Effect of olive leaf phytochemicals on the anti-acetylcholinesterase, anti-cyclooxygenase-2 and ferric reducing antioxidant capacity.

In this study, the phytochemical profile of fifty olive leaves (OL) extracts from Spain, Italy, Greece, Portugal, and Morocco was characterized and their anti-cholinergic, anti-inflammatory, and antioxidant activities were evaluated. Luteolin-7-O-glucoside, isoharmnentin, and apigenin were involved in the acetylcholinesterase (AChE) inhibitory activity, while oleuropein and hydroxytyrosol showed noteworthy potential. Secoiridoids contributed to the cyclooxygenase-2 inhibitory activity and antioxidant capacity. Compounds such as oleuropein, ligstroside and luteolin-7-O-glucoside, may exert an important role in the ferric reducing antioxidant capacity. It should be also highlighted the role of hydroxytyrosol, hydroxycoumarins, and verbascoside concerning the antioxidant activity. This research provides valuable insights and confirms that specific compounds within OL extracts contribute to distinct anti-cholinergic, anti-inflammatory, and anti-oxidative effects.

Dietary antioxidants and lifespan: Relevance of environmental conditions, diet, and genotype of experimental models.

The rise of life expectancy in current societies is not accompanied, to date, by a similar increase in healthspan, which represents a great socio-economic problem. It has been suggested that aging can be manipulated and then, the onset of all age-associated chronic disorders can be delayed because these pathologies share age as primary underlying risk factor. One of the most extended ideas is that aging is consequence of the accumulation of molecular damage. According to the oxidative damage theory, antioxidants should slow down aging, extending lifespan and healthspan. The present review analyzes studies evaluating the effect of dietary antioxidants on lifespan of different aging models and discusses the evidence on favor of their antioxidant activity as anti-aging mechanisms. Moreover, possible causes for differences between the reported results are evaluated.

Involvement of redox signalling in tumour cell dormancy and metastasis.

Decades of research on oncogene-driven carcinogenesis and gene-expression regulatory networks only started to unveil the complexity of tumour cellular and molecular biology. This knowledge has been successfully implemented in the clinical practice to treat primary tumours. In contrast, much less progress has been made in the development of new therapies against metastasis, which are the main cause of cancer-related deaths. More recently, the role of epigenetic and microenviromental factors has been shown to play a key role in tumour progression. Free radicals are known to communicate the intracellular and extracellular compartments, acting as second messengers and exerting a decisive modulatory effect on tumour cell signalling. Depending on the cellular and molecular context, as well as the intracellular concentration of free radicals and the activation status of the antioxidant system of the cell, the signalling equilibrium can be tilted either towards tumour cell survival and progression or cell death. In this regard, recent advances in tumour cell biology and metastasis indicate that redox signalling is at the base of many cell-intrinsic and microenvironmental mechanisms that control disseminated tumour cell fate and metastasis. In this manuscript, we will review the current knowledge about redox signalling along the different phases of the metastatic cascade, including tumour cell dormancy, making emphasis on metabolism and the establishment of supportive microenvironmental connections, from a redox perspective.

Oxidative Stress Amelioration of Novel Peptides Extracted from Enzymatic Hydrolysates of Chinese Pecan Cake.

