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Numerous studies support the protective role of bioactive peptides against cardiovascular diseases. Cereals represent the primary source of carbohydrates, but they also contain substantial amounts of proteins, therefore representing a potential dietary source of bioactive peptides with nutraceutical activities. The analysis of wheat extracts purified by chromatographic techniques by means of HPLC-UV/nanoLC-nanoESI-QTOF allowed the identification of a signal of about 7 kDa which, following data base searches, was ascribed to a nonspecific lipid-transfer protein (nsLTP) type 2 from Triticum aestivum (sequence coverage of 92%). For the first time nsLTP2 biological activities have been investigated. In particular, in experiments with human umbilical vein endothelial cells (HUVEC), nsLTP2 displayed antioxidant and cytoprotective activities, being able to significantly decrease reactive oxygen species (ROS) levels and to reduce lactate dehydrogenase (LDH) release, generated following oxidative (hydrogen peroxide) and inflammatory (tumor necrosis factor α, interleukin-1β, and lipopolysaccharide) stimulation. The obtained promising results suggest potential protective role of nsLTP2 in vascular diseases prevention. PRACTICAL APPLICATION: nsLTP 2 peptide is resistant to proteases throughout the gastrointestinal tract and exerts antioxidant and cytoprotective activities. These characteristics could be exploited in vascular diseases prevention.

Preventing oxidative damage in the heart is subject of considerable investigation and studies developing nutritional intervention methods to attenuate or prevent the resulting pathological state of free radical damage are now emerging. In this light, a dietary intervention directed to increase the daily intake of antioxidant molecules represents a fundamental step to achieve a beneficial result. In this minireview the attention is focused on the damage induced in cultured cardiac cells by the antitumoral doxorubicin, known for its cardiotoxicity, and by hypoxia/reoxygenation that occur in a wide variety of important clinical conditions. The identification of antioxidant molecules having specific effectiveness in a particular cell type may be useful for the development of a prevention strategy specific for free radical induced-diseases related to that cell type. Although the connection between consumption of foods rich in polyphenolic compounds and the decreased risk of cardiovascular disease has been reported, the role of different antioxidant molecules contained in foods is still to be elucidated. The protective effect of the polyphenolic components of green tea in the prevention/counteraction of cell damage induced in the heart by doxorubicin or hypoxia/reoxygenation has been discussed.

In recent years many new dietetics regimens have been proposed with the purpose of helping athletes to improve their performance. The elite athlete is, in fact, the individual that more easily accepts undergoing even the most extravagant of diets in the hopes of improving performance. Unfortunately, a complicating aspect of the field of nutrition is that regimens which could find valid application in very active individuals, such as professional athletes, are often also adopted by the general population. Sedentary or moderately active people who’s desire is not to improve an athletic performance, often follow these dietetic regimens simply to loose weight and/or to reach or maintain a good health status. In the vast spectrum of dietetic regimens followed both by sport enthusiasts and by the general population, high protein-low carbohydrate diets have the most followers. The scarcity of data addressing the health effects of these popular diets is an important public health concern, especially since sedentary people are interested in using them as individualized eating strategies. The aim of this mini-review is to provide a critical evaluation of these dietetic regimens both for highly active subjects (e.g., athletes) and for sedentary or moderately active subjects.

We read with interest the paper published in the journal by Benvenga S, et al. about the complex interplay between thyroid disorders and the intake of omega-3 polyunsaturated fatty acids (PUFAs), whose main dietary source is represented by fish. In their review, Benvenga et al. put a specific warning on the potential heavy metal content in fish and the risks deriving from its consumption, suggesting that there would be the place for the use of nutraceuticals containing omega-3 PUFAs to prevent or contrast autoimmune thyroiditis, overcoming the risk of contaminants in fish. Although pharmacological supplementation would be sometimes useful, also limiting dietary consumption to fishes containing low levels of pollutants and including fish within the framework of a healthy diet represent a good choice.

Aging is a multifactorial phenomenon characterized by degenerative processes closely connected to oxidative damage and chronic inflammation. Recently, many studies have shown that natural bioactive compounds are useful in delaying the aging process. In this work, we studied the effects of an in vivo supplementation of the stilbenoid pterostilbene on lifespan extension in Drosophila melanogaster. We found that the average lifespan of flies of both sexes was increased by pterostilbene supplementation with a higher effect in females. The expression of longevity related genes (Sir2, Foxo, and Notch) was increased in both sexes but with different patterns. Pterostilbene counteracted oxidative stress induced by ethanol and paraquat and up-regulated the antioxidant enzymes Ho e Trxr-1 in male but not in female flies. On the other hand, pterostilbene decreased the inflammatory mediators dome and egr only in female flies. Proteomic analysis revealed that pterostilbene modulates 113 proteins in male flies and only 9 in females. Only one of these proteins was modulated by pterostilbene in both sexes: vacuolar H[+] ATPase 68 kDa subunit 2 (Vha68-2) that was strongly down-regulated. These findings suggest a potential role of pterostilbene in increasing lifespan both in male and female flies by mechanisms that seem to be different in the two sexes, highlighting the need to conduct nutraceutical supplementation studies on males and females separately in order to give more reliable results.

Although it is clearly established that the abuse of alcohol is seriously harmful to health, much epidemiological and clinical evidence seem to underline the protective role of moderate quantities of alcohol and in particular of wine on health. This narrative review aims to re-evaluate the relationship between the type and dose of alcoholic drink and reduced or increased risk of various diseases, in the light of the most current scientific evidence. In particular, in vitro studies on the modulation of biochemical pathways and gene expression of wine bioactive components were evaluated. Twenty-four studies were selected after PubMed, Scopus and Google Scholar searches for the evaluation of moderate alcohol/wine consumption and health effects: eight studies concerned cardiovascular diseases, three concerned type 2 diabetes, four concerned neurodegenerative diseases, five concerned cancer and four were related to longevity. A brief discussion on viticultural and enological practices potentially affecting the content of bioactive components in wine is included. The analysis clearly indicates that wine differs from other alcoholic beverages and its moderate consumption not only does not increase the risk of chronic degenerative diseases but is also associated with health benefits particularly when included in a Mediterranean diet model. Obviously, every effort must be made to promote behavioral education to prevent abuse, especially among young people.

Colorectal cancer (CRC) ranks as the second among the causes of tumor death worldwide, with an estimation of 1.9 million new cases in 2020 and more than 900,000 deaths. This rate might increase by 60% over the next 10 years. These data are unacceptable considering that CRC could be successfully treated if diagnosed in the early stages. A high-fat diet promotes the hepatic synthesis of bile acids (BAs) increasing their delivery to the colonic lumen and numerous scientific reports correlate BAs, especially secondary BAs, with CRC incidence. We reviewed the physicochemical and biological characteristics of BAs, focusing on the major pathways involved in CRC risk and progression. We specifically pointed out the role of BAs as signaling molecules and the tangled relationships among their nuclear and membrane receptors with the big bang of molecular and cellular events that trigger CRC occurrence.

The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 mu M), confirming the design rationale.

Neurodegenerative diseases, characterized by progressive loss in selected areas of the nervous system, are becoming increasingly prevalent worldwide due to an aging population. Despite their diverse clinical manifestations, neurodegenerative diseases are multifactorial disorders with standard features and mechanisms such as abnormal protein aggregation, mitochondrial dysfunction, oxidative stress and inflammation. As there are no effective treatments to counteract neurodegenerative diseases, increasing interest has been directed to the potential neuroprotective activities of plant-derived compounds found abundantly in food and in agrifood by-products. Food waste has an extremely negative impact on the environment, and recycling is needed to promote their disposal and overcome this problem. Many studies have been carried out to develop green and effective strategies to extract bioactive compounds from food by-products, such as peel, leaves, seeds, bran, kernel, pomace, and oil cake, and to investigate their biological activity. In this review, we focused on the potential neuroprotective activity of agrifood wastes obtained by common products widely produced and consumed in Italy, such as grapes, coffee, tomatoes, olives, chestnuts, onions, apples, and pomegranates.

Endothelial damage is recognized as the initial step that precedes several cardiovascular diseases (CVD), such as atherosclerosis, hypertension, and coronary artery disease. It has been demonstrated that the best treatment for CVD is prevention, and, in the frame of a healthy lifestyle, the consumption of vegetables, rich in bioactive molecules, appears effective at reducing the risk of CVD. In this context, the large amount of agri-food industry waste, considered a global problem due to its environmental and economic impact, represents an unexplored source of bioactive compounds. This review provides a summary regarding the possible exploitation of waste or by-products derived by the processing of three traditional Italian crops—apple, pear, and sugar beet—as a source of bioactive molecules to protect endothelial function. Particular attention has been given to the bioactive chemical profile of these pomaces and their efficacy in various pathological conditions related to endothelial dysfunction. The waste matrices of apple, pear, and sugar beet crops can represent promising starting material for producing “upcycled” products with functional applications, such as the prevention of endothelial dysfunction linked to cardiovascular diseases.

