The possible roles of food-derived bioactive peptides in reducing the risk of cardiovascular disease

Vascular diseases such as atherosclerosis, stroke or myocardial infarction are a significant public health problem worldwide. Attempts to prevent vascular diseases often imply modifications and improvement of causative risk factors such as high blood pressure, obesity, an unfavorable profile of blood lipids or insulin resistance. In addition to numerous preventive and therapeutic drug regimens, there has been increased focus on identifying dietary compounds that may contribute to cardiovascular health in recent years. Food-derived bioactive peptides represent one such source of health-enhancing components. They can be released during gastrointestinal digestion or food processing from a multitude of plant and animal proteins, especially milk, soy or fish proteins. Biologically active peptides are considered to promote diverse activities, including opiate-like, mineral binding, immunomodulatory, antimicrobial, antioxidant, antithrombotic, hypocholesterolemic and antihypertensive actions. By modulating and improving physiological functions, bioactive peptides may provide new therapeutic applications for the prevention or treatment of chronic diseases. As components of functional foods or nutraceuticals with certain health claims, bioactive peptides are of commercial interest as well. The current review centers on bioactive peptides with properties relevant to cardiovascular health.     

Medicinal halophytes: potent source of health promoting biomolecules with medical,nutraceutical and food applications

Salt-tolerant plants grow in a wide variety of saline habitats, from coastal regions, salt marshes and mudflats to inland deserts, salt flats and steppes. Halophytes living in these extreme environments have to deal with frequent changes in salinity level. This can be done by developing adaptive responses including the synthesis of several bioactive molecules. Consequently, several salt marsh plants have traditionally been used for medical, nutritional, and even artisanal purposes. Currently, an increasing interest is granted to these species because of their high content in bioactive compounds (primary and secondary metabolites) such as polyunsaturated fatty acids, carotenoids, vitamins, sterols, essential oils (terpenes), polysaccharides, glycosides, and phenolic compounds. These bioactive substances display potent antioxidant, antimicrobial, anti-inflammatory, and anti-tumoral activities, and therefore represent key-compounds in preventing various diseases (e.g. cancer, chronic inflammation, atherosclerosis and cardiovascular disorder) and ageing processes. The ongoing research will lead to the utilisation of halophytes as a new source of healthy products as functional foods, nutraceuticals or active principles in several industries. This contribution focuses on the ethnopharmacological uses of halophytes in traditional medicine and reviews recent investigations on their biological activities and nutraceuticals. The work is distributed according to the different families of nutraceuticals (lipids, vitamins, proteins, glycosides, phenolic compounds, etc.) discussing the analytical techniques employed for their determination. Information about the claimed health promoting effects of the different families of nutraceuticals is also provided together with data on their application.     

Nutritional interactions: credentialing of molecular targets for cancer prevention

Dietary behavior has been identified as one of the most important modifiable determinants of cancer risk. Which personalized modifications are needed remains an area of considerable controversy. Part of this uncertainty may arise from interactions among dietary bioactive compounds and/or food combinations. These interactions may either enhance or negate the response to specific foods. Evidence suggests that the cancer-protective effects of an individual's diet may reflect the combined effects of various vitamins, minerals, and other bioactive components such as flavonoids, isothiocyanates, and/or allium compounds rather than from the effect of a single ingredient. A better understanding of physiologically important interactions is needed to determine the merit of combining foods for maximum efficacy for cancer prevention. Furthermore, the response is complicated, since multiple cellular processes associated with carcinogenesis can be modified simultaneously, including sites such as drug metabolism, DNA repair, cell proliferation, apoptosis, inflammation, differentiation, and angiogenesis. Current evidence suggests that bioactive food components can typically influence more than one process. It is essential to have a better understanding of how the response relates to exposures and credentialing which process is most involved in bringing about a change in tumor incidence and/or tumor behavior. Credentialing is being defined as a determination of which cellular process(es) and which bioactive food components are most important for bringing about a phenotypic change. Additional attention is needed to determine the critical intake of dietary components, their duration, and when they should be provided to optimize the desired physiological response. Further research is also needed on the molecular targets for bioactive components and whether genetic and epigenetic events dictate the direction and magnitude of the response.     

