Next Article in Journal
Sustainable Palm Oil Certification Scheme Frameworks and Impacts: A Systematic Literature Review
Next Article in Special Issue
Cultivation and Biorefinery of Microalgae (Chlorella sp.) for Producing Biofuels and Other Byproducts: A Review
Previous Article in Journal
Sustainable Development of the Energy Sector in a Country Deficient in Mineral Resources: The Case of the Republic of Moldova
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Sustainability
Volume 13
Issue 6
10.3390/su13063262
sustainability-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

A Systemic Review on Microalgal Peptides: Bioprocess and Sustainable Applications

by
Raghunathan Sathya
1,
Davoodbasha MubarakAli
1,2,*,
Jaulikar MohamedSaalis
1 and
Jung-Wan Kim
2,*
1
School of Life Sciences, B. S. Abdur Rahman Crescent Institute of Science and Technology, Chennai 600048, India
2
Division of Bioengineering, Incheon National University, Incheon 22012, Korea
*
Authors to whom correspondence should be addressed.
Sustainability 2021, 13(6), 3262; https://doi.org/10.3390/su13063262
Submission received: 23 February 2021 / Revised: 2 March 2021 / Accepted: 3 March 2021 / Published: 16 March 2021
(This article belongs to the Special Issue Microalgal Bioprocess and Sustainability)
Browse Figure
Versions Notes

Abstract

:
Nowadays, microalgal research is predominantly centered on an industrial scale. In general, multipotent bioactive peptides are the advantages over focal points over utilitarian nourishment as well as nutraceuticals. Microalgal peptides are now profoundly connected with biological properties rather than nutritive. Numerous techniques are employed to purify active peptides from algal protein using enzymatic hydrolysis; it is broadly used for numerous favorable circumstances. There is a chance to utilize microalgal peptides for human well-being as nutritive enhancements. This exhaustive survey details the utilization of microalgal peptides as antioxidant, anti-cancerous, anti-hypersensitive, anti-atherosclerotic, and nutritional functional foods. It is also exploring the novel technologies for the production of active peptides, for instance, the use of algal peptides as food for human health discovered restrictions, where peptides are sensitive to hydrolysis protease degradation. This review emphasizes the issue of active peptides in gastrointestinal transit, which has to be solved in the future, and prompt impacts.

Graphical Abstract

1. Introduction

Generally, algae are renewable sources and oxygenic photosynthetic organisms, including an enormous and wide variety of species grown in aquatic environments. Algae belong to a broad polyphyletic group, ranging from the monarchy of Prokaryotic (Monera) and eukaryotic (Protista). In view of their pigments, shape, cell wall, cellular division, and structural arrangement, algae are comprehensively classified into “microalgae” and “macroalgae”. Macroalgae (seaweeds) are multicellular macroscopic nonvascular plants which grow faster and also contain chlorophyll pigment, and their size ranges up to 60 m in length. Relying upon the chlorophyll pigmentation, macroalgae are divided into chlorophyceae, rhodophyceae, and phaeophyceae, and the unicellular forms are called microalgae [1,2]. Unlike macroalgae, microalgae are microscopic unicellular organisms which cannot be seen with the naked eye. Both terrestrial and aquatic environment microalgae are present [3]. Due to their rapid growth, microalgae have an essential need for sunlight, atmospheric CO2, minerals to produce biomass, biofuels, food feed, and bioactive components. Microalgae are monetarily displayed as pharmaceuticals [4], nutraceuticals [5,6,7], cosmeceuticals, biofuels and pollution control for wastewater treatment, food additives, and aquaculture [8,9,10]. Upon comparin the microalgal biomass produced competes in both quantity and quality and is a rich source of food protein than the traditional food proteins (e.g., fish, egg, and soybeans), [11,12]. Approximately, there are 200,000 species of microalgae present in diverse groups. A significant number of these microalgal species have recently been used for multi-purposes, including phospholipids, fodder, alginic acids or alginates, recycled water treatment, biofuel and cosmeceuticals [6,13,14]. According to various investigation and advancements the enzyme protein hydrolysates from bioactive functional foods, are a good source of nutritional quality and are available at low costs from marine microorganisms [15]. The proteins, and protein hydrolysates or peptides of some notable microalgae species are profoundly connected with biological activities than being highly nutritive. They exhibit anti-oxidant [16], anti-hypertensive [17], immune-modulatory [18], anti-cancer [19], hepato-protective [15], anti-atherosclerotic [20], anticoagulant [21], anti-UV radiation, anti-osteoporosis [22] and anti-microbial [23] activities. Annually, microalgae are produced in low quantity when compared to seaweed, which has 5000 tons of dry matter per year (7.5 × 106 tons). Recently, Chlorella sp. of unicellular green algae has enormously expanded the development state of the nutritive bioactive supplement. The most common and widely used industrial species is C. vulgaris, which contains a high protein and essential amino acids EAA with an average dry weight of 51–58% [24]. The beneficial supplements of Chlorella include Vitamin B, minerals such as calcium, potassium, iron, sodium, and magnesium, carotenoids such as beta-glucan, beta carotene, chlorophyll, and the growth factor of Chlorella sp. [14,25]. Recently, globally, 30% of microalgal biomass production is sold to the feed industries [26]. The principle importance of these novel bioactive peptides, which contain high-quality proteins, and their structural diversity are still undiscovered. The isolation of these microalgal bioactive peptides is a growing demand nowadays [27]. This review emphasizes use of algal peptides bioprocess and its applications as a food for human health and the issue of bioactive peptides in the passage of a gastrointestinal study, which has to be solved in the future.

2. Development of Microalgal Bioactive Peptides from Proteins

Microalgal bioactive peptides comprises 2–20 amino acids in the length of the chain, showing analog as a hormones were released from the parent compound, which containing beneficial properties.The chemical residues gained importance due to its human health benefits and biological activities. Biologically active peptides acquired from microalgae are less revealed as functional constituents [4,28,29]. There are three unique strategies used to provide microalgal bioactive peptides, such as the extraction of chemical solvent, enzymatic protein hydrolysis, and microbial fermentation. Despite the fact that there is a loss of expected chemical residues in the byproducts such as peptides the technique of enzymatic hydrolysis is the most preferable method in the biopharmaceutical and food product industries [30,31]. This enzymatic hydrolysis is extensively used for a further separation method, which involves membrane ultra-filtration with multiple pore sizes such as 3, 5, 10, and 30 KDa and chromatography techniques, viz., size exclusion and ion-exchange [32]. In general, there are two different techniques for processing bioactive peptides such as fractionation and purification. In particular, the ultra-filtration (molecular weight) and chromatographic techniques (purification) such as ion-exchange, affinity, and gel-permeation are used for the fractionation of microalgal peptides. This technique is mainly to study consider the structural features and mass determination of microalgal peptides using LC-MS and LC-MS/MS spectrometry. Investigations are made with protein hydrolysates [31,33] and the preparation of bioactive peptide-derived microalgae proteins with different approaches. Enzymatic hydrolysis is the most common and widely used to synthesize bioactive peptides from microalgal proteins for clinical applications, and it expels the harmful substances to give a good yield and high purity, better than the organic solvent extraction. A few studies reported that enzyme-assisted extraction method provides great yield and a high amount of bioactive components. The hydrolysates of individual peptides showing bioactivity can be identified from the original protein. Currently, crypteins are recently termed peptides of novel therapeutic and they show natural bioactivities [28,34].

3. Isolation of Bioactive Peptides from Proteins

The hydrolysis of proteins into free amino acids can be determined using the equation proposed elsewhere [35]. The search for functional proteins and bioactive peptides from microalgae has increased significantly [36]. However, the isolation of proteins using organic solvent extractions delivered targeted compounds with toxic residues. Therefore, proteolytic enzyme-assisted extractions (PEAEs) were employed, resulting in high yield and enormous activities instead of organic solvent extractions. A few studies have reported ultrasound sonication, and the mechanical grinding method can be employed as well. PEAEs include pepsin, trypsin and α-chymotrypsin (gastrointestinal enzymes) [37,38,39,40,41]. In recent advancement of technology, electrophoresis combines conventional membrane filters to separate highly charged bioactive peptides, thereby making simpler by means of being quicker for separation through chromatography [42].

4. Application of Microalgal Bioactive Peptides

4.1. Antioxidant Microalgal Peptides

In our human system, the antioxidant plays a major role in reducing oxidative stress reactions. Oxidative stress causes major disease factors and mechanical imbalance among vasoconstrictors and vasodilators in hypertension progression [43]. Reactive oxygen species (ROS) is one of the factor to cause diseases, tumors, ageing, hypertension, diabetes, endothelial dysfunction, and neurological disorders [44,45]. Due to certain ecological conditions, pollution, smoke from chemicals, and an increased diet of fat and alcohol, these disorders can be highly increased. It is essential to look through these natural antioxidants as a shelter and elective hotspot for protection against ROS-induced dieases. Therefore, researchers are finding a new way to alternate dietary food supplements as an excellent resource with potent antioxidant ability and one such revelation state that microalgal seaweeds are a nutritious source with natural antioxidant stability among various marine flora and fauna.
The aromatic and hydrophobic amino acids and functional compounds exhibited antioxidant properties [29,46]. The algal peptide is found with abundance and is a source of antioxidant activity that possesses these amino acid properties represented in Table 1.
The bioactive peptides isolated from microalgae such as Navicula incerta and Chlorella sp. were investigated for its antioxidant capacity mainly on the basis of free radical scavenging, molecules, amino acids, molecular weight, and hydrophobicity [52,53]. N. incerta was hydrolyzed using Papain hydrolysates brought about in two antioxidative peptides such as PGWNQWFL and VEVLPPAEL.
Interestingly, these two peptide sequences instigated ethanol to protect the cytotoxic effect in HepG2/CYP2E1 cells due to antioxidant molecules being released by N. incerta [47]. The by-product of C. vulgaris was reported to contain various free radicals which demonstrated resistance to the intestine; however, there was no cytotoxic effect in human lung fibroblasts [46]. From the peptic hydrolysis of Chlorella ellipsiodea a pentapeptide (Leu-Asn-Gly-Asp-Val-Trp) was identified which impacted on the ability of free radical scavenging activity in kidney cells [49]. Another examination on peptide derived from C. pyrenoidosa, reported that antioxidant properties against skin fibroblasts, and also, skin cells treated with UV irradiation demonstrated total cytoprotection within 72 h [48].
Scavenging activity is carried out by C. ellipsoidea, which was found to show a unique impact on DPPH free radicals, and antioxidant peptide (LNGDVW) and enzyme-assisted extraction from Palmaria palmate (red algae) against hydrogen and H2O2 free radicals treated with proteases enzymes [54,55] detailed that Ulva sp. has mitogenic hexapeptide amino acids (Glu-Asp-Arg-Leu-Lys-Pro) denominating the purified peptides (SECMA 1) which are active on human foreskin fibroblasts. The synthesis of peptides (ELWKTF) from Gracilariopsis lemaneiformis using protein hydrolysates provides the high antioxidant activity, and the significance of the DPPH radical-scavenging activity of these peptides (ELWKTF) shows an EC50 value of 1.514 mg mL−1 [56]. The extraction and digestion of Dunaliella salina can obtain four peptides (i.e., Ile-Leu-Thr-Lys-Ala-Ala-Ile-Glu-Gly-Lys, Ile-Ile-Tyr-Phe-Gln-Gly-Lys, Asn-Asp-Pro-Ser-Thr-Val-Lys, and Thr-Val-Arg-Pro-Pro-Gln-Arg), which were identified to contain 500–1000 Da fraction. Therefore, in vitro studies showed that the Dunaliella salina is a highly potent and renewable source that can simulate gastrointestinal digestion [57].

4.2. Anticancer Microalgal Peptides:

The anticancer treatments predominantly adopted to battle malignant growths such as radiotherapy and chemotherapy have been proven to have side effects and develop resistance. In that concern, anticancer bioactive peptides have attracted researchers with their multifunctional potency, sensitivity and stability, and they have shown beneficial activities with the presence of carotenoids, flavonoids, phenolic acids and so on. However, some publications reported that the anticancer peptides from the enzymatic hydrolysis preparation of natural or synthetic peptides derived from food protein sources provide diverse bioactive components, which show anticancer activities [58,59]. A few studies have reported the cytotoxicity on human cancer cells using marine algae-derived peptides, as shown in Table 2.
Table 2, uncovers the capability of marine algae peptides to prevent and treat tumors, and their significancestudied in detail [62], revealed the strategy of activating apoptotic processes, showing the significance of marine algae-derived anti-cancer peptides. In general, the anticancer peptides from marine sources display various mechanisms to kill cancer cells, including the induction of apoptosis, the imbalance of tubulin-microtubule, and the inhibition of angiogenesis [60]. The two well-characterized pathways of apoptosis are primarily initiated through caspase activation in cells [63].

4.3. Antihypertensive Microalgal Peptides

Hypertension is a silent killer disease and is often identified as a cardiovascular impact, prompting strokes and respiratory failures. Worldwide, there are one billion individuals affected due to the cause of hypertension [64]. The systemic blood pressure increases above 140/90 Hg due to food and environmental factors, leading to complex ailments known as hypertension [65]. Therefore, the mechanism involving vasoconstriction and vasodilatation induces ROS and balances the systemic blood pressure. Angiotensin-converting enzyme (ACE-1) is a hydrophobic, monomeric amino acid and metalloprotease enzyme which plays a vital role in regulating blood pressure [66]. ACE-1 removes carboxyterminal dipeptide using proteolytic cleavage for the transformation of ACE-I to ACE-II. Therefore, ACE inhibitory peptides reduce the arterial blood pressure and are widely used to control hypertension [52,67,68]. The conversion from ACE to ACE-I, which directly inhibits the renin enzyme, is due to the blockage of reactive oxygen species (ROS) [69]. The determination of ACE inhibitory peptides mainly depends on the structure and composition of the amino acid (Table 3).
Renin is determined as a single specific enzyme and shows specificity on angiotensinogen. Renin catalyze and controls ROS [46,69] and is also identified as purified peptide sequences, which showed inhibitory activity of ACE-I and stability against gastrointestinal study. In another study, the two species of C. vulgaris and S. platensis treated with protein hydrolysate for a fraction of peptides sequences, Val-Ala-Phe, Ile-Ala-Pro-Gly, and Ile-Ala-Glu were acquired, and they showed the maximum inhibitory concentration of ACE-1. Chlorella sp. derived microalgal sources were similar to study the antihypertensive and antioxidant properties. A few microalgal species, C. vulgaris, C. ellipsiodea, N. incerta, and S. platensis, produce anti-hypertensive peptides. Especially, this pepsin hydrolysate C. vulgaris produced a particularly high yield of antihypertensive peptides in both in vivo and in vitro examination [49,70], and also, isolated C. ellipsiodea derived ACE inhibitory Val-Glu-Gly-Tyr peptides in arterial low blood pressure, which shows that the minimum inhibitory concentration of enzymes binds to the active site. Moreover, food-derived bioactive peptides have been widely investigated, and the antihypertensive and anti-oxidative properties are dissimilar.

4.4. Anti-Atherosclerosis Microalgal Peptides

Fatty materials are responsible for the formation of plaques, resulting in atherogenesis, which leads to hypertension and coronary illness as a result of arteries. C. undeacapeptide derived VECYGPNRPQF amino acids gradually suppressed the gene expression level of E-selectin, endothelin-1, monocyte attractant chemo protein, E-selectin, vascular cell adhere molecule, and intercellular adhere molecule [71]. The interleukin IL-6 promotes atherogenic cytokine activity that occurs in the underlying stage and the implication in the development of atherosclerosis. The formation of Monocyte Chemoattractant protein MCP-1 in atherosclerosis is indicated by attracting into the subendothelial cell layer on monocytes. Both the IL-6 and MCP-1 produced and increased endothelial cell activation [72]. Two bioactive peptides of Spirulina maxima LDAVNR and MMLD from digestive enzymatic hydrolysis on the intestine were reported to inhibit adhesion molecules by the reduction in the growth regulation of Mitogen –Activated Protein Kinase MAPKs, including P and E-selectin. Additionally, these anti-inflammatory peptides reduce reactive oxygen species production, which releases the inhibition of histamine and IL-8 expression [73]. The origin of atherosclerotic vascular diseases such as MCP-1, ET-1 VCAM-1, and ICAM-1 promotes the stage in the process of inflammation on atherosclerotic lesions in endothelial cells effectively [74,75], and these are listed in Table 4.
The key factor responsible for the inflammatory reaction is liable for ROS in the Red Blood Cells RBC activating receptor factor acetyl-hydrolase [76], where the early growth factor is targeted by a few inflammatory genes such as cell molecule adhesion, chemokines, and cytokines, etc. [77]. Thus, a derived form of microalgal peptides could be correlated with target molecules such as a reduction in the cell molecule, activating the red blood cell factor, the inhibition of acetyl hydrolase, and the histamine factor treated with anti-inflammatory reactive oxygen species of atherosclerosis.

4.5. Immuno-Modulatory Microalgal Peptides

The genetic engineering of microalgal bioactive peptides is an option to produce antibodies, pharmaceutical agents, and other valuable products such as vaccines, hormones, blood-clotting factors, growth factors, and anticancer and immune regulators [78]. The immune system activates immune cells to fights against antigens to eradicate the foreign substances, pathogenic agents, and pollutants [79]. Immunomodulating bioactive peptides promote the functioning of immune cells as sustained by increased leucocytes and induced cytokines. Immuno peptides regulate lymphocyte proliferation and also increase the phagocytic activity of macrophages in the human system [80,81]. Similarly, it is reported that C. vulgaris derived protein hydrolysate reported that both are inherited, and its specific immune function increases the lymphoblast, which develops T-lymphocytes and replenishes the delayed action of hypersensitivity. From the perception, the immunomodulatory mechanism of microalgae-derived peptides or proteins represented (Table 5) is prevalently associated with the pathway of T-lymphocyte and B-lymphocyte cytokine regulation [18,35,81]. A nucleotide-peptide complex derived from C. vulgaris possesses a factor for cell growth, promotes tissue repair, and has the capability of recovering the body [82].

4.6. Anti-UV Radiation and Antiosteoporosis Microalgal Peptides

Exposure to solar ultraviolet (UV) causes harmful effects on the epithelial layer of the skin and induces progeria. The mechanism, which includes the protein–protein interaction, increases metalloproteinase expression, the degradation of collagen, increased cysteine residues, and chemoattractant monocyte protein [83]. Cysteine residues are extracellularly abundant and are associated with, signaling the molecule which represses the synthesis of procollagen by reducing the receptor transform growth factor receptor II, where the up-regulation of the metallo-matrix protease enzyme by protein–protein interaction [84] reported that the aqueous extraction from Chlorella sp. has the ability to reduce the production of metalloproteinase1, gene expression, proteins, and the increasing mRNA expression of procollagen, followed by Solar ultraviolet exposure and preventing ultraviolet radiation which suppresses the gene expression of elastin protein. In biotechnological applications of Chlorella-derived bioactive peptides, a handful of studies showed that anti-ultraviolet irradiated to the epithelial layer on the fibroblasts’ skin after solar ultraviolet irradiation reduced [22].
Nowadays, osteoporosis is a type of vitamin deficiency that causes widespread human skeletal disorders, and it is an important health issue around the globe [85]. There are numerous signal transduction pathways involved in bone-forming cells [86]. At this time, osteoblastic cells are activated and highly expressed metalloprotein kinase cascades are activated with different markers, osteocalcin collagen I and alkaline phosphatase [87]. The transcription factors for various target genes (Smad1, Smad5, and Smad8) become phosphorylated, which regulates and interacts with activated bone morphogenetic protein receptors and forms a complex with Smad4 [88,89], identifying the purified Nannochloropsis oculata osteoblast-differentiator peptide (MPDW) from the application of algal by-products. Hence, the increased phosphorylation of peptides are expressed on metalloprotein kinases and smads. The microalgae-derived peptides and anti-UV radiation on antiosteoporosis are shown in Table 6.

4.7. Anti-Microbial/Anti-Bacterial Microalgal Peptides

The antibacterial/antimicrobial activity comprises short-chain peptides (50–100) in the form of complex proteins, and its net charge 3+, which kills microbial pathogens with fewer chances of developing resistance, has been exhibited in some of the recent studies. The Antimicrobial peptides AMPs play a vital role in protection against infection [91]. This microbial cellular process propagated with bacterial cytoplasmic membrane has an amphipathic nature, which binds with both polar and non-polar activate sites [92,93]. Some of the peptides such as aeruginosins, aeruginoguanidins, aeruginosamides, microginins, microviridins and kasumigamide produced by Microcystis aeruginosa are highly toxic due to their toxins such as hepatotoxin cyclic peptide and alkaloid neurotoxin [94].
In vivo and in vitro studies suggested that Spirulina sp. controlled antimicrobial/antibacterial effect. The phenolic extraction of Spirulina sp. inhibits Fusarium graminearum growth, and the production of mycotoxins was also studied elsewhere [95]. Interestingly, microalgae-derived esters also showed significant antimicrobial and antioxidant properties [96]. The S. platensis antibacterial peptides showed Minimum inhibitory concentrationMIC with Escherichia coli and Staphylococcus aureus. Therefore, S. platensis were investigatd and found a potentially promising antimicrobial agent. The overall significance and the mechanism involved in the microalgal bioactive peptides are listed in Table 7 [97,98,99,100,101,102].

5. Isolation and Production of Microalgal Peptides Using Different Technology

5.1. Enzyme-Assisted Extraction Process (EAE)

Microalgal peptides are derived through the protein and enzymatic hydrolysis process. The microalgal peptide-derived enzymatic hydrolysis is extensively used to increase the nutritional and functional values of foods [103]. The cell wall of the microalgal peptides made up of chemically complex heterogeneous molecules contains Ca+ and K+, which have sulfated and branched polysaccharides [104]. This enzymatic hydrolysis is used to break down the larger complex polypeptide molecule into smaller fragment pieces with a different arrangement of amino acid residues. Generally, the microalgal peptides provide molecular size reduction, free amino-acid sequence, and their composition [28]. Enzyme assisted extraction is low-cost, environmentally friendly, non-toxic, yield, catalytic, and bioactivity for the extraction process [105], revealing that the importance of the enzyme assisted extraction process is to maintain the optimum temperature and pH for enzymes for high yield. Compared to the other conventional extraction methods, this enzyme-assisted extraction has obtained higher antioxidant activity [106]. Eventually, this method is useful for the extraction of the bioactive compound and provides a better yield of peptides in our further process.

5.2. Subcritical Water Extraction Process (SWE)

Apart from enzyme assisted extraction, the novelty of this subcritical water extraction (SWE) or pressurized liquid extraction (PHE) is a simple step method that is mainly used in the food industry for the production of different bioactive peptides which promote human health function. SWE is an easy, eco-friendly, and high energy hydrolysis technique [107]. Subcritical water hydrolysis is an advanced technique which provides amino acids and protein from vegetables and animal matter [108]. At an industrial level, this subcritical water technology is mainly applicable, and the cell extraction efficiency is 30- to 167-fold increased significantly [109]. It works at the temperature of 50–200 °C, an pressure of 50–300 psi, and an time of 5–10 min, when a small amount of organic solvent used. According to the published report, this extraction of a bioactive peptide is a most promising technique. While applying high temperature and pressure through extraction, the water has been changed due to the physical and chemical properties [58]. Another study indicates that a higher level of amino acid was degraded due to the compression of hot water treatment at 240 °C, and the concentration of amino acid was higher at 220 °C [110].

5.3. Recent Technological Microalgal Peptide Productions

There is a significant challenge for the synthesis of the industrial scale-up production of microalgal bioactive peptides. Regarding this study, there is an opportunity to produce a larger amount of microalgal bioactive peptides using the biotechnological technique. However, in industrial scale-up, the chemical method is highly expensive and not appropriate for biomass production. The greater advantage of this enzymatic hydrolysis is that it is a common and traditional method for the synthesis of microalgal peptides which contain membrane enzyme reactor systems, and it allows a fast reaction, low cost, increased yielding capacity, and pure byproducts in industrial-scale production [31]. Other than enzymatic hydrolysis, proteolytic enzymes are commonly used for the production of microalgal bioactive peptides (Table 8) [111,112,113,114,115,116,117,118,119,120]. The microbe-derived enzymes are Alcalase, Neutrase, and Flavourzyme. This protein hydrolysis method is the most crucial factor to determine the peptides’ molecular weight and biofunctional activities on microalgal-derived peptides [121]. Additionally, more anti-oxidant protein peptides from beans have been isolated using enzymatic hydrolysis, as recently reported [122]. In addition, peptide extraction and the purification of peptides were separated by nanofiltration, electrodialysis with an ultra-filtration membrane (EDUF). Electrically driven forces were differentiated between mass flux and mass with ultra-filtration membranes. This EDUF provides better results to obtain more peptides [123]. Nonetheless, chromatography is also used to purify bioactive peptides. However, there is a limitation to using the chromatographic techniques dealing small peptides [124,125,126]. Fluorescence lifetime imaging (FLIM) is one of the techniques to investigate the interactive and non-interactive fractions on the binding, confirmation, and composition of a biological compound in the live cell. Hence, this is an inflexible technique determining physical interaction and cellular processing in the bioactive compounds. The mechanism and the interactions have been incredibly expanded to the antimicrobial peptides with bacterial cells [109,127].
Nevertheless, FLIM not only examined the interaction and molecular changes in detail. Currently, in silico and OMICS technology such as transcriptomics, metabolomics and proteomics are being studied. By applying 2D electrophoresis, this can be used to separate proteins based on the isoelectric point and molecular weight in proteomics studies [128]. EAE and SWE are the best methods to implement for the extraction of microalgal peptides. On the other hand, these lactic acid bacteria produced bioactive peptides from fermentation extraction. Simultaneously, this EDUF technology isolated bioactive microalgal peptides which were employed in a mixture of complex peptides. Under another method, FLIM and in silico (proteomics and transcriptomics) finally exhibit the mechanism and action of bioactive peptides.
Considering all the extraction methods above, the synthesis of microalgal bioactive peptides displays diverse bioactivities of functional food, pharmaceuticals, nutraceuticals, and cosmeceuticals, despite the fact that there is a need to change the preparation of microalgal peptides using innovative techniques for scale-up. Upcoming research in this field is very advanced facilitating the investigation of the products of microalgal peptides in the gastrointestinal transit, and to eventually interpret the elaborated significance of in vivo studies. In the future, the market for bioactive peptides could be industrially scaled-up.

6. Conclusions

Recently, studies have reported that algal-derived biologically active peptides play a major part in health and the environment. The enzymatic hydrolysis of microalgal-derived bioactive peptides is a chance to design new biofunctional foods, pharmaceuticals, and cosmeceuticals. This survey reports the utilization of microalgal peptides as antioxidant, anti-cancerous, anti-hypersensitive, anti-atherosclerotic, and nutritional functional food. It also explores novel technologies for the production of active peptides. For instance, the use of algal peptides as food for human health found limitations, such as the sensitivity of peptides to hydrolysis protease degradation. This review emphasized the issue of active peptides in gastrointestinal transit, which has to be unraveled in the future.

