# Bioactive Potential of Brown Algae

Authors: R. R. Remya; Antony V. Samrot; S. Suresh Kumar; V. Mohanavel; Alagar Karthick; V. Kumar Chinnaiyan; Dhamodharan Umapathy; M. Muhibbullah
Journal: Adsorption Science & Technology
 (2022)

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## Abstract

Marine-derived natural products are rich source of secondary metabolites with huge potentials including novel therapeutic agents. Marine algae are considered to be a good source of secondary metabolites with versatile bioactivities. During the last few decades, researches related to natural products obtained from brown algae have remarkably escalated as they contain active compounds with varied biologically activities like antimicrobial, anticancer, antioxidant, anti-inflammatory, antidiabetic, and antiparasitic properties. The main bioactive components such as phlorotannin, fucoxanthin, alginic acid, fucoidan, and laminarin have been briefly discussed here, together with their composition and biological activities. In this review, the biological function of extracts and the metabolites of brown algae as well as their pharmacological impacts with the description of the possible mechanism of their action are described and discussed. Also, this study is expected to examine the multifunctional properties of brown algae that facilitate natural algal products, including the ability to integrate these functional properties in a variety of applications.


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## Body

## 1. Introduction

The oceans are a valuable source of biologically active compounds, where macroalgae and microalgae are the most prolific producers that could be exploited potentially for their high medicinal perspective [1, 2]. There are mainly two types of algae: microalgae found in benthic, coastal, and throughout the sea and macroalgae or seaweeds seen in the coastal region. Macroalgae are eukaryotic organisms that live in saltwater or freshwater and have been discovered as a possible resource of fundamental bioactive molecules. Unlike most terrestrial plants, these macroalgae do not have roots, leaves, and vascular systems and are nurtured through the osmosis process. Based on pigmentation and shape, the algae are grouped as Chlorophyta (green algae), Phaeophyta (brown algae), and Rhodophyta (red algae) [3]. For the past few decades, using electron microscopy pictures and molecular biology analyses, there has been a thoughtful influence on the classification [4]. The presence of chlorophyll pigment renders green color to Chlorophyta, where the same pigment is present in almost all the higher plants. In Phaeophyta, the brown color is due to the presence of fucoxanthin pigment, and the presence of phycocyanin and phycoerythrin pigments in Rhodophyta makes them look red in color [5].More than 150,000 macroalgae or seaweed species are originated from the world’s seas and tropical waters. On the world’s coastlines, about 8000 marine seaweeds have been reported, and some are found up to 270 m deep in the sea. Around 2000 types of brown, 1200 types of green, and 6000 red macroalgae arose globally with an annual production estimating to be 6,756,521 million tons of biomass [6]. The west-central, southwest, and northwest Atlantic and the southwest and central-east Pacific are the primary reservoirs of algae. Due to the long coastline, India has extensive marine reserves along many estuaries and accessible coastlines [7]. Along the southern Tamil Nadu coast between Kanyakumari and Rameswaram, which include21 islands in the Gulf of Mannar, numerous types of red, green, and brown algae with lush growth can be seen [8]. There are almost 814 species of seaweeds on the Indian coast that belong to 217 genera. Many species were recorded on Indian coastlines, including 216 Chlorophyta species, 191 groups of Phaeophyta species, 217 Rhodophyta species, and 3 groups of Xanthophyta species. Among these, approximately 202 species were obtained in Gujarat [9]. More than 1700 species of brown algae have been noticed worldwide, and this group includes some widespread genera. Brown algae are found in 691, 713 locations worldwide. In India, 265 genera and 2040 species of Phaeophyta are reported, where 95% of these groups live in temperate to cold waters [10].Brown algae are a diverse class of algae renowned for their color, ranging from olive green to light golden brown. They range from small filamentous to large groups of complex seaweeds [11]. This is because their chromatophores contain the golden brown xanthophyll pigment fucoxanthin; because of the large amounts of fucoxanthin and carotenoid covering the residual pigments chlorophyll c and a and other xanthophylls, it looks brownish. The size of brown algae varies in small strings to the most significant marine algae, and the majority of brown algae is found in the intertidal zone [12]. Recently, numerous biologically active secondary metabolites were separated from different oceanic reserves, like marine microbes, phytoplankton, zooplankton, tunicates, sponges, seaweeds, and macroalgae red, green, and brown algae [13]. The study of secondary metabolites has concentrated much on macroalgae rather than phytoplanktons as marine algae produces extensive diversity of excellent natural compounds. Although these molecules contribute minimally to the organism’s total biomass, the involvement of these compounds in existence might occasionally be similar to metabolites generated from the primary metabolism. These metabolites exhibit good antimicrobial, antioxidant, anti-inflammatory, antidiabetic, and anticancer properties [14]. Having known about the brown algae, this review concentrates on the characteristics of brown algae and essential secondary metabolites detected in the brown algae, with particular attention on active metabolites with potential pharmaceutical and medicinal applications.