Introduction: Oxidative stress has been proposed as one of the factors concurring in the pathophysiology of autoimmune thyroid diseases. Reactive oxygen species are the main expression of oxidative stress in biological systems, and their production can overcome antioxidant defenses ultimately leading to cell damage, apoptosis, and death. The present review was aimed at describing the state of the art of the relationships between oxidative stress and autoimmune thyroiditis. The most used biomarkers of oxidative stress and their correlation with thyroid function are reported. Evidence acquisition: We conducted a search of the literature in the English language starting from 2000, using the following search terms: "Hashimoto thyroiditis," "autoimmune thyroiditis," "hypothyroidism," "hyperthyroidism," "oxidative stress," "oxidants," "antioxidant," "advanced glycation end products." Both clinical studies and animal models were evaluated. Evidence synthesis: Data form clinical studies clearly indicate that the balance between oxidants and antioxidants is shifted towards the oxidative side in patients with autoimmune thyroiditis, suggesting that oxidative stress may be a key event in the pathophysiology of the disease, irrespective of thyroid function. Studies in animal models, such as the NOD.H2h4 mouse, confirm that thyroidal accumulation of ROS plays a role in the initiation and progression of autoimmune thyroiditis. Conclusions: Oxidant/antioxidant imbalance represent a key feature of thyroid autoimmunity. Oxidative stress parameters could be used as biochemical markers of chronic inflammation, to better predict the disease evolution along its natural history. Dietary habits and antioxidant supplements may provide protection from autoimmunity, opening new perspectives in the development of more tailored therapies.

It's a frightening time due to COVID-19, but the great elderly/centenarians, apparently with more frailty, seem to have a better response to the pandemic. “The South Italy” lifestyle seems an “effective strategy” promoting the well-being embedded in a holistic solution: healthy diet, less exposure to PM10 pollution, protected environment, and moderate physical activity. The European FP7 Project RISTOMED results, since 2010, have shown that dietary intervention improved a heathy status in the elderly people. Based on the RISTOMED results, in addition to sociocultural and environmental factors, the authors suggest an integrated approach for resilience to COVID-19. Such an approach during the next months could make the difference for the success of any government progress policy to fight COVID-19, finalizing long-term well-being and successful aging.

This study was carried out to characterize extracts from nine samples of the apple 'Mela Rosa dei Monti Sibillini' (MR) and to assess the antioxidant and anti-inflammatory activities. The extracts were analysed by High Performance Liquid Chromatography coupled with photodiode array detector and mass spectrometry (HPLC-DAD-MS) for 20 phytochemicals. The extracts from the lyophilized material (ELM) were richer in polyphenolic compounds than the dried ones (EDM). The MR extracts contained noteworthy amounts of the investigated analytes compared to one sample of the commercial varieties Annurca, Golden Delicious and Granny Smith used as reference. Principal component analysis (PCA) revealed that the part of the fruit seems to have a significant influence on the chemical composition of the final extract; thus, the peel extracts exhibited higher levels of phenolic compounds, especially epicatechin, procyanidin B2 and phloridzin, and triterpenes than the pulp ones. In general, the lyophilized material showed higher antioxidant activity than the dried material. The strong antioxidant capacity of the MR has also been revealed by the DPPH, ABTS, FRAP and Folin-Ciocalteau assays. The ELM of MR significantly reduced reactive oxygen species in lipopolysaccharide (LPS)-activated mouse brain microglia cells (BV-2 cells). Real-time polymerase chain reaction (RT-PCR) analysis demonstrated that the EDM and ELM of MR were effective in reducing pro-inflammatory cytokines and enzymes in BV-2 and peripheral blood mononuclear cells (PBMC). These results contribute to the exploitation of this ancient variety as a source of nutraceuticals.

The research of value-added applications for coffee silverskin (CSS) requires studies to investigate potential bioactive compounds and biological activities in CSS extracts. In this study, different ultrasound‐assisted extraction (UAE) methods have been tested to extract bioactive compounds from CSS. The obtained extracts, were characterized using a new HPLC-MS/MS method to detect and quantify 30 bioactive compounds of 2 classes: alkaloids and polyphenols (including phenolic acids, flavonoids, and secoiridoids). CSS extracts obtained with ethanol/water (70:30) as extraction solvent showed the highest levels (p ≤ 0.05) of bioactive compounds (4.01 ± 0.34% w/w). High content of caffeine was observed with levels varying from 1.00% to 3.59% of dry weight of extract (dw). 18 phenolic compounds were detected in CSS extracts with caffeoylquinic acids (3-CQA, 5-CQA and 3,5-diCQA) as the most abundant polyphenols (3115.6 µg g to –5444.0 µg g−1). This study is also one of the first to characterize in-depth flavonoids in CSS revealing the levels of different flavonoids compounds such as rutin (1.63–8.70 µg g−1), quercetin (1.53–2.46 µg g−1), kaempferol (0.76–1.66 µg g−1) and quercitrin (0.15–0.51 µg g−1). Neuroprotective activity of silverskin extracts against H2O2-induced damage was evaluated for the first time suggesting for methanol and ethanol/water (70:30) extracts a potential role as protective agents against neurodegeneration due to their ability to counteract oxidative stress and maintain cell viability. Silverskin extracts were not inhibiting the growth of anyone of the bacterial species included in this study but data obtained by water extract might deserve a deeper future investigation on biofilm-related activities, such as quorum sensing or virulence factors’ expression. From their composition and their evidenced biological activities, CSS extracts could represent valuable ingredients in nutraceutical formulations.

Background Chemoprevention represents the possibility to prevent, stop or reverse the cancerogenetic process. In this context the interest towards natural extracts and botanical drugs has constantly grown due to their phytochemical content. Castanea sativa Mill. (CSM) extracts showed to exert positive effect in the prevention/counteraction of chronic/degenerative diseases, therefore, we evaluated the potential chemopreventive effect of CSM bark extract. Methods Flow cytometry (FCM) analyses of Jurkat cells treated with CSM bark extract (0–500 μg·mL−1) for 24–72 h allowed evaluating its cytotoxicity and ability to induce apoptosis through the intrinsic or extrinsic pathways. Moreover, to evaluate CSM bark extract selectivity towards cancer cells, its cytotoxic and pro-apoptotic effect was also evaluated in human peripheral blood lymphocytes (PBL). Results CSM bark extract induced apoptosis in Jurkat cells in a dose- and time- dependent manner activating the extrinsic pathways as evidenced by the increase of activated caspase-8 positive cells. Moreover, IC50 calculated after 24 h treatment resulted 304 and 128 μg·mL−1 in PBL and Jurkat cells respectively. Conclusions Our data suggest that CSM bark extract might be considered an interesting potential anti-cancer agent, since it induces apoptosis in cancer cells without appreciable cytotoxic effects on non-transformed cells. Electronic supplementary material The online version of this article (doi:10.1186/s12906-017-1756-6) contains supplementary material, which is available to authorized users.

Caveolae/lipid rafts are membrane-rich cholesterol domains endowed with several functions in signal transduction and caveolin-1 (Cav-1) has been reported to be implicated in regulating multiple cancer-associated processes, ranging from tumor growth to multidrug resistance and angiogenesis. Vascular endothelial growth factor receptor-2 (VEGFR-2) and Cav-1 are frequently colocalized, suggesting an important role played by this interaction on cancer cell survival and proliferation. Thus, our attention was directed to a leukemia cell line (B1647) that constitutively produces VEGF and expresses the tyrosine-kinase receptor VEGFR-2. We investigated the presence of VEGFR-2 in caveolae/lipid rafts, focusing on the correlation between reactive oxygen species (ROS) production and glucose transport modulation induced by VEGF, peculiar features of tumor proliferation. In order to better understand the involvement of VEGF/VEGFR-2 in the redox signal transduction, we evaluated the effect of different compounds able to inhibit VEGF interaction with its receptor by different mechanisms, corroborating the obtained results by immunoprecipitation and fluorescence techniques. Results here reported showed that, in B1647 leukemia cells, VEGFR-2 is present in caveolae through association with Cav-1, demonstrating that caveolae/lipid rafts act as platforms for negative modulation of VEGF redox signal transduction cascades leading to glucose uptake and cell proliferation, suggesting therefore novel potential targets.