Author Contributions

R.S.: collected appropriate research articles, compiled the results, wrote and tabulated; J.M.: collected articles and prepared tabulation; J.-W.K.: reviewed the manuscript and proofread; D.M. contributed to designing the work, compiling the content, writing and review. All authors have read and agreed to the published version of the manuscript.

Funding

No fund.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

This study was supportedIncheon National University, Republic of Korea in the year of 2016. The authors are thankful to B.S. Abdur Rahman Crescent Institute of Science and Technology, India.

Conflicts of Interest

No conflict, informed consent, or human or animal rights are applicable to this study.

References

  1. Wang, R.; Xiao, H.; Wang, Y.; Zhou, W.; Tang, X. Effects of three macroalgae, Ulva linza (Chlorophyta), Corallina pilulifera (Rhodophyta) and Sargassum thunbergii (Phaeophyta) on the growth of the red tide microalga Prorocentrum donghaiense under laboratory conditions. J. Sea Res. 2007, 58, 189–197. [Google Scholar] [CrossRef]
  2. Villarruel-López, A.; Ascencio, F.; Nuño, K. Microalgae a potential natural functional food source—A review. Pol. J. Food Nutr. Sci. 2017, 67, 251–263. [Google Scholar] [CrossRef] [Green Version]
  3. Sigamani, S.; Ramamurthy, D.; Natarajan, H. A review on potential biotechnological applications of microalgae. J. App. Pharm. Sci. 2016, 6, 179–184. [Google Scholar] [CrossRef] [Green Version]
  4. Dominic, A.; Danquah, M.K. Industrial-scale manufacturing of pharmaceutical-grade bioactive peptides. Biotechnol. Adv. 2011, 29, 272–277. [Google Scholar]
  5. Guil-Guerrero, J.; Navarro-Juarez, R.; Lopez-Martínez, J.; Campra-Madrid, P.; Rebolloso-Fuentes, M. Functional properties of the biomass of three microalgae species. J. Food Eng. 2004, 65, 511–517. [Google Scholar] [CrossRef]
  6. Chacón-Lee, T.L.; Gonzalez-Mảriño, G.E. Microalgae for “health” foods—Possibilities and challenges. Compr. Rev. Food Sci. Food Saf. 2010, 9, 655–675. [Google Scholar] [CrossRef] [PubMed]
  7. Mohamed, S.; Hashim, S.N.; Rahman, H.A. Seaweeds: A sustainable functional food for complementary and alternative therapy. Trends Food Sci. Technol. 2012, 23, 83–96. [Google Scholar] [CrossRef]
  8. Sekar, S.; Chandramohan, M. Phycobiliprotein as commodity: Trends in applied research, patents and commercialization. J. Appl. Phycol. 2008, 20, 113–136. [Google Scholar] [CrossRef]
  9. Stolz, P.; Obermayer, B. Manufacturing microalgae for skin care. Cosmetics Toiletries 2005, 120, 99–106. [Google Scholar]
  10. Jena, J.; Pradhan, N.; Nayak, R.R.; Dash, B.P.; Sukla, L.B.; Panda, P.K.; Mishra, B.K. Microalga scenedesmus sp.: A potential low-cost green machine for silver nanoparticle synthesis. J. Microbiol. Biotechnol. 2014, 24, 522–533. [Google Scholar] [CrossRef]
  11. Graziani, G.; Schiavo, S.; Nicolai, M.A.; Buono, S.; Fogliano, V.; Pinto, G.; Pollio, A. Microalgae as human food: Chemical and nutritional characteristics of the thermo-acidophilic microalga Galdieria sulphuraria. Food Funct. 2013, 4, 144–152. [Google Scholar] [CrossRef]
  12. Batista, A.P.; Gouveia, L.; Bandarra, N.M.; Franco, J.M.; Raymundo, A. Comparison of microalgal biomass profiles as novel functional ingredient for food products. Algal Res. 2013, 2, 164–173. [Google Scholar] [CrossRef] [Green Version]
  13. Brennan, L.; Owende, P. Biofuels from microalgae—A review of technologies for production, processing and extractions of biofuels and co-products. Renew. Sustain. Energy Rev. 2010, 14, 557–577. [Google Scholar] [CrossRef]
  14. Bleakley, S.; Hayes, M. Algal proteins: Extraction, application, and challenges concerning production. Foods 2017, 6, 33. [Google Scholar] [CrossRef] [Green Version]
  15. Kang, K.H.; Qian, Z.J.; Ryu, B.; Karadeniz, F.; Kim, D.; Kim, S.K. Antioxidant peptides from protein hydrolysate of microalgae Navicula incerta and their protective effects in HepG2/CYP2E1 cells induced by ethanol. Phytother. Res. 2012, 26, 1555–1563. [Google Scholar] [CrossRef]
  16. Karavita, R.; Senevirathne, M.; Athukorala, Y.; Affan, A.; Lee, Y.J.; Kim, S.K.; Lee, J.B.; Jeon, Y.J. Protective effect of enzymatic extracts from microalgae against DNA damage induced by H2O2. Mar. Biotechnol. 2007, 9, 479–490. [Google Scholar] [CrossRef] [PubMed]
  17. FitzGerald, J.R.; Murray, A.B. Bioactive peptides and lactic fermentations. Int. J. Diary Technol. 2007, 59, 118–125. [Google Scholar] [CrossRef]
  18. Morris, H.J.; Carrillo, O.; Almarales, A.; Bermúdez, R.C.; Lebeque, Y.; Fontaine, R.; Llauradó, G.; Beltrán, Y. Immunostimulant activity of protein hydrolysate from green microalga Chlorella vulgaris on undernourished mice. Enzyme Microb. Technol. 2007, 40, 456–460. [Google Scholar] [CrossRef]
  19. Sheih, I.C.; Fang, T.J.; Wu, T.K.; Lin, P.H. Anticancer and antioxidant activities of the peptide fraction from algae protein in waste. J. Agric. Food Chem. 2010, 58, 1202–1207. [Google Scholar] [CrossRef]
  20. Fitzgerald, C.; Gallagher, E.; O’Connor, P.; Prieto, J.; MoraSoler, L.; Grealy, M.; Hayes, M. Development of a seaweed derived platelet activating factor acetyl hydrolase (PAF-AH) inhibitory hydrolysate, synthesis of inhibitory peptides and assessment of their toxicity using the zebrafish larvae assay. Peptides 2013, 50, 119–124. [Google Scholar] [CrossRef]
  21. Athukorala, Y.; Jeon, Y.J. Screening for angiotensin-1-converting enzyme inhibitory activity of Ecklonia cava. Prev. Nutr. Food Sci. 2005, 10, 134–139. [Google Scholar] [CrossRef]
  22. Chen, C.L.; Liou, S.F.; Chen, S.J.; Shih, M.F. Protective effects of Chlorella-derived peptide on UVB-induced production of MMP-1 and degradation of procollagen genes in human skin fibroblasts. Regul. Toxicol. Pharmacol. 2011, 60, 112–119. [Google Scholar] [CrossRef] [PubMed]
  23. Garcia-Vaquero, M.; Lopez-Alonso, M.; Hayes, M. Assessment of the functional properties of protein extracted from the brown seaweed Himanthalia elongata (Linnaeus) SF Gray. Food Res. Int. 2017, 99, 971–978. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Becker, E. Micro-algae as a source of protein. Biotechnol. Adv. 2007, 25, 207–210. [Google Scholar] [CrossRef] [PubMed]
  25. Rodriguez-Garcia, I.; Guil-Guerrero, J.L. Evaluation of the antioxidant activity of three microalgal species for use as dietary supplements and in the preservation of foods. Food Chem. 2008, 108, 1023–1026. [Google Scholar] [CrossRef] [PubMed]
  26. Levasseur, W.; Perré, P.; Pozzobon, V. A review of high value-added molecules production by microalgae in light of the classification. Biotechnol. Adv. 2020, 41, 107545. [Google Scholar] [CrossRef]
  27. Montone, C.M.; Capriotti, A.L.; Cavaliere, C.; La Barbera, G.; Piovesana, S.; Chiozzi, R.Z.; Laganà, A. Peptidomic strategy for purification and identification of potential ACE-inhibitory and antioxidant peptides in Tetradesmus obliquus microalgae. Anal. Bioanal. Chem. 2018, 410, 3573–3586. [Google Scholar] [CrossRef]
  28. Samarakoon, K.; Jeon, Y.J. Bio-functionalities of proteins derived from marine algae—A review. Food Res. Int. 2012, 48, 948–960. [Google Scholar] [CrossRef]
  29. Udenigwe, C.C.; Aluko, R.E. Food protein-derived bioactive peptides: Production, processing and potential health benefits. J. Food Sci. 2012, 77, R11–R24. [Google Scholar] [CrossRef] [PubMed]
  30. Korhonen, H.; Pihlanto, A. Bioactive peptides: Production and functionality. Int. Dairy J. 2006, 16, 945–960. [Google Scholar] [CrossRef]
  31. Fan, X.; Bai, L.; Zhu, L.; Yang, L.; Zhang, X. Marine algae-derived bioactive peptides for human nutrition and health. J. Agric. Food Chem. 2014, 62, 9211–9222. [Google Scholar] [CrossRef] [PubMed]
  32. Chabeaud, A.; Vandanjon, L.; Bourseau, P.; Jaouen, P.; Chaplain-Derouiniot, M.; Guerard, F. Performances of ultrafiltration membranes for fractionating a fish protein hydrolysate: Application to the refining of bioactive peptic fractions. Sep. Purif. Technol. 2009, 66, 463–471. [Google Scholar] [CrossRef]
  33. Kose, A.; Oncel, S.S. Properties of microalgal enzymatic protein hydrolysates: Biochemical composition, protein distribution and FTIR characteristics. Biotechnol. Rep. 2015, 6, 137–143. [Google Scholar] [CrossRef] [Green Version]
  34. Ng, J.H.; Ilag, L.L. Cryptic protein fragments as an emerging source of peptide drugs. Drugs 2006, 9, 343–346. [Google Scholar]
  35. Cian, R.E.; Martínez-Augustin, O.; Drago, S.R. Bioactive properties of peptides obtained by enzymatic hydrolysis from protein byproducts of Porphyra columbina. Food Res. Int. 2012, 49, 364–372. [Google Scholar] [CrossRef]
  36. Harnedy, P.A.; FitzGerald, R.J. Extraction of protein from the macroalga Palmaria palmata. LWT Food Sci. Technol. 2013, 51, 375–382. [Google Scholar] [CrossRef]
  37. Heo, S.J.; Jeon, Y.J.; Lee, J.; Kim, H.T.; Lee, W.K. Antioxidant effect of enzymatic hydrolyzate from a kelp, Ecklonia cava. Algae 2003, 18, 341–347. [Google Scholar] [CrossRef]
  38. Heo, S.J.; Park, E.J.; Lee, K.W.; Jeon, Y.J. Antioxidant activities of enzymatic extracts from brown seaweeds. Bioresour. Technol. 2005, 96, 1613–1623. [Google Scholar] [CrossRef]
  39. Heo, S.J.; Jeon, Y.J. Radical scavenging capacity and cytoprotective effect of enzymatic digests of Ishige okumurae. J. Appl. Phycol. 2008, 20, 1087–1095. [Google Scholar] [CrossRef]
  40. Je, J.Y.; Park, P.J.; Kim, E.K.; Park, J.S.; Yoon, H.D.; Kim, K.R.; Ahn, C.B. Antioxidant activity of enzymatic extracts from the brown seaweed Undaria pinnatifida by electron spin resonance spectroscopy. LWT-Food Sci. Technol. 2009, 42, 874–878. [Google Scholar] [CrossRef]
  41. Kang, K.H.; Qian, Z.J.; Ryu, B.; Kim, S.K. Characterization of growth and protein contents from microalgae Navicula incerta with the investigation of antioxidant activity of enzymatic hydrolysates. Food Sci. Biotechnol. 2011, 20, 183–191. [Google Scholar] [CrossRef]
  42. Bargeman, G.; Koopsb, G.H.; Houwing, J.; Breebaartb, I.; van der Horsta, H.C.; Wesslingb, M. The development of electro-membrane filtration for the isolation of bioactive peptides: The effect of membrane selection and operating parameters on the transport rate. Desalination 2002, 149, 369–374. [Google Scholar] [CrossRef]
  43. Briones, A.M.; Touyz, R.M. Oxidative stress and hypertension: Current concepts. Curr. Hypertens. Rep. 2010, 12, 135–142. [Google Scholar] [CrossRef]
  44. Valko, M.; Leibfritz, D.; Mancol, J.; Cronin, M.T.D.; Mazur, M.; Telser, J. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 2007, 39, 44–84. [Google Scholar] [CrossRef]
  45. Lahera, V.; Goicoechea, M.; de Vinuesa, S.G.; Miana, M.; de Las, H.N.; Cachofeiro, V.; Luno, J. Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: Beneficial effects of statins. Curr. Med. Chem. 2007, 14, 243–248. [Google Scholar] [CrossRef]
  46. Sheih, I.C.; Wu, T.K.; Fang, T.J. Antioxidant properties of a new antioxidative peptide from algae protein hydrolysate in different oxidation systems. Bioresour. Technol. 2009, 100, 3419–3425. [Google Scholar] [CrossRef]
  47. Kang, K.H.; Qian, Z.J.; Ryu, B.M.; Kim, D.; Kim, S.K. Protective effects of protein hydrolysate from marine microalgae Navicular incerta on ethanol-induced toxicity in HepG2/CYP2E1 cells. Food Chem. 2012, 132, 677–685. [Google Scholar] [CrossRef]
  48. Shih, M.F.; Cherng, J.Y. Protective effects of chlorella-derived peptide against UVC-induced cytotoxicity through inhibition of caspase-3 activity and reduction of the expression of phosphorylated FADD and cleaved PARP-1 in skin fibroblasts. Molecules 2012, 17, 9116–9128. [Google Scholar] [CrossRef] [Green Version]
  49. Ko, S.C.; Kim, D.; Jeon, Y.J. Protective effect of a novel antioxidative peptide purified from a marine Chlorella ellipsoidea protein against free radical induced oxidative stress. Food Chem. Toxicol. 2012, 50, 2294–2302. [Google Scholar] [CrossRef]
  50. Lee, S.H.; Chang, D.W.; Lee, B.J.; Jeon, Y.J. Antioxidant activity of solubilized Tetrasel missuecica and Chlorella ellipsoidea by enzymatic digests. J. Food Sci. Nutr. 2009, 14, 21–28. [Google Scholar]
  51. Safitri, N.M.; Herawati, E.Y.; Hsu, J.L. Antioxidant Activity of Purified Active Peptide Derived from Spirulina platensis Enzymatic Hydrolysates. Res. J. Life Sci. 2017, 4, 119–128. [Google Scholar] [CrossRef] [Green Version]
  52. Garcia-Moscoso, J.L.; Obeid, W.; Kumar, S.; Hatcher, P.G. Flash hydrolysis of microalgae (Scenedesmus sp.) for protein extractionand production of biofuels intermediates. J. Supercrit. Fluids 2013, 82, 183–190. [Google Scholar] [CrossRef]
  53. Samaranayaka, A.G.; Li-Chan, E.C. Food-derived peptidic antioxidants: A review of their production, assessment and potential applications. J. Funct. Foods 2011, 3, 229–254. [Google Scholar] [CrossRef]
  54. Wang, T.; Jonsdottir, R.; Kristinsson, H.G.; Hreggvidsson, G.O.; Jonsson, J.O.; Thorkelsson, G.; Ólafsdóttir, G. Enzyme-enhanced extraction of antioxidant ingredients from red algae Palmaria palmate. LWT-Food Sci. Technol. 2010, 43, 1387–1397. [Google Scholar] [CrossRef]
  55. Ennamany, R.; Saboureau, D.; Mekideche, N.; Creppy, E.E. SECMA 1, a mitogenic hexapeptide from Ulva algeae modulates the production of proteoglycans and glycosaminoglycans in human foreskin fibroblast. Hum. Exp. Toxicol. 1998, 17, 18–22. [Google Scholar] [CrossRef]
  56. Zhang, X.; Cao, D.; Sun, X.; Sun, S.; Xu, N. Preparation and identification of antioxidant peptides from protein hydrolysate of marine alga Gracilariopsis lemaneiformis. J. Appl. Phycol. 2019, 31, 2585–2596. [Google Scholar] [CrossRef]
  57. Xia, E.; Zhai, L.; Huang, Z.; Liang, H.; Yang, H.; Song, G.; Tang, H. Optimization and Identification of Antioxidant Peptide from Underutilized Dunaliella salina Protein: Extraction, In Vitro Gastrointestinal Digestion, and Fractionation. BioMed Res. Int. 2019. [Google Scholar] [CrossRef] [Green Version]
  58. Sedighi, M.; Jalili, H.; Darvish, M.; Sadeghi, S.; Ranaei-Siadat, S.O. Enzymatic hydrolysis of microalgae proteins using serine proteases: A study to characterize kinetic parameters. Food Chem. 2019, 284, 334–339. [Google Scholar] [CrossRef]
  59. Kang, K.H.; Kim, S.H. Beneficial effect of peptide from microalgae on anticancer. Curr. Protein Sci. 2013, 14, 212–217. [Google Scholar] [CrossRef]
  60. Wang, X.; Zhang, X. Separation, antitumor activities and encapsulation of polypeptide from Chlorella pyrenoidosa. Biotechnol. Prog. 2013, 29, 681–687. [Google Scholar] [CrossRef]
  61. Zhang, B.; Zhang, X. Separation and nano-encapsulation of antitumor polypeptide from Spirulina platensis. Biotechnol. Prog. 2013, 29, 1230–1238. [Google Scholar] [CrossRef] [PubMed]
  62. Zheng, L.; Lin, X.; Wu, N.; Liu, M.; Zheng, Y.; Sheng, J.; Ji, X.; Sun, M. Targeting cellular apoptotic pathway with peptides from marine organisms. Biochim. Biophys. Acta 2013, 1836, 42–48. [Google Scholar] [CrossRef] [PubMed]
  63. Gupta, S.; Kass, G.E.; Szegezdi, E.; Joseph, B. The mitochondrial death pathway: A promising therapeutic target in diseases. J. Cell. Mol. Med. 2009, 13, 1004–1033. [Google Scholar] [CrossRef] [Green Version]
  64. Ochoa-Méndez, C.E.; Lara-Hernández, I.; González, L.M.; Aguirre-Bañuelos, P.; Ibarra-Barajas, M.; Castro-Moreno, P.; Soria-Guerra, R.E. Bioactivity of an antihypertensive peptide expressed in Chlamydomonas reinhardtii. J. Biotechnol. 2016, 240, 76–84. [Google Scholar] [CrossRef]
  65. Giles, T.D.; Materson, B.J.; Cohn, J.N.; Kostis, J.B. Definition and classification of hypertension: An update. J. Clin. Hypertens. 2009, 11, 611–614. [Google Scholar] [CrossRef] [PubMed]
  66. Hong, F.; Ming, L.; Yi, S.; Zhanxia, L.; Yongquan, W.; Chi, L. The antihypertensive effect of peptides: A novel alternative to drugs? Peptides 2008, 29, 1062–1071. [Google Scholar] [CrossRef]
  67. Sagardia, I.; Roa-Ureta, R.H.; Bald, C. A new QSAR model, for angiotensin I converting enzyme inhibitory oligopeptides. Food Chem. 2013, 136, 1370–1376. [Google Scholar] [CrossRef] [PubMed]
  68. Verdecchia, P.; Angeli, F.; Mazzotta, G.; Gentile, G.; Reboldi, G. The rennin angiotensin system in the development of cardiovascular disease: Role of aliskiren in risk reduction. Vasc. Health Risk Manag. 2008, 4, 971–981. [Google Scholar] [CrossRef] [Green Version]
  69. Fitzgerald, C.; Gallagher, E.; Tasdemir, D.; Hayes, M. Heart health peptides from macroalgae and their potential use in functional foods. J. Agric. Food Chem. 2011, 59, 6829–6836. [Google Scholar] [CrossRef]
  70. Suetsuna, K.; Chen, J.R. Identification of antihypertensive peptides from peptic digests of two microalgae, Chlorella vulgaris and Spirulina platensis. Mar. Biotechnol. 2001, 3, 305–309. [Google Scholar] [CrossRef] [PubMed]
  71. Shih, M.F.; Chen, L.C.; Cherng, J.Y. Chlorella 11-peptide inhibits the production of macrophage-induced adhesion molecules and reduces endothelin-1 expression and endothelial permeability. Mar. Drugs 2013, 11, 3861–3874. [Google Scholar] [CrossRef] [Green Version]
  72. Takaishi, H.; Taniguchi, T.; Takahashi, A.; Ishikawa, Y.; Yokoyama, M. High glucose accelerates MCP-1 production via p38 MAPK in vascular endothelial cells. Biochem. Biophys. Res. Commun. 2003, 305, 22–28. [Google Scholar] [CrossRef]
  73. Vo, T.S.; Ryu, B.M.; Kim, S.K. Purification of novel anti-inflammatory peptides from enzymatic hydrolysate of the edible microalgal Spirulina maxima. J. Funct. Foods 2013, 5, 1336–1346. [Google Scholar] [CrossRef]
  74. Little, P.J.; Ivey, M.E.; Osman, N. Endothelin-1 actions on vascular smooth muscle cell functions as a target for the prevention of atherosclerosis. Curr. Vasc. Pharmacol. 2008, 6, 195–203. [Google Scholar] [CrossRef] [PubMed]
  75. Sheikine, Y.; Hansson, G.K. Chemokines and atherosclerosis. Ann. Med. 2004, 36, 98–118. [Google Scholar] [CrossRef] [PubMed]
  76. Rozenberg, I.; Sluka, S.H.; Rohrer, L.; Hofmann, J.; Becher, B.; Akhmedov, A.; Soliz, J.; Mocharla, P.; Boreén, J.; Johansen, P.; et al. Histamine H1 receptor promotes atherosclerotic lesion formation by increasing vascular permeability for low-density lipoproteins. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 923–930. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Blaschke, F.; Bruemmer, D.; Law, R.E. Egr-1 is a major vascular pathogenic transcription factor in atherosclerosis and restenosis. Rev. Endocr. Metab. Disord. 2004, 5, 249–254. [Google Scholar] [CrossRef]
  78. Mishra, A.; Medhi, K.; Malaviya, P.; Thakur, I.S. Omics approaches for microalgal applications: Prospects and challenges. Bioresour. Technol. 2019, 291, 121890. [Google Scholar] [CrossRef]
  79. FitzGerald, R.J.; O’Cuinn, G. Enzymatic debittering of food protein hydrolysates. Biotechnol. Adv. 2006, 24, 234–237. [Google Scholar] [CrossRef]
  80. Meisel, H.; Goepfert, A.; Gunther, S. ACE-inhibitory activities in milk products. Milchwissenschaft 1997, 52, 307–311. [Google Scholar]
  81. Ahn, G.; Hwang, I.; Park, E.J.; Kim, J.H.; Jeon, Y.J.; Lee, J.H.; Park, J.W.; Jee, Y. Immunomodulatory effects of an enzymatic extracts from Ecklonia cava on murine splenocytes. Mar. Biotechnol. 2008, 10, 278–289. [Google Scholar] [CrossRef] [PubMed]
  82. Pradhan, J.; Das, S.; Das, B.K. Antibacterial activity of freshwater microalgae: A review. Afr. J. Pharm. Pharmacol. 2014, 8, 809–818. [Google Scholar]
  83. Watanabe, H.; Shimizu, T.; Nishihira, J.; Abe, R.; Nakayama, T.; Taniguchi, M.; Sabe, H.; Ishibashi, T.; Shimizu, H. Ultraviolet Ainduced production of matrix metalloproteinase-1 is mediated by macrophage migration inhibitory factor (MIF) in human dermal fibroblasts. J. Biol. Chem. 2004, 279, 1676–1683. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Quan, T.; He, T.; Kang, S.; Voorhees, J.J.; Fisher, G.J. Elevated cysteine-rich 61 mediates aberrant collagen homeostasis in chronologically aged and photoaged human skin. Am. J. Pathol. 2006, 169, 482–490. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Fazzalari, N.L. Bone remodelling: A review of the bone microenvironment perspective for fragility fracture (osteoporosis) of the hip. Semin. Cell Dev. Biol. 2008, 19, 467–472. [Google Scholar] [CrossRef]
  86. Novack, D.V. Role of NF-κB in the skeleton. Cell Res. 2011, 21, 169–182. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Rey, A.; Manen, D.; Rizzoli, R.; Ferrari, S.L.; Caverzasio, J. Evidences for a role of p38 MAP kinase in the stimulation of alkaline phosphatase and matrix mineralization induced by parathyroid hormone in osteoblastic cells. Bone 2007, 41, 59–67. [Google Scholar] [CrossRef] [PubMed]
  88. Miyazono, K.; Maeda, S.; Imamura, T. BMP receptor signaling: Transcriptional targets, regulation of signals and signaling cross-talk. Cytokine Growth Factor Rev. 2005, 16, 251–263. [Google Scholar] [CrossRef] [PubMed]
  89. Nguyena, M.H.T.; Qian, Z.J.; Nguyen, V.T.; Choic, I.W.; Heo, S.J.; Ohd, C.H.; Kang, D.H.; Kime, G.H.; Jung, W.K. Tetrameric peptide purified from hydrolysates of biodiesel byproducts of Nannochloropsis oculata induces osteoblastic differentiation through MAPK and Smad pathway on MG-63 and D1 cells. Process Biochem. 2013, 48, 1387–1394. [Google Scholar] [CrossRef]
  90. Shih, M.F.; Cherng, J.Y. Potential protective effect of fresh grown unicellular green algae component (resilient factor) against PMA- and UVB-induced MMP1 expression in skin fibroblasts. Eur. J. Dermatol. 2008, 18, 303–307. [Google Scholar] [PubMed]
  91. Giordano, D.; Costantini, M.; Coppola, D.; Lauritano, C.; Pons, L.N.; Ruocco, N.; Verde, C. Biotechnological applications of bioactive peptides from marine sources. Int. Adv. Microb. Physiol. 2018, 73, 171–220. [Google Scholar]
  92. Nguyen, L.T.; Haney, E.F.; Vogel, H.J. The expanding scope of antimicrobial peptide structures and their modes of action. Trends Biotechnol. 2011, 29, 464–472. [Google Scholar] [CrossRef] [PubMed]
  93. Lordan, S.; Ross, R.P.; Stanton, C. Marine bioactives as functional food ingredients: Potential to reduce the incidence of chronic diseases. Mar. Drugs 2011, 9, 1056–1100. [Google Scholar] [CrossRef] [Green Version]