Pecan (Carya cathayensis) is an important economic crop, and its hydrolyzed peptides have been evidenced to reduce the effect of oxidative stress due to their antioxidant capacity. Hence, the protocols of ultrafiltration and gel filtration chromatography were established to obtain bioactive peptides from by-products of C. cathayensis (pecan cake). As measured by DPPH/ABTS radical scavenging, the peptides with less molecular weight (MW) possess higher antioxidant capacity. PCPH-III (MW < 3 kDa) presented higher radical scavenging capacity than PCPH-II (3 kDa < MW < 10 kDa) and PCPH-I (MW > 10 kDa) measured by DPPH (IC50: 111.0 µg/ mL) and measured by ABTs (IC50: 402.9 µg/mL). The secondary structure and amino acid composition varied by their MW, in which PCPH-II contained more α-helices (26.71%) and ß-sheets (36.96%), PCPH-III contained higher ratios of ß-turns (36.87%), while the composition of different secondary of PCPH-I was even 25 ± 5.76%. The variation trend of α-helix and random experienced slightly varied from PCPH-I to PCPH-II, while significantly decreased from PCPH-II to PCPH-III. The increasing antioxidant capacity is followed by the content of proline, and PCPH-III had the highest composition (8.03%). With regard to the six peptides identified by LC-MS/MS, two of them (VYGYADK and VLFSNY) showed stronger antioxidant capacity than others. In silico molecular docking demonstrated their combining abilities with a transcription factor Kelch-like ECH-associated protein 1 (Keap1) and speculated that they inhibit oxidative stress through activating the Keap1-Nrf2-ARE pathway. Meanwhile, increased activity of SOD and CAT­antioxidant markers­were found in H2O2-induced cells. The residue of tyrosine was demonstrated to contribute the most antioxidant capacity of VYGYADK and its position affected less. This study provided a novel peptide screening and by-product utilization process that can be applied in natural product developments.

Differences reported in the lifespan and aging of male Wistar rats maintained on diets containing fat with different fatty acid profiles (virgin olive, sunflower or fish oils) are not reflected by histopathological lesions found at death in central nervous and endocrine systems.

The present study was designed to examine if dietary fat sources that have shown differences in lifespan and if some aging-related aspects can modulate the range of histopathologic changes in central nervous and endocrine systems that occur during the lifespan of Wistar rats. Moreover, it was attempted to gain insight into the relationship between longevity and the development of the different pathological changes, as well as possible interaction with diet. In order to achieve this, male Wistar rats were randomly assigned to three experimental groups fed semisynthetic and isoenergetic diets from weaning until death with different dietary fat sources, namely virgin olive, sunflower, or fish oil. An individual follow-up until death of each animal was performed. Incidence, severity, and burden of specific or group (i.e., neoplastic or non-neoplastic proliferative and non-proliferative) of lesions was calculated along with individual's disease and individual organ lesion burden. Most of the histopathological lesions found have been described in previous studies. Neoplasms, and in particular pituitary adenomas followed by brain tumors, were the most prevalent lesions found in the rats and the main cause of death involving both systems. Incidence of brain lesions was associated with age-at-death. Assayed dietary fats did not present differential effects on pathological changes occurring in endocrine and central nervous systems throughout rat lifespan.

Differences in maternal and neonatal cardiometabolic markers and placenta status by foetal sex. The GESTAFIT project.

AIMS: To explore the differences in some maternal-neonatal metabolic markers and placenta status by foetal sex. METHODS: One hundred thirty-nine Caucasian pregnant women from the GESTAFIT project and their new-borns were included in the present cross-sectional study. Serum cardiometabolic markers (i.e. lipid and glycaemic profile and uric acid) were analysed at late pregnancy and at birth. In placenta, telomeres length, proportion of deleted mitochondrial-DNA and mitochondrial-DNA density, some minerals and interleukin 8, epidermal growth factor, fibroblast growth factor-2 and vascular endothelial growth factor were measured. The study was run between November 2015 and April 2018. RESULTS: Mothers carrying a male showed higher serum triglycerides than mothers carrying a female at late pregnancy (p < .05). Serum total and low-density lipoprotein cholesterol were greater in males' umbilical cord blood artery compared to females' new-borns (both, p < .05). Mothers of males and male new-borns presented higher uric acid than mothers of females and female new-borns at birth (p < .05). Female's placentas presented greater placental-newborn weight ratio, manganese content and fibroblast growth factor-2 (all, p ⩽ .05), and evidence of statistical significance in telomeres length, which were 17% longer (p = .076). CONCLUSION: Our findings show weak differences in some cardiometabolic and placental status markers by foetal sex. Notwithstanding, we observed a slightly more proatherogenic profile in both, mothers carrying males' foetuses and male new-borns. We also found lower serum uric acid and better placenta status in mothers carrying a female. These findings indicate that foetal sex might need to be considered for a more personalized follow-up of pregnancies.

