In vivo evidences of the health-promoting properties of bioactive compounds obtained from olive by-products and their use as food ingredient.

Olea europaea L. is the source of virgin olive oil (VOO). During its extraction, a high amount of by-products (pomace, mill wastewaters, leaves, stones, and seeds) is originated, which possess an environmental problem. If the generation of waste cannot be prevented, its economic value must be recovered and its effects on the environment and climate change must be avoided or minimized. The bioactive compounds (e.g., phenols, pectins, peptides) of these by-product fractions are being investigated as nutraceutical due to the beneficial properties it might have. In this review, the aim is to summarize the in vivo studies carried out in animals and humans with bioactive compounds exclusively obtained from olive by-products, aiming to demonstrate the potential health benefits these products can exert, as well as to describe its use in the food industry as bioactive ingredient. Several food matrices have been fortified with olive by-products fractions, leading to an improvement of properties. Animal and human studies suggest the benefits of ingesting olive-derived products to promote health. However, the investigation until now is scarce and consequently, well-designed human studies are required in order to fully address and confirm the safety and health-promoting properties of olive oil by-products.

Lipoprotein Metabolism, Protein Aggregation, and Alzheimer's Disease: A Literature Review.

Alzheimer's disease (AD) is the most common form of dementia. The physiopathology of AD is well described by the presence of two neuropathological features: amyloid plaques and tau neurofibrillary tangles. In the last decade, neuroinflammation and cellular stress have gained importance as key factors in the development and pathology of AD. Chronic cellular stress occurs in degenerating neurons. Stress Granules (SGs) are nonmembranous organelles formed as a response to stress, with a protective role; however, SGs have been noted to turn into pathological and neurotoxic features when stress is chronic, and they are related to an increased tau aggregation. On the other hand, correct lipid metabolism is essential to good function of the brain; apolipoproteins are highly associated with risk of AD, and impaired cholesterol efflux and lipid transport are associated with an increased risk of AD. In this review, we provide an insight into the relationship between cellular stress, SGs, protein aggregation, and lipid metabolism in AD.

GPETAFLR, a peptide from Lupinus angustifolius L. prevents inflammation in microglial cells and confers neuroprotection in brain.

OBJECTIVES: Neuroinflammation is a complex inflammatory process in the central nervous system (CNS) where microglia may play a critical role. GPETAFLR is a peptide isolated from Lupinus angustifolius L. protein hydrolysates with functional activity in mononuclear phagocytes. However, it is unknown whether GPETAFLR has neuroprotective effects. METHODS: We analysed the potential anti-neuroinflammatory activity of GPETAFLR by using two different models of neuroinflammation: BV-2 microglial cells and mice with high-fat diet (HFD)-induced obesity. RESULTS: GPETAFLR hampered LPS-induced upregulation of pro-inflammatory and M1 marker genes in BV-2 cells. This effect was accompanied by an unchanged expression of anti-inflammatory IL-10 gene and by an increased expression of M2 marker genes. GPETAFLR also increased the transcriptional activity of M2 marker genes, while the microglia population remained unchanged in number and M1/M2 status in brain of mice with high-fat diet (HFD)-induced obesity. Furthermore, GPETAFLR counteracted HFD-induced downregulation of IL-10 and upregulation of pro-inflammatory markers in the mouse brain, both at gene and protein levels. DISCUSSION: This is the first report describing that a peptide from plant origin robustly restrained the pro-inflammatory activation of microglial cells in cultures and in brain. Our data suggest that GPETAFLR might be instrumental in maintaining CNS homeostasis by inhibiting neuroinflammation.

Nutraceutical Extract from Dulse (Palmaria palmata L.) Inhibits Primary Human Neutrophil Activation.