A potential novel source of information for screening and monitoring the impact of exotic plants on ecosystems

Exotic invasive species often affect the pools and fluxes of carbon, nutrient elements, and energy, but there are few sources of information that permit these effects to be anticipated. Some plant traits, such as growth rates and tissue nutrient content, are known to influence the ecosystem process, but information about these traits is often not available. I propose that plant secondary chemistry may be a useful trait for assessing the likelihood of ecosystem (and community) impacts. Information about such traits is readily available from several sources, rendering it a good candidate for screening and monitoring programs. Plant secondary chemicals affect a variety of ecosystem processes, largely through their direct and indirect impacts on soil microbial community composition and function. They also have well-known effects on human physiology, as evidenced in the numerous plant-derived bioactive compounds used for their medicinal and other physiological effects. There is a large amount of information available about plant secondary chemistry due to its role in herbal medicine, dietary supplements and the emerging field of nutraceuticals. This information includes databases and traditional texts in ethnobotany, plant chemistry, and alternative medicine. I review evidence that secondary compounds are widespread in invasive species and affect soil microbial communities and microbially-mediated ecosystem processes. Invasion ecology may profit from collaborations with a novel group of scientists, including those in ethnobotany, nutraceuticals, plant chemistry and alternative medicine.     

A review of latest research findings on the health promotion properties of tea

Important progress has been made in the past five years concerning the effects of green and black tea on health. Experimentation with new accurate tools provide useful information about the metabolism of tea components in the body, their mode of action as antioxidants at the cellular level and their protective role in the development of cancer, cardiovascular disease and other pathologies. The use of tea components as nutraceuticals and functional foods are also discussed.     

Building microbial factories for the production of aromatic amino acid pathway derivatives: From commodity chemicals to plant-sourced natural products

The aromatic amino acid biosynthesis pathway, together with its downstream branches, represents one of the most commercially valuable biosynthetic pathways, producing a diverse range of complex molecules with many useful bioactive properties. Aromatic compounds are crucial components for major commercial segments, from polymers to foods, nutraceuticals, and pharmaceuticals, and the demand for such products has been projected to continue to increase at national and global levels. Compared to direct plant extraction and chemical synthesis, microbial production holds promise not only for much shorter cultivation periods and robustly higher yields, but also for enabling further derivatization to improve compound efficacy by tailoring new enzymatic steps. This review summarizes the biosynthetic pathways for a large repertoire of commercially valuable products that are derived from the aromatic amino acid biosynthesis pathway, and it highlights both generic strategies and specific solutions to overcome certain unique problems to enhance the productivities of microbial hosts.     

Nutraceuticals: facts and fiction

Epidemiological studies show a link between the consumption of plant-derived foods and a range of health benefits. These benefits have been associated, at least partially, to some of the phytochemical constituents, and, in particular, to polyphenols. In the last few years, nutraceuticals have appeared in the market. These are pharmaceutical forms (pills, powders, capsules, vials, etc.) containing food bioactive compounds as active principles. The bioactive phytochemicals have become a very significant source for nutraceutical ingredients. Scientific research supports the biological activity of many of these food phytochemicals, but the health claims attributed to the final marketed nutraceutical products have often little or doubtful scientific foundation. This is due to the fact that a lot of the scientific evidence is derived from animal testing and in vitro assays, whereas human clinical trials are scarce and inconclusive. Some key issues such as bioavailability, metabolism, dose/response and toxicity of these food bioactive compounds or the nutraceuticals themselves have not been well established yet. Amongst the phytochemicals, several groups of polyphenols (anthocyanins, proanthocyanidins, flavanones, isoflavones, resveratrol and ellagic acid) are currently used in the nutraceutical industry. In this report, we have reviewed the most recent scientific knowledge on the bioavailability and biological activity of these polyphenols ('fact'), as well as the health claims (which are not always supported by scientific studies) ascribed to the polyphenols-containing nutraceuticals ('fiction'). The in vitro antioxidant capacity, often used as a claim, can be irrelevant in terms of in vivo antioxidant effects. Bioavailability, metabolism, and tissue distribution of these polyphenols in humans are key factors that need to be clearly established in association to the biological effects of these polyphenols-containing nutraceuticals. The future trends of phytochemistry research regarding nutraceuticals are discussed.     

