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Recent Advances in Food Biopeptides: Production, Biological Functionalities And Therapeutic Applications Humaira Hussain PhD Scholar-BCH 10-arid-1763 Contents • • • • • • • • • • • • Introduction Production of biopeptides The production of endogenous peptides Production of biopeptides with enzymatic hydrolysis. Production of biopeptides with microbial fermentation Biopeptide generation during in vitro and in vivo proteolytic digestion Isolation and purification of bioactive peptides Extraction of bioactive peptides Seperation of bioactive peptides Purification of bioactive peptides Biopeptide transportation modes and absorption routes Routes For Peptide’s Transport • • • • Biopeptide Resistance and Bioavailability General concerns related to in vitro biological activities General concerns related to in vivo biological activities Role of Biopeptides In scavenging oxidative stress As antihypertensive agents In modulating the immune disorders Antimicrobial and anti-fungal properties Opiate-like activity Anticoagulant activity • Future prospects • Conclusion Introduction • Many naturally occurring compounds from foods such as rice, vegetables, fruits, and animal products possess properties that help to slow disease progression, inhibit patho physiological mechanisms, or suppress activities of pathogenic molecules. • Proteins and peptides play significant roles in such activities • Gaining importance as nutraceuticals that benefit numerous aspects of health and nutrition. • Peptides are a kind of health protectant present in nature. • Recent developments in the field of proteomics offering promising solutions to solving health problems stimulates the uses of biopeptides as one of the therapeutic. • Functional peptides(Bio peptides) are typically produced from protein via enzymatic hydrolysis. • The attention that has been given to biopeptides is due to their therapeutic and medicinal potential. Production of biopeptides • The common approaches used in the production of biopeptides are as follows: • The production of endogenous peptides • Production of biopeptides with enzymatic hydrolysis • Production of fermentation biopeptides with microbial The production of endogenous peptides • These types of biopeptides usually have an internal origin. • They are secreted with particular routes either by neurons granules or from endocrine cells • Biopeptides are considered as captivating biomarkers in the living systems (cells, tissue, and body fluids) • The identification and characterization of endogenous peptides have proposed many challenges and limitations. Production of biopeptides with enzymatic hydrolysis • The enzymatic hydrolysis is the efficient treatment destined for the production of biopeptides • Milk proteins are an important source in generating biopeptides with different biological activities including antioxidative, antihypertensive. • The incorporation of protein hydrolysates into foods has been increasingly applied in the food industry and is of great interest for human organisms. • The benefit of this technology is to enhance the daily diets of humans. • The physiological effects of biopeptides in regulating blood pressure have prompted the scientists to exploit different food materials such as fish, meat, milk, eggs, beans, and plants. For instances, goby is a kind of fish that can be exploited for deriving biopeptide based hydrolysates. Production of biopeptides with microbial fermentation • The production of biopeptides using microbial fermentation has drawn much of the dairy industry's attention • Milk products remain the captivating materials in generating potent biological peptides by the intervention of particular microbial proteases. • Many examples are elaborated on the potentiality of microbial fermentation in the production of dairy products such as commercial probiotic bacteria, yogurt bacteria,and cheese starter bacteria, all these examples being the outcomes of the process of fermentation . Biopeptide generation during in vitro and in vivo proteolytic digestion • Extraction process is an important step in the production of high yield of targeted compounds. • In the current review more emphasis is given to the enzymatic hydrolysis due to its advantages including High yield Efficient process Time saving treatment and it can be scaled easily in the laboratory • It does not leave residual organic solvents and excess of toxic substances resulting from the secondary metabolites during long fermentation process of foods. • Owing to their low molecular weight, peptides (e.g. polypeptides) behaviors are predictable in unusual fashion in terms of absorption, digestibility, and solubility affinities • Modification process of these bio fragments by using enzymatic methods is preferred in order to improve their resistance, and bioavailability. • The enzymatic hydrolysis is the best technique and in most of the cases it needs to be controlled under specific operational conditions Degradation behavior of Proteolytic Enzymes before and after enzymatic hydrolysis. • The enzymatic hydrolysis has shown a direct influence on the hydrophobicity. • Each enzyme is responsible for the generation of different fragments of peptides ranging between low, middle and high molecular weight. • These short peptides are preferred due to their stability and resistance under gastrointestinal tract conditions, and easy to be carried by specific precursors, with low transmission energy. • Due to their special structure and high molecular mass, proteins are more fragile and unstable. Isolation and purification of bioactive peptides • The emergence of robust technologies of purification and separation science of bioactive systems starts to enforce the research area of bioactive peptides to be more pronounced and mechanistic. • Typically, the variability in molecular weights, charges, affinity of bioactive peptides during separation and purification caused many obstacles • Because of these barriers and challenges related to the purity of peptides the scientists' proposed robust tools and advance instrumentation for solving these encountered issues. Extraction • • • • Size-exclusion chromatography (SEC) Solvent extraction Buffer saline systems. mobile phase that is used to purify peptides from fermented protein hydrolysates is a mixture of the three elements including trifluoroacetic acid (TFA), water, and acetonitrile • Several steps were followed accordingly starting by centrifugation • then the filtration of the supernatant • finally lyophilization of the sample for further liquid chromatography purification and separation. Seperation • • • • • • • HPLC is the common tool in the separation of bioactive compounds. RP-HPLC columns . In contrast the application of normal HPLC is preferred in case when the targeted bioactive peptides are hydrophilic peptides. Other chromatographic techniques including Capillary electrophoresis (CE), Capillary isoelectric focusing (CIEF), Ion-exchange chromatography (IEC) could reach to separate peptides based on their chargeability affinities either positively or negatively charged bioactive peptides Purification • Other techniques of separation and fractionation that can be employed in the purification trajectory are • Ultrafiltration, • Crystallization, • Partition chromatography . • Many of the national and international health centers used these materials to enrich and supplement certain products in order for them to maintain and serve many of the biological activities including antioxidative stress, antihypertensive. Biopeptide transportation modes and absorption routes • Their molecular weight is very low in comparison to the molecular mass of protein. • Short peptides comprising one or two amine bonds are penetrated through the brush border membrane by either • Physical transmission phenomenon • By the intervention of specific proteins transporter agents . • The short peptides have been found to be more active and their rapidity of absorption is favored, thus, in certain cases their penetration routes are expected to be much vital than amino acids. • For instance, some specific carrier of peptide named as PepT1 which highly necessitates the driving force resulting from the electrochemical proton gradient. • Moreover, various intracellular peptidases could be involved • Other amino acids residues will be oriented to the portal circulation via specific transporter agents. Routes For Peptide’s Transport • Basically, there are 5 principal routes for peptides: 1. The paracellular route, which is based on the diffusion mechanism, depending on water-soluble peptides, but independent on energy sources 2. The passive diffusion which is an auto-mechanism independent on energy source ,for hydrophobic peptides 3. By the intervention of specific transporter, this mode of transport usually acts more in the presence of short peptides having hydrolysis-resistance . 4. Endocytosis,, which is usually adaptable with the large polar peptides . 5. Lymphatic system, this mode of transmission, in fact more suitable to the highly lipophilic peptides, because they can be retained easily into the portal circulation Biopeptide Resistance and Bioavailability • Low molecular mass and other properties like hydrophobicity are expected to be one of the dominating factors responsible for their biological activities • Peptide chain comprising two to six amino acids have been found to be transmitted into portal circulation readily than those having long amino acid residues. • Hepatic metabolism can be escaped when the transmission of this active systems occur via the gastrointestinal lymphatic route. • Presence of proline or double proline on the lateral chain of peptides, because they contribute to maintain good resistance and rigidity for peptide. • Excess amount of biopeptides lead to subsaturation of peptide transporters. • Once these active substances remain for a long time within the stomach and under the action of gastric enzyme secretion and later by pancreatic enzymes, the biopeptides in this case will become more fragile and their transportation will be retarded. • For this reason, the microencapsulation is needed to maintain this stability General concerns related to in vitro biological activities • Cell model culture is considered the first choice for fast screening of the biological activity of such vital substances, • The manipulation of this model is easier and more reproducible than animal studies. • The role of these chemical elements have involved in maintaining vital mechanisms such as, antibacterial activity, anticancer activity. General concerns related to in vivo biological activities • Basically, once the biological activities such as antioxidative, are more pronounced during in vitro manipulations screening, in vivo study should be carried out. • An accepted animal model, which is called “Spontaneously Hypertensive Rats”, is one of the animal strains that is getting much acceptance by all researchers. • On the other hand,, due to its similar biological behaviors to the human organisms, particularly in case of an essential hypertensive human. • Researches on antihypertensive activity of biopeptides used SHR Role of biopeptides in scavenging oxidative stress • Many scientists verified the antioxidative properties of milkenriched with fish oil and during the assessment they noted that the lower molecular fractions (3–10 kDa andb3 kDa) are found to have the most effect on iron-chelating activity rather than other fractions having high molecular weight. • Strong oxygen radical- scavenging effect exhibited in a sample of egg white protein. Role of biopeptides as antihypertensive agents • Biopeptides can be defined as authentic components with monobi-and multi-functional biological activities exhibited from their amino acid residues • Capable to serve different mechanism of action like intonation, stimulation, depression, and inhibition once they exist with adequate dosages in the living organism. • The antihypertensive activity of bovine milk-derived biopeptides and other food proteins such as legumes/beans gelatin, and yeast has been reviewed extensively . Role of biopeptides in modulating the immune disorders • However, the immunomodulatory properties of biopeptides are seemed to be not appreciated. • This is perhaps due to the many challenges occurred during the practical application, due to the complexity of chemical reaction and mechanism effect resulting by the end of primary and secondary metabolites within the living system. • Fraction F6 that is obtained from the fermented skim milk displayed a potent immuno stimulating function on the proliferation of murine spleen lymphocytes. • Lactoferricin can be categorized among the potent peptides Biopeptides with antimicrobial and anti-fungal properties • Antimicrobial biopeptides comprised of less than 50 amino acid residues with a molecular mass of less than 10 kDa. • The majority of amino acid residues are hydrophobic in the nature. • They can exhibit an efficient role in the host defense against the most frequent pathogenic bacteria • Agar diffusion assay, which is named as inhibition zone assay is used to identify them Biopeptides with anticancer and antitumor activities • Protein hydrolysates exhibit a pivotal biological role against cancer cells • A recent study has been successfully identified an anti-cancer food from shellfish Mytilus-coruscus by using pepsin hydrolysates. • Biopeptides has become an alternative molecules compared to other efficient drugs because of safety point of view. • Peptides that have the ability of inducing the apoptosis in tumor cells are implicated to be as effective anticancer agents . Biopeptides with opiate-like activity • kind of peptide that can be found in bovine milk. • Reported to play a central role in the nervous network within human body. • Exhibit similarity mode of action of morphin. • This type of peptide acts by adhering with targeted cell receptor. • For example µ-receptor, which can induce the emotional behaviors, and it found to suppress as well the motility of intestine. Biopeptides with anticoagulant activity • Used to decline the bleeding in the same time to regenerate and reconstitute the damaged regions at the wall of the blood vessel. • 13 of plasma serine proteases are encrypted in the mechanism of blood coagulation . • Many of the marine organisms such as Tegillarca granosa (Blood cockle),,Mytilus edulis(blue mussel) used derive biopeptides as an anticoagulant agent. • A potent anticoagulant biopeptides have been isolated from marine macro and microalgae strains. Future prospects • Food biopeptides are versatile materials for regulating human bodily functions. • Still potential exists to verify their bio-resistance to ensure their intact absorption into portal circulation. • Best way to maintain this bio-resistance is by microencapsulation technique. • There is need to emphasize on the resulting metabolites (primary and secondary) effect and their communication at cellular level by coupling both of proteomic and of genomic sciences in combination with chemical engineering. Conclusion • Due to biophysical and biochemical properties biopeptides are valued among the potential ingredients having the capability to regulating food intake, scavenging oxidative stress, reducing the risk of cardiovascular diseases and modulating the immune disorders once they exist with an adequate dosage in the living organisms. • Insufficient findings on immunomodulating properties compared to that done for antioxidative and antihypertensive activities. This is because of the lack of expertise in the area of immunology and due to the absence of a real linkage between major fields such as pharmacy, medicine, biotechnology, and chemical engineering. References • Sami Saadi, Nazamid Saari, Farooq Anwar, Azizah Abdul Hamid, Hasanah Mohd Ghazali. Recent Advances in Food Biopeptides: Production, Biological Functionalities And Therapeutic Applications, Department of Chemistry, Universiti of Sargodha, Sargodha 40100, Pakistan. Biotechnology advances.2014.12.003