molecules

Review
Polysaccharides from the Marine Environment
with Pharmacological, Cosmeceutical and
Nutraceutical Potential
Nadia Ruocco 1,2,3,† , Susan Costantini 4,† , Stefano Guariniello 5 and Maria Costantini 1, *
1 Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn,
Villa Comunale, 80121 Napoli, Italy; [email protected]
2 Department of Biology, University of Naples Federico II, Complesso Universitario di Monte Sant’Angelo,
Via Cinthia, 80126 Napoli, Italy
3 Bio-Organic Chemistry Unit, Institute of Biomolecular Chemistry-CNR, Via Campi Flegrei 34, Pozzuoli,
80078 Naples, Italy
4 CROM, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, 80131 Napoli, Italy;
[email protected]
5 Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli,
80131 Napoli, Italy; [email protected]
* Correspondence: [email protected]; Tel.: +39-081-583-3315; Fax: +39-081-764-1355
† These authors contributed equally to this work.

Academic Editor: Vito Ferro

Received: 15 March 2016; Accepted: 22 April 2016; Published: 27 April 2016

Abstract: Carbohydrates, also called saccharides, are molecules composed of carbon, hydrogen,
and oxygen. They are the most abundant biomolecules and essential components of many natural
products and have attracted the attention of researchers because of their numerous human health
benefits. Among carbohydrates the polysaccharides represent some of the most abundant bioactive
substances in marine organisms. In fact, many marine macro- and microorganisms are good resources
of carbohydrates with diverse applications due to their biofunctional properties. By acting on cell
proliferation and cycle, and by modulating different metabolic pathways, marine polysaccharides
(including mainly chitin, chitosan, fucoidan, carrageenan and alginate) also have numerous
pharmaceutical activities, such as antioxidative, antibacterial, antiviral, immuno-stimulatory,
anticoagulant and anticancer effects. Moreover, these polysaccharides have many general beneficial
effects for human health, and have therefore been developed into potential cosmeceuticals and
nutraceuticals. In this review we describe current advances in the development of marine polysaccharides
for nutraceutical, cosmeceutical and pharmacological applications. Research in this field is opening
new doors for harnessing the potential of marine natural products.

Keywords: cosmeceutics; marine polysaccharides; nutraceutics; pharmaceutics

1. Introduction
Marine species represent about one half of the global biodiversity, containing different and
representative species and belonging to the main taxa also comprising a vast number of microbes and
viruses. About 70% of the Earth’s surface is covered by the oceans, which correspond to about 90%
of the biosphere and offer a great source of novel compounds. In the last decades, marine organisms
have been extensively explored as potential sources of novel bioactive compounds [1]. During their
evolution the different marine organisms such as bacteria, macro- and microalgae, sponges and fish
have developed various kinds of defense mechanisms, based on the use of a great variety of specific
and potent natural molecules, which enable them to survive a hostile environment that includes

Molecules 2016, 21, 551; doi:10.3390/molecules21050551 www.mdpi.com/journal/molecules

Molecules 2016, 21, 551 2 of 16

extreme conditions involving different degrees of salinity, pressure, temperature and light [2], as well
as microbial and viral attacks.
Marine organisms thus represent a rich source for the discovery of novel natural compounds,
comprising both small molecules (terpenoids, polyethers, polyketides, lipoproteins, and small
antimicrobial peptides), usually used as defense systems against predators, and macromolecules with
biotechnological potential, such as proteins, glycoproteins, and polysaccharides, that have also been
identified. These molecules are not used in defense systems, but they have other important biological
roles in marine organisms as cell surface receptors [3], in cell development and differentiation [4] and
the innate immunity system [5]. They probably represent a very ancient defense system, reorganized
during evolution [6,7], due to the direct contact of marine organisms with their environment, which
has high concentrations of bacteria, pathogenic viruses and fungi.
A great number of medicines or drugs have been isolated from terrestrial organisms, whereas far
fewer medicine or drugs have been obtained from marine sources. This is in contrast with the high
level of biodiversity in the marine environment, offering a great deal of opportunity for the discovery
of marine natural products. This is mainly due to the fact the marine environment has not yet been as
extensively explored as a potential source of potential medicines or drugs. Nevertheless, a variety of
compounds has been obtained from marine organisms and are currently under study and in advanced
stages of clinical trials. Some of them have already been marketed as drugs [8–10].
Among marine compounds, marine carbohydrates are considered important organic components
of marine sediments [11,12]. In the biosphere, carbohydrates are the major organic compounds
produced by photosynthetic organisms used as source of energy for heterotrophic organisms [13,14].
They are also important because of their participation in the immune system, fertilization, and
food storage. Because carbohydrates are ubiquitous and abundant, they play an important role
in biogeochemical cycles, occurring in the marine water column and sediment-water interface. In the
marine system, total carbohydrates are present in monosaccharide, disaccharide, and polysaccharide
forms [15–17] and are some of the most important organic compounds that are produced by
photosynthesis in marine living organisms.
Carbohydrates have received broad attention and are extensively studied by many investigators
throughout the world [11,18–21]. A number of these studies have focused on the relationship
between carbohydrates and organic carbon and on their distribution [22]. Of the different classes,
polysaccharides have storage and structural roles both marine and terrestrial organisms. Glycogen
and starch are storage polysaccharides, while the structural units are polysaccharides like cellulose
and chitin. The storage forms of carbohydrates are unstable. They are utilized and degraded by in situ
heterotrophic organisms while they deposit the organic matter from the surface to depths [23]. Besides
the polysaccharides, monosaccharides are useful for humans and can cure many diseases, mainly
those linked to metabolism deficiency such as diabetes [24].
Among carbohydrates, marine polysaccharides have various applications and people have used
them for a long time due to their recognized human health benefits. Recently, much attention has
been given to the structural and compositional properties of marine carbohydrates. Marine organisms,
being very rich in carbohydrates, mostly in the form of sulfated and non-sulfated polysaccharides,
represent a good resources of nutrients. A good example are carbohydrates extracted from marine
algae, which have attracted the attention of several research groups because of their wide range of
important biological activities with applications in the food, pharmaceutical and cosmetic industries.
Seaweeds contain a significant amount of sulfated polysaccharides, used in the cosmeceutical and
pharmaceutical industries. Seaweed-derived sulfated polysaccharides also have potential uses for
blood coagulation, antiviral activity, antioxidant activity, and anticancer activity. Many other marine
organisms are also rich in polysaccharides, such as sulfated galactans. Furthermore, other marine
polysaccharides, such as agar and alginates, have several applications in food production and the
cosmeceutical industry. For example, agar has been extensively used in medicinal or pharmaceutical
industrial applications, as a suspending agent for radiological solutions (such as barium sulfate), as a
Molecules 2016, 21, 5 3 of 16

digestive tract. It is also applied as an ingredient for tablets and capsules to carry and release drugs
[25].
Molecules 2016, 21, 551 3 of 16
In this review we describe the current advances in the use of marine polysaccharides (including
Molecules 2016, 21, 5 3 of 16
chitin, chitosan, fucoidan, carrageenan and alginate; Figure 1) for nutraceutical, cosmeceutical and
bulk laxative with
pharmacological a smooth and non-irritating hydrated bulk in the digestive tract. It is also applied as
applications.
digestive tract. It is also applied as an ingredient for tablets and capsules to carry and release drugs
an ingredient
[25]. for tablets and capsules to carry and release drugs [25].
In this review
In this wewe
review describe the
describe thecurrent
currentadvances inthe
advances in theuse
useofof marine
marine polysaccharides
polysaccharides (including
(including
chitin,
chitin, chitosan, fucoidan, carrageenan and alginate; Figure 1) for nutraceutical, cosmeceutical and and
chitosan, fucoidan, carrageenan and alginate; Figure 1) for nutraceutical, cosmeceutical
pharmacological
pharmacological applications.
applications.

Figure 1. Marine polysaccharides of interest for cosmeceutical, nutraceutical and pharmacological

Figure
applications.
Figure 1. Marine
The marine
1. Marine polysaccharides
ofofinterest
organism sources
polysaccharides interest for
arefor cosmeceutical,
also reported. nutraceutical
cosmeceutical, andand
nutraceutical pharmacological
pharmacological
applications. The marine organism sources are also reported.
applications. The marine organism sources are also reported.
2. Cosmeceutical Applications
2. Cosmeceutical Applications
2. Cosmeceutical Applications
Cosmetics are products
Cosmetics are products applied
appliedtoto the the human
human body bodyforforits its cleansing,
cleansing, beautification
beautification and and
appearance alteration
Cosmetics
appearance are without
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applied to theits
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human bodyand
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for functions.
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beautification as sunscreens
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and in these cases Kligman introduced
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this consideration, Kligman the termas “cosmeceutical”
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about this consideration,
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introduced applied for personal care that have20a combination
ago toofdefine
cosmetic and pharmaceutical
cosmetic products appliedterm “cosmeceutical”
for personal care that about
have ayears
combination cosmetic
of cosmetic products
and applied
pharmaceutical
uses [26–29]. Cosmeceuticals contain active ingredients delivered in the form of creams, lotions, and
for personal
uses [26–29]. care that have
Cosmeceuticals a combination
contain of cosmetic
active ingredients and pharmaceutical
delivered inpills uses
the and/or [26–29].
form of Cosmeceuticals
creams,foods.lotions, and
ointments and ingestible beauty products that are offered as liquids, functional
contain
ointments active ingredients delivered in the form of creams, lotions, and ointments and ingestible
Theyand ingestible with
are formulated beauty products
ingredients that are useful
or nutrients offered as liquids,
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hair and nails at foods.
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andnails
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antioxidants useful to promote healthy skin, hair and nails at the cellular level, including as
the cellular level,(Figure 2).
including as key ingredients vitamins, minerals, botanical extracts and
key ingredients vitamins, minerals, botanical extracts and antioxidants (Figure 2).
antioxidants (Figure 2).

Figure 2. The cosmeceutical and nutraceutical applications of marine polysaccharides.

Figure
Figure Thecosmeceutical
2. 2.The cosmeceuticaland
andnutraceutical
nutraceutical applications
applicationsof
ofmarine
marinepolysaccharides.
polysaccharides.
Molecules 2016, 21, 551 4 of 16

Recently, great interest has been shown by consumers in novel bioactive compounds from
marine natural sources, instead of synthetic ingredients, thanks to their perceived beneficial effects.
Marine organisms have been demonstrated as rich sources of structurally diverse biologically
active compounds with great cosmeceutical potential [30–32]. The increasing advances in marine
biotechnology are offering great help in studies on aging, inflammation, and skin degradation linked to
free radicals. At the same time, dermatological research suggests that the marine bioactive ingredients
used in cosmeceuticals may have greater benefits beyond the traditional moisturizer role (e.g., [28]).
Structural polysaccharides that represent major constituents in plant and microbial cell walls and
diverse marine organisms have been used in many types of industries. Chitin, for example, found in
the structural backbone of the exoskeleton of crustaceans (crab and shrimp shells, forming crystalline
structures to protect crustaceans from predators), and the exopolysaccharides (EPS), secreted by marine
bacteria, offer greater potential in industrial applications. Chitin is a crystalline polysaccharide able
to interact with several cell compounds in living human tissue. The first studies demonstrated that
chitin nanofibrils maintain cutaneous homeostasis and neutralize the activity of free radicals, and
represent a natural carrier for transcutaneous penetration of active principles. Ito et al. [33] verified the
effect of chitin nanofibrils and nanocrystals on skin, using a three-dimensional skin cell culture. Their
findings revealed that nanofibrils and nanocrystals can be applied in improving the epithelial layer and
increasing of granular density of skin. In addition, chitin nanofibrils and nanocrystals application to
the skin induced a lower production of TGF-β compared to that of the control group, thus suggesting
skin protective effects. Chitin can be mechanically altered under acidic conditions to form chitin
nanofibrils, which are biomaterials that are fully compatible with human skin cells, non-toxic and
biodegradable. These nanofibrils are capable of forming complexes with other compounds, such
as vitamins, carotenoids and collagen, facilitating their transcutaneous penetration [34]. Specific
properties of these complexes including degree of cross-linking density, water content and dimension
determine how readily actives are released and the depth of penetration into the skin.
On the other hand, chitosan (a linear polymer obtained by the partial deacetylation of chitin)
is composed by polysaccharide chains of glucasamine and N-acetylglucosamine with free amino
groups, interacting with other biological molecules. It is a cationic pH-sensitive polymer, which can be
molded into various shapes including beads, hydrogels, nanofibers and nanoparticles. As a hydrogel,
chitosan has superior water absorbing properties, making it valuable as a moisturizer. Chitosan
oligomers stimulate fibroblast production, provide wound healing benefits, and exhibit antioxidant and
metalloproteinase inhibiting effects. Another important attribute of chitosan is its broad antimicrobial
activity that includes bacteria, yeast and fungi. Chitosan, in the form of nanoparticles, acts as a delivery
system. These particles help to protect from environmental factors, such as light and oxidation, and
facilitate their delivery to the skin. Thus chitosan has been identified by industry as a novel ingredient
with multiple applications in cosmeceutical formulations [27,35].
Among marine exopolysaccharides, an EPS secreted by Alteromonas macleodii has already found
application in cosmetics [36,37]. Other different polysaccharides, including fucoidan, carrageenan,
alginate and agar, have been used as texture-improving agents in the cosmeceutical industries for
their beneficial cosmetic effects. In fact, the cell walls of marine algae are rich in various bioactive
polysaccharides: fucoidans in brown algae, carrageenans in red algae and ulvans in green algae.
Fucoidan from various brown seaweed sources (Saccharina japonica, Fucus vesiculosus, Undaria pinnatifida
and Hizikia fusiformis) and marine invertebrates, such as sea cucumber [30], represents the most
abundant polysaccharide and the most commercially available. It is a highly sulfated polysaccharide,
made up primarily of L-fucose, exhibiting diverse biological activities [34]. In recent years, fucoidans
have been investigated to develop novel cosmetic products thanks to their property of reacting with
the surface of the skin forming a protective layer that enhances skin hydration [34], when applied
topically to the skin.
In skin-related diseases, UV-B reduces type I procollagen levels, increased matrix metalloproteinase-1
(MMP-1) levels in human skin and plays a major role in the photoaging process [38]. Furthermore,
Molecules 2016, 21, 551 5 of 16

fucoidan treatment increased type I procollagen mRNA and protein expression in a dose-dependent
manner, suggesting that it may prevent UVB-induced MMP-I expression and inhibit down-regulation
of type I procollagen synthesis. According to these results, fucoidan has been suggested to have
wide application as a potential agent to prevent and treat skin photoaging [39]. Considering that
brown edible algae are rich in fucoidan and are a dietary foodstuff, their consumption could be
beneficial in reducing the risk of MMP-related diseases [40]. Another research group reported the
MMP inhibitory effect of a fucoidan fraction from seaweeds on the parameters involved in connective
tissue breakdown. In more details, this in vitro study demonstrated that this fucoidan was able to
successfully inhibit gelatinase with a secretion and stromelysin 1 induction by interleukin-1β on
dermal fibroblasts. In addition, ex vivo studies have revealed that this polysaccharide was able to
minimize human leukocyte elastase activity, to protect human skin elastic fibers against enzymatic
proteolysis [41]. These findings clearly suggest the potential role of seaweed fucoidans in reducing the
risk of some inflammatory pathologies involving extracellular matrix degradation by MMPs [42].
Carrageenan represents one of the most studied sulfated polysaccharides from marine red algae
in the cosmeceutical field [30,43]. It is a sulfated galactan, composed of D-galactose units. Thanks to
its physical and functional ability and antioxidant activity, carrageenan is an important product
in the cosmetic and cosmeceutical industries, and is utilized for its antiaging, antioxidant, and
anticarcinogenic activity (see below). The gelling ability of carrageenan is useful in producing a
thicker texture with higher consistency in cosmetic production. In fact, many products such as skin
lotions, toothpaste binders, and shaving foams utilize carrageenan isolated from marine algae [30,43].
Alginate is found in marine organisms cell walls, such as seaweeds. It is made of two units of
guluronic and mannuronic acids, and is highly dependent on pH and temperature modification. The
first alginate applications in the cosmeceutical field date back to 1927 [30]. Alginates have a wide
range of applications in the cosmeceutical industry because of their high stability, thickening and
gelling agent properties [30]. The biological activities of alginates are closely linked to the molecular
weight, sulfate content and anionic groups, which give it antioxidant activity [44]. Alginate bioactivity
depends on the presence of molecular weights of sulfated content and anionic group that makes
antioxidant activity. For example, it is applicable in skin grafting in plastic surgery. In addition, it has
applications in wound healing, because of hydrogel formation and degradability and providing a
moist environment for wound [45].

3. Nutraceutical Applications
The term nutraceutical derives from joining the terms “nutrition” and “pharmaceutical”. It refers
to foods or food ingredients with medical or health benefits. Through food-based approaches
active substances with pharmaceutical properties are given to the humans to prevent or treat certain
diseases linked to food. Several active compounds produced by different marine organisms have
a wide role in the nutraceutical applications. These marine-derived active ingredients (including
polyunsaturated fatty acids, polysaccharides, polyphenols, bioactive peptides and carotenoids) are
known for their anticancer, anti-inflammatory, antioxidant, and antimicrobial activities and are applied
as nutraceuticals, for example, to combat obesity [25,46–48] (Figure 2).
Human existence depends on meeting our basic physical necessities. The need to eat food is one
of these necessities. In order to respond to this need, man has explored Nature to find foods, so for
example, the history of fishing dates back 40,000 years. Due to the wide range of environments and
organisms that survive underwater, biomolecules derived from marine organisms represent a large
untapped reservoir of bioactive ingredients, often produced efficiently under unique conditions, such
as low temperature or high pressure, that can be used in various food applications, to provide added
nutritional benefits to foods and “natural” pigments, preservatives, or flavors [46,47]. Some important
species of algae are of nutritional interest [49]: Phaeophyceae, brown algae Ascophyllum nodosum,
Ecklonia cava, Ecklonia kurome, Laminaria digitata, Lessonia flavicans, Saccharina japonica, Sargassum horneri,
Undaria pinnatifida; Cholorophyta, green algae, Caulerpa racemosa, Codium fragile, Codium pugniforme,
Molecules 2016, 21, 551 6 of 16