The Effects and Mechanisms of Flavonoids on Cancer Prevention and Therapy: Focus on Gut Microbiota

Flavonoids are a group of polyphenolic compounds which are ubiquitously found in plants and are consumed as part of the human diet in substantial amounts. The verification of flavonoids'' cancer chemopreventive benefits has led to a significant interest in this field. Gut microbiota includes a diverse community of microorganisms and has a close relationship with cancer development. Increasing evidence has indicated that flavonoids exert anticarcinogenic effects by reshaping gut microbiota. Gut microbiota can convert flavonoids into bioactive metabolites that possess anticancer activity. Here, we present a brief introduction to gut microbiota and provide an overview of the interplay between gut microbiota and cancer pathogenesis. We also highlight the crucial roles of flavonoids in preventing cancer based on their regulation of gut microbiota. This review would encourage research on the flavonoid-intestinal microbiota interactions and clinical trials to validate the chemotherapeutic potentials of targeting gut microbiota by dietary bioactive compounds.     

Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells

A high dietary intake of plant foods is thought to contribute to the prevention of colorectal cancers in humans and flavonoids as part of such a diet are considered to contribute to those protective effects. Quercetin is a major dietary flavonoid consumed with a diet rich in onions, tea, and apples. We used HT-29 human colon cancer cells and investigated the effects of quercetin on proliferation, apoptosis, and differentiation as processes shown to be disregulated during cancer development. To identify the cellular targets of quercetin action, two-dimensional gel electrophoresis was performed and proteins altered in expression level after quercetin exposure of cells were identified by mass spectrometry of peptide fragments generated by tryptic digestion. Quercetin inhibited the proliferation of HT-29 cells with an IC(50)-value of 81.2 +/- 6.6 microM. Cell differentiation based on surface expression of alkaline phosphatase was enhanced 4-fold and the activity of the pro-apoptotic effector caspase-3 increased 3-fold. Those effects were associated with the regulation of heat-shock proteins and annexins shown to both play a crucial role in the process of apoptosis. Cytoskeletal caspase substrates were found as regulated as well and various proteins involved in intermediary metabolism and in gene regulation showed altered steady-state expression levels upon quercetin treatment of cells. In conclusion, quercetin alters the levels of a variety of proteins involved in growth, differentiation, and apoptosis of colon cancer cells. Their identification as molecular targets of quercetin may explain the anti-cancer activities of this flavonoid.     

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases--a review

The modern approach to the development of new chemical entities against complex diseases, especially the neglected endemic diseases such as tuberculosis and malaria, is based on the use of defined molecular targets. Among the advantages, this approach allows (i) the search and identification of lead compounds with defined molecular mechanisms against a defined target (e.g. enzymes from defined pathways), (ii) the analysis of a great number of compounds with a favorable cost/benefit ratio, (iii) the development even in the initial stages of compounds with selective toxicity (the fundamental principle of chemotherapy), (iv) the evaluation of plant extracts as well as of pure substances. The current use of such technology, unfortunately, is concentrated in developed countries, especially in the big pharma. This fact contributes in a significant way to hamper the development of innovative new compounds to treat neglected diseases. The large biodiversity within the territory of Brazil puts the country in a strategic position to develop the rational and sustained exploration of new metabolites of therapeutic value. The extension of the country covers a wide range of climates, soil types, and altitudes, providing a unique set of selective pressures for the adaptation of plant life in these scenarios. Chemical diversity is also driven by these forces, in an attempt to best fit the plant communities to the particular abiotic stresses, fauna, and microbes that co-exist with them. Certain areas of vegetation (Amazonian Forest, Atlantic Forest, Araucaria Forest, Cerrado-Brazilian Savanna, and Caatinga) are rich in species and types of environments to be used to search for natural compounds active against tuberculosis, malaria, and chronic-degenerative diseases. The present review describes some strategies to search for natural compounds, whose choice can be based on ethnobotanical and chemotaxonomical studies, and screen for their ability to bind to immobilized drug targets and to inhibit their activities. Molecular cloning, gene knockout, protein expression and purification, N-terminal sequencing, and mass spectrometry are the methods of choice to provide homogeneous drug targets for immobilization by optimized chemical reactions. Plant extract preparations, fractionation of promising plant extracts, propagation protocols and definition of in planta studies to maximize product yield of plant species producing active compounds have to be performed to provide a continuing supply of bioactive materials. Chemical characterization of natural compounds, determination of mode of action by kinetics and other spectroscopic methods (MS, X-ray, NMR), as well as in vitro and in vivo biological assays, chemical derivatization, and structure-activity relationships have to be carried out to provide a thorough knowledge on which to base the search for natural compounds or their derivatives with biological activity.     

