Current Pharmaceutical Design - Volume 13, Issue 8, 2007

In the last two decades fundamental studies have opened a new field of research related to bioactive food components that not only help ensure adequate nutrition, but may provide specific health benefits [for review: 1]. Bioactive components of food origin can be defined as substances, both nutrient and non-nutrient, which may exert regulative activities in the human organism beyond basic nutrition. In particular, food-derived bioactive proteins and peptides are claimed to be health-enhancing components used to reduce the risk of disease or to enhance a certain physiological function. This issue as well as the next Volume 13, Number 9, 2007, focuses on the advances being achieved in the research on the biochemical properties, physiological effects, production, safety and applications of different bioactive components derived from food. Bovine milk and avian eggs contain an array of bioactivities due to proteins and peptides present in active form, such as lactoferrin, immunoglobulins, growth factors and hormones. In addition to these fully active components, many bioactivities are latent in that they are inactive within the protein sequence, requiring enzymatic proteolysis for release of bioactive peptides from protein precursors. Bovine milk is currently the main source of a range of bioactive peptides encrypted in major milk proteins [for review: 2]. Activated peptides may exert quite different bioactivities, such as opioid, ACEinhibitory, immunomodulatory, antimicrobial, mineral binding, antimutagenic and cytomodulatory effects. In the first article, Murray and FitzGerald [3] underline that the biofunctional peptide activity currently most studied in food proteins appears to be those that inhibit Angiotensin-converting-enzyme (ACE) which plays a central role in the regulation of blood pressure. Numerous ACE inhibitory peptides have been isolated from milk proteins. However, a greater understanding of the biological mechanisms surrounding control of the cardiovascular system within the body is necessary in order to effectively design and produce new food derived antihypertensive agents. The article of Cross and Coworkers [4] demonstrates the potential anticariogenicity of casein phosphopeptides (CPP) derived from the bovine milk protein casein. The anticaries efficacy of casein phosphopeptide-amorphous calcium phosphate (CPPACP), which is able to remineralize carious lesions in dental enamel, has been demonstrated in various caries models and clinical trials. It is concluded that the CPP are a safe and novel carrier for calcium, phosphate and hydroxide (fluoride) ions to promote enamel remineralization. The paper of Weinberg [5] gives a complete overview of the numerous biological activities of the mammalian natural defense glycoprotein lactoferrin (LF) and its peptide derivates. Besides its powerful iron scavenging ability, Lf might have additional useful medicinal attributes, for example antibacterial, antifungal, antiprotozoan, antiviral, immunmodulatory, antineoplastic and bone remodelling activity. The article of Parodi [6] focuses its attention on the influence of certain dietary proteins and peptides on carcinogenesis. There is now ample evidence that whey proteins from bovine milk and their peptides have the potential to inhibit cancer development at some sites, particularly the colon and breast. It is suggested that the anticancer action of whey protein is to a large degree due to its content of cystine/cysteine and γ-glutamylcystine dipeptides. Nevertheless, much can still be learnt about mechanisms of anticancer effects. The paper of Korhonen [7] highlights existing modern technologies applicable for the isolation of bioactive native proteins and peptides derived from bovine colostrum, milk and cheese whey, and discusses aspects of potential applications for promotion of human health. Industrial-scale methods have developed for native whey proteins such as immunoglobulins, lactoferrin, lactoperoxidase, α-lactalbumin and β-lactoglobulin. At present, the industrial-scale production of bioactive peptides liberated from precursor milk proteins by proteolysis is limited by a lack of suitable technologies. On the other hand, a number of bioactive peptides have been identified in fermented dairy products......

