Impact of Melatonin Supplementation on Sports Performance and Circulating Biomarkers in Highly Trained Athletes: A Systematic Review of Randomized Controlled Trials.

Melatonin (N-acetyl-5 methoxytryptamine) is an indolic neurohormone that modulates a variety of physiological functions due to its antioxidant, anti-inflammatory, and immunoregulatory properties. Therefore, the purpose of this study was to critically review the effects of melatonin supplementation in sports performance and circulating biomarkers related to the health status of highly trained athletes. Data were obtained by performing searches in the following three bibliography databases: Web of Science, PubMed, and Scopus. The terms used were "Highly Trained Athletes", "Melatonin", and "Sports Performance", "Health Biomarkers" using "Humans" as a filter. The search update was carried out in February 2024 from original articles published with a controlled trial design. The PRISMA rules, the modified McMaster critical review form for quantitative studies, the PEDro scale, and the Cochrane risk of bias were applied. According to the inclusion and exclusion criteria, 21 articles were selected out of 294 references. The dose of melatonin supplemented in the trials ranged between 5 mg to 100 mg administered before or after exercise. The outcomes showed improvements in antioxidant status and inflammatory response and reversed liver damage and muscle damage. Moderate effects on modulating glycemia, total cholesterol, triglycerides, and creatinine were reported. Promising data were found regarding the potential benefits of melatonin in hematological biomarkers, hormonal responses, and sports performance. Therefore, the true efficiency of melatonin to directly improve sports performance remains to be assessed. Nevertheless, an indirect effect of melatonin supplementation in sports performance could be evaluated through improvements in health biomarkers.

Evaluation of Bioactive Effects of Five Plant Extracts with Different Phenolic Compositions against Different Therapeutic Targets.

Plant extracts rich in phenolic compounds have been reported to exert different bioactive properties. Despite the fact that there are plant extracts with completely different phenolic compositions, many of them have been reported to have similar beneficial properties. Thus, the structure-bioactivity relationship mechanisms are not yet known in detail for specific classes of phenolic compounds. In this context, this work aims to demonstrate the relationship of extracts with different phenolic compositions versus different bioactive targets. For this purpose, five plant matrices (Theobroma cacao, Hibiscus sabdariffa, Silybum marianum, Lippia citriodora, and Olea europaea) were selected to cover different phenolic compositions, which were confirmed by the phytochemical characterization analysis performed by HPLC-ESI-qTOF-MS. The bioactive targets evaluated were the antioxidant potential, the free radical scavenging potential, and the inhibitory capacity of different enzymes involved in inflammatory processes, skin aging, and neuroprotection. The results showed that despite the different phenolic compositions of the five matrices, they all showed a bioactive positive effect in most of the evaluated assays. In particular, matrices with very different phenolic contents, such as T. cacao and S. marianum, exerted a similar inhibitory power in enzymes involved in inflammatory processes and skin aging. It should also be noted that H. sabdariffa and T. cacao extracts had a low phenolic content but nevertheless stood out for their bioactive antioxidant and anti-radical capacity. Hence, this research highlights the shared bioactive properties among phenolic compounds found in diverse matrices. The abundance of different phenolic compound families highlights their elevated bioactivity against diverse biological targets.

Antioxidant Supplementation Modulates Neutrophil Inflammatory Response to Exercise-Induced Stress.

The aim of the present report was to evaluate the inflammatory response to a 2000-m running test considering neutrophil myeloperoxidase as an inflammatory marker, and to verify if supplements rich in antioxidants could modulate Post-test antioxidant and anti-inflammatory responses. To this end, a 21-day homogenization period was carried out with three groups: a control group, a supplemented group taking an almond beverage enriched with vitamins C and E and a third group consuming the same beverage but enriched with Lippia citriodora extract. At the end of this period, participants performed a 2000-m run, and blood samples were obtained the day before and immediately after the running test. Plasma and neutrophils were isolated. As a result, plasma creatine kinase and myoglobin increased, indicating Post-test muscle damage. Plasma oxidative markers were increased in all groups, except in the group supplemented with the almond beverage. Neutrophil antioxidant enzymes were significantly increased only in the control group, suggesting an antioxidant effect of the supplements provided in the other groups. Myeloperoxidase activity was significantly increased after the test in the control group, while increased enzyme levels were detected in plasma of the supplement groups. Therefore, antioxidant consumption seems to favour myeloperoxidase release. The connection of this observation with post-exercise recovery will require further investigation.