Rosa x hybrida extracts with dual actions: Antiproliferative effects against tumour cells and inhibitor of Alzheimer disease.

Edible flowers are being used as a new ingredient in modern gastronomy. Recently, these products have also gained interest as an important source of phenolic compounds with potential for biomedical applications. The present work studied a methanolic extract of Rosa x hybrida in which 35 individual phenolic compounds were identified. The extract has been evaluated for its antiproliferative properties in ovarian carcinoma cells. Results showed that the antiproliferative effect was associated with the induction of autophagy and apoptosis with the concomitant ROS increase probably related to mitochondria dysfunction. These antiproliferative effects might be associated with some components of the extract such as quercetin. The extract did not induce damage in healthy cells and that it was able to improve the wound healing activity. The present study also evaluated the properties of the mentioned extract in vivo in C. elegans. Tests demonstrated a lack of toxicity in the worm model. Promising results have been obtained in transgenic strains of C. elegans that produce human beta amyloid peptide, suggesting the possible utility of the extract from the point of view of Alzheimer disease. Altogether, results suggest that Rosa x hybrida extracts could be a new tool for the development of functional foods.

The central role of mitochondria in the relationship between dietary lipids and cancer progression.

Evidence demonstrates the importance of lipid metabolism and signaling in cancer cell biology. De novo lipogenesis is an important source of lipids for cancer cells, but exogenous lipid uptake remains essential for many cancer cells. Dietary lipids can modify lipids present in tumor microenvironment affecting cancer cell metabolism. Clinical trials have shown that diets rich in polyunsaturated fatty acids (PUFA) can negatively affect tumor growth. However, certain n-6 PUFAs can also contribute to cancer progression. Identifying the molecular mechanisms through which lipids affect cancer progression will provide an opportunity for focused dietary interventions that could translate into the development of personalized diets for cancer control. However, the effective mechanisms of action of PUFAs have not been fully clarified yet. Mitochondria controls ATP generation, redox homeostasis, metabolic signaling, apoptotic pathways and many aspects of autophagy, and it has been recognized to play a key role in cancer. The purpose of this review is to summarize the current evidence linking dietary lipids effects on mitochondrial aspects with consequences for cancer progression and the molecular mechanisms that underlie this association.

Ultra-Small Iron Nanoparticles Target Mitochondria Inducing Autophagy, Acting on Mitochondrial DNA and Reducing Respiration.

The application of metallic nanoparticles (materials with size at least in one dimension ranging from 1 to 100 nm) as a new therapeutic tool will improve the diagnosis and treatment of diseases. The mitochondria could be a therapeutic target to treat pathologies whose origin lies in mitochondrial dysfunctions or whose progression is dependent on mitochondrial function. We aimed to study the subcellular distribution of 2-4 nm iron nanoparticles and its effect on mitochondrial DNA (mtDNA), mitochondrial function, and autophagy in colorectal cell lines (HT-29). Results showed that when cells were exposed to ultra-small iron nanoparticles, their subcellular fate was mainly mitochondria, affecting its respiratory and glycolytic parameters, inducing the migration of the cellular state towards quiescence, and promoting and triggering the autophagic process. These effects support the potential use of nanoparticles as therapeutic agents using mitochondria as a target for cancer and other treatments for mitochondria-dependent pathologies.

Role of flavonoids against adriamycin toxicity.

Doxorubicin (DOX), or adriamycin, is an anthracycline antineoplastic drug widely used in the chemotherapy of a large variety of cancers due to its potency and action spectrum. However, its use is limited by the toxicity on healthy cells and its acute and chronic side effects. One of the developed strategies to attenuate DOX toxicity is the combined therapy with bioactive compounds such as flavonoids. This review embraces the role of flavonoids on DOX treatment side effects. Protective properties of some flavonoidss against DOX toxicity have been investigated and observed mainly in heart but also in liver, kidney, brain, testis or bone marrow. Protective mechanisms involve reduction of oxidative stress by decrease of ROS levels and/or increase antioxidant defenses and interferences with autophagy, apoptosis and inflammation. Studies in cancer cells have reported that the anticancer activity of DOX was not compromised by the flavonoids. Moreover, some of them increased DOX efficiency as anti-cancer drug even in multidrug resistant cells.