Food proteins contain latent biofunctional peptide sequences within their primary structures which may have the ability to exert a physiological response in vivo. A large range of biofunctional peptides have been isolated from food proteins including opioid, immunomodulatory, antimicrobial, mineral binding, growth and muscle stimulating, anticancer, proteinase and angiotensin converting enzyme (ACE, EC 3.4.15.1) inhibitory peptides. The biofunctional peptide activity currently most studied in food proteins appears to be those that inhibit ACE. ACE plays a central role in the regulation of blood pressure (BP) through the production of the potent vasoconstrictor, angiotensin (Ang) II , and the degradation of the vasodilator, bradykinin (BK). ACE inhibitory peptides may therefore have the ability to lower BP in vivo by limiting the vasoconstrictory effects of Ang II and by potentiating the vasodilatory effects of BK. These ACE inhibitory peptides can be enzymatically released from intact proteins in vitro and in vivo during food processing and gastrointestinal digestion, respectively. ACE inhibitory peptides may be generated in or incorporated into functional foods in the development of ‘natural’ beneficial health products. Several products are currently on the market or are in development that contain peptide sequences which have ACE inhibitory properties. Detailed human studies are required in order to demonstrate the efficacy of these bioactive peptides prior to their widespread utilisation as physiologically beneficial functional foods/food ingredients.

The casein phosphopeptides (CPP) are derived from the milk protein casein by tryptic digestion. The CPP, containing the sequence -Pse-Pse-Pse-Glu-Glu- where Pse is a phosphoseryl residue, stabilize calcium and phosphate ions in aqueous solution and make these essential nutrients bioavailable. Under alkaline conditions the calcium phosphate is present as an alkaline amorphous phase complexed by the CPP, referred to as casein phosphopeptide-amorphous calcium phosphate (CPP-ACP). The CPP-ACP complexes readily incorporate fluoride ions forming casein phosphopeptideamorphous calcium fluoride phosphate (CPP-ACFP). A mechanism is discussed which provides a rationale for the ability of the CPP-ACP to remineralize carious lesions in dental enamel. Clinical applications of the CPP-ACP as agents in the treatment of dental caries and other hypomineralized conditions are reviewed. It is concluded that the CPP are a safe and novel carrier for calcium, phosphate and hydroxide (fluoride) ions to promote enamel remineralization with application in oral care products, dental professional products and foodstuffs.

Lactoferrin (Lf), a mammalian iron scavenging defense protein, constitutively is present in exocrine secretions that consistently are exposed to microbial flora: milk, tears, tubotympanum and nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervicovaginal mucus, and seminal fluid. Additionally, Lf is promptly delivered by circulating neutrophils to sites of microbial invasion. At these sites, the protein effectively scavenges iron at pH values as low as 3.5. Recombinant bovine and human lactoferrin is now available for development into nutraceutical/preservative/pharma- ceutical products. Among conditions for which the products are being investigated are: angiogenesis; bone remodeling; food preservation; infection in animals, humans, plants; neoplasia in animals, humans; inflammation in intestine, joints; wound healing; as well as enhancement of antimicrobial and antineoplastic drugs, and prevention of iron induced oxidation of milk formula.

A role for the amount and type of dietary protein in the etiology of cancer has not been studied extensively. Nevertheless, there is no compelling evidence from epidemiological studies to indicate that protein, at levels usually consumed, is a risk factor for cancer. On the other hand, animal studies suggest that certain peptides and amino acids derived from dietary proteins may influence carcinogenesis. The predominant protein in milk, casein, its peptides, but not liberated amino acids, have antimutagenic properties. Animal models, usually for colon and mammary tumorigenesis, nearly always show that whey protein is superior to other dietary proteins for suppression of tumour development. This benefit is attributed to its high content of cystine/cysteine and γ-glutamylcyst(e)ine dipeptides, which are efficient substrates for the synthesis of glutathione. Glutathione is an ubiquitous cellular antioxidant that directly or through its associated enzymes destroys reactive oxygen species, detoxifies carcinogens, maintains proteins in a reduced state and ensures a competent immune system. Various experiments showed that tumour prevention by dietary whey protein was accompanied by increased glutathione levels in serum and tissues as well as enhanced splenic lymphocyte proliferation, phagocytosis and natural killer, T helper and cytotoxic T cell activity. Whey protein components, β-lactoglobulin, α-lactalbumin and serum albumin were studied infrequently, but results suggest they have anticancer potential. The minor component lactoferrin has received the most attention; it inhibits intestinal tumours and perhaps tumours at other sites. Lactoferrin acts by induction of apoptosis, inhibition of angiogenesis, modulation of carcinogen metabolising enzymes and perhaps acting as an iron scavenger. Supplementing cows with selenium increases the content of selenoproteins in milk, which on isolation inhibited colon tumorigenesis in rats.