  94. Ishida, K.; Murakami, M. Kasumigamide, an antialgal peptide fromthe cyanobacterium Microcystis aeruginosa. J. Org. Chem. 2000, 65, 5898–5900. [Google Scholar] [CrossRef] [PubMed]
  95. Pagnussatt, F.A.; Ponte, E.M.D.; Garda-Buffon, J.; Furlong, B. Inhibition of Fusarium graminearum growth and mycotoxin production by phenolic extract from Spirulina sp. Pestic. Biochem. Physiol. 2014, 108, 21–26. [Google Scholar] [CrossRef]
  96. MubarakAli, D.; Baldev, E.; Thajuddin, N.; Sang-Yul, L.; Jung-Wan, K. An evidence of C16 fatty acid methyl esters for the effective antimicrobial and antioxidant property. Microb. Pathog. 2018, 115, 233–238. [Google Scholar]
  97. Zhao, Y.; Xu, C. Structure and function of angiotensin converting enzyme and its inhibitors. Chin. J. Biotechnol. 2008, 24, 171–176. [Google Scholar] [CrossRef]
  98. Daskaya-Dikmen, C.; Yucetepe, A.; Karbancioglu-Guler, F.; Daskaya, H.; Ozcelik, B. Angiotensin-I-converting enzyme (ACE)-inhibitory peptides from plants. Nutrients 2017, 9, 316. [Google Scholar] [CrossRef]
  99. Montone, C.M.; Zenezini Chiozzi, R.; Marchetti, N.; Cerrato, A.; Antonelli, M.; Capriotti, A.L.; Laganà, A. Peptidomic Approach for the Identification of Peptides with Potential Antioxidant and Anti-Hyperthensive Effects Derived from Asparagus By-Products. Molecules 2019, 24, 3627. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Sun, Y.; Chang, R.; Li, Q.; Li, B. Isolation and characterization of an antibacterial peptide from protein hydrolysates of Spirulina platensis. Eur. Food Res. Technol. 2016, 242, 685–692. [Google Scholar] [CrossRef]
  101. Sarmadi, B.; Ismail, A. Antioxidative peptides from food proteins: A review. Peptide 2010, 31, 1949–1995. [Google Scholar] [CrossRef]
  102. Doi, R.H.; Kosugi, A. Cellulosomes: Plant-cell-wall-degrading enzyme complexes. Nat. Rev. Microbiol. 2004, 2, 541–551. [Google Scholar] [CrossRef]
  103. Wijesinghe, W.A.; Jeon, Y.J. Enzyme-assistant extraction (EAE) of bioactive components: A useful approach for recovery of industrially important metabolites from seaweeds: A review. Fitoterapia 2012, 83, 6–12. [Google Scholar] [CrossRef]
  104. Park, P.J.; Shahidi, F.; Jeon, Y.J. Antioxidant activities of enzymatic extracts from an edible seaweed Sargassum horneri using ESR spectrometry. J. Food Lipids 2004, 11, 15–27. [Google Scholar] [CrossRef]
  105. Fan, X.; Hu, S.; Wang, K.; Yang, R.; Zhang, X. Coupling of ultrasound and subcritical water for peptides production from Spirulina platensis. Food Bioprod. Process. 2020, 121, 105–112. [Google Scholar] [CrossRef]
  106. Klingler, D.; Berg, J.; Vogel, H. Hydrothermal reactions of alanine and glycine in sub- and supercritical water. J. Supercrit. Fluids 2007, 43, 112–119. [Google Scholar] [CrossRef]
  107. Islam, M.N.; Jo, Y.T.; Jung, S.K.; Park, J.H. Evaluation of subcritical water extraction process for remediation of pesticide-contaminated soil. Water Air Soil Pollut. 2013, 224, 1652. [Google Scholar] [CrossRef]
  108. Cikos, A.M.; Jokić, S.; Šubarić, D.; Jerković, I. Overview on the application of modern methods for the extraction of bioactive compounds from marine macroalgae. Mar. Drugs 2018, 16, 348. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Ueno, H.; Banchereau, J.; Vinuesa, C.G. Pathophysiology of T follicular helper cells in humans and mice. Nat. Immunol. 2015, 16, 142. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Naseri, A.; Marinho, G.S.; Holdt, S.L.; Bartela, J.M.; Jacobsen, C. Enzyme-assisted extraction and characterization of protein from red seaweed Palmaria palmata. Algal Res. 2020, 47, 101849. [Google Scholar] [CrossRef]
  111. Barbarino, E.; Lourenço, S.O. An evaluation of methods for extraction and quantification of protein from marine macro-and microalgae. J. Appl. Phycol. 2005, 17, 447–460. [Google Scholar] [CrossRef]
  112. Kadam, S.U.; Álvarez, C.; Tiwari, B.K.; O’Donnell, C.P. Extraction and characterization of protein from irish brown seaweed Ascophyllum nodosum. Food Res. Int. 2016, 99, 1021–1027. [Google Scholar] [CrossRef]
  113. Alavijeh, R.S.; Karimi, K.; Wijffels, R.H.; van den Berg, C.; Eppink, M. Combined bead milling and enzymatic hydrolysis for efficient fractionation of lipids, proteins, and carbohydrates of Chlorella vulgaris microalgae. Bioresour. Technol. 2020, 309, 123321. [Google Scholar] [CrossRef]
  114. Hildebrand, G.; Poojary, M.M.; O’Donnell, C.; Lund, M.N.; Garcia-Vaquero, M.; Tiwari, B.K. Ultrasound-assisted processing of Chlorella vulgaris for enhanced protein extraction. J. Appl. Phycol. 2020, 32, 1709–1718. [Google Scholar] [CrossRef]
  115. Luengo, E.; Martínez, J.M.; Coustets, M.; Álvarez, I.; Teissié, J.; Rols, M.-P.; Raso, J.A. A comparative study on the effects of millisecond-and microsecond-pulsed electric field treatments on the permeabilization and extraction of pigments from Chlorella vulgaris. J. Membr. Biol. 2015, 248, 883–891. [Google Scholar] [CrossRef]
  116. Postma, P.; Pataro, G.; Capitoli, M.; Barbosa, M.; Wijffels, R.H.; Eppink, M.; Olivieri, G.; Ferrari, G. Selective extraction of intracellular components from the microalga Chlorella vulgaris by combined pulsed electric field–temperature treatment. Bioresour. Technol. 2016, 203, 80–88. [Google Scholar] [CrossRef] [PubMed]
  117. Passos, F.; Carretero, J.; Ferrer, I. Comparing pretreatment methods for improving microalgae anaerobic digestion: Thermal, hydrothermal, microwave and ultrasound. Chem. Eng. J. 2015, 279, 667–672. [Google Scholar] [CrossRef]
  118. Herrero, M.; Cifuentes, A.; Ibanez, E. Sub-and supercritical fluid extraction of functional ingredients from different natural sources: Plants, food-by-products, algae and microalgae: A review. Food Chem. 2006, 98, 136–148. [Google Scholar] [CrossRef] [Green Version]
  119. Chaminda Lakmal, H.H.; Samarakoon, K.W.; Jeon, Y.J. Enzyme-Assisted Extraction to Prepare Bioactive Peptides from Microalgae. Mar. Algae Extr. Process. Prod. Appl. 2015, 305–318. [Google Scholar] [CrossRef]
  120. Wong, F.C.; Xiao, J.; Wang, S.; Ee, K.Y.; Chai, T.T. Advances on the antioxidant peptides from edible plant sources. Trends Food Sci. Technol. 2020, 99, 44–57. [Google Scholar] [CrossRef]
  121. Sánchez, A.; Vázquez, A. Bioactive peptides: A review. Food Qual. Saf. 2017, 1, 29–46. [Google Scholar] [CrossRef]
  122. Lemes, A.C.; Sala, L.; Ores, J.D.C.; Braga, A.R.C.; Egea, M.B.; Fernandes, K.F. A review of the latest advances in encrypted bioactive peptides from protein-rich waste. Int. J. Mol. Sci. 2016, 17, 950. [Google Scholar] [CrossRef] [Green Version]
  123. Coutte, F.; Lecouturier, D.; Firdaous, L.; Kapel, R.; Bazinet, L.; Cabassud, C.; Dhulster, P. Recent trends in membrane bioreactors. In Current Developments in Biotechnology and Bioengineering; Elsevier: Amsterdam, The Netherlands, 2017; pp. 279–311. [Google Scholar]
  124. Becker, W. Fluorescence lifetime imaging—Techniques and applications. J. Microsc. 2012, 247, 119–136. [Google Scholar] [CrossRef]
  125. Gee, M.L.; Burton, M.; Grevis-James, A.; Hossain, M.A.; McArthur, S.; Palombo, E.A.; Wade, J.D.; Clayton, A.H. Imaging the action of antimicrobial peptides on living bacterial cells. Sci. Rep. 2013, 3, 1557. [Google Scholar] [CrossRef] [PubMed]
  126. Ebrecht, R.; Don Paul, C.; Wouters, F.S. Fluorescence lifetime imaging microscopy in the medical sciences. Protoplasma 2014, 251, 293–295. [Google Scholar] [CrossRef]