Currently, the majority of cell-based studies on neurodegeneration are carried out on two-dimensional cultured cells that do not represent the cells residing in the complex microenvironment of the brain. Recent evidence has suggested that three-dimensional (3D) in vitro microenvironments may better model key features of brain tissues in order to study molecular mechanisms at the base of neurodegeneration. So far, no drugs have been discovered to prevent or halt the progression of neurodegenerative disorders. New therapeutic interventions can come from phytochemicals that have a broad spectrum of biological activities. On this basis, we evaluated the neuroprotective effect of three phytochemicals (sulforaphane, epigallocatechin gallate, and plumbagin) alone or in combination, focusing on their ability to counteract oxidative stress. The combined treatment was found to be more effective than the single treatments. In particular, the combined treatment increased cell viability and reduced glutathione (GSH) levels, upregulated antioxidant enzymes and insulin-degrading enzymes, and downregulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 and 2 in respect to peroxide-treated cells. Our data suggest that a combination of different phytochemicals could be more effective than a single compound in counteracting neurodegeneration, probably thanks to a pleiotropic mechanism of action.

Caffeic, syringic, and protocatechuic acids are phenolic acids derived directly from food intake or come from the gut metabolism of polyphenols. In this study, the antioxidant activity of these compounds was at first evaluated in membrane models, where caffeic acid behaved as a very effective chain-breaking antioxidant, whereas syringic and protocatechuic acids were only retardants of lipid peroxidation. However, all three compounds acted as good scavengers of reactive species in cultured cells subjected to exogenous oxidative stress produced by low level of H2O2. Many tumour cells are characterised by increased ROS levels compared with their noncancerous counterparts. Therefore, we investigated whether phenolic acids, at low concentrations, comparable to those present in human plasma, were able to decrease basal reactive species. Results show that phenolic acids reduced ROS in a leukaemia cell line (HEL), whereas no effect was observed in normal cells, such as HUVEC. The compounds exhibited no toxicity to normal cells while they decreased proliferation in leukaemia cells, inducing apoptosis. In the debate on optimal ROS-manipulating strategies in cancer therapy, our work in leukaemia cells supports the antioxidant ROS-depleting approach.

There is an increasing awareness that astrocytes, the most abundant cell type in the central nervous system, are critical mediators of brain homeostasis, playing multifunctional roles including buffering potassium ions, maintaining the blood-brain barrier, releasing growth factors, and regulating neurotransmitter levels. Defects in astrocyte function have been implicated in a variety of diseases including age-related diseases such Alzheimer's disease and Parkinson's disease. However, little is known about the age-related changes that occur in astrocytes and if these cells are able to generate a senescent phenotype in response to stress. In this report we have examined whether astrocytes can initiate a senescence program similar to that described in other cell types in response to a variety of stresses. Our results indicate that after oxidative stress, proteasome inhibition, or exhausted replication, human and mouse astrocytes show changes in several established markers of cellular senescence. Astrocytes appear to be more sensitive to oxidative stress than fibroblasts, suggesting that stress-induced senescence may be more pronounced in the brain than in other tissues.

Despite extensive studies, the fundamental mechanisms responsible for the development and progression of cardiovascular diseases have not yet been fully elucidated. Recent experimental and clinical studies have suggested that reactive oxygen species play a major pathological role. Oxidative stress reduction induced by flavonoids has been regarded by many as the most likely mechanism in the protective effects of these compounds; however, there is an emerging view that flavonoids may also exert modulatory actions on protein kinase and lipid kinase signaling pathways. Quercetin, a major flavonoid present in the human diet, has been widely studied, and its biological properties are consistent with its protective role in the cardiovascular system. However, it remains unknown whether the cardioprotective effects of quercetin may also occur through the modulation of genes involved in cell survival. The main goal of this study was to examine the gene expression profiling of cultured rat primary cardiomyocytes treated with quercetin using DNA microarrays and to relate these data to functional effects. Results showed distinct temporal changes in gene expression induced by quercetin and a strong upregulation of phase 2 enzymes, highlighting quercetin ability to act also with an indirect antioxidant mechanism.

In a single-dosing crossover study, we investigated the ability of apple fruit consumption to protect human lymphocytes against peroxide-induced damage to DNA. Six healthy, non-smoking male volunteers were placed for 2 d on an antioxidant-poor (AP) diet. After 48 h of AP diet, the volunteers were required to consume a homogenate obtained from 600 g of red delicious unpeeled apples or water (500 ml); blood samples were collected 0, 3, 6 and 24 h post-consumption. To evaluate whether the apple intake was sufficient to restore resistance of DNA to oxidative damage, for each subject at any time point the plasma total antioxidant activity, reactive oxygen species (ROS) formation and induction of micronuclei (MN) in isolated lymphocytes following hydrogen peroxide (H2O2) treatment were measured. Results indicated a significant inhibition (58 %, P 2O2-induced MN frequency in the plasma samples collected at 3 h after apple consumption, as compared with plasma samples collected at 0 h (4·17 (sd 1·83) v. 9·85 (sd 1·87) MN/1000 binucleated (BN) cells, respectively). A gradual return towards the value observed at 0 h was recorded starting from 6 to 24 h. MN frequency induced by H2O2 was significantly influenced by plasma total antioxidant activity (r = –0·95, P r = 0·88, P

