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Bioactive Peptides Derived from Seaweed Protein and Their Health Benefits:
Antihypertensive, Antioxidant, and Antidiabetic Properties

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 Hypotheses in Food Science
Bioactive Peptides Derived from Seaweed Protein

Concise Reviews &

and Their Health Benefits: Antihypertensive,
Antioxidant, and Antidiabetic Properties
Habtamu Admassu , Mohammed Abdalbasit. A. Gasmalla, Ruijin Yang, and Wei Zhao

Abstract: Cardiovascular diseases and diabetes are the biggest causes of death globally. Therefore, prevention of these
diseases is a focus of pharmaceuticals and functional food manufacturers. This review summarizes recent research trends
and scientific knowledge in seaweed protein-derived peptides with particular emphasis on production, isolation and
potential health impacts in prevention of hypertension, diabetes and oxidative stress. The current status and future
prospects of bioactive peptides are also discussed. Bioactive peptides have strong potential for use in therapeutic drug
and functional food formulation in health management strategy, especially cardiovascular disease and diabetes. Seaweeds
can be used as sustainable protein sources in the production of these peptide-based drugs and functional foods for
preventing such diseases. Many studies have reported that peptides showing angiotensin converting enzyme inhibition,
antihypertensive, antioxidative and antidiabetics activities, have been successfully isolated from seaweed. However, further
research is needed in large-scale production of these peptides, efficient isolation methods, interactions with functional
foods and other pharmaceuticals, and their ease to digestion in in vivo studies and safety to validate the health benefits of
these peptides.

Keywords: antioxidant activity, antihypertensive effect, antidiabetic properties, bioactive peptides, seaweed

Introduction are among the major groups that have received huge consumer in-
Foods are sources of other promising bioactive substances that terest (Barbé and others 2014) and gained an increased application
have potential impact on human health in addition to common on health-promoting functional foods and in different therapeutics
nutritional components (Barbé and others 2014). Recently, (Thundimadathil 2012), due to desirable physiological responses
consumer knowledge has substantially changed concerning the they trigger (Agyei and others 2016). Nature harbors variety of bi-
relationship between diet and health. The role of diet, beyond the ologically active peptides that serves as the most important sources
basic nutrition, has gained increased acknowledgment. Food, not for drug discovery (Uhliga and others 2014). About, 7000 naturally
only, is intended to satisfy hunger and provide the essential nu- occurring peptides have been identified. These peptides play vital
trients, but also contributes to prevention of nutrition-associated roles in human biological activity and in effective signaling through
diseases, reduce health risks, and improve human well-being (Be- binding to specific cell surface receptors, where they trigger intra-
toret and others 2011; Gupta and Abu-Ghannam 2011; Harnedy cellular effects. In addition to their pharmacological profiles and
and FitzGerald 2011). Cognizance of this, the interest toward intrinsic properties, they have remarkable safety, tolerability, and
functional foods and nutraceuticals has changed significantly. efficacy in humans. Hence, they are excellent starting point for
Nutraceuticals, which combines nutrition and pharmaceuticals the design of novel therapeutic drugs (Fosgerau and Hoffmann
together, and functional foods are food components or food 2015).
additives that provide beneficial health effects to the body by The advent of the modern drug era has started during World
reducing the risk of certain disease or any health concerns War I with the introduction of opiate morphine and the cyclic
(Admassu and others 2015). peptide penicillin and this was quickly followed by the introduc-
Food metabolism in the body releases specific molecular func- tion of the (poly) peptide insulin in early 1920s with the emerging
tional groups or their derivatives. These specific groups are in- of new disease treatment standards (Uhliga and others 2014). Since
volved in the therapeutic activities of functional foods and nu- then, the number of peptide drugs entering to clinical trials is in-
traceuticals (Agyei and Danquah 2012). Dietary bioactive peptides creasing progressively: it was 1.2/y in the 1970s, 4.6 in the 1980s,
9.7 in the 1990s and 16.8 in the 2000s (Danquah and Agyei 2012).
Currently, nearly 140 peptide drugs are in clinical trials, about 500
are in preclinical development (Fosgerau and Hoffmann 2015) and
JFDS-2017-0914 Submitted 6/7/2017, Accepted 11/13/2017. Authors are with more than 60 are in a market approved by U.S. Food and Drug
the State Key Lab. of Food Science and Technology, Jiangnan Univ., 1800 Lihu
Avenue, Wuxi, 214122, Jiangsu, China. Author Admassu is also with the Dept.
Administration (FDA) (Thundimadathil 2012; Fosgerau and Hoff-
of Food Process Engineering, Addis Ababa Science and Technology Univ., P. O. Box mann 2015; Lau and Dunn 2016), as of 2016 (Lau and Dunn 2016)
16417, 1000, Addis, Ababa, Ethiopia. Authors Yang and Zhao is also with the generating more than $13 billion in annual sales. The tremendous
School of Food Science and Technology, Jiangnan Univ., 1800 Lihu Ave Wuxi, increase of interest in peptide-based therapeutics is due to the ad-
214122, Jiangsu, China. Author Gasmalla is also with the Dept. of Nutrition and vances in drug delivery systems in the last 10 y. Certain peptides
Food Technology, Faculty of Science and Technology, Omdurman Islamic Univ., P.O.
Box 382, 14415, Khartoum, Sudan. Direct inquiries to authors Yang and Zhao can pass through cell membranes and are used as carriers for tar-
(E-mail: yrj@jiangnan.edu.cn, zhaow@jiangnan.edu.cn). geted drug delivery. The use of peptides is also growing in medical
diagnostics, nutraceuticals, antimicrobial, and cosmetics.

C 2017 Institute of Food Technologists

 R

doi: 10.1111/1750-3841.14011 Vol. 00, Nr. 00, 2017 r Journal of Food Science 1
Further reproduction without permission is prohibited
Hypotheses in Food Science
Concise Reviews & Bioactive peptides from seaweed . . .

Figure 1–Production and wide range of activities

exhibited by bioactive peptides.

Food-derived bioactive peptides commonly contain 2 to 20 seaweed bioactive constituents including protein are intracellular
amino acids and they are inactive when encrypted in their native under a highly rigid and structural complex algal cell wall, which
protein structure. They need to be released by protein degrada- is a major obstacle to the efficient extraction and digestibility of
protein fractions (Wang and others 2010a, 2010b; Harnedy and
tion in either of the following ways to perform their specific roles
(Moller and others 2008; Udenigwe 2014; Capriotti and others FitzGerald 2011; Fleurence and others 2012). This is indicating
2015): (i) endogenous and exogenous microbial enzymatic action that the nature of seaweed protein is highly cohesive with polysac-
charides.
(fermentation of food); (ii) food processing and gastrointestinal di-
gestion of dietary proteins (in vitro or in vivo digestion) using various
The first step in the production of bioactive peptides is identify-
proteolytic enzymes, such as pepsin, trypsin, alcalase, and pancre-ing appropriate protein sources and selecting extraction methods
atin (Erdmann and others 2008, DiBernardini and others 2011, (Cheung and others 2015; Li-Chan 2015). As mentioned above,
Agyei and Danquah 2012, Capriotti and others 2015). Depend- the cell wall polysaccharides and their structural complexity and
ing on their amino acid sequence, these peptides can accomplish rigidity resulted in inadequate extraction and utilization of the
intracellular bioactive proteins from seaweeds (Wang and others
wide-range of activities (Figure 1) such as antioxidant, cholesterol-
lowering capacity, enhancing mineral absorption, immunomodu- 2010a, 2010b), and this in turn results in low extraction yield and
latory, antimicrobial, antithrombotic, antiobesity & antidiabetics,limited the application of seaweed proteins and peptides. To facil-
and blood pressure-lowering (Hartmann and Meisel 2007; Erd- itate the disruption of the cell wall and gain access to the seaweed
mann and others 2008; Capriotti and others 2015). protein, grinding in liquid nitrogen approach was used. However,
Many bioactive peptides can be derived from a wide range of this approach is not cost effective at industrial scale and not fully
protein-rich resources, such as bovine and human milk, fish of efficient in the degradation of cell wall. The efficiency of classic
various species, egg, meat, soybean, rice, sunflower and different extraction methods is substantially hindered by high viscosity and
cereals. These potential peptides can be used as functional ingre- anionic bonding of these cell-wall polysaccharides with glycopro-
dients in the prevention of diseases (Hartmann and Meisel 2007; teins and their presence in the cell wall in large quantities (Du-
Erdmann and others 2008; Lafarga and Hayes 2016). Recently, may and others 2013). New approaches have recently been avail-
the knowledge of diverse bioactive compounds of seaweed have able to improve protein extraction efficiencies to obtain desirable
opened up potential opportunities for development of pharmaceu- functional properties. These include: microwave-assisted extrac-
ticals (Aneiros and Garateix 2004; Martinez-Augustin and others tion, supercritical fluid extraction, pressurized solvent extraction,
2014). As a result, seaweeds having medicinal applications, and ultrasound-assisted extraction, pulsed electric field-assisted extrac-
their known functional therapeutic properties have been screened tion and enzyme-assisted extraction (Wijesinghe and Jeon 2012;
(Jo and others 2016). This review centers on therapeutic effects Cheung and others 2015). These technologies allow the produc-
of seaweed protein–derived peptides, particularly that have an- tion and isolation of bioactive substances of interest with functional
tihypertensive (ACE inhibition), antioxidant and antidiabetic ef- properties through distraction of the cell wall polysaccharides (Ngo
fects. The isolation methods of peptides, current status and futureand others 2012).
prospects of peptides are also discussed. The use polysaccharidase enzymes such as Viscozyme R
,

R R
Cellulase(Celluclast ), xylanase (Shearzyme ), κ-carrageenase,
Production and Isolation of Bioactive Peptides β-agarase, Ultraflo R
(β-glucanase) for cell disruption prior to pro-
from Seaweed tein extraction appears to increase protein yield (Fleurence 1999;
The structure and biological properties of seaweed proteins are Bleakley and Hayes 2017). It has been reported that a simultaneous
still poorly documented. However, it has been reported that most application of Cellulase and xylanase on Palmaria palmata seaweed

2 Journal of Food Science r Vol. 00, Nr. 00, 2017

 Hypotheses in Food Science
Bioactive peptides from seaweed . . .

Concise Reviews &

improved protein extraction efficiency with a factor of 2.5 to 3.5 bioreactor technology, which coupled enzymatic hydrolysis and
depending on the concentration of enzymes and harvesting sea- membrane separation (CEH-MS) in a multistep recycling sys-
son. Particularly, this treatment has increased the R-Phycoerythrin tem and fractionate the hydrolysates according to ranges of their
protein by 20% to 23% than without enzyme extraction method molecular weight. This system utilizes the benefits of biochemical
(Joubert and Fleurence 2007). Another study reported that xy- engineering and membrane separation techniques to have effi-
lanase increased extracted protein yield from P. palmata by ap- cient separation of target components. Following the chromato-
proximately 67% (Harnedy and FitzGerald 2013a). However, the graphic approaches, liquid chromatography–mass spectrophotom-
enzyme: substrate concentration required (48.0 × 103 units/ etry (LC–MS) and mass–mass spectrophotometry (MS–MS) are
100 g) was high making it less feasible for its applicability in in- performed for the identification of the amino acid sequence of
dustrial scale. the isolated peptides to characterize their molecular structures and
Ultrasound pretreatment for protein extraction from Ascophyl- masses (Samarakoon and Jeon 2012), and then bioactivity is vali-
lum nodosum with a probe type of ultrasound equipment with dated by testing chemically synthesized pure peptides.
750 W capacity and 20 kHz frequency; amplitude levels of 22.8
and 68.4 µm was employed and compared with acid or alka- Bioactivities of Seaweed Protein-Derived Peptides
line treatment alone (Kadam and others 2016). This treatment has As a natural origin, protein-derived peptides can be used as
increased the protein extraction yield by 540% and 27%, respec- persuasive alternatives in the pharmaceutical and biotechnolog-
tively and reduced the processing time from 60 to 10 min (Kadam ical industries for chemosynthetic drug candidates. This is due
and others 2016). In addition, Qu and others (2013a) suggested to an ever-increasing consumer awareness of safety and the low
that the use of 2 alternating counter-current frequencies (15 and price (Jao and others 2015), the discovery of the bioregulatory
20 kHz) improves protein extraction on Porphyra yezoensis, and role of different endogenous peptides in the organism, and the
the yield was increased by 50%, with a reduction of the extraction understanding of the molecular mechanism of actions of bioactive
processing time by 18% when compared with monofrequency peptides on a specific cellular targets has augmented (Aneiros and
ultrasound-assisted extraction. Ultrasound-assisted solvent extrac- Garateix 2004). Due to their extraordinary diversity (Harnedy and
tion to recover high-added value compounds from the microalgae FitzGerald 2011), seaweeds are being explored for various com-
Nannochloropsis spp. was reported as a promising tool. The ex- mercial food, agricultural & horticultural, pharmaceutical, cos-
traction yields for ultrasound-assisted method was 2 times higher metic, and bioenergy applications (Beaulieu and others 2016).
than that of conventional water extraction and processing time They are potential reservoirs of novel biologically active com-
had a significant influence on antioxidant compounds recovery ponents; more specifically, they are rich sources of proteins and
(Parniakov and others 2015). amino acids and thus seaweeds can be used as a potential start-
After the extraction, proteins are subjected to hydrolysis in order ing materials in the production of (Harnedy and FitzGerald 2011)
to release functional peptide fragments with their specific bioac- bioactive peptides with a wide range of bioactivities, depending
tivities. Among the different hydrolysis methods, enzymatic hy- on their structure, composition, and their amino acids sequence
drolysis is favored by nutraceutical and pharmaceutical industries, (Ngo and others 2012; Daud and others 2016).
which avoids harsh chemical and physical treatments. More im-
portantly, functional properties and nutritional values can also be Antihypertensive peptides
preserved (Cheung and others 2015; Li-Chan 2015). As it is noted Cardiovascular diseases (CVD), including heart diseases and
previously, the bioactive peptides from the inner cellular seaweed stroke are major syndromes that affect the human circulatory sys-
like other protein sources, can be obtained basically by hydrolysis tem (Collins and others 2016). The major risk factor for CVD
using digestive enzymes, proteolytic enzymes or proteolytic mi- is hypertension, which is the elevation of arterial blood pressure
croorganisms during fermentation (Samarakoon and Jeon 2012). (Kim and Wijesekara 2010; Fitzgerald and others 2014; Cheung
Table 1 and 2 shows that enzymes, including pepsin, trypsin, pa- and others 2015; Collins and others 2016) and it affects 15% to
pain, chymotrypsin, alcalase, fungal proteases and Flavourzyme, 20% of the global population (Ko and others 2011). Renin and
and Corolase PP have been used more commonly for hydrolysis angiotensin converting enzyme (ACE) are the 2 key enzymes in
of seaweed proteins in producing ACE inhibitory and antioxidant renin-angiotensin system (RAS), the endocrine system that reg-
peptides. In this enzymatic hydrolysis process, the encrypted pep- ulates peripheral blood pressure (Harnedy and FitzGerald 2013b;
tides can be released to play their specific role. These proteolytic Cheung and others 2015). ACE is a multifunctional enzyme which
hydrolyzing enzymes can work either separately or in a serial com- plays a vital role in the regulation of blood pressure (Shi and oth-
bination of them for the production of bioactive peptides, which ers 2004; Collins and others 2016) and bradykinin degradation, a
range from 2 to 20 amino acid compositions. blood pressure lowering peptide in the kallikrein–kinin system (Shi
The hydrolysis products, bioactive peptides, need to be fur- and others 2004; Liu and others 2010). When blood flow to the
ther concentrated and fractionated in to their different molecular kidneys is low, renin is produced, and converts angiotensinogen to
weight cut off (MWCO) to isolate peptide of interest for a particu- inactive angiotensin-I (Decapeptide = Asp-Arg-Val-Tyr-Ile-His-
lar bioactivity. Usually an ultrafiltration membrane and gel perme- Pro-Phe-His-Leu) (Figure 3), which is converted to the potent
ation chromatography are the usual methods used to fractionate vasoconstrictor angiotensin-II (octapeptide = Asp-Arg-Val-Tyr-
and separate peptides from bulk hydrolyzed mixtures into frac- Ile-His-Pro-Phe) by ACE. In addition, angiotensin-II is involved
tions having various molecular weights (Figure 2) (Harnedy and in the release of Na-retaining steroid, aldosterone, from the adrenal
FitzGerald 2011; Cheung and others 2015). Ion exchange, affin- cortex, resulting in raised blood pressure (Shi and others 2004;
ity chromatography and high performance liquid chromatography Torruco-Uco and others 2009; Harnedy and FitzGerald 2013b;
(HPLC) are also the most important chromatographic approaches Cheung and others 2015).
(Figure 2) widely used for purification and enrichment of bioactive One of the key therapeutic approaches in the management
components (Agyei and Danquah 2011; Harnedy and FitzGerald of hypertension is inhibition of ACE (Wijesekara and Kim
2011; Li-Chan 2015). Qu and others (2015) have reported a novel 2010). ACE inhibitors block conversion of angiotensin I into

Vol. 00, Nr. 00, 2017 r Journal of Food Science 3

Hypotheses in Food Science
Concise Reviews & Bioactive peptides from seaweed . . .

Table 1–ACE and renin inhibitory peptides derived from seaweeds: source, enzyme used for hydrolysis, and IC50 value.

Isolated and purified peptides

IC50 value of IC50 values of

Protein source Production method Amino acid sequence peptides positive control Reference
3 3
Palmaria palmata Papain hydrolysis Ile-Arg-Leu-Ile-Ile-Val- 3.344 × 10 µM 1 × 10 µM Fitzgerald and others
Leu-Met-Pro-Ile- 2012
Leu-Met-Ala
Chlorella ellipsoidea Alcalase hydrolysis Val–Glu–Gly–Tyr 128.4 µM Ko and others 2012
Chlorella vulgaris Pepsin hydrolysis Ile–Val–Val–Glu 315.3 µM Suetsuna and Chen
Ala-Phe-Leu 63.8 µM 2001
Phe-Ala-Leu 26.3 µM
Ala-Glu-Leu 57.1 µM
Val-Val-Pro-Pro-Ala 79.5 µM
Ile-Ala-Glu 34.7 µM
Spirulina platensis Pepsin hydrolysis Phe-Ala-Leu, 11.4 µM Suetsuna and Chen
Ala-Glu-Leu, 2001
Ile-Ala-Pro-Gly,
Val-Ala-Phe 35.8 µM
Algae protein waste Pepsin hydrolysis Val-Glu-Cys-Tyr-Gly- 29.6 l µM Sheih and others 2009a
Pro-Asn-Arg-Pro-
Gln-Phe
Wakame Protease S“Amano” Val-Tyr 35.2 µM Sato and others 2002
(Undaria digests Ile-Tyr 6.1 µM
pinnatifida) Ala-Trp 18.8 µM
Phe-Tyr 42.3 µM
Val-Trp 3.3 µM
Ile-Trp 1.5 µM
Leu-Trp 23.6 µM
Wakame Hot water extract Tyr-His 5.1 µM Suetsuna and others
(Undaria Lys-Tyr 7.7 µM 2004
pinnatifida) Phe-Tyr 3.7 µM
Ile-Tyr 2.7 µM
Wakame (Undaria Pepsin digest Ala-Ile-Tyr-Lys 213 µM Suetsuna and Nakano
pinnatifida) Tyr-Lys-Tyr-Tyr 64.2 µM 2000
Lys-Phe-Tyr-Gly 90.5 µM
Tyr-Asn-Lys-Leu 21 µM
Dulse (Palmaria Thermolysin VYRT 0.14 µmol Furuta and others 2016
palmata) hydrolysis LDY 6.1 µmol
LRY 0.044 µml
FEQDWAS >2.8 µmol
Hydrolysates
Aqueous protein extract 0.19 mg/mL
hydrolysate by: >2 mg/mL
Alcalase 0.33 mg/mL
Corolase PP
Flavourzyme
Palmaria palmata Alcalase, Corolase PP Alkaline protein extract 0.41 mg/mL Captopril = 15 µM Harnedy and
and Flavourzyme hydrolysate by: >2 mg/mL Enalapril = 177 µM FitzGerald 2013b
hydrolysis Alcalase 0.78 mg/mL
Corolase PP
Flavourzyme
Alkaline and aqueous 0.28 mg/mL
mixture protein >2 mg/mL
extract hydrolysate by: 0.34 mg/mL
Alcalase
Corolase PP
Flavourzyme
Porphyra yezoensis Alcalase hydrolysis Hydrolysates 1.6 g/L Qu and others 2010
Porphyra yezoensis Alcalase hydrolysis and Hydrolysates 0.516 g/L Qu and others 2015
memb. separation
Dulse Chymotrypsin Protein hydrolysate – Beaulieu and others
(Palmaria palmata) hydrolysis fraction (10 kDa) 2016
Porphyra columbina Fungal protease and Residual seaweed cake – Cian and others 2013
flavourzyme hydrolysate
hydrolysis
Pyropia columbina Alcalase(A) Hydrolysates of (A and 1.2 to 1.7 g/L Cian and others 2015
Flavourzyme (F) AF)

IC50 : The concentration of ACE inhibitory peptides required to inhibit 50% of the ACE activity.

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 Hypotheses in Food Science
Bioactive peptides from seaweed . . .

Concise Reviews &

Table 2–Antioxidant activity of seaweed protein-derived peptides.

Source Production Amino acid Scavenging IC50 value IC50 value of BHT, Reference
method sequence activity peptides Trolox
Algae protein Pepsin hydrolysis VECYGPNRPQF Hydroxyl radical 8.3 µM 44.4 µM, 2.0 µM Sheih and others
waste 2009a
Superoxide radical 7.5 µM 218.1 µM, 24.8 µM
Peroxyl radical Peptide > ascorbic
acid > BHT
DPPH radical 58.0 µM 968.3 µM, 23.0 µM
ABTS radicals 9.8 µM 57.4 µM, 32.5 µM
DPPH radical
Palmaria palmata Chymotrypsin Protein hydrolysate Ferrous – – Beaulieu and others
(dulse) hydrolysis fraction ion-chelating 2016
(<10kDa) ability, Oxygen
radical absorbance
capacity
Porphyra Separate & Protein hydrolysate ABTS radical 2.1 to 2.4 g/L – Cian and others
columbina sequential fraction DPPH radical 2.7to 3.0 g/L 2012b
hydrolysate of Oxygen radical –
trypsin and absorbance –
alcalase capacity (ORAC)
enzyme, Copper-chelating
activity(CCA)
Fungal protease Residual seaweed ABTS radical 1.01 g/L – Cian and others
concentrate & cake hydrolysate DPPH radical 0.91 g/L 2013
Flavourzyme Trolox equivalent –
hydrolysis antioxidant –
capacity(TEAC)
Oxygen radical
absorbance
capacity(ORAC)
Pyropia Alcalase(A) Hydrolysates of ABTS radical 0.6 to 1.0 g/L – Cian and others
columbina Flavourzyme (F) (A and AF) DPPH scavenging 1.0 to 1.6 g/L 2015
activity 2.2 to 4.1
TEAC (mmol 63.4 to 81.2
Trolox 23.2 to 53.8
equivalent g−1
protein)
CCA (mg EDTA
equivalent
g−1 protein)
Reducing
power(µg ascorbic
acid equivalent
g−1protein)
Palmaria palmata Alcalase, Aqueous, alkaline Ferric reducing – – Harnedy and
Corolase PP and mixture of antioxidant power FitzGerald 2013b
Flavourzyme the 2 protein (FRAP)
hydrolysis extract Oxygen radical
hydrolysates antioxidant
capacity (ORAC)

angiotensin II, resulting in blood vessel relaxation and decreased Within the food industry, marine organisms are becoming the
blood pressure (Cheung and others 2015). Pharmaceutical com- focus of research due to their numerous positive health effects.
panies have marketed various ACE inhibitors for the management Several studies have described a number of marine-derived bioac-
of hypertension through the reduction of angiotensin II concen- tive peptides with potent ACE inhibitory activity (Wijesekara and
tration and hence reduction of blood pressure. But these drugs Kim 2010). More specifically, increasing consideration has been
have various undesirable side effects, suggesting the need for nat- given to macro algae (seaweed) as a potential source owing to
ural food derived inhibitors of ACE for controlling hypertension, their high protein content (Walker and others 2009; Harnedy and
with minimal adverse side effects (Torruco-Uco and others 2009). FitzGerald 2011). Studies have reported that bioactive peptides
Food protein-derived peptides are considered to be milder, safer, and protein hydrolysates of seaweed can inhibit ACE and renin
and easily absorbed when compared with synthetic drugs (Liu and enzymes (Table 1) (Shi and others 2004; Sheih and others 2009a;
others 2010; Cheung and others 2015). The peptides with ACE Fitzgerald and others 2012; Ko and others 2012; Harnedy and
inhibitory activity have been isolated from a number of animal and FitzGerald 2013b; Qu and others 2015; Furuta and others 2016).
vegetable sources of protein hydrolysates (Otte and others 2007; Fitzgerald and others (2012) has identified 11 (IRLI-
Je and others 2009; Quist and others 2009; Liu and others 2010; IVLMPILMA, ILMA, MNEIVALMI, ILMA, LMAASWAIY,
Qu and others 2013b; Malomo and others 2015; Zhou and others ILPSILVPLV, PSIL, LVPLVGLV, PLVGLVFPAI, VFPAIAM, FPAI,
2015; Daud and others 2016). and PAIA) renin inhibitory bioactive peptides from papain

Vol. 00, Nr. 00, 2017 r Journal of Food Science 5

Hypotheses in Food Science
Concise Reviews & Bioactive peptides from seaweed . . .

Figure 2–Extraction, purification and isolation procedures of bioactive peptides from seaweed protein.

hydrolysate of Palmaria palmata. All elucidated peptides were chem- VDHY, IKGHY, LKNPG, LDY, LRY, FEQDWAS) were isolated
ically synthesized and assayed for their renin inhibitory abilities from dulse (Palmaria palmata) hydrolysate and the synthetic pep-
and 1 tridecopeptide [IRLIIVLMPILMA (Arg-Leu-Ile-Ile-Val- tide LRY (IC50 : 0.044 µmol) has shown remarkably high ACE
Leu-Met-Pro-Ile-Leu-Met-Ala)] has inhibited renin by 50% at a inhibitory activity (Furuta and others 2016). ACE inhibitory ac-
concentration of 3.344 × 103 µM (±0.31). This peptide was well tivity of the hydrolysates generated by Alcalase, Corolase PP and
comparable with the positive control (Z-Arg-Arg-Pro-Phe-His- Flavourzyme enzymes from aqueous, alkaline and the mixture of
Sta-Ile- His-Lys-(Boc)-OMe), which inhibited renin by 50% at the 2 solvent protein extracts of P. palmata was reported (Harnedy
a concentration of 1 × 103 µM (Fitzgerald and others 2012). In and FitzGerald 2013b). Significantly higher ACE inhibitory activ-
another study, 9 ACE inhibitory peptides (YRD, AGGEY, VYRT, ity was observed with IC50 value of: 0.19, >2, and 0.33 mg/mL for

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 Hypotheses in Food Science
Bioactive peptides from seaweed . . .

Concise Reviews &

Figure 3–Role of ACE blood pressure regulation in renin—angiotensin–aldosterone system and the inhibitory action of ACE inhibitors (Shi and others
2004).

Alcalase, Corolase PP, and Flavourzyme hydrolysates, respectively Most studies mentioned that ACE inhibitory peptides are compet-
from aqueous protein extracts, 0.41, >2, and 0.78 mg/mL for itive inhibitors; however, noncompetitive or uncompetitive mode
Alcalase, Corolase PP, and Flavourzyme hydrolysates, respectively of inhibition has also been reported. For example, a potent ACE
from alkaline protein extracts and 0.28, >2, and 0.34 mg/mL for inhibitory peptide with amino acid sequence, Val–Glu–Gly–Tyr
Alcalase, Corolase PP, and Flavourzyme hydrolysates, respectively (MW: 467.2 Da, IC50 value of 128.4 µM) from green microalgae
from alkaline and aqueous mixture protein extracts. The IC50 (Chlorella ellipsoidea) was isolated and the Lineweaver–Burk plots
values of 15 and 177 nM were obtained for the synthetic ACE suggest competitive inhibition (Ko and others 2012). Furthermore,
inhibitory drugs captopril and enalapril, respectively. ACE and the activity of this purified peptide against ACE was not affected
renin inhibitory peptides derived from seaweed protein including when incubated under simulated gastrointestinal conditions, sig-
their source (seaweed species), method(s) used to produce or type nifying that Val–Glu–Gly–Tyr is stable against gastrointestinal en-
of enzymes used for hydrolysis, and IC50 values of these peptides zymes of pepsin, trypsin and chymotrypsin. The antihypertensive
reported by many researchers are summarized in Table 1. effect of the purified peptide in spontaneously hypertensive rats
Although the precise inhibition mechanism of ACE-inhibitory (SHR) was also evaluated by measuring the change of systolic
peptides is not clearly known, the in vitro inhibition mode of pep- blood pressure (SBP) for 0, 2, 4, 6, and 8 h after single oral ad-
tides is evaluated by performing Line weaver–Burk plots (Shi and ministration with a dose of 10 mg/kg body weight. The peptide
others 2004; He and others 2013) and the potency is stated by their reduced systolic blood pressure significantly and the activities were
IC50 value, which is the concentration of the inhibitory peptides maintained for 6 h. The maximum decrements in SBP of the pep-
required to inhibit 50% of ACE activity (He and others 2013). tide and captopril (positive control) were 22.8 and 35.4 mmHG at

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Hypotheses in Food Science
Concise Reviews & Bioactive peptides from seaweed . . .

4 h, respectively (Ko and others 2012), a reason for optimism that preservatives is pushing the researchers and food manufacturing
peptides could be used as alternatives to synthetic ACE inhibitors. industries to look for safe food antioxidants from various natu-
Another study revealed that noncompetitive pattern of ACE in- ral sources (Kim and others 2001; Heo and others 2005; Kim
hibition was obtained for the peptide (Val-Glu-Cys-Tyr-Gly-Pro- and Wijesekara 2010; Gupta and Abu-Ghannam 2011). In view
Asn-Arg-Pro-Gln-Phe) isolated from algae protein waste (Sheih of this, food protein hydrolysates and bioactive peptides are given
and others 2009a). This purified peptide was subjected to incu- priority (Balti and others 2011). For such and other diverse health-
bation at temperature range of 40 to 100 °C and pH range 2 promoting properties, bioactive peptides from macro algae are be-
to 10 to investigate the pH and heat stability. Interestingly, the ing investigated increasingly with remarkable progresses (Cian and
residual activity showed that the purified peptide retained its ACE others 2012a, 2012b; Harnedy and FitzGerald 2013b; Beaulieu
inhibitory activity. The inhibitory activity of the purified peptide and others 2016, 2013).
was also not affected by the gastrointestinal enzyme digestion of Harnedy and FitzGerald (2013b) have investigated the antioxi-
pepsin and pancreatin (Sheih and others 2009a). Seven ACE in- dant potential of Palmaria palmata for aqueous, alkaline and mix-
hibitory dipeptides with amino acid sequence (Val-Tyr, Ile-Tyr, ture of aqueous and alkaline protein fraction hydrolysates with
Ala-Trp, Phe-Tyr, Val-Trp, Ile-Trp, and Leu-Trp) were isolated the food-grade proteolytic activity (Alcalase 2.4 L, Flavourzyme
from Wakame (Undaria pinnatifida) by (Sato and others 2002). They 500 L, and Corolase PP). The result confirmed that the oxygen
exhibited different inhibition mode against ACE activity. Val-Tyr radical absorbance capacity (ORAC) and ferric reducing antiox-
and Val-Trp showed a competitive inhibition; Ile-Tyr and Leu-Trp idant power (FRAP) values of these hydrolysates ranged from
showed a noncompetitive inhibition, and the other peptides (Ala- 45.17 to 467.54 and from 1.06 to 21.59 µmol trolox equiva-
Trp, Phe-Tyr, and Ile-Trp) showed uncompetitive inhibition. For lents/g protein, respectively. Four hydrolysates of trypsin, alcalase,
the evaluation against spontaneously hypertensive rats (SHRs), and a combination of 2 sequential hydrolysates of first cold water
Val-Tyr, Ile-Tyr, Phe-Tyr, and Ile-Trp significantly reduced the protein extract (PF) derived from Porphyra columbina were analyzed
blood pressure when treated with a single oral administration dose (Cian and others 2012b). These hydrolysates exhibited antioxidant
of 1 mg/kg mouse (Sato and others 2002). In a report by Suetsuna capacity of DPPH, TEAC, ORAC, and copper-chelating activity.
and others (2004), 10 dipeptides (Tyr-His, Lys-Trp, Lys-Tyr, Lys- It has been also described that radical scavenging activities (TEAC
Phe, Phe-Tyr, Val-Trp, Val-Phe, Ile-Tyr, Ile-Trp, and Val-Tyr) iso- and DPPH inhibition) were attributed by the residual cake protein
lated from the hot water extract of U. pinnatifida decreased blood hydrolysate of phycocolloids-obtaining process of red seaweed P.
pressure in SHR. columbina (Cian and others 2013). Identified peptides and protein
hydrolysates from seaweed having potential antioxidant properties
Antioxidant peptides are summarized in Table 2.
The oxidation of lipids and proteins of food products (Dong The transport path of peptides in the body is mainly affected by
and others 2016) during processing or storage by reactive oxygen molecular size and structural properties, such as hydrophobicity.
species (ROS), such as superoxide anion radical (O2 − •), hydroxyl It has been described that peptides with 2 to 6 amino acids are
radical (·OH), hydrogen peroxide (H2 O2 ), singlet oxygen (1 O2 ), absorbed more readily than proteins and free amino acids. Some
and Peroxyl radical (•OOR) (Li and others 2009; Gu and others other researchers reported that small (di-and tripeptides) and large
2014), is the major reason for food deterioration that would re- peptides (10 to 50 amino acids) can exhibit their biological func-
duce consumer acceptability of food due to undesirable changes tions at the tissue level, since they can cross intestinal barrier intact.
of quality and the possible production of toxic compounds (Balti However, in general, the chance of peptides to pass the intestinal
and others 2011; Ganesan and others 2011; Dong and others barrier decreases as their molecular weight increases (Sarmadi and
2016). Consuming these potentially toxic products may trigger Ismail 2010). It has been recorded that presence of proline and
various human chronic diseases, including cancer, arteriosclerosis, hydroxyl proline results in peptide resistance to digestive enzymes,
aging (Ganesan and others 2011; Dong and others 2016) diabetes especially tripeptides with Pro-Pro at the C-terminal that are re-
mellitus, inflammation, coronary heart diseases, and neurological sistant to proline-specific peptides (FitzGerald and Meisel 2000).
disorders, such as Alzheimer’s disease (Kim and Wijesekara 2010; Generally, most of the reported seaweed protein–derived peptides
Balti and others 2011). Therefore, to prevent food products from with antioxidant activity were those with low molecular weights
such deteriorations and protect consumers against the serious dis- (Wang and others 2010a, 2010b; Cian and others 2012a, 2012b,
eases, 1 key strategy is inhibition of lipid peroxidation occurring in 2013, 2015).
the living body and food products by using antioxidant substances
or preservatives (Choe and Min 2009; Balti and others 2011). An- Antidiabetic peptides
tioxidants or preservatives are chemical components in biological Diabetes mellitus (DM) is increasing at alarming rate; 336 mil-
materials, relatively found in low concentrations that prolong the lion people are affected in the world and projected to 552 mil-
shelf life of food by delaying or inhibiting oxidation of a substrate lion people by 2030. DM is creating a detrimental health effects,
in the food (Balboa and others 2013; Power and others 2013). and social and economic burden (Anguizola and others 2013;
Bioactive peptides are the most commonly occurring antioxidant RSC Adv. 2015). The major cause is insufficient insulin pro-
substances in food. duction in the pancreas or insulin resistance resulting in blood
Synthetic substances, for example, butylated hydroxyanisole glucose dysregulation. DM is associated with many cardiovas-
(BHA), butylated hydroxytoluene (BHT), propylgallate, TBHQ cular diseases and related conditions (Barde and others 2015) .
(tert-butyl hydroquinone) have better antioxidant activity and re- Type I (insulin-dependent) and type II (noninsulin dependent) di-
tarding effects of oxidation than those of the natural antioxidants. abetes are the most prevalent forms of this disease. Type-I diabetes,
However, the use of these chemical antioxidants needs strict con- which accounts approximately 5% to 10%, is caused by the failure
trol due to their potential health risks and toxicity (Heo and others of the pancreas to produce insulin due to beta cell destruction
2005; Balti and others 2011; Gu and others 2014). Moreover, in- (Anguizola and others 2013; Kim and others 2014; Chiara and
terest of consumers toward minimally processed foods and natural Adrianna 2016), while type-II diabetes (90% to 95%) is due to

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 Hypotheses in Food Science
Bioactive peptides from seaweed . . .

Concise Reviews &

either low production of insulin or inadequate cellular response to for alkaline protein fraction hydrolysate, 4.24 ± 0.02, >5.00, and
insulin. Obesity, aging, sedentary life, and family history increases 2.26 ± 0.09 mg/mL for aqueous and alkaline combined protein
its incidence and severity (Anguizola and others 2013; Chiara and fraction hydrolysate of Alcalase, Flavourzyme, and Corolase PP en-
Adrianna 2016). Type-II diabetes receives more attention than zyme, respectively. These results suggest the potential of seaweed
type-I diabetes as it is a preventable disease (Chiara and Adrianna peptides for their antidiabetic properties.
2016). Type-I diabetes treatment is mainly dependent on injec-
tion of exogenous insulin to sustain normal life, whereas, type-II Future Prospects of Bioactive Peptides
diabetes requires insulin injection in a very less cases. Food bioactive peptides are multipurpose biological materials
The major source of blood glucose is the hydrolysis of dietary and the potentiality of bioactive peptides has been noted through
carbohydrates by carbohydrate hydrolyzing enzymes and subse- their significant contribution to the human health. The research
quent absorption by small intestine. Therefore, inhibition of these on these multifunctional materials is expected to increase dramati-
enzymes such as α-amylase and α-glucosidase is one of the promis- cally attracting different professionals including food technologists,
ing therapies, especially in the treatment of type II diabetes (Kim biotechnologists, medical doctors, pharmacologists, and neurol-
and others 2008; Xindi and others 2016). The 2 insulinotropic ogists. Certainly, seaweed peptides will find increased usage to
incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose treat health risks such as obesity, hypertension, diabetes and other
independent insulinotropic polypeptide (GIP) are used to enhance metabolic syndromes. The use of membrane-penetrating peptides
glucose-dependent insulin secretion and to regulate postprandial will increase to address the number of intracellular targets, which
blood glucose level. The cleavage of the N-terminal X-Proline are currently “undruggable” targets. Seaweed peptides could be
and X-Alanine sequence from these peptide hormones by DPPIV demonstrated to similar mechanism of action toward health ben-
inactivates these incretin hormones. Therefore, another alternative efits as compared with other efficient drugs and may take the
approach to develop antidiabetic therapies is based on the devel- lead as alternative natural medicinal ingredients. Although peptide
opment of incretin analogues and DPPIV inhibitors (Harnedy and professionals have made a huge stride toward identifying peptides
FitzGerald 2013b). Although it is not well evidenced for the inhi- with therapeutic potential, much remains toward discovering more
bition mechanism of DPPIV by seaweed derived peptides, many natural bioactive peptides using all the biological taxonomy. We
are reported that the analogue has been designed based on the anticipate that extensive screening and exploitation of seaweeds for
knowledge of the enzyme’s substrate specificity. Many are dipep- bioactive peptides will increase. With increasing demand for large
tide derivatives, and are small, low molecular weight compounds quantities of peptides and their greater complexity, it is neces-
with good oral availability, and they function as competitive in- sary to look for better ways of manufacturing peptides. Therefore,
hibitors of the enzyme (Stöckel-Maschek and others 2003; Deacon further advances and improvement in extraction and isolation of
and Holst 2006). peptides from seaweed, purification technology, and solid phase
Managing obesity, changing life style and different oral antidi- peptide synthesis chemistry to tackle current challenges in large-
abetic drug administration such as biguanides, sulfonylureas, α- scale manufacturing of peptides is expected, especially to reduce
glucosidase inhibitors are available therapies. However, their ef- high production costs and to enhance complex modifications.
ficiency is limited and have various side effects. Moreover, they
cannot restore destroyed islet β-cells, and finally causing the patient Conclusion
to be insulin-dependent (Liu and others 2014; Barde and others Among marine organisms, seaweeds have long been known
2015). Therefore, the search for low toxicity and long-acting nat- as therapeutic entities. Due to their rapid growing nature, high
ural antidiabetic drugs is important on improving health and the content of proteins and diverse profile of bioactive compounds,
quality of life (Liu and others 2014). Numerous bioactive pep- seaweeds can be well-positioned as an alternative resource for the
tides with various biofunctions were discovered and isolated from production of peptide-based functional diets. Seaweed derived-

R 
R
marine organisms. Nutripeptin and Hydro MN Peptide from peptides have been shown the potential to prevent CVD and dia-
marine protein hydrolysate are among these bioactive peptides. betes. However, establishing the efficacy of the seaweed peptides
These peptides are capable of lowering the postprandial blood when incorporated into foods, their ease to digestion, and inter-
glucose level and alleviating type-II diabetes (Cheung and others action with other components in the formulation of functional
2015). foods or pharmaceuticals is equivalently important. In addition,
As shown in Table 1 and 2, ACE, renin and food oxidation the problem that hinders for efficient utilization of the intracellular
inhibitory peptides and protein hydrolysates have been identified bioactive peptides due to the high degree of structural complex-
from seaweeds. Many researches has been done on solvent extracts ity and rigidity of the algal cell wall polysaccharides should also
of seaweed which has tremendous antidiabetic role. Recently, there be solved Further studies in the development of large-scale pro-
are some studies focused on antidiabetic enzymatic protein hy- duction, optimization of protein extraction methods, and peptide
drolysates and peptides. For example, Suetsuna and Saito (2001) isolation processes are important.
reported pepsin decomposed boiled laver mixture (P. yezoensis)
hydrolysate fractions that exhibited blood-sugar-lowering activity.
Similarly, Harnedy and FitzGerald (2013b) have identified poten- Acknowledgments
tial precursors for generation of peptides with DPP IV inhibitory This work was supported by the National Natural Science
activity from 3 hydrolyzed fractions of Palmaria palmata protein Foundation of China (grant No. 31522044) and the Funda-
(aqueous, alkaline, and the mixture of aqueous and alkaline pro- mental Research Funds for the Central Universities (grant No.
tein fraction hydrolysates by Alcalase 2.4 L, Flavourzyme 500 L, JUSRP51406A).
and Corolase PP enzymes. These hydrolysates have shown dipep-
tidyl peptidase (DPP) IV inhibitory activity with IC50 values of References
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