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.

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.

Therapeutic potential of polyphenols in cardiovascular diseases: Regulation of mTOR signaling pathway.

Cardiovascular diseases comprise of non-communicable disorders that involve the heart and/or blood vessels and have become the leading cause of death worldwide with increased prevalence by age. mTOR is a serine/threonine-specific protein kinase which plays a central role in many physiological processes including cardiovascular diseases, and also integrates various proliferative signals, nutrient and energy abundance and stressful situations. mTOR also acts as central regulator during chronic stress, mitochondrial dysfunction and deregulated autophagy which are associated with senescence. Under oxidative stress, mTOR has been reported to exert protective effects regulating apoptosis and autophagy processes and favoring tissue repair. On the other hand, inhibition of mTOR has been suggested to have beneficial effects against atherosclerosis, cardiac hypertrophy and heart failure, and also in extending the lifespan. In this aspect, the use of drugs or natural compounds, which can target mTOR is an interesting approach in order to reduce the number of deaths caused by cardiovascular disease. In the present review, we intend to shed light on the possible effects and molecular mechanism of natural agents like polyphenols via regulating mTOR.

Mechanisms of aging and potential role of selected polyphenols in extending healthspan.

Aging became a priority in medicine due to the rapid increase of elderly population and age-related diseases in the Western countries. Nine hallmarks have been identified based on their alteration during aging and their capacity to increase longevity. The pathways and the molecular mechanisms to improve lifespan and healthspan are controlled by behavioral, pharmacologic and dietary factors, which remain largely unknown. Among them, naturally occurring compounds, such as polyphenols, are considered potential antiaging agents, because of their ability to modulate some of the evolutionarily conserved hallmarks of aging, including oxidative damage, inflammation, cell senescence, and autophagy. Initially, these compounds gained researchers' attention due to their ability to extend the lifespan of simple model organisms. More recently, some of them have been proposed as senolytic agents to protect against age-related disorders, such as cancer, cardiovascular and neurodegenerative diseases. The intent of this review is to present the most validated molecular mechanisms regulating ageing and longevity and critically analyze how selected polyphenols, namely resveratrol, quercetin, curcumin and catechins, can interfere with these mechanisms.

Antiproliferative and antioxidant effect of polar hemp extracts (Cannabis sativa L., Fedora cv.) in human colorectal cell lines.

Total phenolic content and antioxidant activity of polar extracts of edible resources from Fedora hemp cultivar (Cannabis sativa L.), namely seed, flour and oil, were evaluated. The main components in the polar extracts were identified using HPLC-DAD and HPLC-ESI-MS/MS. As expected, the molecular profile of components from seeds and flour was strictly similar, dominated by N-trans-caffeoyltyramine. The profile of oil polar extracts contained hydroxycinnamic acid derivatives and cannabinoids at lower extent. While the extracts from hemp seed and flour did not interfere with growth of Caco-2 and HT-29 cell, the one from oil (150 µg/mL) significantly reduced cell viability after 24 h of treatment. This effect was associated with the activation of apoptotic cell death and was independent from the antioxidant capacity of the oil polar extract. Notably, HT-29 cells differentiated with sodium butyrate were not sensitive to the cytotoxic effect of the oil extract.

Comparative Study of Chemical, Biochemical Characteristic and ATR-FTIR Analysis of Seeds, Oil and Flour of the Edible Fedora Cultivar Hemp (Cannabis sativa L.).

A series of chemical and biochemical parameters of edible hemp resources (seeds, oil, and flour) from the monoecious EU registered hemp genotype Fedora, was determined, including fatty acid profile, phytosterol composition, total phenolics, antioxidant activity, macro- and micro-elements. The fatty acid ω-3/ω-6 approached the nutritionally optimal 3/1 ratio. ß-sitosterol and other phytosterols sterols dominated the unsaponifiable fraction. Hemp seeds, flour, and oil contained 767 ± 41, 744 ± 29, and 21 ± 5 mg GAE kg-1 total polyphenols, respectively. The antioxidant potential of Fedora flour and seeds, evaluated through the DPPH (2,2-Diphenyl-1-picrylhydrazyl) assay, was higher than that of oil. K and Mg were the most abundant macro-elements, particularly in flour, while the concentration of trace elements was Fe > Cu > Ni > Mn. The presence of an array of bioactive compound candidate Fedora products as health-promoting food matrices. The ATR-FTIR spectra of hemp-derived products indicated the proximate composition of macro-nutrients.

