Open access peer-reviewed chapter
Peptides/hydrolysates derived from agricultural co-products involved in antihypertension activity.
Abstract
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.
Keywords
- 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.
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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
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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
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 [28, 29]. 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
| Bovine whey lactoferrin | Pepsin | Partially purified hydrolysate (<3 kDa) LIWKI, RPYL and RRWQWR | ACE inhibitory activity, Blocking Ang-II receptor | [33] | |
| Fish (Cobia) skin | Protamex | Hydrolysate WAA, AWW, IWW, WL | 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 | [37] |
| Chicken bone | Pepsin | YYRA | Systolic blood pressure reduction at 10 mg/kg in SHR: −2 mmHg after 6 h | ACE inhibitory activity IC50: 33.9 | [38] |
| Bovine bone gelatin | Alcalase | RGL-(Hyp)-GL and RGM-(Hyp)-GF | Systolic 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 | [39] |
| Bovine blood plasma | Flavourzyme | HPY | ACE inhibitory activity IC50: 0.7 | [40] | |
| Poultry viscera | Autolysis | ARIYH, LRKGNLE and RVWCP | ACE inhibitory activity IC50: 8.9, 8.9 and 4.9, respectively | [29] | |
| Whey | IW | ACE activity reduction in human plasma by 32% at 50 mg administration | [41] | ||
| Wheat bran | Alcalase | Hydrolysate, peptides <1 kDa including NL, QL, FL, HAL, AAVL, AKTVF, TPLTR | 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 meal | Trypsin | AY | Systolic blood pressure reduction at 50 mg/kg in SHR: −9.5 mmHg after 2 h | ACE inhibitory activity IC50: 3.6 | [28] |
| Cottonseed | Papain | FPAIGMK | ACE inhibitory activity IC50: 46.7 | [43] | |
| Flaxseed protein isolate | Thermoase | Partially 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 ( by-product | Trypsin and Alcalase | Hydrolysate | ACE inhibitory activity | [45] | |
Table 1.
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
| Chicken feet | Neutrase | Hydrolysate | Reduction of glycemia in glucose-intolerant rats at 300 mg/kg | DPP-IV inhibitory activity | [49] |
| Collagen from pig and cattle skin, fish scale and chicken feet | Collagenase | GA-Hyp GPA GP-Hyp | DPP-IV inhibitory activity IC50: >20, 5.03 and 2.51 mM, respectively | [50] | |
| Mare whey | Papain | NLEIILR TQMVDEEIM-EKFR | DPP-IV inhibitory activity IC50: 86.3 and 69.84 μM, respectively | [51] | |
| β-Lactoglobulin from bovine whey | Trypsin | VAGTWY | Reduction of glucose level in mice at 300 mg/kg | DPP-IV inhibitory activity IC50: 210 μM | [52] |
| Trypsin | IPAVF | DPP-IV inhibitory activity IC50: 44.7 μM | [53] | ||
| Atlantic salmon skin | Flavourzyme | GPAE, GPGA | DPP-IV inhibitory activity IC50: 49.6 and 41.9 μM, respectively | [54] | |
| Cuttlefish viscera | Crude protease extracts from smooth hound and cuttlefish hepatopancreas | Hydrolysate | Stimulation cholecystokinin (CCK) and GLP-1 release in enteroendocrine STC-1 cells, DPP-IV inhibitory activity | [55] | |
| Bovine haemoglobin | VAAA KAAVT, YGAE, ANVST and TKAVEH | DPP-IV inhibitory activity, IC50: 141 μM Stimulation of GLP-1 secretion in STC-1 | [56] | ||
| Wheat gluten | Debitrase HYW20 | Pro-containing peptides | DPP-IV inhibitory activity | [57] | |
| Protease from ginger | QPQ , QPG, QPF, LPQ , SPQ | DPP-IV inhibitory activity IC50: 79.8, 70.9, 71.7, 56.7, and 78.9 μM, respectively | [58] | ||
| Oat globulin | Trypsin | LQAFEPLR | DPP-IV inhibitory activity IC50: 103.5 μM | [59] | |
| Pepsin Trypsin Alcalsae | Hydrolysate | α-amylase and α-glucosidase inhibitory activity | [60] | ||
| Rice bran | UmamizymeG Alcalase | IP 13 peptides containing 6–32 amino acids | DPP-IV inhibitory activity IC50: 0.41 mM α-amylase and β-glucosidase inhibitory activity | [61] [62] | |
| Hemp seed meal | Alcalase | LR, PLMLP | α-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].
Viscera | Hydrolysate prepared by pepsin | MIC1 (mg/ml) | 2 5 | [66] | |
| Yellowfin tuna viscera | Partially purified (<3 kDa) hydrolysate prepared by Protamex | MIC (mg/ml) | 0.5 0.5 0.5 0.5 | [67] | |
| Bovine hemoglobin | TSKYR obtained by pepsin-hydrolyzed hemoglobin | Total viable colonies Coliform bacteria Yeasts Molds | Reduce microbial counts in ground beef stored in refrigerator | [68] | |
| Porcine blood proteins: albumin globulin | Hydrolysate prepared by Alcalase, Flavourzyme, Protamex, trypsin and papain | IZ2 (mm): 2.30–2.55 | [69] | ||
| Camel whey | Crude hydrolysate prepared by trypsin/partially purified (<3 kDa) | MIC (mg/ml) | 130/65 260/130 NI3/260 NI/260 | [70] | |
| Cow whey | Crude hydrolysate prepared by trypsin/partially purified (<3 kDa) | MIC (mg/ml) | 260/130 260/130 NI/260 NI/260 | ||
| Snow crab co-products | Hydrolysate prepared by Protamex | IZ (mm) | 9 7.5 | [71] | |
| Palm kernel cake | Hydrolysate prepared by Alcalase | MIC (μg/ml) | 150 150 200 250 450 | [72] | |
| CAILTHKR obtained by Protamex-hydrolyzed meal | MIC (μg/ml) | 29 46 58 45 34 68 | [73] | ||
| Rice bran | KVDHFPL obtained by bromelain-hydrolyzed bran | MIC (μg/ml) | 0.25 8 | [74] | |
| LRRHASEGGHGPHW EKLLGKQDKGVIIRA SSFSKGVQRAAF obtained by pepsin-hydrolyzed bran | IC50: (PG, CA; μM) | 289, ND4 ND, 75.6 ND, 78.5 | [75] | ||
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.
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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].
| VLPVPQK | ACE inhibitor Antioxidant | VLPVPQK, VLPVPQ | PepT1/SOPT2 | [85] |
| LHLPLP | ACE inhibitor Antihypertensive | LHLPLP, HLPLP | Paracellular | [86] |
| IPP, LKP | ACE inhibitor | IPP, LKP | PepT1 and paracellular | [87] |
| IWHHT | ACE inhibitor Antihypertensive Antioxidant Anti-inflammatory | IWHHT, IWH, IW | Paracellular, PepT1 and paracellular, PepT1 | [88] |
| YQEPVLGPVRGPFPIIV | Immunomodulatory | YQEPVLGPVRGPFPIIV, QEPVLGPVRGPFPIIV, YQEPVLGPVR-GPFPII | Transcytosis | [89] |
| LSW | ACE inhibitor Anti-inflammatory | LSW, SW | PepT1 and paracellular | [90] |
| RRWQWR | ACE inhibitory Antihypertensive | RWQ , WQ | Paracellular | [91] |
| WDHHAPQLR | Antioxidant | WDHHAPQLR, DHHAPQLR, WDHHAP, QLR | Paracellular PepT1 | [92] |
| YWDHNNPQIR | Antioxidant | YWDHNNPQIR, WDHNNPQIR, DHNNPQIR and YWDHNNPQ | Transcytosis | [93] |
| YFCLT, GLLLPH | Antioxidant | YFCLT, GLLLPH | Paracellular and transcytosis | [94] |
| WGAPSL | Cholesterol- Lower | WGAPSL, WGAPS, WGAP, GAPSL, GAP, SL | Paracellular | [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.
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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
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Acknowledgments
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.
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