Open access peer-reviewed chapter

Bioactive Peptides from Agriculture and Food Industry Co-Products: Peptide Structure and Health Benefits

Written By

Jirawat Yongsawatdigul and Ali Hamzeh

Submitted: May 14th, 2020 Reviewed: November 9th, 2020 Published: July 14th, 2021

DOI: 10.5772/intechopen.94959

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Co-products from food processing are typically disposed or turned into low value animal feed. Proteinaceous co-products can be converted to bioactive peptides exerting health benefits, which can lead to development of nutraceuticals and functional foods. This is an effective means for valorization of these co-products. The release of encrypted peptides exhibits various bioactivities, including antihypertension, antioxidant, immunomodulatory activities among others, in vitro, and some activities have been demonstrated in vivo. Structure modification of bioactive peptides occurring under gastrointestinal digestion and cellular transport remains the important factor determining the health benefits of bioactive peptides. Understanding peptide transformation in gastrointestinal tract and in blood circulation before reaching the target organs would shed some lights on its bioavailability and subsequently ability to exert physiological impact. In this chapter, the potential health promoting properties of peptides encrypted in various sources of co-products will be reviewed based on evidence on in vitro, in vivo and clinical trial studies. Structural changes of bioactive peptides under physiological condition will also be discussed in relation to its bioactivities.


  • bioactive peptide
  • transepithelial transport
  • bioavailability
  • peptide sequence

1. Introduction

A large number of food co-products is annually generated from various plant-and animal-based food processing plants. The Food and Agriculture Organization (FAO) recently reported that 14% of global food production is lost prior to getting the retails [1]. There is also an estimation of generating co-products and waste of 38 percent in food processing industries [2]. These co-products are usually disposed, landfilled, incinerated and/or processed into animal feed and other low value products such as compost and fertilizer [3], which would cause economic losses and environmental concerns.

Bioactive peptide production is a promising approach to fully utilize proteinaceous co-products. These peptides could also exert physiological functions, leading to health benefits, such as antioxidant, antihypertension, antidiabetic, immunomodulatory activities among others. But these peptides are encrypted in the protein chain and needed to be released to exert bioactivities. Fermentation, enzymatic and chemical (by acid or alkali) hydrolysis could be applied to produce bioactive peptides as well as using solvents which is normally used to extract natural peptides. Among them, enzymatic hydrolysis known to be more effective as it is a mild, ecofriendly, and controllable process. Bioactivities of the released peptides are affected by their size, hydrophobicity, charge, amino acid composition and their sequence which are different based on various enzyme and substrate as well as the hydrolysis conditions. After production of peptides with the certain bioactivity, their structural modification upon gastrointestinal digestion and epithelial transportation and absorption must be taken into consideration to determine their potential bioavailability. Several bioactivities and physiological functions of peptides derived from both animal and plant-based agricultural co-products have been reported, which are mainly focused on their antioxidant, antihypertensive, antidiabetic and antibacterial properties. In this chapter, their main biological activities along with the associated structure will be considered. Besides, the structure-bioavailability relation of the peptides will be demonstrated and procedures to keep them intact upon gastrointestinal digestion and transepithelial transportation will also be proposed.


2. Agricultural co-products as a source of bioactive peptides

Agricultural co-products involve a vast variety of materials with great potential as a substrate for bioactive peptide production due to the low value and high protein content. It is estimated that about 9000 tons in dairy, 3 and 9 million tons in seafood and livestock industries, respectively, are annually discarded [4]. Skins, bones and heads are rich in collagen. Collagen is known as a promising source of peptides with several bioactivities which could exert physiological functions. Collagen comprises of hydrophobic amino acids, particularly proline and hydroxyproline, offering a higher chance of being absorbed through epithelial membrane. These amino acids also make them stable against proteases in gastrointestinal digestion tract and brush border, so that the intact peptides could be absorbed and reach the target organ. Blood is also high-protein co-product obtained in a large volume in a slaughterhouse. It has been reported that about 2.5 billion tons of blood are annually generated only in Europe [5]. Hemoglobin in red corpuscles and albumin, globulins, and fibrinogen in plasma are the major proteins [6]. Whey is a predominant co-product of dairy industry with an annual production of approximately 180–190 million tons [7]. The whey-derived peptides have also lower allergenicity beyond their bioactivities, because β-lactoglobulin (β-lg) as a main whey protein contributing to allergenicity would degrade within hydrolysis process [8].

Production of bioactive peptide from some plan-based materials are restricted due to difficulties in protein recovery from their unique rigid structure of polysaccharides. To meet the challenge, pretreatment of these substrates would improve protein recovery and provide other benefits such as reduction of time and energy consumption, leading to a higher efficacy in bioactive peptide production [9]. Corn gluten meal was immersed in alkali solution, treated with α-amylase and cooked prior to proteolysis [10]. Ultrasound exposure of watermelon seed caused structural changes, leading to production of peptides with higher antioxidant activity than those without any treatment. Ultrasound could degrade interactions in matrix and unfold proteins, so that more hydrophobic residues and reactive sites are exposed, resulting in a higher efficacy in protein hydrolysis [9]. Oat bran polysaccharide was digested by cellulase and viscozyme to ease protein recovery prior to proteolysis and production of antioxidant peptides [11].

Bran from rice and wheat, is a main protein-rich co-product in cereal industry with production of about 50–60 and 90 million tons every year, respectively. Albumin, globulin, prolamin and glutelin are the major proteins in bran with a total protein content of 12–20% [12]. Seeds are also another source of bioactive peptides, among them those harvested for oil production generate a large mass of co-product. Soybean, rapeseed and canola meals with the crude protein contents of about 48, 36 and 38%, respectively, are important cases of protein-rich co-products obtained from oil industries [13]. Corn gluten meal is also a major proteinaceous co-product generated in a large quantity from corn wet milling process in which, zein and glutelin are the main proteins (68 and 28%, respectively). Zein composes of mainly hydrophobic amino acids by which, more hydrophobic peptides are likely produced [14]. Hydrophobicity is an important feature of peptides to exert some bioactivities such as antioxidant and antihypertensive properties.

Thus far, peptides with various bioactivities in vitro and in vivo levels have been recognized from these low value co-products. Conversion of these co-products to more value-added hydrolysates and/or peptides would ultimately lead to development of health promoting food products.


3. Biological activities

Several bioactivities and physiological functions of peptides derived from both animal- and plant- based agricultural co-products have been reported. These activities include antioxidant, antihypertensive, antidiabetic and antibacterial properties.

3.1 Antioxidant activity

Reactive oxygen species (ROS) are formed during normal cellular metabolism of providing energy, respiration and also when cells are exposed to exogenous oxidative stress [15, 16]. Normally, these products are neutralized by endogenous antioxidant defense systems, such as antioxidant enzymes (superoxide dismutase: SOD, glutathione peroxidase: GPx and catalase), glutathione (GSH) and others. But, the excessive level of ROS could result in many health disorders, such as cancer, cardiovascular, respiratory, neurodegenerative and other diseases [16, 17]. Therefore, antioxidant-containing diet could help to overcome ROS and subsequently their corresponding disorders. Nowadays, attempts have been made to find new antioxidant compounds from natural resources due to their benefits over synthetic compounds. To that direction, antioxidant peptides from agricultural co-products are gaining more attractions, because of their nontoxicity and safety besides their nutritional properties. Antioxidant hydrolysates/peptides production from agricultural co-products including skins, bones, viscera, whey as animal-based and brans, seeds, leaves, gluten as plant-based co-products have been extensively reviewed [17, 18, 19, 20, 21].

Lower molecular weight (MW) peptides with hydrophobic and aromatic amino acids (HAAs and AAA, respectively) have been generally reported to exert good antioxidant activities [22]. The HAAs could improve peptides accessibility toward ROS through binding with lipid and reaching to free radicals, so that the peptides could quench them effectively. The AAAs including Trp, Phe and Tyr are also correlated with the strong antioxidant activity via their high electron transferring capacities of their aromatic rings. Besides HAAs and AAAs, some of hydrophilic amino acids, such as His could improve the activity through its imidazole ring which has been indicated as strong electron donator [23]. Presence of charged amino acids in peptide structure could also improve the activity. A higher negatively charged amino acids (NCAA) have been observed in plasma hydrolysates prepared from chicken blood that showed higher antioxidant activity than those prepared from blood corpuscles with lower NCAAs [6]. Presence of NCAAs are reported to correlate with the strong antioxidant activity, because they can neutralize free radicals by giving their excess electrons.

Although antioxidant activity of agricultural co-product has been widely evaluated, few studies were conducted to assess the activity in vivo and there is still a gap for clinical trial. The chemical in vitro studies are not able to reflect the activity in biological systems due to their complicated physiological conditions. In addition, cellular evaluation might be able to provide a comparable environment to biological systems. Antioxidant properties of peptides from fish sauce increased with the increasing of peptides concentration based on chemical assays, while these peptides could act as pro-oxidants in higher concentration (>50 μg L-leucine equivalent/ml) in cellular experiments [24]. Hydrolysates prepared from corn gluten meal and ham seed meal as well as ACFL, a peptide from horse mackerel viscera, increased the level of antioxidant enzymes based on in vivo models upon exposure to oxidative stress [10, 25, 26]. In a human trial study, a reduction in plasma malondialdehyde and an increase in SOD level was observed after daily ingestion of 4.5 g black soy derived peptides for 8 weeks [27].

3.2 Antihypertensive activity

Hypertension is a major risk for many disorders including coronary heart disease, stroke, heart failure, vision loss, chronic kidney disease, and dementia [2829]. Renin-angiotensin system (RAS) is responsible in blood pressure regulation. The liver-released angiotensin is converted to angiotensin-I (Ang-I) by renin, then the Ang-I is easily degraded to Ang-II, a potent vasoconstrictor, by angiotensin converting enzyme (ACE), leading to vasoconstriction and hypertension. Thus, hypertension can be controlled using renin and ACE inhibitors, in which the latter is more important due to its dual functions, catalyzing Ang-II (a potent vasoconstrictor) and inactivation of bradykinin (a vasodilator) [30]. However, controlling blood pressure by peptides from agricultural co-products also reported to be achieved through other mechanisms, such as nitric oxide production and blocking calcium channel and Ang-II receptor. The receptor blockers are able to hinder vasoconstriction and other functions mediated by Ang-II. Calcium channel blocker can avoid calcium availability in blood vessel cell wall and heart which make them to have a lower extent contraction, leading to relaxation and lower blood pressure [27, 31]. Arg-containing peptides have also been reported to suppress hypertension as Arg is a precursor in nitric oxide production. Nitric oxide (NO) is synthesized by the reaction of Arg and oxygen in the presence of nitric oxide synthase as a catalyst. NO is a vasodilator which act against Ang-II and a balanced level of these two compounds could lead to normal blood pressure [32]. Peptides namely, LIWKL, RPYL, RRWQWR, blocking the Ang-II receptor and HRW, a calcium channel blocker, have been reported to exert antihypertensive effects [33, 34].

The antihypertensive activity of peptides depends on several factors including amino acid composition and their position, molecular weight and charge. Normally, peptides with lower molecular weight exert higher activity due to their higher affinity to bind with ACE, in which the most potent reported peptides are di- and tri-peptide. Moreover, small peptides can stay intact through gastrointestinal digestion and epithelial transportation, reaching to blood circulation system and the target organ [31]. The structure–activity relationship of 168 dipeptides and 140 tripeptides with ACE inhibitory activity was assessed [35]. The authors reported that presence of bulky side chain and hydrophobic amino acids in dipeptides could result in higher activity, while presence of aromatic amino acids at C-terminus and positively charged amino acids in the middle and hydrophobic residues at N-terminus brought them higher ACE inhibitory activity. The interaction of peptides with zinc ion in active site of ACE could effectively deactivate the enzymes. It has been reported that Leu could bind with Zn2+ by its carboxyl group and inhibit the enzyme activity [36].

Antihypertensive activity of hydrolysates/peptides from agricultural co-products was extensively explored by in vitro and in vivo studied, mostly based on their inhibition capacity against ACE and rat with hypertension (either SHR or hypertensive-induced rat), respectively (Table 1). However, clinical studies are still needed to confirm their health benefits. Clinical studies on the antihypertensive effect of IPP and VPP showed a controversial result as it reduced systolic and diastolic blood pressure in Asian case studies to a higher extent than Caucasians, while no effect was observed in Dutch and Danish cases [46, 47]. They reported that the difference could be associated to variations in genetics and dietary habit which should be taken into consideration. Kwak et al. [27] reported antihypertensive effect of black soy peptide in human trial, in which systolic blood pressure decreased in hypertensive subjects likely through reduction in ACE activity and increase in nitric oxide production. The authors concluded that the activity of black soy peptides might also be associated with higher arginine content which is a substrate for nitric oxide formation, known as a strong vasodilator.

In vivoIn vitro
Animal based co-products
Bovine whey lactoferrinPepsinPartially purified hydrolysate (<3 kDa)
ACE inhibitory activity,
Blocking Ang-II receptor
Fish (Cobia) skinProtamexHydrolysate
Systolic and diastolic blood pressure reduction at 600 mg/kg:
−21.9 and − 15.5 mmHg, respectively, after 4 h in SHR
ACE inhibitory activity
ACE inhibitory activity
IC502: 41, 4.3, 0.2 and 8.5, respectively
Chicken bonePepsinYYRASystolic blood pressure reduction at 10 mg/kg in SHR: −2 mmHg after 6 hACE inhibitory activity
IC50: 33.9
Bovine bone gelatinAlcalaseRGL-(Hyp)-GL and RGM-(Hyp)-GFSystolic blood pressure reduction at 30 mg/kg:
−31.3 and
−38.6 mmHg for RGL and RGM after 4 and 6 h, respectively, in SHR
ACE inhibitory activity
IC50: 0.9 and 6.9, respectively
Bovine blood plasmaFlavourzymeHPYACE inhibitory activity
IC50: 0.7
Poultry visceraAutolysisARIYH, LRKGNLE and RVWCPACE inhibitory activity
IC50: 8.9, 8.9 and 4.9, respectively
WheyIWACE activity reduction in human plasma by 32% at 50 mg administration[41]
Plant based co-products
Wheat branAlcalaseHydrolysate,
peptides <1 kDa including
Systolic blood pressure reduction at 100 mg/kg in SHR1:
−20 and − 35 mmHg after 6 h for hydrolysates and the peptides <1 kDa, respectively
Renin and ACE inhibition activity[42]
Corn gluten mealTrypsinAYSystolic blood pressure reduction at 50 mg/kg in SHR:
−9.5 mmHg after 2 h
ACE inhibitory activity
IC50: 3.6
CottonseedPapainFPAIGMKACE inhibitory activity
IC50: 46.7
Flaxseed protein isolateThermoasePartially purified hydrolysate
(3–5 kDa)
Systolic blood pressure reduction at 200 mg/kg in SHR:
−37 mmHg after 8 h
Renin and ACE inhibitory activity[44]
Red seaweed (Porphyra columbina)
Trypsin and AlcalaseHydrolysateACE inhibitory activity[45]

Table 1.

Peptides/hydrolysates derived from agricultural co-products involved in antihypertension activity.

Spontaneously hypertensive rat.

IC50 based on μg/ml.

3.3 Antidiabetic activity

The diabetes is a chronic health problem which involved 463 million adults in 2019 and it is estimated to reach 700 million by 2045. In the health disorder, the elevated blood glucose cannot be treated properly due to either pancreas failure in insulin production (type-I) or insulin resistance in the body (type-II), in which the latter comprised the majority of about 90–95% [48].

The diabetes type-I treatment is associated to insulin injection, while the diabetes type-II can be prevented by controlling the pathways, by which the blood glucose elevates. The enzymes, α-amylase and α-glucosidase, play roles in carbohydrate digestion through breaking them down to oligosaccharides and subsequently to glucose, which is easily absorbed from intestine to blood, leading to hyperglycemia. In addition, dipeptidyl peptidase IV (DPP-IV), a protease located on endothelial, epithelial and some other cells, could easily degrade hormones stimulating insulin secretion during food ingestion, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), and cause dysregulation of blood glucose. Therefore, many studies have attempted to find bioactive peptides to inhibit these enzymes, so that the diabetes type-II would be cured or prevented. Bioactive peptide with in vitro enzyme inhibitory and in vivo antidiabetic activities derived from agricultural co-products are summarized in Table 2.

In vivoIn vitro
Animal based co-products
Chicken feetNeutraseHydrolysateReduction of glycemia in glucose-intolerant rats at 300 mg/kgDPP-IV inhibitory activity[49]
Collagen from pig and cattle skin, fish scale and chicken feetCollagenaseGA-Hyp
DPP-IV inhibitory activity
IC50: >20, 5.03 and 2.51 mM, respectively
Mare wheyPapainNLEIILR
DPP-IV inhibitory activity
IC50: 86.3 and 69.84 μM, respectively
β-Lactoglobulin from bovine wheyTrypsinVAGTWYReduction of glucose level in mice at 300 mg/kgDPP-IV inhibitory activity
IC50: 210 μM
TrypsinIPAVFDPP-IV inhibitory activity
IC50: 44.7 μM
Atlantic salmon skinFlavourzymeGPAE, GPGADPP-IV inhibitory activity
IC50: 49.6 and 41.9 μM, respectively
Cuttlefish visceraCrude protease extracts from smooth hound and cuttlefish hepatopancreasHydrolysateStimulation cholecystokinin (CCK) and GLP-1 release in enteroendocrine STC-1 cells,
DPP-IV inhibitory activity
Bovine haemoglobinin vitro GI digestion by pepsin and pancreatinVAAA
DPP-IV inhibitory activity, IC50: 141 μM
Stimulation of GLP-1 secretion in STC-1
Plant based co-products
Wheat glutenDebitrase HYW20Pro-containing peptidesDPP-IV inhibitory activity[57]
Protease from gingerQPQ , QPG, QPF, LPQ , SPQDPP-IV inhibitory activity
IC50: 79.8, 70.9, 71.7, 56.7, and 78.9 μM, respectively
Oat globulinTrypsinLQAFEPLRDPP-IV inhibitory activity
IC50: 103.5 μM
Luffa cylindrica seedPepsin
Hydrolysateα-amylase and α-glucosidase inhibitory activity[60]
Rice branUmamizymeG
13 peptides containing 6–32 amino acids
DPP-IV inhibitory activity
IC50: 0.41 mM
α-amylase and β-glucosidase inhibitory activity
Hemp seed mealAlcalaseLR, PLMLPα-glucosidase inhibitory activity[63]

Table 2.

Examples of agricultural by-product peptides and hydrolysates exhibiting antidiabetic activity.

In a clinical study, Goudarzi and Madadlou [64] indicated that hydrolysate prepared from whey proteins stimulated insulin production, so that plasma glucose got back to normal level in postprandial hyperglycaemia cases, while the hydrolysate had no effect in prehypertensive cases. Although studies indicated that hydrolysates/peptides might stimulate secretions of hormones involving in insulin production [55, 56, 64], most studies have focused on major enzymes involving in carbohydrate digestion and DPP-IV. The structure–activity relation of peptides possessing the diabetes-involving-enzyme inhibition has not been completely understood yet. Nongonierma et al. [57] identified di- and tri-peptides inhibiting DPP-IV in wheat gluten hydrolysate. These peptides had some main characteristics including the presence of Pro at carboxyl terminus or penultimate position and Phe or Leu at amino terminus. Li-Chan et al. [54] described that peptides with DPP-IV inhibitory activity required presence of hydrophobic amino acids, particularly Pro, as Pro placed at 1–4 (preferably at second) positions from N-terminal end and bounded with Leu, Val, Phe, Ala and Gly. Dipeptides as X-Pro with X as a small size hydrophobic amino acid would likely be an effective inhibitor. Presence of hydrophobic and aromatic amino acids at N-terminal end of peptides with DPP-IV inhibitory activity was also reported by Lima et al. [65]. Ren et al. [63] evaluated the α-glucosidase inhibitory capacity of peptides from hemp seed and indicated that hydrophobicity of peptides was a prime factor affecting inhibitory activity and molecular weight as a second priority. The authors have also reported that larger molecular weight peptides could also enhance α-glucosidase activity. α-Amylase is another enzyme involving in carbohydrate digestion and it has been reported that presence of branched and aromatic amino acids such as Lys, Phe, Tyr and Trp and positively charged amino acid could help to inhibit the enzyme [60].

3.4 Antibacterial activity

The antibacterial activity of hydrolysates/peptides has been studied to a lesser extent when compared to other aforementioned properties. Hydrolysates/peptides with antibacterial activity have been obtained from co-products of milk, seafood, meat and others which are summarized in Table 3. Conventional antibiotics and preservatives are extensively applied to control pathogens, which lead to antibiotic-resistant strains. Therefore, an alternative antimicrobial agent has been sought. Peptides with antibacterial properties could be one of alternative agents as they are non-toxic and could act against both Gram-negative and Gram-positive as well as antibiotic-resistant bacteria [76]. Typically, chemical antibiotics have specific targets and bacteria can develop various defense strategies towards antibiotics. In contrast, antimicrobial peptides target cell membrane and can cause serious damage which make it difficult to develop resistance [77].

SourcePeptide/HydrolysateTest bacteriaActivityRef.
Animal based by-products
Rainbow trout
Hydrolysate prepared by pepsinFlavobacterium psychrophilum,
Renibacterium salmoninarum
MIC1 (mg/ml)2
Yellowfin tuna visceraPartially purified (<3 kDa) hydrolysate prepared by ProtamexListeria. monocytogenes,
Staphylococcus aureus,
Escherichia coli,
Pseudomonas aeruginosa
MIC (mg/ml)0.5
Bovine hemoglobinTSKYR obtained by pepsin-hydrolyzed hemoglobinTotal viable colonies
Coliform bacteria
Reduce microbial counts in ground beef stored in refrigerator[68]
Porcine blood proteins:
Hydrolysate prepared by Alcalase, Flavourzyme, Protamex, trypsin and papainBacillus cereusIZ2 (mm):
Camel wheyCrude hydrolysate prepared by trypsin/partially purified (<3 kDa)E. coli
S. aureus
Salmonella typhimurium
Streptococcus mutans
MIC (mg/ml)130/65
Cow wheyCrude hydrolysate prepared by trypsin/partially purified (<3 kDa)E. coli
S. aureus
S. typhimurium
S. mutans
MIC (mg/ml)260/130
Snow crab co-productsHydrolysate prepared by ProtamexE. coli
L. innocua
IZ (mm)9
Plant-based co-products
Palm kernel cakeHydrolysate prepared by AlcalaseLisinibacillus sphaericus
Bacillus thuringiensis
B. cereus
Clostridium perfringens
B. subtilis
MIC (μg/ml)150
Jatropha curcas mealCAILTHKR
obtained by Protamex-hydrolyzed meal
E. coli
Shigella dysenteriae
P. aeruginosa
S. aureus
B. subtilis
S. pneumoniae
MIC (μg/ml)29
Rice branKVDHFPL
obtained by bromelain-hydrolyzed bran
Listeria monocytogenes
L. monocytogenes biofilm
MIC (μg/ml)0.25
obtained by pepsin-hydrolyzed bran
Porphyromonas gingivalis (PG),
Candida albicans (CA)
(PG, CA; μM)
289, ND4
ND, 75.6
ND, 78.5

Table 3.

