully solving the ecotoxicity while maintaining CNS sorbent properties. A safe environmental application of the resulting conditioned CNS for seawater pollution remediation is envisaged.

Molecular Docking of Natural Compounds for Potential Inhibition of AhR.

The aryl hydrocarbon receptor (AhR) is a highly conserved environmental sensor, historically known for mediating the toxicity of xenobiotics. It is involved in numerous cellular processes such as differentiation, proliferation, immunity, inflammation, homeostasis, and metabolism. It exerts a central role in several conditions such as cancer, inflammation, and aging, acting as a transcription factor belonging to the basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) protein family. A key step in the canonical AhR activation is AhR-ARNT heterodimerization followed by the binding to the xenobiotic-responsive elements (XREs). The present work aims to investigate the potential AhR inhibitory activity of selected natural compounds. Due to the absence of a complete structure of human AhRs, a model consisting of the bHLH, the PAS A, and the PAS B domains was constructed. Blind and focused docking simulations revealed the presence of further binding pockets, different from the canonical one presented in the PAS B domain, which could be important for AhR inhibition due to the possibility to impede AhR:ARNT heterodimerization, either preventing conformational changes or masking crucial sites necessary for protein-protein interaction. Two of the compounds retrieved from the docking simulations, i.e., ß-carotene and ellagic acid, confirmed their capacity of inhibiting benzo[a]pyrene (BaP)-induced AhR activation in in vitro tests on the human hepatoma cell line HepG2, validating the efficacy of the computational approach.

Senolytic Flavonoids Enhance Type-I and Type-II Cell Death in Human Radioresistant Colon Cancer Cells through AMPK/MAPK Pathway.

Resistance to cancer therapies remains a clinical challenge and an unsolved problem. In a previous study, we characterized a new colon cancer cell line, namely HT500, derived from human HT29 cells and resistant to clinically relevant levels of ionizing radiation (IR). Here, we explored the effects of two natural flavonoids, quercetin (Q) and fisetin (F), well-known senolytic agents that inhibit genotoxic stress by selectively removing senescent cells. We hypothesized that the biochemical mechanisms responsible for the radiosensitising effects of these natural senolytics could intercept multiple biochemical pathways of signal transduction correlated to cell death resistance. Radioresistant HT500 cells modulate autophagic flux differently than HT29 cells and secrete pro-inflammatory cytokines (IL-8), commonly associated with senescence-related secretory phenotypes (SASP). Q and F inhibit PI3K/AKT and ERK pathways, which promote p16INK4 stability and resistance to apoptosis, but they also activate AMPK and ULK kinases in response to autophagic stress at an early stage. In summary, the combination of natural senolytics and IR activates two forms of cell death: apoptosis correlated to the inhibition of ERKs and lethal autophagy dependent on AMPK kinase. Our study confirms that senescence and autophagy partially overlap, share common modulatory pathways, and reveal how senolytic flavonoids can play an important role in these processes.

Stillage Waste from Strawberry Spirit Production as a Source of Bioactive Compounds with Antioxidant and Antiproliferative Potential.

The production of fruit distillates generates solid residues which are potentially rich in bioactive compounds worthy of valorization and exploitation. We report herein the in vitro antioxidant and antiproliferative properties of an extract obtained from the waste of fermented strawberry distillate production. The main low molecular weight phenolic components of the extract were identified as ellagic acid and p-coumaric acid using spectroscopic and chromatographic analysis. The extract exhibited high antioxidant properties, particularly in the ferric reducing/antioxidant power (FRAP) assay, and a high total phenolic content (TPC). It was also able to induce an antiproliferative effect on different human cancer cell lines. A strong decrease in viability in human promyelocytic leukemia (HL-60) cells through a rapid and massive apoptosis were observed. Moreover, at an early time (<30 min), reactive oxygen species (ROS) production and inactivation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) pathway were detected. Notably, the antiproliferative activity of the sample was comparable to that observed with an analogous extract prepared from unfermented, fresh strawberries. These results bring new opportunities for the valorization of fruit distillery by-products as low-cost resources for the design of bioactive formulations of comparable value to that from fresh food.

Carotenoid-Enriched Nanoemulsions and γ-Rays Synergistically Induce Cell Death in a Novel Radioresistant Osteosarcoma Cell Line.

We previously demonstrated that SAOS human osteosarcoma cells, incubated with carotenoid-enriched nanoemulsions (CEN), activated a nonprotective form of autophagy and delayed cell proliferation. The present work focuses on the biological effects of CEN on a derivative of SAOS cells named SAOS400, recently described for their radiation resistance and higher expression of therapy-induced senescence (TIS) markers. SAOS400 cells, incubated with CEN, activated a "cytostatic" form of autophagy confirmed by cell cycle arrest in the G2/M phase and increased expression of autophagic proteins. Treatment of SAOS400 cells with CEN also resulted in decreased expression of the senescence marker p16INK4. However, when SAOS400 cells were γ-irradiated in combination with CEN, the threshold for cell death was reached (>60% after 96 h). We showed that this type of cell death corresponded to 'cytotoxic' or 'lethal' autophagy and that the combined treatment of CEN plus γ-rays was synergistic, with the combination index < 1. Since CEN contained ß-carotene, the pure compound was used in SAOS400 cells at the same concentration present in CEN and up to 10 times higher. However, no radio-sensitizing effect of ß-carotene was observed, suggesting that the biological effect of CEN was due to less abundant but more bioactive molecules, or to the synergistic activity of multiple components present in the extracts, confirming the functional pleiotropy of natural extracts enriched in bioactive molecules.

A critical evaluation of risk to reward ratio of quercetin supplementation for COVID-19 and associated comorbid conditions.

The interim results of the large, multinational trials on coronavirus disease 2019 (COVID-19) using a combination of antiviral drugs appear to have little to no effect on the 28-day mortality or the in-hospital course. Therefore, there is a still vivid interest in finding alternate re-purposed drugs and nutrition supplements, which can halt or slow the disease severity. We review here the multiple preclinical studies, partially supported by clinical evidence showing the quercetin's possible therapeutic/prophylaxis efficacy against severe acute respiratory syndrome coronavirus (SARS-CoV) as well as comorbidities like chronic obstructive pulmonary disease (COPD), diabetes mellitus, obesity, coagulopathy, and hypertension. Currently, 14 interventional clinical trials are underway assessing the efficacy of quercetin along with other antiviral drugs/nutritional supplements as prophylaxis/treatment option against COVID-19. The present review is tempting to suggest that, based on circumstantial scientific evidence and preliminary clinical data, the flavonoid quercetin can ameliorate COVID-19 infection and symptoms acting in concert on two parallel and independent paths: inhibiting key factors responsible for SARS-CoV-2 infections and mitigating the clinical manifestations of the disease in patients with comorbid conditions. Despite the broad therapeutic properties of quercetin, further high power randomized clinical trials are needed to firmly establish its clinical efficacy against COVID-19.

Phenolic Extract from Extra Virgin Olive Oil Induces Different Anti-Proliferative Pathways in Human Bladder Cancer Cell Lines.

Regular consumption of olive oil is associated with protection against chronic-degenerative diseases, such as cancer. Epidemiological evidence indicates an inverse association between olive oil intake and bladder cancer risk. Bladder cancer is among the most common forms of cancer; in particular, the transitional cell carcinoma histotype shows aggressive behavior. We investigated the anti-proliferative effects of a phenolic extract prepared from an extra virgin olive oil (EVOOE) on two human bladder cancer cell lines, namely RT112 and J82, representing the progression from low-grade to high-grade tumors, respectively. In RT112, the EVOOE reduced cell viability (IC50 = 240 µg/mL at 24 h), triggering a non-protective form of autophagy, evidenced by the autophagosome formation and the increase in LC-3 lipidation. In J82, EVOOE induced a strong decrease in cell viability after 24 h of treatment (IC50 = 65.8 µg/mL) through rapid and massive apoptosis, assessed by Annexin V positivity and caspase-3 and -9 activation. Moreover, in both bladder cancer cell lines, EVOOE reduced intracellular reactive oxygen species, but this antioxidant effect was not correlated with its anti-proliferative outcomes. Data obtained suggest that the mixture of phenolic compounds in extra virgin olive oil activates different anti-proliferative pathways.

