Current Pharmaceutical Design - Volume 13, Issue 9, 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 previous Volume 13, Number 8, 2007, focuses on the advances being achieved in the research on the biochemical properties, physiological effects, production, safety and applications of different bioactive components, with emphasis on milk and egg protein-derived proteins and peptides. Bovine milk and avian eggs contain an array of bioactivities due to proteins and peptides present in active form, such as lysozyme, 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, ACE-inhibitory, immunomodulatory, antimicrobial, mineral binding, antimutagenic and cytomodulatory effects. In the first article, Mine [3] focuses on biological activities of proteins and peptides derived from avian egg, and review their applications in the food and pharmaceutical industries. Several biological activities have been associated with egg components, including anti-microbial, immunomodulatory, anti-cancer and anti-hypertensive activities, anti-adhesive and anti-oxidant properties, protease inhibitors, nutrient bioavailability and functional lipids. In the paper of Shimizu and Dong Ok Son [4] food-derived peptides and intestinal functions are discussed with very interesting considerations. Although dietary peptides are mostly hydrolyzed by digestive enzymes in the intestinal tract, some could be absorbed intact and act in their target organs. Moreover, the intestine is the main target site for functional peptides, i.e. intestine-modulatory peptides can express their functions in the intestinal tract or modulate intestinal epithelial cell functions. These modulatory peptides are showing promising functions in preventing intestinal diseases. The article of Hartmann and Coworkers [5] deals with the assessment of cytotoxic and allergenic potential of bioactive proteins and peptides. When evaluating cytotoxic proteins and peptides of plant and animal origin it is evident that some of these compounds seem to be most effective towards malignant cells leading to the assumption that a cancer protective effect could exist for such bioactive proteins and peptides. Some peptide fragments may conserve part of the allergenicity of the native protein and thus can also be considered as allergens. The data presented on the relationship between the structure of food proteins and peptides and their allergenicity shows the difficulty in trying to assess the “non-allergenicity” of products derived from an allergenic source, even if the process used involved extensive hydrolysis of the native protein. Finally, the paper of Martin and Meisel [6] reviews nucleoprotein-derived and naturally occurring free ribonucleosides as bioactive compounds, including their effects in human cell systems and their functions as marker molecules in cancer disease. Naturally occurring and chemically modified ribonucleosides have interesting bioactive effects, e.g. the ability to enhance gut growth and maturation, to increase iron absorption and to induce apoptosis in human cells. Chemically modified ribonucleosides have already found interesting applications as pharmaceutically active compounds in the treatment of different illnesses. Regarding therapeutic and pharmaceutical aspects, further studies are required to evaluate the bioactive efficacy of indigenous ribonucleosides........

Egg is the largest biological cell known which originates from one cell division and is composed of various important chemical substances that form the basis of life. The avian egg is an important source of nutrients, containing all of the proteins, lipids, vitamins, minerals and growth factors required by the developing embryo, as well as a number of defence factors to protect against bacterial and viral infection. This review mainly focuses on biological activities of proteins and peptides derived from egg components. Several biological activities have now been associated with egg components, including novel anti-microbial activities, anti-adhesive properties, immunomodulatory, anti-cancer, and anti-hypertensive activities, anti-oxidant properties, protease inhibitors, nutrient bioavailability and functional lipids, highlighting the importance of egg and egg components in human health, and disease prevention and treatment.

The intestines are an important organ responsible for nutrient absorption, metabolism and recognition of food signals. The organ also acts as a physical and biological barrier against harmful substances including food pathogens and environmental chemicals. Food-derived peptides with a variety of physiological functions have been discovered in the past several decades. Although dietary peptides would mostly be hydrolyzed by digestive enzymes in the intestinal tract, possibly losing their biological functions during this step, some could be absorbed intact and act in their target organs. The intestines are also one of the targets for functional peptides. The intestine-modulatory peptides can be classified into two categories: (1) peptides that express their functions in the intestinal tract and (2) peptides that modulate intestinal epithelial cell functions. The 1st group includes peptides that regulate the intestinal absorption of nutrients. Enhancing mineral absorption by casein phosphopeptides, and suppressing dietary cholesterol absorption by soybean peptides are typical examples. The 2nd group includes such glutamine-containing peptides as Ala-Gln that show interesting properties in preventing and/or repairing damage caused by oxidative stress and inflammatory reactions. We have found that carinosine (β- Ala-His) suppressed the secretion of such inflammatory cytokines as IL-8 in human intestinal epithelial cells, suggesting its anti-inflammatory function in the intestines. Peptides that modulate such intestinal immune functions as secretory IgA production and cytokine secretion, and opioid peptides regulating intestinal motility are also included in this group. These intestine-modulatory peptides would be useful as ingredients of future functional foods to prevent lifestyle-related diseases and promote gut health.