Antibacterial peptide/hydrolysate prepared from agricultural co-products.

Minimum inhibitory concentration.

Inhibition zone.

No inhibition.

Not detected.

The antibacterial activity of these peptides is associated to their molecular weight, charge and hydrophobicity [67]. Peptides are attached by negatively-charged residues of cell membrane, like lipopolysaccharides and lipoteichonic acid on Gram-negative and Gram-positive bacteria, respectively, through electrostatic interactions, by which the structure of cell surface was disrupted. Subsequently, peptides could permeate to the cell and reach to cytoplasmic membrane, causing leakage of cytoplasmic fluid [78].

Antibacterial activity of hydrolysates and/or peptides has mostly evaluated by their directly exposure to pathogens and less studies have conducted to assess their application in food. A peptide, TSKYR, obtained from bovine hemoglobin [68] and hydrolysate prepared from yellowfin tuna waste [67] were added to ground beef and minced fish, respectively. The peptide, TSKYR, could reduce total viable colonies, yeasts, molds and particularly coliform bacteria within 14 days storage in a refrigerator. Moreover, the peptide (0.5% w/w) in ground beef was able to diminish lipid oxidation by 60% which was reported to be comparable to BHT. Pezeshk et al. [67] reported that hydrolysates prepared from yellowfin tuna were able to increase fish (silver carp) mince shelf-life in a refrigerator through inhibition of psychrophilic and total count bacteria as well as prevention of oxidative degradation.


4. Bioavailability

Studies revealed that peptides prepared from agricultural co-products have great potential of health promoting properties. However, bioavailability of these peptides is a challenge, in which they need to stay intact within gastrointestinal tract (GIT) and epithelial transportation to reach their target organs and exert physiological functions. Proteases and peptidases in GIT, brush border and cytoplasm are able to break down the peptide bond to a higher extent, leading to changes in structure and subsequently the activity. However, some peptides have been reported to be stable within the digestion and transportation. There are several factors affecting the peptides stability, which are associated to proteases specificities in GIT. Lower molecular weight, negatively charged, hydrophilic and acidic amino acid containing peptides are reported to be more stable against GI digestion. Negatively charged peptides from milk are more stable against GI digestion followed by positively charged and neutral peptides [79, 80]. Hydrophobic peptides reported to have less stability, which might be due to pepsin specificity towards hydrophobic amino acids [81]. Peptides containing more acidic amino acids, and also those with lower molecular weight showed more stability against GI digestion [6, 79]. Peptides with the molecular weight of larger than 3 kDa were easily digested by GI proteases, while peptides with <1 kDa mostly survived and no change in their antioxidant activity upon GI digestion [82]. Savoie et al. [83] reported that peptides from animal- (casein and cod fish) and plant- (soy and gluten) based substrates with Pro and Glu showed higher stability. Pro has a rigid ring structure bonded to β-carbon which makes it resistant against proteolytic degradation [80]. Thus, Pro containing peptides, IAGRP and PTPVP, have been reported to stay intact after in vitro GI digestion [84].

Epithelial permeation of bioactive peptides into blood circulation system is another challenge that affects physiological activities. Peptides may undergo some structural modification induced by brush border proteases (Table 4). For instance, a peptide with ACE inhibitory activity, KPLL, can be degraded to KP and LL within epithelial permeation, resulting in lower activity than the intact form [96]. The permeation could occur through four pathways, including peptide transporter 1 (PepT1), passive paracellular transportation through tight junctions, transcytosis and simple passive transcellular diffusion. Peptide properties such as size, hydrophobicity, charge and amino acid sequence are important factors affecting their absorption. Briefly, small (di- and tri-) peptides can be transported via PepT1 route, however peptide properties have effects on its efficacy. Non charged and hydrophobic peptides have higher affinity towards PepT1. Hydrophilic and negatively charged low molecular weight peptides can pass through energy-independence paracellular route. Transcytosis is an energy-dependent route, by which long chain peptides, particularly hydrophobic, can be transported. A highly hydrophobic peptide is likely transported through simple passive transcellular diffusion. To evaluate the effect of molecular weight on the permeation, Wang and Li [97] reported that hydrolysates with the molecular weight lower than 500 Da (mostly di- and tri-peptides) showed higher bioavailability and were able to pass through Caco2 cell via PepT1 route, while those with the molecular weight ranging 500–1000 and 1300–1600 Da permeated through paracellular route. Besides molecular weight, peptide sequence also affects its bioavailability. A Pro-containing peptide has more stability towards brush border proteases and peptides with Leu at N-terminus have been reported to be highly susceptible to hydrolysis [86, 90, 91].

PeptideBioactivityPermeated peptidesRoute of transportRef.
VLPVPQKACE inhibitor
LHLPLPACE inhibitor
LHLPLP, HLPLPParacellular[86]
IPP, LKPACE inhibitorIPP, LKPPepT1 and paracellular[87]
IWHHTACE inhibitor
PepT1 and paracellular,
LSWACE inhibitor
LSW, SWPepT1 and paracellular[90]
RRWQWRACE inhibitory
RWQ , WQParacellular[91]
Paracellular and transcytosis[94]
WGAPSLCholesterol- LowerWGAPSL, WGAPS, WGAP, GAPSL, GAP, SLParacellular[95]

Table 4.

Peptide modification within epithelial permeation and their transportation route across Caco-2 cell.

Peptides structural changes usually occur in GI tract and transepithelial transportation that would likely have effects on their physiological functions. To meet the challenge, some approaches have been applied to improve the stability of these peptides such as using permeation enhancer, enzyme inhibitor and encapsulation. Sodium caprate has been used to improve the permeability of two antihypertensive peptides, IPP and LKP, through paracellular route in Caco2 cell [98]. The authors reported that sodium caprate could intensify the peptides absorption via paracellular mechanism and inhibited PepT1 route, leading to antihypertensive effect in SHRs model. An antihypertensive peptide, RLSFNP, would degrade to RLSF, SFNP, FNP and F during the epithelial transportation. Permeation enhancers including sodium glycocholate hydrate, sodium deoxycholate and Na2EDTA as well as enzyme inhibitors, bacitracin and leupeptin, have been applied to improve the intact peptide bioavailability [99]. Na2EDTA was the most effective to enhance RLSFNP absorption through enlarging intracellular junctions. They also reported that bacitracin could exert permeation enhancer activity beyond its protease inhibitory effect. Permeation enhancer is believed to cause damages in cell membrane in case of long-term usage, leading to inflammation. However, major destructive effects were not observed by using bacitracin in rat intestine [100]. Besides, encapsulation of RLSFNP by liposome could also facilitate the intact peptide transportation through transcytosis in Caco2 cell [101]. In addition, Li et al. [102] used nano-encapsulation of antidiabetic peptides made by chitosan coated liposome to maintain the stability of peptides.


5. Conclusions

Co-products are inevitably generated in food production, distribution, processing and consumption. These protein rich and low value materials could provide a great source of bioactive peptides production. Many peptides with various activities have been purified and identified, however, their activities need to be confirmed via in vivo studies and human trials, so that they could be further develop to functional food products. The main obstacle of developing these peptides in functional foods is their structural modification after ingestion via proteolytic degradation in gastrointestinal tract and epithelial absorption, which would likely lead to a reduction in bioactivity. Although some peptides, particularly those containing Pro, could stay intact within digestion and absorption, structural modification usually happen in the route. Encapsulation of susceptible peptides or applying protease inhibitor as well as permeation enhancer in epithelial cells could facilitate the intact peptides absorption. Although these strategies might allow peptides to reach the target organ and exert certain physiological effect, their safety, particularly the use of protease inhibitors, needs further investigation regarding their side effects under physiological condition.



This work was financially supported by the National Research Council of Thailand under the project Food Innovation for Safety and Value Creation of Nakhonchaiburin (SUT3-305-61-12-06). Postdoctoral fellowship to AH supported by Suranaree University of Technology is also greatly appreciated.


Conflict of interest

The authors declare no conflict of interest.


  1. 1. The state of food and agriculture. 2019. The Food and Agriculture Organization:
  2. 2. Bharat Helkar P, Sahoo A. Review: Food Industry By-Products used as a Functional Food Ingredients. International Journal of Waste Resources. 2016; 6:3. DOI:10.4172/2252-5211.1000248
  3. 3. Lin CSK, Pfaltzgraff LA, Herrero-Davila L, Mubofu EB, Abderrahim S, Clark JH, et al. Food waste as a valuable resource for the production of chemicals, materials and fuels. Current situation and global perspective. Energy and Environmental Science. 2013; 6: 426-64. DOI: 10.1039/C2EE23440H
  4. 4. Moreno-Hernández JM, Benítez-García I, Mazorra-Manzano MA, Ramírez-Suárez JC, Sánchez E. Strategies for production, characterization and application of protein-based biostimulants in agriculture: A review. Chilean Journal of Agricultural Research. 2020; 80: 274-89. DOI: 10.4067/S0718-58392020000200274
  5. 5. Toldrà M, Lynch SA, Couture R, Álvarez C. Blood proteins as functional ingredients. In: Galanakis CM, editor. Sustainable Meat Production and Processing. Academic Press; 2019. p. 85-101. DOI: 10.1016/C2017-0-02230-9
  6. 6. Hamzeh A, Wongngam W, Kiatsongchai R, Yongsawatdigul J. Cellular and chemical antioxidant activities of chicken blood hydrolysates as affected by in vitro gastrointestinal digestion. Poultry Science. 2019;98(11): 6138-6148. DOI: 10.3382/ps/pez283
  7. 7. Oliveira D, Fox P, ƠMahony J. Byproducts from dairy processing. In: Simpson BK, Aryee ANA, Toldrá F, editors. Byproducts from Agriculture and Fisheries: Adding Value for Food, Feed, Pharma and Fuels. Wiley; 2020 p. 57-106. DOI: 10.1002/9781119383956
  8. 8. Brandelli A, Daroit DJ, Corrêa APF. Whey as a source of peptides with remarkable biological activities. Food Research International. 2015; 73: 149-61. DOI: 10.1016/j.foodres.2015.01.016
  9. 9. Wen C, Zhang J, Zhang H, Duan Y, Ma H. Effects of divergent ultrasound pretreatment on the structure of watermelon seed protein and the antioxidant activity of its hydrolysates. Food Chemistry. 2019; 299: 125165. DOI: 10.1016/j.foodchem.2019.125165
  10. 10. Liu X, Zheng X, Song Z, Liu X, Kopparapu NK, Wang X, Zheng Y. Preparation of enzymatic pretreated corn gluten meal hydrolysate and in vivo evaluation of its antioxidant activity. Journal of Functional Foods. 2015; 18: 1147-57. DOI: 10.1016/j.jff.2014.10.013
  11. 11. Esfandi R, Willmore WG, Tsopmo A. Antioxidant and anti-apoptotic properties of oat bran protein hydrolysates in stressed hepatic cells. Food 2019; 8: 1-12. DOI: 10.3390/foods8050160
  12. 12. Akanbi TO, Dare KO, Aryee ANA. High-Value Products from cereal, nuts, fruits, and vegetables wastes. In: Simpson BK, Aryee ANA, Toldrá F, editors. Byproducts from Agriculture and Fisheries: Adding Value for Food, Feed, Pharma and Fuels. Wiley; 2020 p. 349-368. DOI: 10.1002/9781119383956
  13. 13. Yun HM, Lei XJ, Lee SI, Kim IH. Rapeseed meal and canola meal can partially replace soybean meal as a protein source in finishing pigs. Journal of Applied Animal Research. 2018; 2119: 195-199. DOI: 10.1080/09712119.2017.1284076
  14. 14. Yang Y, Guanjun TAO, Ping LIU, Liu JIA. Peptide with angiotensin I-converting enzyme inhibitory activity from hydrolyzed corn gluten meal. Journal of Agricultural and Food Chemistry 2007; 55: 7891-95. DOI: 10.1021/jf0705670
  15. 15. Poljsak B, Šuput D, Milisav I. Achieving the balance between ROS and antioxidants: When to use the synthetic antioxidants. Oxidative Medicine and Cellular Longevity. 2013; 956792. DOI: 10.1155/2013/956792
  16. 16. Liu Z, Ren Z, Zhang J, Chuang CC, Kandaswamy E, Zhou T, et al. Role of ROS and nutritional antioxidants in human diseases. Frontiers in Physiology 2018; 9: 477. DOI: 10.3389/fphys.2018.00477
  17. 17. Liu R, Xing L, Fu Q , Zhou G, Zhang W. A Review of Antioxidant Peptides Derived from Meat Muscle and By-Products. Antioxidants. 2016; 5: 32. DOI: 10.3390/antiox5030032
  18. 18. Sila A, Bougatef A. Antioxidant peptides from marine by-products: Isolation, identification and application in food systems. A review. Journal of Functional Foods. 2016; 21: 10-26. DOI: 10.1016/j.jff.2015.11.007
  19. 19. Corrochano AR, Buckin V, Kelly PM, Giblin L. Invited review: Whey proteins as antioxidants and promoters of cellular antioxidant pathways. Journal of Dairy Science. 2018; 101: 4747-61. DOI: 10.3168/jds.2017-13618
  20. 20. Görgüç A, Gençdağ E, Yılmaz FM. Bioactive peptides derived from plant origin by-products: Biological activities and techno-functional utilizations in food developments – A review. Food Research International. 2020; 136: 109504. DOI: 10.1016/j.foodres.2020.109504
  21. 21. Esfandi R, Walters ME, Tsopmo A. Antioxidant properties and potential mechanisms of hydrolyzed proteins and peptides from cereals. Heliyon. 2019; 5: e01538. DOI: 10.1016/j.heliyon.2019.e01538
  22. 22. Silveira Coelho M, de Araujo Aquino S, Machado Latorres J, de las Mercedes Salas-Mellado M. In vitro and in vivo antioxidant capacity of chia protein hydrolysates and peptides. Food Hydrocolloids 2019; 91: 19-25. DOI: 10.1016/j.foodhyd.2019.01.018
  23. 23. Nwachukwu ID, Aluko RE. Structural and functional properties of food protein-derived antioxidant peptides. Journal of Food Biochemistry. 2019: 1-13. DOI: 10.1111/jfbc.12761
  24. 24. Hamzeh A, Noisa P, Yongsawatdigul J. Characterization of the antioxidant and ACE-inhibitory activities of Thai fish sauce at different stages of fermentation. Journal of Functional Foods. 2020; 64: 103699. DOI: 10.1016/j.jff.2019.103699
  25. 25. Sampath Kumar NS, Nazeer RA, Jaiganesh R. In vivo antioxidant activity of peptide purified from viscera protein hydrolysate of horse mackerel (Magalaspis cordyla). International Journal of Food Science and Technology. 2012; 47: 1558-62. DOI: 10.1111/j.1365-2621.2012.03002.x
  26. 26. Girgih AT, Alashi AM, He R, Malomo SA, Raj P, Netticadan T, et al. A novel hemp seed meal protein hydrolysate reduces oxidative stress factors in spontaneously hypertensive rats. Nutrients 2014; 6: 5652-66. DOI: 10.3390/nu6125652