Do nutrients and other bioactive molecules from foods have anything to say in the treatment against COVID-19?

The repositioning of therapeutic agents already approved by the regulatory agencies for the use of drugs is very interesting due to the immediacy of their use; similarly, the possibility of using molecules derived from foods, whether nutrients or not, is of great importance, also because of their immediate therapeutic applicability. Candidates for these natural therapies against COVID-19 should show certain effects, such as restoring mitochondrial function and cellular redox balance. This would allow reducing the susceptibility of risk groups and the cascade of events after SARS-CoV-2 infection, responsible for the clinical picture, triggered by the imbalance towards oxidation, inflammation, and cytokine storm. Possible strategies to follow through the use of substances of food origin would include: a) the promotion of mitophagy to remove dysfunctional mitochondria originating from free radicals, proton imbalance and virus evasion of the immune system; b) the administration of transition metals whose redox activity would lead to their own oxidation and the consequent generation of a reduced environment, which would normalize the oxidative state and the intracellular pH; c) the administration of molecules with demonstrated antioxidant capacity; d) the administration of compounds with anti-inflammatory and vasodilatory activity; e) the administration of immunomodulatory compounds.

Reductive Stress, Bioactive Compounds, Redox-Active Metals, and Dormant Tumor Cell Biology to Develop Redox-Based Tools for the Treatment of Cancer.

Significance: Cancer is related to redox biology from many points of view, such as initiation and promotion, metabolism and growth, invasion and metastasis, vascularization, or through the interaction with the immune system. In addition, this extremely complex relationship depends on the redox homeostasis of each cellular compartment, which might be used to fight cancer. Recent Advances: New ways of modulating specific and little explored aspects of redox biology have been revealed, as well as new delivery methods or uses of previously known treatments against cancer. Here, we review the latest experimental evidence regarding redox biology in cancer treatment and analyze its potential impact in the development of improved and more effective antineoplastic therapies. Critical Issues: A critical issue that deserves particular attention is the understanding that both extremes of redox biology (i.e., oxidative stress [OS] and reductive stress) might be useful or harmful in relation to cancer prevention and treatment. Future Directions: Additional research is needed to understand how to selectively induce reductive or OS adequately to avoid cancer proliferation or to induce cancer cell death.

Longevity and Cause of Death in Male Wistar Rats Fed Lifelong Diets Based on Virgin Olive Oil, Sunflower Oil, or Fish Oil.

Extending life by delaying the aging process has been proven to be the most effective way to fight multiple chronic diseases in elderly adults. Evidence suggests that longevity is inversely related to unsaturation of membrane phospholipids. This study investigated how different unsaturated dietary fats affect life span and cause of death in male Wistar rats fed diets based on virgin olive oil (V), sunflower oil (S), or fish oil (F), which were supplemented or not with Coenzyme Q10 (CoQ10). Previous results suggest that individual longevity and survival probability at different ages may be modulated by an appropriate dietary fat treatment. Lifelong feeding with V or F diets would reduce death probability compared to feeding with S diet at certain ages, although the effects of V diet would be maintained for most of life. Furthermore, the addition of lower amounts of CoQ10 reduced mortality associated with S diet, but CoQ10 had no effect on survival when combined with virgin olive oil or fish oil. Supplementation with low doses of CoQ10 failed to increase the maximum life span potential of rats fed a V or F diet. No clear evidence showing that monounsaturated fatty acids, n-3 polyunsaturated fatty acids, or CoQ10 exerted the observed effects by modulating the rate of aging has been found.

In vitro study of the protective effect of manganese against vanadium-mediated nuclear and mitochondrial DNA damage.

We aimed to study the effect of vanadium(V) exposure on cell viability, nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) and to elucidate if these effects can be reverted by co-exposure to V and manganese (Mn). HepG2 cells were incubated with various concentrations of bis(maltolato)oxovanadium(IV) or MnCl2 for 32 h for viability study. The higher concentrations (59   µM V, 54 nM Mn and 59   µM V+54 nM Mn) were used to study DNA damage and uptake of V and Mn. Comet assay was used for the study of nDNA damage; mtDNA damage was studied by determining deletions and number of copies of the ND1/ND4 mtDNA region. Cellular content of V and Mn was determined using ICPMS. Cellular exposure to 59   µM V decreased viability (14%) and damaged nDNA and mtDNA. This effect was partially prevented by the co-exposure to V + Mn. Exposure to V increased the cellular content of V and Mn (812.3% and 153.5%, respectively). Exposure to Mn decreased the content of V and Mn (62% and 56%, respectively). Exposure to V + Mn increased V (261%) and decreased Mn (56%) content. The positive effects on cell viability and DNA damage when incubated with V + Mn could be due to the Mn-mediated inhibition of V uptake.

Heart Histopathology and Mitochondrial Ultrastructure in Aged Rats Fed for 24 Months on Different Unsaturated Fats (Virgin Olive Oil, Sunflower Oil or Fish Oil) and Affected by Different Longevity.

Diet plays a decisive role in heart physiology, with lipids having especial importance in pathology prevention and development. This study aimed to investigate how dietary lipids varying in lipid profile (virgin olive oil, sunflower oil or fish oil) affected the heart of rats during aging. Heart histopathology, mitochondrial morphometry, and oxidative status were assessed. Typical histopathological features associated with aging, such as valvular lesions, endomyocardical hyperplasia, or papillary muscle calcification, were found at a low extent in all the experimental groups. The most relevant finding was that inflammation registered by fish oil group was lower compared to the other treatments. At the ultrastructural level, heart mitochondrial area, perimeter, and aspect ratio were higher in fish oil-fed rats than in those fed on sunflower oil. Concerning oxidative stress markers, there were differences only in coenzyme Q levels and catalase activity, lower in sunflower oil-fed animals compared with those fed on fish oil. In summary, dietary intake for a long period on dietary fats with different fatty acids profile led to differences in some aspects associated with the aging process at the heart. Fish oil seems to be the fat most protective of heart during aging.

An update on the mechanisms related to cell death and toxicity of doxorubicin and the protective role of nutrients.

Doxorubicin (DOX), is a very effective chemotherapeutic agent against cancer whose clinical use is limited by toxicity. Different strategies have been proposed to attenuate toxicity, including combined therapy with bioactive compounds. This review update mechanisms of action and toxicity of doxorubicin and the role of nutrients like vitamins (A, C, E), minerals (selenium) and n-3 polyunsaturated fatty acids. Protective activities against DOX toxicity in liver, kidney, skin, bone marrow, testicles or brain have been reported, but these have not been evaluated for all of the reviewed nutrients. In most cases oxidation-related effects were present either, by reducing ROS levels and/or increasing antioxidant defenses. Antiapoptotic and anti-inflammatory mechanisms are also commonly reported. In some cases, interferences with autophagy and calcium homeostasis also have shown to be affected. Notwithstanding, there is a wide variety in duration and doses of treatment tested for both, compounds and DOX, which make difficult to compare the results of the studies. In spite of the reduction of DOX cardiotoxicity in health models, DOX anti-cancer activity in cancer cell lines or xenograft models usually did not result compromised when this has been evaluated. Importantly, clinical studies are needed to confirm all the observed effects.

Industrial-Scale Decontamination Procedure Effects on the Content of Acaricides, Heavy Metals and Antioxidant Capacity of Beeswax.

Beeswax is useful for the beekeeping sector but also for the agro-food, pharmaceutical or cosmetics sectors. Frequently, this bee product is contaminated with pesticides reducing its utility and causing the decline in its market. This study aimed to prove the effectiveness of an industrial-scale decontamination method in removing acaricides from beeswax. Chlorfenvinphos and coumaphos decrease was higher than 90%, whereas tau fluvalinate decrease was only 30%. No changes were observed in the beeswax content of hydrocarbons and monoesters, whereas a decrease in the concentrations of Ca, Fe, Zn, Hg, Mn and P, and an increase in the concentrations of As and Si were found after the decontamination. Filtration reduced total phenolics, flavonoids and the antioxidant capacity of the lipophilic extract. These results demonstrate that the industrial method used was as effective as the method previously tested on a laboratory scale. The study also contributes to a better knowledge and characterization of beeswax, specially related to trace and ultra-trace elements and antioxidant capacity. Moreover, it offers the chance to further develop a method to effectively detect wax adulterations based on the chemical elements profile.

Autophagy in Human Health and Disease: Novel Therapeutic Opportunities.

SIGNIFICANCE: In eukaryotes, autophagy represents a highly evolutionary conserved process, through which macromolecules and cytoplasmic material are degraded into lysosomes and recycled for biosynthetic or energetic purposes. Dysfunction of the autophagic process has been associated with the onset and development of many human chronic pathologies, such as cardiovascular, metabolic, and neurodegenerative diseases as well as cancer. Recent Advances: Currently, comprehensive research is being carried out to discover new therapeutic agents that are able to modulate the autophagic process in vivo. Recent evidence has shown that a large number of natural bioactive compounds are involved in the regulation of autophagy by modulating several transcriptional factors and signaling pathways. CRITICAL ISSUES: Critical issues that deserve particular attention are the inadequate understanding of the complex role of autophagy in disease pathogenesis, the limited availability of therapeutic drugs, and the lack of clinical trials. In this context, the effects that natural bioactive compounds exert on autophagic modulation should be clearly highlighted, since they depend on the type and stage of the pathological conditions of diseases. FUTURE DIRECTIONS: Research efforts should now focus on understanding the survival-supporting and death-promoting roles of autophagy, how natural compounds interact exactly with the autophagic targets so as to induce or inhibit autophagy and on the evaluation of their pharmacological effects in a more in-depth and mechanistic way. In addition, clinical studies on autophagy-inducing natural products are strongly encouraged, also to highlight some fundamental aspects, such as the dose, the duration, and the possible synergistic action of these compounds with conventional therapy.

Relevance of functional foods in the Mediterranean diet: the role of olive oil, berries and honey in the prevention of cancer and cardiovascular diseases.

The traditional Mediterranean diet (MedDiet) is a well-known dietary pattern associated with longevity and improvement of life quality as it reduces the risk of the most common chronic pathologies, such as cancer and cardiovascular diseases (CVDs), that represent the principal cause of death worldwide. One of the most characteristic foods of MedDiet is olive oil, a very complex matrix, which constitutes the main source of fats and is used in the preparation of foods, both raw as an ingredient in recipes, and in cooking. Similarly, strawberries and raspberries are tasty and powerful foods which are commonly consumed in the Mediterranean area in fresh and processed forms and have attracted the scientific and consumer attention worldwide for their beneficial properties for human health. Besides olive oil and berries, honey has lately been introduced in the MedDiet thanks to its relevant nutritional, phytochemical and antioxidant profile. It is a sweet substance that has recently been classified as a functional food. The aim of this review is to present and discuss the recent evidence, obtained from in vitro, in vivo and epidemiological studies, on the potential roles exerted by these foods in the prevention and progression of different types of cancer and CVDs.

Targeting molecular pathways in cancer stem cells by natural bioactive compounds.

Cancer Stem Cells (CSCs) or Tumor-Initiating Cells (TICs) are a small sub-population of cells within the tumor, able to give chemio- and radio-resistance and cause the onset of metastasis and the presence of relapses; for these reasons, they are recently becoming a potential target for anticancer therapy. One of the main characteristics of these cells is the self-renewal through the capability of modulating different molecular signalling pathways, including Wnt/ß-Catenin, Sonic Hedgehog and Notch pathways. Natural bioactive compounds such as resveratrol, epigallocatechin, curcumin, quercetin, ellagic acid, anthocyanins and other compounds and extracts can have a direct or indirect effect on these molecular pathways, decreasing the pathological activities of CSCs. This review aims to report and summarize the in vitro and in vivo studies about the preventive, therapeutic and chemosensitizing effects of these natural bioactive compounds on CSCs deriving from different types of tumors.