Redox regulation by carotenoids: Evidence and conflicts for their application in cancer.

Carotenoids have been constantly investigated since the early fifty for their chemical, biochemical and biological properties being presence in foods. Among the more than 1100 carotenoids synthesized by plants and microorganisms, approximately 50 are present in the human diet, and about 20 can be detected in human blood and tissues. Review articles that discuss the anticancer and cancer preventing activity of phytochemicals have often in common the difficulty to find a coherency between the results deriving from experimental studies and the controversial or weak clinical indications arising from epidemiological and interventional studies. In this scenario, the class of carotenoids does not represent an exception. In fact, according with World Cancer Research Fund, strong evidence exists that high-dose supplementation of ß-carotene increases the risk of lung cancer, while for other types of cancer, the protective or harmful effects of food-containing carotenoids or carotenoid supplements have been considered limited, suggestive or unlikely. The analysis of the mechanistic evidence is complicated by the double nature of carotenoids being molecules acting either as antioxidant or pro-oxidant compounds. The present review analyzes the ambiguity and the unexpected results deriving from the epidemiological and interventional studies and discusses how the effects of carotenoids on cancer risk can be explained by understanding their capacity to modulate the cellular antioxidant response, depending on the concentration applied and the cellular metabolism. In the final part, a new global approach is proposed to study the contribution of carotenoids, but also of other phytochemicals, to disease prevention, including cancer.

STL1, a New AKT Inhibitor, Synergizes with Flavonoid Quercetin in Enhancing Cell Death in A Chronic Lymphocytic Leukemia Cell Line.

Using a pharmacophore model based on the experimental structure of AKT-1, we recently identified the compound STL1 (ZINC2429155) as an allosteric inhibitor of AKT-1. STL1, was able to reduce Ser473 phosphorylation, thus inhibiting the PI3K/AKT pathway. Moreover, we demonstrated that the flavonoid quercetin downregulated the phosphorylated and active form of AKT. However, in this case, quercetin inhibited the PI3K/AKT pathway by directly binding the kinases CK2 and PI3K. In the present work, we investigated the antiproliferative effects of the co-treatment quercetin plus STL1 in HG-3 cells, derived from a patient affected by chronic lymphocytic leukemia. Quercetin and STL1 in the mono-treatment maintained the capacity to inhibit AKT phosphorylation on Ser473, but did not significantly reduce cell viability. On the contrary, they activated a protective form of autophagy. When the HG-3 cells were co-treated with quercetin and STL1, their association synergistically (combination index < 1) inhibited cell growth and induced apoptosis. The combined treatment caused the switch from protective to non-protective autophagy. This work demonstrated that cytotoxicity could be enhanced in a drug-resistant cell line by combining the effects of different inhibitors acting in concert on PI3K and AKT kinases.

The Pro-Oxidant Activity of Red Wine Polyphenols Induces an Adaptive Antioxidant Response in Human Erythrocytes.

The protective effect of dealcoholized red wine on human health has been partially associated with its polyphenolic components, suggesting that the pool of polyphenols, including flavonoids and anthocyanins, can be responsible for the functional effects of this beverage. We hypothesize a new role of red wine polyphenols (RWp) in modulating the antioxidant potential of erythrocytes, protecting them against oxidative stress. We previously demonstrated that RWp activated the Plasma Membrane Redox System (PMRS), which is involved in neutralizing plasma free radicals. Here, we investigated the underlying mechanism triggered by RWp in the activation of PMRS via the involvement of GSH. Hence, treatment of human erythrocytes with RWp (73 µg/mL Gallic Acid Equivalents) increased GSH intracellular concentration, which depends upon the activation of glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD), whose enzymatic activities increase of about 30% and 47%, respectively. Changes in the GSH pathway induced by RWp were associated with a slight but significant increase in reactive oxygen species (ROS). We conclude that the pro-oxidant effect of RWp promoted an adaptive stress response in human erythrocytes, which enhances their antioxidant defense.