Palmaria palmata L. (Palmariaceae), commonly known as "dulse", is a red alga that grows on the northern coasts of the Atlantic and Pacific oceans, and is widely used as source of fiber and protein. Dulse is reported to contain anti-inflammatory and antioxidant compounds, albeit no study has investigated these effects in primary human neutrophils. Implication strategies to diminish neutrophil activation have the potential to prevent pathological states. We evaluated the ability of a phenolic dulse extract (DULEXT) to modulate the lipopolysaccharide (LPS)-mediated activation of primary human neutrophils. Intracellular reactive oxygen species (ROS) were measured by fluorescence analysis and nitric oxide (NO) production using the Griess reaction. Inflammatory enzymes and cytokines were detected by ELISA and RT-qPCR. The results show that DULEXT diminished the neutrophil activation related to the down-regulation of TLR4 mRNA expression, deceased gene expression and the LPS-induced release of the chemoattractant mediator IL-8 and the pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α. ROS, NO, and myeloperoxidase (MPO) were also depressed. The data indicated that DULEXT has the potential to disrupt the activation of human primary neutrophils and the derived inflammatory and prooxidant conditions, and suggest a new role for Palmaria palmata L. in the regulation of the pathogenesis of health disorders in which neutrophils play a key role, including atherosclerosis.

Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPARγ-Dependent Monocyte Differentiation and Function.

OBJECTIVE: Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) mediates inflammatory and potentially proatherogenic effects, whereas the role of intracellular NAMPT (iNAMPT), the rate limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD)+ generation, in atherogenesis is largely unknown. Here we investigated the effects of iNAMPT overexpression in leukocytes on inflammation and atherosclerosis. APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice with hematopoietic overexpression of human iNAMPT (iNAMPThi), on a western type diet, showed attenuated plaque burden with features of lesion stabilization. This anti-atherogenic effect was caused by improved resistance of macrophages to apoptosis by attenuated chemokine (C-C motif) receptor 2-dependent monocyte chemotaxis and by skewing macrophage polarization toward an anti-inflammatory M2 phenotype. The iNAMPThi phenotype was almost fully reversed by treatment with the NAMPT inhibitor FK866, indicating that iNAMPT catalytic activity is instrumental in the atheroprotection. Importantly, iNAMPT overexpression did not induce any increase in eNAMPT, and eNAMPT had no effect on chemokine (C-C motif) receptor 2 expression and promoted an inflammatory M1 phenotype in macrophages. The iNAMPT-mediated effects at least partly involved sirtuin 1-dependent molecular crosstalk of NAMPT and peroxisome proliferator-activated receptor γ. Finally, iNAMPT and peroxisome proliferator-activated receptor γ showed a strong correlation in human atherosclerotic, but not healthy arteries, hinting to a relevance of iNAMPT/peroxisome proliferator-activated receptor γ pathway also in human carotid atherosclerosis. CONCLUSIONS: This study highlights the functional dichotomy of intracellular versus extracellular NAMPT, and unveils a critical role for the iNAMPT-peroxisome proliferator-activated receptor γ axis in atherosclerosis.

Virgin olive oil and its phenol fraction modulate monocyte/macrophage functionality: a potential therapeutic strategy in the treatment of systemic lupus erythematosus.

Monocytes and macrophages are critical effectors and regulators of inflammation and innate immune response, which appear altered in different autoimmune diseases such as systemic lupus erythematosus (SLE). Recent studies suggested that virgin olive oil (VOO) and particularly its phenol compounds might possess preventive effects on different immune-inflammatory diseases, including SLE. Here, we evaluated the effects of VOO (and sunflower oil) on lipopolysaccharide (LPS)-activated peritoneal macrophages from a model of pristane-induced SLE in BALB/c mice, as well as those of the phenol fraction (PF) from VOO on the immune-inflammatory activity and plasticity in monocytes and monocyte-derived macrophages from healthy volunteers. The release of nitrite and inflammatory cytokines was lower in LPS-treated peritoneal macrophages from pristane-SLE mice fed the VOO diet when compared with the sunflower oil diet. PF from VOO similarly decreased the secretion of nitrite and inflammatory cytokines and expression of inducible nitric oxide, PPARγ and Toll-like receptor 4 in LPS-treated human monocytes. PF from VOO also prevented the deregulation of human monocyte subset distribution by LPS and blocked the genetic signature of M1 macrophages while favouring the phenotype of M2 macrophages upon canonical polarisation of naïve human macrophages. For the first time, our study provides several lines of in vivo and in vitro evidence that VOO and PF from VOO target and counteract inflammatory pathways in the monocyte-macrophage lineage of mice with pristane-induced SLE and of healthy subjects, which is a meaningful foundation for further development and application in preclinical and clinical use of PF from VOO in patients with SLE.