Gayralia oxysperma, Monostroma latissimum, Ulva australis, Ulva conglobata, Ulva lactuca; Rhodophyta, red
algae, Cryptonemia crenulata, Grateloupia indica, Gigartina skottsbergii, Nemalion elminthoides, Nothogenia
fastigiata, Pyropia haitanensis, Schizymenia binderi. Most of these species have higher biomass and their
possible edibility is an attractive characteristic feature for using them in medicinal foods by direct
consumption through the diet and indirect consumption through their extracted nutraceuticals and
functional food molecules [46]. The anticoagulant sulfated galactans and fucans from Ulva fasciata,
for example, have uses in functional foods and nutraceuticals. Microalgal biomass rich in carbohydrates
has been used directly for animal feed. Marine waste materials can in turn be redirected to process
them for the extraction of carbohydrate molecules of nutraceutical interest [50]. Shellfish wastes from
scallops (Chlamys hastate), cockles (Cerastoderma edule, Clinocardium nuttalli), whelks (Buccinum undatum),
clams and mussels (Mercenaria mercenaria, Mytilus galloprovincialis, Mytilus edulis), oysters (Crassostrea
gryphoides, Crassostrea gigas), and crustaceans (crab Cancer pagurus; lobster Nephrops norvegicus and
Homarus americanus; shrimp Crangon crangon) have been redirected toward the development of various
biopolymers, which can be used as nutritional substances and animal feed. With the emerging interest
in using animal foods, especially of marine origin, the rate of consumption of several shellfish species
has been increasing annually, although the processing of these shellfish wastes is still costly and only a
few regions in the world would be able to produce the required quantities of chitin, chitosan, and their
derivatives to meet the demand in the biological and biomedical fields [51].
Most Asian countries use macroalgae as foods for human consumption. Microalgae also have
wide industrial applications, for example, as gelling, stabilizing and binding agents. The antioxidant
properties of marine algal polysaccharides have been represented an important point in developing
them as potential functional foods and nutraceuticals [49]. It is important to consider that the dietary
fibers of seaweeds contain valuable nutritional substances. For these reasons, in the last years there
has been increased attention paid to the use of seaweeds as functional foods for human consumption
with nutraceutical and medicinal applications [52,53].
Reduced plasma total cholesterol, LDL cholesterol, and triacylglycerol (TAG) have been
observed, attributable to the polysaccharides in edible seaweed [54]. Marine carbohydrates such
as algins and exopolysaccharides from cyanobacteria can be used for the stabilization of emulsions
or as bioflocculants. These properties allow a wide variety of unique food products to evolve.
Polysaccharides are a common solution in food product formulation problems to achieve a certain
texture, mouthfeel and body by thickening the food. Most polysaccharides have an ability, consisting
in a viscosity increase or decrease with increasing shear rate, once they are dispersed in water. Some
stabilizers result in a certain solution yield value, i.e., a shear stress or applied force below which the
solution will not flow (e.g., ketchup). Because of the thickening effect and the yield value, addition of
suitable polysaccharides to an aqueous system can stabilize the suspending dispersed phase (could
be a solid, liquid, or gas) and prevent it from separating out. Carrageenan has a unique functional
property in its reactivity to proteins and for this property it is usually used to stabilize milk protein [55].
Normally, carrageenan is used in combination with other hydrocolloids such as starch, locust bean
gum, and carboxymethyl cellulose. Furcellaran has a similar function, is used but less extensively in
food. Many functional requirements and various applications such as fortification, natural pigments,
stabilization, and antimicrobial food coatings are met by the use of simple and complex carbohydrates
derived from marine foods. Cyanobacteria from marine environments also represent an important
source of exopolysaccharides: for example, Cyanothece sp. ATCC 51142 produces a polymer capable of
gel formation very useful in food industries [56].
Red algae like Gelidium, Gracilaria, Hypnea and Gigartina are the main sources of agar [57,58]. Agar
E406 has been used in the food industry for gel formation and food gums, as well as food additives,
thanks to its properties as an emulsifying and gelling agent [59,60].
Recently, chitooligosaccharide (COS) has been studied in the nutraceutical field for its
antidiabetic [61] and hypocholesterolemic [62] properties and adipogenesis inhibition [63]. In the food
industry, chitosan and COS have been used as dietary food additives [64] and as dietary supplements
Molecules 2016, 21, 5 7 of 16
Molecules 2016, 21, 551 7 of 16

supplements to decrease body weight and serum lipids [48]. The importance of the application of
chitosan depends
to decrease from the
body weight andfact that:lipids
serum (i) it [48].
is notThespecifically
importance digested in the gastrointestinal
of the application tract by
of chitosan depends
binding
from theandfactprecipitating fatnot
that: (i) it is in the intestines,digested
specifically so that itin
is not
the absorbed; (ii) hastract
gastrointestinal the property
by binding to swell
and
to give a feeling of satiety in the stomach; (iii) is able to reduce the absorption
precipitating fat in the intestines, so that it is not absorbed; (ii) has the property to swell to give of dietary fat in
intestines through inhibition of pancreatic lipase activity. The cationic chitosan can
a feeling of satiety in the stomach; (iii) is able to reduce the absorption of dietary fat in intestines link to the fatty
acids andinhibition
through bile acids,ofinterfering
pancreaticwith
lipaseemulsification
activity. Theofcationic
neutralchitosan
lipids like cholesterol
can and
link to the other
fatty sterols
acids and
by binding them with hydrophobic interaction, thus reducing intestinal absorption
bile acids, interfering with emulsification of neutral lipids like cholesterol and other sterols by binding of fat and
cholesterol.
them with hydrophobic interaction, thus reducing intestinal absorption of fat and cholesterol.

4. Pharmacological
PharmacologicalApplications
Applications
The resurgence of natural products-initiated
products-initiated drug drug discovery
discovery is is tied to the exploration of novel
natural resources and organisms, such such as those in the marine world, which represents the largest
unexplored
unexplored resource. In In the
the past decade a dramatic increase in the number of preclinical anticancer
lead compounds
compounds from fromdiverse
diversemarine
marinelife
lifeform
formsintering
sinteringhuman
human trials hashas
trials beenbeenreported.
reported.It is also
It is
important to consider
also important that Nature
to consider is been
that Nature considered
is been an ancient
considered pharmacy.
an ancient New trends
pharmacy. New trendsin drug in
discovery from from
drug discovery natural sources
natural emphasize
sources emphasize investigation of the
investigation of marine
the marine ecosystem
ecosystem to explore
to explore its
numerous
its numerouscomplex
complexand novel chemical
and novel entities.
chemical These entities
entities. are sources
These entities are of new leads
sources for treatment
of new leads for
of many diseases
treatment such as such
of many diseases cancer, AIDS,AIDS,
as cancer, inflammatory
inflammatory conditions
conditionsandanda large
a largevariety
varietyofof viral,
viral,
bacterial and
andfungal
fungaldiseases
diseases [65].
[65]. Among
Among natural
natural products
products fromfrom the marine
the marine environment,
environment, the marinethe
marine carbohydrates
carbohydrates represent represent a goodin pharmaceutical
a good challenge challenge in pharmaceutical
field, because offield, because of their
their anti-inflammatory,
anti-inflammatory,
immunomodulation, immunomodulation,
anti-coagulant andanti-coagulant and anticancer
anticancer activities (Figureactivities
3). Another(Figure 3). Another
application of
application
polysaccharidesof polysaccharides
in pharmaceutical in pharmaceutical industries
industries consists of, forconsists
example, of, for
the example,
use of agar theand
useagarose
of agar
and
beadsagarose beads for
for sustained sustained
release release
of water of water
soluble drugssoluble drugs
[66]. This [66]. Thisisapplication
application based on the is based on the
significantly
significantly lower sulfate
lower sulfate content of thesecontent of these two
two compounds, compounds,
on their better opticalon clarity
their better optical gel
and increased clarity and
strength.
increased
For example,gel water
strength. Forand
soluble example,
hypnoticwater
drugs soluble and hypnotic
have been prepared drugs
with agarhave been(instantaneously
beads prepared with
agar
formbeads (instantaneously
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containing by gelification),sodium.
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that agar studies
beads can
indicated
be used forthattheagar beads can
preparation ofbe used forrelease
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dosage forms.of sustained release dosage forms.

Figure 3.Properties
3. Propertiesof
ofmarine
marinepolysaccharides
polysaccharidesand
andtheir
theirapplications
applications in
in pharmacology.
pharmacology.

4.1. Anti-Inflammatory
Anti-Inflammatory and Immunomodulatory Activities
In “in vivo”
vivo” studies
studies the
the heterofucan
heterofucan from
from the
the seaweed
seaweed Dictyota menstrualis (Phaeophyceae,
(Phaeophyceae,
brown algae)
algae) induced
induced an
aninhibition
inhibitionofofleukocyte
leukocytemigration
migrationwith
witha related decrease
a related decrease in in
thethe
levels of
levels
pro-inflammatory
of pro-inflammatory cytokines [67].
cytokines OnOn
[67]. thethe
other
otherhand,
hand,the
thefucoidan
fucoidanfrom
fromthe
thealga
alga E.
E. cava
cava decreased
cyclooxygenase-2, nitric oxide and prostaglandin E2 levels [68,69]. The polysaccharides from the
Molecules 2016, 21, 551 8 of 16

cyclooxygenase-2, nitric oxide and prostaglandin E2 levels [68,69]. The polysaccharides from the
green seaweed Ulva rigida [70] and the marine dinoflagellate Gymnodinium impudicum [71] activate the
production of nitric oxide and immunostimulate the production of cytokines in macrophages.
Other molecules from U. pinnatifida (Phaeophyceae), Porphyridium (Rhodophyta), Phaeodactylum
(Bacillariophyta), and Chlorella stigmatophora (Chlorophyta)had immune-suppressant effects in “in vitro”
and “in vivo” studies by blocking the Th2 activity [72,73].
However, Tabarsa et al. [74] reported that the polysaccharide from Codium fragile (Chlorophyta)
was able to induce NO release only when it was bound to the protein moiety by activating NF-κB
and MAPK pathways. These authors demonstrated that in the case of polysaccharides from C. fragile
their sulfate content was not necessary for their activity [74] in contrast to the results published
from Leiro et al. [70] on polysaccharides from the cyanobacterium U. rigida. In addition, some algal
polysaccharides are able to bind toll-like receptor-4 or pattern recognition receptors, involved in the
innate immune response [75,76].
Concerning chitin and chitosan, it has been shown that administration of chitin through the
vascular system enhances the release of cytokines by macrophages [77]. Moreover, it up-regulates
Th1 immunity and down-regulates Th2 immunity [78]. In vivo studies demonstrated that chitinase
enzymes can increase immunity in the presence of infection. In fact, clinical trials were conducted on
allergic and asthmatic patients, in which there is an over-expression of chitinases [79,80]. Moreover,
considering the polymeric properties of the chitin, some authors have focused on the utility of
chitosan polymer composites cross-linked with resin and demonstrated that they can be used as
alternative vehicles for oral delivery of aceclofenac, a non-steroidal anti-inflammatory drug [81]. Also
the chitosan (Ch)/poly-(γ-glutamic acid) (γ-PGA) nanoparticles created as vehicle for diclofenac,
another non-steroid anti-inflammatory drug, resulted able to inhibit the prostaglandin E2 production
of activated macrophages, and to stifle local inflammatory reactions [82].
Laminaran (or laminarin) was first discovered in the Laminaria species (brown algae), being the
food reserve of all these algae. Laminaran is a water-soluble polysaccharide and has a good inhibitory
effect on virus proliferation. It is able to inhibit the adsorption of HIV on lymphocytes and the activity
of HIV reverse transcriptase. These results suggests that laminaran exerts a good inhibitory effect on
HIV replication [83,84].

4.2. Anti-Coagulant Activities

In the literature it is reported that some carbohydrates from seaweeds have anticoagulant effects
by inhibiting thrombin or by activating anti-thrombin III or by increasing the clotting time both in the
intrinsic and extrinsic pathways. Moreover, these molecules can also have an antithrombotic activity by
blocking thrombin activity, mediated through the heparin cofactor II [85–89]. However, other authors
evidenced that they also interfere in the PT (prothrombin) pathway, and, therefore, are not able to
affect the extrinsic coagulation pathway [90].
Furthermore, an important role of the content in sulfate has been assigned in the anticoagulant
activities, as the presence of sulfate and its distribution pattern play an important role in the processes
of coagulation and/or platelet aggregation [91,92]. In particular, in the case of some fucoidans and
fucans, the anticoagulant properties resulted to be related: (i) to the content of sulfate or disulfate
or fucose [91]; (ii) to the higher molecular weight that usually induced a stronger anticoagulant
activity [93]; and (iii) if the molecule presents a linear backbone [94]. Laminaran is also an example of
a marine polysaccharide which exerts anticoagulant activity after structural modification like sulfation,
reduction or oxidation [95].
Some in vivo studies also showed the anticoagulant properties of marine carbohydrates by
increasing the clot formation time [96]. A S-galactofucan from the brown seaweed Spatoglossum
schröederi showed a strong antithrombotic activity in an in vivo study [97]. Moreover, spirulan
from Arthrospira platensis interfered with the blood coagulation-fibrinolytic system and exhibited
anti-thrombogenic properties [98].
Molecules 2016, 21, 551 9 of 16

The degree of sulfation of chitosan is an important point. In fact, highly sulfated chitosans induce
an increase of thrombin, activated partial thromboplastin time and thrombin time [99].

4.3. Anti-Cancer Effects

As also reported above, chitin is certainly the most abundant biopolymer in the marine
environment and it can be converted into chitosan, the acid-soluble form of chitin, by N-deacetylation.
Some pharmaceutical functions of chitin and chitosan are due to their unique physicochemical
properties. In fact, both are non-toxic, renewable and biodegradable. Chitin and chitosan are
two polymers that represent promising therapeutic candidates with therapeutic applications in
drug delivery and gene therapy [100]. Recently, chitosan samples obtained through enzymatic
deproteinization of chitin from Norway lobster (Nephrops norvegicus) were used to evaluate their
anti-proliferative capacity. In details, the cytotoxic effects of chitosan samples were tested on human
colon carcinoma cells HCT116. Chitosan showed an anti-proliferative capacity against this cancer cell
line in a manner dependent on the dose and the degree of acetylation [101].
Moreover, Muanprasat et al. [102] investigated the effect of COS on AMP-activated protein kinase
(AMPK) in intestinal epithelial cells. COS activated AMPK in two human colorectal adenocarcinoma
cell lines, HT-29 and Caco-2, and inhibited NF-κB transcriptional activity and NF-κB-mediated
inflammatory response. Moreover, the oral administration of COS was able to block the development
of aberrant crypt foci in a mouse model of colitis-associated colorectal cancer (CRC) by β-catenin
suppression and caspase-3 activation [102]. Different carrier systems based on chitosan are prepared
to study the release and the cellular permeability of different molecules and drugs. For example,
naringenin encapsulated in nanoparticles had a release of about 5% in gastric fluid and cytotoxic effects
on lung cancer cells [103]. Moreover, other authors created nanoparticles of caffeic acid conjugated
chitosan (ChitoCFA/CMD) and incorporated doxorubicin into them. Mouse colon carcinoma cell
line, CT26, treated with doxorubicin-incorporated nanoparticles revealed strong fluorescence intensity
while free doxorubicin revealed weak fluorescence intensity, indicating that doxorubicin-loaded
ChitoCFA/CMD nanoparticles are a promising vehicle for anticancer drug targeting [104]. Finally,
Lee et al. [104] showed that chitosan-coated nanoparticles containing curcumin caused a significant cell
viability reduction on a human oral cancer cell line in a way dependent both from the concentration
and the time and reduced the cytotoxicity to normal cells, when compared with the free drug [105].
Among the carbohydrates having anti-cancer activity it is important to mention also the
role played by both macro- and microalgae. In fact, S-fucoidans from Cladosiphon okamuranus
(Phaeophyceae) have shown anti-proliferative activity on myeloid cancer and leukaemia cell lines by
inducing cell apoptosis [106,107]. Moreover, the fucoidan from Saccharina gurjanovae (Phaeophyceae)
is able to inactivate the epidermal growth factor receptor (EGFR), an important player in cell
transformation, differentiation and proliferation [108,109].
Other polysaccharides from Sargassum sp. and Laminaria (Phaeophyceae) showed anti-cancer
activity on lung cancer and melanoma [110], and on colon and breast cancer cell lines [111,112].
Moreover, a fucoidan extracted from the marine brown alga U. pinnatifida has been found to induce
osteoblastic cell differentiation by increasing the activity of alkaline phosphatase and the levels of
osteocalcin, and to have positive effects on bone morphogenic protein-2 that is the most important
factor for bone formation, remodeling and mineralization [113]. Also the alga C. racemosa (Chlorophyta)
polysaccharide (CRP) showed anti-cancer activity. In fact, all its fractions induced inhibition of both
melanoma cells and of hepatoma (H22) tumors transplanted in mice [114].
From a metabolic point of view, these compounds induce the release of pro-inflammatory
cytokines, such as IL-2, IL-12 and INF-γ, increased activity of natural killer cells, Toll-like receptor-4,
cluster of differentiation 14, and competent receptor 3 that in turn are able to induce the production
of nitric oxide and apoptosis [115,116]. Considering these properties of S-fucoidans, they resulted
able to protect damaged gastric mucosa [117], and to inhibit the activity of Helicobacter pylori on the
stomach mucosa of Mongolian gerbils and to block the development of gastric cancer [118]. Recently,
Molecules 2016, 21, 551 10 of 16

an unfractionated fucoidan from the alga A. nodosum showed apoptosis effects on human colon cancer
cells (HCT116) by activation of caspases 3 and 9 and the PARP cleavage that induced an alteration of
mitochondrial membrane permeability [119]. Moreover, S-laminaran resulted able to reduce metastasis
formation by inhibition of heparanase that is known to be associated with the metastasis process [120].
Also, six glycosylated polyhydroxysteroids isolated from the starfish Culcita novaeguineae showed
cytotoxic activities on hepatoma, melanoma, and epidermoid, prostate and breast cancer cell lines [121].
On the other hand laminaran has been tested on colon cancer cells, HT-29 and LOVO, and resulted to
be involved in ErbB and IGF-IR signaling pathways [122,123] and to increase the intracellular level
of ROS and Ca [124]. In details, in HT-29 cells it induced cell death in a dose-dependent manner,
decreased MAPK and ERK phosphorylation, and inhibited the heregulin-stimulated phosphorylation
of ErbB2 [122,123].
Some carbohydrates are reported as able to block carcinogenesis. For example, the polysaccharide
DAEB, isolated from the green alga Ulva intestinalis (Chlorophyta) and composed from rhamnose,
xylose, galactose, and glucose, was tested on mice. DAEB induced the secretion of TNF-alpha and
nitric oxide, phagocytosis and the lymphocyte proliferation [125].
In the case of the anti-cancer activity, the degree of sulfation may also have an important role.
In fact, fucoidan fractions from brown seaweeds are able to inhibit the leukaemia development but not
that of sarcoma in mice [126].

5. Conclusions
The marine environment contains a number of micro- and macroorganisms, which have developed
particular metabolic mechanisms for the biosynthesis of secondary metabolites with specific activities,
useful for their survival. Functional materials from the marine environment include polyunsaturated
fatty acids, polysaccharides, minerals, vitamins, antioxidants, enzymes, and bioactive peptides.
All these biologically active compounds provide great human health benefits and represent an
inexhaustible source of materials for the pharmaceutical, nutraceutical and cosmeceutical industries.
The recent advances in molecular biology approaches, Next Generation Sequencing and methods to
isolate and cultivate marine microorganisms have greatly contributed to the exploration of the marine
environment biodiversity.
In conclusion, the challenges to use marine resources in different fields linked to human health is
fully in-line with the Horizon 2020 strategic activity: “targeted approach towards specific activities
focusing on “...exploration of the . . . biodiversity ... for ... helping us to understand for example how
organisms that can withstand extremes of temperature and pressure and grow without light could be
used to develop new industrial enzymes or pharmaceuticals...”.

Acknowledgments: Nadia Ruocco (Ph.D. in Biology, University of Naples Federico II) has been supported by
a Ph.D fellowship co-funded by the Stazione Zoologica Anton Dohrn and Bio-Organic Chemistry Unit of the
Institute of Biomolecular Chemistry-CNR, Pozzuoli, Naples (Italy).
Conflicts of Interest: The authors declare no conflict of interest.

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