A Phenolic Extract Obtained from Methyl Jasmonate-Treated Strawberries Enhances Apoptosis in a Human Cervical Cancer Cell Line.

In the present study, we evaluated the effect of methyl jasmonate (MeJA) treatment on strawberry phenolic composition. Strawberry extracts contain a mixture of phenolic compounds possessing several biological properties. We demonstrated that these extracts were more effective in inducing apoptosis in HeLa cells compared to phenolic preparations derived from untreated strawberries. Treatment of strawberries with 0.5% MeJA resulted in increased polyphenols content (from 7.4 to 8.6 mM quercetin equivalents) and antioxidant properties (from 3.9 to 4.6 mM quercetin equivalents). The identification and quantification of phenolic compounds by liquid chromatography-mass spectrometry in the strawberry extracts showed that cyanidin glucoside, pelargonidin glucoside, and ellagic glucoside acid were significantly higher in strawberries treated with MeJA. Phenolic extracts from MeJA-treated strawberries significantly decreased the cell viability in HeLa cells, compared to extracts derived from untreated fruits. We hypothesized that the enhanced apoptotic activity of MeJA-treated strawberries was due to a synergistic or additive effect of different phenolic compounds present in the extract, rather than the activity of a single molecule.

Red Wine Inhibits Aggregation and Increases ATP-diphosphohydrolase (CD39) Activity of Rat Platelets in Vitro.

Moderate consumption of red wine has been shown to exert a peculiar cardioprotective effect compared with other alcoholic beverages; inhibition of platelet aggregation seems to be one of the mechanisms underlying this beneficial effect. CD39/ATP-diphosphohydrolase is an integral membrane glycoprotein metabolizing ATP and ADP to AMP; in concert with CD73/ecto-5'-nucleotidase, it contributes to extracellular adenosine accumulation. CD39 is considered a key modulator of thrombus formation; it inhibits platelet aggregation by promoting ADP hydrolysis. There is evidence that red wine consumption increases CD39 activity in platelets from streptozotocin-induced diabetic rats. Here we show that two kinds of Aglianico red wines inhibit aggregation and increase ATP--and ADPase activity in rat platelets.

Neuroprotective Role of Natural Polyphenols.

Neurodegenerative diseases cause a progressive functional alteration of neuronal systems, resulting in a state of dementia which is considered one of the most common psychiatric disorders of the elderly. Dementia implies an irreversible impairment of intellect that increases with age causing alteration of memory, language and behavioral problems. The most common form, which occurs in more than half of all cases, is Alzheimer's disease, characterized by accumulation of amyloid plaques and neurofibrillary tangles. Neuroinflammation and oxidative stresses have been considered as a hallmark of Alzheimer disease, playing a crucial role in neurotoxicity. For this reason, an adequate antioxidant strategy may improve the treatment of neurodegenerative diseases and dementia. Several studies support the neuroprotective abilities of polyphenolic compounds resulting in neuronal protection against injury induced by neurotoxins, ability to suppress neuroinflammation and the potential to promote memory, learning and cognitive functions. We critically reviewed here the therapeutic potential of pure herbal compounds (e.g., green tea polyphenol (-)- epigallocatechin-3-gallate, resveratrol, curcumin, quercetin and others) and extracts enriched in polyphenols showing the most promising neuroprotective effects. We are also presenting data on the ability of an extract derived from elderberry, Sambucus nigra, possessing elevated polyphenolic content and antioxidant capacity to protect neuronal cells against oxidizing agents.

Α-Cyclodextrin encapsulation of supercritical CO2 extracted oleoresins from different plant matrices: A stability study.

Here we describe the encapsulation in α-cyclodextrins (α-CDs) of wheat bran, pumpkin and tomato oleoresins, extracted by supercritical carbon dioxide, to obtain freeze-dried powders useful as ready-to-mix ingredients for novel functional food formulation. The stability of tocochromanols, carotenoids and fatty acids in the oleoresin/α-CD complexes, compared to the corresponding free oleoresins, was also monitored over time in different combinations of storage conditions. Regardless of light, storage at 25°C of free oleoresins determined a rapid decrease in carotenoids, tocochromanols and PUFAs. α-CD encapsulation improved the stability of most bioactive compounds. Storage at 4°C synergized with encapsulation in preventing degradation of bioactives. Unlike all other antioxidants, lycopene in tomato oleoresin/α-CD complex resulted to be more susceptible to oxidation than in free oleoresin, likely due to its selective sequestration from the interaction with other lipophilic molecules of the oleoresin.

Understanding genistein in cancer: The "good" and the "bad" effects: A review.

Nowadays, diet and specific dietary supplements are seen as potential adjuvants to prevent different chronic diseases, including cancer, or to ameliorate pharmacological therapies. Soybean is one of the most important food components in Asian diet. A plethora of evidence supports the in vitro and in vivo anticancer effects of genistein, a soybean isoflavone. Major tumors affected by genistein here reviewed are breast, prostate, colon, liver, ovarian, bladder, gastric, brain cancers, neuroblastoma and chronic lymphocytic leukemia. However, it is not always clear if and when genistein is beneficial against tumors (the "good" effects), or the opposite, when the same molecule exerts adverse effects (the "bad" effects), favouring cancer cell proliferation. This review will critically evaluate this concept in the light of the different molecular mechanisms of genistein which occur when the molecule is administered at low doses (chemopreventive effects), or at high doses (pharmacological effects).

Omega-3 polyunsaturated fatty acids and cancer: lessons learned from clinical trials.

Over the past decades, extensive studies have addressed the therapeutic effects of omega-3 polyunsaturated fatty acids (omega-3 FAs) against different human diseases such as cardiovascular and neurodegenerative diseases, cancer, etc. A growing body of scientific research shows the pharmacokinetic information and safety of these natural occurring substances. Moreover, during recent years, a plethora of studies has demonstrated that omega-3 FAs possess therapeutic role against certain types of cancer. It is also known that omega-3 FAs can improve efficacy and tolerability of chemotherapy. Previous reports showed that suppression of nuclear factor-κB, activation of AMPK/SIRT1, modulation of cyclooxygenase (COX) activity, and up-regulation of novel anti-inflammatory lipid mediators such as protectins, maresins, and resolvins, are the main mechanisms of antineoplastic effect of omega-3 FAs. In this review, we have collected the available clinical data on the therapeutic role of omega-3 FAs against breast cancer, colorectal cancer, leukemia, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, lung cancer, head and neck cancer, as well as cancer cachexia. We also discussed the chemistry, dietary source, and bioavailability of omega-3 FAs, and the potential molecular mechanisms of anticancer and adverse effects.

Identification and Quantification of Flavonoids from Two Southern Italian Cultivars of Allium cepa L., Tropea (Red Onion) and Montoro (Copper Onion), and Their Capacity to Protect Human Erythrocytes from Oxidative Stress.

Onions (Allium cepa) are consumed worldwide and represent an important source of dietary phytochemicals with proven antioxidant properties, such as phenolic acids, flavonoids, thiosulfinates, and anthocyanins. Epidemiological and experimental data suggest that regular consumption of onions is associated with a reduced risk of degenerative disorders. Therefore, it is of interest to investigate the biological properties of different varieties of onions. Here, we characterized for the first time a variety of onion, called Ramata di Montoro (coppery onion from Montoro), grown in a niche area in southern Italy, and compared its phenolic profile and antioxidant properties to a commercial ecotype of red onion, Tropea, also present in southern Italy. An analytical method based on high-performance liquid chromatography coupled with UV detection and mass spectrometry was used to separate and characterize the phenolic fraction (anthocyanins and flavonols) extracted from both coppery and red types. The main compounds detected in the two ecotypes were quercetin and quercetin glucosides, isorhamnetin glucosides, kaempferol glucoside, and, among anthocyanins, cyanidin glucosides. Tropea ecotype onion showed a higher content of flavonols (632.82 mg/kg fresh weight) than Montoro type onion (252.91 mg/kg fresh weight). Accordingly, the antioxidant activity of the former was 2.8-fold higher compared to the latter. More pronounced were the differences existing between the four anthocyanins detected in the two ecotypes, with those in the Tropea ecotype onion present at concentrations 20-230-fold higher than in the Montoro type onion. Both extracts reduced LDL oxidation about 6-fold and protected human erythrocytes from oxidative damage induced by HClO by about 40%. In addition, as a consequence of HClO treatment, glutathione concentration in erythrocytes was reduced about 50% and pretreatment with onion extracts induced a recovery of glutathione level by about 15-22%. Qualitative differences highlighted in the chemical composition of the two phenolic extracts, especially the total content of anthocyanins, which was 30-fold higher in Montoro type onion compared to Tropea ecotype, can be associated with the protective effects measured against oxidative damage induced in human erythrocytes.

The flavonoid quercetin in disease prevention and therapy: facts and fancies.

