Available via license: CC BY 4.0
Content may be subject to copyright.
Citation: Flores-Contreras, E.A.;
Araújo, R.G.; Rodríguez-Aguayo,
A.A.; Guzmán-Román, M.;
García-Venegas, J.C.;
Nájera-Martínez, E.F.;
Sosa-Hernández, J.E.; Iqbal, H.M.N.;
Melchor-Martínez, E.M.;
Parra-Saldivar, R. Polysaccharides
from the Sargassum and Brown
Algae Genus: Extraction, Purification,
and Their Potential Therapeutic
Applications. Plants 2023,12, 2445.
https://doi.org/10.3390/
plants12132445
Academic Editor: Hazem
Salaheldin Elshafie
Received: 25 May 2023
Revised: 20 June 2023
Accepted: 21 June 2023
Published: 25 June 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
plants
Review
Polysaccharides from the Sargassum and Brown Algae
Genus: Extraction, Purification, and Their Potential
Therapeutic Applications
Elda A. Flores-Contreras 1,2, Rafael G. Araújo 1,2 , Arath A. Rodríguez-Aguayo 1, Muriel Guzmán-Román1,
Jesús Carlos García-Venegas 1, Erik Francisco Nájera-Martínez 1,2, Juan Eduardo Sosa-Hernández 1,2 ,
Hafiz M. N. Iqbal 1,2 , Elda M. Melchor-Martínez 1,2, * and Roberto Parra-Saldivar 1, 2, *
1Tecnologico de Monterrey, School of Engineering and Sciences, Monterrey 64849, Mexico;
eldafc@tec.mx (E.A.F.-C.); rafael.araujo@tec.mx (R.G.A.); a01209135@tec.mx (A.A.R.-A.);
a01658784@tec.mx (M.G.-R.); a01383937@tec.mx (J.C.G.-V.); a00832573@tec.mx (E.F.N.-M.);
eduardo.sosa@tec.mx (J.E.S.-H.); hafiz.iqbal@tec.mx (H.M.N.I.)
2Tecnologico de Monterrey, Institute of Advanced Materials for Sustainable Manufacturing,
Monterrey 64849, Mexico
*Correspondence: elda.melchor@tec.mx (E.M.M.-M.); r.parra@tec.mx (R.P.-S.)
Abstract:
Brown macroalgae represent one of the most proliferative groups of living organisms in
aquatic environments. Due to their abundance, they often cause problems in aquatic and terrestrial
ecosystems, resulting in health problems in humans and the death of various aquatic species. To
resolve this, the application of Sargassum has been sought in different research areas, such as food,
pharmaceuticals, and cosmetics, since Sargassum is an easy target for study and simple to obtain.
In addition, its high content of biocompounds, such as polysaccharides, phenols, and amino acids,
among others, has attracted attention. One of the valuable components of brown macroalgae is
their polysaccharides, which present interesting bioactivities, such as antiviral, antimicrobial, and
antitumoral, among others. There is a wide variety of methods of extraction currently used to obtain
these polysaccharides, such as supercritical fluid extraction (SFE), pressurized liquid extraction (PLE),
subcritical water extraction (SCWE), ultrasound-assisted extraction (UAE), enzyme-assisted extraction
(EAE), and microwave-assisted extraction (MAE). Therefore, this work covers the most current
information on the methods of extraction, as well as the purification used to obtain a polysaccharide
from Sargassum that is able to be utilized as alginates, fucoidans, and laminarins. In addition, a
compilation of bioactivities involving brown algae polysaccharides in
in vivo
and
in vitro
studies is
also presented, along with challenges in the research and marketing of Sargassum-based products
that are commercially available.
Keywords:
brown macroalgae; bioactivity; biopolymer; extraction methods; fucoidan; laminarin;
alginates
1. Introduction
The seaweed problem is a global environmental issue that has recently been receiv-
ing attention due to the inundation of beaches by seaweed. This problem is caused by
Ulva, a green seaweed, and a golden/brown floating or pelagic seaweed, Sargassum,
causing a change in the color of the tides, observed as gold, mainly in West Africa and the
Caribbean [
1
]. The currents that bring these seaweeds to the coastlines begin in the Sargasso
Sea, a region with a strong presence of these algae; the Sargasso Sea is considered the main
source of pelagic Sargassum. In addition, it has been considered that this excessive increase
in Sargassum may be due to the large amount of nutrients in the ocean that come from the
sand of the Sahara Desert and from the deforestation of the Amazon in the Brazilian basins.
There is also the hypothesis that the lack of cyclones in the last few decades has prevented
Plants 2023,12, 2445. https://doi.org/10.3390/plants12132445 https://www.mdpi.com/journal/plants
Plants 2023,12, 2445 2 of 26
the dispersion of Sargasso, allowing it to concentrate in certain regions [
2
]. Sargassum
clogs up beaches, which harms marine life by blocking sunlight from reaching the algae
and seagrass below it. It includes economic problems, such as reduction of tourism and
alteration of local fishing activities [2].
To solve the problem of Sargassum, different applications have been sought, such as
using it as a source of food, extracting its health-related biomolecules, finding agricultural
uses for it, utilizing it in the bioremediation of effluents, taking advantage of it as a
clean energy source, or extracting molecules from it, polysaccharides being the most
important [3].
The large extensions of the macroalgae can capture large amounts of CO
2
, most
of which are converted to polysaccharides, which play a key role in carbon cycling [
4
].
The most important polysaccharides are mainly laminarins, alginates, carrageenan, and
fucoidans [
5
,
6
]. These have high potential for biological applications in pharmaceutical
products, cosmeceuticals, and functional foods; additionally, its structure and composition
are determined by the algae species, but these can be influenced by other factors causing
variation in the formation of these polysaccharides.
Macroalgae have high fiber content attributed to the non-digestible polysaccharides in
the cell wall. To obtain such biocompounds, it is essential to find the most efficient extraction
method and optimize the key parameters for a better yield and extraction composition [
7
].
Due to the disadvantages brought by the traditional methods that caused organic and
environmental pollution, new techniques were developed with a better outcome overall.
These new methods are faster, more efficient, and sustainably extract biocompounds from
natural resources. Modern methods, such as supercritical fluid extraction (SFE), pressurized
liquid extraction (PLE), subcritical water extraction (SCWE), ultrasound-assisted extraction
(UAE), enzyme-assisted extraction (EAE), and microwave-assisted extraction (MAE) are
now used for the extraction of specific compounds [8].
As mentioned before, marine algae are rich in nutrients and biocompounds [
9
]. Phyco-
colloids are polysaccharides derived from seaweeds and have very diverse physicochemical
characteristics [
10
]. The phycocolloids found in Sargassum sp. are fucoidan, alginate, and
laminarin [
11
]. They are believed to attribute different biological activities, such as neu-
roprotective effects [
12
], antioxidant activities [
13
], antitumor potentials, anti-collagenase
activity, antimicrobial effects, and more [14].
Fucoidans are claimed to be the major bioactive compound found in Sargassum sp.;
its main monomer is the fucose. The chemical structure of fucoidans depends on several
factors, such as the species, geographical location of recovery, climatic conditions, etc.
Extracting the fucoidan impacts its biological activities, but these activities also depend on
their degree of sulphation, structural formations, and weight. Fucoidans can have antibac-
terial properties, are antiviral, contain antioxidants, and have anti-cancer and antitumor
properties [
11
]. Some marine sources of fucoidan from brown algae are mozuku, kombu,
limu moui, bladderwrack, and wakame [12].
Alginates are alginic acid salts and their derivatives. Their predominate function is to
provide structure as a cell wall component due to their physicochemical properties, such as
gel formation and viscosity [
12
]. Studies have demonstrated that alginic acid prevents the
absorption of heavy metals in the body. It has also been proven that some derivates from
alginate act as potential preventive neurodegeneration biocompounds. In addition, alginic
acid reduces cholesterol and plays an important role as a dietary fiber, which makes it
beneficial for health [
15
]. Some of the sources of alginate are Laminaria hyperborea,L. digitata,
Macrocystis pyrifera,Ascophyllum nodosum, and L. japonica [16].
The phycocolloid laminarin is a biodegradable and non-toxic linear polysaccharide
and the storage carbohydrate in brown algae it is extracted from the cell wall of different
species, such as Laminariaceae,Laminaria,Saccharina,Eisenia, or Fucus. This biocompound
has the capacity to act as an antitumor, antioxidant, and anti-inflammatory agent, and also
has prebiotic properties [
17
]. Researchers have shown that some chemical modifications and
processing alterations can enhance laminarin’s bioactivity and therapeutic properties, such
Plants 2023,12, 2445 3 of 26
as anti-inflammatory, anti-apoptotic, antitumor, antioxidant, and anticoagulant activities.
Even though some strategies have resulted successfully, difficulties have been encountered
during various modification attempts [18].
Due to the physicochemical properties that are present within the biocompounds
extracted from different sources of brown seaweeds, there exists a wide range of industries
that are more and more interested in the application of them in various products, such
as the food industry, pharmaceutical, cosmetics, and paint, each one being unique and
versatile [9].
In recent years, biocompounds of marine sources have caught the most attention from
the pharmacological industry, which has discovered an anticancer purpose for prostate
cancer and compounds that are helpful in preventing osteoporosis; an antidiabetic treat-
ment is also being investigated [
19
]. The food industry is one of the largest, and edible
seaweeds have offered the capacity to develop functional foods for many years. Researchers
have made a great effort in the past 15 years to discover new ways to include bioactive
compounds in different meat products with the purpose of improving their nutritional
value [
20
]. There are other types of industries, such as aquaculture, in which it is possible
to use the biocompounds effectively to prevent diseases. The cosmetic industry has also
used marine biocompounds as viscosifiers, stabilizers, and gelling agents [21].
Taking these numerous benefits into account, the purpose of this review is to collect
recent literature about the methods of extraction and purification of polysaccharides from
brown algae by means of the most innovative technologies, as well as to determine their
different functionalities and applications as natural therapeutic agents that are currently
available on the market.
2. Advanced Methods for Extraction and Purification of Brown Seaweed Polysaccharides
In recent years, the extraction process of polymers has transitioned from conventional
methods to new techniques, due to the time- and energy-consuming practices of older
methodologies. These emerging extraction methods have an impact on the biocompounds’
properties and biological activities, effectively improving the extraction process overall,
Figure 1a. This is achieved by optimizing the extraction parameters, such as time, power,
temperature, solvent, etc., and developing pre-treatments depending on the matrix of use
and the conditions that are presented [
22
]. The aim of using these recent methodologies is
to obtain a higher yield and better quality of the bioactive compounds of interest [
23
]. For
potential industrial applications, it is also important to maintain the structural integrity
and beneficial properties of the polymers [24,25].
Technologies such as microwave-assisted extraction (MAE) work via a dipole rotation
of a polar solvent due to the radiation conducted by the dissolved ions. Ultrasound-assisted
extraction (UAE) is based on cavitation, sound waves, and heat and enzyme-assisted
extraction (EAE) utilizes enzyme hydrolysis, which breaks the bonds and liberates the
biocompounds; both of these methods are considered non-traditional techniques [
26
].
These three are the most reported techniques, although there are plenty of others, such as
negative pressure cavitation (NPC); hydro-diffusion extraction (HDE); supercritical fluid
extraction (SFE); subcritical water extraction (SCWE) [
27
]; or combined methods, such as
enzyme-ultrasonic-assisted extraction (EUAE) and microwave-assisted aqueous two-phase
extraction (MAATPE). Several treatments have been tested, but unfortunately, a universal
extraction method has not yet been selected [28].
As mentioned before, biocompound extraction involves several steps (sample prepa-
ration, pre-treatment, extraction, polymer recovery, and purification) and optimization of
the parameters [
23
]. The most recent parameters of polysaccharides extraction from brown
seaweed are shown in Table 1.
Plants 2023,12, 2445 4 of 26
Table 1. Recently used methods of extraction of polysaccharides from several brown algae species.
Algae Polysaccharide Pre-Treatment Extraction Method Extraction Details Recovery References
Sargassum siliquosum Fucoidan
Washed with (H2O); dried (60 ◦C)
for 48 h;
powdered with single-shaft extruder
under conditions of 115 ◦C, 10 kg/h.
360 rpm;
sieved with 20 mesh sieves.
MAE & UAE
1 g powder
Solvent: EtOH 10 mL/g 25 ◦C for 4 h.
MAE: 750 W; 10 min; 15 mL/g UAE:
100 W; 10 min; 15 mL/g
MAE 6.94%
UAE4.78% [29]
Fucus vesiculosus
Fucus serratus Fucus
evanescens
Laminarin &
Fucoidan
Grind-dried seaweed, washed with EtOH
and acetone. MAE
1.5 g
Solvent: 25 mL sulfuric acid [10 mM]
120 ◦C for 30 min. Precipitation of
laminarin EtOH (40% v/v); precipitation
of fucoidan EtOH (70% v/v)
Laminarin
8.68%
Fucoidan 5.56%
[30]
Ascophyllum nodosum Fucoidan 80% EtOH; 20 h; room temp. 80% EtOH;
5 h; 70 ◦C. UAE 0.01 M HCl, 35 min, 40% amplitude;
20 kHz 2% CaCl2, overnight; 4 ◦C. 4.56% [22]
Nizamuddinia
zanardinii Fucoidan
Washed, dried (40
◦
C), milled, and stored
in the freezer.
(50 g) suspended in 500 mL of 85% EtOH,
stirred (24 h, 25 ◦C), rinsed with acetone,
and dried under laminar hood
(22 ±2◦C).
EAE & UAE & EUAE
(Alcalase)
EAE (2.5 mL/dry material weight, pH 7,
solid-to-solvent ratios 1:30 g/mL) for 24 h
at 50 ◦C.
UAE sonicated with distilled water
(1:76 g/mL) with (frequency 20 kHz, max
power 400 W, Ø = 1.3 cm) at 196
and 70 ◦C for 59 min.
EUAE (2.5 mL/dry material weight,
pH 7, temperature 50
◦
C, solid-to-solvent
ratios 1:30 g/mL) for 23 h. Sonication
(196 W, 70 ◦C, 59 min)
EAE 5.58%
UAE 3.6%
EUAE 7.87%
[31]
Saccharina Japonica Fucoidan
Washed, chopped, freeze-dried (−80 ◦C.
72 h), ground. Samples that passed
through a 710 µm sieving mesh
were used.
SCWE
200 cm3batch system
0.1% NaOH
80 bars
S/L ratio 0.05 g mL−1, 127.01 ◦C,
300 rpm, 11.98 min
13.56% [32]
Nizamuddinia
zanardinii Fucoidan Washed with water, dried at 40 ◦C for
72 h, sieved (<0.5 mm). SCWE 29 min, 150 ◦C. Raw material to water
ratio 21 g (mL) 25.98% [31]
Plants 2023,12, 2445 5 of 26
Table 1. Cont.
Algae Polysaccharide Pre-Treatment Extraction Method Extraction Details Recovery References
Ascophyllum nodosum Fucoidan
Oven-dried (50 ◦C). Ground for 9 days
(1 mm particle size).
Maceration 10 min, 0.1 M HCl,
room temperature.
UMAE
Sonication: 50 W, 20 kHz, 100% ultrasonic
amplitude. Microwave 2450 MHz 1000 W,
5 min.
3.53% [33]
Nizamuddinia
zanardinii Fucoidan
Cleaned, rinsed on the spot with seawater.
Washed with distilled water and
oven-dried at 40 ◦C for 72 h. Powdered.
1. Alcalase
2. Flavourzyme
3. Celluclast
4. Viscozyme
1. (5% v/v, pH 8, 50 ◦C, 24 h).
2. (5% v/v, pH 7.5, 50 ◦C, 24 h).
3. (5% w/v, pH 4.5, 50 ◦C, 24 h).
4. (5% v/v, pH 4.5, 50 ◦C, 24 h).
Boiled at 95 ◦C 15 min and cooled in ice
bath. Centrifugation (10 min at 9000 rpm)
1. 5.58%
2. 4.36%
3. 4.80%
4. 4.28%
[31]
Sargassum muticum Alginate Washed with H2O. UAE v/m20:1 (wt) Solvent: H2O; 25 ◦C,
30 min, 1.5 A, 50 W, 40 Hz. 15% [34]
Sargassum binderi Alginates
Washed with H2O, dried,
milled with a blender.
Stored under vacuum.
EtOH treatment for dried seaweed
(overnight) 25 ◦C. Filtered with 10 µL
Millipore nylon mesh.
Washed with distilled water.
UAE
10 g/L
Solvent: H2O
pH: 11
150 W
30 min
90 ◦C.
25 kHz
27% [35]
MAE—microwave-assisted extraction; UAE—ultrasound-assisted extraction; EAE—enzyme-assisted extraction; EUAE—enzyme-ultrasonic-assisted extraction; SCFE—supercritical fluid
extraction; SCWE—subcritical water extraction.
Plants 2023,12, 2445 6 of 26
Fucoidan MAE extraction with Sargassum siliquosum provided a yield of 6.94% under
the conditions of 750 W, 10 min, and 15 mL/g with EtOH as a solvent [
36
]. While using
Fucus sp. as a matrix, the optimal conditions were a 30 min treatment at 120
◦
C with sulfuric
acid as a solvent, resulting in a 5.56% yield [
30
]. It should be noted that investigations
about alginate UAE extraction have reported a 27% recovery with Sargassum binderi by
adjusting the parameters to 150 W for 30 min at 90
◦
C, 25 kHz in a water solvent, and
controlled pH [
35
]. Ultrasound extraction has also proven successful while applying 1.5 A,
50 W, and 40 Hz for 30 min at room temperature with water as a solvent; this provides a
15% yield [34].
Plants 2023, 12, x FOR PEER REVIEW 7 of 27
Figure 1. (a) Novel extraction techniques and main purification methods for biocompound recovery.
MAE—microwave-assisted extraction; UAE—ultrasound-assisted extraction; EAE—enzyme-as-
sisted extraction; and SCWE—subcritical water extraction; (b) Purification methods: Chromatog-
raphy, Ultrafiltration and Dialysis. Created with BioRender.com and extracted under premium
membership.
The purification of polysaccharides is important to understand the sulfated
variations of chemical structures of the different species from which these biocompounds
are obtained; this also depends on the extraction methods, harvesting time, and the
location of the algae, Figure 1b [37].
The most researched methods for purifying polysaccharides are anion-exchange
chromatography [38], DEAE cellulose (diethylaminoethyl-cellulose) ion-exchange
column chromatography [39], lyophilization, and ultrafiltration combined with IEX (ion-
exchange chromatography) [40]. Anion-exchange chromatography can separate a large
range of molecules by segregating them based on their net surface charge.
Chromatography and its variations are the most common methods to purify
biocompounds. Lyophilization or freeze-drying consists of eliminating the water from the
sample of interest by freezing the water; afterwards, the frozen water is removed by a
vacuum, bypassing the matter from the solid state to vapor (via sublimation), and the
unfrozen water is eliminated by desorption [41]. Ultrafiltration is the separation of
materials, such as fats, particles, and proteins, among others, of the sample of interest
through the use of membranes that can have a pore size of 0.01 or 0.1 μm, as well as
pressure ranging from 3.4 to 8.3 bar [42]. On the other hand, in the dialysis purification
technique, the solution to be dialyzed is immersed in a specific buffer and placed in a
sealed semi-permeable membrane, which allows the passage of small molecules through
diffusion, balancing the compounds of interest and the dialysate. This is accomplished
through the selective permeability of the membrane, which allows small molecules and
buffer salts to pass through, resulting in an alteration of the concentration of salt and the
molecule of interest in the dialyzed solution [43].
These methods are commonly used to purify polysaccharides, fucoidans, proteases,
and alginates. These products are obtained by different extraction methods, and they are
Figure 1.
(
a
) Novel extraction techniques and main purification methods for biocompound recovery.
MAE—microwave-assisted extraction; UAE—ultrasound-assisted extraction; EAE—enzyme-assisted
extraction; and SCWE—subcritical water extraction; (
b
) Purification methods: Chromatography,
Ultrafiltration and Dialysis. Created with BioRender.com and extracted under premium membership.
The purification of polysaccharides is important to understand the sulfated variations
of chemical structures of the different species from which these biocompounds are obtained;
this also depends on the extraction methods, harvesting time, and the location of the algae,
Figure 1b [37].
The most researched methods for purifying polysaccharides are anion-exchange chro-
matography [
38
], DEAE cellulose (diethylaminoethyl-cellulose) ion-exchange column chro-
matography [
39
], lyophilization, and ultrafiltration combined with IEX (ion-exchange
chromatography) [
40
]. Anion-exchange chromatography can separate a large range of
molecules by segregating them based on their net surface charge. Chromatography and
its variations are the most common methods to purify biocompounds. Lyophilization or
freeze-drying consists of eliminating the water from the sample of interest by freezing
the water; afterwards, the frozen water is removed by a vacuum, bypassing the matter
from the solid state to vapor (via sublimation), and the unfrozen water is eliminated by
desorption [
41
]. Ultrafiltration is the separation of materials, such as fats, particles, and
proteins, among others, of the sample of interest through the use of membranes that can
have a pore size of 0.01 or 0.1
µ
m, as well as pressure ranging from 3.4 to 8.3 bar [
42
]. On the
other hand, in the dialysis purification technique, the solution to be dialyzed is immersed
in a specific buffer and placed in a sealed semi-permeable membrane, which allows the
Plants 2023,12, 2445 7 of 26
passage of small molecules through diffusion, balancing the compounds of interest and the
dialysate. This is accomplished through the selective permeability of the membrane, which
allows small molecules and buffer salts to pass through, resulting in an alteration of the
concentration of salt and the molecule of interest in the dialyzed solution [43].
These methods are commonly used to purify polysaccharides, fucoidans, proteases,
and alginates. These products are obtained by different extraction methods, and they are
derived mostly from brown algae and the different species of Sargassum. Polysaccharides
of great interest because of their biological properties, since they act as anti-lipogenic,
antioxidant, anticoagulant, anti-inflammatory, antiviral, and antitumor. The bioactivities
of fucoidan are influenced due to its structural features, such as its chemical composition,
molecular weight, and degree of sulfation [38].
The purification methods and conditions of different species of Sargassum, as well
as the yield obtained are summarized in Table 2. Some methods seem to have obtained
high yields of purification. A study based on the purification of Sargassum ilicifolium [
44
]
obtained a maximum yield of 8
±
0.9%. This study used different extraction methods,
showing better results with the sonication–microwave method than the hot water method.
The extraction method makes a difference in the yield of the purified products obtained
from the Sargassum; one example is the aforementioned study of Sargassum ilicifolium.
However, there are more conditions that may change the purification yield, such as the
extraction times and temperatures, which can be observed in the study of Sargassum
polycystum: this study was based on the extraction of different polysaccharides, such as
fucoidans, alginates, and laminarin [
45
]. The final application of the bioactive compounds
extracted from macroalgae will define the extraction and purification strategies, since
the characteristics, such as the degree of purity and properties or bioactivities of the
compounds of interest, are defined in each treatment, which can decrease or increase the
specific bioactive potential of the compounds.
Table 2. Polysaccharide purification methods from brown macroalgae.
Algae Purification Method Purification Conditions Yield Reference
Sargassum
ilicifolium Chromatography
Dissolved in 5 mL distilled water.
Loaded to a pre-equilibrated DEAE
cellulose 52 columns.
The stepwise gradient elution with 0.05
M Tris–HCl buffer (pH 7.0) containing
0.5, 2.0, 3.5, and 5.0 M NaCl. Fractions
of 4 mL per tube were collected and
monitored at 490 nm by the
phenol–sulfuric acid (H2SO4) method.
Fucoidan yield from
sonication–microwave
extraction: 8 ±0.9%.
Hot water extraction:
6±0.5%.
[44]
Sargassum
autumnale Chromatography
Twice the volume of 99.5% ethanol
solution was added to the
enzyme-assisted hydrolysates
precipitate and collected by
centrifugation.
Different extraction
methods: Distilled water
extract: 17.23 ±0.28.
Ultraflo extract:
23.50 ±0.56.
Protamex extract:
23.89 ±0.42.
[46]
Sargassum
aquifolium
Isopropyl alcohol
purification process Not reported 21.74 ±2135 [47]
Sargassum patens Dialysis Pr: (NH4)2SO485%
Pu: DI (kDa n.s.) 8.2% [38]
Sargassum
polycystum Ultrafiltration Not reported 7.27% [48]
Plants 2023,12, 2445 8 of 26
Table 2. Cont.
Algae Purification Method Purification Conditions Yield Reference
Sargassum
siliquosum
Anion-exchange
chromatography Protein and uronic acid were removed. 5.08 ±1.17% [49]
Sargassum natans Gel permeation
chromatography Not reported Maximum of 21.21% [13]
Sargassum
fusiforme Lyophilization Not reported On the sample ASFF:
11.24 ±0.94a [50]
Sargassum swartzii
High-performance
liquid
chromatography
A total of 1 mg of lyophilized SP was
dissolved in 1 mL distilled water.
Filtered through a 0.22 µm syringe tip
filter and subjected to HPLC analysis.
Hot water
extraction: 3.6%
HCl method: 1.2%
[45]
3. Structural Description of the Main Polysaccharides Found in Brown Macroalgae
Brown algae are a source of protein, fatty acids, carbohydrates, minerals, and vitamins
(Figure 2). Polysaccharides are the main component, with a range of 50–60% dry water
(DW), which functions as storage energy [
22
,
51
,
52
]. Polysaccharides are mainly made up
of mannose, glucose, galactose, and fucose, along with small proportions of arabinose
and rhamnose. Brown algae are mainly composed of three polysaccharides, which are
fucoidans, alginate, and laminarin, but their conformation varies depending on the species
of brown algae. These variations in the content of polysaccharides are due to conditions
such as population age, temperature, and geographic location, and this is reflected in their
biological activities that allow them to act as anti-inflammatory, anticoagulant, antiviral, or
antioxidant agents, among others [22,52].
Plants 2023, 12, x FOR PEER REVIEW 9 of 27
Sargassum
natans
Gel permeation
chromatography Not reported Maximum of 21.21% [13]
Sargassum
fusiforme Lyophilization Not reported
On the sample ASFF:
11.24 ± 0.94a [50]
Sargassum
swartzii
High-performance
liquid
chromatography
A total of 1 mg of lyophilized SP
was dissolved in 1 mL distilled
water.
Filtered through a 0.22 μm syringe
tip filter and subjected to HPLC
analysis.
Hot water extraction:
3.6%
HCl method: 1.2%
[45]
3. Structural Description of the Main Polysaccharides Found in Brown Macroalgae
Brown algae are a source of protein, fatty acids, carbohydrates, minerals, and
vitamins (Figure 2). Polysaccharides are the main component, with a range of 50–60% dry
water (DW), which functions as storage energy [22,51,52]. Polysaccharides are mainly
made up of mannose, glucose, galactose, and fucose, along with small proportions of
arabinose and rhamnose. Brown algae are mainly composed of three polysaccharides,
which are fucoidans, alginate, and laminarin, but their conformation varies depending on
the species of brown algae. These variations in the content of polysaccharides are due to
conditions such as population age, temperature, and geographic location, and this is
reflected in their biological activities that allow them to act as anti-inflammatory,
anticoagulant, antiviral, or antioxidant agents, among others [22,52].
Figure 2. Scheme showing the composition of brown algae, with carbohydrates representing the
highest percentage (12.2–60% of DW). Within this group are polysaccharides, which are of great
interest due to their therapeutic properties, including laminarin (22–49% DW), fucoidans (5–38% of
the DW), and alginate (40% DW). Created with BioRender.com and extracted under premium mem-
bership.
3.1. Fucoidans
Fucoidans are anionic sulfated polysaccharides located in the intracellular space and
cell wall. Fucoidans are mainly made up of repeating units of L-fucose (α (1→3)-L-
fucopyranose residues, alternating α (1→3) and α (1→4)-linked L-fucopyranosyls, or both
forms, and the sulfate groups that correspond to 5% to 38% depend on the species of
brown algae. Fucoidans are also composed of uronic acid, acetyl groups, proteins, and
other monosaccharides, such as galactose, mannose, glucose, rhamnose, and xylose. These
Figure 2.
Scheme showing the composition of brown algae, with carbohydrates representing the high-
est percentage (12.2–60% of DW). Within this group are polysaccharides, which are of great interest
due to their therapeutic properties, including laminarin (22–49% DW), fucoidans (5–38% of the DW),
and alginate (40% DW). Created with BioRender.com and extracted under premium membership.
3.1. Fucoidans
Fucoidans are anionic sulfated polysaccharides located in the intracellular space
and cell wall. Fucoidans are mainly made up of repeating units of L-fucose (
α
(1
→
3)-
L-fucopyranose residues, alternating
α
(1
→
3) and
α
(1
→
4)-linked L-fucopyranosyls, or
both forms, and the sulfate groups that correspond to 5% to 38% depend on the species
Plants 2023,12, 2445 9 of 26
of brown algae. Fucoidans are also composed of uronic acid, acetyl groups, proteins,
and other monosaccharides, such as galactose, mannose, glucose, rhamnose, and xylose.
These polysaccharides span molecular weights from 7 to 2300 kDa, corresponding to 4 to
10% of the DW of brown algae. Being a very heterogeneous polysaccharide, it presents a
diversity of structures. It has been observed that its biological activity is correlated with
the molecular weight, the monosaccharides that make it up, and its chemical composition,
sulfation degree, position of the sulfate groups, and glycosidic bonds [22,52–54].
3.2. Alginate
Another polysaccharide of great interest is alginate, which is located in the cell wall
and in the intracellular matrix of the different species of brown algae and represents
40% of the DW. Alginate is a linear polysaccharide mostly made up of
α
-L-guluronic
acid (G) and
β
-D-mannuronic acid (M) isomeric residues, which are linked by the 1,4-
glycosidic configuration, giving rise to three types of arrangements, namely, GG, MM, and
GM, depending on the proportion. This configuration allows the alginate to increase its
viscosity and gelling properties; for example, the viscosity is assigned by the M blocks, and
the gelling properties are provided by the G blocks. This type of block presents greater
solubility in water than the M blocks. These properties can also be increased with Ca
2+
ions [22,52–54].
3.3. Laminarin
Laminarin is a polysaccharide found in cell vacuoles. It represents 22 to 49% of DW
and serves as an energy reserve in brown algae. In addition, it has a high concentration
of neutral sugars, and a low amount of uronic acid. This polysaccharide of low molecular
weight (approx. 5 kDa) is soluble in water and is made up of
β
-glucan consisting of
β
-1,3-
D-glucopyranose residues, linked by
β
-1,6-intrachain unions and at their ends. Reduced
laminarin may have residues of glucose or mannitol; the degree of polymerization is
between 20–25 moieties of glucose. This polysaccharide has various biological properties,
such as the ability to stimulate an antitumor response, promoting wound repair, and
enhancing the activity of the immune system [22,52,55].
4. Exploring the Potential Relationship between Polysaccharides Structures and
Their Bioactivities
Brown macroalgae polysaccharides are known for their several potential therapeutic
properties; in fact, they are used as an ingredient or component in a wide range of industries,
including pharmaceutical, medical, food, and cosmetics [
54
]. The most promising activities
are in the field of medicine due to their antiviral, anti-inflammatory, antioxidant, and
anticarcinogenic actions, Figure 3[52].
4.1. Anticancer Activity
Cancer is considered the main cause of death worldwide; in 2021, more than 10 million
people died from this disease. Cancer is defined as a malignant tumor or neoplasm of
abnormal tissue mass, which has the potential to metastasize and attack any part of the
body with a high risk of death [
56
]. Therefore, research and science have been focused
on developing precise and effective alternative techniques to reduce cancer’s impact on
health and improve conventional treatments. New technologies using nanomedicine
and biomaterials are under evaluation in clinical trials and others are already in clinical
practice [
57
]. Biocompatible materials have been promising elements because they can
be bioengineered in different forms as nanoparticles with important advantages, such as
selectivity and efficacy in the attack on tumor cells [58].
Several researchers around the world have been promoting and reporting the anti-
cancer activity of brown algae and the behavior of cancer cell lines in
in vitro
assays. One
study reported the anticancer activity of laminarin by using L. japonica at a concentration
of 35 mg/mL to significantly decrease the Bel-7404 (human hepatoma cell line) viability;
Plants 2023,12, 2445 10 of 26
for 48 h, the viability was only 46.20%, and for HepG2, it was only 42.85%. Regarding the
apoptosis rate for the Bel-7404 cell line, it was 2.72 higher with laminarin, and for HepG2,
it was 8.18 times higher than without treatment (Table 3) [59].
Plants 2023, 12, x FOR PEER REVIEW 10 of 27
polysaccharides span molecular weights from 7 to 2300 kDa, corresponding to 4 to 10% of
the DW of brown algae. Being a very heterogeneous polysaccharide, it presents a diversity
of structures. It has been observed that its biological activity is correlated with the
molecular weight, the monosaccharides that make it up, and its chemical composition,
sulfation degree, position of the sulfate groups, and glycosidic bonds [22,52–54].
3.2. Alginate
Another polysaccharide of great interest is alginate, which is located in the cell wall
and in the intracellular matrix of the different species of brown algae and represents 40%
of the DW. Alginate is a linear polysaccharide mostly made up of α-L-guluronic acid (G)
and β-D-mannuronic acid (M) isomeric residues, which are linked by the 1,4-glycosidic
configuration, giving rise to three types of arrangements, namely, GG, MM, and GM,
depending on the proportion. This configuration allows the alginate to increase its
viscosity and gelling properties; for example, the viscosity is assigned by the M blocks,
and the gelling properties are provided by the G blocks. This type of block presents
greater solubility in water than the M blocks. These properties can also be increased with
Ca
2+
ions [22,52–54].
3.3. Laminarin
Laminarin is a polysaccharide found in cell vacuoles. It represents 22 to 49% of DW
and serves as an energy reserve in brown algae. In addition, it has a high concentration of
neutral sugars, and a low amount of uronic acid. This polysaccharide of low molecular
weight (approx. 5 kDa) is soluble in water and is made up of β-glucan consisting of β-1,3-
D-glucopyranose residues, linked by β-1,6-intrachain unions and at their ends. Reduced
laminarin may have residues of glucose or mannitol; the degree of polymerization is
between 20–25 moieties of glucose. This polysaccharide has various biological properties,
such as the ability to stimulate an antitumor response, promoting wound repair, and
enhancing the activity of the immune system [22,52,55].
4. Exploring the Potential Relationship between Polysaccharides Structures and Their
Bioactivities
Brown macroalgae polysaccharides are known for their several potential therapeutic
properties; in fact, they are used as an ingredient or component in a wide range of
industries, including pharmaceutical, medical, food, and cosmetics [54]. The most
promising activities are in the field of medicine due to their antiviral, anti-inflammatory,
antioxidant, and anticarcinogenic actions, Figure 3 [52].
Figure 3.
Bioactivities and therapeutic perspectives of brown algae polysaccharides. Created with
BioRender.com and extracted under premium membership.
The bioactivity of fucoidan has been widely used due to its inherent anticancer prop-
erties, favorable drug delivery behavior, and promising targeting ability, resulting in the
induction of cell apoptosis and inhibition of angiogenesis [
60
]. For example, in some species
of brown seaweed, such as Turbinaria conoides, the anticancer effect on the hepatoblastoma-
derived (HepG2) cell line has been studied through a cell viability assay, using 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MTT and different concentrations
(0–200
µ
g/mL) of fucoidan/quercetin treatments for 48 h. The results show that the
fucoidan/quercetin treatment reduced cell viability to less than 50% in a concentration-
dependent manner. A concentration of 200
µ
g/mL demonstrated a better performance.
The results conclude that fucoidan had more significant anticancer activity compared to
quercetin [61].
On the other hand, alginate has not been as widely used in anticancer activity as other
brown algae polysaccharides, even though some reports of the cytotoxic effects alone or
in combination with different compounds have demonstrated the potential that alginate
could contribute to cancer treatments. A study using polysaccharides from brown algae
C. Sinuosa showed the bioactivity of alginate by promoting a significant decrease in the
cell viability of HCT-116 cells, with an IC50 of 690
µ
g/mL
−
1 and a 37.1% inhibition rate at
750
µ
g/mL
−1
. Nevertheless, fucoidan at similar high concentrations resulted in a better
inhibition rate of 45% [
62
]. Alginate can play a major role in encapsulation as alginate-based
hydrogels for cancer therapy, which can control and target drug administration, improving
the stability and minimizing unwanted effects, time, and effort [
63
,
64
]. Recent research
has reported that low-weight alginate oligosaccharides have better anticancer activity than
complete polysaccharide because they prevent cancer cell proliferation and reduce tumor
metastasis, in addition to providing antioxidant and anti-inflammation properties [65].
Plants 2023,12, 2445 11 of 26
Table 3. Biomedicine and therapeutic applications of polysaccharides from brown algae species.
Brown Algae Polysaccharide Bioactivity Bioassay Bioactivity Results Reference
L. japonica Laminarin Anticancer
Cell viability detected by WST-8 cell
proliferation assay, flow cytometry in 96-well
plate in human HCC cell lines, including
Bel-7404 and HepG2, when incubated with
different concentrations of laminarin. Hepa
1–6 tumor-bearing mice were injected with
different concentrations and tumors
were measured.
Cell viability;
;aminarin concentrations of 35 mg/mL
significantly decreased the Bel-7404 viability, with
only 46.20% at 48 h.
HepG2 was only 42.85% of that of cells without
treatment. Apoptosis rate of Bel-7404 was
2.72 higher with laminarine and 8.18 times higher
for HepG2 than without treatment.
Tumor growth inhibition was higher at
1200 mg/k.d of laminarin with 67.92%.
[59]
Padina pavonioca Sulfated
polysaccharides Anticancer Antioxidant
DPPH
Cell viability: MTT assay cytotoxic activity in
HeLa cancer cell lines cultured in
DMEM supplemented.
A total of 1 mg/mL increases scavenging activity
up to 63%.
Low doses (0.05–0.1 mg/mL) exhibit cytotoxic
activity in HeLa cancer cell line.
[66]
Sargassum ilicifolium Fucoidan
Antioxidant Osteogenic
ability (bone
regeneration)
DPPH expression of osteoblast differentiation
media in DMEM supplemented with murine
mesenchymal stem cells (C3H10T1/2).
IC50 0.96 mg/mL (crude) and 2.51 mg/mL
(purified).
A total of 1 µg/mL of purified fucoidan provides
cell proliferation (130%) on C3H10T1/2 at 48 h.
[38]
Silvetia Compressa
Ecklonia arborea
Sulfated
polysaccharides
(fucoidan, laminarin,
alginate) and
phlorotannins
Antioxidant DPPH & ORAC
DPPH IC50 (mg/mL)
S.Compressa 1.7
E. arborea 3.7
ORAC (mmol Trolox equivalent/g)
S.Compressa 0.817
E. arborea 0.801.
[67]
Sargassum siliquosum
Fucoidan Antioxidant
Anti-inflammatory
DPPH (absorbance of 50% methanol solution
mixed with the sample solution was the blank).
Cell viability: RAW264.7 cell line in 24-well
plate. TNF-αcontent level after
lipopolysaccharide LPS exposure reflected the
anti-inflammatory activity. Quercetin was used
as a positive control.
Antioxidant results: EC50 of purified fucoidan
2.58 mg/mL, higher antioxidant ability showed
crude extract with an EC50 of 0.34 mg/mL. Cell
Viability: Inhibition of TNF-
α
reached 14.8% with
0.25 µg/mL of fucoidan-treated compared to
LPS control.
[36]
Plants 2023,12, 2445 12 of 26
Table 3. Cont.
Brown Algae Polysaccharide Bioactivity Bioassay Bioactivity Results Reference
Sargassum horneri Alginic acid Anti-Inflammatory
Cell culture RAW 264.7 mouse macrophages
and HaCaT (human keratinocytes) cultured in
DMEM, 10% FBS, and 1% antibiotics. In 24-well
plates, HaCaT were seeded with SHA and
Chinnese fine dust CFD at 125 µg/mL under
optimized conditions. MTT assay was used for
cell viability.
Cell viability: A concentration of SHA
25–100 µg/mL decreased viability of HaCaT in a
range of 20%.
[37]
Sargassum horneri Fucoidan Anti-inflammatory
Cell culture and viability assay
RAW 264.7 macrophages were cultured in
DMEM, 10% FBS, and 1% antibiotics. MTT test
in 24-well plate. Negative control had untreated
macrophages, positive control was only treated
with PBS.
Fucoidan in concentrations of 12.5–50 µg/mL
inhibited the production in LPS-activated RAW
264.7 macrophages with IC50 = 40 µg/mL.
[68]
Sargassum fulvellum Sulfated
polysaccharides Anti-inflammatory
Anti-inflammatory activity in RAW
264.7 macrophages cultured in DMEM medium.
Stress induced by E. coli lipopolysaccharides.
In vivo tests applied in zebrafish embryos to
measure their survival rate after 3 days. Levels
of ROS, heartbeat, and cell death after stress
induced by E. coli lipopolysaccharides.
Viability of RAW 264.7 cells increased by 94.6%,
while the production of nitric oxide (NO) in RAW
264.7 decreased by 40.7%. Zebrafish survival, cell
death, and ROS/NO production decreased in a
dose-dependent manner.
[29]
Turbinaria decurrens Fucoidan Anti-inflammatory
Swiss albino mice were subjected to
formalin-induced paw edema. The mice were
treated with the extracted fucoidan, which was
administered orally, to evaluate the
anti-inflammatory effect.
The mice treated with fucoidan showed reduction
in the perception of the wound by the mice. The
licking time was reduced by more than 50%. In
addition, the anti-inflammatory effect of the
fucoidan in paw edema showed a reduction
of 52%.
[69]
Sargassum fusiforme Sulfated
polysaccharides Anti-inflammatory
Sulfated polysaccharides extracted by an
enzymatic method were tested in RAW 264.7
cells stressed with lipopolysaccharide (LPS). To
study the anti-inflammatory effects of the
polysaccharides, the level of expression of NO
and inflammatory cytokines, such as TNF-α,
IL-1β, IL-6, and PGE2, were determined.
The sulfated polysaccharides showed an
anti-inflammatory activity with a dose-dependent
behavior. The addition of the polysaccharides
successfully reduced the expression of TNF-α,
IL-1β, IL-6, and PGE2. Additionally, the
production of NO was reduced, while the cellular
viability increased.
[70]
Plants 2023,12, 2445 13 of 26
Table 3. Cont.
Brown Algae Polysaccharide Bioactivity Bioassay Bioactivity Results Reference
L. japonica Polysaccharides Antiviral
The polysaccharides isolated by ethanol
precipitation were tested in HEK293 cells
infected with the respiratory syncytial virus
(RSV) to study the antiviral activity of the
polysaccharides. The expression of IRF3 and
IFN-αwere analyzed.
The polysaccharide extracts demonstrated
significant antiviral activity against RSV by
increasing IFN-αexpression via regulation of the
IRF3 signaling pathway in HEK293 cells.
[71]
Sargassum
polycystum
Fucoidan fraction-2
(Fu-F2) Antibacterial
The MIC and MBC were determined for
bacterial strains Streptococcus mutans,
Staphylococcus aureus,Pseudomonas aeruginosa,
and E. coli. A 48-well microtiter plate was used.
The antibacterial activity was determined by
disk diffusion assay. Test bacteria were grown
on Luria-Bertani agar medium and a crude
fucoidan loaded disk was placed with the
standard antibiotic disk (tetracycline).
The highest antibacterial activity (21 ±1.0 mm)
was obtained at 50 µg/mL against Pseudomonas
aeruginosa, and the lowest activity (16
±
0.53 mm)
was against Staphylococcus aureus.
[72]
Fucus vesiculosus Fucoidan Anti-angiogenesis Use of crude extracted fucoidan over
endothelial cells and chicken embryos.
A concentration of fucoidan at 0.5 mg/mL was
able to prevent the formation of tubular structures
in epithelial cells. Chicken embryos presented a
reduction in blood vessel formation, as well as in
the tumoral mass.
[73]
Fucus distichus subsp.
evanescens Fucoidan Anti-angiogenesis
Measurement of the gene expression of the
angiopoietins 1 and 2, vascular endothelial
growth factors, and stromal-derived factors in
mono- and co-cultured systems of human
outgrowth endothelial and human
mesenchymal stem cells. Cells were treated for
seven days with extracts obtained enzymatically
from Fucus distichus subsp. evanescence. The
anti-angiogenic activity of co-cultured cells was
analyzed by measuring the length and area of
the tube-like structures created by the
endothelial and mesenchymal cells.
In monoculture: The fucoidan extract
downregulates the expression of vascular
endothelial growth factor and stromal-derived
factor-1 in mesenchymal stem cells; however, the
angiopoietins-1 and angiopoietins-2 in the
outgrowth endothelial cells’ levels were not
affected by the fucoidan extract. The fucoidan
extract with the higher sulfate content was able to
disturb the formation of the tube-like structures;
length and area were both reduced.