Quercetin metabolites from Hibiscus sabdariffa contribute to alleviate glucolipotoxicity-induced metabolic stress in vitro.

Polyphenols from Hibiscus sabdariffa (HS) alleviate obesity-related metabolic complications but the metabolites responsible for such effects are unknown. We aimed to elucidate which of the potential plasma metabolites from a polyphenol-enriched HS (PEHS) extract contributed for the reversion of glucolipotoxicity-induced metabolic stress using 3T3-L1 adipocyte and INS 832/13 pancreatic ß-cell models under glucolipotoxic conditions. PEHS extract, quercetin (Q) and quercetin-3-O-glucuronide (Q3GA) showed stronger capacity to decrease glucolipotoxicity-induced ROS generation than ascorbic acid or chlorogenic acid. PEHS extract, Q and Q3GA decreased secretion of cytokines (leptin, TNF-α, IGF-1, IL-6, VEGF, IL-1α, IL-1ß and CCL2) and reduced CCL2 expression at transcriptional level. In addition, PEHS extract, Q and Q3GA reduced triglyceride accumulation, which occurred through fatty acid synthase (FASN) downregulation, AMPK activation and mitochondrial mass and biogenesis restoration via PPARα upregulation. Electron microscopy confirmed that PEHS extract and Q3GA decreased mitochondrial remodeling and mitophagy. Virtual screening leads us to postulate that Q and Q3GA might act as agonists of these protein targets at specific sites. These data suggest that Q and Q3GA may be the main responsible compounds for the capacity of PEHS extract to revert glucolipotoxicity-induced metabolic stress through AMPK-mediated decrease in fat storage and increase in fatty acid oxidation, though other compounds of the extract may contribute to this capacity.

Differential effects of a combination of Hibiscus sabdariffa and Lippia citriodora polyphenols in overweight/obese subjects: A randomized controlled trial.

Plant-polyphenols have shown the capacity to ameliorate obesity-induced metabolic disturbances, both in cell and animal models, where most therapeutic approaches have failed. On the basis of previous research, a dietary supplement containing 500 mg of a combination of polyphenolic extracts from Lippia citriodora L. and Hibiscus sabdariffa L. (LC-HS), in the context of an equilibrated isocaloric diet, was evaluated in a double blind, placebo-controlled and randomized trial in 56 obese/overweight subjects for two months. Compared to controls, the consumption of the LC-HS polyphenols showed significant improvements in body weight, abdominal circumference of overweight subjects (-6.79 ± 0.80 cm in overweight LC-HS group vs -1.85 ± 0.83 cm in controls, p < 0.001) and body fat % (-1.33 ± 0.15% in overweight LC-HS group vs -0.66 ± 0.17% in controls, p < 0.05). Heart rate and systolic blood pressure also presented significant improvements in overweight LC-HS participants. However, changes were more modest in obese subjects. Further, LC-HS extract significantly reduced lipid content and increased AMPK activity in a hypertrophied adipocyte cell model. Therefore, consumption of 500 mg/day of LC-HS extracts enriched in polyphenols for two months in the context of an isocaloric diet by overweight subjects decreased symptoms associated to obesity-related diseases. Modulation of fat metabolism in adipose tissue, probably mediated by AMPK activation, is proposed as a molecular target to be explored in future research.

Rosemary (Rosmarinus officinalis) extract causes ROS-induced necrotic cell death and inhibits tumor growth in vivo.

Colorectal cancer is the third most common diagnosed cancer globally. Although substantial advances have been obtained both in treatment and survival rates, there is still a need for new therapeutical approaches. Natural compounds are a realistic source of new bioactive compounds with anticancer activity. Among them, rosemary polyphenols have shown a vast antiproliferative capacity against colon cancer cells in vitro and in animal models. We have investigated the antitumor activity of a rosemary extract (RE) obtained by using supercritical fluid extraction through its capacity to inhibit various signatures of cancer progression and metastasis such as proliferation, migration, invasion and clonogenic survival. RE strongly inhibited proliferation, migration and colony formation of colon cancer cells regardless their phenotype. Treatment with RE led to a sharp increase of intracellular ROS that resulted in necrosis cell death. Nrf2 gene silencing increased RE cytotoxic effects, thus suggesting that this pathway was involved in cell survival. These in vitro results were in line with a reduction of tumor growth by oral administration of RE in a xenograft model of colon cancer cells using athymic nude mice. These findings indicate that targeting colon cancer cells by increasing intracellular ROS and decreasing cell survival mechanisms may suppose a therapeutic option in colon cancer through the combination of rosemary compounds and chemotherapeutic drugs.