Hypoxia/reoxygenation (H/R) is one of the causes of the increased expression of inducible nitric oxide synthase (iNOS) in cardiomyocytes. Since an aberrant NOS induction has detrimental consequences, we evaluated the effect of a green tea extract (GTE) on the NOS induction and activity in H/R-cardiomyocytes to define a nutritional strategy. Cultured rat cardiomyocytes were exposed to H/R in the presence of two concentrations of a green tea extract (GTE), which is reported to inhibit NOS expression and activity in different cells. In cultured cardiomyocytes two NOS isoforms were constitutively expressed, but only iNOS was induced by H/R. GTE supplementation at the lowest concentration, comparable to that in human plasma after dietary consumption, was ineffective, while the highest, comparable to that achievable by dietary supplements, counteracted the effect of H/R on iNOS induction and activity. It is necessary to verify in humans the relationship between the modulation of NO production and green tea dietary consumption.

OBJECTIVES: To assess the impact of a personalized diet, with or without addition of VSL#3 preparation, on biomarkers of inflammation, nutrition, oxidative stress and intestinal microbiota in 62 healthy persons aged 65-85 years. DESIGN: Open label, randomized, multicenter study. PRIMARY ENDPOINT: High-sensitivity C-reactive protein. SETTING: Community. INTERVENTIONS: Eight week web-based dietary advice (RISTOMED platform) alone or with supplementation of VSL#3 (2 capsules per day). The RISTOMED diet was optimized to reduce inflammation and oxidative stress. MEASUREMENTS: Blood and stool samples were collected on days 1 and 56. RESULTS: Diet alone reduced ESR (p = 0.02), plasma levels of cholesterol (p < 0.01) and glucose (p = 0.03). Addition of VSL#3 reduced ESR (p = 0.05) and improved folate (p = 0.007), vitamin B12 (p = 0.001) and homocysteine (p < 0.001) plasma levels. Neither intervention demonstrated any further effects on inflammation. Subgroup analysis showed 40 participants without signs of low-grade inflammation (hsCRP

In the last decade, the generation and the role of reactive oxygen species (ROS), particularly hydrogen peroxide, in cell signalling transduction pathways have been intensively studied, and it is now clear that an increase of ROS level affects cellular growth and proliferation pathways related to cancer development. Hydrogen peroxide (H2O2) has been long thought to permeate biological membranes by simple diffusion since recent evidence challenged this notion disclosing the role of aquaporin water channels (AQP) in mediating H2O2 transport across plasma membranes. We previously demonstrated that NAD(P)H oxidase (Nox)-generated ROS sustain glucose uptake and cellular proliferation in leukaemia cells. The aim of this study was to assess whether specific AQP isoforms can channel Nox-produced H2O2 across the plasma membrane of leukaemia cells affecting downstream pathways linked to cell proliferation. In this work, we demonstrate that AQP inhibition caused a decrease in intracellular ROS accumulation in leukaemia cells both when H2O2 was produced by Nox enzymes and when it was exogenously added. Furthermore, AQP8 overexpression or silencing resulted to modulate VEGF capacity of triggering an H2O2 intracellular level increase or decrease, respectively. Finally, we report that AQP8 is capable of increasing H2O2-induced phosphorylation of both PI3K and p38 MAPK and that AQP8 expression affected positively cell proliferation. Taken together, the results here reported indicate that AQP8 is able to modulate H2O2 transport through the plasma membrane affecting redox signalling linked to leukaemia cell proliferation.