A review of fish-derived antioxidant and antimicrobial peptides: their production, assessment, and applications

Fishes are rich sources of structurally diverse bioactive compounds. In recent years, much attention has been paid to the existence of peptides with biological activities and proteins derived from foods that might have beneficial effects for humans. Antioxidant and antimicrobial peptides isolated from fish sources may be used as functional ingredients in food formulations to promote consumer health and improve the shelf life of food products. This paper presents an overview of the antioxidant and antimicrobial peptides derived from various fishes. In addition, we discuss the extraction of fish proteins, enzymatic production, and the techniques used to isolate and characterize these compounds. Furthermore, we review the methods used to assay the bioactivities and their applications in food and nutraceuticals.     

An integrated database of flavonoids

Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin. Some of these molecules exhibit various physiological activities. Among existing drugs, there are a huge number of compounds bearing a flavonoid-related skeleton. Because of the relevance for pharmaceutical research, it would be beneficial to collect these compounds into a database. Recently, various databases of chemicals were compiled to help biological and/or chemical research, but no comprehensive database of flavonoids with chemical structures and physicochemical parameters, supposedly related to their activity, is available yet. The aim of this research was to merge the information about flavonoids of plant origin and flavonoids used as medicines into a database. Moreover, predictions of activities against various targets were performed using a virtual screening procedure to demonstrate a possible application of the database for pharmaceutical research.     

The concept of endocrine disruption and human health

In Europe, endocrine disruptors (EDs) have been defined as substances foreign to the body that have deleterious effects on the individuals or their descendants, due to changes in endocrine function. In the United States, EDs have been described as exogenous agents that interfere with the production, release, transport, metabolism, binding, action or elimination of the natural ligands responsible for maintaining homeostasis and regulating body development. These two definitions are complementary, but both indicate that the effects induced by EDs probably involve mechanisms relating in some way to hormonal homeostasis and action. EDs are generally described as substances with anti-oestrogenic, oestrogenic, anti-androgenic or androgenic effects. More recently, other targets have been evidenced such as the thyroid and immune system. Many different EDs are present in the various compartments of the environment (air, water and land) and in foods (of plant and animal origin). They may originate from food packaging, combustion products, plant health treatments, detergents and the chemical industry in general. In addition to the potential effects of these compounds on adults, the sensitivity of embryos and fetuses to many of the xenobiotic compounds likely to cross the placenta has raised considerable concern and led to major research efforts. With the exception of the clearly established links between diethylstilbestrol, reproductive health abnormalities and cancers, very little is known for certain about the effects of EDs on human health. Given the lack of available data, current concerns about the possible involvement of EDs in the increase in the incidence of breast cancer, and possibly of endometriosis and early puberty in girls, remain hypothetical. Conversely, the deterioration in male reproductive health is at the heart of preoccupations and progress in analyses of the relationship between EDs and human health. This literature review aims to describe the current state of knowledge about endocrine disruption, focusing in particular on the problem of food contaminants.     

Enhancement of mitochondrial biogenesis with polyphenols: combined effects of resveratrol and equol in human endothelial cells

Emerging evidence suggests that combinatorial action of numerous biologically active compounds may be a valuable source in a variety of therapeutic applications. Several nutraceuticals have demonstrated to augment the efficacy of pharmacological approaches or provide physiological benefit to improve age-related decline. Recently, the possibilities of anti-ageing interventions have multiplied also to ameliorate the mitochondrial alterations in ageing-associated diseases. In this report, we approached a novel treatment strategy by combining two bioactive dietary constituents (resveratrol and equol) to determine their effect on mitochondrial function. Taking into account that the biological activities of resveratrol and equol has been observed in a wide range of biological processes, they were selected to examine whether combining them would be more effective to modulate mitochondrial function. In HUVEC cells our results demonstrate that the co-administration of these natural products increased mitochondrial mass and mitochondrial DNA content. Additionally, combined use of both compounds increased SIRT1 enzymatic activity and induced mitochondrial biogenesis factors such as PGC1-α, TFAM and NRF-1. Therefore, identification of this novel synergism may provide a new perspective for future treatments aiming to modulate the mitochondrial activity with implications in maintaining endothelial function which is crucial in the regulation of immune response. Further studies to discover the molecular details of this crosstalk and to identify new combinations of active compounds affecting the mitochondrial function will be extremely beneficial to prevent mitochondrial decline.     

bioNMR-based identification of natural anti-Aβ compounds in Peucedanum ostruthium

The growing interest in medicinal plants for the identification of new bioactive compounds and the formulation of new nutraceuticals and drugs prompted us to develop a powerful experimental approach allowing the detailed metabolic profiling of complex plant extracts, the identification of ligands of macromolecular targets of biomedical relevance and a preliminary characterization of their biological activity. To this end, we selected Peucedanum ostruthium, a plant traditionally employed in Austria and Italy for its several potential therapeutic applications, as case study. We combined the use of NMR and UPLC-HR-MS for the identification of the metabolites present in its leaves and rhizome extracts. Due to the significant content of polyphenols, particularly chlorogenic acids, recently identified as anti-amyloidogenic compounds, polyphenols-enriched fractions were prepared and tested for their ability to prevent Aβ1-42 peptide aggregation and neurotoxicity in a neuronal human cell line. STD-NMR experiments allowed the detailed identification of Aβ oligomers’ ligands responsible for the anti-amyloidogenic activity. These data provide experimental protocols and structural information suitable for the development of innovative molecular tools for prevention, therapy and diagnosis of Alzheimer’s disease.     

Triterpene glycosides and the structural-functional properties of membranes

Triterpene glycosides have been found in many plant species and some marine animals. Many of these compounds are physiologically active and possess a broad range of medico-biological action. The physiological activity of triterpene glycosides is based on their ability to interact with the components of biological systems, primarily with sterols comprising the structure of biomembranes. The interaction of glycosides with sterols causes disturbance of selective permeability in plasmic membranes. Triterpene glycosides affect the liposome ionic permeability and flat bilayer lipid membranes. The rate of glycoside effect depends on quantitative and qualitative sterol level in the membrane. These compounds are used by organisms in the struggle for life and in maintaining the biological equilibrium in the antagonistic interactions of biological systems and ensure plant immunity against fungal diseases. Triterpene glycosides as substances of exogenous origin exhibit physiological activity towards warm-blooded animals. They affect the metabolism, the functional state of the organs and the organism as a whole.     

Bioactive substances produced by marine isolates of Pseudomonas

Pseudomonas is a genus of non-fermentative gram-negative Gammaproteobacteria found both on land and in the water. Many terrestrial isolates of this genus have been studied extensively. While many produce bioactive substances, enzymes, and biosurfactants, other Pseudomonas isolates are used for biological control of plant diseases and bioremediation. In contrast, only a few marine isolates of this genus have been described that produce novel bioactive substances. The chemical structures of the bioactive substances from marine Pseudomonas are diverse, including pyroles, pseudopeptide pyrrolidinedione, phloroglucinol, phenazine, benzaldehyde, quinoline, quinolone, phenanthren, phthalate, andrimid, moiramides, zafrin and bushrin. Some of these bioactive compounds are antimicrobial agents, and dibutyl phthalate and di-(2-ethylhexyl) phthalate have been reported to be cathepsin B inhibitors. In addition to being heterogeneous in terms of their structures, the antibacterial substances produced by Pseudomonas also have diverse mechanisms of action: some affect the bacterial cell membrane, causing bacterial cell lysis, whereas others act as acetyl-CoA carboxylase and nitrous oxide synthesis inhibitors. Marine Pseudomonas spp. have been isolated from a wide range of marine environments and are a potential untapped source for medically relevant bioactive substances.     

Flavanols: digestion,absorption and bioactivity

Flavanols, or flavan-3-ols, are a family of bioactive compounds present in cocoa, red wine, green tea, red grapes, berries and apples. With a basic monomer unit of (−)-epicatechin or (+)-catechin, flavanols can be present in foods and beverages as monomers or oligomers (procyanidins). Most, but not all, procyanidins are degraded into monomer or dimer units prior to absorption. The bioavailability of flavanols can be influenced by multiple factors, including food processing, cooking, digestion, and biotransformation. Flavanols are potent antioxidants, scavenging free radicals in vitro and in vivo. While some of the actions of flavanols can be linked to antioxidant activities, other modes of action may also occur, including modulation of intracellular signaling, effects on membrane fluidity and regulation of cytokine release or action. Physiologically, flavanol-rich foods and beverages can affect platelet aggregation, vascular inflammation, endothelial nitric oxide metabolism, and may confer protective effects against neurodegeneration. Epidemiological data suggests that intake of cocoa, a rich source of flavanols, is inversely associated with 15-year cardiovascular and all-cause mortality in older males. (−)-Epicatechin and its metabolite, epicatechin-7-O-glucuronide, have been identified as independent predictors of some of the vascular effects associated with the consumption of a flavanol-rich beverage. Targeted dietary components and nutrition supplements that can influence the vascular system will be of great value in the prevention and treatment of chronic disease.