## 2. Characteristics of Brown Algae

Most of this group is either unicellular or multicellular. The size may vary from microscopic filaments with branches to macroscopic thalli [15]. A thallus contains stipes, blades, or frond and also a holdfast. As seen in roots of higher plants, the holdfast attaches thallus to the substratum. The stipe is comparable to the stems of higher plants, and fronds are analogous to leaves. The stipe and fronds organization are one of the major morphological characters for identifying several species of brown algae. Morphological changes of the algae are possible based on specific environmental conditions [16, 17]. Some of the familiar brown algae are (1) Laminaria, which has a large-sized sporophyte body, grows up to 1-3 m and is attached to bedrock with the help of holdfast; (2) Dictyota is a dichotomously branched sporophytic thallus, and the sporangia produce four haploid spores (Figure 1); (3) Sargassum is a free-floating or attached form, where the attached form has three parts, holdfast, main axis, and laterals (Figure 1); (4) Ectocarpus is a filamentous alga fix to solid substratum using its prostate portion and rhizoid; and (5) Fucus is a leathery flat branched brown alga where the branches have conceptacles. Some of these species’ cling to the rocks or other supporting substances, whereas others drift on the surface of the water, forming single-celled or pluricellular colonies, while others cling to the seabed through root-like structures (holdfasts). The significant pigments in brown algae consist of chlorophyll a, c1, c2, β-carotene, lutein, fucoxanthin, dioanthin, and violaxanthin. Also, some storage food includes laminarin, mannitol, and some oils, and the brown algae cell walls are made up of cellulose and alginic acid [18].Figure 1
Characteristics of some brown algae (a)Laminaria, (b) Dictyota, and (c) Sargassum.
(a)(b)(c)


### 2.1. Composition of Brown Algae

Brown macroalgae are abundant in minerals ranging from 14 to 35% of dry matter. They have relatively lower total protein levels (8–13%) forLaminaria and Saccharina, respectively, whereas it is about 6–11% for Sargassum, 7–13% for Macrocystis pyrifera (M. pyrifera), and 5–12% for Ascophyllum nodosum (A. nodosum). Black (1950a and b) discovered significant variations in chemical composition depending on the year’s season, with crude protein ranging from 4–8% in autumn to 12–14% dry matter in spring. Cell walls are made up of alginic acid and cellulose, a heteropolysaccharide with long, abundant chains (20–27%, 20–45%, and 15–30% for M. pyrifera, Laminaria digitata (L. digital), and A. nodosum, respectively) [19, 20]. Fucoidans are made up of polysaccharide units with varying amounts of sulfation, and they make up the cell walls of many brown macroalgae, especially Laminariales and Fucales [21]. Distinct from the other seaweeds in which the storage carbohydrate is starch, brown seaweeds store carbohydrates in the form of laminarin, a glucose polysaccharide [22]. Sodium (2.2% in L. digitata and 4% in A. nodosum), potassium (3.8% and 3% in L. digitata and A. nodosum, respectively), and iodine (1.1% and 0.1% in L. digitata and A. nodosum, respectively) are high in brown seaweeds. Certainly, Laminaria can absorb iodine at a rate more than thirty thousand times the rate of iodine concentration in the ocean [23]. The composition varies depending on various features; for example, M. pyrifera cultivated in the summer along the Mexican shore contains more amino acids and minerals than M. pyrifera harvested in the winter [24]. The phenolic compounds (phlorotannins) contained in A. nodosum are not soluble in the animals’ digestive tract. Many types of seaweed have high amount of free glutamic acid, which is responsible for the “umami” flavor found in Japanese dishes and is used as a flavor improver in food. Sargassum is low in protein but high in carbohydrates and is an easily accessible mineral. They are also abundant in vitamins and β-carotene and are free of antinutrients [25].


## 2.1. Composition of Brown Algae

Brown macroalgae are abundant in minerals ranging from 14 to 35% of dry matter. They have relatively lower total protein levels (8–13%) forLaminaria and Saccharina, respectively, whereas it is about 6–11% for Sargassum, 7–13% for Macrocystis pyrifera (M. pyrifera), and 5–12% for Ascophyllum nodosum (A. nodosum). Black (1950a and b) discovered significant variations in chemical composition depending on the year’s season, with crude protein ranging from 4–8% in autumn to 12–14% dry matter in spring. Cell walls are made up of alginic acid and cellulose, a heteropolysaccharide with long, abundant chains (20–27%, 20–45%, and 15–30% for M. pyrifera, Laminaria digitata (L. digital), and A. nodosum, respectively) [19, 20]. Fucoidans are made up of polysaccharide units with varying amounts of sulfation, and they make up the cell walls of many brown macroalgae, especially Laminariales and Fucales [21]. Distinct from the other seaweeds in which the storage carbohydrate is starch, brown seaweeds store carbohydrates in the form of laminarin, a glucose polysaccharide [22]. Sodium (2.2% in L. digitata and 4% in A. nodosum), potassium (3.8% and 3% in L. digitata and A. nodosum, respectively), and iodine (1.1% and 0.1% in L. digitata and A. nodosum, respectively) are high in brown seaweeds. Certainly, Laminaria can absorb iodine at a rate more than thirty thousand times the rate of iodine concentration in the ocean [23]. The composition varies depending on various features; for example, M. pyrifera cultivated in the summer along the Mexican shore contains more amino acids and minerals than M. pyrifera harvested in the winter [24]. The phenolic compounds (phlorotannins) contained in A. nodosum are not soluble in the animals’ digestive tract. Many types of seaweed have high amount of free glutamic acid, which is responsible for the “umami” flavor found in Japanese dishes and is used as a flavor improver in food. Sargassum is low in protein but high in carbohydrates and is an easily accessible mineral. They are also abundant in vitamins and β-carotene and are free of antinutrients [25].


## 3. Major Bioactive Molecules of Brown Algae

### 3.1. Phlorotannins

Polyphenols are also known as phytochemicals because they are present in plants. Polyphenols are a wide and heterogeneous group of naturally emerging molecules with phenolic characteristics in aquatic and terrestrial environments as secondary metabolites. Due to their broad range of biological applications, these naturally occurring polyphenols have been identified as possible substitutes for a range of industrial formulations comprising nutraceuticals, foods supplements, cosmeceuticals, and pharmaceuticals [26]. Tannins are polyphenolic compounds that are naturally occurring in plants. They are found in both marine and terrestrial plants. Unlike tannins found in the terrestrial environment, only marine brown algae have been found to contain phlorotannins. They have a simpler structure than terrestrial tannins and are made completely from phloroglucinol polymerization. Many studies over the years have been conducted on the functions and roles of phlorotannins. Moreover, various phlorotannin derivatives were extracted from a range of brown algae: Ecklonia kurome, Ecklonia cava, Ecklonia bicyclis, and Ecklonia radiate [27]. Phlorotannins are reported to have sleep-promoting [28], antibacterial [29], antioxidant [30, 31], and algicidal effects [32]. It has been found to have inhibitory action against HIV-1 reverse transcriptase [33].


### 3.2. Fucoxanthin

Fucoxanthin is one of the most prevalent xanthophylls variants in brown algae, a natural pigment that belongs to the carotenoid family. Along with carotene, it is present in edible brown seaweeds likeHyalogonium fusiforme, Undaria pinnatifida, Laminaria japonica, and Sargassum fulvellum. It is one of the most common carotenoids. Externally, in all algal species, the presence of fucoxanthin can be easily accessed by observing their color [34]. As the name implies, it is used as an additive stain in the chloroplasts of brown seaweeds and many other heterokonts, providing them an olive green or brown color. Much research is currently being reported about extracting fucoxanthin from certain brown algal species, which would enable the substance to be used in a variety of functional applications. According to some nutritional and metabolic studies conducted at Hokkaido University on mice and rats, fucoxanthin stimulates fat burning within the white adipose tissue by increasing the thermogenin expression. Furthermore, fucoxanthin has been discovered to offer a broad spectrum of bioapplications, like antioxidant and anti-inflammatory activities [35].


### 3.3. Alginic Acid and Fucoidan

Polysaccharides based on bioactive natural products have attracted a great deal of interest in pharmacology over the past few years. Seaweeds are rich in soluble polysaccharides and can be used as roughage. Brown algae, in particular, are found to develop efficient polysaccharides, including fucoidans and alginates. Antitumoral, anticoagulant, antiviral, and anti-inflammatory activities are among the different biological properties of alginic acid and fucans derivatives [36, 37]. Alginic acid (algin or alginate) is a gelling polysaccharide of -L-Gulu-ironic, and 1, 4-linked β-D-mannuronic acid arranged in an irregular order through the chain. This hydrophilic colloidal polysaccharide is commonly found in brown algae’s intracellular substances and cell walls [38, 39]. It is also one of the most significant structural polysaccharides of brown algae. Fucoidan and alginic acid make up most of the acid polysaccharides in the cell walls of brown algae. Brown algae alginate is commonly used in a variety of pharmaceutical formulations. It is also a beneficial thickening agent for jellies, beverages, and ice cream in the food industry. It is also used for cosmetic production as a water-binding and thickening agent since alginate absorbs water easily, making it a useful additive in cosmetic formulations [40].Fucoidan is a polysaccharide that comprises significant amounts of sulfate ester and L-fucose groups and is present in many brown algae species. Brown algae have this sulfated polysaccharide in their cell wall [41]. Sulfated polysaccharides, also known as fucoidans in marine brown algae, have potential antioxidant and anti-inflammatory activity. Fucoidans’ high degree of sulfation appears to determine their biological functions, but these functions are based on their molecular weight and fine structure [42]. Fucoidan also has the potential to improve the cosmetic properties of the skin. Hence, it is a versatile ingredient with applications in essential cosmetic formulations. Polygalactosides bind with an external layer that protects the skin, forming a protective moisturizing complex by the ion-ion interaction, whereas fucose polymers are absorbent and act like moisturizing substances. Fucus has a high content of essential and nonessential amino acids such as lysine, proline, and glycine, which are present in the skin’s elastic fibers. From this perspective, the sulfated polysaccharide fucoidan of brown algae could help maintain skin elasticity by enhancing hydration and thus strengthening the flexible nature of the skin [43, 44].


### 3.4. Laminarin/Laminarans

Brown seaweed contains essential storage polysaccharide called laminaran or laminarin (e.g.,Laminariaor saccharine), accounting for up to 32–35% (d.w.) of the total storage polysaccharides. Laminarin are glucans that have polysaccharides that are linear, made up of β-glucose in a 3 : 1 ratio with random β-(1Ñ6) intrachain branching. The amount of polymerization differs from 20 to 50 units. The polymer chains have been classified into two types: G chains with a glucose residue and M chains with a D-mannitol residue. Depending on the degree of polymerization (usually 25), the molecular weight of laminarians is about 5 kDa. It has been reported that laminarin possesses a lot of biological activities, including antitumor, antiapoptotic, anti-inflammatory, anticoagulant, and antioxidant potentials. Remya et al. reported the extraction of laminarin utilizing brown seaweed Turbinaria ornata which acts as a potential bioactive component [45].


### 3.5. Other Bioactive Molecules of Brown Algae

Brown seaweeds are primarily utilized to cure stomach ailments, asthma, headache, hypothyroidism, cellulite, cough, and fatigue. Besides helping with skincare, brown seaweeds also facilitate weight loss. The prospective antioxidant metabolites in brown seaweeds were recognized as almost polyphenols and pigments [46]. They are present in many plants and seaweeds and are well known for their antioxidant activity through reactive oxygen species (ROS) scavenging and the lipid peroxidation inhibition activity. Brown seaweeds are recognized to have enormous of polysaccharides in their cell wall, the most prominent of which are the sulfated polysaccharide fucoidan, which is absent in terrestrial plants. Fucoidan contains a significant amount of sulfated ester and L-fucose groups and has an extensive assortment of pharmacological and biomedicinal properties; there have been more than a few investigations on the diverse bioactivities, structural parameters, molecular weights, and physiological features of seaweed polysaccharides [47]. The list of various species of brown seaweeds and their isolated compounds is mentioned in Table 1.Table 1
List of different species of brown algae and their compounds.
S.noBrown algaeCompoundsReferences1.Ascophyllum nodosumPhlorotannin, flavonoids[48]2.Fucus vesiculosusPhlorotannins[48]3.Bifurcaria bifurcataPhlorotannin, alginate[48, 49]4.Caulocystis cephalornithos6-Undecylsalicylic acid and 6-tridecylsalicylic acid[50]5.Sargassum ilicifolium10,2-Trinorsqualenol, glycolipid 1-O-palmitoyl-2-O-stearidonoyl-3-O-b-D-galactopyranosylglycerol[51]6.Turbinaria ornataApo-90-fucoxanthinone, 24-ketocholesterol, (22E)-3b-hydroxycholesta-5,22-dien-24-one, saringosterol[51]7.Ishige okamuraeDiphlorethohydroxycarmalol[52]8.Dictyota ciliolataRutein, quercetin, palmitic acid, diterpines[53, 54]9.Ecklonia cava8,8′-bieckol[55]10.Sargassum polycystumFucoidan[56]11.Ecklonia maximaEckol and phloroglucinol[57]12.Dictyota pfaffiiDiterpenes[58]13.Sargassum thunbergiiIndole derivatives[59]14.Cystoseira tamariscifoliaIsololiolide[60]15.Stochospermum marginatumSpatane diterpenoids[61]


## 3.1. Phlorotannins

Polyphenols are also known as phytochemicals because they are present in plants. Polyphenols are a wide and heterogeneous group of naturally emerging molecules with phenolic characteristics in aquatic and terrestrial environments as secondary metabolites. Due to their broad range of biological applications, these naturally occurring polyphenols have been identified as possible substitutes for a range of industrial formulations comprising nutraceuticals, foods supplements, cosmeceuticals, and pharmaceuticals [26]. Tannins are polyphenolic compounds that are naturally occurring in plants. They are found in both marine and terrestrial plants. Unlike tannins found in the terrestrial environment, only marine brown algae have been found to contain phlorotannins. They have a simpler structure than terrestrial tannins and are made completely from phloroglucinol polymerization. Many studies over the years have been conducted on the functions and roles of phlorotannins. Moreover, various phlorotannin derivatives were extracted from a range of brown algae: Ecklonia kurome, Ecklonia cava, Ecklonia bicyclis, and Ecklonia radiate [27]. Phlorotannins are reported to have sleep-promoting [28], antibacterial [29], antioxidant [30, 31], and algicidal effects [32]. It has been found to have inhibitory action against HIV-1 reverse transcriptase [33].


## 3.2. Fucoxanthin

Fucoxanthin is one of the most prevalent xanthophylls variants in brown algae, a natural pigment that belongs to the carotenoid family. Along with carotene, it is present in edible brown seaweeds likeHyalogonium fusiforme, Undaria pinnatifida, Laminaria japonica, and Sargassum fulvellum. It is one of the most common carotenoids. Externally, in all algal species, the presence of fucoxanthin can be easily accessed by observing their color [34]. As the name implies, it is used as an additive stain in the chloroplasts of brown seaweeds and many other heterokonts, providing them an olive green or brown color. Much research is currently being reported about extracting fucoxanthin from certain brown algal species, which would enable the substance to be used in a variety of functional applications. According to some nutritional and metabolic studies conducted at Hokkaido University on mice and rats, fucoxanthin stimulates fat burning within the white adipose tissue by increasing the thermogenin expression. Furthermore, fucoxanthin has been discovered to offer a broad spectrum of bioapplications, like antioxidant and anti-inflammatory activities [35].


## 3.3. Alginic Acid and Fucoidan

Polysaccharides based on bioactive natural products have attracted a great deal of interest in pharmacology over the past few years. Seaweeds are rich in soluble polysaccharides and can be used as roughage. Brown algae, in particular, are found to develop efficient polysaccharides, including fucoidans and alginates. Antitumoral, anticoagulant, antiviral, and anti-inflammatory activities are among the different biological properties of alginic acid and fucans derivatives [36, 37]. Alginic acid (algin or alginate) is a gelling polysaccharide of -L-Gulu-ironic, and 1, 4-linked β-D-mannuronic acid arranged in an irregular order through the chain. This hydrophilic colloidal polysaccharide is commonly found in brown algae’s intracellular substances and cell walls [38, 39]. It is also one of the most significant structural polysaccharides of brown algae. Fucoidan and alginic acid make up most of the acid polysaccharides in the cell walls of brown algae. Brown algae alginate is commonly used in a variety of pharmaceutical formulations. It is also a beneficial thickening agent for jellies, beverages, and ice cream in the food industry. It is also used for cosmetic production as a water-binding and thickening agent since alginate absorbs water easily, making it a useful additive in cosmetic formulations [40].Fucoidan is a polysaccharide that comprises significant amounts of sulfate ester and L-fucose groups and is present in many brown algae species. Brown algae have this sulfated polysaccharide in their cell wall [41]. Sulfated polysaccharides, also known as fucoidans in marine brown algae, have potential antioxidant and anti-inflammatory activity. Fucoidans’ high degree of sulfation appears to determine their biological functions, but these functions are based on their molecular weight and fine structure [42]. Fucoidan also has the potential to improve the cosmetic properties of the skin. Hence, it is a versatile ingredient with applications in essential cosmetic formulations. Polygalactosides bind with an external layer that protects the skin, forming a protective moisturizing complex by the ion-ion interaction, whereas fucose polymers are absorbent and act like moisturizing substances. Fucus has a high content of essential and nonessential amino acids such as lysine, proline, and glycine, which are present in the skin’s elastic fibers. From this perspective, the sulfated polysaccharide fucoidan of brown algae could help maintain skin elasticity by enhancing hydration and thus strengthening the flexible nature of the skin [43, 44].


## 3.4. Laminarin/Laminarans

Brown seaweed contains essential storage polysaccharide called laminaran or laminarin (e.g.,Laminariaor saccharine), accounting for up to 32–35% (d.w.) of the total storage polysaccharides. Laminarin are glucans that have polysaccharides that are linear, made up of β-glucose in a 3 : 1 ratio with random β-(1Ñ6) intrachain branching. The amount of polymerization differs from 20 to 50 units. The polymer chains have been classified into two types: G chains with a glucose residue and M chains with a D-mannitol residue. Depending on the degree of polymerization (usually 25), the molecular weight of laminarians is about 5 kDa. It has been reported that laminarin possesses a lot of biological activities, including antitumor, antiapoptotic, anti-inflammatory, anticoagulant, and antioxidant potentials. Remya et al. reported the extraction of laminarin utilizing brown seaweed Turbinaria ornata which acts as a potential bioactive component [45].