  27. 27. Kwak JH, Kim M, Lee E, Lee SH, Ahn CW, Lee JH. Effects of black soy peptide supplementation on blood pressure and oxidative stress: A randomized controlled trial. Hypertension Research. 2013; 36: 1060-66. DOI: 10.1038/hr.2013.79
  28. 28. Yang Y, Guanjun TAO, Ping LIU, Liu JIA. Peptide with angiotensin I-converting enzyme inhibitory activity from hydrolyzed corn gluten meal. Journal of Agricultural and Food Chemistry 2007; 55: 7891-95. DOI: 10.1021/jf0705670
  29. 29. Mane S, Jamdar SN. Purification and identification of Ace-inhibitory peptides from poultry viscera protein hydrolysate. Journal of Food Biochemistry. 2017; 41: 1-10. DOI: 10.1111/jfbc.12275
  30. 30. Shih YH, Chen FA, Wang LF, Hsu JL. Discovery and study of novel antihypertensive peptides derived from Cassia obtusifolia seeds. Journal of Agricultural and Food Chemistry. 2019; 67: 7810-20. DOI: 10.1021/acs.jafc.9b01922
  31. 31. Abdelhedi O, Nasri M. Basic and recent advances in marine antihypertensive peptides: Production, structure-activity relationship and bioavailability. Trends in Food Science and Technology. 2019; 88: 543-57. DOI: 10.1016/j.tifs.2019.04.002
  32. 32. Udenigwe CC, Adebiyi AP, Doyen A, Li H, Bazinet L, Aluko RE. Low molecular weight flaxseed protein-derived arginine-containing peptides reduced blood pressure of spontaneously hypertensive rats faster than amino acid form of arginine and native flaxseed protein. Food Chemistry. 2012; 132: 468-75. DOI: 10.1016/j.foodchem.2011.11.024
  33. 33. Fernández-Musoles R, Castelló-Ruiz M, Arce C, Manzanares P, Ivorra MD, Salom JB. Antihypertensive mechanism of lactoferrin-derived peptides: Angiotensin receptor blocking effect. Journal of Agricultural and Food Chemistry. 2014; 62: 173-81. DOI: 10.1021/jf404616f
  34. 34. Tanaka M, Watanabe S, Wang Z, Matsumoto K, Matsui T. His-Arg-Trp potently attenuates contracted tension of thoracic aorta of Sprague-Dawley rats through the suppression of extracellular Ca2+ influx. Peptides 2009; 30: 1502-7. DOI: 10.1016/j.peptides.2009.05.012
  35. 35. Wu J, Aluko RE, Nakai S. Structural requirements of angiotensin I-converting enzyme inhibitory peptides: Quantitative structure-activity relationship study of Di- and tripeptides. Journal of Agricultural and Food Chemistry. 2006; 54: 732-38. DOI: 10.1021/jf051263l
  36. 36. Pan D, Cao J, Guo H, Zhao B. Studies on purification and the molecular mechanism of a novel ACE inhibitory peptide from whey protein hydrolysate. Food Chemistry. 2012; 130: 121-26. DOI: 10.1016/j.foodchem.2011.07.011
  37. 37. Lin YH, Chen CA, Tsai JS, Chen GW. Preparation and identification of novel antihypertensive peptides from the in vitro gastrointestinal digestion of marine cobia skin hydrolysates. Nutrients 2019; 11. DOI: 10.3390/nu11061351
  38. 38. Nakade K, Kamishima R, Inoue Y, Ahhmed A, Kawahara S, Nakayama T, et al. Identification of an antihypertensive peptide derived from chicken bone extract. Animal Science Journal. 2008; 79: 710-15. DOI: 10.1111/j.1740-0929.2008.00584.x
  39. 39. Cao S, Wang Y, Hao Y, Zhang W, Zhou G. Antihypertensive effects in vitro and in vivo of novel angiotensin-converting enzyme inhibitory peptides from bovine bone gelatin hydrolysate. Journal of Agricultural and Food Chemistry. 2020; 68: 759-68. DOI: 10.1021/acs.jafc.9b05618
  40. 40. Lee SH, Song KB. Isolation of an angiotensin converting enzyme inhibitory peptide from irradiated bovine blood plasma protein hydrolysates. Journal of Food Science. 2003; 68: 2469-72. DOI: 10.1111/j.1365-2621.2003.tb07047.x
  41. 41. Kaiser S, Martin M, Lunow D, Rudolph S, Mertten S, Möckel U, et al. Tryptophan-containing dipeptides are bioavailable and inhibit plasma human angiotensin-converting enzyme in vivo. International Dairy Journal. 2016; 52: 107-14. DOI: 10.1016/j.idairyj.2015.09.004
  42. 42. Zou Z, Wang M, Wang Z, Aluko RE, He R. Antihypertensive and antioxidant activities of enzymatic wheat bran protein hydrolysates. Journal of Food Biochemistry. 2020; 44: 1-13. DOI: 10.1111/jfbc.13090
  43. 43. Gao D, Zhang F, Ma Z, Chen S, Ding G, Tian X, et al. Isolation and identification of the angiotensin-I converting enzyme (ACE) inhibitory peptides derived from cottonseed protein: optimization of hydrolysis conditions. International Journal of Food Properties. 2019; 22: 1296-1309. DOI: 10.1080/10942912.2019.1640735
  44. 44. Nwachukwu ID, Girgih AT, Malomo SA, Onuh JO, Aluko RE. Thermoase-derived flaxseed protein hydrolysates and membrane ultrafiltration peptide fractions have systolic blood pressure-lowering effects in spontaneously hypertensive rats. International Journal of Molecular Sciences. 2014; 15: 18131-47. DOI: 10.3390/ijms151018131
  45. 45. Cian RE, Martínez-Augustin O, Drago SR. Bioactive properties of peptides obtained by enzymatic hydrolysis from protein byproducts of Porphyra columbina. Food Research International. 2012; 49: 364-72. DOI: 10.1016/j.foodres.2012.07.003
  46. 46. Engberink MF, Schouten EG, Kok FJ, Van Mierlo LAJ, Brouwer IA, Geleijnse JM. Lactotripeptides show no effect on human blood pressure: Results from a double-blind randomized controlled trial. Hypertension 2008; 51: 399-405. DOI: 10.1161/HYPERTENSIONAHA.107.098988
  47. 47. Martínez-Maqueda D, Miralles B, Recio I, Hernández-Ledesma B. Antihypertensive peptides from food proteins: A review. Food and Function. 2012; 3: 350-61. 10.1039/c2fo10192k
  48. 48. Diabetes facts and figures. 2020. International Diabetes Federation:
  49. 49. Casanova-Martí À, Bravo FI, Serrano J, Ardévol A, Pinent M, Muguerza B. Antihyperglycemic effect of a chicken feet hydrolysate: Via the incretin system: DPP-IV-inhibitory activity and GLP-1 release stimulation. Food and Function. 2019; 10: 4062-70. DOI: 10.1039/c9fo00695h
  50. 50. Hatanaka T, Kawakami K, Uraji M. Inhibitory effect of collagen-derived tripeptides on dipeptidylpeptidase-IV activity. Journal of Enzyme Inhibition and Medicinal Chemistry. 2014; 29: 823-28. DOI: 10.3109/14756366.2013.858143
  51. 51. Song JJ, Wang Q , Du M, Ji XM, Mao XY. Identification of dipeptidyl peptidase-IV inhibitory peptides from mare whey protein hydrolysates. Journal of Dairy Science. 2017; 100: 6885-94. DOI: 10.3168/jds.2016-11828
  52. 52. Uchida M, Ohshiba Y, Mogami O. Novel dipeptidyl peptidase-4-inhibiting peptide derived from β-lactoglobulin. Journal of Pharmacological Sciences 2011; 117: 63-66. DOI: 10.1254/jphs.11089SC
  53. 53. Silveira ST, Martínez-Maqueda D, Recio I, Hernández-Ledesma B. Dipeptidyl peptidase-IV inhibitory peptides generated by tryptic hydrolysis of a whey protein concentrate rich in β-lactoglobulin. Food Chemistry. 2013; 141: 1072-77. DOI: 10.1016/j.foodchem.2013.03.056
  54. 54. Li-Chan ECY, Hunag SL, Jao CL, Ho KP, Hsu KC. Peptides derived from Atlantic salmon skin gelatin as dipeptidyl-peptidase IV inhibitors. Journal of Agricultural and Food Chemistry. 2012; 60: 973-78. DOI: 10.1021/jf204720q
  55. 55. Cudennec B, Balti R, Ravallec R, Caron J, Bougatef A, Dhulster P, et al. In vitro evidence for gut hormone stimulation release and dipeptidyl-peptidase IV inhibitory activity of protein hydrolysate obtained from cuttlefish (Sepia officinalis) viscera. Food Research International. 2015; 78: 238-45. DOI: 10.1016/j.foodres.2015.10.003
  56. 56. Caron J, Cudennec B, Domenger D, Belguesmia Y, Flahaut C, Kouach M, et al. Simulated GI digestion of dietary protein: Release of new bioactive peptides involved in gut hormone secretion. Food Research International. 2016; 89: 382-90. DOI: 10.1016/j.foodres.2016.08.033
  57. 57. Nongonierma AB, Hennemann M, Paolella S, Fitzgerald RJ. Generation of wheat gluten hydrolysates with dipeptidyl peptidase IV (DPP-IV) inhibitory properties. Food and Function. 2017; 8: 2249-57. DOI: 10.1039/c7fo00165g
  58. 58. Taga Y, Hayashida O, Kusubata M, Ogawa-Goto K, Hattori S. Production of a novel wheat gluten hydrolysate containing dipeptidyl peptidase-IV inhibitory tripeptides using ginger protease. Bioscience, Biotechnology and Biochemistry. 2017; 81: 1823-28. DOI: 10.1080/09168451.2017.1345615
  59. 59. Wang F, Yu G, Zhang Y, Zhang B, Fan J. Dipeptidyl Peptidase IV Inhibitory peptides derived from oat (Avena sativa L.), buckwheat (Fagopyrum esculentum), and highland barley (Hordeum vulgare trifurcatum (L.) Trofim) proteins. Journal of Agricultural and Food Chemistry. 2015; 63: 9543-49. DOI: 10.1021/acs.jafc.5b04016
  60. 60. Arise RO, Idi JJ, Mic-Braimoh IM, Korode E, Ahmed RN, Osemwegie O. In vitro Angiotesin-1-converting enzyme, α-amylase and α-glucosidase inhibitory and antioxidant activities of Luffa cylindrical (L.) M. Roem seed protein hydrolysate. Heliyon. 2019; 5: e01634. DOI: 10.1016/j.heliyon.2019.e01634
  61. 61. Hatanaka T, Inoue Y, Arima J, Kumagai Y, Usuki H, Kawakami K, et al. Production of dipeptidyl peptidase IV inhibitory peptides from defatted rice bran. Food Chemistry. 2012; 134: 797-802. DOI: 10.1016/j.foodchem.2012.02.183
  62. 62. Uraipong C, Zhao J. Rice bran protein hydrolysates exhibit strong in vitro α-amylase, β-glucosidase and ACE-inhibition activities. Journal of the Science of Food and Agriculture. 2016; 96: 1101-10. DOI: 10.1002/jsfa.7182
  63. 63. Ren Y, Liang K, Jin Y, Zhang M, Chen Y, Wu H, et al. Identification and characterization of two novel α-glucosidase inhibitory oligopeptides from hemp (Cannabis sativa L.) seed protein. Journal of Functional Foods. 2016; 26: 439-50. DOI: 10.1016/j.jff.2016.07.024
  64. 64. Goudarzi M, Madadlou A. Influence of whey protein and its hydrolysate on prehypertension and postprandial hyperglycaemia in adult men. International Dairy Journal. 2013; 33: 62-66. DOI: 10.1016/j.idairyj.2013.06.006
  65. 65. Lima RDCL, Berg RS, Rønning SB, Afseth NK, Knutsen SH, Staerk D, et al. Peptides from chicken processing by-product inhibit DPP-IV and promote cellular glucose uptake: Potential ingredients for T2D management. Food and Function. 2019; 10: 1619-28. DOI: 10.1039/c8fo02450b
  66. 66. Wald M, Schwarz K, Rehbein H, Bußmann B, Beermann C. Detection of antibacterial activity of an enzymatic hydrolysate generated by processing rainbow trout by-products with trout pepsin. Food Chemistry. 2016; 205: 221-28. DOI: 10.1016/j.foodchem.2016.03.002
  67. 67. Pezeshk S, Ojagh SM, Rezaei M, Shabanpour B. Fractionation of protein hydrolysates of fish waste using membrane ultrafiltration: investigation of antibacterial and antioxidant activities. Probiotics and Antimicrobial Proteins. 2019; 11: 1015-22. DOI: 10.1007/s12602-018-9483-y
  68. 68. Przybylski R, Firdaous L, Châtaigné G, Dhulster P, Nedjar N. Production of an antimicrobial peptide derived from slaughterhouse by-product and its potential application on meat as preservative. Food Chemistry. 2016; 211: 306-13. DOI: 10.1016/j.foodchem.2016.05.074
  69. 69. Jin SK, Choi JS, Yim DG. Hydrolysis conditions of porcine blood proteins and antimicrobial effects of their hydrolysates. Food Science of Animal Resources. 2020; 40: 172-82. DOI: 10.5851/kosfa.2020.e2
  70. 70. Wang R, Han Z, Ji R, Xiao Y, Si R, Guo F, He J, Hai L, Ming L, Yi L. Antibacterial activity of trypsin-hydrolyzed camel and cow whey and their fractions. Animals 2020; 10(2):327. DOI: 10.3390/ani10020337
  71. 71. Doyen A, Saucier L, Beaulieu L, Pouliot Y, Bazinet L. Electroseparation of an antibacterial peptide fraction from snow crab by-products hydrolysate by electrodialysis with ultrafiltration membranes. Food Chemistry. 2012; 132: 1177-84. DOI: 10.1016/j.foodchem.2011.11.059
  72. 72. Tan YN, Ayob MK, Wan Yaacob WA. Purification and characterisation of antibacterial peptide-containing compound derived from palm kernel cake. Food Chemistry. 2013; 136: 279-84. DOI: 10.1016/j.foodchem.2012.08.012
  73. 73. Xiao J, Zhang H. An escherichia coli cell membrane chromatography-offline LC-TOF-MS method for screening and identifying antimicrobial peptides from Jatropha curcas meal protein isolate hydrolysates. Journal of Biomolecular Screening. 2012; 17: 752-60. DOI: 10.1177/1087057112442744
  74. 74. Pu C, Tang W. The antibacterial and antibiofilm efficacies of a liposomal peptide originating from rice bran protein against: Listeria monocytogenes. Food and Function. 2017; 8: 4159-69. DOI: 10.1039/c7fo00994a
  75. 75. Taniguchi M, Saito K, Nomoto T, Namae T, Ochiai A, Saitoh E, et al. Identification and characterization of multifunctional cationic and amphipathic peptides from soybean proteins. Biopolymers 2017; 108: 287-96. DOI: 10.1002/bip.23023
  76. 76. Hu F, Wu Q , Song S, She R, Zhao Y, Yang Y, et al. Antimicrobial activity and safety evaluation of peptides isolated from the hemoglobin of chickens. BMC Microbiology. 2016: 1-10. DOI: 10.1186/s12866-016-0904-3
  77. 77. Bahar AA, Ren D. Antimicrobial peptides. Pharmaceuticals. 2013; 6: 1543-75. DOI: 10.3390/ph6121543
  78. 78. Perez Espitia PJ, de Fátima Ferreira Soares N, dos Reis Coimbra JS, de Andrade NJ, Souza Cruz R, Alves Medeiros EA. Bioactive peptides: synthesis, properties, and applications in the packaging and preservation of food. Comprehensive Reviews in Food Science and Food Safety. 2012; 11: 187-204. DOI: 10.1111/j.1541-4337.2011.00179.x