  127. Cambri, G.; de Sousa, M.M.L.; de Miranda Fonseca, D.; Marchini, F.K.; da Silveira, J.L.M.; Paba, J. Analysis of the biotechnological potential of a Lentinus crinitus isolate in the light of its secretome. J. Proteome Res. 2016, 15, 4557–4568. [Google Scholar] [CrossRef] [PubMed]
  128. Yücetepe, A.; Özçelik, B. Bioactive Peptides Isolated from Microalgae Spirulina platensis and their Biofunctional Activities. Acad. Food J. 2016, 14, 412–417. [Google Scholar]
Table
Table 1. Microalgae-derived anti-oxidant peptides.
Table 1. Microalgae-derived anti-oxidant peptides.
Source of Microalgal PeptidesEnzymatic TreatmentActivityReference
Navicula sp.N. incertaPapain Cytotoxic effect in HepG2/CYP2E1 cells[47]
N. incertaPepsinShows DPPH superoxide radical quenching activity [41]
N. incertaPapainAntioxidant in HepG2/CYP2E1 cells[47]
Chlorella sp.C. pyrenoidosaAqueous; Filtration and centrifugation Cytotoxicity in skin fibroblasts[48]
C. vulgarisPepsinSuperoxide radical quenching growth inhibition and results in cell cycle arrest in human gastric cell lines[6,46]
C. ellipsiodeaHydrolysis with pepsinFree radical scavenging activity [49]
C. ellipsiodeaAqueous extractionIt shows moderate free radical scavenging[50]
Tetraselmis sp.Tetraselmis suecicaAqueous extractionFree radical scavenging; H2O2 in a monkey kidney cell line[49]
Spirulina sp.Spirulina platensisThermolysinDPPH radical scavenging activity, peptides exhibited increased antioxidant activity with an IC50[51]
Table
Table 2. Anticancer peptides using a microalgal source.
Table 2. Anticancer peptides using a microalgal source.
Peptide SequenceSourceCellsIn Vitro/In VivoReference
Polypeptide VECC. vulgarisGastric cancer Anti- proliferative gastric cancer AGS cellsIn vitro[46]
Polypeptide CPAPC. pyrenoidosaHepG-2 cellsIn vitro[60]
Polypeptide Y2S. platensisMCF-7 and HepG-2 cellsIn vitro[61]
Table
Table 3. Microalgal-derived Angiotensin Converting Enzymes ACE inhibitory peptides.
Table 3. Microalgal-derived Angiotensin Converting Enzymes ACE inhibitory peptides.
Amino Acid SequenceSource of PeptidesTreatmentIC50 (mM)Reference
Ile-Val-Val-Glu
Ala-Phe-Leu
Phe-Ala-Leu
Ala-Glu-Leu
Val-Val-Pro-Pro-Ala		C. vulgarisHydrolysis with pepsin; chromatography315.3
63.8
26.3
57.1
79.5		[70]
Val-Glu-Cys-Tyr-Gly-Pro Asn-Arg-Pro-Gln-PheC. vulgarisHydrolysis with pepsin29.6[19]
Val-Glu-Gly-TyrC. ellipsiodeaHydrolysis with alcalase128.4[49]
Ile-Ala-Glu
Phe-Ala-Leu
Ala-Glu-Leu
Ile-Ala-Pro-Gly
Val-Ala-Phe		S. platensisHydrolysis with pepsin; chromatography34.7
11.4
11.4
11.4
35.8		[70]
Gly-Met-Asn-Asn-Leu-Thr-Pro
Leu-Glu-Gln		Nannochloropsis oculataHydrolysis with pepsin; chromatography123
173		[28]
Table
Table 4. Microalgae-derived anti-atherosclerotic peptides.
Table 4. Microalgae-derived anti-atherosclerotic peptides.
Peptide SequencesSourceIn Vitro/In VivoReference
VECYGPNRPQFChlorella sp.In vitro (endothelial cells Svec4-10 and macrophage RAW 264.7 cells)[71]
NIGKPalmaria palmataIn vitro[20]
LDAVNR, MMLDFS. maximaIn vitro (EA hy926 cells and U937 cells)[73]
Table
Table 5. Microalgae-derived Immuno-modulating peptides.
Table 5. Microalgae-derived Immuno-modulating peptides.
Peptide Name or SequenceSourceIn Vitro/In VivoReference
Protein hydrolysatesC. vulgarisIn vivo in mice[18]
Protein hydrolysatesEcklonia cava (Macroalgae)In vivo in mice[81]
Protein hydrolysatesPorphyra columbina (Macroalgae)In vivo in rats[35]
Table
Table 6. Microalgae-derived anti-UV radiation and antiosteoporosis peptides.
Table 6. Microalgae-derived anti-UV radiation and antiosteoporosis peptides.
Peptide Name or SequenceSourceIn Vitro/In VivoReference
Chlorella derived peptideChlorella sp.In vitro studies in skin fibroblast of 966SK[22,90]
MPDWN. oculataIn vitro studies in human osteosarcoma and murine mesenchymal stem cell [89]
Table
Table 7. Significance of microalgal bioactive peptides.
Table 7. Significance of microalgal bioactive peptides.
S.NoPeptide SequencesSourceMode of PreparationMechanism and ApplicationsReferences
1.VECYGPNRPQFC. vulgarisPepsin hydrolysate Peptides prevent cell death due to the cause of hydroxyl radicals and also protect DNA damage. No cytotoxicity effect in human lung fibroblast cell line (WI38). It promotes gastrointestinal digestion. [46]
2.Val-Glu-Cys-Tyr-Gly-Pro-Asn-Arg-Pro-Gln-Phe Acaudina molpadioideaBromelain and alcalase Peptide inhibiting the activity was increased with gastrointestinal proteases.[97]
3.VECYGPNRPQFC. vulgarisPepsin hydrolysates Inhibits the growth and also promotes cell cycle arrest in human gastric cell lines. [19]
4.Pro-Gly- Trp-Asn-Gln-Trp-Phe-Leu—Val-Glu-Val-Leu-Pro-Pro-Ala-Glu-Leu N. incertaPapain hydrolysatesCytotoxic effects in HepG2/CYP2E1 cells.[15]
5.Gly-Met-Asn-Asn-Leu-Thr-Pro- Leu-Glu-Gln N. oculataProtein hydrolysate Hydrolysate fractions on human umbilical vein endothelial cell line (HUVECs). [28]
6.Ile-Ala-Glu, Phe-Ala-Leu, Ala-Glu-Leu, Ile-Ala-Pro-Gly and Val-Ala-Phe S. platensisEnzymatic hydrolysisAntioxidant activity, antihypertensive activity, antimicrobial activity, antidiabetics activity and anti-obesity activity. [98]
7.WPRGYFL, GPDRPKFLGPF, WYGPDRPKFL, SDWDRF Tetradesmus obliquusProtein hydrolysate Identification of antioxidant and ACE inhibitory peptides. [99]
8.GIVAGDVTPIS. platensisEnzymatic hydrolysisExerts an antihypertensive effect.[100]
9.Asp-Ala-GluPorphyra columbinaProtein extract hydrolysateImmunosuppressive effect on rat splenocytes and also enriched IL-10 production.
Protein extract hydrolysate gives high immunosuppressive effect, antihypertensive effect and antioxidant capacity.		[35]
10. PHA,PHP,PHSArthospira maxima OF15Enzymatic hydrolysis Antioxidant, anti-hyluronase, anticollagenase, and anti-inflammatory activity.[101]
11.FGMPLDR
MELVLR		U. intestinalisProtein hydrolysatesACE inhibitors with IC50 values of 219.35 μM were obtained.[102]
12.ELWKTFGracilariopsis lemaneiformisEnzymatic hydrolysisGlu-Lys is reliable for more antioxidant peptides, ELWKTF established from G. lemaneiformis. This marine algae gives a natural source as a novel antioxidant peptide.[56]
Table
Table 8. Protein extraction method from microalgae.
Table 8. Protein extraction method from microalgae.
Protein Extraction MethodsTypesReference
Conventional protein extraction methodsEnzymatic hydrolysis[58,112]
Physical Process[36,113]
Chemical extraction[105,114]
Current extraction methodsUltrasound-Assisted Extraction[115,116]
Pulsed Electric Field[117,118]
Other methodsMicrowave assisted extraction (MAE)[111,119]
Subcritical wave extraction (SWE)[116,120]
Supercritical fluid extraction (SFE)[120]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Sathya, R.; MubarakAli, D.; MohamedSaalis, J.; Kim, J.-W. A Systemic Review on Microalgal Peptides: Bioprocess and Sustainable Applications. Sustainability 2021, 13, 3262. https://doi.org/10.3390/su13063262

AMA Style

Sathya R, MubarakAli D, MohamedSaalis J, Kim J-W. A Systemic Review on Microalgal Peptides: Bioprocess and Sustainable Applications. Sustainability. 2021; 13(6):3262. https://doi.org/10.3390/su13063262

Chicago/Turabian Style

Sathya, Raghunathan, Davoodbasha MubarakAli, Jaulikar MohamedSaalis, and Jung-Wan Kim. 2021. "A Systemic Review on Microalgal Peptides: Bioprocess and Sustainable Applications" Sustainability 13, no. 6: 3262. https://doi.org/10.3390/su13063262

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop