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Medicinal and pharmaceutical uses of seaweed natural products: A review

August 2004
Journal of Applied Phycology 16(4):245-262

August 2004
16(4):245-262

DOI:10.1023/B:JAPH.0000047783.36600.ef

Authors:

University of the Western Cape

In the last three decades the discovery of metabolites with biological activities from macroalgae has increased significantly. However, despite the intense research effort by academic and corporate institutions, very few products with real potential have been identified or developed. Based on Silverplatter MEDLINE and Aquatic Biology, Aquaculture & Fisheries Resources databases, the literature was searched for natural products from marine macroalgae in the Rhodophyta, Phaeophyta and Chlorophyta with biological and pharmacological activity. Substances that currently receive most attention from pharmaceutical companies for use in drug development, or from researchers in the field of medicine-related research include: sulphated polysaccharides as antiviral substances, halogenated furanones from Delisea pulchra as antifouling compounds, and kahalalide F from a species of Bryopsis as a possible treatment of lung cancer, tumours and AIDS. Other substances such as macroalgal lectins, fucoidans, kainoids and aplysiatoxins are routinely used in biomedical research and a multitude of other substances have known biological activities. The potential pharmaceutical, medicinal and research applications of these compounds are discussed.

. Idealised structures of μ -carrageenan ( 1 ), λ -carrageenan ( 2 ), κ -carrageenan ( 3 ) and ı -carrageenan ( 4 ). Some carrageenans have potent antiviral activities against several strains of HSV types 1 and 2. A carrageenan-based microbicide, Carraguard, is currently un- dergoing phase III clinical trials; it is used to block HIV and other sexually transmitted diseases in vitro . Chondriamide A ( 5 ) from Chondria atropurpurea shows antiviral activity against HSV type II and cytotoxicity against human nasopharyngeal and colorectal cancer cells. Chondriamide C ( 6 ), also from Chondria atropurpurea , displays cytotoxic and in vitro anthelmintic properties. The cyclic depsipeptides kahalalide A ( 7 ) and F ( 8 ) are produced by a species of Bryopsis . Both show in vitro activity against Mycobacterium tuberculosis . Kahalalide F has anti-HIV qualities which are being further studied in clinical trials and its effectiveness as treatment of lung cancers and tumours are also being studied. (5 Z )-4-bromo-5-(bromomethylene)-3-butyl- 2(5 H )-furanone ( 9 ) is a halogenated compound from Delisea pulchra which displays strong antifouling properties.

…

. α -Kainic ( 10 ) and domoic acids ( 11 ) are pyrrolidine dicarboxylates with excitatory and excitotoxic activities. Kainoids occur in some pennate diatoms where they cause amnesic shellfish poisoning, but they are also produced by some members of the Ceramiales. They are used as tools in research into neurophysiological disorders such as Alzheimer’s and Parkinson’s disease, and epilepsy. Domoic acid-containing extracts of Digenea simplex and Chondria armata have been used by the Japanese as anthelmintic agent, and it also has insecticidal properties. Aplysiatoxin ( 12 ) and debromoaplysiatoxin ( 13 ) are potent tumour promoters used in medical research, and are responsible for non-fatal poisonings associated with eating Gracilaria coronopifolia . The related manauealide A ( 14 ), manauealide B ( 15 ) and manauealide C ( 16 ) which also occur in Gracilaria coronopifolia were shown to induce diarrhoea in mice. Polycavernoside A ( 17 ) has been isolated from the red alga Polycavernosa tsudae . Polycavernosides are complex glycosidic toxins belonging to a class of macrocyclic lactones and are the causative agents for the fatal human poisonings following consumption of Polycavernosa tsudae . Prostaglandin E 2 ( 18 ) is a product of PUFA metabolism in some species of Gracilaria and is the causative agent responsible for the fatal ‘ogonori’ poisoning resulting from the consumption of species of Gracilaria .

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Journal of Applied Phycology 16: 245–262, 2004.

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2004 Kluwer Academic Publishers. Printed in the Netherlands.

245

Review

Medicinal and pharmaceutical uses of seaweed natural products: A review

Albertus J. Smit

Department of Botany, University of Cape Town, Rondebosch, 7700, South Africa; Current address: School of

Biology, Faculty of Science, University of KwaZulu-Natal, Westville Campus, Private Bag X54001, Durban, 4000,

South Africa

∗

Author for correspondence (e-mail: ajsmit@science.uct.ac.za)

Received 15 August 2003; revised and accepted 21 April 2004

Key words: biological activity, macroalga, medicine, pharmaceuticals, pharmacology, seaweeds

Abstract

In the last three decades the discovery of metabolites with biological activities from macroalgae has increased

signiﬁcantly. However, despite the intense research effort by academic and corporate institutions, very few products

with real potential have been identiﬁed or developed. Based on Silverplatter MEDLINE and Aquatic Biology, Aqua-

culture & Fisheries Resources databases, the literature was searched for natural products from marine macroalgae

in the Rhodophyta, Phaeophyta and Chlorophyta with biological and pharmacological activity. Substances that

currently receive most attention from pharmaceutical companies for use in drug development, or from researchers

in the ﬁeld of medicine-related research include: sulphated polysaccharides as antiviral substances, halogenated

furanones from Delisea pulchra as antifouling compounds, and kahalalide F from a species of Bryopsis as a possible

treatment of lung cancer, tumours and AIDS. Other substances such as macroalgal lectins, fucoidans, kainoids and

aplysiatoxins are routinely used in biomedical research and a multitude of other substances have known biological

activities. The potential pharmaceutical, medicinal and research applications of these compounds are discussed.

Introduction

Global utilisation of macroalgae is a multi-billion dol-

lar industry. Much of this is based on farming of edible

species or on the production of agar, carrageenan and

alginate. Of all seaweed products, hydrocolloids have

had the biggest inﬂuence on modern western societies.

They have attained commercial signiﬁcance through

their use in various industries which exploit their phys-

ical properties such as gelling, water-retention and their

ability to emulsify (Renn, 1997). Little commercial

exploitation of products extracted from seaweeds oc-

curs outside the hydrocolloid industry. However, in

recent years pharmaceutical ﬁrms have started look-

ing towards marine organisms, including seaweeds,

in their search for new drugs from natural products.

These products are also increasingly being used in

medical and biochemical research. Prior to the 1950s,

the medicinal properties of seaweeds were restricted to

traditional and folk medicines (Lincoln et al., 1991).

During the 1980s and 90s, compounds with biological

activities or pharmacological properties (bioactivities)

were discovered in marine bacteria, invertebrates and

algae (Mayer & Lehmann, 2000). According to Ireland

et al. (1993), algae have been the source of about 35% of

the newly discovered chemicals between 1977–1987,

followed by sponges (29%) and cnidarians (22%). The

discovery of new products from seaweeds has de-

creased since 1995 and attention has now shifted to

marine micro-organisms (Kelecom, 2002).

Modern screening programmes are motivated

by the chemical ecology of marine organisms. The

selection of samples for assays of biological activities

useable in drug development is often based on

ecological observations and includes specimens with

unique (usually chemical) mechanisms for coping with

environmental pressures (Haefner, 2003). Another

avenue for discovery of novel compounds is through

assaying for marine toxins. Toxins in macroalgae are

scarcer than in microalgae and cyanophytes, and only

a handful of such toxins have been described. Research

into the active ingredients of seaweeds used in folk

246

remedies underlies another area of drug discovery.

Since pharmaceutical companies have access to

extensive libraries of natural products, and many

compounds are of marine origin, high-throughput

automated systems can be used for rapid screening in

the search for new drugs (Cordell, 2000).

This review focuses on important bioactive chemi-

cals identiﬁed in macroalgae in the Rhodophyta, Phaeo-

phyta and Chlorophyta over the last three decades

and describes the range of biological activities for

which they are responsible. Focus is placed on the

main classes of compounds that could be of medici-

nal and pharmaceutical value. The use of macroalgal

constituents as research tools in medical research is

also covered. Emphasis is placed on active substances

that elicit biochemical responses in animals and plants,

rather than those that are used for their physical prop-

erties such as mycosporine-like amino acids as UV

sunscreens, phycobiliproteins as ﬂuorescent tags, or

alginates and carrageenans in tissue engineering. The

health beneﬁts of constituents of edible seaweeds and

their role in nutrition and disease prevention is also ex-

cluded from the review, as much research remains to

be done before science-based dietary recommendations

can be made (Kris-Etherton et al., 2002).

Methods

The largest part of the peer-reviewed publications

was obtained from literature searches of two on-

line databases. Silverplatter MEDLINE was used

to ﬁnd records of present and potential medicinal,

bio-medical and pharmaceutical uses of macroalgal-

derived products. MEDLINE covers the period from

1966 to present, and includes more than 11 800 000

records in 3 800 journals from about 70 countries

(http://www.ovid.com). The research journals Aquatic

Biology, and Aquaculture & Fisheries Resources ac-

cessible via Biblioline (http://www.nisc.com) were

also used. This database contains more than 1 100 000

records and extends back to 1971. English records were

extracted using the list of search terms:

(seaweed* or macroalg*) and ((biol* and activ*) or

(secondary and metabolite*) or anti* or cytotox* or

carrageenan* or agar* or algin* or inhibit*).

The wildcard ‘*’ is used to expand the abbreviated

term in the search; for example, anti* searches for any

term in which ‘anti’ occurs as a preﬁx, such as an-

tiviral, antibacterial or antitumour. A series of review

articles on marine natural products was also located,

and this gave additional information that might have

been missed by the electronic searches.

Much of the work on biological activities has been

done using crude aqueous extracts and fractions of

these extracts and these are usually not reported here.

The review was limited only to activities that have been

associated with a particular known compound or at the

very least a broad group of compounds such as sul-

phated polysaccharides.

Antiviral activity

Some sulphated polysaccharides from red algae

show antiviral activities towards viruses responsi-

ble for human infectious diseases. Most notable are

Aghardhiella tenera and Nothogenia fastigiata.

Witvrouw et al. (1994) tested a galactan sulphate

from Aghardhiella tenera, and Damonte et al. (1994)

and Kolender et al., (1995) a xylomannan sulphate

from Nothogenia fastigiata against human immunode-

ﬁciency virus (HIV), Herpes simplex virus (HSV) types

1 and 2 and respiratory syncytial virus (RSV). These

polysaccharides are active during the ﬁrst stage of the

RNA virus replication when the virus adsorbs onto the

surface of the cell (De Clercq, 1996, 2000). An impor-

tant requirement of an antiviral polysaccharide is that it

must have very low cytotoxic activities towards mam-

malian cells, and most of the algal polysaccharides, par-

ticularly those of Aghardhiella tenera and Nothogenia

fastigiata,have this characteristic (De Clercq, 1996).

Carrageenans (Figure 1) demonstrate potential in

vitro antiviral activity. Carlucci et al. (1997, 1999a,

1999b) noted that λ-carrageenan and partially cyclized

µ/´ı-carrageenan from Gigartina skottsbergii have po-

tent antiviral effects against different strains of HSV

types 1 and 2 during the virus adsorption stage. Car-

rageenans from cystocarpic and tetrasporophytic stages

of Stenogramme interrupta show similar antiherpetic

activity (C´aceres et al., 2000). Zeitlin et al. (1997)

tested a range of antiviral substances for their possi-

ble effectiveness as vaginal microbicide against gen-

ital herpes in mice, and found that carrageenan and

fucoidan, or fucoidin, are good candidates for further

development. None of these studies have shown that

carrageenans exhibit signiﬁcant levels of cytotoxicity

or anticoagulant activity. A carrageenan-based vagi-

nal microbicide called Carraguard has been shown to

block HIV and other sexually transmitted diseases in

vitro. Carraguard entered phase III clinical trials involv-

ing 6000 non-pregnant, HIV-negative women in South

Africa and Botswana in 2003 (Spieler, 2002).

247

Figure 1. Idealised structures of µ-carrageenan (1), λ-carrageenan (2), κ-carrageenan (3) and

ı-carrageenan (4). Some carrageenans have

potent antiviral activities against several strains of HSV types 1 and 2. A carrageenan-based microbicide, Carraguard, is currently un-

dergoing phase III clinical trials; it is used to block HIV and other sexually transmitted diseases in vitro. Chondriamide A (5) from

Chondria atropurpurea shows antiviral activity against HSV type II and cytotoxicity against human nasopharyngeal and colorectal cancer

cells. Chondriamide C (6), also from Chondria atropurpurea, displays cytotoxic and in vitro anthelmintic properties. The cyclic depsipep-

tides kahalalide A (7) and F (8) are produced by a species of Bryopsis. Both show in vitro activity against Mycobacterium tuberculosis.

Kahalalide F has anti-HIV qualities which are being further studied in clinical trials and its effectiveness as treatment of lung cancers and tu-

mours are also being studied. (5Z )-4-bromo-5-(bromomethylene)-3-butyl- 2(5H )-furanone (9)isahalogenated compound from Delisea pulchra

which displays strong antifouling properties.

248

A sulphated polysaccharide from Schizymenia

paciﬁca inhibits HIV reverse transcriptase in vitro

(Nakashima et al., 1987a, 1987b), a later stage in HIV

replication. It has minimal effect on human DNA and

RNA polymerase activity. Some agaroids such as high

molecular weight galactan sulphate from Gracilaria

corticata have antiviral properties against HSV types

1 and 2, and this action is likely due to an inhibition of

the initial virus attachment to the host cell (Mazumder

et al., 2002).

Fucoidan has potent antiviral properties towards

viruses such as RSV (Malhotra et al., 2003), HIV,

(Sugawara et al., 1989), HSV types 1 and 2 and hu-

man cytomegalovirus (Feldman et al., 1999; Majczak

et al., 2003; Ponce et al., 2003). The antiviral prop-

erties of fucoidan seem to stem from inhibiting bind-

ing of the viral particle to the host cell (Baba et al.,

1988). It has the additional beneﬁt of inhibiting bind-

ing of sperm to the zona pellucida in humans (Oeninger

et al., 1991), thus allowing for the compound to be de-

veloped into a possible vaginal microbicide with con-

traceptive properties. Uncharacterised polysaccharide

fractions obtained from Caulerpa sp., Corallina sp.,

Hypnea charoides, Padina arborescens and Sargassum

patens also have high antiviral activity against HSV

types 1 and 2 while maintaining low levels of cytotox-

icity (Zhu et al., 2003).

The antiviral activities discussed thus far are for

algal polysaccharides, but other compounds exhibit

similar properties. Chondriamide A (Figure 1) from

Chondria atropurpurea shows antiviral activity against

HSV type II (Palermo et al., 1992). Kahalalide F

(Figure 1) produced by a species of Bryopsis has

also been noted for its effectiveness in some AIDS

study cases, and its antiHIV qualities are being further

studied in clinical trials (Hamann et al., 1996; Haefner,

2003).

Antibiotic activity

Chemicals responsible for antibiotic activities are

widespread in macroalgae. Interesting substances in

particular are the halogenated compounds such as

haloforms, halogenated alkanes and alkenes, alcohols,

aldehydes, hydroquinones and ketones (Lincoln et al.,

1991). The list of terpenoids with antibiotic qualities is

especially long, and many of these are also halogenated.

Compounds such as sterols and heterocyclic and phe-

nolic compounds sometimes have antibiotic properties.

Many of these could be developed into antiseptics and

cleansing agents, but their antibiotic activity in vivo is

often only achieved at toxic concentrations (Lincoln

et al., 1991).

The depsipeptides kahalalide A (Figure 1) and F

from Bryopsis sp. were noted for their in vitro activity

against Mycobacterium tuberculosis (el Sayed et al.,

2000), but the future of these peptides seems to lie

with the development of kahalalide F for treatment of

lung cancer, tumours and AIDS.

A promising antibacterial agent is a halogenated

furanone, or ﬁmbrolide, that belong to a class of

lactones (Figure 1) from Delisea pulchra.Ithas been

examined for its effectiveness as an active ingredient

in bacterial antifouling agents (Kjelleberg & Stein-

berg, 2001), and as a possible treatment for chronic

Pseudomonas aeruginosa infection. Pseudomonas

aeruginosa infection is characterised by the production

of mucoid alginate and formation of a ‘bioﬁlm’ in

the lungs of cystic ﬁbrosis sufferers (Høiby, 2002).

Inhibition of bacterial colonisation is achieved by the

inhibiting effect of furanone on the quorum sensing

mechanism of cells by functioning as an intercellular

signal antagonist. The result is a disruption of intra-

and inter-species cell-cell communication (Rasmussen

et al., 2000). The effect has been observed in a wide

range of Gram-negative bacteria. Effects are seen on

the swarming of Serratia liquefaciens (Rasmussen

et al., 2000) and the bioluminescence and virulence

in several pathogenic Vibrio species (Maneﬁeld et al.,

2000; Kjelleberg & Steinberg, 2001). It also inhibits

carbapenem antibiotic synthesis and exoenzyme

virulence factor production in the phytopathogen

Erwinia carotovora (Maneﬁeld et al., 2001).

Agglutination, coagulation and the stimulation

of cell migration

Macromolecule recognition processes are common in

cells and their speciﬁcity is their most important char-

acteristic. Many research programs exploit recognition

events and these have become focus areas of research

in biology, chemistry, medicine and pharmacology.

Biological reactions that involve recognition events

include processes such as cell agglutination and

coagulation, the stimulation of cell migration and

fertilisation.

Lectins, sometimes referred to as haemagglutinins

or agglutinins, are glycoproteins with an ability to ag-

glutinate red blood cells (Boyd & Reguera, 1949). Vari-

ous polysaccharides are present on cell surfaces, and as

a result many cells including microbes and yeasts (e.g.

Patchett et al., 1991; Bird et al., 1992; Cisar et al., 1995),

249

tumour cells (Hori et al., 1986) and erythrocytes are

selectively agglutinated by lectins (Chen et al., 1995).

Lectins are inhibited by sugars of the same type as those

on the surface of the cells being agglutinated (Sharma &

Sahni, 1993). They are useful in exploring properties of

biological structures and processes, and have found ap-

plications in biology, cytology, biochemistry, medicine

and food science and technology. Lectins from Codium

spp. have been developed into commercially available

reagents and are routinely used in biochemical studies.

Lectins with haemagglutinating properties occur in

avariety of red, green and brown algae (e.g. Rogers &

Hori, 1993; Benevides et al., 1998; Shanmugan et al.,

2002). They react with a wide array of erythrocytes,

including human blood group types. Agglutination re-

actions with human blood groups have led to their use

in assays for blood typing. Lectins are also used to char-

acterise cell-surface polysaccharides or to examine cell

binding patterns in lectinosorbent assays (Llovo et al.,

1993; Wu et al., 1996; Wu et al., 1998). Lectins from

Codium fragile subsp. tomentosoides have been devel-

oped into a histochemical reagent by coupling them to

colloidal gold, forming a lectin-gold conjugate. This

conjugate is useful for studies of the surface topogra-

phy of cells of animal tissues (Grifﬁn et al., 1995).

Other common examples of lectins from macroal-

gae are hypnins A—D in Hypnea japonica (Hori et al.,

1986), a sulphated polysaccharide in Gracilaria ver-

rucosa (Kakita et al., 1997) and a haemagglutinin in

an ammonium sulphate fraction of a buffer extract of

Gracilaria chorda (Kakita & Kitamura, 2003). Anti-

coagulant effects are often related to the sulphate and

sugar content of the components (Jurd et al., 1995;

Shanmugam et al., 2002). Cell migration is also stim-

ulated by lectins. For example, the lectin amansin

from Amansia multiﬁda, induces neutrophil migration

in vitro and in vivo in the peritoneal cavity or dor-

sal air pouch of mice (Neves et al., 2001). Lastly,

lectins from Gracilaria verrucosa induce morphologi-

cal changes and growth suppression in the dinoﬂagel-

late Chatonella antiqua (Tanabe et al., 1993).

Activities related to cellular growth

Mitogenic activity

Mitogenic activities, the stimulation of mitosis in pre-

viously non-dividing cells, have been demonstrated

in mouse lymphocytes using lectins from Eucheuma

serra (Kawakubo et al., 1997). Amansin isolated from

Amansia multiﬁda has been found to stimulate periph-

eral blood mononuclear cells and causes a gradual

reduction in mitogenic capacity with progressive in-

crease in the lectin concentration (Lima et al., 1998).

Fucoidan enhances new blood vessel formation by

modulating the expression of surface proteins (Matou

et al., 2002), and lipogenic activity has been demon-

strated for lectins from Codium fragile in isolated rat

and hamster adipocytes (Ng et al., 1989).

Effects on fertilisation and larval development

Various seaweed-derived compounds affect fertili-

sation and larval or embryonic development in both

invertebrates and vertebrates. Fucoidan inhibits the

initial binding of sperm and subsequent recognition

events necessary for penetration of the human zona

pellucida (Oehninger et al., 1991; Patankar et al.,

1993). This property of fucoidan, together with its

antiviral activity, makes it a potential candidate for

development into vaginal microbicide with contracep-

tive properties (Baba et al., 1988; Zeitlin et al., 1997).

Premakumara et al. (1996) identiﬁed a sphingosine

derivative from Gelidiella acerosa as a post-coital

contragestative agent in studies on pregnant rats.

The action of the orally administered substance is

via an antiprogesterone mechanism with no maternal

toxicity (Premakumara et al., 1995). The lectin

diabolin isolated from Laminaria diabolica causes

the development of a fertilisation envelope around

unfertilised eggs of the sea urchin Hemicentrotus

pulcherrimus, thus preventing cleavage (Nakamura

& Moriya, 1999; Nomura et al., 2000). Terpenoids

are also known for their effects on fertilisation and

subsequent development of embryos. For example,

caulerpenyne, a sesquiterpene from Caulerpa taxi-

folia,affects embryogenesis, larval development and

metamorphosis of the sea urchin Paracentrotus lividus

(Pesando et al., 1996, 1998). It also interferes with

microtubule-dependent events during the ﬁrst mitotic

cycle of sea urchin eggs (Pedrotti & Lemee 1996),

and affects regulation of intracellular pH in sea urchin

eggs and sea bream hepatocytes (Galgani et al., 1996).

Cytotoxicity, antimitogenic, anticancer and

antitumour properties

Kahalalide F which is produced by Bryopsis sp. and

subsequently assimilated by the grazer Elysia rufescens

has anticancer and antitumour properties (Hamann

& Scheuer, 1993; Hamann et al., 1996). It is effec-

tive in controlling tumours that cause lung, colon and

250

prostate cancer (Horgen et al., 2000; Nuijen et al., 2000;

Sparidans et al., 2001), and has been patented for use

as a possible active substance in therapeutics for the

treatment of human lung carcinoma (Scheuer et al.,

2000). It has entered phase II clinical studies for liver

carcinoma treatment. Kahalalide F functions by acting

on the lysosomal membrane (Stokvis et al., 2002), a

mechanism that distinguishes it from all other known

antitumour agents. It also induces cell necrosis in vivo

and selectively targets tumour cells in vitro. The cyto-

toxic activity of Kahalalide F is not mediated by mRNA

and protein synthesis de novo, nor caspase activation.

Kahalalides O and G, also from Bryopsis sp. (and Elysia

ornata)donot show signiﬁcant cytotoxicity towards

the cancer lines tested (Hamann et al., 1996; Goetz

et al., 1997; Horgen et al., 2000; el Sayed et al., 2000).

Several sulphated macroalgal polysaccharides have

cytotoxic properties. Fucoidans are known to have

antitumour, anticancer, antimetastatic and ﬁbrinolytic

properties in mice (Coombe et al., 1987; Maruyama

et al., 1987), and they also reduce cell proliferation

(Religa et al., 2000). Translam, the 1 → 3:1 → 6-β-

D-

glucans produced by enzymatic action on laminaran

(laminarin), has antitumour properties (Saito et al.,

1992). Kaeffer et al. (1999) noted that ulvan has cyto-

toxicity or cytostaticity targeted to normal or cancerous

colonic epithelial cells.

Chondriamide A (Figure 1) isolated from Chon-

dria atropurpurea shows cytotoxicity against human

nasopharyngeal and colorectal cancer cells (Palermo

et al., 1992). Terpenes are exceptionally wide in

their range of cytotoxic and antitumour activities.

Examples include (S)-12-hydroxygeranylgeraniol and

(S)-13-hydroxygeranylgeraniol derivatives from Bifur-

caria bifurcata which are toxic towards fertilised sea

urchin eggs (Valls et al., 1995; Culioli et al., 2001);

caulerpenyne from Caulerpa taxifolia which is cyto-

toxic towards several human cell lines and as such

has anticancer, antitumour and antiproliferative prop-

erties (Fischel et al., 1995; Parent-Massin et al., 1996;

Barbier et al., 2001); the hydroquinone diterpene,

mediterraneol, from Cystoseira mediterranea which is

an inhibitor of mitotic cell division (Francisco et al.,

1985); and the meroterpenes, usneoidone E and Z, from

Cystophora usneoides which have antitumour proper-

ties (Urones et al., 1992).

Antithrombic and anticoagulant activities

Fucoidans have in vivo and in vitro heparin-like an-

tithrombic and anticoagulant activities that are medi-

ated by blood coagulation inhibitors such as heparin

cofactor II or antithrombin III (Church et al., 1989;

Colliec et al., 1991; Matou et al., 2002). The anticoag-

ulation activity is the result of direct fucan-thrombin in-

teraction (Graufel et al., 1989), and it usually increases

with the amount of sulphation (Nishino & Nagumo,

1991, 1992). Sulphated fucans from Fucus vesiculo-

sus and Ascophyllum nodosum have been patented as

anticoagulant substances. The work was motivated by

the need to ﬁnd a potential replacement for cattle-

derived heparin and the fear of the transmission of

bovine spongiform encephalitis (BSE) through the use

of bovine-derived products (Trento et al., 2001). Sul-

phated fucoidan has several advantages over heparin. It

shows concentration-dependent inhibition of thrombin

generation from platelets; it exhibits concentration-

dependent inhibition of thrombin-induced platelet ag-

gregation; it lacks the hypotensive effect found in

thrombin; it reduces the sticking of polymorphonucle-

ated leukocytes to rabbit aorta; and it shows a dose-

dependent inhibition of thrombin-induced thrombosis

(Trento et al., 2001). Some older literature reports lam-

inaran as having anticoagulant properties (Hoppe &

Schmid, 1962, cited by Chapman, 1970), but it is pos-

sible that this activity comes from fucoidan which is of-

ten present in the same extracted fraction as laminaran.

Toxins—vermifuges, insecticides, ichthyotoxins,

neurotoxins and others

Toxins are better know from microalgae and

cyanophytes, but some are also known from macroal-

gae. Bioactivities of these compounds vary from being

neurologically active in humans and other mammals,

to algicidal, anthelmintic, insecticidal and ichthyotoxic

activities. In some cases they show acute toxicity and

may cause death in humans at naturally occurring

concentrations. The most important compounds

are kainoids, aplysiatoxin and polycavernosides.

Prostaglandin E

is also sometimes noted for its acute

toxicity, and is discussed in a later section.

Amino acid toxins

Kainoids are pyrrolidine dicarboxylates with excitatory

and excitotoxic activities (Carcache et al., 2003). They

are unusual amino acids structurally related to, and hav-

ing similar functions as, glutamic and aspartic acids,

both well-known neuronal excitants (agonists) or neu-

rotransmitters (Laycock et al., 1989). Kainoids are im-

251

portant tools in research (Higa & Kuniyoshi, 2000) into

neurophysiological disorders such as Alzheimer’s and

Parkinson’s disease and epilepsy (Ben-Ari & Cossart,

2000; Hopkins et al., 2000; Carcache et al., 2003).

Figure 2. α-Kainic (10) and domoic acids (11) are pyrrolidine dicarboxylates with excitatory and excitotoxic activities. Kainoids occur in

some pennate diatoms where they cause amnesic shellﬁsh poisoning, but they are also produced by some members of the Ceramiales. They are

used as tools in research into neurophysiological disorders such as Alzheimer’s and Parkinson’s disease, and epilepsy. Domoic acid-containing

extracts of Digenea simplex and Chondria armata have been used by the Japanese as anthelmintic agent, and it also has insecticidal properties.

Aplysiatoxin (12) and debromoaplysiatoxin (13) are potent tumour promoters used in medical research, and are responsible for non-fatal

poisonings associated with eating Gracilaria coronopifolia. The related manauealide A (14), manauealide B (15) and manauealide C (16) which

also occur in Gracilaria coronopifolia were shown to induce diarrhoea in mice. Polycavernoside A (17) has been isolated from the red alga

Polycavernosa tsudae. Polycavernosides are complex glycosidic toxins belonging to a class of macrocyclic lactones and are the causative agents

for the fatal human poisonings following consumption of Polycavernosa tsudae. Prostaglandin E

(18)isaproduct of PUFA metabolism in

some species of Gracilaria and is the causative agent responsible for the fatal ‘ogonori’ poisoning resulting from the consumption of species of

Gracilaria.

Pennate marine diatoms in the genera Nitzschia,

Pseudo-nitzschia and Amphora are the best known

sources of domoic acid (Figure 2), the compound

responsible for amnesic shellﬁsh poisoning (Bates,

252

1998, 2000). Domoic acid and another kainoid,

kainic acid (Figure 2), have also been isolated from

the macroalgae Digenea simplex, Chondria armata,

Chondria baileyana, Alsidium corallium, Amansia

glomerata, Vidalia obtusiloba, Laurencia papillosa

and Centroceras clavulatum (Ceramiales) (Takemoto

& Daigo, 1958; Impellizzeri et al., 1975; Laycock et al.,

1989; Smith & Kitts, 1994; Sato et al., 1996). A re-

lated compound, N-methyl-

D,L-aspartic acid, occurs

in Bryopsis plumosa, Gloiopeltis furcata, Coelothrix

charoides, Ahnfeltia paradoxa, Gymnogongrus ﬂa-

belliformis, Chondrus elatus and Amansia glomerata

(Sato et al., 1996). Zaman et al. (1997) reported the

isolation of isodomoic acids A, B, E, F, G and H from

Chondria armata. Curiously, kainic acid was also de-

tected in two spontaneous dwarf mutants of Palmaria

palmata (Palmariales) (Laycock et al., 1989; Ramsey

et al., 1994). Other neuronal agonists such as

L-cysteic

acid in Caulerpa racemosa and

D-homocysteic acid in

Palmaria palmata are known (Laycock et al., 1989), but

domoic and kainic acids are the most potent. The com-

plex molecular structure of these receptor-speciﬁc neu-

ronal agonists makes them difﬁcult to synthesise and

they are usually extracted from algal material, mainly

Digenea simplex,asrequired. Kainoids are high-value

products, and their production through biotechnology

might be a viable option for the future development of

algal cultivation for specialised chemicals.

Domoic acid-containing extracts of Digenea sim-

plex and Chondria armata have been used by the

Japanese as an anthelmintic agent for centuries (Higa &

Kuniyoshi, 2000). In addition to their toxicity to round-

worms, kainoids have insecticidal activities against

houseﬂies and cockroaches (Maeda et al., 1984, 1986,

1987) and are effective when applied both intraperi-

toneally and topically. Despite much research into the

toxicity of domoic and kainic acids, particularly on di-

atoms in the light of amnesic shellﬁsh poisoning, and

also the studies of Maeda et al. (1984, 1986, 1987) on

domoic acid in Chondria armata, the physiological or

ecological roles of the kainoids remain unknown.

Aplysiatoxins

Aplysiatoxins were ﬁrst isolated from the digestive-

gland of the sea hare Stylocheilus longicauda (Kato

& Scheuer, 1974) and later from the blue-green

alga, Lyngbya majuscula (Serdula et al., 1982). Sev-

eral cases of non-fatal poisonings were attributed

to aplysiatoxin (Figure 2) and debromoaplysiatoxin

(Figure 2) in Gracilaria coronopifolia (Nagai et al.,

1996, 1997). The characteristic clinical symptoms

of the ﬁrst aplysiatoxin poisonings of people eating

Gracilaria coronopifolia in Hawaii in 1994 were vom-

iting, diarrhoea and a burning sensation of the mouth

and throat (Nagai et al., 1996). The burning sensation

appears to distinguish the aplysiatoxin poisonings from

‘ogonori’ poisonings associated with a prostaglandin

(Ito & Nagai, 2000). In subsequent experiments on

mice, aplysiatoxin poisoning resulted in death caused

by haemorrhagic shock resulting from bleeding of the

small intestine (Ito & Nagai, 1998, 2000). The re-

lated manauealides A, B and C (Figure 2) were also

isolated from Gracilaria coronopifolia and they were

shown to induce diarrhoea in mice (Nagai et al., 1997).

Also extracted from Gracilaria coronopifolia were

malyngamides M and N (Kan et al., 1998).

Although a few isolated cases of Gracilaria poison-

ings were known before the incidents in Hawaii, these

were the ﬁrst reported cases of aplysiatoxin poisoning

following consumption of Gracilaria coronopifolia.

There is some confusion as to whether aplysiatoxin

is produced by Gracilaria coronopifolia or by its epi-

phytic cyanophytes. Aplysiatoxin is found in Lyngbya

majuscula, together with lyngbyatoxin A (Osborne

et al., 2001) and other cyanophytes such as Schizothrix

calcicola and Oscillatoria nigroviridis (Mynderse

& Moore, 1978; Serdula et al., 1982; Entzeroth

et al., 1985). Lyngbya majuscula is responsible for

swimmer’s itch, a severe form of contact dermatitis

(Moore et al., 1982). Nagai et al. (1996) observed

epiphytic blue-green algae on the thallus surface of

Gracilaria coronopifolia and isolated aplysiatoxin

from a particulate residue washed off the macroalgal

samples, and suggest that these epiphytes might be

the true source of the toxins that caused the non-fatal

poisonings in Hawaii. Aplysiatoxin from Lyngbya

was shown to increase malignant transformation,

stimulate DNA synthesis and inhibit the binding

of phorbol-12,13-dibutyrate and epidermal growth

factor to cell receptors. Debromoaplysiatoxin from

Lyngbya inhibits the binding of these two substances

as strongly as aplysiatoxin, but does not increase

malignant transformation or stimulate DNA synthesis.

Aplysiatoxin and debromoaplysiatoxin have

received much attention in the medical literature,

because of their potent tumour-promoting properties

(Ito & Nagai, 2000). They are placed in the same

class as the commonly used tumour-promoters 12-

O-tetradecanoylphorbol-13-acetate (TPA) derived

from species of Euphorbia, and teleocidin (Fujiki &

Suganuma, 1996; Levine, 1998). Examples of their

253

use in cancer and pharmacological research include

the studies by Mullin et al. (1990), Fujiki et al. (1991),

Hennings et al. (1992), Ueyama et al. (1995) and

Levine (1998). Although progress has been made in

the chemical synthesis of aplysiatoxin (Okamura et al.,

1991, 1993), the toxin still appears to be extracted

as required. Nothing is known about the biological

function of the aplysiatoxins.

Polycavernosides

Polycavernoside A (Figure 2) and its analogues poly-

cavernosides A

,Band B

have been isolated from

the red alga Polycavernosa tsudae (Yotsu-Yamashita

et al., 1995) and subsequently several other analogues

have been synthesised and reported by Barriault et al.

(1999). It should be noted that the literature associates

Polycavernosa tsudae with Gracilaria edulis, which it

calls a synonym (Yotsu-Yamashita et al., 1993, 1995),

and with Gracilaria tsudae (Nagai et al., 1996; Ito &

Nagai, 2000).

Polycavernosides are complex glycosidic toxins be-

longing to a class of macrocyclic lactones (Barriault

et al., 1999). Polycavernoside A is the causative agent

for the fatal human poisonings in Guam in 1991,

following consumption of Polycarvernosa tsudae

(Yotsu-Yamashita et al., 1993). Due to the association

between Polycarvernosa tsudae and Gracilaria edulis

in the literature, it is sometimes seen as a third form of

Gracilaria poisoning together with aplysiatoxins and

prostaglandins (Higa & Kuniyoshi, 2000). The toxic-

ity of polycavernoside A in mouse bioassays was es-

tablished at 0.2–0.4 mg kg

−1

, and symptoms include

progressive onset of severe scratching of the face and

body, spasms, paralysis, acute eye damage and death

(Barriault et al., 1999). In humans, the symptoms are

more severe than those reported for aplysiatoxin poi-

soning: diarrhoea, vomiting, abdominal pain, low blood

pressure, and in some cases paresthesia, convulsions

or loss of consciousness. In extreme cases it results in

death (Ito & Nagai, 2000). Polycavernoside A is very

rarely produced as a natural marine toxin and chemical

synthesis is the only source of this compound (White

et al., 2001). Nothing is known about the biological

role in the producing organism.

Algicides, fungicides, vermifuges, insecticides and

ichthyotoxic compounds

The anthelmintic and insecticidal properties of

kainoids have been discussed earlier. Other substances

toxic to insects, worms and ﬁshes are present in

macroalgae. The bis-indolic amides chondriamides A,

B and C have been isolated from Chondria atropur-

purea (Palermo et al., 1992; Davyt et al., 1998). Chon-

driamides A and C, 3-indoleacrylamide and the O,

,N1



-trimethyl derivative of chondriamide B, also

from Chondria atropurpurea, display cytotoxic and

in vitro anthelmintic properties against Nippostrongy-

lus brasiliensis,agastrointestinal nematode parasite

in rats (Davyt et al., 1998). Terpenoids are very di-

verse in their algicidal, fungicidal and insecticidal ac-

tivities, and they also include ichthyotoxic compounds.

Often these compounds function as antifeedants in the

producer seaweeds, but relevant bioactivities towards

test organisms are produced when applied in vitro or

in vivo. Some compounds may prove to be useful

in household, industrial or aquaculture applications if

they could be developed into suitable products. One

example is crenulacetal C, a diterpene from Dictyota

dichotoma which inhibits Polydora websterii,aharm-

ful lugworm damaging pearl cultivation (Takikawa

et al., 1998). A second example includes a variety

of sesquiterpenes isolated from Laurencia scorparia

that show anthelmintic activity in vitro against the

parasitic stage of Nippostrongylus brasiliensis (Davyt

et al., 2001). A third example is the polyhalogenated

monoterpenes, aplysiaterpenoid A and telfairine iso-

lated from Plocamium telfairiae, that show insecti-

cidal activity against mosquito larvae (Culex pipiens

pallens and Anopheles gambiae) and German cock-

roaches (Blatella germanica)(Watanabe et al., 1989,

1990).

Anti-inﬂammatory activity and effects on the

immune response

Macroalgae, especially red algae, are rich in 20-carbon

atom polyunsaturated fatty acids (PUFAs), chieﬂy

eicosapentaenoic and docosahexanoic acids (Stefanov

et al., 1988; Gerwick & Bernart, 1993). Seaweeds

are capable of metabolising various C20-PUFAs via

oxidative pathways (Gerwick et al., 1993) and in the

Gracilariales, prostaglandins are one of the products.

Two alternative pathways for the production of

prostaglandin have been proposed. The ﬁrst involves

fatty acid cyclooxygenase acting on arachidonic acid,

as in mammalian systems (Noguchi et al., 1994).

The other mechanism uses lipoxygenase, also acting

on arachidonic acid (Gregson et al., 1979). In many

red algae, the metabolised products of PUFAs, called

oxylipins, resemble eicosanoid hormones in higher

254

plants and humans which fulﬁl a range of physio-

logically important functions (Gerwick et al., 1993;

Imbs et al., 2001). The anomalous production of these

compounds underlies a number of diseases related

to inﬂammation (Gerwick & Bernart, 1993), and so

eicosanoids and their derivatives have received much

research attention in the search for development of

new classes of antiinﬂammatory drugs (Jacobs et al.,

1993). Gerwick and Bernart (1993) list studies on

macroalgal eicosanoids with antiviral, antimicrobial

and antihypertensive properties and showing various

enzyme-inhibiting activities.

The eicosanoid prostaglandin E

(PGE

) (Figure 2)

is the likely agent responsible for ‘ogonori’ poison-

ing resulting from the human consumption of a species

of Gracilaria (Fusetani & Hashimoto, 1984; Noguchi

et al., 1994). The cases of ogonori poisoning appear

to have been brought about by soaking the seaweed

in freshwater, thus causing the production of PGE

PGE

production was further enhanced interacting with

a diet rich in seafood, leading to the high availabil-

ity of arachidonic acid, the precursors of PGE

. More

PGE

was produced via the action of fatty acid cy-

clooxygenase, causing haemorrhaging of the victim’s

stomach. Symptoms included nausea, vomiting and hy-

potension and death resulted from hypotensive shock

(Noguchi et al., 1994). Symptoms are similar to those of

misoprostol overdose. Misoprostol is a PGE

analogue

used for the prevention of nonsteroidal antiinﬂam-

matory drug-induced gastropathy (Graber & Meier,

1991). Poisonings involving prostaglandins are rare but

have been mentioned in medical literature (Al Hassan

et al., 1987; Graber & Meier, 1991; Bond & van Zee,

1994).

PGE

and PGF

were detected in Gracilaria

lichenoides (Gregson et al., 1979). PGE

and 15-keto-

PGE

were found in G. asiatica (Sajiki, 1997; Sajiki

& Kakimi, 1998) and G. verrucosa was found to con-

tain PGA

, PGE

, PGF

, and 15-keto-PGE

(Fusetani

& Hashimoto, 1984; Imbs et al., 2001).

Eicosanoids such as leukotrienes and hydroxye-

icotetraenoic acid have physiologically active char-

acteristics such as chemoattraction of neutrophils or

smooth muscle cells, the contraction of muscles, and

have connections with various kinds of diseases in

mammals (Gurr & Harwood, 1991; Sajiki & Kakimi,

1998). The combined effect of prostaglandins and ex-

pansion of Laminaria stipes is also well-known in ob-

stetrics and gynaecology where it is used as a cervi-

cal dilator (Blumenthal, 1988; el Refaey & Templeton,

1995; Lee et al., 1998).

Translam, 1→3:1→6-β-

D-glucans produced from

laminaran, has immunostimulating activities in an-

imals and plants and it has been suggested that

they might serve as radioprotective substances in

patients with radiation illness (Kuznetsova et al., 1994;

Zaporozhets et al., 1995; Chertkov et al., 1999).

Preparations containing 1→3:1→6-β-

D-glucans, lam-

inaran, and fucoidan are manufactured by the health

industry and marketed for their beneﬁcial proper-

ties on the immune system. The producers of these

tablets cite numerous papers discussing the biolog-

ical activities of the 1→3:1→6-β-

D-glucans. Lami-

narans themselves generally have very low levels of

bioactivity, but their immunomodulatory effect on an-

terior kidney leukocytes of the salmon Salmo salar has

been noted (Dalmo & Seljelid, 1995; Dalmo et al.,

1996). Porphyran likely contributes to macrophage

stimulating activity in mice (Yoshizawa et al., 1995).

The compound 6-n-tridecylsalicylic acid was isolated

from Caulocystis cephalornithos and shown to be

active after oral administration in both acute and

chronic animal models of inﬂammation such that it

has similar antiinﬂammatory activity but less ulcero-

genic activity on a molar basis than salicylic acid

(Buckle et al., 1980; Kazlauskas et al., 1980). Lastly,

carnosadine identiﬁed in Grateloupia carnosa has been

patented as an antiinﬂamatory agent with positive

carcinostatic and immunological effects (Wakamiya

et al., 1984).

Antilipemic, hypocholesterolaemic, hypoglycemic,

hypotensive and related activities

High plasma cholesterol levels and high blood pressure

are causes of cardiovascular disease. Some macroal-

gal polysaccharides and ﬁbres such as alginate, car-

rageenan, funoran, fucoidan, laminaran, porphyran and

ulvan have been noted to produce hypocholesterolemic

and hypolipidemic responses due to reduced choles-

terol absorption in the gut (Kiriyama et al., 1968;

Lamela et al., 1989; Panlasigui et al., 2003). This is

often coupled with an increase in the faecal choles-

terol content and a hypoglycaemic response (Ito &

Tsuchida, 1972; Nishide et al., 1993; Dumelod et al.,

1999). Others have reported lowering of systolic blood

pressure (antihypertensive responses) (Renn et al.,

1994a, 1994b) and lower levels of total cholesterol,

free cholesterol, triglyceride and phospholipid in the

liver (Nishide & Uchida, 2003). Evidence suggests

that ulvan as a dietary ﬁbre plays a protective role

in the rat such that it modulates the stimulatory ef-

255

fect of mucin secretion by goblet cells into the colon

(Barcelo et al., 2000). A crude methanolic extract from

Pelvetia babingtonii showed potent α-glucosidase in-

hibitory activity which could make it effective in

suppressing postprandial hyperglycemia (Ohta et al.,

2002). Hypolipidemic activities have been identiﬁed

in ethanolic extracts of Solieria robusta, Iyengaria

stellata, Colpomenia sinuosa, Spatoglossum asperum

and Caulerpa racemosa,asshown by decreases in the

serum total cholesterol, triglyceride and low density

lipoprotein cholesterol levels in rats (Ara et al., 2002).

PGE

from Gracilaria lichenoides has antihyperten-

sive properties when administered intravenously to hy-

pertensive rats (Gregson et al., 1979). Some of these

substances, most notably the ﬁbres, are likely to be ex-

ploited by ‘nutraceutical’ companies that market them

as health products.

Carcinogens and ulcer-causing compounds

Carrageenan is used in experimental research in

animals where it induces pleurisy and ulceration of the

colon (Noa et al., 2000). The carrageenan-induced rat

paw edema assay and carrageenan air pouch models

are widely used as test systems for the evaluation of

non-steroidal antiinﬂammatory drugs and cyclooxy-

genase activity (Wallace, 1999; Dannhardt & Kiefer,

2001). Despite its role in inducing ulceration in ani-

mals, carrageenan is an important ingredient in many

types of processed food. The role of carrageenans, par-

ticularly low molecular weight degraded carrageenans,

in promoting colorectal ulcers, tumours and cancers

in humans is controversial and much debated and is

the subject of other reviews (eg. Tobacman, 2001).

The molecular weight of carrageenan seems to be

at the centre of the safety debate. The International

Agency for Research on Cancer classiﬁed degraded

carrageenan as a possible human carcinogen, but

native carrageenan remains unclassiﬁable with respect

to causing human cancers (Carthew, 2002) and it is

generally regarded as safe (Tobacman, 2001).

Enzyme inhibitors and stimulants

In humans, secreted phospholipase A

(PLA

)isin-

volved in the development of a variety of inﬂammatory

diseases via the production of arachidonic acid, the

precursor of prostaglandins and leukotrienes (Flower

& Blackwell, 1976). Secreted phospholipase A

could

therefore act as target for a class of antiinﬂammatory

drugs and a substantial research effort has been fo-

cused on this group of enzymes. Several macroalgae

show potent bee venom-derived PLA

activity. Com-

pounds active against PLA

include rhiphocephalin,

a linear sesquiterpene from Rhipocephalus phoenix;

caulerpenyne, a sesquiterpene from Caulerpa prolif-

era;cymopol and cyclocymopol, prenylated bromo-

hydroquinones from Cymopolia barbata;anacetylene

containing fatty acid derivative from Liagora farinosa;

a macrocyclic enol-ether from Phacelocarpus labil-

lardieri; and stypoldione, an orthoquinone from Sty-

popodium zonale (Mayer et al., 1993). Fucoidan also

inhibits cytotoxic and myotoxic activities of several

PLA

myotoxins from crotaline snake venoms that re-

sult in muscle necrosis caused by snake bites (Angulo

& Lomonte, 2003).

An inhibitor of pancreatic lipase has been puriﬁed

from an extract of Caulerpa taxifolia (Bitou et al.,

1999). The substance, caulerpenyne, competitively

inhibits lipase activities, and in vivo oral adminis-

tration to rats demonstrated a reduced and delayed

peak plasma triacylglycerol concentration. Phlorofu-

cofuroeckol A is an antiplasmin inhibitor found in

Ecklonia kurome (Fukuyama et al., 1989, 1990). The

compound 5



-deoxy-5-iodotubercidin isolated from

Hypnea valentiae strongly inhibits the action of adeno-

sine uptake into rat and guinea-pig brain slices, and

inhibits adenosine kinase obtained from guinea-pig

brain and rat brain and liver Davies et al., 1984).

Its also causes muscle relaxation and hypothermia

when injected into mice (Davies et al., 1984). Inosine-



-monophosphate dehydrogenase is inhibited by the

brominated diphenylmethane derivative, isorawsonol,

which has been isolated from Avrainvillea rawsonii

(Chen et al., 1994). The linear diterpenes eleganolone

and elegandiol, isolated from Cystoseira brachycarpa

var. balearica, inhibit contractile activities of acetyl-

choline and histamine on ileum musculature of guinea

pigs (Della Pieta et al., 1993, 1995). Patier et al. (1993)

noted the effect of laminaran in enhancing

D-glycanase

activities in suspended cell cultures of Rubus fruti-

cosus.Afucoidan isolated from Cladosiphon okamu-

ranus has shown antipeptic activity and this character-

istic has been suggested to protect the gastric mucosa

from ulceration (Shibata et al., 2000).

Conclusions

Writing this review involved a thorough search of med-

ical literature not usually read by phycologists. Phycol-

ogists may be surprised to discover how frequently sea-

256

weed natural products are discussed in medicine. Many

bioactive substances must have evolved due to ecolog-

ical pressures acting on seaweeds. Examples are com-

petition for space and the maintenance of clean thallus

surfaces, grazing pressures by herbivores, tolerance to

dangerous levels of sunlight or UV-B radiation, des-

iccation during exposure at low tide or highly saline

waters and conditions resulting from thallus break-

age and wound formation. The chemical means that

are employed by algae to overcome these problems

can be potentially useful to humans and may result

in new technologies such as natural antifoulants and

novel UV-sunscreens. Investigations of natural models

can provide a more efﬁcient way of discovering novel

chemicals with unique pharmacological properties or

biomedical uses.

The list of compounds in this review are by no

means exhaustive, but they do cover the most impor-

tant classes of active substances in seaweeds and much

of the breadth of biological activities exhibited by sea-

weed natural products. Some have great potential as

a source of environmentally-friendly pesticides, agro-

chemical compounds and drugs and tools for use in

biochemical, pharmaceutical and medical research. An

understanding of the chemical constituents of macroal-

gae is important, not only for the discovery of new ther-

apeutic substances, but because such information may

be of value to those interested in the scientiﬁc basis that

underlies folklore remedies.

The ecological function of the toxins and bioactive

substances isolated from macroalgae is generally un-

known. One exception includes terpenoids which usu-

ally function as feeding deterrents and antifoulants.

Some compounds such as the polysaccharides are

thought to simply be storage carbohydrates, but do they

exhibit similar bioactivities (especially antiviral and an-

tibiotic properties) in the producer organism as shown

in in vitro and in vivo assays in a range of animal and

plant systems? The ecological role of the macroalgal

kainoids, aplysiatoxins and polycavernosides is almost

completely unknown. Perhaps this review will also

spark renewed interest in secondary metabolites and

toxins in seaweeds, and prompt researchers to discover

the ecological signiﬁcance of many of the products for

which in vivo and in vitro bioactivities are known, but

whose ecological importance remains a mystery.

Acknowledgements

The author would like to thank Rob Anderson, John

Bolton and two anonymous reviewers for valuable

comments regarding the structure and content of the

manuscript. The search for the literature upon which

the review is based was made possible by the Sea-

weedAfrica project (http://www.seaweedafrica.org/),

which is funded under the INCO-DEV section of the

ﬁfth framework programme. Lastly, I wish to acknowl-

edge the critical advice and comments of Prof. Brian

Whitton during the review stages of the manuscript.

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Towards environmental sustainability: further evidences from decarbonization projects in Kenya’s Blue Economy

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Study of Freshwater Algal Biodiversity in and around of Bhawanipatna, Kalahandi, Odisha

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New food sources and production systems (NFPS) are garnering much attention, driven by international trade, changing consumer preferences, potential sustainability benefits, and innovations in climate‐resilient food production systems. However, NFPS can introduce new challenges for food safety agencies and food manufacturers. Most food safety hazards linked to new foods have been identified in traditional foods. However, there can be some food safety challenges that are unique to new foods. New food ingredients, inputs, and processes can introduce unexpected contaminants. To realize the full potential of NFPS, there is a need for stakeholders from governments, the food industry, and the research community to collectively work to address and communicate the safety of NFPS products. This review outlines known food safety hazards associated with select NFPS products on the market, namely, plant‐derived proteins, seaweeds, jellyfish, insects, microbial proteins, as well as foods derived from cell‐based food production, precision fermentation, vertical farming, and 3D food printing. We identify common elements in emerging NFPS regulatory frameworks in various countries/regions. Furthermore, we highlight current efforts in harmonization of terminologies, use of recent scientific tools to fill in food safety knowledge gaps, and international multi‐stakeholder collaborations to tackle safety challenges. Although there cannot be a one‐size‐fits‐all approach when it comes to the regulatory oversight for ensuring the safety of NFPS, there is a need to develop consensus‐based structured protocols or workflows among stakeholders to facilitate comprehensive, robust, and internationally harmonized approaches. These efforts increase consumers’ confidence in the safety of new foods and contribute toward fair practices in the international trade of such foods.

Antithrombin Activity of Fucoidan

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Full-text available

Feb 1989

Fucoidan, poly(L-fucopyranose) linked primarily α 1→2 with either a C3- or a C4-sulfate, is an effective anticoagulant in vitro and in vivo (Springer, G. F., Wurzel, H. A., McNeal, G. M., Jr., Ansell, N. J., and Doughty, M. F. (1957) Proc. Soc. Exp. Biol. Med. 94, 404–409). We have determined the antithrombin effects of fucoidan on the glycosaminoglycan-binding plasma proteinase inhibitors antithrombin III and heparin cofactor II. Fucoidan enhances the heparin cofactor II-thrombin reaction more than 3500-fold. The apparent second-order rate constant of thrombin inhibition by heparin cofactor II increases from 4×10⁴ (in the absence of fucoidan) to 1.5×10⁸ M⁻¹ min⁻¹ as the fucoidan concentration increases from 0.1 to 10 µg/ml and then decreases as fucoidan is increased above 10 µg/ml. The fucoidan reaction with heparin cofactor II-thrombin is kinetically equivalent to a “template model.” Apparent fucoidan-heparin cofactor II and fucoidan-thrombin dissociation constants are 370 and 1 nM, respectively. The enhancement of thrombin inhibition by fucoidan, like heparin and dermatan sulfate, is eliminated by selective chemical modification of lysyl residues either of heparin cofactor II or of thrombin. The fucoidan-antithrombin III reactions with thrombin and factor Xa are accelerated maximally 285- and 35-fold at fucoidan concentrations of 30 and 500 µg/ml, respectively. Using human plasma and ¹²⁵I-labeled thrombin in an ex vivo system, the heparin cofactor II-thrombin complex is formed preferentially over the antithrombin III-thrombin complex in the presence of 10 µg/ml fucoidan. Our results indicate that heparin cofactor II is activated by fucoidan in vitro and in an ex vivo plasma system and suggest that the major antithrombin activity of fucoidan in vivo is mediated by heparin cofactor II and not by antithrombin III.

BIOLOGICALLY-ACTIVE OXYLIPINS FROM SEAWEEDS

Conference Paper

Full-text available

Jun 1993

Our previous research has shown that many red algae metabolize polyunsaturated fatty acids to oxidized products resembling the eicosanoid hormones from mammals. We have extended these studies to members of the Phaeophyceae and Chlorophyta and find they also possess similar biosynthetic pathways. From several we have identified novel prostaglandin-like substances. Studies of the molecular mechanisms by which some of these marine oxylipins are formed have revealed that novel oxidative reactions are utilized. Understanding of these biosynthetic pathways in detail has allowed their utilization to produce research biochemicals of high value, such as 12S-hydroperoxyeicosatetraenoic acid (12S-HPETE). Because of their biological properties, seaweed-derived oxylipins have potential utility as pharmaceuticals and research biochemicals.

Sea Vegetables (Algae as Food for Man). Seaweeds and their Uses

Article

Jan 1980

3. ed.

Kahalalides: Bioactive peptide from a marine mollusk Elysia rufescens and its algal diet Bryopsis sp

Article

Sep 1996

In addition to the previously reported bioactive kahalalide F six new peptides are described. Six of these, including kahalalide F, are cyclic depsipeptides, ranging from a C-31 tripeptide to a C-75 tridecapeptide isolated from a sacoglossan mollusk, Elysia rufescens. The mollusk feeds on a green alga, Bryopsis sp., which has also been shown to elaborate some of these peptides in smaller yields, in addition to an acyclic analog of F, kahalalide G. The bioassay results of antitumor, antiviral, antimalarial, and OI (activity against AIDS opportunistic infections) tests are reported.

The influence of translam on some factors of natural resistance of the irradiated organism

Article

Mar 1994

It has been studied the influence of translam-B-1,3; 1,6-glucan, extracted form seaweed Laminaria, on the isolation of E. coli from spleen and on the functional activity of peritoneal macrophages of sublethal irradiated and infected mice. It has been shown the reduction of the number of bacteria, isolated from spleen and stimulation of ingestive and digestive activity of macrophages following the introduction of translam in mice. These results show the increase of natural resistance of irradiated organism under translam action and characterize this glucan as effective stimulator of immunity.

Inhibitory effect of extracts of marine algae from Hong Kong against Herpes simplex viruses

Article

Jan 2003

Biomedical Potential of Marine Natural Products

Chapter

Jan 1993

Marine natural products, the secondary or nonprimary metabolites produced by organisms that live in the sea, have received increasing attention from chemists and pharmacologists during the last two decades. Interest on the part of chemists has been twofold: natural products chemists have probed marine organisms as sources of new and unusual organic molecules, while synthetic chemists have followed by targeting these novel structures for development of new analogs and new synthetic methodologies and strategies (Albizati et al., 1990). The rationale for investigating the chemistry of marine organisms has changed over the past several decades. Early investigations were largely of a “phytochemical” nature, reporting detailed metabolite profiles similar to those reported for terrestrial plants in previous decades. However, analogous to investigations of terrestrial plants, more recent studies of marine organisms have focused on their potential applications, particularly to the treatment of human disease and control of agricultural pests (Fautin, 1988). Pharmacological evaluations of marine natural products have likewise undergone an evolution over the past two decades: beginning with the early investigations of toxins, followed by studies of cytotoxic and antitumor activity, to the present day, where a myriad of activities based on whole-animal models and receptor-binding assays are being pursued. The intent of this chapter is to look back at the evolution of biomedically oriented natural product studies of marine organisms, to chronicle the key developments, discoveries, and advances in the level of sophistication that have fueled further interest in this field, and finally to look forward at the future biomedical potential of marine natural products.

Purification and partial characterization of a lectin-like protein from the sea algae Laminaria diabolica that induces fertilization envelope formation in sea urchin eggs

Article

Apr 1999

When unfertilized eggs of the sea urchin Hemicentrotus pulcherrimus were treated with the extracts from the sea algae Laminaria diabolica, fertilization envelope formation (FEF) was observed in 1.5 to 2 min without subsequent cleavage. The molecular mass of the FEF-inducing protein purified from the Laminaria extracts was estimated by gel-filtration to be 120 kDa, and it induced a 100% FEF at a concentration of 525 ng/ml (4.4 nM). The FEF activity of the purified protein was completely inhibited by GIcNAc, less effectively by GlcN, and not at all by various other sugars and amino-sugars, suggesting its nature as a lectin. Normal FEF and cleavage were observed when eggs were inseminated in the presence of GlcNAc. Immunohistochemical observations using antibodies against purified protein revealed its specific localization in the cells lining the wall of mucilaginous lacunae and in secretory products in the lumen. The purified protein did not activate the pretreated with verapamil ordiltiazem, while ionomycin, a Ca2+-ionophore, did induce activation of the similarly pretreated eggs. These results indicate that the Laminaria lectin triggers a very initial step in the cascade of the egg cortical reactions leading to FEF, independently of those induced by sperm.

Bioactive compounds from algae

Article

Jan 1991

Study on Antihypertensive and Antihyperlipidemic Effects of Marine Algae

Article

Jan 1994
FISHERIES SCI

A total of 26 species of seaweeds (1 green, 21 brown, and 4 red algae) and 6 polysaccharides were screened for their antihypertensive and antihyperlipidemic activities using rats in order to evaluate their potential application for the prevention of cardiovascular diseases. Although diets containing some pulverized seaweeds moderately elevated total cholesterol (TC), free cholesterol (FC), and low density lipoprotein (LDL), marked antihypertensive and antihypercholesterolemic activities were found in almost all seaweeds, some of which are commonly used as food. In addition, serum levels of high density lipoprotein (HDL) were enhanced 46.0% by seaweed powder diets. Six polysaccharides derived from active 'seaweed species were investigated, and appreciable suppression of hypertension and hypercholesterolemia was observed for all samples. They also markedly enhanced the serum level of HDL. © 1994, The Japanese Society of Fisheries Science. All rights reserved.

Medicinal and pharmaceutical uses of seaweed natural products: A review

Abstract and Figures

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