Food and Chemical Toxicology: Sciencedirect

Food and Chemical Toxicology 135 (2020) 111013
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Food and Chemical Toxicology

journal homepage: www.elsevier.com/locate/foodchemtox
Bioactive compounds in seaweeds: An overview of their biological T

properties and safety
Kannan RR. Rengasamya,∗, Mohamad Fawzi Mahomoodallyb,∗∗,
Muhammad Zakariyyah Aumeeruddyb, Gokhan Zenginc, Jianbo Xiaod, Doo Hwan Kima
a
Department of Bio-resources and Food Science, Konkuk University, Seoul, 05029, South Korea
b
Department of Health Sciences, Faculty of Science, University of Mauritius, Réduit, Mauritius
c
Department of Biology, Science Faculty, Selcuk University, Campus, Konya, Turkey
d
International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
ARTICLE INFO ABSTRACT
Keywords: Seaweeds are among the significant currently exploited marine plant resources which are gaining full applica-
Marine foods tions in culinary, cosmetic, pharmaceutical, and biotechnological processes. Much attention has been devoted to
Pharmacology seaweeds based on their proven health benefits and is considered as a rich source of structurally different
Biopharmaceutical bioactive metabolites for the discovery of novel functional food-based pharmacophores/drugs. Nonetheless,
Biomedicine
there is still a dearth of updated compilation and analysis of the in-depth pharmacological activities of these
Metabolites
compounds. This review, therefore, aims to provide a piece of up-to-date detailed information on the major
Non-communicable
compounds isolated from various seaweed species together with their in-vitro and in-vivo biological properties.
These compounds were found to possess broad pharmacological properties and inhibitory enzyme activities
against critical enzymes involved in the aetiology of noncommunicable diseases. However, their toxicity, clinical
efficacy, mechanisms of action, and interaction with conventional foods, are still less explored and require more
attention in future studies.
1. Introduction compound annual growth rate (CAGR) of 6.1% (Research, 2017). For
the past decades, researchers have shown great interest towards the
The importance of dietary food habits was already mentioned in the isolation of health-promoting substances from these fruits and vege-
earlier quote by Hippocrates in 460 BC that “Let food be thy medicine and tables. Both the Natural Health Products (NHP) and Nutraceuticals and
medicine be thy food’’. The improper dietary habits or unhealthy diet is a Functional Foods (NFF) focused much research on bioactive foods from
critical concern for the currently alarming health disorders including natural resources to develop healthy foods (Goldberg, 2012; Nice,
diabetes, obesity, cancer, and cardiovascular diseases. The intake of 1997).
unhealthy foods and the low intake of fruits and vegetables causes Marine life offers 70% of earth's surface with the vast diversity of
about 2.7 million deaths including 14% of gastrointestinal cancer life and biodiversity in the seas is only partially explored although
deaths (14%), ischaemic heart disease deaths (11%) and nearly stroke marine represents a rich source of novel metabolites with various ap-
deaths (9%) (WHO Fact Sheet, accessed on June 19, 2018, http://www. plications includes cosmeceutical, nutraceuticals, agrochemicals,
who.int/dietphysicalactivity/fruit/en/index2.html). It is well known pharmaceuticals and other industrially relevant chemicals (Faulkner,
that vegetables and fruits are important sources of phytocompounds 2012). Recent research emphasises that drug discovery from marine
which perform a key role in the prevention of a panoply of diseases. The resources is increasing alarmingly and various biomolecules are in the
global phytonutrients/nutraceutical market value, regarding value, is clinical pipeline.
projected to reach $4.63 Billion in 2020, at a CAGR of 7.2% from 2015
to 2020 (Markets and Markets, 2015). Likewise, the global market for 2. Global trends in marine biodiscovery
the botanical and plant-derived drug was estimated $29.4 billion in
2017 and is projected to escalate to 39.6 billion in 2022 with a In 2018, the world market for drugs derived from marine sources
∗
Corresponding author.
∗∗
Corresponding author.
E-mail addresses: [email protected] (K.R. Rengasamy), [email protected] (M.F. Mahomoodally).
https://doi.org/10.1016/j.fct.2019.111013
Received 27 September 2019; Received in revised form 20 November 2019; Accepted 29 November 2019
Available online 30 November 2019
0278-6915/ © 2019 Elsevier Ltd. All rights reserved.
Table 1
Seaweed polysaccharides and their biological properties.
Polysaccharide Source Biological properties Model used Findings Reference
Fucoidan (1) Ascophyllum nodosum, Cladosiphon okamuranus, Fucus spiralis, Anticoagulant, anti-inflammatory, In-vitro and Inhibits the leucocyte recruitment in an inflammation model in rats. In In- Cumashi et al.
K.R. Rengasamy, et al.
F. distichus, F. evanescens, F. vesiculosus, F. serratus, Laminaria antiadhesive and antiangiogenic in-vivo vitro, P-selectin-mediated neutrophil adhesion to platelets showed that only (2007)
digitata, L. saccharina fucoidans from A. nodosum, F. distichus, F. evanescens, F. serratus, F.
spiralis, L. digitata and L. saccharina could serve as P-selectin inhibitors.
Besides, all fucoidans, except that from C. okamuranus, displayed
anticoagulant activity by APTT while fucoidans from F. distichus, F.
evanescens, F. serratus, L. digitata and L. saccharina, showed strong
antithrombin action in the platelet aggregation assay. These fucoidans also
inhibited HUVEC tubulogenesis. Lastly, fucoidans from F. distichus, and F.
vesiculosus, F. serratus, L. digitata and L. saccharina, blocked MDA-MB-231
breast carcinoma cell adhesion to platelets.
Kelp Tyrosinase inhibition In-vitro Showed competitive inhibition of tyrosinase toward L-tyrosine Yu and Sun
(IC50 = 0.82 mg/mL), and the inhibitory constant Ki obtained from double- (2014)
reciprocal plots was 0.99 mg/mL.
Fucus vesiculosus Anti-atopic dermatitis In vivo Ameliorated atopic dermatitis, accompanied by the decreased inflammatory Tian et al. (2019)
cell infiltration, splenocytes proliferation, and CD4+ T cell response
F. evanescens Antitumor In-vivo Administration of fucoidan at 10 mg/kg, displayed moderate antimetastatic Alekseyenko et
and antitumor activities. It also potentiates the antimetastatic effects of al. (2007)
cyclophosphamide in C57Bl/6 mice with transplanted Lewis lung
adenocarcinoma.
Sargassum fusiforme Anti-angiogenic In-vitro Inhibits the migration of HMEC-1 and tube formation dose-dependently. Cong et al.
(2016)
S. fusiforme Anti-cancer In-vitro and Inhibited lung cancer cell growth through the disruption of angiogenesis via Chen et al.
In-vivo blocking VEGFR2/Erk/VEGF signalling and targeting VEGFR2/VEGF. (2016)
Sargassum hornery, Eclonia cava, Costaria costata Anti-cancer In-vitro Blocks colony formation in colon cancer cells cell line and human melanoma. Ermakova et al.
2
(2011)
Cladosiphon okamuranus Anti-cancer In-vitro and In ATL patients, fucoidan inhibits the growth of HTLV-1-infected T-cell lines Haneji et al.
In-vivo and peripheral blood mononuclear cells. (2005)
Adenocystis utricularis Antiretroviral In-vitro Inhibitor of anti-HIV-1 activity against both drug-resistant and wild-type Trinchero et al.
HIV-1 strains by blocking of viral entry and revealed no virucidal activity. (2009)
A. utricularis Antiviral In-vitro Galactofucans potentially inhibited HSV 1 and 2, without any cytotoxic Ponce et al.
effect, while the uronofucoidans displayed no antiviral activity. (2003)
C. okamuranus Cardioprotective In-vivo Cardioprotective effect was noticed with Fucoidan against isoproterenol- Thomes et al.
induced myocardial infarction in rats. Fucoidan also improved lactate (2010)
dehydrogenase, creatinine phosphokinase, aspartate transaminase and
alanine transaminase. Also, fucoidan enhanced the antioxidant defence
system in treated rats by reducing oxidative stress induced by isoproterenol.
Moreover, fucoidan treatment reverses the effects of isoproterenol by
decreasing total cholesterol, triglycerides, LDL cholesterol and increasing
HDL cholesterol.
C. okamuranus Anti-proliferative In-vitro Oversulfated fucoidan dose-dependently reduced the U937 cell proliferation, Teruya et al.
induces the apoptosis by an activation-dependent pathway of caspase-3 and (2007)
-7. On the other hand, the weak activity of native fucoidan suggests that the
sulfate group substitution and sulfate content influence the anti-proliferative
activity in U937 cells.
C. okamuranus Gastric protection In-vitro Protect the gastric mucus layer and stimulate ulcer healing power owing to Shibata et al.
its anti-peptic and basic fibroblast growth factor (bFGF) stabilising activity. (2000)
C. okamuranus Antiprion In-vivo Dietary fucoidan, administered orally for six days after infection, delays the Doh-ura et al.
disease onset thoroughly in infected mice with scrapie, but not when given (2007)
before the infection.
F. evanescens Anticoagulant In-vitro & In- Showed anticoagulant activity through plasma antithrombin III mediated. Kuznetsova et al.
vivo Thrombin inhibition. (2003)
F. vesiculosus Anti-inflammatory In-vitro Fucoidan inhibits the excess PGE2 and NO production in LPS-stimulated BV2 Park et al.
microglia. Also diminished the iNOS, MCP-1, COX-2, MCP-1, TNF-α and L-1β (2011a)
(continued on next page)
Table 1 (continued)
expression. Besides, fucoidan suppresses the NF-κB activation and down-