Ginger rhizome enhances the anti-inflammatory and anti-nociceptive effects of paracetamol in an experimental mouse model of fibromyalgia.

BACKGROUND: The dried rhizome of ginger has been widely used for more than 2500 years in folk medicine for the treatment of various diseases that involve inflammation or are caused by oxidative stress. AIMS: This study was designed to compare the anti-nociceptive and anti-inflammatory effect of dried powdered ginger rhizome (GR) and paracetamol (APAP) on an experimental mouse model of fibromyalgia syndrome (FMS) induced by intermittent cold stress (ICS). METHODS: Forty-eight female C57BL/6 J mice were used for the experiments. The animals were allocated in six groups (n = 8). Each group received one of the following treatments for 8 weeks: healthy control, ICS group, ICS + APAP (40 mg/Kg/day), ICS + GR (0.5%); ICS + GR (1%), and ICS + GR (0.5%) + APAP (40 mg/Kg/day). After treatment, symptoms of FMS were induced by intermittent cold stress (ICS). RESULTS AND CONCLUSIONS: GR consumption improved mechanical and thermal allodynia and mechanical hyperalgesia and improved behavioural changes related to cognitive disturbances, anxiety, and depression. In addition, GR also significantly decreased the inflammatory response of proinflammatory mediators such as NO, PGE2, TXB2, and IL-1ß in LPS-stimulated macrophages. The effects of APAP were significantly enhanced by co-administration with GR. These findings provide evidence that the daily consumption of GR enhances the anti-nociceptive effect of APAP in mice, improves other cognitive disturbances associated with chronic pain, and reduces the inflammatory state generated in an experimental FMS model.

Effects of immediate-release niacin and dietary fatty acids on acute insulin and lipid status in individuals with metabolic syndrome.

BACKGROUND: The nature of dietary fats profoundly affects postprandial hypertriglyceridemia and glucose homeostasis. Niacin is a potent lipid-lowering agent. However, limited data exist on postprandial triglycerides and glycemic control following co-administration of high-fat meals with a single dose of niacin in subjects with metabolic syndrome (MetS). The aim of the study was to explore whether a fat challenge containing predominantly saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) or MUFAs plus omega-3 long-chain polyunsaturated (LCPUFAs) fatty acids together with a single dose of immediate-release niacin have a relevant role in postprandial insulin and lipid status in subjects with MetS. RESULTS: In a randomized crossover within-subject design, 16 men with MetS were given a single dose of immediate-release niacin (2 g) and ∼15 cal kg-1 body weight meals containing either SFAs, MUFAs, MUFAs plus omega-3 LCPUFAs or no fat. At baseline and hourly over 6 h, plasma glucose, insulin, C-peptide, triglycerides, free fatty acids (FFAs), total cholesterol, and both high- and low-density lipoprotein cholesterol were assessed. Co-administered with niacin, high-fat meals significantly increased the postprandial concentrations of glucose, insulin, C-peptide, triglycerides, FFAs and postprandial indices of ß-cell function. However, postprandial indices of insulin sensitivity were significantly decreased. These effects were significantly attenuated with MUFAs or MUFAs plus omega-3 LCPUFAs when compared with SFAs. CONCLUSION: In the setting of niacin co-administration and compared to dietary SFAs, MUFAs limit the postprandial insulin, triglyceride and FFA excursions, and improve postprandial glucose homeostasis in MetS. © 2017 Society of Chemical Industry.

Membrane composition and dynamics: a target of bioactive virgin olive oil constituents.

The endogenous synthesis of lipids, which requires suitable dietary raw materials, is critical for the formation of membrane bilayers. In eukaryotic cells, phospholipids are the predominant membrane lipids and consist of hydrophobic acyl chains attached to a hydrophilic head group. The relative balance between saturated, monounsaturated, and polyunsaturated acyl chains is required for the organization and normal function of membranes. Virgin olive oil is the richest natural dietary source of the monounsaturated lipid oleic acid and is one of the key components of the healthy Mediterranean diet. Virgin olive oil also contains a unique constellation of many other lipophilic and amphipathic constituents whose health benefits are still being discovered. The focus of this review is the latest evidence regarding the impact of oleic acid and the minor constituents of virgin olive oil on the arrangement and behavior of lipid bilayers. We highlight the relevance of these interactions to the potential use of virgin olive oil in preserving the functional properties of membranes to maintain health and in modulating membrane functions that can be altered in several pathologies. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

Validation and additional support for an experimental animal model of fibromyalgia.

OBJECTIVES: In the current study, we have evaluated the intermittent cold stress (ICS) induction in mice, in order to validate and optimize its utility as a fibromyalgia-like model. METHODS: Twenty-four mice of 5-week old, female Swiss, weighing 18-22 g were used for the experiments. These mice were divided into three groups of eight animals per group [health control group (control), ICS group (ICS), and Gabapentin group (GBP)]. When in-vivo tests were completed, we proceeded to isolation and culture of peritoneal macrophages in order to determine the effects of the ICS on the release of proinflammatory mediators. RESULTS: The results showed that this model is suitable to induce mechanical allodynia, thermal allodynia, and hyperalgesia. It is also able to reproduce behavioral changes related to cognitive disturbances, anxiety, and depression. Besides, ICS model might increase the inflammatory response in LPS-macrophages stimulated from stressed mice. CONCLUSIONS: Our results show that ICS is a useful animal model to assess hypothesis about underlying mechanisms involved in the development of fibromyalgia as well as to evaluate possible future therapies.

Food-derived vesicles as immunomodulatory drivers: Current knowledge, gaps, and perspectives.

Extracellular vesicles (EVs) are lipid-bound membrane vesicles released from cells, containing active compounds, which can be found in different foods. In this review, the role of food-derived vesicles (FDVs) as immunomodulatory drivers is summarized, with a focus on sources, isolation techniques and yields, as well as bioavailability and potential health implications. In addition, gaps and perspectives detected in this research field have been highlighted. FDVs have been efficiently extracted from different sources, and differential ultracentrifugation seems to be the most adequate isolation technique, with yields ranging from 108 to 1014 EV particles/mL. Animal studies show promising results in how these FDVs might regulate different pathways related to inflammation. Further investigation on the production of stable components in a cost-effective way, as well as human studies demonstrating safety and health-promoting properties, since scarce information has been reported until now, in the context of modulating the immune system are needed.

Production, characterisation, and biological properties of Tenebrio molitor-derived oligopeptides.

Three protein hydrolysates from Tenebrio molitor were obtained by enzymatic hydrolysis employing two food-grade proteases (i.e. Alcalase and Flavourzyme), and a complete characterisation of their composition was done. The digestion-derived products were obtained using the INFOGEST protocol. In vitro antioxidant activity and anti-inflammatory activities were evaluated. Tenebrio molitor flour and the protein hydrolysates showed a high ability to scavenge the DPPH radical (EC50 values from 0.30 to 0.87 mg/mL). The hydrolysate obtained with a combination of the two food-grade proteases could decrease the gene expression of pro-inflammatory genes after being digested. Furthermore, the peptidome was fully determined for the first time for T. molitor hydrolysates and digests, and 40 peptides were selected based on their bioactivity to be evaluated by in silico tools, including prediction tools and molecular docking. These results provide new perspectives on the use of edible insects as sustainable and not nutritionally disadvantageous food for human consumption.

Edible insects as a source of biopeptides and their role in immunonutrition.

Many edible insect species are attracting the attention of the food industry and consumers in Western societies due to their high content and quality of protein, and consequently, the potential to be used as a more environmentally friendly dietary source could be beneficial for humans. On the other hand, prevention of inflammatory diseases using nutritional interventions is currently being proposed as a sustainable and cost-effective strategy to improve people's health. In this regard, finding bioactive compounds such as peptides with anti-inflammatory properties from sustainable sources (e.g., edible insects) is one area of particular interest, which might have a relevant role in immunonutrition. This review aims to summarize the recent literature on the discovery of immunomodulatory peptides through in vitro studies from edible insects, as well as to describe cell-based assays aiming to prove their bioactivity. On top of that, in vivo studies (i.e., animal and human), although scarce, have been mentioned in relation to the topic. In addition, the challenges and future perspectives related to edible-insect peptides and their role in immunonutrition are discussed. The amount of literature aiming to demonstrate the potential immunomodulatory activity of edible-insect peptides is scarce but promising. Different approaches have been employed, especially cell assays and animal studies employing insect meal as supplementation in the diet. Insects such as Tenebrio molitor or Gryllodes sigillatus are some of the most studied and have demonstrated to contain bioactive peptides. Further investigations, mostly with humans, are needed in order to clearly state that peptides from edible insects may contribute to the modulation of the immune system.

Mediterranean Diet Combined with Regular Aerobic Exercise and Hemp Protein Supplementation Modulates Plasma Circulating Amino Acids and Improves the Health Status of Overweight Individuals.

Plant protein is considered a sustainable health-promoting strategy to prevent metabolic syndrome. Lifestyle changes (including dietary patterns and exercise) have been demonstrated to exert an effect on human health by modulating the biochemical status in humans. The objective of this study was to assess whether supplementation with hemp protein within a Mediterranean diet context together with exercise could help to ameliorate the metabolic statuses of patients prone to developing metabolic syndrome. For this study, 23 patients followed with Mediterranean diet and engaged in aerobic exercise according to the WHO's recommendations, while also being supplemented with hemp protein, for 12 weeks. A comparison of anthropometric, biochemical, and mineral data as well as amino acid values was made between the start and the end of the study, with the subjects acting as their own control group. Statistical analyses included a paired t-test, Wilcoxon paired test, Pearson correlation coefficient, and Sparse Partial Least Squares Discriminant Analysis to evaluate significant differences and correlations among parameters. There were statistically significant changes in total cholesterol, HDL-C (+52.3%), LDL-C (-54.0%), and TAG levels (-49.8%), but not in glucose plasma levels. Following the intervention, plasma concentrations of some amino acids, including α-aminoadipic acid, phosphoethanolamine, and 1-metylhistidine, increased, whereas those of asparagine and alanine declined. Different correlations between amino acids and the other parameters evaluated were reported and discussed. A Mediterranean diet combined with regular aerobic exercise, together with protein supplementation, can highly improve the metabolic parameters and anthropometric parameters of subjects with obesity and impaired glucose levels, ameliorating their health status and likely delaying the development of metabolic syndrome.

Identification, characterization, and molecular docking of immunomodulatory oligopeptides from bioavailable hempseed protein hydrolysates.

Promoting dietary patterns in which the content of vegetables is higher than the current consumption of them is one of the strategies to achieve a sustainable food system while promoting health in humans. Hemp (Cannabis sativa L.) protein contains bioactive peptides that can be released via enzymatic hydrolysis. These peptides must reach the target organ in order to potentially exert bioactivity and regulate specific metabolic pathways. The peptides contained in two bioavailable hempseed protein hydrolysates (bioHPHs) showing anti-inflammatory activity were identified using a transwell system employing CACO-2 cell culture as absorption model and subjected to in silico analysis to select 10 unique peptides. These sequences were chemically synthetized to verify their activity in primary human monocytes (assessing gene expression of IL-1ß, IL-6, TNF-α, IL-4, IL-10, and TLR4), in addition to evaluate the interaction with TRL4/MD2 by molecular docking. Six peptides (DDNPRRF, SRRFHLA, RNIFKGF, VREPVFSF, QADIFNPR and SAERGFLY) showed high immunomodulatory activity in in vitro and the mechanisms of interaction with TLR4/MD2 were described. Bioavailable anti-inflammatory hempseed-derived peptides were identified, and their activity verified, suggesting the health benefits that the ingestion of HPHs could exert in humans. These findings open new opportunities for developing nutritional strategies with hemp as a dietary source of biopeptides to prevent the development and progression of inflammatory-related diseases.

Identification of the Bioavailable Peptidome of Chia Protein Hydrolysate and the In Silico Evaluation of Its Antioxidant and ACE Inhibitory Potential.