Milk proteins are known to exert a wide range of nutritional, functional and biological activities. Apart from being a balanced source of valuable amino acids, milk proteins contribute to the consistency and sensory properties of various dairy products. Furthermore, many milk proteins possess specific biological properties which make them potential ingredients of health-promoting foods. These properties are attributed to both native protein molecules and to physiologically active peptides encrypted in the protein molecules. Considerable progress has been made over the last twenty years in technologies aimed at separation, fractionation and isolation in a purified form of many interesting proteins occurring in bovine colostrum and milk. Industrial-scale methods have been developed for native whey proteins such as immunoglobulins, lactoferrin, lactoperoxidase, α-lactalbumin and β-lactoglobulin. Their large-scale manufacture and commercial exploitation is still limited although validated research data about their physiological health benefits is rapidly accumulating. Promising product concepts and novel fields of use have emerged recently, and some of these molecules have already found commercial applications. The same applies to bioactive peptides derived from different milk proteins. Active peptides can be liberated during gastrointestinal digestion or milk fermentation with proteolytic enzymes. Such peptides may exert a number of physiological effects in vivo on the gastrointestinal, cardiovascular, endocrine, immune, nervous and other body systems. However, at present the industrial-scale production of such peptides is limited by a lack of suitable technologies. On the other hand, a number of bioactive peptides have been identified in fermented dairy products, and there are already a few commercial dairy products enriched with blood pressure-reducing milk protein peptides. There is a need to develop methods to optimise the activity of bioactive peptides in food systems and to enable their optimum utilisation in the body. This review highlights existing modern technologies applicable for the isolation of bioactive native proteins and peptides derived from bovine colostrum, milk and cheese whey, and discusses aspects of their current and potential applications for human nutrition and promotion of human health.

Mitochondria produce large amounts of free radicals and play an important role in the life and death of a cell. Thus, mitochondrial oxidative damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions including ischemia-reperfusion injury, sepsis, diabetes, atherosclerosis and, consequently, cardiovascular diseases (CVD). In fact, endothelial dysfunction, characterized by a loss of nitric oxide (NO) bioactivity, occurs early on in the development of atherosclerosis, and determines future vascular complications. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are not yet clear, oxidative stress seems to play an important role. This review considers the process of CVD from a mitochondrial perspective. Accordingly, strategies for the targeted delivery of antioxidants to mitochondria are being developed. In this review, we will provide a summary of the following areas: the cellular metabolism of reactive oxygen species (ROS) and its role in pathophysiological processes such as CVD; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; recent developments in mitochondrially-targeted antioxidants that concentrate on the matrix-facing surface of the inner mitochondrial membrane and therefore protect against mitochondrial oxidative damage, and their therapeutic potential for future treatment of CVDs. More pre-clinical and clinical studies, however, are necessary in order to evaluate the effectiveness and toxicity of mitochondrially-targeted antioxidants.

Unlike the more commonly used diuretics, aquaretic agents can induce an increase in urinary volume without incurring a loss of electrolytes. These molecules belong to a family of vasopressin receptor antagonists, V2 in particular, that regulate optional renal water re-absorption via the synthesis and expression of aquaporin-2. In view of their properties, they have become the agent of choice in the treatment of hyponatremic states with water retention, and different studies have demonstrated that they are more effective and practical to use than other traditional approaches in the treatment of diseases such as cirrhosis-related ascites, SIADH and, above all, heart failure. However, the future probably holds the promise of new and unexpected applications for this type of drug in the treatment of several conditions, including polycystic kidney and glomerular disease, glaucoma and Meniere's syndrome.