regulation of an extracellular JNK, MAPK, ERK and AKT pathways.
F. vesiculosus Anti-obesity In-vitro Fucoidan reduced lipid accumulation by stimulating lipolysis via increasing Park et al.
HSL and by expression of phosphorylated HSL and reduction of glucose (2011b)
uptake into adipocytes.
Undaria piaantifida Immunostimulatory In-vitro Fucoidan enhanced the probiotic properties of lactic acid bacteria on Kawashima et al.
immune functions by enhancing the production of IL-12 in response to a (2012)
strain of LAB, Tetragenococcus halophilus KK221, disseminating production
of IFN-γ. In in-vivo study with ovalbumin immunized mice, the enhanced
immunobalance of T helper type 1/type 2 (Th1/Th2) was observed.
L. japonica Antioxidant In-vitro Exhibited scavenging effects on hypochlorous acid and superoxide radical (Zhao et al.,
and inhibition of LDL oxidation induced by Cu2+. 2005)
L. japonica Anti-inflammatory In-vitro & In- In an In-vivo air pouch inflammation model, coadministration of fucoidan or Kyung et al.
vivo Cistanche tubulosa extract synergistically suppressed nitric oxide production, (2012)
carrageenan-induced vascular exudation, prostaglandin E2 concentrations.
Lessonia vadosa Anticoagulant and elicitor In-vitro Native fucoidan showed good anticoagulant activity and activation of Chandía and
defence enzyme activities of PAL, LOX and GST in tobacco plants. Matsuhiro (2008)
U. pinnatifida Antiplasmodial In-vitro & In- Fucoidan fractions inhibited the P. falciparum merozoites mediated Chen et al.
vivo erythrocytes invasion and IC50 values againt chloroquine sensitive P. (2009)
falciparum 3D7 stain for the three fucoidan fractions were 9.17, 7.28, and
1.95 μg/ml and 7.03, 4.74, and 2.21 μg/ml in chloroquine resistant P.
falciparum K1 strain. About 37% suppressive effect against the control group
and a delay in death associated with anemia was observed in P. berghei-
infected mice with fucoidan.
U. pinnatifida Anti-allergy In-vivo The suppressive effect of Th2 cytokines production in bronchoalveolar lavage Maruyama et al.
fluid wa snoticed, and IFN-γ amount was not increased in fucoidan treated (2005)
3
mice.
U. pinnatifida Antitumor In-vitro & In- Fucoidan mediated tumor destruction via the response of Th1 and NK cells. Maruyama et al.
vivo (2006)
U. pinnatifida Antitumor In-vitro Displayed antitumor activity against PC-3, HeLa, A549, and HepG2 cells. Synytsya et al.
(2010)
Alginate (2) Commercial sodium alginate Inhibition of putrefactive compound In-vitro & In- In human fecal culture and rat cecum, inhibited the putrefactive compound Kuda et al.
vivo formation. (2005)
Eucheuma cottonii and Sargassum polycystum Antidiabetic In-vitro IC50 of (0.075–0.103) mg/ml, also a mixed-type inhibition. Zaharudin et al.
(2018)
Commercial sodium alginate Antibacterial In-vitro & In- Approximately 70–90% inhibition againt L. monocytogenes V. Kuda et al.
vivo parahaemolyticus and S. typhimurium to human enterocyte-like HT-29-Luc (2015)
cells was observed with sodium alginate (0.1%). In addition, sodium alginate
potentially inhibited 70% of S. typhimurium invasion. Incubation with
sodium alginate for 18 h also Increased transepithelial electrical resistance of
HT-29-Luc monolayer cells was also observed with 18 h incubation of sodium
alginate. Moreover, decreased liver pathogen count was noticed in alginate
fed mice.
Commercial sodium alginate Antibacterial In-vivo Alginate-based coating containing lactate and diacetate was effective in Neetoo et al.
controling The controlled growth of L. monocytogenes and enhanced (2010)
microbial safety of sliced and filleted smoked salmon was reported with
alginate coated lactate and diacetate.
Commercial sodium alginate Antibacterial In-vivo Alginate-based antimicrobial coatings enhanced the microbiological safety of Juck et al. (2010)
poached and deli turkey products by controling L. monocytogenes growth.
– Gastroesophageal reflux disease Systematic Effective in the treatment of symptomatic gastroesophageal reflux disease Leiman et al.
treatment review & and were superior to placebo and antacids. Compared to proton pump (2017)
meta- inhibitors or histamine-2 receptor antagonists, alginates appear less effective.
analysis
Commercial sodium alginate Anticancer In-vitro Markeb et al.
(2016)

Table 1 (continued)
The novel paclitaxel-loaded alginate nanoparticle promoted decreased

viability, cell-cycle arrest and induced apoptosis in patient's breast cancer
cells superior to those of paclitaxel alone.

Commercial sodium alginate Anti-inflammatory In-vivo Amelioration of mRNA expression in inflammation-related molecules and Horibe et al.
protected indomethacin-induced mucin depletion in the small intestine was (2016)
reported in mice pretreated with sodium alginate prior to the administration
of indomethacin.
Commercial sodium alginate Anti-inflammatory In-vivo Prevention of methotrexate-induced small intestinal mucositis and decreased Yamamoto et al.
hemoglobin, hematocrit levels and red blood cell counts in rats. (2013)
Commercial sodium alginate Anti-inflammatory In-vivo Sodium alginate prevented the increase in SOD, GPx, catalase activity and Yamamoto et al.
microvascular permeability and also prevented decreases in white and red (2014)
blood cells in small intestinal damage induced by indomethacin.
Commercial Antioxidant In-vitro Low molecular weight alginates produced by thermal treatment of alginate Kelishomi et al.
polymer showed scavenging activity against ABTS and superoxide radicals. (2016)
L. hyperborean Wound healing In-vivo Calcium alginate enhanced skin collagen I expression from day 3 to day 14 Wang et al.
with higher collagen I/III in alginate-group ratio than vaseline (control)- (2015)
group at day 7 and 14. In addition, higher level of hydroxyproline in skin
homogenate of alginate-group than the vaseline (control)-group from day 3
to day 14.
Laminarin (3) Laminaria spp. Anti-inflammatory In-vivo Combined laminarin and fucoidan treatment enhanced diarrhoeal scores, O'Shea et al.
body-weight loss, and clinical variables linked with a dextran sodium sulfate (2016)
experiment in pigs, together with s decrease in colonic IL-6 mRNA
abundance.
Eisenia bicyclis Antibacterial In-vitro Laminarin (0.1%) inhibited the adhesion About 70–90% inhibition of L. Kuda et al.
monocytogenes, S. typhimurium and V. parahaemolyticus adhesion to (2015)
human enterocyte-like HT-29-Luc cells with laminarin (0.1%).
4
Commercial Hepatoprotective In-vivo The increase in serum ALT, AST and LDH activities - reflecting hepatic Neyrinck et al.
alterations - was reduced after lipopolysaccharides injection in laminarin- (2007)
treated rats than control groups. Laminarin also decreased serum monocytes
number, TNF-α and nitrite.
NI Immunostimulatory In-vitro Showed immunostimulatory effect through the transcription factor pathway Lee et al. (2012a)
in macrophages by increasing the release of H2O2, NO, calcium, MCP-1, LIF,
VEGF, and G-CSF with enhancing expression of STAT1, STAT3, c-Fos, c-Jun,
and COX-2 mRNA in RAW 264.7 cells.
Commercial Anticancer In-vitro Through mitochondrial pathway, induces the apoptosis of human colon Ji et al. (2012)
cancer LOVO cells.
Commercial Anticancer In-vitro Induce apoptosis of LoVo cells. The TRAIL, DR4, DR5, Bid, tBid, FADD and Ji and Ji (2014)
Bax expression levels were upregulated, while the Bcl-2, pro-caspase-3 and 8,
expression levels were downregulated. Moreover, the casapse-8, -3, -6 and -7
activities were increased.
E. bicyclis Anticancer In-vitro The colony formation of human melanoma SK-MEL-28 and colon cancer Menshova et al.
DLD-1 cells were inhibited by laminarin and its enzymatic hydrolysed (2014)
products.
Laminaria digitata Anticancer In-vitro In HT-29 colon cancer cells, laminaric induces apoptosis through ErbB Park et al. (2013)
signaling pathway.
Carrageenan Commercial Anti-inflammatory In-vitro Carrageenan did not induce IL-6, IL-8, or MCP-1 (CCL2) in HT-29 and HCT- McKim et al.
(4)‘ 8 cell lines at 0.1, 1.0, and 10.0 mg/mL. (2016)
Commercial Anticancer In-vitro & In- In B16–F10 and 4T1 bearing mice, carrageenan inhibited tumor growth in Luo et al. (2015)
vivo and enhanced immune response by increasing the number of tumor-
infiltrating dentritic cells, M1 macrophages, and additional stimulated
CD4+CD8+ T lymphocytes in spleen.
Commercial Anti-allergic In-vivo λ-Carrageenan was identified as potentially new ligand for TLR4/MyD88 Tsuji et al. (2003)
which triggers innate immunity, induced Th1-cytokines, PRRs recognised λ-
carrageenan, and suppression of IgE production via reduced histamine
release.

K.R. Rengasamy, et al. Food and Chemical Toxicology 135 (2020) 111013
A549, alveolar carcinoma; AKZ; ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, Aspartate transaminase; ATL, Adult T-cell leukemia; BoHV-1, bovine herpesvirus type 1; ERK, signal-
terminal kinase; LDH, lactate dehydrogenase; LDL, low density lipoprotein; LIF, Leukemia Inhibitory Factor; LOX, lipoxygenase; MAPK, p38 mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1;
regulated kinase; G-CSF, Granulocyte colony-stimulating factor; GPx, glutathione peroxidase; GST, glutathione-S-transferase; HeLa, cervical cancer; HepG2, hepatocellular carcinoma; HIV, human immune deficiency
virus; HMEC-1, human microvascular endothelial cells; HSL, hormone sensitive lipase; HSV, herps simples virus; HTLV-1, human T-cell leukemia virus type 1; HUVEC, human umbilical vein endothelial cell; JNK, c-Jun N-
NK cells, nature killer cells; PAL, phenylalanine-ammonia lyase; PC-3, prostate cancer 3; PRRs, pattern recognition receptors; STAT, Signal Transducer and Activator of Transcription; SuHV-1, suid herpesvirus type 1;
was around $ 10,486.8 billion, which is forecasted to touch $21,955.6
billion by 2025 at a CAGR of 11.25% for the five-year period of
Sokolova et al.
Cáceres et al.
(Zhou et al.,
2019–2025 (Infinium Global Research, 2019). Marine-based US FDA
Diogo et al.
Zhou et al.
Reference
approved drugs mainly consist of marine metabolites or their synthetic
(2006)
(2011)
(2015)
(2000)
2004)
analogues. Also, most of the marine-derived medicines isolated from

various marine resources, but the contribution of marine algae is only
about 30% (Blunt et al., 2007).
carrageenan was the causative agent for tumor cell pycnosis and necrosis in
Exhibited reducing power and inhibition of hydroxyl radicals and superoxide

From the histopathological in λ-carrageenan-treated mice indicated that λ-
Reduced infectivity of the viruses BoHV-1 strain Cooper and SuHV-1 strain
λ-carrageenan enhances antitumor activities of Fluorouracil (5-Fu) and
different degree. In H22 and S180 tumor cells, λ-carrageenan showed
3. Recent developments in algal drug research
Seaweeds or marine macroalgae reside in the littoral zone and are

now considered as primary resources of the oceans in terms of eco-
Bartha; this effect was more pronounced against BoHV-1.
Showed anti-viral activity against herpes simplex virus
nomic and ecological significance (Dhargalkar and Pereira, 2005).

progress the immunocompetence damaged by 5-Fu.
Taxonomically, seaweeds are grouped into three major phyla: (i)

Phaeophyceae (brown algae), which are primarily brown in color due
to its fucoxanthin content – xanthophyll pigment fucoxanthin (ii)
Chlorophyceae (green algae) - primarily dominated by chlorophyll ‘a’
and ‘b’, and other specific xanthophyll pigments; and (iii) Rhodophy-
ceae (red algae) primarily comprised of phycocyanin and phycoerythrin
(O’Sullivan et al., 2010). Approximately more than 1500 brown, 900
antitumor activity in-vitro.
green and 4000 red seaweeds are available worldwide (Dawes, 1998).
The subtropical and tropical waters are entirely occupied by red and
green seaweeds, while cold temperate waters are predominantly occu-
anion radicals.
pied by brown seaweeds (Khan and Satam, 2003).

The interest in the discovery of health-promoting substances of
Findings
marine origin is increasing especially from marine plants such as sea-

weeds, seagrass and mangroves for the past decades (El Gamal, 2010;
Rengasamy et al., 2014b). Among these, seaweeds or marine macro-
In-vitro & In-
In-vitro & ex
algae have much attracted functional food researchers. Recent shreds of

Model used
evidence suggest that seaweeds have been regularly consumed as food

In-vitro
In-vitro
In-vivo
vivo
vivo
in East Asian countries including Korea, China, Japan, and this dietary
habit as widespread throughout Europe, North America and, Southern
American countries (McHugh, 2003). Noticeably, long-life expectancy
and the lower rate of cardiovascular diseases among the Japanese
people are likely to be associated with their dietary habits including
their regular consumption of seaweeds (Shimazu et al., 2007).
The recent review by Rengasamy et al. (2014a) compiled various
Biological properties
bioactive compounds isolated from seaweeds and their role as enzyme

inhibitors to treat multiple diseases including cancer, diabetes, in-
Antioxidant
flammation, dementia and others. Seaweeds are not only targeted for
Antitumor
Antitumor
Anti-viral
Anti-viral
drug development to treat various human health illness, but also play a
significant part as plant growth regulators, fungicides, pesticides, and in
part in plant growth such as auxin, cytokinin, gibberellins, betains
(Stirk et al., 2014), oligosaccharides, and phenolic compounds
(Rengasamy et al., 2014b, 2015). The biological properties of various
bioactive metabolites from marine algae have been recently extensively
reviewed by many researchers including enzyme inhibitors (Rengasamy
et al., 2014a), phlorotannins (Karadeniz and Kim, 2015; Sanjeewa
et al., 2016) polysaccharides (Wang et al., 2014), protein hydrolysates
and bioactive peptides (Harnedy and FitzGerald, 2013; Samarakoon
Gigartinaceae and Tichocarpaceae algae
and Jeon, 2012), alkaloids (Güven et al., 2010), halogenated terpenoids

(Wang et al., 2013) and pigments (D’Orazio et al., 2012; Dumay et al.,
2015; Kim and Pangestuti, 2011). In this context, this review mainly
VEGF, Vascular endothelial growth factor.
focuses on the bioactive compounds isolated from seaweeds and their

Stenogramme interrupta
in-depth biological properties (see detailed activities in Tables 1–6 and

Gigartina skottsbergii
Fig. 5).
Chondrus ocellatus
4. The primary bioactive compound in seaweeds

C. ocellatus
Source
4.1. Polysaccharides
Table 1 (continued)
Polysaccharides are carbohydrate biopolymers consisting of simple

Polysaccharide
sugars linked by glycoside bonds and are classified into structural

polysaccharides, mucopolysaccharides and storage polysaccharides.
The study of the structure, biosynthesis and functions of sugar mole-
cules including polysaccharides are known as glycobiology and has
5
Table 2
Seaweed phlorotannins and their biological properties.
Phlorotannins Source Biological activity Model used Findings Reference
Phloroglucinol (5) E. cava Antioxidant In-vitro Showed scavenging effects against free radicals: DPPH, HO• and O2•− and Ahn et al. (2007)
protect against H2O2-mediated DNA damage.

E. maxima Antioxidant In-vitro Potent DPPH radical scavenger at 0.13 μM Rengasamy et al. (2013)
E. maxima Anti-Alzheimer's In-vitro Inhibits acetylcholinesterase (AChE) at 50% at a concentration of 579.32 μM. Kannan et al. (2013)
E. maxima Antidiabetic In-vitro Inhibited 50% of α-glucosidase at a concentration of 1991 μM. Rengasamy et al. (2013)
E. kurome Antibacterial In-vitro Displayed an MBC (Minimum bactericidal concentration) value of 0.79 of μmol/ Nagayama et al. (2002)
mL against Campylobacter jejuni.
- Anti-cancer In vitro Phloroglucinol engineered Ag nanoparticles displayed cytotoxic effect and Kumar et al. (2018)
morphological features of apoptotic cell death in MCF-7 cell lines
Dibenzo [1,4] dioxine-2,4,7,9-tetraol (6) E. maxima Antioxidant In-vitro Displayed an EC50 value of 0.01 μM against DPPH radical. Rengasamy et al. (2013)
E. maxima Anti-Alzheimer's In-vitro Caused a 50% inhibition of AChE at a concentration of 84.48 μM. Kannan et al. (2013)
E. maxima Antidiabetic In-vitro Exhibited α-glucosidase inhibition with an IC50 value of 33.69 μM. Rengasamy et al. (2013)
Eckol (7) E. cava Anti-influenza In-vitro Showed inhibitory effects on Influenza Virus NA (rvH1N1) with IC50 value of Ryu et al. (2011)
89.5 μM and A/Chicken/Korea/MS96/96 (H9N2, with IC50 value of 152.1 μM.
E. cava Skin protective In vitro Inhibition of PM2.5-induced cell apoptosis by eckol was through MAPK signaling Zhen et al. (2019)
pathway
E. stolonifera Anti-tyrosinase In vitro Reduced cellular melanin content and tyrosinase activity, Also downregulated Manandhar et al. (2019)
melanogenesis enzymes expression such as tyrosinase, tyrosinase-related protein
(TRP)-1, and TRP-2 in B16F10 melanoma cells
E. bicyclis, Antioxidant In-vitro Exerted scavenging effect against DPPH and superoxide anion with EC50 value of Shibata et al. (2008)
E. cava and E. 26 μM and 107 μM, respectively.
kurome
E. stolonifera Antioxidant In-vitro Exerted DPPH scavenging effect (EC50 = 10.6 μM) and also inhibited ROS Lee et al. (2012b)
production in tacrine-treated HepG2 cells.
E. maxima Antioxidant In-vitro Potent DPPH radical scavenger at 0.01 μM EC50 value. Rengasamy et al. (2013)
6
E. cava Antibacterial In-vitro Displayed antibacterial activity against Staphylococcus aureus at MIC values Choi et al. (2010)
varying from 125 to 250 μg/mL and against Salmonella strains at MIC values of
125–250 μg/mL. The combinations of eckol and ampicillin exhibited a
synergistic or additive effect.
E. kurome Antibacterial In-vitro Showed bactericidal activity against S. aureus, Bacillus cereus, Escherichia coli, C. Nagayama et al. (2002)
jejuni, S. typhimurium, S. enteritidis, and Vibrio parahaemolyticus with MBC values
in the range 0.08–1.08 μmol/mL.
E. stolonifera Anti-hypertension In-vitro Exhibited marked inhibitory activity against ACE with an IC50 value of 70.82 μM. Jung et al. (2006)
E. stolonifera Hepatoprotective In-vitro In tacrine-treated HepG2 cells, eckol potentially inhibits the Fas-mediated cell- Lee et al. (2012b)
death protein expression and also inhibit the cytochrome c release from the
mitochondria to cytosol.
E. maxima Anti-Alzheimer's In-vitro Caused a 50% inhibition of AChE at a concentration of 76.70 μM. Kannan et al. (2013)
E. stolonifera Anti-photoaging In-vitro Caused a reduced expression of MMP-1 human dermal fibroblasts by inhibiting Joe et al. (2006)
AP-1 dependent reporter gene activity and NF-κB.
E. cava Anti-photoaging In-vitro Showed photoprotective effect against UV-B -induced cell damage. Heo and Jeon (2009b)
E. bicyclis Anti-diabetic In-vitro Exhibited α-amylase inhibition (87.5% inhibition) and antiglycation activity Okada et al. (2004)
(96.2% inhibition) at 1 mM.
E. maxima Anti-diabetic In-vitro Displayed α-glucosidase inhibition at 11.163 μM IC50 value. Rengasamy et al. (2013)
Dieckol (8) E. cava Immunomodulatory In-vivo The ionising radiation suppressed immune cell differentiation and proliferation Park et al. (2010)
was enhanced. Dieckol increased thymidine incorporation by splenocytes as
much as 8.8-fold above that in irradiated mice without dieckol treatment. Also,
the number of CD4+ helper T cells, CD8+ cytolytic T cells, CD45R/B220+ pan B
cells, and CD11b+ macrophages showed a marked increase in dieckol-treated
irradiation group compared with irradiation-only control group at three days
after irradiation.
E. stolonifera Anti-photoaging In-vitro Caused a reduced expression of MMP-1 human dermal fibroblasts by inhibiting Joe et al. (2006)
AP-1 dependent reporter gene activity and NF-κB.
E. cava Anti-photoaging In-vitro Displayed photoprotective effect against UV-B -induced cell damage. Heo et al. (2009)
E. cava Anti-allergy In-vitro Le et al. (2009)
Table 2 (continued)
Histamine release was inhibited dose-dependently from both KU812 and RBL2H3
cell lines.
E. stolonifera Antibacterial In-vitro Exhibited antibacterial activity against MSSA and MSRA S. aureus with MIC Lee et al. (2008)
values ranged from 32 to 128 μg/mL. The combination of dieckol with ampicillin
or penicillin displayed a synergistic activity against MRSA.
E. bicyclis Anti-diabetic In-vitro Exhibited inhibitory activity on glycation (86.7% inhibition) and α-amylase Okada et al. (2004)
(97.5% inhibition) at 1 mM.
E. cava Anti-diabetic In-vitro Showed inhibitory activity against α-glucosidase (IC50 = 10.8 μmol/L) and α- Lee et al. (2009)
amylase (IC50 = 124.9 μmol/L). It also displayed a non-competitive type of
inhibition against α-glucosidase.
E. cava Matrix metalloproteinases In-vitro In human osteosarcoma cell, dieckol Inhibits the mRNA gene and protein levels Ryu et al. (2009)
inhibition of iNOS, COX-2, MMP-1, MMP-3, and MMP-13. Dieckol also inhibits the JNK and
p38 MAPK phosphorylation.
E. cava Anti-inflammatory In-vivo The PGE2, NO, and HMGB-1 production significantly inhibited in the serum of Yang et al. (2016)
mice with LPS-induced septic shock.
E. cava Cytoprotective Ex vivo In neonatal mouse cochlea, dieckol showed a dose dependent partial protective Chang et al. (2016)
effect against gentamicin-induced hair cell.
E. bicyclis, E. cava Antioxidant In-vitro Exerted scavenging effect against DPPH and superoxide anion with EC50 value of Shibata et al. (2008)
and E. kurome 13 μM and 7.6 μM, respectively.
2-Phloroeckol (9) E. stolonifera Hepatoprotective In-vitro In tacrine-treated HepG2 cells, eckol potentially inhibits the Fas-mediated cell- Lee et al. (2012b)
death protein expression and also inhibit the cytochrome c release from the
mitochondria to cytosol.
E. stolonifera Antioxidant In-vitro Exerted DPPH scavenging effect (EC50 = 35.2 μM) and also inhibited ROS Lee et al. (2012b)
production in tacrine-treated HepG2 cells.
E. stolonifera Anti-inflammatory In-vitro Showed inhibition of NO production (EC50 = 85.3 μmol/L) in LPS-stimulated Wei et al. (2016)
RAW 264.7 cells.
7
Dioxinodehydroeckol (10) E. Cava Anti-cancer In-vitro In MCF-7 human breast cancer cells, Dioxinodehydroeckol significantly induced Kong et al. (2009)
proliferative inhibition and apoptosis.
E. stolonifera Antioxidant In-vitro Showed DPPH scavenging activity (EC50 = 8.8 μM) which is more effective than Kim et al. (2009)
L-ascorbic acid (EC50 = 10.3 μM).
E. cava UV protective In-vitro Protects the human keratinocyte cells from UVB-induced apoptosis. Ryu et al. (2015)
6,6′ Bieckol (11) E. cava Anti-HIV In-vitro Displayed inhibition against lytic effects, HIV-1 induced syncytia formation and Artan et al. (2008)
viral p24 antigen production at EC50 values of 1.23, 1.72 and 1.26 μM
respectively. Also, selective inhibition against HIV-1 RT enzyme
(EC50 = 1.07 μM).
E. cava Anti-inflammatory In-vitro Through negative regulation of the NF-κB pathway, 6,6′ Bieckol down-regulated Yang et al. (2012)
COX-2, iNOS, and pro inflammatory cytokines in LPS-stimulated macrophages.
E. stolonifera Anti-inflammatory In-vitro Showed inhibition of NO production (EC50 = 63.9 μmol/L) in LPS-stimulated Wei et al. (2016)
RAW 264.7 cells.
E. stolonifera Anti-inflammatory In-vitro Down-regulated NF-κB activation in LPS-stimulated microglial cells through JNK, Kim et al. (2016)
p38 MAPK and Akt.
E. cava Anti-allergy In-vitro Histamine release was inhibited dose-dependently from both KU812 and RBL2H3 Le et al. (2009)
cell lines.
8,8′-Bieckol (12) E. cava Anti-HIV In-vitro Displayed HIV-1 RT and protease inhibition at IC50 = 0.51 and 81.5 μM Ahn et al. (2004)
respectively.
E. kurome Antibacterial In-vitro Showed bactericidal activity against S. aureus, Bacillus cereus, Escherichia coli, C. Nagayama et al. (2002)
and E. kurome 15 μM and 6.5 μM, respectively.
7-Phloroeckol (13) E. cava Anti-influenza In-vitro Exhibited inhibitory effects on Influenza Virus NA (rvH1N1), A/Hong Kong/8/68 Ryu et al. (2011)
(H3N2), A/Chicken/Korea/MS96/96 (H9N2) and, A/PR/8/34 (H1N1), with IC50
values of 44.2 μM, 37.4 μM, 32.2 μM and 41.2 μM, respectively.
Phlorofucofuroeckol-A (14) E. kurome Antibacterial In-vitro Nagayama et al. (2002)
Table 2 (continued)
Showed bactericidal activity against S. aureus, Bacillus cereus, Escherichia coli, C.


E. kurome Algicidal In-vitro Showed anti-algicidal activity against red tide dinoflagellates such as K. mikimotoi Nagayama et al.
and C. polykrikoides. (2003)
E. stolonifera Anti-hypertension In-vitro Exhibited ACE inhibition with an IC50 value of 12.74 μM. Jung et al. (2006)
E. stolonifera Anti-diabetic In-vitro Exerted inhibition against AGE (IC50 = 165.20 μM) and aldose reductase Jung et al. (2008)
(IC50 = 125.45 μM).
E. stolonifera Anti-inflammatory In-vitro Inhibited LPS-induced NO and PGE2 production and by down-regulating inducible Kim et al. (2009)
NO synthase and COX- 2 protein expressions.
E. stolonifera Anti-inflammatory In-vitro In LPS-stimulated RAW 264.7 cells, Phlorofucofuroeckol-A inhibits the production of Wei et al. (2016)
NO (EC50 = 6.95 μmol/L).
and E. kurome 15 μM and 6.5 μM, respectively Exerted scavenging effect against DPPH and
superoxide anion with EC50 value of 12 μM and 8.4 μM, respectively
E. stolonifera Antioxidant In-vitro Showed radical scavenging activities against DPPH (EC50 = 4.7 μM). Also Kim et al. (2009)
suppressed the intracellular ROS concentration in LPS-induced RAW 264.7 cells
Phlorofucofuroeckol B (15) E. stolonifera Antioxidant In-vitro Exerted DPPH scavenging effect (EC50 = 4.9 μM) and also inhibited the intracellular Lee et al. (2012b)
ROS in tacrine-treated HepG2 cells.
E. stolonifera Anti-inflammatory In-vitro Displayed anti-inflammatory activity based on the inhibition of NO production Wei et al. (2016)
(EC50 = 12.1 μmol/L) in LPS-stimulated RAW 264.7 cells.
E. arborea Anti-allergy In-vitro Exhibited dose-dependent inhibition of histamine release from rat basophile Sugiura et al. (2006)
leukemia-2H3 cells (IC50=7.8 μM).
Triphlorethol-A (16) E. cava Antioxidant In-vitro Showed scavenging effect against intracellular ROS and DPPH radical and prevented Kang et al. (2005)
lipid peroxidation.
E. cava Antioxidant In-vitro Increased cellular antioxidant defense by inducing HO-1 via ERK–NF–E2 related Kang et al. (2007)
8
factor 2(Nrf2)-ARE signaling pathway, thereby protecting cells from oxidative stress.
E. cava Sedative In vivo 50 mg/kg dose decreased sleep latency) in C57BL/6N mice and increased the Yoon and Cho (2018)
amount of non-rapid eye movement sleep (NREMS, without affecting rapid eye
movement sleep
Trifucodiphlorethol A (17) F. vesiculosus L. Chemopreventive In-vitro Exerted scavenging effect against DPPH (IC50 = 14.4 μg/ml) and peroxyl radicals Parys et al. (2010)
(IC50 = 3.5 μg/ml). Also inhibited cytochrome P450 1A (IC50 = 20.0 μg/ml) and
aromatase (Cyp19) activity (IC50 = 3.3 μg/ml).
Trifucotriphlorethol A (18) F. vesiculosus L. Chemopreventive In-vitro Exerted scavenging effect against DPPH (IC50 = 13.8 μg/ml) and peroxyl radicals Parys et al. (2010)
(IC50 = 3.2 μg/ml). Also inhibited aromatase (Cyp19) activity (IC50 = 5.6 μg/ml)
and cytochrome P450 1A (IC50 = 17.9 μg/ml).
Fucotriphlorethol A (19) F. vesiculosus L. Chemopreventive In-vitro Exerted scavenging effect against DPPH (IC50 = 10.0 μg/ml) and peroxyl radicals Parys et al. (2010)
(IC50 = 3.3 μg/ml). Also inhibited cytochrome P450 1A (IC50 = 33.7 μg/ml) and
aromatase (Cyp19) activity (IC50 = 1.2 μg/ml).
Diphlorethohydroxycarmalol (20) Ishige okamurae Anti-diabetic In-vitro Diphlorethohydroxycarmalo inhibits the high glucose-induced glucotoxicity and Lee et al. (2012c)
apoptosis at 10 or 50 μg/mL. Diphlorethohydroxycarmalol also decreases NO level,
intracellular ROS generation and thiobarbituric acid reactive substances increased by
high glucose.
I. okamurae Anticancer In-vitro In human promyelocytic leukemia (HL60) cells, Diphlorethohydroxycarmalol Kang et al. (2012)
induces the apoptosis in via a reduction in the Bcl-2 levels and simultaneous
mitochondrial signaling through Bax, ultimately leading to mitochondrial
dysfunction.
I. okamurae Radioprotective In-vitro & Protected cells from apoptosis through ROS scavenging effect and also protects bone Ahn et al. (2011)
In-vivo marrows cells and intestinal progenitor cells.
I. okamurae Antioxidant In-vitro Displayed scavenging effect on ABTS radical and intracellular ROS, and also prevents Heo and Jeon
H2O2-induced cell damage. (2009a)
I. okamurae Photoprotective In-vitro Prevents UV-B radiation-induced cell damage in human fibroblast cell line. Heo et al. (2010a)
I. okamurae Antityrosinase In-vitro Showed potent inhibitory effect against tyrosinase with an IC50 value of 142.20 μM Heo et al. (2010a)
compared to the positive control arbutin (IC50 = 384.82 μM).
I. okamurae Antimelanogenic In-vitro Heo et al. (2010a)

power; HO•, hydroxy; KU812, human basophilic leukemia; LPS, lipopolysaccharide; MIC, minimum inhibitory concentration; MSRA, methicillin resistant; MSSA, methicillin-susceptible; O2•−, superoxide anion radical;
ACE, angiotensin-converting enzyme; AGE, advanced glycation endproducts; ARE, antioxidant response element; DPP- IV, dipeptidyl peptidase IV; DPPH, 1,1-diphenyl-2-picrylhydrazyl; FRAP, ferric reducing antioxidant
offered enormous untapped potential in the discovery of new drug
targets. The high molecular weight polysaccharides and their de-
Kawamura-Konishi
Heo et al. (2012)
Lee et al. (2016)

gradation products of low molecular weight oligosaccharides are eco-
et al. (2012)
nomically very important owing to the numerous biological properties
with minimal toxicity. Most polysaccharides are used as stabilisers,
Reference
thickeners, and emulsifiers in food industries (Tseng, 2001). Seaweeds

or marine macroalgae contain a wide range of polysaccharides which
are described to possess a plethora of pharmacological activites in-
Exerted a melanin inhibition with an IC50 value of 37.73 μM and the inhibition was
Prevents H2O2-induced damage in neuronal cells and reduces the Bax expression.
amylases. Displayed inhibitory effects against α-amylase (IC50 = 3.2 μg/mL), α-
cluding anticancer, antiinflammatory, and excellent antioxidant activ-

Suppressed the hydrolysis of amylopectin by human salivary and pancreatic α-
glucosidase from rat intestinal (IC50 = 25.4 μg/mL) and sucrase and maltase
ities. The significant polysaccharides found in marine algae are algi-

nates, agarans, carrageenan, fucoidan, laminarin, and ulvans
In type 2 diabetic db/db mice, Octoplorethol A significantly improves
(Rengasamy et al., 2014b). Although polysaccharides have potential

biological properties, their viscosity and poor solubility make them
inefficient for pharmaceutical applications. This problem has been
potent than retinol, a positive control (IC50 = 50.25 μM).
overcome with the discovery of oligosaccharides which are derived

from hydrolysis of polysaccharides either by using acid hydrolysis or
enzyme hydrolysis method. Recent research emphasises the importance
of oligosaccharides such as alginate oligosaccharides (derived from al-
ginate), fucoidan oligosaccharides (derived from fucoidan), laminarin
hyperinsulinemia and impaired glucose.
oligosaccharides (derived from Laminarin) and carrageenan oligo-

saccharides (derived from carrageenan). The polysaccharides and oli-
gosaccharides prepared from seaweeds or marine macroalgae and their
biological properties are summarised in Table 1 and the chemical
structures of important polysaccharides are shown in Fig. 1.
(IC50 = 114 μg/mL).
4.2. Phlorotannins
Phlorotannins, more commonly known as algal polyphenols, are

Findings
polymers of phloroglucinols which comprise up to 15% of dry weight of

brown algae. Laminariacea have been documented to be the most
abundant source of phlorotannins in marine algae. The molecular
weight of phlorotannins ranges from 126 kDa to 650 kDa. In the past
Model used
In-vitro
In-vitro
In-vivo
two decades, there have been a considerable literature on the isolation

ORAC, oxygen radical absorbance capacity; RBL2H3, rat basophilic leukemia; ROS, reactive oxygen species.
and pharmacological properties of phlorotannins from brown algal

species such as Eisienia bycycles, Ecklonia cava, E. stolonifera and E.
maxima (Kannan et al., 2013; Rengasamy et al., 2013; Rengasamy et al.,
2014a, b). Phlorotannins have also been found to possess numerous
biological/pharmacological properties such as antimicrobial
(Nagayama et al., 2002), antioxidant (Kim et al., 2009), anti-HIV (Artan
Biological activity
Neuroprotective
et al., 2008), antiproliferative (Kong et al., 2009), anticancer (Parys

Anti-diabetic
Anti-diabetic
et al., 2010), anti-inflammatory (Kim et al., 2009), antidiabetes

(Kannan et al., 2013; Rengasamy et al., 2013, 2014a), anti-Alzheimer
disease (Kannan et al., 2013), antihypersensitive (Jung et al., 2006),
anticoagulant (Li et al., 2007), and radioprotective (Moon et al., 2008).
Further comprehensive evidence on the isolation and pharmacological
properties of brown algal phlorotannins are listed in Table 2 and the
chemical structures of important phlorotannins are shown in Fig. 2A
I. okamurae
and B.
I. foliacea
S. patens
Source
4.3. Protein hydrolysates

2-(4-(3,5 dihydroxyphenoxy)-3,5-dihydroxyphenoxy)
Protein hydrolysates are mixtures of amino acids generally re-

cognised as peptides or peptones, which are made from purified protein
by acid hydrolysis or using proteolytic enzymes and further subjected to
purification. To date, various protein hydrolysates have been reported
from seaweeds with potent pharmacological properties. Lately much
benzene-1,3,5-triol (DDBT) (21)
consideration has been diverted to the seaweed proteins and protein

hydrolysates. Seaweed protein hydrolysates have been presented to
possess many biological potential such as antibacterial activity
(Beaulieu et al., 2016), anti-hypertension (Pan et al., 2016; Qu et al.,
Octoplorethol A (22)
Table 2 (continued)
2010; Sai-kun et al., 2012; Sheih et al., 2009; Suetsuna et al., 2004),
anticoagulant (Indumathi and Mehta, 2016), antiplatelet aggregation
Phlorotannins
(Cian et al., 2012), antioxidant (Beaulieu et al., 2016; Cian et al., 2012,
2013) and chelating properties (Cian et al., 2016). Wakeme jelly pep-
tide and Peptide Nori S are the commercially available anti-hy-
persensitive peptides from the Japanese seaweed Undaria finnatifida
9
Table 3
Biological properties of seaweed protein hydrolysates.
Source Biological properties Model Findings Reference
Palmaria palmate Antioxidant In-vitro Hydrolysed fractions post-treatment with either chymotrypsin or trypsin, showed DPPH scavenging, FRAP, and Bondu et al. (2015)
ORAC.
Antioxidant In-vitro Showed antioxidant effect with ORAC value of 45.17–467.54 and FRAP value of 1.06–21.59 μmol trolox equivalents/ Harnedy and FitzGerald
g. (2013b)
Antihypertensive In-vitro < 10-kDa fraction hydrolysed with chymotrypsin showed ACE inhibition with an IC50 of 460.05 mg/mL. Bondu et al. (2015)
Antihypertensive In-vivo The tridecapeptide IRLIIVLMPILMA derived from papain hydrolysate of P. palmata exhibited renin inhibitory activity. Fitzgerald et al. (2014)
In spontaneously hypertensive rats, seaweed protein hydrolysate showed a drop-in blood pressure.
Cardioprotective and antidiabetic In-vitro Showed inhibition against ACE (IC50 = 0.19–0.78 mg/mL) and DPP-IV (IC50 = 1.65–4.60 mg/mL). Harnedy and FitzGerald
(2013a)
Renin inhibitory In-vitro Fraction obtained from P. palmata protein hydrolysate exhibited 58.97% renin inhibition at 1 mg/mL. Fitzgerald et al. (2012)
Undaria pinnatifida Antihypertensive In-vitro & In- Showed inhibition against ACE In-vitro. Four tetrapeptides administrated orally into spontaneously hypertensive rats Suetsuna and Nakano
vivo displayed antihypertensive activity. (2000)
Antihypertensive In-vitro & In- Decreased blood pressure was observed with synthetic Phe-Tyr, and Ile-Tyr Tyr-His, Lys-Tyr, Ile-Tyr and Phe-Tyr in Suetsuna et al. (2004)
vivo spontaneously hypertensive rats when administrated orally.
Porphyra yezoensis Antihypertensive In-vitro About 55% of ACE inhibition was noticed with an IC50 value of 1.6 g/L. Qu et al. (2010)
10
Anticoagulant In-vitro The purified peptide derived from pepsin hydrolysate displayed prolonged APTT l 35 s–320 s with an IC50 of 0.3 μM. Indumathi and Mehta
(2016)
Porphyra columbina Antioxidant In-vitro The residual cake hydrolysate exhibited ABTS and DPPH radical scavenging activity with IC50 value of 1.01 and Cian et al. (2013)
0.91 g/L, respectively. High copper chelating activity (≈97.5%) was also noticed.
Antihypertensive In-vitro Residual cake hydrolysate showed 45.65% inhibition against. Cian et al. (2013)
Antihypertensive In-vitro Hydrolysates showed ACE inhibition by uncompetitive mechanism, the highest activity being IC50%, 1.2 g/L. Cian et al. (2015)
Antioxidant In-vitro Displayed ABTS and DPPH scavenging, β-carotene bleaching, and copper-chelating activity Cian et al. (2015)
Antiplatelet aggregation In-vitro The peptides showed antiplatelet aggregation activity, and the activity of peptides produced from alkaline protease Cian et al. (2015)
was increased after simulated digestion process.
Chelating agent and anticariogenic In-vitro P. columbina hydrolysate showed high iron-chelating activity (33%), copper-chelating activity (β-carotene oxidation Cian et al. (2016)
rate: Ro; 0.7 min−1), and inhibition of phosphorus and Ca2+ release (87 and 81%, respectively).
Immunomodulation, Antihypertensive, In-vitro and ex Both cold-water protein extract (PF) and PF hydrolysates (PFH) displayed immunosuppressive properties on rat Cian et al. (2012)
Antioxidant vivo splenocytes by enhancing IL-10 production and inhibiting the production of TNF-α and IFN-γ. PFH also showed
> 35% of ACE inhibition and antioxidant effect (DPPH, TEAC, ORAC and copper-chelating activity).
Enteromorpha clathrata Antihypertensive In-vitro Alcalase was found to be more suitable for the preparation of ACE inhibitory peptides from E. clathrata proteins than Sai-kun et al. (2012)
alkaline protease and trypsin. Under optimum condition, a hydrolysate with ACE inhibition (IC50 = 0.66 mg/mL) was
obtained.
Antihypertensive In-vitro Fractions less than −10 kDa exhibited higher ACE inhibition than > 10 kDa fraction. The identified active peptide Pan et al. (2016)
namely Pro-Ala-Phe-Gly showed ACE inhibition (IC50 = 35.9 μM).
Ulva rigida Antihypertensive In-vitro The hydrolysate produced under optimal proteolysis with pepsin plus bromelain, showed ACE inhibiton Paiva et al. (2016)
(IC50 = 0.483 mg/mL). Fraction < 1 kDa fraction exhibited the highest ACE inhibition (IC50 = 0.095 mg/mL).
Purification by chromatographic techniques followed by Edman degradation yielded Ile-Pro (IP) and Ala-Phe-Leu
(AFL) and these two peptides potentially inhibited ACE, with IC50 values of 0.020 and 0.023 mg/mL, respectively.
Table 4
Biological properties of seaweed terpenoids.
Terpenoids Source Biological activity Model Findings References
used
Udoteafuran (23) Udotea flabellum Antibacterial In-vitro Growth inhibition of S. aureus. Fenical and Paul
Udoteatrial (24) U. flabellum Antibacterial In-vitro Growth inhibition of S. aureus. (1984)
Flexilin (25) U. conglutinata Antimicrobial In-vitro Inhibited S. aureus, Vibrio splendida, Dreschleria haloides, and
Candida albicans.
U. conglutinata Cytotoxic In-vitro Inhibition of cell division in the sea urchin egg first cleavage
(ED100 = 16 μg/ml).
Halimedatrial (26) Halimeda spp. Antimicrobial In-vitro Inhibited S. aureus, Bacillus subtilis, Serratitia marinorubra,
Vibrio splendida, V. harvevi, V. leiognathi, Lulworthia sp…,
Alternaria sp…, D. haloides, C. albicans.
Halimeda spp… Cytotoxic In-vitro Inhibition of cell division in the sea urchin egg first cleavage
(ED100 = 1 μg/ml).
Elatol (27) Laurencia dendroidea Acaricidal and repellent Exhibited strong repellent activity against T. urtica with Born and Bianco
activity moderate toxicity. (2012)
L. dendroidea Larvicidal Potent larvicidal effect with an LC50 value of 10.7 ppm. Bianco et al.
(2013)
L. dendroidea Antileishmanial In-vitro In Leishmania amazonensis, elatol inhibits promastigote and Santos et al.
activity intracellular amastigote forms with an IC50 of 4.0 μM and (2010)
0.45 μM, respectively.
L. microcladia Anti-tumor In-vitro Prompted cell cycle arrest in the G1 and the sub-G1 phases, Campos et al.
and In- leading cells to apoptosis. Elatol also decreased the (2012)
vivo expression of cyclin-D1, cyclin-E, cyclindependent kinase
(cdk)2 and cdk4. A decrease in bcl-xl and an increase in
bak, caspase-9 and p53 expression was also observed.
Treatment in-vivo with elatol also decreased tumor growth
11
in C57Bl6 mice.
Diterpenoid seco-dolastane (4R,9S,14S)-4alpha-acetoxy-9beta, 14alpha-dihydroxydolast-1 C. cervicornis Acaricidal and repellent Exhibited moderate toxicity, but a high degree of repellent
(15),7-diene (28) activity activity against T. urticae.
Mertensene (29) and violacene (30) and two derivatives (dibromomertensene (31) and Plocamium Insecticidal activity Toxicity of violacene to Schizaphis graminum aphids was Argandona et al.
dihydromertensene (32) cartilagineum higher than other compounds, causing 92% mortality of (2000)
aphid after 48 h. It was similar to insecticides used as
aphicides. Violacene, dibromomertensene, and
dihydromertensene decreased the reproduction index of
aphids. Also, dibromomertensene and violacene protected
tomato plants against the tomato moth Tuta absolute.
Pterocladiella Anti-cancer In vitro Mertensene induced G2/M cell cycle arrest and caspase Tarhouni-Jabberi
capillacea dependent apoptosis of Human Colon Adenocarcinoma et al. (2017)
HT29 cell line via the modulation of ERK-1/-2, AKT and NF-
kB signaling.
Telfairine (33) P. telfairiae Insecticidal activity Exhibited 100% larvicidal activity against Culex pipiens Watanabe et al.
pallens at 10 ppm in solution. (1989)
Isoparguerol (34), isoparguerol-16-acetate (35), isoparguerol-7,16-diacetate (36), Jania rubens Anti-tumor In-vitro The isolated compounds inhibited viability of Ehrlich Awad (2004)
parguerol-16-acetate (37), deoxyparguerol (38), parguerol-7,16-diacetate (39), carcinoma tumor cells (90, 90, 100, 80, 90, 70, 80%
deoxyparguerol-7-acetate (40) inhibition, respectively). Isoparguerol derivatives displayed
slightly greater efficacy than parguerol derivatives.
J. rubens Anthelmintic In-vitro Anthelmintic activities (against earthworms -Allolobophora Awad (2004)
caliginosa). Isoparguerol and parguerol derivatives were
more effective than deoxyparguerol series. These
compounds displayed high anthelmintic activity when
compared with the same concentration (10%) of the
reference anthelmintic drug mebendazole.
Table 4 (continued)

used
Neoirietetraol (41) Laurencia Toxicity In-vivo Displayed toxicity to the Artemia salina (brine shrimp) with Takahashi et al.
yonaguniensis an LC50 of 40.1 μM. (1998)

L. yonaguniensis Antibacterial In-vitro Displayed least antibacterial activities against Alcaligenes Takahashi et al.
aquamarinus and Escherichia coli. (2002)
Stypoquinonic acid (42) Stypopodium zonale Tyrosine Kinase In-vitro Showed inhibitory effect on tyrosine kinase Wessels et al.
Inhibitor (IC50 = 79.7 μg/mL). (1999)
S. zonale Antibacterial In-vitro Inhibited the growth of Bacillus megaterium and E. coli. Wessels et al.
(1999)
Dehydrothyrsiferol (43) Laurencia viridis Antitumor In-vitro Inhibited human breast cancer cell lines, viz. ZR-75-1, Pec et al. (1999)
Hs578T and T47D with IC50 of 16.0, 18.9 and 13.5 μM,
respectively.
Stypolactone (44) S. zonale Antitumor In-vitro Showed weak cytotoxic property against A-549 (human Dorta et al. (2002)
lung carcinoma) and HT-29 and H-116 (human colon
carcinoma) cell lines, with IC50 values of > 25.0 μg/ml, in
each case.
Aplysiaterpenoid A (45) Plocamium telfairiae Insecticidal Displayed strong insecticidal activities against the mosquito Watanabe et al.
larvae (Anopheles gambiae) and German cockroach (Blatella (1990)
germanica).
Telfairine (46) P. telfairiae Insecticidal Displayed strong insecticidal activities against the mosquito Watanabe et al.
larvae (Anopheles gambiae) and German cockroach (Blatella (1990)
germanica).
Dictyterpenoid A (47) and B (48) Dilophus okamurae Feeding-deterrent Displayed feeding-deterrent activity against abalone Haliotis Suzuki et al.
discus hannai. (2002)
Scopariol (49), isorigidol (50), (+)-3-(Z)-bromomethylidene-10β-bromo-β-chamigrene (51) Laurencia scoparia Anthelmintic In-vitro Showed anthelmintic effect against Nippostrongylus Davyt et al. (2001)
brasiliensis
12
2β,3α-epitaondiol (52), flabellinol (53), flabellinone (54), stypotriolaldehyde (55), Stypopodium Neurotoxic In-vitro Moderate toxicity to murine neuro-2a cells Sabry et al. (2005)
stypohydroperoxide (56) flabelliforme (LC50 = 2–25 μM) was observed for alln the compounds.
2β,3α-epitaondiol, flabellinol, and flabellinone possessed
potent sodium channel blocking activity. In addition,
stypotriolaldehyde displayed a biphasic effect on the
concentration of intracellular Ca2+ in rat cerebellar granule
neurons.
2β,3α-epitaondiol (52), flabellinol (53), flabellinone (54) S. flabelliforme Antitumor In-vitro Exhibited moderate cytotoxic effect with NCI–H460 human Sabry et al. (2005)
lung cancer cell line.
(6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (57) Dictyota menstrualis Feeding-deterrence Displayed feeding-deterrent properties against the Pereira et al.
amphipod Parhyale hawaiensis Dana. (2000)
3,7-dihydroxy-dihydrolaurene (58) Laurencia obtusa Cytotoxicity In-vitro Displayed cytotoxic effect on K562, MCF7, PC3, HeLa, Kladi et al. (2006)
A431, and CHO cell lines, with IC50 values of > 300, 201.7,
182.3, 121.3, 176.4, 234.7 μM, respectively.
Perforenol B (59) L. obtusa Cytotoxicity In-vitro Displayed cytotoxic effect on K562, MCF7, PC3, HeLa, Kladi et al. (2006)
A431, and CHO cell lines, with IC50 values of 67.4, 28.2,
54.8, 50.9, 73.2, 80.2 μM, respectively.
(1S*, 2R*, 6R*, 8S*, 9R*)-8-bromo2,5,6,9-tetramethyltricyclo-[7.2.0.0]undec-4-en-3-one L. obtusa Cytotoxicity In-vitro Displayed cytotoxic effect on K562, MCF7, PC3, HeLa, Kladi et al. (2006)
(60) A431, and CHO cell lines, with IC50 values of > 300,
> 300, 126.2, 111.3, 137.1, > 300 μM, respectively.
7-hydroxylaurene (61) L. obtusa Cytotoxicity In-vitro Displayed cytotoxic effect on K562, MCF7, PC3, HeLa, Kladi et al. (2006)
18.1, 40.5, 23.9, 78.2 μM, respectively.
Table 4 (continued)

used
Isolaurenisol (62) L. obtusa Cytotoxicity In-vitro Displayed cytotoxic effect on K562, MCF7, PC3, HeLa, Kladi et al. (2006)
103.2, 88.6, 122.0, 165.5 μM, respectively.
(E)-2-tridecyl-2-heptadecenal (63) L. obtusa and L. Cytotoxicity In-vitro Displayed cytotoxic effect on K562, MCF7, PC3, HeLa, Kladi et al. (2006)
microcladia A431, and CHO cell lines, with IC50 values of 82.7, 51.4,
71.6, 51.8, 45.8, 107.6 μM, respectively.
Perforenone A (64) L. obtusa Cytotoxicity In-vitro Displayed cytotoxic effect on K562, MCF7, PC3, HeLa, Kladi et al. (2006)
A431, and CHO cell lines, with IC50 values of > 300,
> 300, 138.3, 117.7, 105.1, > 300 μM, respectively.
3-epi-perforenone A (65) L. obtusa Cytotoxicity In-vitro Displayed cytotoxic effect on K562, MCF7, PC3, HeLa, Kladi et al. (2006)
A431, and CHO cell lines, with IC50 values of > 300,
> 300, 144.4, 154.2, 151.9, > 300 μM, respectively.
Laurinterol (66) L. microcladia Cytotoxicity In-vitro Displayed cytotoxic effect on K562, MCF7, PC3, HeLa, Kladi et al. (2006)
76.6, 83.9, 74.6, 165.8 μM, respectively.
Bromolaurenisol (67) L. microcladia Cytotoxicity In-vitro Displayed cytotoxic effect on K562, MCF7, PC3, HeLa, Kladi et al. (2006)
92.4, 105.8, 81.6, > 200 μM, respectively.
Amijiol (68)Amijiol acetate (69) Dolabellatrienol (70), Dolastane mijiol-7-10-diacetate (71), Dictoyota dichotoma DNA protective, In-vitro Showed DNA protective effect, and cytotoxicity against Ayyad et al. (2011)
Pachydictyol A (72), Isopachydictyol cytotoxicity, HepG2, WI-38 and MCF-7 cell lines. Also displayed
A (73), 8b-hydroxypachydictyol A (74),Isodictyohemiacetal (75), and Dictyol C (76) antioxidant antioxidant effect by means of ABTS and erythrocytes
hemolysis.
Capisterone A (77) and B (78) Penicillus capitatus Antifungal In-vitro Showed effective antifungal activity against the marine Puglisi et al.
fungi (Lindra thallasiae). (2004)
(1S,2S,4R,5R,1′E)- 2-bromo-1-bromomethyl-1,4-dichloro-5-(2′-chloroethenyl)-5- Plocamium hamatum Antifungal, In-vitro Showed potent antialgal activity towards Chlorella fusca, König et al. (1999)
13
methylcyclohexane (79) antibacterial and antinfungal effect on Ustilago violacea and Mycotypha
antialgal microspora, and antibacterial effect against Bacillus
megaterium.
Labda-14-ene-8-ol (80), Labda-14-ene3α,8α-diol (81), ent-Labda-13 (16),14-diene-3-one Ulva fasciata Antibacterial In-vitro Inhibited the growth of Vibrio alginolyticus, V. Chakraborty et al.
(82),Labda-14-ene-8α,9α-diol (83), ent-Labda-13 (16),14-diene-3α-ol (84), ent-Labda- parahaemolyticus and V. vulnificus and with MIC values (2010)
13 (16),14-diene (85) ranging from 30 to 250 μg/ml.
Peyssonoic acid A (86) Peyssonnelia sp. Antimicrobial and In-vitro Inhibited the growth of the bacterial pathogen of marine Lane et al. (2010)
antineoplastic algae, Pseudoalteromonas bacteriolytica (IC50 = 799 μM),
and Lindra thalassiae (IC50 = 506 μM), and also showed
least antineoplastic activity against ovarian cancer cells
(IC50 = 34.5 μM).
Peyssonoic acid B (87) Peyssonnelia sp. Antimicrobial and In-vitro Inhibited the growth of P. bacteriolytica (IC50 = 377 μM), Lane et al. (2010)
antineoplastic and L. thalassiae (IC50 = 331 μM), and also showed least
antineoplastic activity against ovarian cancer cells
(IC50 = 13.5 μM).
2,5,5-Trimethyl-4-(4-methylpent-3-enyl)-2-cyclohexen-1-ol (88) Ulva fasciata Antioxidant In-vitro Displayed DPPH and ABTS scavenging effect Chakraborty and
(IC50 = 13.74 mM and 66.8% inhibition at 50 μM, Paulraj (2010)
respectively).
4- Isopentyl-3,4,5,5-tetramethyl-2-cyclohexen-1-ol (89) U. fasciata Antioxidant In-vitro Displayed DPPH scavenging effect Chakraborty and
(IC50 = 23.60–20.83 mM). Paulraj (2010)
6-Isopentyl-1,5,5,6-tetramethyl-1-cyclohexene (90) U. fasciata Antioxidant In-vitro Displayed DPPH and ABTS scavenging effect Chakraborty and
(IC50 = 80.56 mM and 12.8% inhibition at 50 μM, Paulraj (2010)
respectively).
3,4,5,5-Tetramethyl-4-(3-oxopentyl)-2-cyclohexene-1-one (91) U. fasciata Antioxidant In-vitro Displayed DPPH and ABTS scavenging effect Chakraborty and
(IC50 = 10.24 mM and 78% inhibition at 50 μM, Paulraj (2010)
respectively).
and Porphyra yasoensis, respectively (Harnedy and FitzGerald, 2013).
Yang et al. (2015)
Yang et al. (2015)

Although protein hydrolysates possess various biological properties,
Kubo and Smith
isolation of anti-hypertension inhibitory peptides from seaweed is now
References
(1998) getting much momentum among researchers worldwide. The detailed

information on the proteins, peptides, and other protein hydrolysates
isolated from seaweeds are given in Table 3.
phosphatase 1B (PTP1B), T-cell PTPase (TC-PTP) and cell

4.4. Terpenoids
division cycle 25 homolog B (CDC25B) with IC50 values

Showed inhibitory effects against protein tyrosine
Terpenoids, sometimes referred to as terpenes, are a huge group of
(MIC = 50 μg/ml), Brevibacterium ananoniagenes
(MIC = 25 μg/ml), Trichophyton mentagrophytes
natural products commonly found in plants. They are a unique class of

Exhibited moderate cytotoxic effect on HL-60
(MIC = 400 μg/ml), Propionibacterium acnes
hydrocarbon moiety comprising of terpenes attached to an oxygen-

(MIC = 100 μg/ml), Streptococcus mutans
(MIC = 50 μg/ml), Staphylococcus aureus
Showed inhibition against Bacillus subtilis
2.30, 12.56, and 42.92 μM, respectively. containing group. In the current market, more than 60–75% drugs are
employed for the treatment/management of infectious diseases and
cancer, among these more than 23000 molecules belong to the class of
terpenoid (Wang et al., 2005). For instance, the currently available
commercial antimalarial drug Artemisinin and the anticancer drug
paclitaxel (Taxol®) are terpenoid biomolecules, and many terpenoid
(MIC = 25 μg/ml).
(IC50 = 49.3 μM).
molecules are in the clinical pipeline. Terpenoids are commonly clas-

sified as monoterpenoids, sesquiterpenes, diterpenes, sesterterpenes
based on their chemical structure. Marine organisms are well-known to
Findings
be a reservoir of these four categories of terpenes which have been

documented to have numerous pharmacological properties. Seaweeds
or marine macroalgae are a vast source of structurally diverse terpe-
noids especially red seaweeds, which are reported to have high amount
In-vitro
In-vitro
In-vitro
Model
used
of terpenoids. Among the seaweeds, the family Rhodomelaceae is

considered as a terpenoid pool due to its vast chemical diversity and
structurally different terpenoids. More than 1058 molecules harnessed
naturally have been identified and characterised from this family which
Enzyme inhibitory
Biological activity
accounts to 20% of the total halogenated compounds characterised

Antibacterial
from all marine organisms (Wang et al., 2013). The comprehensive

Cytotoxicity
activities
information on the pharmacological properties of terpenoids from

seaweeds are shown in Table 4 and the chemical structures of important
terpenoids are shown in Fig. 3A–C.
Caulerpa racemosa
4.5. Alkaloids
Sargassum tortile
C. racemosa
In 1819 Meissner proposed the term “alkaloid” which originated

Source
from the Arabic words “al kaly” and the Greek “eidos”, meaning alkali-
like. Alkaloids are heterocyclic nitrogenous compounds having Br-, I-,
Cl-, and S- in their structure (Güven et al., 2010, 2013). Alkaloids are
well known diverse group of natural biomolecules reported to have
enormous health benefits and biological potential. The well-known
example is Galanthamine; a commercially available anticholinesterase
inhibitor used to treat dementia over the years. A more recent book
written by Aniszewski (2015) described the applications of alkaloids in
pharmaceutical and agricultural industries. Although alkaloids are ex-
tensively studied, research on marine algal-based alkaloids is still
under-explored. The first alkaloid molecule was isolated from marine
red algae Phyllophora nervosa is hordenine in 1969 (Güven et al., 1969,
1970). The alkaloids isolated from various marine algae and its phar-
macological properties are listed in Table 5 and the chemical structures
of important alkalaoids are shown in Fig. 4.
4.6. Photosynthetic pigments