The incorporation of novel, functional, and sustainable foods in human diets is increasing because of their beneficial effects and environmental-friendly nature. Chia (Salvia hispanica L.) has proved to be a suitable source of bioactive peptides via enzymatic hydrolysis. These peptides could be responsible for modulating several physiological processes if able to reach the target organ. The bioavailable peptides contained in a hydrolysate obtained with Alcalase, as functional foods, were identified using a transwell system with Caco-2 cell culture as the absorption model. Furthermore, 20 unique peptides with a molecular weight lower than 1000 Da and the higher statistical significance of the peptide-precursor spectrum match (-10 log P) were assessed by in silico tools to suggest which peptides could be those exerting the demonstrated bioactivity. From the characterized peptides, considering the molecular features and the results obtained, the peptides AGDAHWTY, VDAHPIKAM, PNYHPNPR, and ALPPGAVHW are anticipated to be contributing to the antioxidant and/or ACE inhibitor activity of the chia protein hydrolysates.

Current Research on Antioxidant, Anti-Inflammatory and Anti-Obesity Potential of Food Extracts.

The immune-inflammatory, glucose homeostasis, and antioxidant response have a crucial role in the prevention of non-communicable chronic diseases, according to the World Health Organization (WHO) [...].

Nutritional composition and biological activity of narrow-leafed lupins (Lupinus angustifolius L.) hydrolysates and seeds.

Lupins are an interesting source of nutrients, part of the Fabaceae family. More specifically, narrow-leafed lupin (Lupinus angustifolius L.) is a legume, largely produced in Australia, which is used both for human food and animal fodder. There is a growing interest in plant proteins-derived products due to benefits for the ecosystem and lower production costs compared to traditional animal sources of protein. This review aimed to summarize major and minor chemical components in Lupinus angustifolius L., and potential health benefits of this plant and product thereof. In particular, the protein fraction of Lupinus and their biological properties are described. L. angustifolius seed and proteins by-products can be used as a valuable source of high value-added compounds for diverse food products with the goal to maximize its economic value.

Effects of Malnutrition on the Immune System and Infection and the Role of Nutritional Strategies Regarding Improvements in Children's Health Status: A Literature Review.

Malnutrition refers to a person's status as under- or overnourished, and it is usually associated with an inflammation status, which can subsequently imply a different health status, as the risk of infection is increased, along with a deterioration of the immune system. Children's immune systems are generally more susceptible to problems than adults. In the situation of malnutrition, because malnourished children's immune systems are compromised, they are more likely to die. However, little is known about the underlying mechanism of altered immune functioning and how it relates to starvation. Nutritional interventions have been reported as cost-effective strategies to prevent or treat the development of malnourishment, considering the link between food intake and health, especially in children, and also the susceptibility of this population to diseases and how their health status during childhood might affect their long-term physiological growth. The ingestion of specific nutrients (e.g., vitamins or oligoelements) has been reported to contribute to the proper functioning of children's immune systems. In this review, we aim to describe the basis of malnutrition and how this is linked to the immune system, considering the role of nutrients in the modulation of the immune system and the risk of infection that can occur in these situations in children, as well as to identify nutritional interventions to improve their health.

Mediterranean Diet and Melatonin: A Systematic Review.

The Mediterranean diet (MD) has beneficial effects on human health, which is evidenced by the observation of lower incidence rates of chronic diseases in Mediterranean countries. The MD dietary pattern is rich in antioxidants, such as melatonin, which is a hormone produced mainly by the pineal gland and controls several circadian rhythms. Additionally, melatonin is found in foods, such as fruit and vegetables. The purpose of this systematic review was to assess the melatonin content in Mediterranean foods and to evaluate the influence of the MD on melatonin levels in both humans and model organisms. A comprehensive search was conducted in four databases (PubMed, Scopus, Cochrane Library and Web of Science) and data were extracted. A total of 31 records were chosen. MD-related foods, such as tomatoes, olive oil, red wine, beer, nuts, and vegetables, showed high melatonin contents. The consumption of specific MD foods increases melatonin levels and improves the antioxidant status in plasma.