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Algal Polysaccharides and Health

  • Ladislava MišurcováEmail author
  • Jana Orsavová
  • Jarmila Vávra Ambrožová
Living reference work entry

Abstract

Freshwater and marine algae cover a wide group of various organisms living in diversified, terrestrial, or water habitats. Various environment conditions are important factors for the formation of many defense mechanisms to survive unfavorable climate leading to a wide scale of chemical compounds created by algae. Many of them show interesting and important biological activities with health benefits, which are the reason of algae being in the focus of scientists worldwide. Generally, algae can be considered as an abundant source of many nutrients, besides the polysaccharides, responsible for their different physicochemical properties with health beneficial effects. Fundamental seaweed polysaccharides with economic impact are presented by alginates, agars, carrageenans, ulvanes, and fucoidans used as a raw material mostly in the food and pharmaceutical industry. From medicinal point of view, especially sulfate polysaccharides are an important source of bioactive natural compounds exhibiting anticoagulant, antithrombotic, antitumor, antimicrobial, antimutagenic, anti-inflammatory, immunomodulatory, and antiviral activities. Thus, significant attention of this chapter has been focused on sulfate polysaccharides derived from algae with anticoagulant activities.

Keywords

Freshwater algae Seaweed Sulfate polysaccharides Anticoagulants Heparin 

1 Introduction

Increasing interest in healthy human food across the world introduces also a rising consumption of algae due to the presence of many bioactive compounds. Algae represent a wide group of very diverse organisms formed by more than thirty thousand of species of microscopic or huge dimensions both freshwater algae and seaweed. According to the scientific classification, algae belong to the domain Bacteria with prokaryotic cells and Eucarya with eukaryotic cells. They are able to colonize different types of habitats from terrestrial types to rivers, lakes, seas, oceans, and hot springs, and they live in all biogeographic areas from tropic to polar areas. Various environment and living conditions of algae are responsible for enormous algal diversity resulting in different dimension, shapes, colors, and heterogeneous chemical composition (Dawczynski et al. 2007; Marsham et al. 2007; Ogbonda et al. 2007). Frequently, general classification according to their pigments as red (Rhodophyta), brown (Phaeophyta), green (Chlorophyta), and blue-green (Cyanophyceae) algae is used. Microalgae cover unicellular green and red algae as well as cyanobacteria (known as blue-green algae) and also diatoms and dinoflagellates. Macroalgae are represented by three groups of brown (Phaeophyceae), red (Rhodophyceae), and green (Chlorophyceae) seaweed.

Different biomes of algae together with many abiotic and biotic factors, such as geographic location, water temperature, light intensity, a level of nutrition in water, algal species, the time of harvest, and stage of life cycle, predominantly determine their different structure and significantly affect the occurrence of miscellaneous compounds in various concentration in algae. The high nutritional value of algae results from the content of proteins with essential amino acids, minerals, essential fatty acids, and vitamins. Many other compounds present in algal biomass possessing health beneficial impacts on human body, such as phenolic compounds, are secondary metabolites evolved as protective agents toward unfavorable environmental conditions (Dawczynski et al. 2007; El Gamal 2010; Marsham et al. 2007; MacArtain et al. 2007; Mišurcová 2011, Mišurcová et al. 2011a, b, 2014).

Among the fundamental compounds, i.e., polyphenols, vitamins, minerals, and proteins, algal polysaccharides have been in the focus of researches due to many important beneficial impacts on human health. Algal polysaccharides are located mostly in algal cell walls as structural compounds. Their structure and composition were found crucial for their activities on signaling pathway regulating defense of algal cells of unicellular organisms or plant tissue of multicellular algae against the environmental surroundings (Jaulneau et al. 2010; Patron and Keeling 2005; Aquino et al. 2011; Rodrigues et al. 2012). Polysaccharides do not participate on the nutritional value of algae. Therefore, algal polysaccharides are considered as a source of dietary fiber resistant to enzymatic hydrolysis of intestinal microflora of human digestive tract (Jiménez-Escrig and Sánchez-Muniz 2000; Warrand 2006; Kim 2011). Polysaccharides of seaweed have been widely investigated for their chemical properties and important biological effects in recent years. Chemical composition of algal polysaccharides is responsible for their different functions. Exceptionality and variety of algal polysaccharides functions are based on the ability to bind sulfate groups to hydroxyl groups of sugar molecules so their biological activities are caused mainly by their diverse composition and the extent of sulfation (Percival 1979 ; Athucorala et al. 2007; Costa et al. 2010; Damonte et al. 1994; De Zoysa et al. 2008). Generally, acidic sulfated polysaccharides, such as alginic acids and carrageenans, are able to reduce cholesterol absorption in the gut due to their production of indigestible ionic colloid and in the case of neutral polysaccharides agars, thanks to their water dispersibility (Jiménez-Escrig and Sánchez-Muniz 2000). Further, algal polysaccharides are in the focus of many researches as they are an important source of bioactive natural compounds with specific biological functions; they show many health benefits provided by their anticoagulant, antioxidant, antiproliferative, antitumoral, anti-inflammatory, and antiviral properties (Mišurcová et al. 2012; Costa et al. 2010). This chapter gives details on the characterization of algal polysaccharides and their physiological function as anticoagulants.

2 Chemical Composition of Algal Polysaccharides

Different phylogenesis of many cyanobacterial and algal species determines various chemical composition and structure of polysaccharides that are extensively studied for their different physiological functions. Polysaccharide composition of algae has been described in many research papers. Common feature evaluated from these investigations is their enormous variability stemming from different algal species; further, cultivation methods of freshwater algae as well as different algal habitats and other environmental conditions affect their growth (Aquino et al. 2011; Rodrigues et al. 2012; Rodrigues and da Silva Bon 2011; Becker 2007; Cheng et al. 2011). Moreover, composition and proportions of algal polysaccharides vary with the morphological phase of algal life stages, and their location in algal cells determines also their functions (Usov 1998). Storage polysaccharides are the main source of energy, while structural polysaccharides have solidifying and protective functions.

2.1 Storage Polysaccharides of Algae

Fundamental energy storage polysaccharides could be divided into three groups according to their synthesis, different structures, and localization in cell bodies. Thus, starch is a storage polysaccharide of green plant including algae, floridean starch is deposited in red algae, and glycogen is a storage polysaccharide of blue-green algae belonging to Cyanobacteria. Storage polysaccharides of freshwater blue-green and green algae are glycogen and starch, respectively. The molecules of both polysaccharides, starch and glycogen, are formed by α-(1,4)-linked glucose units with α-(1,6)-branch points, whereas length and number of branches alter in dependence on the species of organisms (Chao and Bowen 1971). The fundamental difference between starch, floridean starch, and glycogen is their distinct positions in algal cells. While starch synthesis is localized within the plastids because of relocalization of green algal branching enzymes and probably phosphoglucomutase to the plastid, floridean starch and glycogen syntheses are accumulated in the cytosol (Patron and Keeling 2005).

2.1.1 Starch

Further, studies concerning starch structure diversity among the various species of green algae have shown a highly various percentage of amylose. Green algal starch consists of about 70 % of branched polymer amylopectin, the remaining 30 % is a non-branched or slightly branched polymer of amylose. However, differences of starch structure also depend on the established cultivation conditions. Environmental factors, mainly temperature, light, and nutrient content in growth medium, are responsible for the quantitative distribution of amylose. Saturated cultures of three green algae Chlamydomonas reinhardtii, Dunaliella bioculata, and Haematococcus pluvialis grown on acetate and light accumulated starch with a low concentration of up to 5 % of amylose. On the other hand, nutrient-starved cells accumulated significantly a higher amount of amylose, from 15 % to 30 % (Ball and Deschamps 2009). Polymodal distribution of chain lengths within amylopectin molecules allows them to form granules in the matrix consisting of alternating, concentric, amorphous, and semicrystalline lamellae (Myers et al. 2000). Amylopectin synthesized by green plant has highly organized tandem-cluster structure while the bacteria and animals continue to produce random branched glycogen (Nakamura et al. 2005). Further, similar features between starch synthesis in Chlorophyta and glycogen synthesis in bacteria are attributable to the origin of chloroplasts from endosymbiotic cyanobacteria (Viola et al. 2001).

2.1.2 Glycogen

The main storage polysaccharide of blue-green algae is glycogen, and its production is strongly dependent on the conditions of algal cultivation, nitrate concentration, and light intensity. Higher production of glycogen may be caused by nitrate deficiency. Low nitrate concentration favors the accumulation of glycogen; however, it leads to lower biomass production (Aikawa et al. 2012).

2.1.3 Floridean Starch

The main storage polysaccharide of red seaweed is floridean starch. It has a similar structure as starch of green seaweed and plant, however, without amylose. Nevertheless, it was confirmed that some species of red algae form also amylose units (McCracken and Cain 1981). Another difference is the imposition of granules of floridean starch outside the plastids (Shimonaga et al. 2007; Viola et al. 2001). In red algae, isoamylases and starch synthases are plastid-derived enzymes operating in the cytosol where they use uridine diphosphate (UDP) glucose as a glucan donor, resulting in cytosolic starch synthesis. Thus, starch granules in red algae are exclusively synthesized in the cytoplasm (Patron and Keeling 2005; Viola et al. 2001).

2.1.4 Laminaran

The main storage polysaccharide of brown seaweed is laminaran, also called laminarin, and its chemical structure is formed by (1,3)-β-d-glucan with β-(1,6) branching with different reducing endings that can have either mannitol or glucose residues. Laminaran contains also a large amount of neutral sugars with a low concentration of uronic acid, whose proportions vary according to different species (Rioux et al. 2007). The extent of branching predestinates different solubility of laminarans. Highly branched laminaran is soluble in the cold water, whereas a lower degree of branching enables solubility only in the warm water (Jaulneau et al. 2010; Rupérez et al. 2002). As well as previous mentioned storage polysaccharides, also laminaran content varies in dependence on the season, age of population, seaweed species, and geographic location. Seasonal changes of laminaran and mannitol in different species of brown seaweed have also been reported, concerning a different stage of the life cycle (Iwao et al. 2008; Zvyagintseva et al. 2005).

2.2 Structural Polysaccharides of Algae

Structural polysaccharides have the main function to protect algal cells and tissues. Obviously, algal structural polysaccharides are formed as miscellaneous mixtures of heterogenic compounds with sulfated and branched polysaccharides, proteins, and also inorganic ions, such as calcium and potassium.

2.3 Freshwater Algae

The cell wall of blue-green alga Spirulina platensis is formed by four layers marked as LI, LII, LIII, and LIV without cellulose. All layers are very weak except for the layer LII consisting of peptidoglycan that gives the cell wall its rigidity. The LI layer consists of β-(1,2)-glucan, a polysaccharide that is nondigestible by human gastrointestinal tract. LIII is possibly composed of protein fibrils, and the most external membrane layer LIV is composed of material arranged straight, parallel with the trichome axis, and which is considered to be analogous to that one present in the cell wall of gram-negative bacteria (Ciferri 1983; Mišurcová et al. 2012). It was reported that the variable sugar content is in the range of 8–14 % in biomass of Spirulina platensis in dependence on different parts of cell structures (Becker 2007) and also on various species, when in algal biomass of Spirulina maxima a lower amount of 2.0 % of polysaccharides presented by xylose, rhamnose, and glucose was observed. The cell wall contains of 10.0 % of polysaccharides with glucose being the major representative. In external cellular wall layers, there have been established polysaccharides formed by a mixture of six neutral monosaccharides including fucose, rhamnose, xylose, mannose, galactose, and glucose, and finally, two uronic acids have been presented by glucuronic and galacturonic acids (Nie et al. 2002).

The cell walls of the freshwater green algae of Chlorella strains are composed of up to 80 % of polysaccharides including cellulose, and they may be constructed by three different types of structures varying among the miscellaneous strains (Rodrigues and da Silva Bon 2011). The first type of cell structure is formed by a trilaminar outer cell wall layer, the second by a thin outer monolayer, and the third is without an outer layer (Yamada and Sakaguchi 1982).

Trilaminar cell wall consists of algaenan, generally known as non-hydrolyzable macromolecular components, such as glycoproteins and glucosamine-containing biopolymers (Burczyk et al. 1999). The second cell wall type consists of an outer non-trilaminar layer and inner microfibrillar layer, which is probably composed of β-linked polysaccharides, such as cellulose, and of a little amount of pectin. The third type of cell wall consisted of one microfibrillar layer in which a bigger amount of pectin and a small amount of β-linked polysaccharides were established (Yamada and Sakaguchi 1982; Mišurcová et al. 2012). The chemical composition of the cell walls of green freshwater algae would vary depending on algal species and other types of their cell wall structure, but it has been also reported that cultivation conditions have the impact on chemical composition of the cell wall in Chlorella variabilis NC64A; different levels of neutral sugar, uronic acid, and amino sugar in the cell wall have been found when cultured in different nitrogen sources and concentrations (Cheng et al. 2011). Rigid cell walls of Chlorella species contain mannose as a major sugar component, further glucose, and glucosamine. Rhamnose, fucose, arabinose, xylose, mannose, galactose, and glucose have been determined in the wall matrix (Takeda 1996).

2.4 Seaweed

Structural polysaccharides of seaweed cell walls usually consist of an outer amorphous mucilage matrix commonly formed by linear sulfated galactan polymers (carrageenans, agars, and alginates) and of an inner rigid component from cellulose microfibrils (Arad and Levy-Ontman 2010). However, cellulose as a neutral structural polysaccharide is rarely present in the cell walls of red and brown seaweed as a pure β-(1,4) glucan; more frequently the wall contains other sugars than glucose and is also presented in lower levels than in higher plants, in a relatively small amount of 2–10 % in the majority of red algae. Moreover, its amount and configuration of microfibrils differs according to different life stage of algae. Whereas the concholices phase of red algae Porphyra tenera, Bangia atropurpurea, and Bangia fuscopurpurea contains cellulose and minor amount of mannan in their cell walls, the generic phase of the same species contains (1,4)-linked β-d-mannan as the main structural polysaccharide of their cell walls (Gretz et al. 1980; Usov 2001). Further, the cell wall of red seaweed Palmaria palmata contains cellulose in a small amount, and in the genus P. tenera, it has been even replaced by insoluble mannose, galactose, and xylose (Deniaud et al. 2003; Rupérez and Toledano 2003). Galactose and glucose are determined as the main neutral sugars in cell walls of red seaweed Chondrus crispus (Rupérez and Toledano 2003).

The cell walls of red microalgae are without cellulose microfibrils. They are rather encapsulated within the gel matrix from sulfated polysaccharides (Arad and Levy-Ontman 2010). The main part of red and brown seaweed cell walls is represented by sulfated galactans, which are known as agar, alginate, and carrageenan; fucans described as fucoidin, fucoidan, ascophylan, sargassan, and glucuronoxylofucan; and also cellulose. However, their amounts and distribution are variable due to enormous algal diversity and also during different stages of their live cycles (Popper and Tuohy 2010; Percival 1979).

2.4.1 Cellulose

The main structural polysaccharide of some algal species as well as terrestrial plants is cellulose. Its linear molecules are formed by the condensation of d-glucose units through β-(1,4) glycosidic bonds. The hydrogen bonding patterns in cellulose are considered as one of the most important factors on its physical and chemical properties including the solubility, crystallinity, and hydroxyl reactivity. Several different crystalline structures are known in dependence on the location of hydrogen bonds between and within cellulose fibrils. Cellulose I with structures Iα and Iβ is natural and Iα occurs in bacteria and some algae and the latter in higher plants (Nishiyama et al. 2003; Kroon-Batenburg and Kroon 1997). Cellulose obtained from algal species is substantially different from cellulose in higher plant; it has a porous or spongy structure.

2.4.2 Alginate

Alginates without sulfate groups are constituents located in the cell wall and in the matrix of brown seaweeds together with fucans and heteroglycans rich in sulfated l-fucoses. Alginates consist of two chain-forming heteropolysaccharides made up of blocks of β-(1,4)-linked d-mannuronic (M) and α-(1,4)-linked l-guluronic (G) acids, and their structure varies in dependence on the monomer position in the chain, forming either homopolymeric (MM or GG) or heteropolymeric (MG or GM) blocks (Rioux et al. 2007; Miller 1996). The alginate composition is significantly dependent on the algal species, diverse location, various season, as well as different parts of thallus from which the extraction of alginate is made, i.e., the stipe has other mechanical requirements in comparison with the fronds. Thus, a higher content of guluronate has been required in plant parts with higher rigidity. Physical properties of alginates as well as formation of gels depend on the relative proportion of these blocks. The ability of alginates to form gels in the presence of divalent calcium ions is one of their main biofunctional properties and has a great industrial significance (Larsen et al. 2003). The evaluation of the M/G ratio is fundamental for the detection of gel properties. High M/G ratio is the signature of alginate giving elastic gels, while low M/G ratio provides brittle gels (Fenoradosoa et al. 2010).

3 Sulfate Polysaccharides

From a wide scale of different algal polysaccharides, sulfate polysaccharides are the most important from biological activity point of view. They are observed in all groups of algae in contrast to terrestrial plants. Their occurrence in marine algae is connected with a possible correlation with salt stress, and these compounds are also related to mechanical, ionic, and osmotic regulation, helping the survival of algae in the marine environment (Aquino et al. 2011; Rodrigues et al. 2012). The nomenclature of algal sulfated polysaccharides has been often based on the name of algal species, such as spirulan, furcellaran, ulvan, fucan, etc. Generally, sulfated polysaccharides, naturally occurring glycosaminoglycans, are a class of compounds containing hemiester sulfate groups in their sugar residues (Shanmugam and Mody 2000). Red algae produce sulfated galactans consisting entirely of the β-galactose or α-galactose units. The first always belongs to d-series, while the latter is either d-series in carrageenans or l-series in agars (Usov 1998). Sulfated glucans, sulfated galactans, and sulfate arabinogalactans are produced by green algae, and spirulan is known as sulfated polysaccharides of blue-green algae (Aquino et al. 2011; Costa et al. 2010; Shanmugam and Mody 2000).