[74]
Plants 2023,12, 2445 14 of 26
Table 3. Cont.
Brown Algae Polysaccharide Bioactivity Bioassay Bioactivity Results Reference
Ascophyllum
nodosum Sodium alginate Prebiotic
Alg-MAE (microwave-assisted extraction) L.
delbruecki ssp. bulgaricus and L. Casei growth
media. Inulin (positive prebiotic control),
glucose (the negative control in a 96-well-plate.
Alg- MAE improved the growth rate of L.
delbruecki ssp. bulgaricus by 75% (at 0.10% (w/v)
inclusion), 150% (at 0.50% (w/v)), 40% (at 0.10%
(w/v)), and 34% (at 0.30% (w/v)) for L. casei when
compared to the unsupplemented media.
[24]
Sargassum
glaucescens Fucoidan Hair growth-promoting
(alopecia treatment)
Cell proliferation: Human follicle dermal
papilla cells (HFDPC) in DMEM with 1% FBS
for 24 h, then treated with different molecular
weight fucoidans (HHP-1-MW, SCW-1, and
SCW-5; 1 mg/mL). HFDPC treated by glucose
(1 mg/mL) as control; cell viability was
measured with CCK-8 assay. Hair follicle
culture assay: 5-week-old male C57BL/6 mice.
Cultured in William’s medium with or without
the supplementation of SCW-5 (1 mg/mL) or
minoxidil (1 µM).
Cell proliferation was higher than glucose or PBS
treated control. SCW-1 was the most effective
with cell viability (200%) of HFDPC. The hair
follicles treated by SCW-5 after 69 days of
treatment had better hair growth than the
minoxidil and control groups (p< 0.05).
[75]
Sargassum
angustifolium Fucoidan Wound healing
The wound healing effect of crude fucoidan
extracts on adipose-derived mesenchymal stem
cells (ADMSCs) was determined by MTT and
scratch assays.
The crude extracts of fucoidans were
demonstrated by the MTT assay to improve
growth up to 1.5 times. With the scratching
technique, an increase in cell migration of 76 and
142% was observed after 48 and 72 h of
incubation, respectively, in ADMSC cells.
[76]
Plants 2023,12, 2445 15 of 26
4.2. Antioxidant Activity
Reactive oxygen species (ROS) are involved in biological reactions and intracellular
signaling pathways. They are normal products derived from metabolism, such as hydroxyl
radicals (OH
•
), superoxide radicals (
•
O
2−
), peroxyl radicals (ROO
•
), peroxide organics
(ROOR’), peroxynitrite (ONOO
−
), and hydrogen peroxide (H
2
O
2
). However, a major
problem is caused when oxidative stress is present due to the abnormal proliferation of ROS,
which has the potential to induce damage in cells in a significant range; vital biomolecules,
such as DNA, proteins, and lipids, among others, are affected by oxidative stress and
can cause serious diseases, including neurodegeneration diseases, cancer, arthritis, and
atherosclerosis [
54
,
65
]. Thus, scientists have been searching for years for potential solutions,
such as antioxidants that have a significant role in inhibiting oxidation reactions caused
by ROS.
Nowadays, it is known that synthetic antioxidants have generally been used in the
food industry as additives. Their long-term use produces side effects, bringing notable
attention to natural antioxidants. Algal extracts from different species have demonstrated
a crucial opportunity to contribute to this sector; in fact, more than fifty species of brown
algae from around the globe have been reported to show significant antioxidant activ-
ities [
77
]. The main bioactive compounds with antioxidant activity in brown seaweed
species are phlorotannin, fucoxanthin, and polysaccharides, such as alginic acid, fucoidan,
and laminarin. These have been studied extensively due to the interest in their potential
implementation in pharmaceuticals [78].
Laminarin presents potential antioxidant activity, especially against oxidative stress
caused by ROS and free radicals. Crude laminarin extract from brown algae L. hyperborean
has exhibited higher DPPH radical scavenging (38.62%) compared to commercial laminarin
standard (13.93%) from Sigma
TM
(Sigma-Aldrich, St. Louis, MO, USA). These results agree
with the theory that the polysaccharides’ structures have antioxidant activity [
79
].
In vivo
trials have been reported, usually in rats and porcine, to demonstrate the potential effect of
laminarin in pulmonary and lipid oxidations, in addition to increased natural antioxidant
properties and mitigating ROS generation [18].
Fucoidan antioxidant assays have been applied alone and combined with other sul-
fated polysaccharides. Fucoidan from C. Sinuosa displayed a high antioxidant capacity in
2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and superoxide dismutase (SOD) assays,
showing remarkable scavenging activity of 89% at 750
µ
g/mL
−1
, DPPH IC
50
of 46.2, and
SOD IC50 23.7 [
62
]. Sulfated fucoidan of Sargassum polycitum has also demonstrated an-
tioxidant behavior using the ferric reducing antioxidant power (FRAP) method; the results
of IC
50
of 41,667 ppm show intense activity [
80
]. Other recent fucoidan antioxidant re-
sults demonstrating the activities of Sargassum ilicifolium,Silvetia Compressa, and Sargassum
siliquosum are described in Table 3.
Alginate has been widely used as an antioxidant agent, including as a crude extract,
combined, and even as base material for encapsulation. The polysaccharide has indicated
an ability to scavenge free radicals and reduce ROS disorder. Favorable antioxidant results
of alginate alkaline treatment have been reported in a range from 35.83 to 120.48
µ
MTEg
−1
and temperature stable up to 50
◦
C, decreasing in the temperature range of 70–100
◦
C [
81
].
However, recent studies have suggested that alginate oligosaccharides have a better and sig-
nificant enhancement in antioxidant activities and the capacity to protect endothelial cells,
providing a possible therapeutic application for atherosclerosis and related diseases [29].
4.3. Anti-Inflammatory Activity
External stimuli, such as injuries or the appearance of pathogenic microorganisms, as
well as internal stimuli, such as stress that is considered harmful for any living system, trig-
ger the natural response of inflammation. The inflammatory reaction includes the activation
of the immune system, particularly the macrophage and neutrophil cells, which, during
the inflammation process, generate secondary factors, such as pro-inflammatory cytokines,
Plants 2023,12, 2445 16 of 26
nitric oxide (NO), and prostaglandin E2 (PGE2) [
82
]. The cytokines known as interleukin-1B
(IL-1B), interleukin 6 (IL-6), tumor necrosis factor (TNF-alfa), and interleukin-12 (IL-12), as
well as enzymes, such as cyclooxygenase (COX-2) and matrix metalloproteinase-9 (MMP-9),
are global biomarkers of inflammation [83–85].
The biopolymers from brown macroalgae have shown strong anti-inflammatory activ-
ities in
in vitro
and
in vivo
models. Wang et al. [
29
] obtained a rich sulfated polysaccharide
extract from the Sargassum fulvellum and tested its anti-inflammatory properties against
RAW 264.7 macrophages and zebrafish embryos stressed by E. coli lipopolysaccharides.
The extract was able to increase the cell viability of the macrophages up to 94.6%, while the
levels of NO, PGE2, TNF-alfa, and interleukins 1 and 6 decreased significantly (Table 3). In
a similar way, the zebrafish embryos treated with the sulfated polysaccharides increased
their survivability by 70%; in addition, the NO levels, the reactive oxygen species, and the
overall cell death was reduced as an effect of the sulfated polysaccharides. Both
in vivo
and
in vitro
experiments showed a concentration-dependent behavior, and the best results were
obtained with the higher polysaccharide concentration of 100
µ
g/mL. Another study by
Manikandan et al. based on an
in vivo
model reported high anti-inflammatory activity from
a fucoidan extracted from brown algae [
69
]. They used fucoidan extracted from Turbinaria
decurrens to explore its activity against formalin-induced paw edema in Swiss albino mice.
Their results demonstrate that the polysaccharide administered orally was able to reduce
the licking time of the mice of the paw edema by more than 55%, meaning it reduced the
mice’s perception of the wound. In addition, the inflammation of the paw edema was
reduced by 52% utilizing the standard treatment drug called dexamethasone. An analysis of
the paw tissues of the mice reported a reduction in the expression of the COX-2, IL-1B, and
MMP-9 genes in comparison to the gene’s expression of the untreated mice with induced
paw edema. A study exploring the anti-inflammatory activity of polysaccharides from
brown algae was made by Wang et al. [
36
]: they extracted sulfated polysaccharides from the
Sargassum fusiforme by an enzymatic method and tested the extracts on LPS-induced stress
RAW 264.7 macrophages. The anti-inflammatory activity was analyzed by reading the level
of expression of common inflammatory factors, such as NO, TNF-
α
, IL-1
β
, IL-6, and PGE2.
The sulfated polysaccharides were able to decrease the level of expression of these markers
in a dose-dependent behavior; in addition, the cellular viability was enhanced as a result of
the reduction of the NO levels.
4.4. Antiviral Activity
Viral infections have caused a severe burden on public health around the globe,
especially with the pandemic caused by SARS-CoV-2. Viruses are divided into two types:
simple (or non-enveloped), which are made up of nucleic acid and a protein capsid, and
complex (enveloped), which have a lipoprotein envelope over the protein capsid, making
them stronger to protect against environmental factors and conferring protection from
viruses to disinfectants or antiviral agents. Nevertheless, to reduce collateral effects from
synthetic drugs, pharmacology has been searching for and developing novel, natural,
and antiviral agents in order to help alleviate symptoms, shorten the disease period, and
minimize side effects and toxicity [
86
]. Recently, it has been reported in several studies
that the antiviral properties of sea life is not only limited to polysaccharides from brown
algae, but can also be found in sea cucumber, navicula, green algae, blue–green algae, red
algae, and even in chondroitin sulfate from sharks. Recent research indicates the capacity
to mitigate viruses by preventing them from interacting with host cells, inhibiting RNA
replication and protein synthesis [87].
In this sense, a wide range of studies has been reported on alginate-based materials
to verify the antiviral properties of more than 15 types of viruses that can infect different
organisms. Alginic acid has been tested against the rabies virus in chicken embryo-related
cells, showing a dose-dependent inhibitory effect from 1 to 100
µ
g/mL. Sodium alginate
has also inhibited potato virus X by 95% using Chenopodium quinoa as a host; a strong
Plants 2023,12, 2445 17 of 26
antiviral effect was demonstrated at a concentration of 1
µ
g/
µ
L [
88
]. Furthermore, these
previous studies led to research lines for alginate-based biomaterials against SARS-CoV-2.
Laminarin acts by promoting the humoral immune response of virus-infected host
cells and activating natural killer (NK) cells and T-lymphocytes [
89
]. Therefore, lami-
narin isolated from brown seaweed could be a source of new alternatives against HIV.
Shi et al. [
90
] used a concentration of 50 mg/mL and demonstrated low cytotoxicity; fur-
thermore, they were able to block the adsorption of the virus and suppress the reverse
transcriptase. Additionally, other authors have found a positive antiviral response from the
laminarin of L. japonica against respiratory viruses, such as H5N1 and the RSV virus [71].
Fucoidan is the brown algae biopolymer with the largest spectrum of antiviral proper-
ties reported; nevertheless, its bioactive capacity depends on the large size chain, molar
composition, and structural attributes, such as the molecular weight and chemical com-
positions, which can be affected by variations in the season and the specie [
91
]. There is a
wide range of viruses that fucoidan can be inhibit as an antiviral, such as RNA and DNA
viruses, including HIV, HSV1-2, ASFV, HTLV-1, MPMV, dengue virus, and cytomegalovirus.
Moreover, fucoidan can regulate mitosis or cellular apoptosis due to its capacity to inhibit
digestive enzymes and interrupt glucose absorption. It has been shown to have positive
responses against HIV. Fucoidan from Sargassum henslowianum was used against the herpes
virus (HSV-1 and HSV-2) and demonstrated an IC50 of 0.82–0.89
µ
g/mL by plaque reduc-
tion assay; it also showed 0.48 µg/mL against HSV-2 [92]. Recently, the antiviral action of
fucoidan has been tested to determine its usefulness against the current pandemic; in fact,
in vitro
models have demonstrated efficacy against SARS-CoV-2, significantly inhibiting the
effect of viral spike protein binding [
93
]. Fucoidan concentrations between 9.10–15.6
µ
g/mL
have inhibited SARS-CoV-2
in vitro
via S glycoprotein binding. In addition, some reports
of comparations of different weights of fucoidan have been performed using Saccharina
japonica in HMW (8.3 µg/mL), significantly better than LMW (16 µg/mL) [94,95].
4.5. Non-Conventional Activities
Besides the known variety of studied bioactivities of polysaccharides extracted from
brown algae, these polysaccharides have recently been tested in new applications. The
latest evidence proves that these polysaccharides are able to benefit the gastrointestinal
tract, improve the angiogenesis process, soothe metabolic syndrome, and enhance bone
health [96].
The process in which new blood vessels are formed from old blood vessels is known
as angiogenesis. This process consists of four stages: (1) the vascular permeability rises,
(2) the endothelial cells travel through the extracellular matrix, (3) the differentiation
occurs, and finally, (4) the new vessels form and mature after a short time [
97
]. The
failure of any part of this process can lead to metabolic and cardiovascular disorders,
but most importantly, can also lead to the growth of carcinogenic cells and therefore to
cancer and potential metastasis [
98
]. Brown macroalgae biopolymers have been used as a
countermeasure for uncontrolled angiogenesis. Oliveira et al. [
73
] used a fucoidan extracted
from Fucus vesiculosus to prevent the formation of new blood vessels in endothelial cells
and in chicken embryos. The extracted fucoidan at a concentration of 0.5 mg/mL was able
to prevent the formation of more tubular formations on epithelial cells and the presence
of the platelet-derived growth factor (PDGF) was downregulated; this factor is necessary
for the proper maturation of blood vessels. In addition, the cells treated with this fucoidan
presented a tendency to aggregate instead of spreading and connecting with each other.
The chicken embryos treated with the fucoidan presented a decrement of blood vessels
and the tumoral mass, supporting the activity of fucoidan as a component to prevent
tumor progression. Another similar experiment was conducted by Ohmes et al. [
74
]. They
tested fucoidan extracted from Fucus distichus subsp. evanesces into mono- and co-cultured
human outgrowth endothelial cells (OEC) and human mesenchymal stem (MSC) cells.
The fucoidan was obtained by enzymatic extraction with cellulases and alginate lyases,
then different concentrations of fucoidan were tested in the different cultures. The level of
Plants 2023,12, 2445 18 of 26
expression of different genes, such as angiopoietins-1 (ANG-1), angiopoietins-2 (ANG-2),
vascular endothelial growth factor (VEGF), and stromal-derived factor 1 (SDF-1), were
measured to analyze the anti-angiogenic properties of the fucoidan extracted, as well as
the length and area of the tube-like structures formed by the co-culture of the cells. The
fucoidan was able to downregulate the expression of all the genes in MSC; however, the
ANG-1 and ANG-2 in the OEC did not decrease because of the fucoidan. The fucoidan
extract was able to disrupt and decrease the length and area of the tube-like structures
formed during the co-culture of both MSC and OEC cells, showing a strong bioactivity
against angiogenesis.
In addition, several researchers have found a prebiotic effect on human intestinal
microbiota in brown algae polysaccharides. This is because they are not digestible by
hydrolytic enzymes and are fermented in the colon by Lactobacillus and Bifidobacterium,
improving growth and decreasing the concentrations of pathogens. However, digestion
affects the activity of algae polysaccharides, therefore it is essential to verify resistance to
hydrolysis under
in vitro
conditions [
99
]. Okolie et al. [
24
] worked with sodium alginate
extracted from Ascophyllum nodosum by different extraction methods. The prebiotic activity
was demonstrated by the
in vitro
growth rate of the Lactobacillus delbruecki ssp bulgaricus
strain in growth media supplemented at 0.10, 0.30, and 0.50% (w/v). It was shown that
the activity level depends on the concentration compared to the medium without supple-
ments as a control; it was also shown that there are no significant differences between the
techniques of extraction methods. It is important to note that
in vivo
experiments have
generally been performed on rats, pigs, and mice. Zheng et al. [
100
] reviewed many of
these and reported studies for the three brown algae biopolymers that had shown the
prebiotic effect, especially by the Bacteroides genus, which projects the great potential of
these macroalgae biocomposites for functional foods and drugs.
Polysaccharides from brown algae have attracted particular attention in the biomedical
field due to their unique properties, such as biocompatibility, biodegradability, non-toxic,
non-immunogenic, moisture-retaining, swelling ability, and resembling the structure of the
extracellular matrix. Over the last few decades, polysaccharides have been used in biomedi-
cal treatments, especially for drug delivery systems, wound healing, and tissue engineering
using modern polymer-production technologies, such as 3D-bioprinting or electrospin-
ning [
101
]. Wound healing consists of several overlapping phases that are intended to
restore the anatomical structure and retrieve function of damaged skin. Tissue engineering
aims to regenerate damaged tissue/organs using cells, growth factors, and scaffolds [
102
].
Biopolymers, such as alginate, collagen, and chitosan, are the most used raw material
for scaffold manufacturing due to their good plasticity behavior, drug compatibility, and
biodegradability; however, synthetic biomaterials improve mechanical properties [
103
].
Alginate-based biomaterials have been the most used brown algae biopolymer due to their
superior capacity to form scaffolding materials, including hydrogels, microcapsules, foams,
sponges, and fibers [
104
]. Iglesias-Metujo and García-Gonzalez designed 3D-printing
aerogel scaffolds for bone regeneration in an alginate concentration range of 6–10 wt%
and a CaCl
2
concentration of 0.5 M. In this study, the authors added hydroxyapatite to
preserve the geometry of the strands, while the structural stability and yielding scaffolds
were improved. The alginate–hydroxyapatite scaffolds were highly porous; furthermore,
they were able to attach and proliferate mesenchymal stem cells, in addition to presenting
an enhancement of the fibroblast migration in damaged tissue, which supports the bone
regeneration potential. There currently exists a wide range of commercial wound dressing
products using sodium or calcium alginate in combination with bioactive compounds
for specific applications in biomedicine, such as Algicell
™
, Integra LifeSciences Corp
™
,
Biatain™, Comfeel Plus™, and Nu-derm™, among others [105].
Plants 2023,12, 2445 19 of 26
5. Challenges in Research and Marketing of Products Based on Brown
Algae Polysaccharides
The emphasis on brown macroalgae is reflected in its worth in the global market, which
is stipulated to be USD 16.6 billion in 2020 with a growing rate of 10.8% annually [
106
].
The global market for fucoidan, alginate, and carrageenan were valued at USD 70.0, 728.4,
and 871.7 million, respectively, in 2022, and is expected to continue growing, registering a
compound annual growth rate (CAGR) of 11.8, 5.0, and 5.4%, respectively, over the forecast
period (2022–2030) [107–109].
As explained in the sections above, polysaccharides from brown algae offer important
industrial applications, as well as potential benefits for human health. In fact, the food
industry makes use of approximately 40% of the total seaweed produced annually, with a
value close to 24 million tons, which does not include the macroalgae used as hydrogels and
thickeners in the food processing industry [
52
]. Due to its composition, novel snacks can be
easily produced that complement their nutrimental value with proteins, polysaccharides,
minerals, and lipids from brown macroalgae, which are also labeled as a vegan type of
food [
110
]. The recent interest in the polysaccharides from brown macroalgae has led to
the use of them against several cancer lines, human pathogens, and other microorganisms,
and they have proved to be effective against them. Macroalgal preparations are not
allowed to be used as medicines since
in vivo
validation and application studies are still
lacking to support these extracts in meeting the various global, national, and local medical
regulations [
77
]. In addition to the conditions that prevent the use of polysaccharides from
brown macroalgae as a therapy for diseases is the lack of an efficient drug delivery method
with great adsorption and bioavailability.
Fucoidan is the most studied polysaccharide and has the most properties and benefits
reported in various studies. Some of its more beneficial properties include anticancer; anti-
inflammatory; immunomodulatory effects; protection against neurological diseases, such
as Alzheimer’s; and shielding against bacterial and viral infections. Many other studies
have examined other benefits, such as its form of application from oral to intravenous
and its bioavailability. However, despite several advances, patents, and developments,
currently, the only regulatory approval for the use of fucoidan in the U.S. and Europe is for
supplements and cosmetics [111].
The numerous biological, antimicrobial, and pharmaceutical properties that fucoidan
presents have triggered different strategies for its formulation, release, and application.
Different studies have shown different forms of application of fucoidan, from oral adminis-
tration to inhalable dosage forms and even topical and injectable dosage forms [112].
The oral administration of fucoidan as a powder, tablet, and nanoparticles, which
is possible due to its low solubility and low gastric absorption, is often selected when
administering it as a gastroprotective dietary supplement, an anti-inflammatory, and a
suppressor of oxidative stress to treat gastric ulcers. Fucoidan also has prebiotic effects
due to the production of oligosaccharides derived from the degradation by the flora of the
gastrointestinal tract, which induces the production of beneficial fatty acids [113].
Even though there is no industrial production of items comprising brown algae that
target specific medical applications, there is a wide list of items and patents of products
derived from brown algae that cover important needs. Some of the most important applica-
tions include an already commercialized crop-stimulating agent that induces a protective
response of wheat and durum against a pathogen fungus known as Zymoseptoria tritici.
Several patents have been reported that explain the process to create organic fertilizers,
a flocculant agent, a composite for cosmetic purposes, and a nutritive gel from brown
algae. This demonstrates the undiscovered potential of different compounds from brown
algae [113].
Besides the limitation caused by normativity, there is a disadvantage regarding the use
of the polysaccharides from brown algae: in higher amounts, brown algae has a tendency
to absorb heavy metals during its growing process. The Sargassum sp. are recognized as a
natural biosorbent for pollutants, such as pesticides, mining waste components, oil spills,
Plants 2023,12, 2445 20 of 26
and heavy metals; therefore, it is necessary to remove the contaminants before extracting
the polysaccharides, which makes the use of these biopolymers more expensive [
114
]. For
industrial applications based on the use of a Sargassum biomass, the main challenge to
establish a process for the extraction of biocompounds derived from Sargassum is its the
arrival to the coasts due to the temporality of its season; brown algae is only available during
certain months of the year, typically between April and October, with great variations
in the amounts of macroalgae, which can limit or saturate the harvesting, drying, and
processing. Regulations for its collection should be followed in some regions to avoid
changes in the environmental dynamics and because Sargassum is treated as a protected
natural resource. [115].
Estimating the seasonal arrivals to the impacted regions by monitoring technologies
through remote sensors, such as satellite information, has been reported, but these technolo-
gies present limitations, such as the loss of information on the movement of Sargassum due
to the presence of clouds, which can last for days. An additional limitation includes spatial
resolution, since only small areas are monitored. It should also be borne in mind that the
main complication is that Sargassum is a living organism that interacts and responds to a
highly changing and complex environment, just as sea currents generate variations in the
arrival of Sargassum to different coastlines [116].
Currently, Sargassum is little used compared to the ton that arrive on beaches every
year in several regions along the Atlantic Ocean. Despite all the efforts to explore its
potential applications and to enhance its security, there are still opportunities to engage
leaders from various sectors to promote the use of brown algae to accomplish a common
goal. For example, government entities, industry experts, and researchers could face the
environmental problems derived from Sargassum together. Finally, the extraction of high
value compounds, the limitations of harvesting and storing large quantities of seaweed,
and the processing of Sargassum, as well as planning for occasions when it does not arrive
are all factors that need to be considered [
117
]. Although the macroalgae market already
represents a very high economic volume, its use is based on biopolymers, such as alginates,
laminarin, fucoidan, and other compounds. This shows that the full potential of macroalgae
is not being fully exploited as an integral system of a biorefinery to take advantage of all
the valuable compounds, such as phenolic compounds, pigments, different polymers, or
minerals, nor is biochar produced with the residue of the previous processes.
6. Conclusions
The current stress on the environment to obtain natural resources for food use, bioma-
terials, medicines, and many other applications, has resulted in catastrophic consequences
for the environment and all living beings due to contamination, increased incidence of
diseases, new viruses and pandemics, and many other problems that we may be unaware
of today. Valorizing natural resources that abound in ecosystems, such as macroalgae,
without interfering or causing damage to the ecosystems in which they are found can be
the solution to generate new products, such as food, medicines, and biomaterials with low
environmental impact. Sargassum has presented a great environmental problem due to its
increasing presence on the coasts, causing the death of various aquatic species, along with
serious tourism and human health problems, resulting in great economic losses worldwide.
Therefore, to reverse the negative impact of this brown macroalgae, its application has
been sought in various fields, particularly in the medical field, due to its large number of
biocompounds, consisting mainly of polysaccharides, which have been shown to contain
diverse therapeutic properties to treat cancer and immune system diseases, regulate blood
pressure regulation and cholesterol, and act as probiotics. The extraction methods for
obtaining the polysaccharides, namely, SFE, SCWE, UAE, EAE, and MAE, are considered
green technologies because they make less of an impact on the environment and use of
organic solvents. The yields of bioactive compounds depend on the extraction method
used and the conditions, as well as the environmental conditions, season, temperature,
Plants 2023,12, 2445 21 of 26
and location, causing large variations in compound yields and bioactivities. Therefore, the
products obtained from Sargassum will vary between batches according to these factors.
Food derived from Sargassum is currently on the market due to its high nutritional
value; it is also available as aquafeed and food for pets. In the therapeutic area, even with
many scientific articles and patents demonstrating the bioactivities and different applica-
tions of Sargassum extracts and compounds, such as polymers, more studies are required
to validate the stability of these formulations and their safety for human consumption.
However, many nutraceutical or functional products based on Sargassum and other brown
algae are marketed as alternative medicine for the treatment of certain diseases or ailments.
In the near future, ocean resources may be utilized as sustainable, renewable, and abundant
natural resources that can be exploited as a source of food, medicines, and supplies for the
most essential human needs.
Author Contributions:
E.M.M.-M. and E.A.F.-C.—Conceptualization, revision, and writing of the
manuscript. M.G.-R., A.A.R.-A., J.C.G.-V., E.F.N.-M., R.G.A. and J.E.S.-H.—Manuscript writing.
E.M.M.-M., R.P.-S. and H.M.N.I.—Revision and editing of the manuscript. All authors have read and
agreed to the published version of the manuscript.
Funding:
This work received the financial support of the project GCRFNGR4/1388 “Algae bloom:
waste resource for aquaculture and bioenergy industry in Mexico” and from Tecnologico of Monterrey
with Challenge-Based Research Funding Program 2022, with the project titled “Development of smart
edible coating for the preservation of berries”, ID: I025-IAMSM005-C3-T1-T.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments:
This work was supported by Consejo Nacional de Ciencia y Tecnología (CONA-
CyT) and Tecnológico de Monterrey under Sistema Nacional de Investigadores (SNI) program
awarded to Elda A. Flores-Contreras (CVU: 631205), Rafael Gomes Araújo (CVU: 714118), Elda M.
Melchor-Martínez (CVU: 230784), Roberto Parra-Saldívar (CVU: 35753), and Hafiz M.N. Iqbal (CVU.
735340). Biorender was utilized to develop the figures of this work.
Conflicts of Interest: The authors declare no conflict of interest.
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