Biochemical and genetic studies on cellular and animal models on the mechanism(s) of action of phytochemicals provide a functional explanation of how and why a diet rich in fruits and vegetables is considered healthy. It is not unusual to find molecules that protect against diseases, which greatly differ from a physiopathological point of view, such as cancer and cardiovascular disorders. Quercetin falls into this category and possesses a broad range of biological properties. Uptake, metabolism and circulating concentrations of quercetin and its metabolites suggest that a regular diet provides amounts of quercetin (<1 µM) not compatible with its chemopreventive and/or cardioprotective effects. However, it appears relatively easy to increase total quercetin concentrations in plasma (>10 µM) by supplementation with quercetin-enriched foods or supplements. Multiple lines of experimental evidence suggest a positive association between quercetin intake and improved outcomes of inflammatory cardiovascular risk. The ameliorating effect of quercetin administration can be extended to other chronic inflammatory disorders but only if supplementation occurs in patients. Quercetin can be considered the prototype of a naturally-occurring chemopreventive agent because of its key roles in triggering the "hallmarks of cancer". However, several critical points must be taken into account when considering the potential therapeutic use of this molecule: (1) pharmacological versus nutraceutical doses applied, (2) specificity of its mechanism of action compared to other phytochemicals, and (3) identification of "direct" cellular targets. The design of specific clinical trials is extremely warranted to depict possible applications of quercetin in adjuvant cancer therapy.

Commentary on 'resveratrol commonly displays hormesis: occurrence and biomedical significance'.

The review by Calabrese et al. describes the hormetic dose responses induced by phytoalexin resveratrol in a wide range of biological models. We agree and support the authors' strategy to present an impressive number of experiments furnished with an exhaustive bibliography to emphasize that 'many effects induced by resveratrol are dependent on dose and that opposite effects occur at low and high doses, being indicative of a hormetic dose response.' We also highly appreciate the holistic view of the hormetic behavior of resveratrol provided by the authors spanning from tumor and non-tumor cell lines to human and parasitic diseases. In our comments, we touched minor points whose discussion would have strengthened the work of Calabrese, such as contradictions on the role of resveratrol in the 'French Paradox,' its effect on aromatase activity, glutamate cysteine ligase expression and glutathione levels. Overall, we encourage colleagues working in this field to read the present review and consider its relevant biological implications. The vision of Calabrese et al. is far too important to be ignored.

Phytochemicals in cancer prevention and therapy: truth or dare?

A voluminous literature suggests that an increase in consumption of fruit and vegetables is a relatively easy and practical strategy to reduce significantly the incidence of cancer. The beneficial effect is mostly associated with the presence of phytochemicals in the diet. This review focuses on a group of them, namely isothiocyanate, curcumin, genistein, epigallocatechin gallate, lycopene and resveratrol, largely studied as chemopreventive agents and with potential clinical applications. Cellular and animal studies suggest that these molecules induce apoptosis and arrest cell growth by pleiotropic mechanisms. The anticancer efficacy of these compounds may result from their use in monotherapy or in association with chemotherapeutic drugs. This latter approach may represent a new pharmacological strategy against several types of cancers. However, despite the promising results from experimental studies, only a limited number of clinical trials are ongoing to assess the therapeutic efficacy of these molecules. Nevertheless, the preliminary results are promising and raise solid foundations for future investigations.

Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention.

Linoleic acid (LA) and alpha linolenic acid (ALA) belong to the n-6 (omega-6) and n-3 (omega-3) series of polyunsaturated fatty acids (PUFA), respectively. They are defined "essential" fatty acids since they are not synthesized in the human body and are mostly obtained from the diet. Food sources of ALA and LA are most vegetable oils, cereals and walnuts. This review critically revises the most significant epidemiological and interventional studies on the cardioprotective activity of PUFAs, linking their biological functions to biochemistry and metabolism. In fact, a complex series of desaturation and elongation reactions acting in concert transform LA and ALA to their higher unsaturated derivatives: arachidonic acid (AA) from LA, eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) from ALA. EPA and DHA are abundantly present in fish and fish oil. AA and EPA are precursors of different classes of pro-inflammatory or anti-inflammatory eicosanoids, respectively, whose biological activities have been evoked to justify risks and benefits of PUFA consumption. The controversial origin and clinical role of the n-6/n-3 ratio as a potential risk factor in cardiovascular diseases is also examined. This review highlights the important cardioprotective effect of n-3 in the secondary prevention of sudden cardiac death due to arrhythmias, but suggests caution to recommend dietary supplementation of PUFAs to the general population, without considering, at the individual level, the intake of total energy and fats.