Peptides and their physiological role in nutrition

Numerous scientific studies have shown that endogenous peptides are involved in the formation of a compensatory-adaptive response of the body to stress and disorders of homeostasis.

Despite a multi-level hierarchy, all regulatory mechanisms of homeostasis perform the same task - coordinating biosynthesis and maintaining a stable genetic composition of organ and tissue cells. Disorders in peptide regulation and, consequently, in the transfer of information molecules between cells leads inevitably to the development of pathological conditions which are associated with a reduced resistance of the organism to destabilizing exogenous and endogenous factors.

Recent advances have been made in the development of peptide-based drugs. The clinical efficacy of these drugs is being extensively studied to justify their use in combination therapy for various diseases and disorders. This approach is based on the fact that bioregulation in the organism is mediated by various oligopeptides that selectively transmit information between the immune cells, nerve cells and other cells. These oligopeptides are formed during the partial protein hydrolysis of precursor proteins (e.g. cytokines, growth and thymus factors, immunoglobulins) in the immediate vicinity of the corresponding receptor systems.

The general principle underlying the organization of the protein molecule is that higher structures are determined by lower structures. This means that the primary sequence of amino acids contains information necessary for the formation of the protein molecule. According to the current state of knowledge, the information can be transferred specifically from peptide molecules that consist of 2-4 amino acid residues. However, such molecules are said to consist exclusively of amino acid residues with polar side radicals.

With the improvement of the examination methods it became increasingly clear that the homology of the protein sequences of most peptide hormones of the gastrointestinal tract, insulin, calcitonin and pituitary hormones have a common origin. For example, an investigation into the development of these hormones found that insulin is synthesized in the gastrointestinal mucosa of molluscs. In addition, it was found that insulin and insulin-like growth factor have the same evolutionary origin and that insulin is also similar to growth factors of the nerve nodes. A peptide with insulin-like activity has also been discovered. The amino acid sequence of this peptide is similar to that of trypsin inhibitor, somatomedin and relaxin. A comparative analysis of the structure of biologically active substances that are secreted by cells of the diffuse neuroendocrine system shows a common origin of peptide hormones.

Studies show that an entire molecule is not absolutely necessary to influence physiological processes. Sometimes fragments of 3-4 amino acid residues are more effective than native compounds. The regulation and coordination of bodily functions can therefore be realized by processing of polypeptides. Depending on the needs of the organism, fragments with different activity, specificity and effect on different physiological systems are split off from relatively long chains in this process. Process regulation is most typical for peptide compounds with a linear structure. These molecules offer a variety of opportunities for significant conformational changes. Even after a single amino acid residue was cleaved from the bulky end of the amino acid chain. In addition, various molecular properties can change significantly during this cleavage. For example the degree of their hydrophobicity. This is crucial for the molecule to penetrate the cell membranes and the blood-tissue barrier.

A growing body of data suggests that regulatory oligopeptides are involved in the processes of growth, development, and regeneration. Many oligopeptides are well-researched compounds that regulate various physiological functions of the organism. It is believed that there is a uniform regulatory system at the oligopeptide level. This applies to embryonic, regenerative and growth types, as well as to the functions of the formed organism.

The results of intensive studies on regulatory peptides in recent decades have led to fundamental changes in the understanding of the regulatory mechanisms of physiological functions, the principles of homeostasis coordination and the adaptation of the functional systems of the organism to the environment.

The Nutrition is one of the most important environmental factors that have a lifelong impact on the human organism. Nutrients are converted into structural cell elements and ensure physical and mental activity, determine health and lifespan. Nutritional disorders always lead to negative consequences. In this context, a balanced diet that is appropriate for age, employment and health status is considered the most important factor in the prevention of various human diseases, including cardiovascular diseases, cancer, gastrointestinal tract diseases, Metabolic disorders.

In industrialized countries, people consume substantial amounts of industrial food. Such products are usually subjected to intensive processing. This process leads, if not to a complete, but to a significant reduction in the content of vitamins, minerals and other very important biologically active substances that regulate the metabolism and the functional activity of various organs and systems in the organism. In today's modern urbanized society, people with a traditional diet are literally exposed to various nutrient deficiency symptoms. This determines the inability of the organism's protective systems to respond appropriately to harmful environmental factors and increases the risk of various diseases. The experience of economically developed countries shows that it is impossible to improve the structure and quality of nutrition using traditional methods. In this context, the search for alternative methods to solve this important problem by developing technologies for the production of chemically pure biologically active substances from natural sources is extremely topical.

In the long years of searching and the practical use of biologically active substances, many facts have been collected. These show that a large number of different chemical compounds with a fully or partially known structure have biological activity. Due to the diverse possibilities of biologically active substances for regulating the human organism (treatment of diseases, correction of mental and physical disorders), a whole direction emerged in this research area. In addition to the use of such substances in traditional areas, science is also researching completely new applications. The emergence of new biologically active substances with fundamentally new mechanisms of action on living matter made research into these substances even more interesting and attractive for science.

There is a good reason to introduce the term "systemic preparation", the components of which are involved in regulating different phases of the same key process, for example by not only activating certain phases of this process but also by reducing the negative consequences thereof.

In addition to products from molecular biology, medicines are developed from traditionally used plant and animal substances, regardless of their understanding of how they work. An increasingly widespread use of natural medicines inevitably brings them closer to food products.

The P.K. Anochin's proposed theory of functional systems extends and refines the idea of the regulatory mechanisms of homeostasis that are directly related to nutrition. The regulation of nutrient balance, the removal of xenobiotics or foreign antigens with the involvement of the functional system means the ability of such a system to recognize the exogenous substrates or their associated metabolites and to transmit the information about them to other members of the system. After receiving the exogenous substance or the metabolite and integrating information from other regulatory systems, the control element of this regulatory system generates a signal that activates the control or effector member. Information about the discovery of receptor structures of certain substances is transmitted through the participation of hormones or mediators that differ in their chemical structure from the nutrients. Therefore, regulatory systems can clearly distinguish between food substrates and signals. This type of information transfer enables the organism to keep the required signal at a high level even under conditions of pronounced nutrient deficiency. When examining the secondary messenger substances of signals, it became clear that many of them are formed from compounds that are essential for the body. These cannot be synthesized in the body and must be ingested with food.

Information about the metabolic status of the organism is perceived by old (intracellular) and evolutionarily young regulatory systems (endocrine and nervous systems). Allosteric, one of the oldest regulatory systems, is responsible for fine adaptive reactions. Regulation at the level of gene activation and suppression is activated in order to adapt the body generally to changes in the absorption of substances from the environment.

It cannot be excluded that endogenous and exogenous metabolic states are perceived similarly. The information is broken down into components, the intensity of which is determined by receptors of the nervous system and other regulatory systems in the main stages of the metabolic processes.

There is no doubt that the transmission of information is impaired under pathological conditions. The release and accumulation of endogenous compounds, including peptides, that transmit the abnormal information disrupt the smooth functional activity of regulatory systems in the organism. The intake of biologically active substances with food therefore serves as one of the methods for combating the information chaos in the patient's regulatory systems.

According to the scientists, all regulatory systems of the organism are designed to always achieve the positive result. It should be emphasized that the effectiveness of the regulatory systems has developed over a long period of evolution and therefore the systems remained bound to certain environmental conditions during phylogenesis. Outside of these conditions, the beneficial result of their effects may even fail. The negative impact of various anthropogenic factors on the coordinated activity of regulatory systems is therefore obvious.

Compounds that have transmitted the signals in regulation systems of the front link in the food chain reach the organism of the next link as a food component. There they can (as far as the organism systems of these neighboring members are similar) act specifically on regulation systems of the recipient organism. In this case, not only energy, nutrients and toxins, but also information is transferred via the food chain.

It is known, that the transport of peptides, which arise from proteins during digestion, is realized significantly faster by the intestinal regulation systems than the absorption of a mixture of free amino acids. In the course of evolution, the human organism has not adapted to the nutrition with amino acids. The small intestine contains di- and tri-peptide transporters, which enable the absorption of short peptides. As a result, some peptides are transported much faster than the amino acids that make them up. Peptidases in the brush border of enterocytes cleave most short peptides (40% - 60%) only up to di- and tri-peptides. This fact also confirms the high nutritional value of the biologically active substances ingested with food and their ability to coordinate the functions of the regulatory systems of the organism.

It should also be emphasized that the sensitivity of short peptides (especially dipeptides) to hydrolysis with peptidases varies. Some peptides are weakly hydrolyzed in the brush border of the enterocytes. Other dipeptides such as glycylglycyl, proline and hydroxyproline dipeptides, glycyl sarcosine, carnosine and tripeptide glycyl sarcosyl sarcosine are not subject to complete intracellular hydrolysis and reach the portal vein intact.

An interesting discovery for the scientists was the fact that insulin, vasopressin and other hormones contain fragments of peptides that stimulate the growth of microorganisms. These observations initially provided a basis for deep conclusions about similarities in hormonal regulation in highly developed animals and the regulation of cell division in microorganisms. Because these fragments differ in amino acid sequence, the idea arose that the peptides should have some common steric configuration with a stimulating effect. Further research has shown that these fragments provided the bacteria with amino acids that were missing in your environment. This made the subsequent amino acid complex more balanced. A similar explanation has also been proposed for the stimulating effect of casein di- and tripeptides on the growth of nematodes. This led to the conclusion that peptides of this class are not endogenous regulatory factors.

The scientists discovered that adding Gln-containing dipeptides Ala-Gln and Gly-Gln to parenteral nutrition can help prevent the development of disorders caused by stress and malnutrition.

In a study in mice infected with the H1N1 influenza virus, the scientists found that parenteral nutrition enriched with the Gly-Gln dipeptide compared to standard parenteral nutrition prevents atrophy of the lymphoid tissue in the small intestine and promotes secretory immunity. This is due to the increase in IgA levels in the lining of the intestine and upper respiratory tract.

In surgical patients aged between 42 and 86 years after surgery on abdominal organs, the scientists found that parenteral nutrition enriched with the Ala-Gln dipeptide helps normalize nitrogen balance and maintain intracellular Gln levels. It also restores the total number of peripheral blood lymphocytes, intestinal permeability and absorption. As a result, the length of hospital stay for patients has been significantly reduced.

Many oral peptide preparations with different pharmacological activity are currently being synthesized and intensively investigated. However, these peptides are characterized by low resistance to enzyme hydrolysis in the stomach and small intestine. The synthesis of modified peptides or enzyme-resistant polymer conjugates would solve this problem. A large number of scientific papers have dealt with the study of the pharmacokinetics of peptides in parenteral nutrition and the role of peptide transport in the small intestine.

It should be emphasized that in the mucous membrane of different areas of the gastrointestinal tract, an inevitable accumulation of involution processes occurs during aging. This is most likely related to changes in the rate of regeneration and the development of dystrophic and atrophic changes. These processes are characterized by shortening and thickening of the villi, decrease in the microvilli and structural impairment of the glicocalix. Changes in the activity of enzymes involved in the final cleavage of disaccharides, dipeptides and esters of phosphoric acid have also been observed. Age-related changes in the intestinal mucosa and the peculiarities of the absorption of short peptides formed the basis for the development of a biologically active dietary supplement based on carnosine (β-Ala-His). The geroprotective effect of this preparation is mainly due to the antioxidant effect of this peptide.

In a study of rats with memory impairments, the scientists found that oral administration of the tetrapeptide Asn-Leu-Pro-Arg (NLPR) increases cognitive abilities, induces behavioral reactions and promotes the expression of nerve growth factor (NGF) in the brain. It is believed that NLPR can improve memory by inducing nerve growth factor expression. This peptide is therefore very promising for the therapy of memory disorders.

An investigation of the structure-functional properties of these substances was of particular importance for the formation of an idea about the mechanisms of action of peptides. Based on the analysis of the immunobiological and physicochemical properties of amino acid sequences of natural polypeptides, copies of some of these sequences (= structural analogs) were synthesized. For example, the Russian scientists constructed the dipeptide Lys-Glu (called "Vilon") after analyzing the thymus peptide complex and the tetrapeptide Ala-Glu-Asp-Gly (called "Epithalon") after analyzing the pineal peptide complex.

Computer analysis of the amino acid sequences of the polypeptides recorded in the PIR library (Eucaryotae database) showed that the peptide fragments Lys-Glu and Ala-Glu-Asp-Gly are present in various endogenous regulatory peptides. Lys-Glu was found to be a fragment of, for example, the following peptides: interleukin-1ß (IL-1ß), IL-2, IL-3, IL-4, IL-5, IL-6, interferon-γ splenin , Splenopentin, thymosins α1, β4 and β7 -β14, thymopoietins I and II, motilin, parathyroid hormone and somatoliberin. Ala-Glu-Asp-Gly is part of the composition of prothymosin, parathymosin, cytostatin, troponin, thyroglobulin, neuron adhesion molecules, glyceraldehyde-3-phosphate dehydrogenase and calmodulin-binding proteins GAP-43 and P-57. The data suggest that the peptides Lys-Glu and Ala-Glu-Asp-Gly are formed in the organism from various precursor proteins during proteolysis. A comparative study of the biological activity of polypeptides and synthetic short peptides showed that they have similar effects on different organs and tissues under normal and pathological conditions. Of particular interest is the evaluation of the effect of short peptides during oral administration. When examining the splitting of Vilon and Epithalon in media with different pH values, but also under the influence of proteases of the stomach, the content and the homogenate of the mucous membrane in the proximal area of the small intestine, it was found that these belong to a group of poorly hydrolyzable or hydrolysis-resistant peptides. Based on the discovered properties of Vilon and Epithalon, oral preparations with these peptides have been developed to prevent and correct immune deficiency and premature aging of the organism.

Oral administration of Vilon and Epithalon to male and female Wistar rats aged 3 and 11 months was found to alter the activity of digestive enzymes (sucrose, maltase, alkaline phosphatase, amino and dipeptidases) required for the hydrolysis of carbohydrates, proteins and phosphoric acid esters in different parts (stomach, duodenum, ileum and colon) of the digestive system are. Enzyme activity increased most markedly in 11-month-old animals. As a result, the difference between the activity of such enzymes was less pronounced in all rats of different age groups examined. These findings suggest that peptides Vilon and Epithalon regulate enzyme activity in the gastrointestinal tract during aging.

Oral administration of Vilon and Epithalon over a period of 1 month improved the transport properties of the small intestine in old rats. These peptides had a special effect on the passive and active transport of glucose. Compared to the values at the old control rates, the administration of Vilon leads to a 1.6-fold passive enrichment of glucose in the serous fluid of the diverticulum, the administration of epithalon leads to a 2.2-fold passive enrichment of glucose in the medial Part of the small intestine. Vilon and Epithalon increased the active absorption of glucose. Vilon doubled the active accumulation of glucose in the serous fluid of the diverticulum in the medial part of the small intestine. Epithalon intensifies this process by 6 times in the proximal parts of the small intestine and by 8 times in the medial parts. Peptides had no effect on the passive absorption of glycine. Only the use of Epithalon leads to an increase in the active absorption of glycine in the proximal and medial part of the small intestine.

While studying the influence of Vilon and Epithalon on the activity of digestive enzymes and the absorption of glucose and glycine in the small intestine of old rats, the scientists observed an improvement in food intake and a normalization of digestion. Since this effect was only observed after the use of Vilon and Epithalon, the scientists have reason to believe that these peptides can improve or normalize the functions of enzyme and transport systems of the small intestine during aging.

Modern knowledge about nutrition and the effects of nutrient components on the regulatory systems of the organism as well as success in the areas of the study of the mechanisms of action of short peptides and the development of oral medicines and parapharmaceuticals based on them show that the composition of therapeutic and preventive diets should be significantly supplemented become. Short peptides have geroprotective properties, which justifies their usefulness as a food supplement. It is believed that when peptides are administered exogenously, the impaired element of physiological regulation is briefly replaced. This enables the organism to restore the reduced or lost function and then maintain it for a long period of time. These data confirm the view that functional compensation systems can be formed in old organisms. The scientists assume that this mechanism of action is primarily based on the ability of the peptides to normalize protein biosynthesis in the corresponding organs and to keep them at a level typical for a young organism. As a result, proteins are restored in cell receptors, which normalizes the sensitivity of the cells to other humoral regulators.

It makes sense to use physiologically active short peptides as components of dietary supplements at any age to support normal metabolic processes, prevent or treat various diseases, for rehabilitation after serious illnesses, after trauma and surgery, and to delay the aging processes. This is the essential physiological role of peptides in the nutrition.

The timely and justified use of dietary supplements based on short peptides opens up new possibilities for a new area of "integral medicine". Pharmaceutical food products in combination with modern diagnostic and procedural methods occupy a promising place as an effective and safe method for maintaining health and longevity.