This review article deals with the assessment of cytotoxic and allergenic potential of bioactive proteins and peptides. It is evident that ‘novel’ foods or nutraceuticals containing bioactive proteins and peptides must fulfill their proposed “health claim”. Furthermore, there is a need to assess their potential to exert adverse effects before they can be made widely available to consumers. A brief overview of compounds (i.e. proteins and peptides of animal and plant origin) and mechanisms involved in cytotoxic and allergenic (adverse) reactions is given along with some recent results obtained from ongoing studies. There are numerous proteins and peptides of plant and animal origin that are known to exhibit cytotoxic effects. There is evidence that many cytotoxic compounds described in the literature exclusively affect malignant cells leading to the assumption that a cancer protective effect could exist for such bioactive proteins and peptides. All the constituents that are responsible for the allergenicity of foods (as well as of pollens) are proteinaceous in nature. Some protein breakdown products, i.e. peptide fragments, may conserve part of the allergenicity of the native protein and thus can also be considered as allergens. The molecular basis of IgE recognition underlying cow's milk protein allergy is described. Some results from studies on volunteers fed caseinophosphopeptides or potentially hypotensive milk protein hydrolysates illustrate the major difference between allergenicity and immunogenicity. The data presented on the relationship between the structure of food proteins and peptides and their allergenicity shows the difficulty in trying to assess the “non-allergenicity” of products derived from an allergenic source, even if the process used involved extensive hydrolysis of the native protein(s). A ‘weight of evidence approach’ for assessing the potential allergenicity of a novel protein with no history of prior allergenicity is also presented with regard to the current EU Regulations.

Naturally occurring and chemically modified ribonucleosides have interesting bioactive effects. Dietary ribonucleosides are ingested mainly as nucleoproteins and are converted in the course of intestinal digestion to monomeric compounds. Different bioactive effects of dietary ribonucleosides have been described, including the ability to enhance gut growth and maturation and to increase iron absorption. Cytochemical studies with human cells showed that several ribonucleosides can induce apoptosis in human cells, and therefore may be potentially anticancerogenic compounds. Even if suboptimal concentrations of single bioactive nucleo compounds are available from food, the total content of different bioactive ribonucleosides may reach physiologically effective concentrations in vivo where intestinal cells may represent the main target sites of a selective apoptotic activity. Modified ribonucleosides serve as valuable pathobiochemical marker molecules for cancer. Chemically modified ribonucleosides have already found interesting applications as pharmaceutically active compounds in the treatment of different illnesses including AIDS. Regarding therapeutic and pharmaceutical aspects, further studies are required to evaluate the bioactive efficacy of indigenous ribonucleosides. The findings demonstrate the great variety of potential applications of ribonucleosides, e.g. in functional foods as well as pharmaceutical preparations.

Poly(ADP-ribose) polymerase (PARP) comprise of a family of enzymes which catalyses poly(ADPribosyl) ation of DNA-binding proteins. To date, seven isoforms have been identified: PARP-1, PARP-2, PARP-3, PARP- 4 (Vault-PARP), PARP-5 (Tankyrases), PARP-7 and PARP-10 with structural domains and different functions. PARP-1, the best characterised member, works as a DNA damage nick-sensor protein that uses beta-NAD+ to form polymers of ADP-ribose and has been implicated in DNA repair, maintenance of genomic integrity and mammalian longevity. The generation of free radicals, reactive oxygen species, and peroxynitrite causes overactivation of PARP resulting in the depletion of NAD+ and ATP and consequently in necrotic cell death and organ dysfunction. PARP has also been involved in the up-regulation of numerous pro-inflammatory genes through the activation of several transcription nuclear factors. Thus, PARP plays an important role in the pathogenesis of several diseases, such as, stroke, myocardial infarction, circulatory shock, diabetes, neurodegenerative disorders, including Parkinson and Alzheimer diseases, allergy, colitis and other inflammatory disorders. Pharmacological modulation of PARP activity may constitute a suitable target to enhance the cytotoxicity of certain DNA-damaging anticancer drugs. Also, PARP inhibition may be a viable strategy to control viral infections. This review is intended to provide an appreciation of new pharmacological perspectives of these remarkable drugs, summarize novel underlying mechanisms and discuss their potential clinical implications.

The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic agents due to their substantial antitumor and immunomodulating activity. However, several intrinsic limitations have been uncounted during the clinical use of these oxazaphosphorines, including substantial pharmacokinetic variability, resistance and severe host toxicity. To circumvent these problems, new oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity. These include mafosfamide (NSC 345842), glufosfamide (D19575, β-Dglucosylisophosphoramide mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567 (aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide thiazolidine). Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA. Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a β-D-glucose molecule. Phase II studies of glufosfamide in the treatment of pancreatic cancer, non-small cell lung cancer (NCSLC), and recurrent glioblastoma multiform (GBM) have recently completed and Phase III trials are ongoing, while Phase I studies of intrathecal mafosfamide have recently completed for the treatment of meningeal malignancy secondary to leukemia, lymphoma, or solid tumors. S-(-)- bromofosfamide is a bromine-substituted IFO analog being evaluated in a few Phase I clinical trials. The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists.