Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 8, 2007
Contents
Food-Derived Bioactive Proteins and Peptides as Potential
Components of Nutraceuticals
Executive Editor: H. Meisel
Editorial Pp. 771-772
Angiotensin Converting Enzyme Inhibitory Peptides
Derived from Food Proteins: Biochemistry, Bioactivity and
Production Pp. 773-791
B.A. Murray and R.J. FitzGerald
[Abstract]
Casein Phosphopeptides in Oral Health - Chemistry
and Clinical Applications Pp. 793-800
K.J. Cross, N.L. Huq and E.C. Reynolds
[Abstract]
Antibiotic Properties and Applications of Lactoferrin
Pp. 801-811
E.D. Weinberg
[Abstract]
A Role for Milk Proteins and their Peptides in Cancer
Prevention Pp. 813-828
P.W. Parodi
[Abstract]
Technological Options for the Production of Health-Promoting
Proteins and Peptides Derived from Milk and Colostrum
Pp. 829-843
H. Korhonen and A. Pihlanto
[Abstract]
General Articles
Targeting Antioxidants to Mitochondria: A Potential New Therapeutic
Strategy for Cardiovascular Diseases Pp. 845-863
V.M. Victor and M. Rocha
[Abstract]
Aquaretic Agents: What’s Beyond the Treatment
of Hyponatremia? Pp. 865-871
D. Bolignano, G. Coppolino, M. Criseo, S. Campo, A. Romeo
and M. Buemi
[Abstract]
Abstracts
[Back to top]
Editorial: Food-Derived Bioactive Proteins and Peptides
as Potential Components of Nutraceuticals
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, ACE-inhibitory, 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 (CPP-ACP),
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.
There has been a growing interest in using biologically active
proteins and peptides for application within the food industry.
Accordingly, food researchers are presently considering different
bioactive substances of food origin as health enhancing ingredients
for use in foods commonly referred to as functional foods
or nutraceuticals [1, 2]. Furthermore, food-derived proteins
and peptides, which can be manufactured on an industrial scale,
have already been considered for interesting applications
as medical foods or pharmaceutical preparations. Medical food
products and drugs are designed to supply missing nutrients
to prevent, treat or cure a disease where pharmacologically
active compounds are needed. Food producers are forbidden
to claim that their products can cure, prevent or treat a
disease. They can, however, make health claims about their
products, providing they are able to produce sufficient scientific
evidence.
Even if food and pharmaceutics are to be treated as separate
entities, with different purposes and modes of action, the
research on bioactive proteins and peptides has some common
objectives:
- providing evidence that the constituent is present in a
quantity and in a form needed to exert a specific function,
- basing the reduction of disease risk claims as well as pharmaceutical
effects indicated on the label on human studies, having a
scientific valid design for showing a persistent effect of
the food or pharmaceutical preparation,
- evaluating the risks the consumption of the products could
pose to public health, including allergic potential.
Regarding the discovery of novel peptide drugs, the chemical
properties of food-derived peptides (and proteins) can be
readily modified in systematic ways for drug design and development.
It is worth noting that very small changes in structure can
lead to dramatic changes in bioactive potency and function,
and that peptides are generally less toxic than other organic
'natural molecules'.
Future research should focus on establishing novel production
technologies and understanding the interaction of different
bioactive proteins and peptides with multiple components during
production and within a complex food of an overall diet. There
are many unknown factors regarding to physicochemical and
biological interactions of bioactive ingredients, which may
result in inactivation or in synergisms and antagonisms. Understanding
the mechanisms of possible interactions is important to develop
an adequate packaging system, like microencapsulation, to
enable the improved delivery and protection of bioactive ingredients.
Research continues to discover novel bioactive proteins /peptides,
functions and health benefits - all of which reveal the striking
potential for natural selection through evolution to produce
food molecules that act beyond simply providing nutrients.
Discovering these benefits and potential applications remains
a great challenge for both nutrition research and pharmaceutical
design.
References
[1] Mine Y, Shahidi F. In: Mine Y, Shahidi F Eds, Nutraceutical
proteins and peptides in health and disease: an overview.
Boca Raton, CRC Press Taylor & Francis Group. 2006; 3-9.
[2] Meisel H. Biochemical properties of peptides encrypted
in bovine milk proteins. Curr Med Chem 2005; 12: 1905-1919.
[3] Murray BA, FitzGerald RJ. Angiotensin converting enzyme
inhibitory peptides derived from food proteins: biochemistry,
bioactivity and production. Curr Pharm Des 2007; 13(8): 773-791
[4] Cross KJ, Huq NL, Reynolds EC. Casein phosphopeptides
in oral health – chemistry and clinical applications.
Curr Pharm Des 2007; 13(8): 793-800.
[5] Weinberg ED. Antibiotic properties and applications of
Lactoferrin. Curr Pharm Des 2007; 13(8): 801-811.
[6] Parodi PW. A Role for milk proteins and their peptides
in cancer prevention. Curr Pharm Des 2007; 13(8): 813-828.
[7] Korhonen H, Pihlanto A. Technological options for the
production of health-promoting proteins and peptides derived
from milk and colostrum. Curr Pharm Des 2007; 13(8): 829-843.
Hans Meisel, Prof. Dr.
Institute of Dairy Chemistry and Technology
Federal Research Centre for Nutrition and Food (BfEL) - Location
Kiel
Hermann-Weigmann-Str. 1
D-24103 Kiel
Germany
E-mail: hans.meisel@bfel.de
[Back to top]
Angiotensin Converting Enzyme Inhibitory Peptides Derived
from Food Proteins: Biochemistry, Bioactivity and Production
B.A. Murray and R.J. FitzGerald
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, anti-cancer,
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.
[Back to top]
Casein Phosphopeptides in Oral Health - Chemistry
and Clinical Applications
K.J. Cross, N.L. Huq and E.C. Reynolds
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 phosphopeptide-amorphous 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.
[Back to top]
Antibiotic Properties and Applications of Lactoferrin
E.D. Weinberg
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/pharmaceutical
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.
[Back to top]
A Role for Milk Proteins and their Peptides in Cancer
Prevention
P.W. Parodi
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.
[Back to top]
Technological Options for the Production of Health-Promoting
Proteins and Peptides Derived from Milk and Colostrum
H. Korhonen and A. Pihlanto
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.
[Back to top]
Targeting Antioxidants to Mitochondria: A Potential New Therapeutic
Strategy for Cardiovascular Diseases
V.M. Victor and M. Rocha
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.
[Back to top]
Aquaretic Agents: What’s Beyond the Treatment
of Hyponatremia?
D. Bolignano, G. Coppolino, M. Criseo, S. Campo, A. Romeo
and M. Buemi
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.
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