  79. 79. Picariello G, Ferranti P, Fierro O, Mamone G, Caira S, Di Luccia A, et al. Peptides surviving the simulated gastrointestinal digestion of milk proteins: Biological and toxicological implications. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences. 2010; 878: 295-308. DOI: 10.1016/j.jchromb.2009.11.033
  80. 80. Mirzaei M, Mirdamadi S, Safavi M, Soleymanzadeh N. The stability of antioxidant and ACE-inhibitory peptides as influenced by peptide sequences. Lwt. 2020; 130: 109710. DOI: 10.1016/j.lwt.2020.109710
  81. 81. Xie N, Wang B, Jiang L, Liu C, Li B. Hydrophobicity exerts different effects on bioavailability and stability of antioxidant peptide fractions from casein during simulated gastrointestinal digestion and Caco-2 cell absorption. Food Research International. 2015; 76: 518-26. DOI: 10.1016/j.foodres.2015.06.025
  82. 82. Chen M, Li B. The effect of molecular weights on the survivability of casein-derived antioxidant peptides after the simulated gastrointestinal digestion. Innovative Food Science and Emerging Technologies. 2012; 16: 341-48. DOI: 10.1016/j.ifset.2012.07.009
  83. 83. Savoie L, Agudelo RA, Gauthier SF, Marin J, Pouliot Y. Free amino acids during the digestion of food proteins. Journal of AOAC International. 2005; 88: 935-48. DOI: 10.1093/jaoac/88.3.935
  84. 84. Escudero E, Mora L, Toldrá F. Stability of ACE inhibitory ham peptides against heat treatment and in vitro digestion. Food Chemistry. 2014; 161: 305-11. DOI: 10.1016/j.foodchem.2014.03.117
  85. 85. Vij R, Reddi S, Kapila S, Kapila R. Transepithelial transport of milk derived bioactive peptide VLPVPQK. Food Chemistry. 2016; 190: 681-88. DOI: 10.1016/j.foodchem.2015.05.121
  86. 86. Quirós A, Dávalos A, Lasunción MA, Ramos M, Recio I. Bioavailability of the antihypertensive peptide LHLPLP: Transepithelial flux of HLPLP. International Dairy Journal. 2008; 18: 279-86. DOI: 10.1016/j.idairyj.2007.09.006
  87. 87. Gleeson JP, Brayden DJ, Ryan SM. Evaluation of PepT1 transport of food-derived antihypertensive peptides, Ile-Pro-Pro and Leu-Lys-Pro using in vitro, ex vivo and in vivo transport models. European Journal of Pharmaceutics and Biopharmaceutics. 2017; 115: 276-284. DOI: 10.1016/j.ejpb.2017.03.007
  88. 88. Fan H, Xu Q , Hong H, Wu J. Stability and transport of spent hen-derived ACE-inhibitory peptides IWHHT, IWH, and IW in human intestinal Caco-2 cell monolayers. Journal of Agricultural and Food Chemistry. 2018; 66: 11347-11354. DOI: 10.1021/acs.jafc.8b03956
  89. 89. Regazzo D, Mollé D, Gabai G, Tomé D, Dupont D, Leonil J, et al. The (193-209) 17-residues peptide of bovine β-casein is transported through caco-2 monolayer. Molecular Nutrition and Food Research. 2010; 54: 1428-35. DOI: 10.1002/mnfr.200900443
  90. 90. Lin Q , Xu Q , Bai J, Wu W, Hong H, Wu J. Transport of soybean protein-derived antihypertensive peptide LSW across Caco-2 monolayers. Journal of Functional Foods. 2017; 39: 96-102. DOI: 10.1016/j.jff.2017.10.011
  91. 91. Fernández-Musoles R, Salom JB, Castelló-Ruiz M, Contreras M del M, Recio I, Manzanares P. Bioavailability of antihypertensive lactoferricin B-derived peptides: Transepithelial transport and resistance to intestinal and plasma peptidases. International Dairy Journal. 2013; 32: 169-74. DOI: 10.1016/j.idairyj.2013.05.009
  92. 92. Xu F, Zhang J, Wang Z, Yao Y, Atungulu GG, Ju X, et al. Absorption and metabolism of peptide wdhhapqlr derived from rapeseed protein and inhibition of HUVEC apoptosis under oxidative stress. Journal of Agricultural and Food Chemistry. 2018; 66: 5178-89. DOI: 10.1021/acs.jafc.8b01620
  93. 93. Xu F, Wang L, Ju X, Zhang J, Yin S, Shi J, et al. Transepithelial transport of YWDHNNPQIR and its metabolic fate with cytoprotection against oxidative stress in human intestinal Caco-2 cells. Journal of Agricultural and Food Chemistry. 2017; 65: 2056-65. DOI: 10.1021/acs.jafc.6b04731
  94. 94. Ding L, Wang L, Zhang T, Yu Z, Liu J. Hydrolysis and transepithelial transport of two corn gluten derived bioactive peptides in human Caco-2 cell monolayers. Food Research International. 2018; 106: 475-80. DOI: 10.1016/j.foodres.2017.12.080
  95. 95. Zhang H, Duan Y, Feng Y, Wang J. Transepithelial transport characteristics of the cholesterol- Lowing soybean peptide, WGAPSL, in Caco-2 cell monolayers. Molecules 2019; 24. DOI: 10.3390/molecules24152843
  96. 96. Sangsawad P, Roytrakul S, Choowongkomon K, Kitts DD, Chen XM, Meng G, et al. Transepithelial transport across Caco-2 cell monolayers of angiotensin converting enzyme (ACE) inhibitory peptides derived from simulated in vitro gastrointestinal digestion of cooked chicken muscles. Food Chemistry. 2018; 251: 77-85. DOI: 10.1016/j.foodchem.2018.01.047
  97. 97. Wang B, Li B. Effect of molecular weight on the transepithelial transport and peptidase degradation of casein-derived peptides by using Caco-2 cell model. Food Chemistry. 2017; 218: 1-8. DOI: 10.1016/j.foodchem.2016.08.106
  98. 98. Gleeson JP, Frías JM, Ryan SM, Brayden DJ. Sodium caprate enables the blood pressure-lowering effect of Ile-Pro-Pro and Leu-Lys-Pro in spontaneously hypertensive rats by indirectly overcoming PepT1 inhibition. European Journal of Pharmaceutics and Biopharmaceutics. 2018; 128: 179-87. DOI: 10.1016/j.ejpb.2018.04.021
  99. 99. Guo Y, Gan J, Zhu Q , Zeng X, Sun Y, Wu Z, et al. Transepithelial transport of milk-derived angiotensin I-converting enzyme inhibitory peptide with the RLSFNP sequence. Journal of the Science of Food and Agriculture. 2018; 98: 976-83. DOI: 10.1002/jsfa.8545
  100. 100. Muheem A, Shakeel F, Jahangir MA, Anwar M, Mallick N, Jain GK, et al. A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives. Saudi Pharmaceutical Journal. 2016; 24: 413-28. DOI: 10.1016/j.jsps.2014.06.004
  101. 101. Zhang T, Su M, Jiang X, Xue Y, Zhang J, Zeng X, et al. Transepithelial transport route and liposome encapsulation of milk-derived ace-inhibitory peptide Arg-Leu-Ser-Phe-Asn-Pro. Journal of Agricultural and Food Chemistry. 2019; 67: 5544-51. DOI: 10.1021/acs.jafc.9b00397
  102. 102. Li Z, Paulson AT, Gill TA. Encapsulation of bioactive salmon protein hydrolysates with chitosan-coated liposomes. Journal of Functional Foods. 2015; 19: 733-43. DOI: 10.1016/j.jff.2015.09.058

Written By

Jirawat Yongsawatdigul and Ali Hamzeh

Submitted: May 14th, 2020 Reviewed: November 9th, 2020 Published: July 14th, 2021