Extracts fromStevia rebaudianaBertoni, a plant native to Central and South America, have been used as a sweetener since ancient times. Currently,Steviaextracts are largely used as a noncaloric high-potency biosweetener alternative to sugar, due to the growing incidence of type 2 diabetes mellitus, obesity, and metabolic disorders worldwide. Despite the large number of studies onSteviaand steviol glycosidesin vivo, little is reported concerning the cellular and molecular mechanisms underpinning the beneficial effects on human health. The effect of four commercialSteviaextracts on glucose transport activity was evaluated in HL-60 human leukaemia and in SH-SY5Y human neuroblastoma cells. The extracts were able to enhance glucose uptake in both cellular lines, as efficiently as insulin. Our data suggest that steviol glycosides could act by modulating GLUT translocation through the PI3K/Akt pathway since treatments with both insulin andSteviaextracts increased the phosphorylation of PI3K and Akt. Furthermore,Steviaextracts were able to revert the effect of the reduction of glucose uptake caused by methylglyoxal, an inhibitor of the insulin receptor/PI3K/Akt pathway. These results corroborate the hypothesis thatSteviaextracts could mimic insulin effects modulating PI3K/Akt pathway.

Parkin, a RING-between-RING-type E3 ubiquitin ligase associated with Parkinson's disease, has a wide neuroprotective activity, preventing cell death in various stress paradigms. We identified a stress-protective pathway regulated by parkin that links NF-kappa B signaling and mitochondrial integrity via linear ubiquitination. Under cellular stress, parkin is recruited to the linear ubiquitin assembly complex and increases linear ubiquitination of NF-kappa B essential modulator (NEMO), which is essential for canonical NF-kappa B signaling. As a result, the mitochondrial guanosine triphosphatase OPA1 is transcriptionally upregulated via NF-kappa B-responsive promoter elements for maintenance of mitochondrial integrity and protection from stress-induced cell death. Parkin-induced stress protection is lost in the absence of either NEMO or OPA1, but not in cells defective for the mitophagy pathway. Notably, in parkin-deficient cells linear ubiquitination of NEMO, activation of NF-kappa B, and upregulation of OPA1 are significantly reduced in response to TNF-alpha stimulation, supporting the physiological relevance of parkin in regulating this antiapoptotic pathway.

Estrogens play a protective role in coronary artery disease. The mechanisms of action are still poorly understood, although a role for estrogens in stimulation of angiogenesis has been suggested. In several cell types, estrogens modulate the Notch pathway, which is involved in controlling angiogenesis downstream of vascular endothelial growth factor A (VEGF-A). The goal of our study was to establish whether estrogens modulate Notch activity in endothelial cells and the possible consequences on angiogenesis. Human umbilical vein endothelial cells (HUVECs) were treated with 17β-estradiol (E2) and the effects on Notch signalling were evaluated. E2 increased Notch1 processing as indicated by i) decreased levels of Notch1 transmembrane subunit ii) increased amount of Notch1 in nuclei iii) unaffected level of mRNA. Similarly, E2 increased the levels of the active form of Notch4 without altering Notch4 mRNA. Conversely, protein and mRNA levels of Notch2 were both reduced suggesting transcriptional repression of Notch2 by E2. Under conditions where Notch was activated by upregulation of Delta-like ligand 4 (Dll4) following VEGF-A treatment, E2 caused a further increase of the active form of Notch1, of the number of cells with nuclear Notch1 and of Hey2 mRNA. Estrogen receptor antagonist ICI 182.780 antagonized these effects suggesting that E2 modulation of Notch1 is mediated by estrogen receptors. E2 treatment abolished the increase in endothelial cells sprouting caused by Notch inhibition in a tube formation assay on 3D Matrigel and in mouse aortic ring explants. In conclusion, E2 affects several Notch pathway components in HUVECs, leading to an activation of the VEGF-A-Dll4-Notch1 axis and to a modulation of vascular branching when Notch signalling is inhibited. These results contribute to our understanding of the molecular mechanisms of cardiovascular protection exerted by estrogens by uncovering a novel role of E2 in the Notch signalling-mediated modulation of angiogenesis.

Cardiovascular disease is a broad term used to describe a range of diseases that affect heart and blood vessels. While the term technically refers to any disease that affects the cardiovascular system such as infection, inflammation, vascular relaxation, platelet aggregation, hypertension, and cardiac hypertrophy, however, in developed countries, the main underlying problem is atherosclerosis. The major preventable risk factors for cardiovascular disease are tobacco smoking, high blood pressure, high blood cholesterol, insufficient physical activity, overweight and obesity, poor nutrition, and diabetes. Most cardiovascular diseases reflect chronic conditions that develop or persist over a long period of time. However, sometimes, the outcome of cardiovascular disease could be acute events such as heart attacks that occur suddenly when a vessel supplying blood to the heart becomes blocked. Many studies have investigated the role of quercetin in preventing cardiovascular disease, and interestingly, it has been shown that quercetin has multiple effects in counteracting the different diseases that affect heart and blood vessels.

Sulforaphane (SF), one of the most important isothiocyanates in the human diet, present in cruciferous vegetables, is known to have chemopreventive activities in different tissues. No data are available on its effects in the prevention of skeletal muscle damage. In this study, we investigated the potential protective effects of SF treatment on muscle damage and oxidative stress induced by an acute bout of exhaustive exercise in rats. Male Wistar rats were treated with SF (25 mg/kg body wt ip) for 3 days before undergoing an acute exhaustive exercise protocol in a treadmill (+7% slope and 24 m/min). Acute exercise resulted in a significant increase in plasma lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) activities. It also resulted in a significant increase in thiobarbituric acid-reactive substances, in a significant decrease in tissue total antioxidant capacity, and in a significant decrease in NAD(P)H:quinone oxidoreductase 1 (NQO1) expression and activity in vastus lateralis muscle. SF treatment significantly increased muscle NQO1, glutathione- S-transferase, and glutathione reductase expression and activity, with no effect on glutathione peroxidase and thioredoxin reductase. The observed SF-induced upregulation of phase II enzymes was accompanied by a significant increase in nuclear erythroid 2 p45-related factor 2 expression and correlated with a significant increase in total antioxidant capacity and a decrease in plasma LDH and CPK activities. Our data demonstrate that SF acts as an indirect antioxidant in skeletal muscle and could play a critical role in the modulation of the muscle redox environment, leading to the prevention of exhaustive exercise-induced muscle damage.

GLUT1 is the predominant glucose transporter in leukemia cells, and the modulation of glucose transport activity by cytokines, oncogenes or metabolic stresses is essential for their survival and proliferation. However, the molecular mechanisms allowing to control GLUT1 trafficking and degradation are still under debate. In this study we investigated whether plasma membrane cholesterol depletion plays a role in glucose transport activity in M07e cells, a human megakaryocytic leukemia line. To this purpose, the effect of cholesterol depletion by methyl-beta-cyclodextrin (MBCD) on both GLUT1 activity and trafficking was compared to that of the cytokine Stem Cell Factor (SCF). Results show that, like SCF, MBCD led to an increased glucose transport rate and caused a subcellular redistribution of GLUT1, recruiting intracellular transporter molecules to the plasma membrane. Due to the role of caveolae/lipid rafts in GLUT1 stimulation in response to many stimuli, we have also investigated the GLUT1 distribution along the fractions obtained after non ionic detergent treatment and density gradient centrifugation, which was only slightly changed upon MBCD treatment. The data suggest that MBCD exerts its action via a cholesterol-dependent mechanism that ultimately results in augmented GLUT1 translocation. Moreover, cholesterol depletion triggers GLUT1 translocation without the involvement of c-kit signalling pathway, in fact MBCD effect does not involve Akt and PLC&gamma phosphorylation. These data, together with the observation that the combined MBCD/SCF cell treatment caused an additive effect on glucose uptake, suggest that the action of SCF and MBCD may proceed through two distinct mechanisms, the former following a signalling pathway, and the latter possibly involving a novel cholesterol dependent mechanism.

Alzheimer’s disease (AD) is the most common cause of dementia, clinically characterized by loss of memory and progressive deficits in different cognitive domains. An emerging disease-modifying approach to face the multifactorial nature of AD may be represented by the development of Multi-Target Directed Ligands (MTDLs), i.e., single compounds which may simultaneously modulate different targets involved in the neurodegenerative AD cascade. The structure of tacrine, an acetylcholinesterase (AChE) inhibitor (AChEI), has been widely used as scaffold to provide new MTDLs. In particular, its homodimer bis(7)tacrine represents an interesting lead compound to design novel MTDLs. Thus, in the search of new rationally designed MTDLs against AD, we replaced the heptamethylene linker of bis(7)tacrine with the structure of cystamine, leading to cystamine-tacrine dimer. In this study we demonstrated that the cystamine-tacrine dimer is endowed with a lower toxicity in comparison to bis(7)tacrine, it is able to inhibit AChE, butyrylcholinesterase (BChE), self- and AChE-induced beta-amyloid aggregation in the same range of the reference compound and exerts a neuroprotective action on SH-SY5Y cell line against H2O2-induced oxidative injury. The investigation of the mechanism of neuroprotection showed that the cystamine-tacrine dimer acts by activating kinase 1 and 2 (ERK1/2) and Akt/protein kinase B (PKB) pathways. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.