The Era of Nanomaterials: A Safe Solution or a Risk for Marine Environmental Pollution?

In recent years, the application of engineered nanomaterials (ENMs) in environmental remediation gained increasing attention. Due to their large surface area and high reactivity, ENMs offer the potential for the efficient removal of pollutants from environmental matrices with better performances compared to conventional techniques. However, their fate and safety upon environmental application, which can be associated with their release into the environment, are largely unknown. It is essential to develop systems that can predict ENM interactions with biological systems, their overall environmental and human health impact. Until now, Life-Cycle Assessment (LCA) tools have been employed to investigate ENMs potential environmental impact, from raw material production, design and to their final disposal. However, LCA studies focused on the environmental impact of the production phase lacking information on their environmental impact deriving from in situ employment. A recently developed eco-design framework aimed to fill this knowledge gap by using ecotoxicological tools that allow the assessment of potential hazards posed by ENMs to natural ecosystems and wildlife. In the present review, we illustrate the development of the eco-design framework and review the application of ecotoxicology as a valuable strategy to develop ecosafe ENMs for environmental remediation. Furthermore, we critically describe the currently available ENMs for marine environment remediation and discuss their pros and cons in safe environmental applications together with the need to balance benefits and risks promoting an environmentally safe nanoremediation (ecosafe) for the future.

The Mediterranean diet from past to future: Key concepts from the second "Ancel Keys" International Seminar.

The year 2020 celebrated the tenth anniversary of the recognition of the Mediterranean Diet as Intangible Cultural Heritage of Humanity by the UNESCO Intergovernmental Committee. This event represented a milestone in the history of nutrition, as the Mediterranean diet was the first traditional food practice to receive such award. Since then, a lot has been discussed not only on the beneficial aspects of the Mediterranean diet, but also on its complex role as a lifestyle model that includes a set of skills, knowledge and intercultural dialogue. This process ended up with the recognition in 2019 of Mediterranean diet as a possibly universal model of healthy diet from the EAT-Lancet Commission. These concepts were widely debated at the 2019 "Ancel Keys" International Seminar, held in Ascea (Italy) (for more information see: www.mediterraneandietseminar.org) with the aim to stimulate interest and awareness of a young group of participants on the current problems inherent to the effective implementation of the Mediterranean diet. The present article collects the contributions of several lecturers at the Seminar on key issues such as methodological and experimental approach, sustainability, molecular aspects in disease prevention, future exploitation, without neglecting a historical view of the Seven Countries Study. From the Seminar conclusions emerged a still vibrant and modern role of Mediterranean diet. The years to come will see national and international efforts to reduce the barriers that limit adherence to Mediterranean diet in order to plan for multi-factorial and targeted interventions that would guide our populations to a sustainable healthy living.

Virtual Screening of Natural Compounds as Potential PI3K-AKT1 Signaling Pathway Inhibitors and Experimental Validation.

A computational screening for natural compounds suitable to bind the AKT protein has been performed after the generation of a pharmacophore model based on the experimental structure of AKT1 complexed with IQO, a well-known inhibitor. The compounds resulted as being most suitable from the screening have been further investigated by molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis and toxicity profiles. Two compounds selected at the end of the computational analysis, i.e., ZINC2429155 (also named STL1) and ZINC1447881 (also named AC1), have been tested in an experimental assay, together with IQO as a positive control and quercetin as a negative control. Only STL1 clearly inhibited AKT activation negatively modulating the PI3K/AKT pathway.

Biochemical and Cellular Characterization of New Radio-Resistant Cell Lines Reveals a Role of Natural Flavonoids to Bypass Senescence.

Cancer is one of the main causes of death worldwide, and, among the most frequent cancer types, osteosarcoma accounts for 56% of bone neoplasms observed in children and colorectal cancer for 10.2% of tumors diagnosed in the adult population. A common and frequent hurdle in cancer treatment is the emergence of resistance to chemo- and radiotherapy whose biological causes are largely unknown. In the present work, human osteosarcoma (SAOS) and colorectal adenocarcinoma (HT29) cell lines were γ-irradiated at doses mimicking the sub-lethal irradiation in clinical settings to obtain two radio-resistant cellular sub-populations named SAOS400 and HT500, respectively. Since "therapy-induced senescence" (TIS) is often associated with tumor response to radiotherapy in cancer cells, we measured specific cellular and biochemical markers of senescence in SAOS400 and HT500 cells. In detail, both cell lines were characterized by a higher level of expression of cyclin-dependent kinase inhibitors p16INK4 and p21CIP1 and increased positivity to SAß-gal (senescence-associated ß-galactosidase) with respect to parental cells. Moreover, the intracellular levels of reactive oxygen species in the resistant cells were significantly lower compared to the parental counterparts. Subsequently, we demonstrated that senolytic agents were able to sensitize SAOS400 and HT500 to cell death induced by γ-irradiation. Employing two natural flavonoids, fisetin and quercetin, and a BH3-mimetic, ABT-263/navitoclax, we observed that their association with γ-irradiation significantly reduced the expression of p16INK4, p21CIP1 and synergistically (combination index < 1) increased cell death compared to radiation mono-alone treatments. The present results reinforce the potential role of senolytics as adjuvant agents in cancer therapy.

Regulation of p27Kip1 and p57Kip2 Functions by Natural Polyphenols.

In numerous instances, the fate of a single cell not only represents its peculiar outcome but also contributes to the overall status of an organism. In turn, the cell division cycle and its control strongly influence cell destiny, playing a critical role in targeting it towards a specific phenotype. Several factors participate in the control of growth, and among them, p27Kip1 and p57Kip2, two proteins modulating various transitions of the cell cycle, appear to play key functions. In this review, the major features of p27 and p57 will be described, focusing, in particular, on their recently identified roles not directly correlated with cell cycle modulation. Then, their possible roles as molecular effectors of polyphenols' activities will be discussed. Polyphenols represent a large family of natural bioactive molecules that have been demonstrated to exhibit promising protective activities against several human diseases. Their use has also been proposed in association with classical therapies for improving their clinical effects and for diminishing their negative side activities. The importance of p27Kip1 and p57Kip2 in polyphenols' cellular effects will be discussed with the aim of identifying novel therapeutic strategies for the treatment of important human diseases, such as cancers, characterized by an altered control of growth.

Roles of flavonoids against coronavirus infection.

In terms of public health, the 21st century has been characterized by coronavirus pandemics: in 2002-03 the virus SARS-CoV caused SARS; in 2012 MERS-CoV emerged and in 2019 a new human betacoronavirus strain, called SARS-CoV-2, caused the unprecedented COVID-19 outbreak. During the course of the current epidemic, medical challenges to save lives and scientific research aimed to reveal the genetic evolution and the biochemistry of the vital cycle of the new pathogen could lead to new preventive and therapeutic strategies against SARS-CoV-2. Up to now, there is no cure for COVID-19 and waiting for an efficacious vaccine, the development of "savage" protocols, based on "old" anti-inflammatory and anti-viral drugs represents a valid and alternative therapeutic approach. As an alternative or additional therapeutic/preventive option, different in silico and in vitro studies demonstrated that small natural molecules, belonging to polyphenol family, can interfere with various stages of coronavirus entry and replication cycle. Here, we reviewed the capacity of well-known (e.g. quercetin, baicalin, luteolin, hesperetin, gallocatechin gallate, epigallocatechin gallate) and uncommon (e.g. scutellarein, amentoflavone, papyriflavonol A) flavonoids, secondary metabolites widely present in plant tissues with antioxidant and anti-microbial functions, to inhibit key proteins involved in coronavirus infective cycle, such as PLpro, 3CLpro, NTPase/helicase. Due to their pleiotropic activities and lack of systemic toxicity, flavonoids and their derivative may represent target compounds to be tested in future clinical trials to enrich the drug arsenal against coronavirus infections.