3.1 Red, Green, and Blue-Green Algae Sulfated Polysaccharides

Sugar presentations of sulfated polysaccharides of some red and green seaweed and of some blue-green algae are shown in Table 1. It is evident that sugar composition as well as the extent of sulfation is very miscellaneous not only across the algal species but also within the same algal strains. While the abundant galactose residues have been established in red seaweeds, rhamnose and glucose residues and uronic acids have been determined in higher amounts in most green seaweeds. Different localities of Ulva conglobata affect the composition of their sulfated polysaccharides, especially in the amount of sulfate (Mao et al. 2006). Apparently, the separation processes are also responsible for the different amounts and distribution of neutral sugar and amounts of sulfate in polysaccharide molecules. Mostly hot or cold water is used for the extraction of sulfate polysaccharides from seaweeds. While in species, i.e., Codium dwarkense, C. tenue, Avrainvillea erecta, cold water extraction has been more effective than hot water extraction on the sulfate amounts, in the second seaweed group presented by Udotea indica and Halimeda gracilis, significant differences in chemical composition of sulfated polysaccharides in hot or cold water extracts have not been observed (Shanmugam et al. 2002).
Table 1

Chemical composition of sulfate polysaccharides of some blue-green algae and some red and green seaweeds

Algal species

Neutral sugar residues (NSR)

Unit of NSR

UA

S

Reference

Rha

Fuc

Xyl

Man

Glu

Gal

(%)

 

Red seaweeds

Schizymenia binderi

  

1.8

 

0.5

49.8

%

4

24.7

Zúniga et al. 2006

Chondrus crispus E

3.6

0

2.8

1.4

5.4

120.7

g/kg

  

Rupérez and Toledano 2003

Porphyra tenera E

4.3

0.5

2.7

1.9

4.8

107

g/kg

  

Rupérez and Toledano 2003

Nothogenia fastigiata H

  

21.5

62.3

 

16.2

mol %

 

17.6

Kolender et al. 1997

Green seaweeds

Ulva conglobata H

71.9

0.82

1.06

3.32

20.77

2.13

mol %

12.6

35.2

Mao et al. 2006

Ulva conglobata H

72.26

1.02

1.98

1.51

22.03

1.2

mol %

14.9

23

Mao et al. 2006

Monostroma latissimum

86.77

 

6.29

 

6.94

 

mol %

3.24

23.6

Mao et al. 2009

Monostroma latissimum

78.65

 

7.83

2.03

11.49

 

mol %

10.8

21.2

Zhang et al. 2008

25.4 kDaW

Monostroma latissimum

85.77

 

5.72

 

7.29

1.22

mol %

12.1

25.5

Zhang et al. 2008

61.9 kDaW

Monostroma latissimum

80.35

 

5.28

1.43

10.07

2.87

mol %

14.6

27.3

Zhang et al. 2008

26 kDaW

Monostroma latissimum

78.28

 

8.6

1.66

10.02

1.44

mol %

13.5

24.3

Zhang et al. 2008

10.6 kDaW

Monostroma nitidum

79.4

 

5.2

 

10.1

5.3

mol %

7.92

28.2

Mao et al. 2008

870 kDaW

Monostroma nitidum

78.2

 

14.7

3.4

3.7

 

mol %

6.76

34.4

Mao et al. 2008

70 kDaW

Codium dwarknese C

     

43.62

mol %

1.79

28.5

Shanmugam et al. 2002

Codium dwarknese H

1.9

  

32.4

7.68

12.23

mol %

3.23

19.5

Shanmugam et al. 2002

Codium tenue C

      

mol %

1.66

31.1

Shanmugam et al. 2002

Codium tenue H

      

mol %

2.91

24.4

Shanmugam et al. 2002

Avrainvillea erecta C

      

mol %

5.6

32.1

Shanmugam et al. 2002

Avrainvillea erecta H

9.68

 

7.56

8.1

66.32

7.94

mol %

7.68

27.9

Shanmugam et al. 2002

Udotea indica C

      

mol %

2.37

12.5

Shanmugam et al. 2002

Udotea indica H

      

mol %

1.43

12.6

Shanmugam et al. 2002

Halimeda gracilis C

      

mol %

7.15

13.5

Shanmugam et al. 2002

Halimeda gracilis H

      

mol %

6.79

14.4

Shanmugam et al. 2002

Blue-green algae

GUA

Arthrospira platensis UF

49.7

 

5.9

0.9

4.3

5.8

%

32.0

 

Majdoub et al. 2009

Spirulina platensis H

1

   

0.16

 

mg/g

18.30

2.35

Abd El Baky et al. 2013

Spirulina platensis Et

    

0.06

0.57

mg/g

2.46

5.02

Abd El Baky et al. 2013

Rha rhamnose, Fuc fucose, Xyl xylose, Man mannose, Glu glucose, Gal galactose, UA uronic acid, GUA guluronic acid, S amount of sulphate

Superscripts mean typ of extraction: W water, H or C hot or cold water, E enzymatic, UF ultrafiltration, Et ethanol

Two main sulfated polysaccharides of red seaweed are agar and carrageenan known as hydrocolloids. They are widely used as texturing agents for many applications in food industry, such as gelling, thickening, and stabilizing agents in different food production and also in many nonfood applications (Lahaye 2001; Sartal et al. 2011). Structural variability of these sulfated galactans occurs among diverse algal species. It is based on different environmental conditions, the season of the collection, and on the extraction methods. Furthermore, various hydroxyl groups may be substituted by sulfate ester, methyl groups, pyruvic acid acetal, or additional monosaccharides. However, the major structural variation is the sulfation pattern (Pomin and Mourão 2008; Usov 1998).

3.1.1 Agar

Generally, agar consists of two major polysaccharides, neutral agarose as a gelling fraction and charged acid agaropectin as a non-gelling fraction. Its molecule is composed of a linear chain of alternating 3-linked β-d-galactopyranosyl and 4-linked of 3,6-anhydro-α-l-galactopyranosyl residues. This backbone may be substituted in varying percentages of half-ester sulfate, methoxyl, or pyruvate groups, and the character of backbone modification may strongly influence gelling properties, i.e., a high content of 3,6-anhydrogalactose and low sulfate content are necessary for a gelling ability (Miller et al. 1993; Usov 1998). Agar is localized in extracellular matrix and is secreted by the Golgi apparatus, and its composition has been documented as very changeable in dependence on the season, seaweed species, different life phases of algae, and also the extraction methods (Praiboon et al. 2006).

3.1.2 Carrageenan

Other sulfated galactan is carrageenan extracted from red seaweed, especially species belonging to the family Gigartinaceae. This galactan consists of linear chains of repeating disaccharide units with alternating 3-linked β-d-galactopyranose (G-units) and 4-linked α-d-galactopyranose (D-units) or 3,6-anhydro-α-d-galactopyranose (DA-units). Furthermore, they usually contain more sulfate than agars in the range of 22–35 % (Jiao et al. 2011; Shanmugam and Mody 2000). Their classification into fifteen different groups, i.e., kappa, iota, lambda, gamma, theta, epsilon, and mu (κ, ι, λ, γ, τ, ε, and μ), is based on the presence and localization of sulfate esters and on the presence of the 3,6-anhydro-d-galactose linked in (1,4) (Shanmugam and Mody 2000; Usov 1998; Lahaye 2001). The main copolymers from industrial point of view are kappa, iota, and lambda carrageenans showing a different ability to form gels with dissimilar characteristics. Thus, κ-carrageenan forms strong rigid gels, ι-carrageenan forms soft elastic gels, and λ-carrageenan does not form any gels but produces the highest viscosities in the water (Sartal et al. 2011). While the main repeating dimer structure of κ-carrageenan is G4S-DA, in ι-carrageenan, it is repeating disaccharide structure of G4S-DA2S, and finally, λ-carrageenan consists of G2S-D2S,6S of dimer structure (De Ruiter and Rudolph 1997; Lahaye 2001). Variations in carrageenan structures occur not only between different species of the Gigartinaceaes but also within the same species in dependence on different life stages.

3.1.3 Furcellaran

Furcellaran, known as Danish agar, is extracted from red seaweed of genus Furcellaria. Besides agar and carrageenan, furcellaran is further anionic sulfated polysaccharide that is considered to be a copolymer of β- and κ-carrageenan. The composition of furcellaran extracted from red seaweed F. lumbricalis consists mainly of 3-linked β-d-galactopyranose, 4-linked 3,6-anhydro-α-d-galactopyranose, and 3-linked β-d-galactopyranose 4-sulphate (Laos and Ring 2005; Laos et al. 2005). Hydroxyl groups in polysaccharide chain may be substituted by sulfate, methyl groups, and other sugar monomers, such as xylose and glucose. Furcellaran can be commercially used as a gelling agent for its ability to form gels in the presence of specific gel-promoting cations, especially K+ and Ca2+ (Laos et al. 2005).

3.1.4 Porphyran

Porphyran as the main polysaccharide of red alga Porphyra umbilicalis has been established by structural analysis. It has been observed that it consists of d- and l-galactose residues in the amount of 24–45 %; 3,6-anhydro-l-galactose has been present in the amount of 5–19 %, 6-o-methyl-d-galactose in the amount of 3–28 %, and ester sulfate in the amount of 6–11 %. Further, the ester sulfate seems to occur always as 1,4-linked l-galactose 6-sulfate, even if its content is variable. 3,6-anhydro-l-galactose and l-galactose 6-sulfate have been interchangeable between the polysaccharides, and d-galactose and 6-o-methyl-d-galactose have been related in a similar way. Moreover, 3,6-anhydro-l-galactose and l-galactose 6-sulfate introduce approximately a half of sugar units, and d-galactose together with 6-o-methyl-d-galactose form the other half of sugar units (Rees and Convay 1962).

3.1.5 Ulvan

The cell wall matrix of green seaweed contains highly sulfated complex of heteropolysaccharides named ulvans whose molecules consist of different sugar residues in dependence on the seaweed strain mainly of the order Ulvales (Ulva and Enteromorpha sp.). Ulvans are water-soluble polysaccharides consisting mainly of rhamnose, xylose residues, iduronic and glucuronic acids, and sulfate groups. These sulfated galactans tend to be more complex and heterogeneous in the structure than sulfated galactans from red seaweed (Jiao et al. 2011). The main ulvan constituents are sulfated rhamnose residues linked to uronic acids resulting in repeated disaccharide unit β-d-glucuronosyl-(1,4)-α-l-rhamnose 3-sulfate, called aldobiouronic acid (Jaulneau et al. 2010; Lahaye et al. 1997). Also other neutral sugars, such as xylose, mannose, galactose, and glucose, participate in different amounts on the composition of sulfated polysaccharides of green seaweed (Mao et al. 2006, 2009; Zhang et al. 2008; Shanmugam et al. 2002).

3.1.6 Spirulan

Calcium spirulan (Ca-SP) and sodium spirulan (Na-SP) are sulfated polysaccharides obtained from hot water extracts of blue-green alga Spirulina platensis. They are composed of rhamnose, 3-o -methylrhamnose (acofriose), 2,3-di-o-methylrhamnose, 3-o-methylxylose, uronic acids, sulfate, and calcium or sodium ions. The backbone consists of 1,3-linked rhamnose and 1,2-linked 3-o-methylrhamnose units with some sulfate substitution at the 4-position; the polymer is terminated at nonreducing end by 2,3-di-o-methylrhamnose and 3-o-methylxylose residues (Yamamoto et al. 2003; Lee et al. 2000). In Ca-SP molecules, there are two types of disaccharide repeating units, o -rhamnosyl-acofriose and o-hexuronosyl-rhamnose (aldobiuronic acid). Component sugar analysis of Ca-SP determines 52.3 of % rhamnose and 32.5 % of 3-o-methyl-6-deoxyhexose, together with 4.4 % of 2,3-di-o-6-deoxyhexose, 4.8 % of 3-o-methylpentose, and trace amounts of other sugars (Lee et al. 1998). Ca-SP has been found as an antiviral agent as well as an anticoagulant with heparin cofactor II-dependent antithrombin activities but also as a potent inducer of tissue-type plasminogen activator (t-PA) production (Lee et al. 1998; Hayakawa et al. 1997). However, Ca-SP has a very low anticoagulant activity in comparison with Na-S, which has been studied for its strong antithrombin activity (Yamamoto et al. 2003).

3.2 Brown Algae Sulfated Polysaccharides

Fucans that include polydisperse molecules based on sulfate l-fucose and also heterofucans called fucoidans are observed in brown seaweeds. The chemical compositions of sulfated polysaccharides of some brown seaweed species are expressed in Table 2. Evidently, fucose is the neutral sugar abundantly presented in sulfate polysaccharides of brown seaweeds, in which different extent of sulfation has been observed. Other sugar residues, such as xylose, mannose, glucose, and galactose, participate on the composition of sulfated polysaccharides of brown seaweeds in different amounts. Galactose and xylose sugar residues occur in higher amounts following the fucose residues, the former especially in species of Laminaria, and in Fucus alternating galactose and xylose residues (Ushakova et al. 2009; Dürig et al. 1997; Rupérez and Toledano 2003). However, in Panina species, xylose has been the second most abundant sugar residue, and even in Sargassum polycystum, Turbinara ornate, and Undaria pinnatifida, galactose has been contained in higher amounts of 13.7 %, 25.6 %, and 6.4 % in relation to fucose which is 20.3 %, 30.3 %, and 7.1 %, respectively (Thuy et al. 2015; Rupérez and Toledano 2003).
Table 2

Chemical composition of sulfated polysaccharides of some brown seaweeds

Brown algal species

Neutral sugar residues (NSR)

Unit of NSR

UA

S

Reference

Rha

Fuc

Xyl

Man

Glu

Gal

(%)

 

Laminaria saccharina IE

 

36.7

1.2

1

2.2

4.6

%

4.8

29.6

Ushakova et al. 2009

Laminaria digitata IE

 

30.1

1.9

1.7

1.4

6.3

%

7

27.5

Ushakova et al. 2009

Laminaria digitata E

2.9

12.1

1.4

2.6

4.8

6.7

g/kg

  

Rupérez and Toledano 2003

Fucus distichus IE

 

40.8

0.8

  

0.8

%

<1

34.8

Ushakova et al. 2009

Fucus serratus IE

 

24.8

2.4

2.1

2

4.8

%

8.2

29.2

Ushakova et al. 2009

Fucus evanescens IE

 

58.7

1.6

  

1.6

%

<1

36.3

Ushakova et al. 2009

Fucus spiralis IE

 

33

2.8

1.4

1.2

3

%

8.2

25.9

Ushakova et al. 2009

Fucus vesiculosus IE

 

26.1

2.4

3.1

2.2

5

%

10.3

23.6

Ushakova et al. 2009

Fucus vesiculosus

 

86.3

   

14

%

 

10.2

Dürig et al. 1997

100 kDaIE

Fucus vesiculosus

 

92.5

   

7.5

%

 

9.13

Dürig et al. 1997

150 kDaIE

Fucus vesiculosus

 

92.3

   

7.7

%

 

10.8

Dürig et al. 1997

100 kDaIE

Fucus vesiculosus

 

92.6

   

7.3

%

 

9.2

Dürig et al. 1997

50 kDaIE

Fucus vesiculosus

 

76.1

9.4

7.6

 

6.9

%

 

7.6

Dürig et al. 1997

100 kDaIE

Fucus vesiculosus Et

 

43.9

4.7

2.7

30

5.6

g/kg

  

Rupérez and Toledano 2003

Ascophyllum nodosum IE

 

26.6

4.4

2.6

1.1

4.7

%

9.4

24.4

Ushakova et al. 2009

Ascophyllum nodosum Et

       

9.3

22.3

Rioux et al. 2007

Chorda filum IE

 

64

0.6

0.5

0.5

1.3

%

 

26.5

Ushakova et al. 2009

Analipus japonicus IE

 

44.1

2.2

  

5.8

%

5.9

22.9

Ushakova et al. 2009

Punctaria plantaginea AqCl

 

44.3

17

tr

tr

2.6

%

2.3

19.2

Bilan et al. 2014

Saccharina longicruris Et

       

8.2

14.2

Rioux et al. 2007

Cladosiphon okamuranus IE

 

30.9

0.7

 

2.2

 

%

23.4

15.1

Ushakova et al. 2009

Padina tetrastromatica W

2

54

18

9

9

9

mol %

14

 

Karmakar et al. 2009

Panina tetrastromatica W

5

59

23

3

tr

10

mol %

9

 

Karmakar et al. 2009

Panina tetrastromatica W

tr

72

25

  

3

mol %

4.5

 

Karmakar et al. 2009

Panina tetrastromatica W

tr

70

24

  

6

mol %

  

Karmakar et al. 2009

Sargassum mcclurei MCW

 

40

6.2

11

10

20

mol %

 

30.5

Thuy et al. 2015

Sargassum polycystum MCW

 

20.3

2.6

1.9

1.1

14

mol %

 

23.4

Thuy et al. 2015

Turbinaria ornata MCW

 

30.3

tr

tr

tr

26

mol %

 

25.6

Thuy et al. 2015

Undaria pinnatifida E

 

7.1

  

tr

6.4

g/kg

  

Rupérez and Toledano 2003

Rha rhamnose, Fuc fucose, Xyl xylose, Man mannose, Glu glucose, Gal galactose, UA uronic acid, GUA guluronic acid, S amount of sulphate

Superscripts mean typ of extraction: IE ion exchange, W water, E enzymatic, Et ethanol, AqCl aqueous calcium chloride, MCW methanol:chloroform:water (4:2:1)

3.2.1 Fucoidans

Cell walls of several orders of brown seaweed, particularly Fucales and Laminariales, consist mainly of fucoidans, which are composed from variable amounts of saccharide units, such as fucose, xylose, glucuronic acid, galactose, and mannose with a different degree of sulfation (Berteau and Mulloy 2003). Their various structures derived from different sugar distribution and diverse sulfate group contents have been described as fucoidin, fucoidan, ascophyllan, sargassan, and glucuronoxylofucan (Percival 1979). Depending on their chemical composition, fucoidans could be further divided into xylofucoglycuronans and glycourunogalactofucans consisting of α-(1,3)-linked sulfated l-fucose as a fundamental subunit and a branch unit of α-d-galactose, d-mannose, d-xylose, and glucuronic acid (Jiménez-Escrig and Sánchez-Muniz 2000; Karmakar et al. 2009; Jiao et al. 2011). Contents, chemical composition, and the structure of fucans are changeable in dependence on different environmental conditions, time of collection, seaweed life stage, and extraction procedures (Silva et al. 2005). Besides, the extent of fucoidan content changes is variable and dependent on the seaweed species. Thus, fucoidans have been classified into two groups derived either from L. saccharina, L. digitata, Analipus japonicus or from Ascophyllum nodosum and Fucus sp.; and their central chains are composed of (1,3)-linked α-l-fucopyranose residues and of (1,3)- and (1,4)-linked α-l-fucopyranose residues, respectively (Jiao et al. 2011; Ushakova et al. 2009).

Different structures of fucoidans have been reported by Silva et al. (2005) who analyzed the chemical composition of heterofucan obtained from brown algae Padina gymnospora. The fraction (18 kDa) of heteroglycans consists of 3- or 4-linked β-d-glucuronic acid with minor amounts of 3- or 4-linked galactose units, where almost 50 % of 3-linked glucuronic acid units are branched at C-2 and the branches of galactoses are at C-6, C-2, or C-3 on disubstituted galactose. The fucose chains are formed by 3- or 4-linked fucose units and minor amounts of 4-linked fucose are branched at C-2 with the chains of xylose and/or fucose. Furthermore, for F. vesiculosus, two possible structures have been determined. In the first case, fucoidan has been presented as a polymer consisting of α-(1,2)-linked fucose with sulfate branches in the position of 4, whereas in the second structure, fucoidan possesses α-(1,3)-linked fucose with sulfate branches in the same position of 4 (Percival and McDowel 1967; Pomin and Mourão 2008). Fucoidan from a commercial source extracted from F. vesiculosus has α-(1,3)-linkages between fucose units, and the ending fucose units have been observed to hold branching with α-(1,2)-linkages or α-(1,4)-linkages (Patankar et al. 1993).

4 Biological Activities of Algal Polysaccharides

Importantly, algae are known as a great source of enormous compounds necessary to protect themselves from the exposure of external environmental factors, such as pollution, mechanical stress, and UV radiation. Both freshwater algae and seaweed have been found as producers of many bioactive compounds. Among these, structurally diverse polysaccharides stimulate human health because of their antimicrobial, antiviral, antimutagenic, anticancer, blood anticoagulant, immunomodulating, and anti-inflammatory activities, as well as hypolipidemic and hypocholesterolemic effects (Ye et al. 2008; Holdt and Kraan 2011; Costa et al. 2010). Polysaccharides have been considered as a dietary fiber from the nutrition point of view. Although dietary fiber does not belong between nutrients, it forms a very important part of diet, and its low intake in some Western countries is one of the reasons leading to the growth of the number of incidence and mortality due to cardiovascular diseases and colorectal cancer. Generally, the main physiological functions of different parts of dietary fiber are based on their solubility or insolubility in water and degradability or fermentability by intestinal microflora that was reported earlier (Mišurcová et al. 2012). Besides, the important algal polysaccharides performing biological activities are sulfated polysaccharides that have been developing as a new generation of nutraceuticals and drugs (Holdt and Kraan 2011; Shi et al. 2007; Blunt et al. 2010; Bouhlal et al. 2010; Kim 2011).

4.1 Anticoagulant Activity

The human blood coagulation system is the process leading to the arrest of bleeding (hemostasis) and includes the transformation of liquid blood into a solid state in order to reduce the loss of blood from injured blood vessels. This process covers three mechanisms such as formation of prothrombinase, conversion of prothrombin into the thrombin which is a key protein of coagulating cascade, where thrombin activates a series of coagulant factors, and, finally, conversion of soluble fibrinogen into insoluble fibrin (Fig. 1).
Fig. 1

The scheme of coagulation cascade

The blood coagulation system consists of cellular elements (blood platelets, white cells, to some extent red cells, and microvascular remnants or microparticles), coagulation enzymes, proteins cofactors, and a number of anticoagulant proteins (Spronk et al. 2003). The mechanism of blood coagulation is based on the enzyme cascade divided in the intrinsic, extrinsic, and common pathway, where a series of coagulation factors promote the formation of the end product fibrin (Spronk et al. 2003; Wijesekara et al. 2011). As it can be concluded from Fig. 1, during the intrinsic pathway activated Stuart-Prower factor (X) can also be activated by the extrinsic pathway. Firstly, the intrinsic cascade begins with the formation of primary complex of collagen by high molecular weight kininogen (HMWK), prekallikrein, and Hageman factor (XII). During the activation, the single-chain protein of the native Hageman factor is divided into two chains of different molecular weights (28 and 58 kDa). However, both chains remain linked by a disulfide bond. The 28 kDa light chain contains the active site, and this molecule is called as activated Hageman factor (XIIa), which can activate plasma thromboplastin antecedent (PTA) or antihemophilic factor – C (XI). Further, HMWK, known as Fitzgerald factor, binds to the factor XI, and in the presence of Ca2+ ions, it facilitates the activation process of factor XIa. This factor XIa activates Christmas factor, plasma thromboplastin component (PTC), or antihemophilic B factor (factor IX) in the reaction requiring Ca2+ ions, factor VIII, and phospholipids. Antihemophilic factor VIII is obviously an essential factor for this step of coagulation cascade, and its deficiency is associated with hemophilia A, while the deficiency of factor IX is connected with hemophilia B (Adelson et al. 1963). Activated IXa factor further activates Stuart-Prower factor (X) to factor Xa; and factor X is the first molecule of the common pathway of coagulation cascade. The extrinsic pathway could be considered as an alternative way of the activation of factor X in the cooperation with two main components – tissue factor (TF) and factor VII. Blood coagulation factor VII, formerly known as proconvertin, belongs to the serine protease enzyme class, and its main role in extrinsic pathway is to initiate the coagulation process in conjunction with TF.

TF is constitutively present on cell membranes within and around the vessels and serves as the cell surface receptor for serine protease factor VIIa. Carboxylated GLA domain of factor VIIa binds to negatively charged phospholipids in the presence of calcium. Binding of VIIa to negatively charged phospholipids greatly enhances the protein-protein binding of VIIa to TF. Upon a vessel injury, tissue factor, normally found outside of blood vessels, is exposed to the blood where it forms a catalytic complex with factor VIIa activating factor IX and catalyzing the conversion of inactive protease factor X into active protease factor Xa (Spronk et al. 2003; Mirzaahmadi et al. 2011).

Both intrinsic and extrinsic pathways lead to the activation of factor X into factor Xa (the common pathway) which combines with its cofactor – activated proaccelerin (factor Va) – in the presence of calcium and phospholipid to produce thrombin for the conversion of fibrinogen to fibrin. Fibrin monomers spontaneously polymerize and form an insoluble gel (clots) which is held together by noncovalent and electrostatic forces and is stabilized by fibrin-stabilizing factor XIII catalyzing the formation of peptide bonds between fibrin monomers. Clots together with aggregated platelets (thrombi) block damaged blood vessel and prevent further bleeding (Chatterjee et al. 2010).

Hemostatic abnormalities can lead to serious health problems, such as excessive bleeding or thrombosis. Thus, the human coagulation mechanism has to be strictly regulated by the inactivation of procoagulant enzymes, fibrinolysis, and hepatic clearance of activated clotting factors (Kalafatis et al. 1997) via tissue pathway inhibitor (TFPI), heparin-antithrombin pathway, and protein C pathway (Esmon 2005). The first inhibitor process TFPI inactivates factor VIIa bound to tissue factor (TF). The second antithrombin (ATIII)-heparin mechanism inactivates factor Xa, thrombin, factor IXa, and factor VIIa bound to cell surface tissue factor (Rao et al. 1995). The latter protein C pathway is based on the activation of protein C by the thrombin-thrombomodulin complex on endothelium. This natural anticoagulant system exerts its anticoagulant effect by regulating an activity of factors VIIIa and Va, cofactors in tenase, and prothrombinase complexes, respectively (Dahlbäck and Villoutreix 2005; Esmon 2003).

Heparin, a highly sulfated glycosaminoglycan, is naturally produced by basophils and mast cells; in medicine it is principally used as an anticoagulant to treat and prevent blood clots in the veins and arteries. Heparin molecule possesses a specific local structure, and it is composed of pentasaccharide sequence with a specific pattern of sugar residues along with a sulfation pattern required to induce a conformational activation of antithrombin. Heparin has also an additional anticoagulant mechanism in which polysaccharide brings antithrombin and thrombin in a ternary complex in which both the inhibitor and proteinase are bound to the same polysaccharide chain (Pereira et al. 2002; Streusand et al. 1995). The heparin usage is limited due to several side effects, i.e., a serious side effect resulting in degradation of platelets causing thrombocytopenia (Bick and Frenkel 1999; Castelli et al. 2007).

4.2 Anticoagulant Activity of Algae

Therefore, the requirement of finding alternative sources of anticoagulants has arisen. Heparin-like substances extracted from seaweed have been greatly studied in vitro as potential blood anticoagulants. So far, about 150 species across three major divisions of marine red (Rhodophyta), brown (Phaeophyta), and green (Chlorophyta) algae have been reported to have blood anticoagulant activities. Examples of anticoagulant activities of some algal species across three major divisions of green, red, and brown seaweed as well as blue-green algae are shown in Table 3.
Table 3

Anticoagulant activity of some species of brown, red, and green seaweeds and blue- green freshwater algae

Algae

 

Polysaccharide

Reference

Brown

Spatoglossum schroederi

Sulfated galactofucan

Rocha et al. 2005

Ecklonia cava

Sulfated polysaccharide

Wijesinghe et al. 2011

Ascophyllum nodosum

Fucoidan

Chevolot et al. 2001

Fucus vesiculosus

Fucoidan

Dürig et al. 1997

Fucus vesiculosus

Fucan

Bernardi and Springer 1962

Dictyota cervicornis

Sulfated polysaccharide

Costa et al. 2010

Dictyopteris delicatula

Sulfated polysaccharide

Costa et al. 2010

Dictyota mertensis

Sulfated polysaccharide

Costa et al. 2010

Laminaria saccharina

Fucoidan

Ushakova et al. 2009

Laminaria digitata

Fucoidan

Ushakova et al. 2009

Fucus distichus

Fucoidan

Ushakova et al. 2009

Fucus serratus

Fucoidan

Ushakova et al. 2009

Fucus evanescens

Fucoidan

Ushakova et al. 2009

Fucus spiralis

Fucoidan

Ushakova et al. 2009

Lessonia vadosa

Fucoidan

Chandía and Matsuhiro 2008

Sargassum vulgare

Fucan

Dore et al. 2013

Red

Porphyra haitanensis

Porphyran

Zhang et al. 2010

Schizymenia binderi

Sulfated galactan

Zúniga et al. 2006

Botryocladia occidentalis

Sulfated galactan

Farias et al. 2000

Gelidium crinale

Sulfated galactan

Pereira et al. 2005

Corallina

Sulfated galactan

Sebaaly et al. 2014

Corallina

Carrageenan

Sebaaly et al. 2014

Lomentaria catenata

Sulfated galactan

Pushpamali et al. 2008

Gigartina skottsbergii

Carrageenan

Carlucci et al. 1997

Grateloupia indica

Sulfated galactan

Sen et al. 1994

Stenogramme interrupta

Carrageenan

Cáceres et al. 2000

Nothogenia fastigiata

Xylomannan

Kolender et al. 1997

Green

Codium dwarkense

Sulfated polysaccharide

Shanmugam et al. 2002

Codium indicum

Sulfated polysaccharide

Shanmugam et al. 2002

Caulerpa prolifera

Sulfated polysaccharide

Costa et al. 2010

Caulerpa sertularioides

Sulfated polysaccharide

Costa et al. 2010

Codium isthmocladum

Sulfated polysaccharide

Costa et al. 2010

Caulerpa cupressoides

Sulfated polysaccharide

Rodrigues et al. 2011

Ulva conglobata

Sulfated polysaccharide – rhamnose

Mao et al. 2006

Monostroma nitidum

Sulphated polysaccharide – rhamnose

Mao et al. 2008

Monostroma latissimum

Sulfated polysaccharide – rhamnose

Mao et al. 2009

Enteromorpha clathrata

Sulfated polysaccharide

Qi et al. 2012

Enteromorpha linza

Sulfated polysaccharide – rhamnose

Wang et al. 2013

Blue-green

Spirulina platensis

Sulfated polysaccharide

Abd El Baky et al. 2013

Arthrospira platensis

Sulfated polysaccharide – rhamnose

Majdoub et al. 2009

Spirulina platensis

Calcium spirulan – sulfated polysaccharide

Hayakawa et al. 2003

Generally, anticoagulant activity of sulfated polysaccharides has been usually measured by different in vitro method, such as activated partial thromboplastin time (APTT), prothrombin (PT), and thrombin (TT) times. The first assay indicates the precise anticoagulant potency of analyzed polysaccharides, and it is expressed as international units (IU) per mg of polysaccharide using the non-fractionated heparin (HEP, 193 IU/mg). The latter assays (PT, TT) have been performed by using normal human plasma in which algal polysaccharide extract is added and clotting time is recorded after the clotting induction by addition of thrombo reagent (Rodrigues et al. 2011; Padmanaban et al. 2013; Mao et al. 2008). The mechanism of anticoagulant activities of algal sulfated polysaccharides in the clotting cascade could be identified by all assays, APTT, PT, and TT as well. APTT assay could identify the mechanism of anticoagulant activities of algal sulfated polysaccharides in the intrinsic pathway of clotting cascade by inhibiting factors XII, XI, X, IX, VIII, and prothrombin; the PT assay could identify the mechanism of ulvans, fucans, and galactans in extrinsic pathway by inhibiting factors X, V, and prothrombin; and TT assay could be helpful to investigate the effect of sulfated polysaccharides on thrombin-accelerated clot formation in platelet poor plasma (Padmanaban et al. 2013; Mao et al. 2008). Anticoagulant activity of algal polysaccharides varies depending on their chemical composition and particularly on different contents and positions of sulfate radicals, molecular weight, and sugar position. Moreover, the influence of the extractive methods used for the isolation of algal polysaccharides on anticoagulant activity has been confirmed. Leite et al. (1998) investigated the anticoagulant activity of acidic polysaccharide extracts from brown alga Spatoglossum schröederi. Polysaccharide extracts were obtained by ion-exchange chromatography using different salt molarities (0.15–3.0 M NaCl) and lower concentrations from the range of 0.5–0.7 and 1.0–1.5 M of salt resulting in higher content of alginic acid and xylose in obtained extract, respectively, while the extracts enriched with sulfated xylofucan were obtained with using higher concentrations (2.5–3.0 M) of salt. Anticoagulant activities of all polysaccharide fractions were low (0–22.4 IU/mg) in comparison with heparin activity of 150.0 IU/mg. However, all acidic polysaccharide fractions showed the ability to stimulate the synthesis of antithrombotic heparin sulfate produced by the rabbit aorta endothelial cells in culture to the same amount of heparin Leite et al. (1998). Neutral polysaccharides are usually extracted with cold or hot water, due to low or very high molecular weight, respectively. Higher anticoagulant activity of green algae Codium spp. and Udotea spp. has been reported in the fraction obtained by cold or hot water extraction, respectively (Shanmugam and Mody 2000). Finally, it has been also reported that polysaccharides isolated by proteolytic digestion from green seaweed Caulerpa cupressoides have a low anticoagulant potential in relation with polysaccharide extract obtained by ion-exchange chromatography (Rodrigues et al. 2011). Further, the strength of anticoagulant activity is also influenced by algal genus. Generally, sulfated polysaccharide extracts of brown seaweeds exhibit higher anticoagulant activity than red and green algae extracts. However, in comparative analysis, it has been observed that red seaweed Gelidium contained higher content of total saccharides and total sulfate content than brown seaweed Sargassum and green seaweed Ulva, and their anticoagulant activities are in correlation with sugar and sulfate contents. So, the extract from red seaweed Gelidium exhibits the highest anticoagulant activity, followed by the extract from brown seaweed Sargassum, while the extract from green seaweed Ulva has showed the lowest anticoagulant activity (Padmanaban et al. 2013).

4.2.1 Blue-Green Algae

Calcium spirulan (Ca-SP) is sulfated polysaccharide extracted from blue-green alga Spirulina platensis. It has been reported that Ca-SP exhibits anticoagulant activity by potential inhibition of thrombin mediated by heparin cofactor II (HCII), however, in a different mechanism from that of heparin (Hayakawa et al. 2003). Heparin cofactor II is a plasma serine protease inhibitor which selectively inhibits thrombin. Its ability to inhibit α-thrombin is accelerated by a variety of sulfated polysaccharides in addition to heparin and dermatan sulfate. The mechanism of activation of HCII is based on the fact that binding of either heparin or dermatan sulfate to HCII displaces the N-terminal acidic domain of the inhibitor, which normally occupies the glycosaminoglycan-binding site. Then, N-terminal acidic domain binds to anion-binding exosite I of thrombin, facilitating proteolytic attack on the reactive site of peptide bond of HCII resulting in a significant decrease of the rate of α-thrombin inhibition in the presence of either heparin or dermatan sulfate. Hayakawa et al. (2000) has suggested that the stimulatory effect of Ca-SP is not mediated through N-terminal acidic domain of HCII, but the anion-binding exosite I of α-thrombin is essential for the rapid inhibition of the reaction by HCII in the presence of Ca-SP. The allosteric activation of HCII by Ca-SP has been observed through Arg103 – Leu mutant bound to Ca-SP-Toyopearl with the normal affinity and inhibited α-thrombin in a manner similar to native rHCII.

Moreover, sodium spirulan (Na-SP) isolated from blue-green alga S. platensis has been observed as a strong anticoagulant agent in the blood coagulation-fibrinolytic system. Not only because it activates heparin cofactor II, physiologic inhibitor of thrombin, but it also exhibits fibrinolytic property through varying effects on the endothelial fibrinolytic protein secretion, where it stimulates the release of anticoagulant heparan and dermatan sulfate proteoglycans from the vascular endothelial cell layers (Yamamoto et al. 2003).

4.2.2 Green Algae

The mechanism of anticoagulant activity of green algal sulfated polysaccharides has been assigned to common pathway, primarily heparin cofactor II (HCII)-mediated anticoagulant action (Shanmugam and Mody 2000). According to Wijesekara et al. (2011), sulfated arabinan and sulfated arabinogalactan extracted from two green algae species Codium dwarkense and C. tomentosum have been the most active coagulants; the former shows higher coagulant activity, while the latter is relatively less active. Further, it has been reported that the coagulant activity is directly proportional to sugar and sulfate contents of proteoglycan and inversely proportional to protein content of proteoglycans. Thus, proteoglycans with 18.4 % content of sulfate show the greatest anticoagulant activity, followed by sulfated polysaccharides with the content of 10.2 % and 7.5 % of sulfate (Wijesekara et al. 2011). Further, highly sulfated galactan (13.1 % of sulfate) containing mainly galactose with a small amount of glucose from green algae C. cylindricum has been found as an anticoagulant with the similar activity compared with heparin, but weaker than heparin (Matsubara et al. 2001). Anticoagulant activity of sulfated polysaccharides isolated from green seaweed Monostroma nitidum has also been described. Among two sulfated polysaccharides of M. nitidum with different structure of their molecules, different extent of anticoagulant activities has been evaluated. Evidently, both polysaccharide fractions exhibit high anticoagulant activities; however, differences between them are directly due to their structural feature discrepancy, and sulfated polysaccharide with a lower molecular size and higher sulfate content show notably higher anticoagulant activity (Mao et al. 2008). Further, sulfated polysaccharide composed mainly of (1,2)-linked l-rhamnose residues with sulfate groups substituted at positions C-3 and/or C-4 isolated from marine green algae M. latissimum show high anticoagulant activities proved by APTT and TT assays. Anticoagulant property of this sulfate polysaccharide has been mainly attributed to powerful potentiation of thrombin by HP II (Mao et al. 2009). The influence of different concentrations of extraction solutions (0.50, 0.75, and 1.00 M NaCl) used for the elution of sulfated polysaccharides of three species – Caulerpa cupresoides, C. racemosa, and C. prolifera – has been confirmed. Dissimilarity in the presence of sulfate groups in chemical structures of their sulfated polysaccharides obtained by ion-exchange chromatography has been observed. Lower content of sulfate groups has been established in C. cupressoides, followed by C. racemosa, and higher content has been determined in C. prolifera which is in accordance with the extent of their anticoagulant activities of 17.37, 22.17, and 25.64 IU/mg, respectively, in comparison with heparin activity of 193 IU/mg (Rodrigues et al. 2012). Green seaweed Ulva conglobata collected from three various locations in China (coasts of Quigdao, Yantai, and Rizhao) exhibited different polysaccharide compositions with major representation of rhamnose 71.90, 72.26, and 63.77 mol%, respectively; variable contents of glucose and fucose; and trace amounts of xylose, galactose, and mannose. Their sulfate ester contents were 35.20 %, 23.04 %, and 28.06 %, respectively. The highest anticoagulant activity was established in hot water extract from U. conglobata collected from the coast of Quigdao in comparison with extracts from the other locations. Polysaccharide extract from the coast of Rizhao possessed higher content of sulfated ester and lower content of rhamnose than extract from the coast of Yantai, the former showing lower anticoagulant activity than the latter (Mao et al. 2006). The extent of anticoagulant activity of algal polysaccharides varied in dependence on different sugar residues and their proportion, as well as on sulfation content and structural features.

4.2.3 Red Seaweed

Anticoagulant activity has been studied in over 40 species of red algae. Generally, the mechanism of anticoagulant activity of galactan sulfate of red seaweed could be realized through the inhibition of thrombin and could be either directly, even though the mechanism has been still unknown, or indirectly via HCII. Anticoagulant activity of sulfated galactans depends on the nature of sugar residue, sulfate content, and the position sulfate groups. Furthermore, carrageenans with high molecular weight and high sulfate content have shown higher anticoagulant activity than low molecular weight and low sulfate content (Wijesekara et al. 2011).

The mechanism of anticoagulant activity of carrageenans and other sulfated galactans is exhibited via thrombin inhibition. Carrageenans appear to inhibit amidolysis of thrombin directly and via ATIII; however, only ATIII potentiated Xa amidolysis has been observed (Shanmugam and Mody 2000). Anticoagulant properties of three types, κ-, ι-, and λ-carrageenans with different sulfate amounts of 17.89 %, 27.20 %, and 33.38 %, respectively, were established by APTT and PT assays and compared with unfractionated heparin from bovine lung. The compounds may act only on intrinsic pathways of the blood coagulation system, not on extrinsic pathways which could be confirmed by very low results of PT assay in the case of κ- and ι-carrageenans. Only λ-carrageenan showed similar anticoagulant activity of 120 s at 20 μg, as heparin did. All types of analyzed carrageenans had very low anticoagulant activity when compared to heparin by APTT assay. While κ- and ι-carrageenans exhibited the anticoagulant activity of 132.2 and 240 s at the concentration of 100 μg, λ-carrageenans displayed elevated anticoagulant activity of 240 s at 20 μg, and heparin showed the anticoagulant activity of 250 s at 2.5 μg (Silva et al. 2010).

Moreover, the strength of anticoagulant activity between different types of carrageenans appeared to be due to various amounts of sulfate content. λ-carrageenan showed greater antithrombotic activity than κ-carrageenan, although it also showed higher toxicity which is dependent on the molecular weight (Shanmugam and Mody 2000).

The extent of anticoagulant activity of carrageenans seemed to be influenced also by a different composition of polysaccharides extracted from red seaweed in various stages of their life cycle. Anticoagulant activity of carrageenans of λ-type and the mixture of κ-/ι-type extracted from cystocarpic (reproductive) and sterile plants of Chondrus pinnulatus harvested on the Russian Pacific coast had extremely high values exceeding 600 s established by APTT assay in contrary to that from sterile plants. Since molecular weights of cystocarpic plant carrageenans were almost twice higher (420 and 389 kDa) than molecular weights of carrageenans from sterile plants (290 and 220 kDa), high anticoagulant activity may be caused by high molecular weight of this polysaccharide (Yermak et al. 2006).

Sulfated galactans and carrageenan were extracted from red algae Corallina collected at the Lebanese coast in the yields of 2.5 % and 10 %, and their anticoagulant activities were determined by ATPP assay. Carrageenans exhibited more powerful anticoagulant activity from 78.4 to 120 s at doses of 0.05 and 0.5 μg, respectively, than sulfated galactans that reached 104.3 s at their highest dose of 5 μg, but only λ-carrageenan was used for analyses (Sebaaly et al. 2014).

Further, it was reported that 2,3-di-o-sulfated d-galactan from red seaweed Botryocladia occidentalis exhibited anticoagulant activity comparable to heparin, which appeared to be due to the inhibition of thrombin and factor X. Furthermore, 2,3-di-o-sulfated galactose has an amplifying effect on the anticoagulant activity of sulfated galactans. From the three fractions with sulfate contents of 0.69 %, 1.47 %, and 2.08 % eluted by using different concentrations of NaCl 1.0, 2.2, and 3.0 M, respectively, the fraction with the sulfate content of 1.47 % showed the highest anticoagulant activity of 150 IU/mg by APTT assay, while the fraction with the highest sulfate content showed a lower anticoagulation effect of 130 IU/mg and the fraction with the lowest sulfate content showed even no effect. Finally, desulfation had the abolish effect on the anticoagulant activity of the sulfated galactans (Farias et al. 2000). The proportion and/or distribution of 2,3-di-sulfated galactose along the polysaccharide chain modulated the interaction of polysaccharides with specific proteases in the coagulation system. It was reported that 2,3-di-sulfated galactose obtained from B. occidentalis inhibited intrinsic tenase and prothrombinase complexes crucial for factor Xa and thrombin generation, respectively (Jiao et al. 2011). Porphyran derivate obtained from red seaweed Porphyra haitanensis with fully sulfated modification showed the highest anticoagulant activities by APTT, TT, and PT assays 396.47 s, 311.70 s, and 298.03 s, respectively, in a dose of 100 μg/ml. Besides the degree of sulfation, distribution of sulfated group was also an important factor influencing the anticoagulant activity of porphyran, which has a linear backbone of alternating 3-linked β-d-galactosyl units and 4-linked α-l-galactosyl 6-sulfate or 3,6-anhydro-α-l-galactosyl units. In the case of alkali treatment of porphyran, 6-o-desulphatation in (1,4)-linked residue was carried out, nevertheless almost without any change of anticoagulant activity. Moreover, 6-o-sulfated derivate showed a lower anticoagulant effect than 2,2′,4-o-sulfated derivate. From these results, it could be concluded that sulfate groups at C-6 were not necessary for the anticoagulant activity, whereas an increase in the overall molecular weight and position of sulfate groups at C-2, C-3, and C-4 was a dominant factor for the anticoagulant effect of porphyran (Zhang et al. 2010).

4.2.4 Brown Seaweed

Anticoagulant activity of fucoidans, like heparin, is based on the inhibition of thrombin activity by influencing directly the enzyme or through the activation of thrombin inhibitors, including antithrombin III (ATIII) and heparin cofactor II (HCII). Some fucoidans activate only antithrombin, whereas others interact with both inhibitors (Cumashi et al. 2007). Almost all fucoidans exhibit anticoagulant activity that may be related to the content and position of the sulfate group, molecular weight, and sugar position (Berteau and Mulloy 2003).

It has been documented that fucans with high sulfate and low uronic acid content show higher anticoagulant activity than those with high uronic acid and low sulfate content (Wijesinghe and Jeon 2012; Cumashi et al. 2007; Shanmugam and Mody 2000). It has been reported that anticoagulant activity of the fucoidans does not depend on the content of neutral sugar residues in their molecules or on the structure of the main chain. However, the degree of sulfation of their molecules has been reported as an important factor to affect their anticoagulant activities (Ushakova et al. 2009). Thus, it has been documented that higher content of sulfate groups is related to higher anticoagulant activity in native fucoidans (e.g., Hizikia fusiformis, Ecklonia kurome), and furthermore, the position of the sulfate groups on sugar residues is a very important factor of influence on the anticoagulant activity of fucoidans, relating to the concentration especially of C-2 sulfate and C-2,3 disulfate (Li et al. 2008). The structural analysis has established that a central core of fucan obtained from brown algae Padina gymnospora is composed of 3- or 4-linked β-d-glucuronic acid with minor amounts of 3- or 4-linked galactose units. High content of nonreducing fucose and xylopyranose terminal residues indicates that these heteroglycans are highly branched polymers. Subsequent desulfation of this heteroglycans fraction obtained by solvolysis in dimethyl sulfoxide caused the reduction of the sulfate groups by about 76 % due to the removal of 3,4-disubstituted fucosyl residues mostly sulfated at C-3, resulting in an abolishment of its anticoagulant activity. Thus, the presence of (1,4)-linked 3-o-sulfated fucose could be related to higher anticoagulant activity (Silva et al. 2005). Moreover, sulfated fucan obtained from brown seaweed Laminaria brasiliensis shows a strong anticoagulant activity of 30.0 IU/mg; however, desulfation of this fucan totally abolishes its anticoagulant activity (Pereira et al. 1999). According to Ushakova et al. (2009), fucoidans originated from brown seaweeds L. saccharina, L. digitata, and Fucus distichus contained the highest amount of sulfate in the range of 27.5–34.8 % and the lowest amount of uronic acid and showed the highest anticoagulant activity by APTT assay in the amounts of 33.0, 24.2, and 26.9 U/mg, respectively, and by PT assay in the amounts of 40.8, 33.2, and 33.0 s, respectively; and, finally, anticoagulant activities performed by TT assay were in the amounts of 72.8, 36.0, and 29.0 s, respectively. In accordance with the previous author, in brown seaweeds, L. saccharina, L. digitata, and F. distichus have been established as the highest anticoagulant activities of 33.0, 24.2, and 26.9 U/mg, respectively. In other brown seaweeds, such as F. serratus, F. evanescens, F. spiralis, and Ascophyllum nodosum, lower anticoagulant activities have been determined in the amounts of 19.1, 15.1, 16.6, and 13.4 U/mg, respectively. On the other hand, sulfated polysaccharide of Cladosiphon okamuranus with the highest content of 23.4 % of uronic acids and the lowest content of sulfate groups of 15.1 % has showed almost no anticoagulant effect (Cumashi et al. 2007). Analyses of anticoagulant activities of fucoidans have demonstrated that native fucoidans interact with ATIII like heparin and promoted thrombin activation followed by the formation of a complex with thrombin and ATIII. However, in contrast to heparin, they may directly inhibit thrombin (Ushakova et al. 2009). Molecular weight is also important for the anticoagulant activity of fucoidans because of long enough sugar chain, and suitable conformation is needed to bind thrombin. A slight decrease in molecular weight of sulfated fucan dramatically reduces its effect on thrombin inactivation mediated by HCII. Although sulfated fucan with 45 tetrasaccharide repeating units could bind to HCII, it is unable to link efficiently the plasma inhibitor and thrombin because for this action chains with 100 or more tetrasaccharide repeating units are necessary. The template mechanism may predominate over the allosteric effect in the case of linear sulfated fucan inactivation of thrombin heparin cofactor II being present. Linear sulfated fucan requires significantly longer chains than mammalian glycosaminoglycans to achieve the anticoagulant activity (Li et al. 2008; Pomin et al. 2005). Molecular size of the most active fucoidans has been approximately between 50 and 100.000 daltons, whereas fractions with higher molecular weight have exceeded 850.000 Da inclined to lower the anticoagulant activity (Shanmugam and Mody 2000).

Anticoagulant activity of 75 % fucoidan from U. pinnatifida consisted of 24.7 % fucose, 20.35 % galactose, no mannose, 29.07 % sulfate, 2.19 % protein, and 7 % bond ions evaluated by APTT, TT, PT, and ATIII assays. It was established that this fucoidan exhibited a very strong hemostasis effect. It prolonged APTT time from 38.8 s for control to 172.5 s at 63 mg/l; TT time was also prolonged at a higher rate in which it was 15.2 s at baseline and went up to 240.1 s at 15.6 mg/l. Further, ATIII decreased with the fucoidan treatment from 108 % for control to 89 % at 10 000 mg/l; and finally, low concentration of fucoidan had no effect on PT until the concentration of 125 mg/l of PT when it began to increase (Irhimeh et al. 2009). Also crude polysaccharide fraction of brown seaweed Sargassum horneri consisted of 97 % of polysaccharide and 2 % of protein showed a strong anticoagulant effect exceeding 300 s by APTT assay, whereas anticoagulant active compounds were mainly concentrated in the fraction with molecular weight higher than 30 kDa (Athucorala et al. 2007). Brown seaweed Dictyopteris polypodioides growing on the Lebanese coast was collected in two different seasons in May and July. It was rich in polysaccharides whose main component was alginic acid (11 %) as well as water-soluble polysaccharides, such as fucoidan, laminaran, and mannuronan, whose amounts differed depending on the season between 3.75 % in May and 5.8 % in July. The anticoagulant activities were established in different fractions of polysaccharides composed from fucose and laminaran residues (FL), mixture of fucose, laminaran and mannuronan (FLM), and mannuronan (M). The highest anticoagulant activities of 42.5, 43.1, and 42.1 s by APTT assay in the application doses of 2.5 μg of different fractions FL, FLM, and M were determined, respectively (Karaki et al. 2013).

Laminaran is known as a storage polysaccharide of brown seaweed, and it does not naturally contain sulfate groups. However, laminarin sulfate obtained by sulfation could possess 0.6–2.2 sulfate groups per glucose unit, and its molecule consists of o-sulfated β-(1,3)-linked glucose residues. It has been observed that laminarin sulfate with about two sulfate units per glucose exhibits the maximum anticoagulant activity of about 30–40 % of the anticoagulant activity of heparin, and it is therapeutically effective in the prevention and treatment of cerebrovascular diseases (Miao et al. 1995; Adams and Thorpe 1957).

It has been also observed that the degree of sulfation influences the anticoagulant activity of sulfated laminarin, i.e., derivate with 2.31 degree of sulfation is less anticoagulant (26.2 USP-U/mg and 3.1 U/mg by APTT and TT assays, respectively) than derivate of laminarin with a degree of sulfation of 1.98 that shows the highest anticoagulant activity of 36.2 USP-U/mg and 14 U/mg by APTT and TT assays, respectively, while laminarin derivates with 0.3 and 0.64 degree of sulfation exhibits no effect (Hoffmann et al. 1995).

Sulfated β-aminoethyl ether derivates of laminaran, (1,3)-linked glucan of L. digitata containing both o-sulfated and n-sulfated groups have been found to show anticoagulant activity rather than isolated o-sulfated groups. Further, partially oxidized laminaran with a sulfate content of 15.9 % gave the activity of 26 IU/mg in APTT test, while partially reduced sulfated alginic acid with the maximum of sulfate of 13.4 % and the lowest uronic acid content of 20 % gave the highest activity of 55 IU/mg in APTT test than low sulfated one (Shanmugam and Mody 2000). The sargassan obtained from brown seaweed S. linifolium was composed of d-glucuronic acid, d-mannose, d-galactose, d-xylose, l-fucose, and a protein moiety. The backbone of sargassan seems to be composed of glucuronic acid, mannose, and galactose residues with partially sulfated side chains consisting of galactose, xylose, and fucose residues, and it exhibited high coagulant activity (Fattah et al. 1974).

Alginic acid is naturally a polymer of d-mannuronic and l-guluronic acids without sulfate contents. Sulfated derivate of alginic acid also shows anticoagulant activity; however, it is much lower and much more toxic than heparin. Also aminated fraction of sulfated alginic acid derivate shows anticoagulant activity in APTT assay by binding to immobilized ATIII (Shanmugam and Mody 2000).

5 Conclusion

High interest in algae is their perspective to be served as food with high nutritional value, as nutraceuticals and medicinal food for their health benefits of presented bioactive compounds. Freshwater algae and seaweed are a natural source representing many other interests for medical, therapeutic, and nutritional fields in many applications in the food industry, cosmetic industry, and medicine and pharmaceutical industry by the reason of searching for new natural and less toxic bioactive compounds than synthetic products.

Recently, algal polysaccharides alongside nutritious important compounds, such as proteins, amino acids, minerals, and vitamins, are in the focus of many researches all over the world for their health beneficial activities, such as anticoagulant, antioxidant, antiproliferative, antitumoral, anti-inflammatory, and antiviral properties, as well as skin protecting and antiaging activities. Heparin has been identified and used for more than fifty years as a commercial anticoagulant. However, some of the side effects of heparin, i.e., thrombocytopenia, hemorrhagic effect, and incapacity to inhibit thrombin bound to fibrin, lead to an increasing interest in discovering new anticoagulants to replace heparin. Algal-derived sulfated polysaccharides have been found to possess anticoagulant activity similar to or higher than heparin. Thus, the results of many research studies suggest that algal sulfated polysaccharides have a promising potential to be used as anticoagulant agents and medication for thrombotic disorders.

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© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Ladislava Mišurcová
    • 1
    Email author
  • Jana Orsavová
    • 2
  • Jarmila Vávra Ambrožová
    • 1
  1. 1.Department of Food Analysis and Chemistry, Faculty of TechnologyTomas Bata University in ZlínZlínCzech Republic
  2. 2.Language Centre, Faculty of HumanitiesTomas Bata University in ZlínZlínCzech Republic

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