Racemobutenolid A (93) and B (94)
4′,5′-dehydrodiodictyonema A (95)
Plants possess various photosynthetic pigments such chlorophylls,

carotenoids, anthocyanins, betains, and research on the biological
properties of these colourful pigments is gaining much attention due to
its health-promoting effects. Like other terrestrial plants seaweeds,
Table 4 (continued)
marine macroalgae are listed as one of the primary resources of these

beneficial health pigments including carotenoids, fucoxanthin (xan-
Crinitol (92)
thophyll pigments found in brown seaweeds), phycocyanin and phy-

Terpenoids
coerythrin (found in red seaweeds). The importance of carotenoids

especially β-carotene, α-carotene, β-cryptoxanthin, lycopene, lutein
and zeaxanthin has already been well documented (Rodriguez-Amaya,
14
Table 5
Biological properties of seaweed alkaloids.
Alkaloid Source Biological activity Model used Findings References
Caulerpin (96) Caulerpa racemosa Antinociceptive In-vivo In the abdominal constriction test, the alkaloid exerted a reduction in the De Souza et al. (2009)
acetic acid-induced nociception at 0.0945 μmol (0.0103–1.0984).
Caulerpin also caused a favourable nociception inhibition in the hot plate
test at 100 μmol/kg, p.o.
C. racemosa Anti-inflammatory In-vivo 100 μmol/kg, p.o og caulerpin showed a high anti-inflammatory activity.
This effect was further established on (i) capsaicin-induced ear edema
model (% inhibition of 55.8) and (ii) the carrageenan-induced peritonitis
(number of recruit cells decreased by 48.3%)
C. racemosa Anti-viral In-vitro Showed antiviral activity against bovine viral diarrhea virus Pinto et al. (2012)
(EC50 = 2.0 μM).
Caulerpa sp. Spasmolytic Ex vivo using Repressed phasic contractions induced by carbachol, histamine, and Ayyad and Badria
guinea pig serotonin in a non-selective manner. A dose-dependent inhibition against (1994)
ileum serotonin-induced cumulative contractions. It also relaxed KCl-pre-
contracted ileum and carbachol in a dose-dependent manner.
Caulerpa lentilifera, Antibacterial In-vitro Presented moderate antibacterial action against 8 bacterial species Vairappan (2004)
C. racemosa, Caulerpa isolated from algal surface.
15
microphysa and Caulerpa
sertularoides
Almazole C (97) Haraldiophylum sp. Antibacterial In-vitro Showed antibacterial activity against Gram-negative pathogens. Fresneda et al. (2007)
Lophocladine A (98) and B (99) Lophocladia sp. Anticancer In-vitro Exhibited cytotoxicity to MDAMB-435 breast cancer and NCI–H460 Gross et al. (2006)
human lung tumor cell lines. The activity was correlated with
microtubule inhibition.
Lophocladia sp. Neuroprotective In-vitro Showed affinity for NMDA receptors and found to be a δ-opioid receptor
antagonist.
4. Martefragin A (100) Martensia fragilis Antioxidant Ex vivo In in rat liver microsomes, Martefragin A inhibited NADPH-dependent Takahashi et al.
lipid peroxidation (IC50 = 2.8 μM). (1998)
5. Racemosin A (101) Caulerpa racemosa Neuroprotective In-vitro Reduced the Aβ25–35-induced SH-SY5Y cell damage with a 14.6% Liu et al. (2013)
increase in cell viability at 10 μM compared to the positive control EGCG
(16.57% increaseat 10 μM).
6. Racemosin C (102) Caulerpa racemosa Tyrosine phosphatase-1B In-vitro Exhibited significant PTP1B (human protein tyrosine phosphatase-1B) Yang et al. (2014)
inhibitory activity inhibitory activity with IC50 values of 5.86 μM compared to the positive
control oleanolic acid (IC50 = 3.03 μM).
7. Azocinyl morpholinone (103) [3-(2-ethyl-6- Gracilaria opuntia Antioxidant In-vitro Showed scavenging effect against DPPH radicals (IC50 = 0.086 mg/mL). Makkar and
((3Z,7Z)-1,2,5,6-tetrahydroazocin-5-yl)hexyl) Chakraborty (2018)
morpholin6-one] (104) G. opuntia Anti-inflammatory In-vitro and In- Inhibited COX-2 (IC50 = 0.84 mg/mL) and 5-lipoxidase Makkar and
vivo (IC50 = 0.85 mg/mL). Chakraborty (2018)
Table 6
Biological properties of fucoxanthin from seaweeds.
Source Biological activity Model used Findings Reference
Eisenia bicyclis and Undaria pinnatifida Antidiabetic In-vitro Displayed inhibitory activity against AGE formation (IC50 = 86.48 μM), HRAR (IC50 = 108.31 μM), RLAR (IC50 = 264.67 μM), Jung et al. (2012)
and PTP1B activity (IC50 = 4.80 μM).
U. pinnatifida Antidiabetic In-vivo Fucoxanthin improved hyperglycemia in diabetic/obese KK-Ay mice. It enhanced the insulin signaling pathway, with Nishikawa et al. (2012)
translocation of GLUT4, and by stimulating expression of GLUT4 in the soleus and extensor digitorum longus muscles,
respectively.
U. pinnatifida Antioxidant In-vitro Decreased TBARS values on day 1 and 6 in ground chicken breast meat during chilled storage after cooking. Sasaki et al. (2008)
Halocynthia roretzi Anticancer In-vitro Fucoxanthinol significantly decreased viability of HL-60 human leukemia cells at 12.5 μM. Konishi et al. (2006)
U. pinnatifida Anticancer In-vitro Fucoxanthin significantly decreased the viability of Caco-2 (human colorectal carcinoma), HCT116 (human colorectal Kotake-Nara et al. (2005)
adenocarcinoma) and PC-3 human prostate cancer cells at 10 μM.
U. pinnatifida Anticancer In-vitro Strong inhibitory effect was noticed 13-cis and 13′-cis fucoxanthin on Caco-2 cells and HL-60 cells. Nakazawa et al. (2009)
Hijikia fusiforme Anticancer In-vivo In C3H/He male mice, fucoxanthin suppressed liver tumorigenesis. Besides, in the skin of ICR mice, antitumor-promoting effect Nishino (1998)
was noticed with fucoxanthin in a two-stage carcinogenesis experiment.
H. fusiforme Anticancer In-vivo In B6C3F1 male mice, drinking water mixed with 0.01% fucoxanthin for 7 weeks significantly decreased the number of putative Kim et al. (1998)
preneoplastic aberrant crypt foci (ACF)/mouse from 63.3 for the control group to 47.1 value.
Laminaria japonica Neuroprotective In-vitro Pre-treatment with fucoxanthin reduced β-amyloid protein (Aβ)-induced cell death in cortical cultured neurons or PC12 cells. Zhao et al. (2015)
L. japonica Anti-pigmentary In-vitro and In- Inhibited melanogenesis in melanoma, UVB-induced skin pigmentation and tyrosinase. The application of 1% fucoxanthin Shimoda et al. (2010)
vivo topically also suppressed mRNA expression of COX-2, NTR, endothelin receptor A, EP1, MC1R and tyrosinase-related protein 1.
L. japonica Anti-osteoporosis In-vitro Suppression of osteoclastogenesis by inhibiting differentiation of osteoclast and apoptosis induction through caspase-3 Das et al. (2010)
activation in osteoclast-like cells.
Myagropsis myagroides Anti-inflammatory In-vitro Inhibited NO production, inducible nitric oxide synthase (iNOS), COX-2 protein expressions and slightly reduced the PGE2 Heo et al. (2010b)
production. Fucoxanthin also dose-dependently reduced the release of TNF-α, IL-1β, and IL-6.
16
Petalonia binghamiae Anti-obesity In-vitro Promotion of 3T3-L1 adipocyte differentiation was noticed with fucoxanthin treatment during the early stage of differentiation Kang et al. (2011)
(D0-D2) and it was proved by the increased accumulation of tryglycerides. Besides, fucoxanthin dose-dependently increased
protein expression of PPARγ, C/EBPα, SREBP1c, aP2, and adiponectin mRNA expression. Fucoxanthin reduced the expression
of PPARγ, C/EBPα, and SREBP1c during the intermediate (D2–D4) and late stages (D4–D7) of differentiation.
U. pinnatifida Anti-obesity In-vivo Lowered body weight and viscerafat-pads weights in diet-induced obesity mice fed a high-fat diet without altering food intake. Woo et al. (2009)
U. pinnatifida Anti-obesity In-vivo In diabetic/obese KK-Ay mice, fucoxanthin effectively regulated the mRNA expression of inflammatory adipocytokines involved Hosokawa et al. (2010)
in iNOS, insulin resistance and COX-2 in white adipose tissue.
U. pinnatifida Anti-obesity In-vitro and In- Inhibited lipase enzyme in the gastrointestinal lumen and suppressed absorption of triglyceride in rats. Moreover, fucoxanthin Matsumoto et al. (2010)
vivo was further converted to fucoxanthinol in the intestine and finally released into the lymph.
U. pinnatifida Anti-obesity In-vivo Dietary fucoxanthin caused an increase in serum HDL, non-HDL-cholesterol levels, total cholesterol levels via the activation of Beppu et al. (2012)
SREBP signaling and by suppressing serum cholesterol uptake in the liver via decreasing LDLR and SR-B1 expression in KK-Ay
mice. Fucoxanthin also promoted LDLR degradation through up-regulation of PCSK9 and leads to increased non-HDL-
cholesterol levels.
Sargassum heterophyllum Antiplasmodicidal In-vitro Displayed excellent antiplasmodial effect against chloroquine-sensitive strain (D10) of Plasmodium falciparum with an IC50 Afolayan et al. (2008)
value of 1.5 μM.
Sargassum siliquastrum Cytoprotective In-vitro Inhibited DNA damage, apoptosis induced by H2O2 and intracellular ROS formation, Heo et al. (2008)
S. siliquastrum Photoprotective In-vitro Fucoxanthin treatment effectively decreased generation of Intracellular ROS by exposure to UV-B radiation. In addition, the Heo and Jeon (2009b)
protective effect of fucoxanthin was also confirmed through Hoechst 33342/PI staining.
U. pinnatifida Anti-angiogenic In-vitro and ex Suppressed proliferation and tuve formation of HUVEC at more than 10 μM, but showed no significant effect on HUVEC Sugawara et al. (2006)
vivo chemotaxis. Moreover, fucoxanthin suppressed microvessel outgrowth, using a rat aortic ring, in a dose-dependent manner.
C/EBPα, CCAAT/enhancer-binding protein α; EP1, prostaglandin E receptor 1; HRAR, human recombinant aldose reductase; HUVEC, human umbilical vein endothelial cells; iNOS, inducible nitric oxide synthase; LDLR,
low-density lipoprotein receptor; MC1R, melanocortin 1 receptor; NTR, p75 neurotrophin receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; PGE2, prostaglandin E2; PPARγ, protein expression of peroxisome
proliferator-activated receptor γ; RLAR, rat lens aldose reductase; SR-B1, scavenger receptor class B type 1; SREBP, sterol regulatory element binding protein; SREBP1c, sterol regulatory element-binding protein 1c;
TBARS, thiobarbituric acid reactive substances.
Fig. 1. Chemical structures of biological active polysaccharides from seaweeds.
2016). The global fucoxanthin production market was about 500 tons in seaweeds. Phycocyanin comprises of two similar α and β subunits of
2015 and is expected to grow at a CAGR of 5.3% from 2016 to 2021 proteins with molecular weight of 17000 and 19500 Da, respectively.
(ResearchnReports, 2016). In seaweeds, fucoxanthin and astaxanthin The importance of phycocyanin was critically reviewed by Romay et al.
are the two primary available carotenoid pigments. Fucoxanthin (2003) followed by many other researchers. Phycoerythrins are made
(C42H58O6) is contributing to 10% of the total carotenoid production up of two peptides such as α and β subunits with 160–180 amino acids
globally (Dembitsky and Maoka, 2007). In recent years, scientific re- (Anwer et al., 2015; Sonani et al., 2017). The detailed information on
search on fucoxanthin have attracted considerable interest owing to the isolation and bioactivity of fucoxanthin, phycocyanin and phy-
their potential pharmacological properties including antimicrobial, coerythrin are listed in Table 6.
antimalarial activities, antioxidant, anti-obese, antidiabetic, anti-in- 4.7. Polyunsaturated fatty acids (PUFA)
flammatory, anticancer, antiangiogenic, and its protective effects on the
various organs (D’Orazio et al., 2012; Gammone and D'Orazio, 2015; PUFA, consist of long hydrocarbon chains which terminate with
Kim and Pangestuti, 2011; Peng et al., 2011; Rengasamy et al., 2014b). hydroxyl groups. They are also commonly termed as long-chain PUFA
The other essential seaweed pigments are phycocyanin and phycoery- (LC-PUFA). Depending on the position of the first carbon-carbon double
thrin which are predominantly available in microalgae and red bond (C]C), it is classified into omega 3 or omega six fatty acids.
17
Fig. 2A. Chemical structures of biological active phlorotannins from seaweeds.
Alpha-linolenic acid (18 carbons and three double bonds), EPA (20 disease and arthritis (Swanson et al., 2012). Nearly half of the total
carbons and five double bonds) and DHA (22 carbons and six double fatty acid content in various seaweeds are comprised of EPA (C20:5, n-
bonds) are three main omega three fatty acids which play a crucial role 3) (Dawczynski et al., 2007; MURATA and Nakazoe, 2001). The other
in healthy human physiology (Rengasamy et al., 2014b). Among these, interesting point to note is that seaweeds are the only source for n-3
EPA and DHA are now gaining much attention from the marine func- PUFA 18:4, n-3 (Rengasamy et al., 2014). Owing to the high con-
tional food researchers due to their health beneficial effects including centrations of PUFA, especially omega three fatty acids, seaweeds are
the reduction of the risk factors linked to fetal development, assisting excellent candidates for the development of nutracetuticals/dietary
visual and neurodevelopment, cardiovascular disorders, Alzheimer's supplements for human health.
disease hypertension, and improving conditions such as coronary artery
18
Fig. 2B. Chemical structures of biological active phlorotannins from seaweeds.
4.8. Polyamines Polyamines are also reported to have various biological importance in
cancer prevention, inflammation, and their role as antioxidants, anti-
Polyamines are low molecular weight water-soluble aliphatic com- aging effect, and their effect on gut maturation (Larqué et al., 2007).
pounds consists of two or more amino groups which are least studied Apart from human health benefits, polyamines also have a beneficial
bioactive natural compounds available in all the living organisms in- impact on plant growth and development. However, research on the
cluding bacteria, fungi, plants and mammalian cells. The first poly- discovery of polyamines from various natural resources, including
amine, spermine, was isolated from human semen in 1678. Three seaweeds or marine macroalgae, is still in infancy stage.
known vital polyamines were putrescine (1,4-butane diamine or tetra-
methylenediamine), spermidine (N-(3-aminopropyl)-1,4-butane dia-
mine or aminopropyl-tetramethylenediamine), spermine (N, N0-bis(3- 5. Safety and toxicity of seaweed compounds
aminopropyl)-1,4-butane diamine or diaminopropyl-tetra-
methylenediamine) and agmatin, a polyamine derivative derived from Although seaweeds have gained much interest in food industrial
arginine. Spermine and spermidine are reported to have anti-glycation applications for their nutritive values, it is important to determine their
effect, and it is well documented that glycation has an essential role in toxicological profile for the safety of consumers. Few studies have
the genesis of diabetes complications (Gugliucci and Menini, 2003). probed into the safety profile of seaweeds compounds. For instance, the
toxicity of fucoidan in Sprague-Dawley rats was tested by Kim et al.
19
Fig. 3A. Chemical structures of terpenoids from seaweeds.
(2010). Fucoidan (1350 mg/kg bw/day) for 4 weeks) did not cause Food-grade carrageenan has also been shown to be relatively non-toxic
significant differences in groups matched by gender with respect to by oral, dermal and inhalation routes of exposure in animal species,
body weight, ophthalmoscopy, urinalysis, hematology, and histo- mutagenicity studies and reproductive toxicity studies (Weiner, 1991).
pathology. Also, Fucoidan did not affect prothrombin time or activated It is also important to point out that many bioactive compounds,
partial thromboplastin time, which indicates an inability to change especially the terpenoids, have not been tested in toxicological studies.
blood clotting. Moreover, Vidal et al. (1984) carried out toxicity studies Considering the fact that some of these compounds are known to pos-
on two metabolites present in Caulerpa species, caulerpin and cau- sess insecticidal properties such as mertensene, violacene (Argandona
lerpicin, and demonstrated that these two substances are not toxic. et al., 2000), telfairine (Watanabe et al., 1989), aplysiaterpenoid A
20
Fig. 3B. Chemical structures of terpenoids from seaweeds.
(Watanabe et al., 1990), elatol (Bianco et al., 2013), it is necessary that and polyamines still in infancy stage; it might be due to inadequate
future studies aim to determine their safety profile in vitro and on an- knowledge on isolation and structural chemistry with seaweed biolo-
imal species. gist. Recent evidences suggest that dietary polyamines not only possess
health benefits but also possess significant role in plant growth and
development, nonetheless, not much information is available on sea-
6. Concluding remarks and future prospects
weed polyamines. Marine algae have been frequently reported for their
potential as enzyme inhibitors against various health illness including
Marine macroalgae or seaweeds are considered as one among the
cancer, diabetes, inflammation, gout, dementia, and others (Rengasamy
economically important biological resources which offer an extensive
et al., 2014). Therefore, it is necessary to initiate algal drug discovery
assortment of phytonutrients and phytochemicals comprising of vita-
research platform to focus on enzyme inhibitors which is now a hot
mins, proteins, micro and macro elements, poly- and oligosaccharides,
topic of research among both the natural product chemists as well as
polyunsaturated fatty acids, terpenoids, alkaloids, polyphenols espe-
commercial drug market.
cially phlorotannins and polyamines with potential pharmacological
properties. Among these bioactive compounds, research on alkaloids
21
Fig. 3C. Chemical structures of terpenoids from seaweeds.
Fig. 4. Chemical structures of alkaloids from seaweeds.
22
Fig. 5. Biological properties of different classes of seaweed compounds.
Author contributions racemosa. Alexandria. J. Pharm. Sci. 8 217-217.

Ayyad, S.-E.N., Makki, M.S., Al-kayal, N.S., Basaif, S.A., El-Foty, K.O., Asiri, A.M., Alarif,
W.M., Badria, F.A., 2011. Cytotoxic and protective DNA damage of three new di-
K.R.R.R and M.F. conceptualized the study. K.R.R.R, M.F and MZA terpenoids from the brown alga Dictoyota dichotoma. Eur. J. Med. Chem. 46,
conducted the literature collection, and prepared the first draft. All 175–182.
authors were involved in improving and polishing the manuscript. Beaulieu, L., Sirois, M., Tamigneaux, É., 2016. Evaluation of the in vitro biological ac-
tivity of protein hydrolysates of the edible red alga, Palmaria palmata (dulse) har-
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Declaration of competing interest Beppu, F., Hosokawa, M., Niwano, Y., Miyashita, K., 2012. Effects of dietary fucoxanthin
on cholesterol metabolism in diabetic/obese KK-A y mice. Lipids Health Dis. 11, 112.
Bianco, E.M., Pires, L., Santos, G.K., Dutra, K.A., Reis, T.N., Vasconcelos, E.R., Cocentino,
The authors declare that they have no known competing financial A.L., Navarro, D.M., 2013. Larvicidal activity of seaweeds from northeastern Brazil
interests or personal relationships that could have appeared to influ- and of a halogenated sesquiterpene against the dengue mosquito (Aedes aegypti).
ence the work reported in this paper. Ind. Crops Prod. 43, 270–275.
Blunt, J.W., Copp, B.R., Hu, W.-P., Munro, M., Northcote, P.T., Prinsep, M.R., 2007.
Marine natural products. Nat. Prod. Rep. 24, 31–86.
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Food and Chemical Toxicology 135 (2020) 111013

Contents lists available at ScienceDirect

Food and Chemical Toxicology

Bioactive compounds in seaweeds: An overview of their biological T

ARTICLE INFO ABSTRACT

Polysaccharide Source Biological properties Model used Findings Reference

expression. Besides, fucoidan suppresses the NF-κB activation and down-

(continued on next page)

Polysaccharide Source Biological properties Model used Findings Reference

The novel paclitaxel-loaded alginate nanoparticle promoted decreased

cells superior to those of paclitaxel alone.

(continued on next page)

approved drugs mainly consist of marine metabolites or their synthetic

analogues. Also, most of the marine-derived medicines isolated from

Exhibited reducing power and inhibition of hydroxyl radicals and superoxide

3. Recent developments in algal drug research

Seaweeds or marine macroalgae reside in the littoral zone and are

nomic and ecological significance (Dhargalkar and Pereira, 2005).

Taxonomically, seaweeds are grouped into three major phyla: (i)

pied by brown seaweeds (Khan and Satam, 2003).

marine origin is increasing especially from marine plants such as sea-

algae have much attracted functional food researchers. Recent shreds of

evidence suggest that seaweeds have been regularly consumed as food

bioactive compounds isolated from seaweeds and their role as enzyme

and Jeon, 2012), alkaloids (Güven et al., 2010), halogenated terpenoids

focuses on the bioactive compounds isolated from seaweeds and their

in-depth biological properties (see detailed activities in Tables 1–6 and

4. The primary bioactive compound in seaweeds

Polysaccharides are carbohydrate biopolymers consisting of simple

sugars linked by glycoside bonds and are classified into structural

protect against H2O2-mediated DNA damage.

Phlorotannins Source Biological activity Model used Findings Reference

Phlorotannins Source Biological activity Model used Findings Reference

Showed bactericidal activity against S. aureus, Bacillus cereus, Escherichia coli, C.

in the range 0.08–0.66 μmol/mL.

(continued on next page)

Lee et al. (2016)

thickeners, and emulsifiers in food industries (Tseng, 2001). Seaweeds

amylases. Displayed inhibitory effects against α-amylase (IC50 = 3.2 μg/mL), α-

cluding anticancer, antiinflammatory, and excellent antioxidant activ-

ities. The significant polysaccharides found in marine algae are algi-

(Rengasamy et al., 2014b). Although polysaccharides have potential

overcome with the discovery of oligosaccharides which are derived

oligosaccharides (derived from Laminarin) and carrageenan oligo-

Phlorotannins, more commonly known as algal polyphenols, are

polymers of phloroglucinols which comprise up to 15% of dry weight of

two decades, there have been a considerable literature on the isolation

and pharmacological properties of phlorotannins from brown algal

et al., 2008), antiproliferative (Kong et al., 2009), anticancer (Parys

et al., 2010), anti-inflammatory (Kim et al., 2009), antidiabetes

4.3. Protein hydrolysates

Protein hydrolysates are mixtures of amino acids generally re-

consideration has been diverted to the seaweed proteins and protein

Terpenoids Source Biological activity Model Findings References

yonaguniensis an LC50 of 40.1 μM. (1998)

Terpenoids Source Biological activity Model Findings References

and Porphyra yasoensis, respectively (Harnedy and FitzGerald, 2013).

Yang et al. (2015)

Yang et al. (2015)