Hibiscus and lemon verbena polyphenols modulate appetite-related biomarkers in overweight subjects: a randomized controlled trial.

TRIAL DESIGN: Plant-derived polyphenols have shown potential to alleviate obesity-related pathologies by a multi-targeted mechanism in animal models and human intervention studies. A dietary supplement based on a combination of Lippia citriodora (LC) and Hibiscus sabdariffa (HS) polyphenolic extracts was assayed in a double blind and placebo-controlled intervention study with 54 overweight subjects. METHODS: Blood pressure, body weight, height, triceps, biceps and abdominal skinfold thickness, and arm and abdominal circumferences were taken at the baseline, 30 and 60 days of the intervention period. The validated Visual Analogue Scale used to record hunger and satiety-related sensations was passed at the beginning and at 15, 30, 45 and 60 days of the intervention. Subjective health status was assessed through the validated SF-36 questionnaire at the beginning and end of the study. Finally, plasma from fasting blood samples was obtained at the beginning, 30 and 60 days of the study. RESULTS: The results showed an improvement of anthropometric measurements, decreased blood pressure and heart rate and a more positive perception in the overall health status. We also observed that plant polyphenols increased anorexigenic hormones (glucagon-like peptide-1) and decreased orexigenic hormones (ghrelin). CONCLUSIONS: Based on previous evidence we postulate that AMP-activated protein kinase may have a role in such effects through its capability to modulate energy homeostasis, total daily energy expenditure and lipid management. Although further research may be required, we propose that this polyphenolic combination may be used for weight management by increasing long-term weight loss maintenance through the modulation of appetite biomarkers. This may help to avoid the undesired weight regain typical of calorie restriction diets.

Nutraceuticals for Skin Care: A Comprehensive Review of Human Clinical Studies.

The skin is the body's largest organ, it participates in sensitivity and offers protection against microorganisms, chemicals and ultraviolet (UV) radiation. Consequently, the skin may suffer alterations such as photo-ageing, immune dysfunction and inflammation which may significantly affect human health. Nutraceuticals represent a promising strategy for preventing, delaying, or minimising premature ageing of the skin and also to alleviate certain skin disorders. Among them, bioactive peptides and oligosaccharides, plant polyphenols, carotenoids, vitamins and polyunsaturated fatty acids are the most widely used ingredients. Supplementation with these products has shown evidence of having an effect on the signs of ageing and protection against UV radiation ageing in several human trials. In this review, the most relevant human studies on skin nutraceuticals are evaluated and the statistical resolution, biological relevance of their results, and, the trial protocols are discussed. In conclusion, quality and rigorousness of the trials must be improved to build credible scientific evidence for skin nutraceuticals and to establish a cause-effect relationship between the ingredients the beneficial effects for the skin.

Plant-Derived Polyphenols in Human Health: Biological Activity, Metabolites and Putative Molecular Targets.

BACKGROUND: Hibiscus sabdariffa, Lippia citriodora, Rosmarinus officinalis and Olea europaea, are rich in bioactive compounds that represent most of the phenolic compounds' families and have exhibited potential benefits in human health. These plants have been used in folk medicine for their potential therapeutic properties in human chronic diseases. Recent evidence leads to postulate that polyphenols may account for such effects. Nevertheless, the compounds or metabolites that are responsible for reaching the molecular targets are unknown. OBJECTIVE: data based on studies directly using complex extracts on cellular models, without considering metabolic aspects, have limited applicability. In contrast, studies exploring the absorption process, metabolites in the blood circulation and tissues have become essential to identify the intracellular final effectors that are responsible for extracts bioactivity. Once the cellular metabolites are identified using high-resolution mass spectrometry, docking techniques suppose a unique tool for virtually screening a large number of compounds on selected targets in order to elucidate their potential mechanisms. RESULTS: we provide an updated overview of the in vitro and in vivo studies on the toxicity, absorption, permeability, pharmacokinetics and cellular metabolism of bioactive compounds derived from the abovementioned plants to identify the potential compounds that are responsible for the observed health effects. CONCLUSION: we propose the use of targeted metabolomics followed by in silico studies to virtually screen identified metabolites on selected protein targets, in combination with the use of the candidate metabolites in cellular models, as the methods of choice for elucidating the molecular mechanisms of these compounds.

Multi-Targeted Molecular Effects of Hibiscus sabdariffa Polyphenols: An Opportunity for a Global Approach to Obesity.

Improper diet can alter gene expression by breaking the energy balance equation and changing metabolic and oxidative stress biomarkers, which can result in the development of obesity-related metabolic disorders. The pleiotropic effects of dietary plant polyphenols are capable of counteracting by modulating different key molecular targets at the cell, as well as through epigenetic modifications. Hibiscus sabdariffa (HS)-derived polyphenols are known to ameliorate various obesity-related conditions. Recent evidence leads to propose the complex nature of the underlying mechanism of action. This multi-targeted mechanism includes the regulation of energy metabolism, oxidative stress and inflammatory pathways, transcription factors, hormones and peptides, digestive enzymes, as well as epigenetic modifications. This article reviews the accumulated evidence on the multiple anti-obesity effects of HS polyphenols in cell and animal models, as well as in humans, and its putative molecular targets. In silico studies reveal the capacity of several HS polyphenols to act as putative ligands for different digestive and metabolic enzymes, which may also deserve further attention. Therefore, a global approach including integrated and networked omics techniques, virtual screening and epigenetic analysis is necessary to fully understand the molecular mechanisms of HS polyphenols and metabolites involved, as well as their possible implications in the design of safe and effective polyphenolic formulations for obesity.

An Updated Review on Marine Anticancer Compounds: The Use of Virtual Screening for the Discovery of Small-Molecule Cancer Drugs.

Marine secondary metabolites are a promising source of unexploited drugs that have a wide structural diversity and have shown a variety of biological activities. These compounds are produced in response to the harsh and competitive conditions that occur in the marine environment. Invertebrates are considered to be among the groups with the richest biodiversity. To date, a significant number of marine natural products (MNPs) have been established as antineoplastic drugs. This review gives an overview of MNPs, both in research or clinical stages, from diverse organisms that were reported as being active or potentially active in cancer treatment in the past seventeen years (from January 2000 until April 2017) and describes their putative mechanisms of action. The structural diversity of MNPs is also highlighted and compared with the small-molecule anticancer drugs in clinical use. In addition, this review examines the use of virtual screening for MNP-based drug discovery and reveals that classical approaches for the selection of drug candidates based on ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering may miss potential anticancer lead compounds. Finally, we introduce a novel and publically accessible chemical library of MNPs for virtual screening purposes.

AMPK modulatory activity of olive-tree leaves phenolic compounds: Bioassay-guided isolation on adipocyte model and in silico approach.

SCOPE: Olive-tree polyphenols have demonstrated potential for the management of obesity-related pathologies. We aimed to explore the capacity of Olive-tree leaves extract to modulate triglyceride accumulation and AMP-activated protein kinase activity (AMPK) on a hypertrophic adipocyte model. METHODS: Intracellular triglycerides and AMPK activity were measured on the hypertrophic 3T3-L1 adipocyte model by AdipoRed and immunofluorescence microscopy, respectively. Reverse phase high performance liquid chromatography coupled to time-of-flight mass detection with electrospray ionization (RP-HPLC-ESI-TOF/MS) was used for the fractionation of the extract and the identification of the compounds. In-silico molecular docking of the AMPK alpha-2, beta and gamma subunits with the identified compounds was performed. RESULTS: Olive-tree leaves extract decreased the intracellular lipid accumulation through AMPK-dependent mechanisms in hypertrophic adipocytes. Secoiridoids, cinnamic acids, phenylethanoids and phenylpropanoids, flavonoids and lignans were the candidates predicted to account for this effect. Molecular docking revealed that some compounds may be AMPK-gamma modulators. The modulatory effects of compounds over the alpha and beta AMPK subunits appear to be less probable. CONCLUSIONS: Olive-tree leaves polyphenols modulate AMPK activity, which may become a therapeutic aid in the management of obesity-associated disturbances. The natural occurrence of these compounds may have important nutritional implications for the design of functional ingredients.

Correlation between the cellular metabolism of quercetin and its glucuronide metabolite and oxidative stress in hypertrophied 3T3-L1 adipocytes.

BACKGROUND: Quercetin (Q) is one of the most abundant flavonoids in human dietary sources and has been related to the capacity to ameliorate obesity-related pathologies. Quercetin-3-O-ß-d-glucuronide (Q3GA) is supposed to be the main metabolite in blood circulation, but the intracellular final effectors for its activity are still unknown. HYPOTHESIS/PURPOSE: To identify and quantitate the intracellular metabolites in hypertrophied adipocytes incubated with Q or Q3GA and to correlate them with the intracellular generation of oxygen radical species (ROS). METHODS: Cytoplasmic fractions were obtained and quercetin metabolites were determined by liquid chromatography coupled to a time-of-flight mass detector with electrospray ionization (HPLC-DAD-ESI-TOF). Intracellular ROS generation was measured by a ROS-sensitive fluorescent probe. RESULTS: Both Q and Q3GA were absorbed by hypertrophied adipocytes and metabolized to some extent to Q3GA and Q, respectively, but Q absorption was more efficient (1.92 ± 0.03µg/µg protein) and faster than that of Q3GA (0.12 ± 0.0015µg/µg protein), leading to a higher intracellular concentration of the aglycone. Intracellular decrease of ROS correlated with the presence of the most abundant quercetin metabolite. CONCLUSION: Q and Q3GA are efficiently absorbed by hypertrophied adipocytes and metabolized to some extent to Q3GA and Q, respectively. The intracellular decrease of ROS in a hypertrophied adipocyte model treated with Q or Q3GA is correlated with the most abundant intracellular metabolite for the first time. Both compounds might be able to reach other intracellular targets, thus contributing to their bioactivity.

Lemon balm extract (Melissa officinalis, L.) promotes melanogenesis and prevents UVB-induced oxidative stress and DNA damage in a skin cell model.

BACKGROUND: Solar ultraviolet (UV) radiation is one of the main causes of a variety of cutaneous disorders, including photoaging and skin cancer. Its UVB component (280-315nm) leads to oxidative stress and causes inflammation, DNA damage, p53 induction and lipid and protein oxidation. Recently, an increase in the use of plant polyphenols with antioxidant and anti-inflammatory properties has emerged to protect human skin against the deleterious effects of sunlight. OBJECTIVE: This study evaluates the protective effects of lemon balm extract (LBE) (Melissa Officinalis, L) and its main phenolic compound rosmarinic acid (RA) against UVB-induced damage in human keratinocytes. METHODS: The LBE composition was determined by HPLC analysis coupled to photodiode array detector and ion trap mass spectrometry with electrospray ionization (HPLC-DAD-ESI-IT-MS/MS). Cell survival, ROS generation and DNA damage were determined upon UVB irradiation in the presence of LBE. The melanogenic capacity of LBE was also determined. RESULTS: RA and salvianolic acid derivatives were the major compounds, but caffeic acid and luteolin glucuronide were also found in LBE. LBE and RA significantly increased the survival of human keratinocytes upon UVB radiation, but LBE showed a stronger effect. LBE significantly decreased UVB-induced intracellular ROS production. Moreover, LBE reduced UV-induced DNA damage and the DNA damage response (DDR), which were measured as DNA strand breaks in the comet assay and histone H2AX activation, respectively. Finally, LBE promoted melanogenesis in the cell model. CONCLUSIONS: These results suggest that LBE may be considered as a candidate for the development of oral/topical photoprotective ingredients against UVB-induced skin damage.

Permeability Study of Polyphenols Derived from a Phenolic-Enriched Hibiscus sabdariffa Extract by UHPLC-ESI-UHR-Qq-TOF-MS.

Previous findings on the capacity of Hibiscus sabdariffa (HS) polyphenols to ameliorate metabolic disturbances justify the necessity of studies oriented to find the potential metabolites responsible for such an effect. The present study examined the intestinal epithelial membrane permeability of polyphenols present in a phenolic-enriched Hibiscus sabdariffa extract (PEHS), free and encapsulated, using the Caco-2 cell line. Additionally, selected polyphenols (quercetin, quercetin-3-glucoside, quercetin-3-glucuronide, and N-feruloyltyramine) were also studied in the same absorption model. The powerful analytical platform used ultra-high-performance liquid chromatography coupled with ultra-high-resolution quadrupole time-of-flight mass spectrometry (UHPLC-ESI-UHR-Qq-TOF-MS), and enabled the characterization of seven new compounds in PEHS. In the permeation study, only a few compounds were able to cross the cell monolayer and the permeability was lower when the extract was in an encapsulated form. Pure compounds showed a moderate absorption in all cases. Nevertheless, these preliminary results may need further research to understand the complete absorption mechanism of Hibiscus polyphenols.

Lemon verbena (Lippia citriodora) polyphenols alleviate obesity-related disturbances in hypertrophic adipocytes through AMPK-dependent mechanisms.

BACKGROUND: There is growing evidence that natural products, mostly plant-derived polyphenols, are important in the relationship between nutrients and health in humans. PURPOSE: We aimed to investigate if verbascoside (VB) and other lemon verbena polyphenols could ameliorate obesity-induced metabolic disturbances, as well as their putative mechanism. STUDY DESIGN: We used an insulin-resistant hypertrophic 3T3-L1-adipocyte model to test the effects of VB or lemon verbena extract on triglyceride accumulation, inflammation and oxidative stress and a murine model of diet-induced obesity to assess the in vivo metabolic response. RESULTS: Polyphenols decreased triglyceride accumulation, the generation of reactive oxygen species (ROS) and restored mitochondrial membrane potential in adipocytes. The underlying mechanisms seemed to occur via ROS-mediated downregulation of nuclear factor kappa-B transcription factor (NF-κB) and peroxisome proliferator-activated receptor gamma (PPAR-γ)-dependent transcriptional upregulation of adiponectin. We also observed a potent activation of AMP-activated protein kinase (AMPK), the mRNA expression upregulation of PPAR-α and the mRNA expression downregulation of fatty acid synthase. Experiments in mice suggested a significant improvement in fat metabolism. CONCLUSION: Decreased lipogenesis, enhanced fatty acid oxidation and the activation of the energy sensor AMPK, probably through activating transcriptional factors, are involved in the observed beneficial effects. VB effects were less potent than those observed with the extract, so a potential synergistic, multi-targeted action is proposed. The polypharmacological effects of plant-derived polyphenols from lemon verbena may have the potential for clinical applications in obesity.

Molecular promiscuity of plant polyphenols in the management of age-related diseases: far beyond their antioxidant properties.

The use of plant-derived polyphenols for the management of diseases has been under debate in the last decades. Most studies have focused on the specific effects of polyphenols on particular targets, while ignoring their pleiotropic character. The multitargeted character of polyphenols, a plausible consequence of their molecular promiscuity, may suppose an opportunity to fight multifactorial diseases. Therefore, a wider perspective is urgently needed to elucidate whether their rational use as bioactive food components may be valid for the management of diseases. In this chapter, we discuss the most likely targets of polyphenols that may account for their salutary effects from a global perspective. Among these targets, the modulation of signalling and energy-sensitive pathways, oxidative stress and inflammation-related processes, mitochondrial functionality, epigenetic machinery, histone acetylation and membrane-dependent processes play central roles in polyphenols' mechanisms of action.Sufficient evidence on polyphenols has accumulated for them to be considered a serious option for the management of non-communicable diseases, such as cancer and obesity, as well as infectious diseases. The remaining unresolved issues that must be seriously addressed are their bioavailability, metabolite detection, specific molecular targets, interactions and toxicity. The Xenohormesis hypothesis, which postulates that polyphenols are the product of plant evolutive adaptation to stress and conferee their resistance to mammals, offers a reasonable explanation to justify the beneficial and non-toxic effects of plant mixtures, but do not fully meet expectations. Hence, future research must be supported by the use of complex polypharmacology approaches and synergic studies focused on the understanding of the pleiotropic effects of polyphenols. Revisiting polyphenol mechanisms of action with the help of these techniques may allow for the improvement of human health and wellness by using intelligent nutritional intervention.

Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: a new family of gerosuppressant agents.

Aging can be viewed as a quasi-programmed phenomenon driven by the overactivation of the nutrient-sensing mTOR gerogene. mTOR-driven aging can be triggered or accelerated by a decline or loss of responsiveness to activation of the energy-sensing protein AMPK, a critical gerosuppressor of mTOR. The occurrence of age-related diseases, therefore, reflects the synergistic interaction between our evolutionary path to sedentarism, which chronically increases a number of mTOR activating gero-promoters (e.g., food, growth factors, cytokines and insulin) and the "defective design" of central metabolic integrators such as mTOR and AMPK. Our laboratories at the Bioactive Food Component Platform in Spain have initiated a systematic approach to molecularly elucidate and clinically explore whether the "xenohormesis hypothesis," which states that stress-induced synthesis of plant polyphenols and many other phytochemicals provides an environmental chemical signature that upregulates stress-resistance pathways in plant consumers, can be explained in terms of the reactivity of the AMPK/mTOR-axis to so-called xenohormetins. Here, we explore the AMPK/mTOR-xenohormetic nature of complex polyphenols naturally present in extra virgin olive oil (EVOO), a pivotal component of the Mediterranean style diet that has been repeatedly associated with a reduction in age-related morbid conditions and longer life expectancy. Using crude EVOO phenolic extracts highly enriched in the secoiridoids oleuropein aglycon and decarboxymethyl oleuropein aglycon, we show for the first time that (1) the anticancer activity of EVOO secoiridoids is related to the activation of anti-aging/cellular stress-like gene signatures, including endoplasmic reticulum (ER) stress and the unfolded protein response, spermidine and polyamine metabolism, sirtuin-1 (SIRT1) and NRF2 signaling; (2) EVOO secoiridoids activate AMPK and suppress crucial genes involved in the Warburg effect and the self-renewal capacity of "immortal" cancer stem cells; (3) EVOO secoiridoids prevent age-related changes in the cell size, morphological heterogeneity, arrayed cell arrangement and senescence-associated ß-galactosidase staining of normal diploid human fibroblasts at the end of their proliferative lifespans. EVOO secoiridoids, which provide an effective defense against plant attack by herbivores and pathogens, are bona fide xenohormetins that are able to activate the gerosuppressor AMPK and trigger numerous resveratrol-like anti-aging transcriptomic signatures. As such, EVOO secoiridoids constitute a new family of plant-produced gerosuppressant agents that molecularly "repair" the aimless (and harmful) AMPK/mTOR-driven quasi-program that leads to aging and aging-related diseases, including cancer.

Bioavailability study of a polyphenol-enriched extract from Hibiscus sabdariffa in rats and associated antioxidant status.

The aqueous extracts of Hibiscus sabdariffa have been commonly used in folk medicine. Nevertheless, the compounds or metabolites responsible for its healthy effects have not yet been identified. The major metabolites present in rat plasma after acute ingestion of a polyphenol-enriched Hibiscus sabdariffa extract were characterized and quantified in order to study their bioavailability. The antioxidant status of the plasma samples was also measured through several complementary antioxidant techniques. High-performance liquid chromatography coupled to time-of-flight mass spectrometry (HPLC-ESI-TOF-MS) was used for the bioavailability study. The antioxidant status was measured by ferric reducing ability of plasma method, thiobarbituric acid reactive substances assay, and superoxide dismutase activity assay. Seventeen polyphenols and metabolites have been detected and quantified. Eleven of these compounds were metabolites. Although phenolic acids were found in plasma without any modification in their structures, most flavonols were found as quercetin or kaempferol glucuronide conjugates. Flavonol glucuronide conjugates, which show longer half-life elimination values, are proposed to contribute to the observed lipid peroxidation inhibitory activity in the cellular membranes. By contrast, phenolic acids appear to exert their antioxidant activity through ferric ion reduction and superoxide scavenging at shorter times. We propose that flavonol-conjugated forms (quercetin and kaempferol) may be the compounds responsible for the observed antioxidant effects and contribute to the healthy effects of H. sabdariffa polyphenolic extract.

Synergism of plant-derived polyphenols in adipogenesis: perspectives and implications.

Dietary polyphenols may exert their pharmacological effect via synergistic interactions with multiple targets. Putative effects of polyphenols in the management of obesity should be primarily evaluated in adipose tissue and consequently in well-documented cell model. We used Hibiscus sabdariffa (HS), a widely recognised medicinal plant, as a source of polyphenols with a number of salutary effects previously reported. We present here the full characterisation of bioactive components of HS aqueous extracts and document their effects in a model of adipogenesis from 3T3-L1 cells and in hypertrophic and insulin-resistant adipocytes. Aqueous extracts were up to 100 times more efficient in inhibiting triglyceride accumulation when devoid of fibre and polysaccharides. Significant differences were also observed in reactive oxygen species generation and adipokine secretion. We also found that, when polyphenols were fractionated and isolated, the benefits of the whole extract were greater than the sum of its parts, which indicated a previously unnoticed synergism. In conclusion, polyphenols have interactive and complementary effects, which suggest a possible application in the management of complex diseases and efforts to isolate individual components might be irrelevant for clinical medicine and/or human nutrition.