## 3.5. Other Bioactive Molecules of Brown Algae

Brown seaweeds are primarily utilized to cure stomach ailments, asthma, headache, hypothyroidism, cellulite, cough, and fatigue. Besides helping with skincare, brown seaweeds also facilitate weight loss. The prospective antioxidant metabolites in brown seaweeds were recognized as almost polyphenols and pigments [46]. They are present in many plants and seaweeds and are well known for their antioxidant activity through reactive oxygen species (ROS) scavenging and the lipid peroxidation inhibition activity. Brown seaweeds are recognized to have enormous of polysaccharides in their cell wall, the most prominent of which are the sulfated polysaccharide fucoidan, which is absent in terrestrial plants. Fucoidan contains a significant amount of sulfated ester and L-fucose groups and has an extensive assortment of pharmacological and biomedicinal properties; there have been more than a few investigations on the diverse bioactivities, structural parameters, molecular weights, and physiological features of seaweed polysaccharides [47]. The list of various species of brown seaweeds and their isolated compounds is mentioned in Table 1.Table 1
List of different species of brown algae and their compounds.
S.noBrown algaeCompoundsReferences1.Ascophyllum nodosumPhlorotannin, flavonoids[48]2.Fucus vesiculosusPhlorotannins[48]3.Bifurcaria bifurcataPhlorotannin, alginate[48, 49]4.Caulocystis cephalornithos6-Undecylsalicylic acid and 6-tridecylsalicylic acid[50]5.Sargassum ilicifolium10,2-Trinorsqualenol, glycolipid 1-O-palmitoyl-2-O-stearidonoyl-3-O-b-D-galactopyranosylglycerol[51]6.Turbinaria ornataApo-90-fucoxanthinone, 24-ketocholesterol, (22E)-3b-hydroxycholesta-5,22-dien-24-one, saringosterol[51]7.Ishige okamuraeDiphlorethohydroxycarmalol[52]8.Dictyota ciliolataRutein, quercetin, palmitic acid, diterpines[53, 54]9.Ecklonia cava8,8′-bieckol[55]10.Sargassum polycystumFucoidan[56]11.Ecklonia maximaEckol and phloroglucinol[57]12.Dictyota pfaffiiDiterpenes[58]13.Sargassum thunbergiiIndole derivatives[59]14.Cystoseira tamariscifoliaIsololiolide[60]15.Stochospermum marginatumSpatane diterpenoids[61]


## 4. Mechanism of Bioactivity of Brown Algae

### 4.1. Antimicrobial Activity

The method of extraction and conditioning may affect the yield of bioactive compounds. The drying stage is crucial because high temperatures can cause the deficit of unsteady antimicrobials associated with fresh algae (terpenoid, hydrogen peroxide, bromo-ether compounds, and volatile fatty acids) [62, 63]. Improved cell membrane permeability was observed and discovered in high-temperature treated dried seaweed extracts which showed broader inhibition zones against Listeria innocua, Pseudomonas aeruginosa, Salmonella enteritidis, and Staphylococcus aureus. It was found that dried Chondrus crispus crude ethanolic extracts had a lower MIC than extracts from fresh seaweed against the growth of phytoplankton and bacterial species [64]. Similarly, during drying and hydrothermal processing, a decline was discovered in the antioxidants and the total phenolic content against H. elongate. The phytochemical content was increased, and enhanced inhibitory potential was observed by drying followed by boiling. Storage and cell wall polysaccharides attained in red, brown, and green algae, such as laminarin, alginates, carrageenans, fucans, and ulvans, can activate plant resistance pathogen control mechanisms [65]. Oligosaccharides produced by depolymerization of algal polysaccharides protect plants from bacterial, fungal, and viral infections, resulting in the accumulation of antimicrobial compounds and proteins. Cytotoxicity study against the murine cell line of macrophages RAW264.7 as well as acute toxicity test on mice indicated that the moderate doses of radioactive E. cava derivatives can be used safely by humans [66, 67]. Evidence of significant antimicrobial activity was observed in various algal species. In one study, the effect of Spatoglossum asperum brown algal solvent extracts on dermatophytes and nondermatophytes was assessed. The maximum potential of chloroform extract against the nondermatophytic fungus Aspergillus flavus was determined. The methanolic extract showed significant antifungal activity against the dermatophyte fungi Candida albicans and Candida tropicalis in relation to other solvent extracts [68]. In another study, the brown algal extracts from Laminaria digitata and Undaria pinnatifida showed the strongest antifungal activity against Botrytis cinerea on strawberries and Monilinia laxa on peaches, followed by Penicillium digitatum on lemons [69]. The different solvent extracts from algae were tested against some of the pathogenic human fungi Candida albicans, Candida parapsilosis, Fusarium sp., Aspergillus flavus, and Aspergillus fumigatus. Hexane, chloroform, and ethanolic extracts were found to be highly inhibitory against Candida albicans and Candida parapsilosis [70]. Some compounds isolated from brown seaweeds also possess certain antimicrobial activities. The phlorotannin isolated from brown seaweeds has been reported to have antifungal activity against dermal and plant fungi [71]. In the Chnoospora bicanaliculata, Sargassum wightii, Padina tetrastromatica, and Stocheospermum marginatum extracts derived from India’s southwestern shore provide credible information that brown seaweeds sustain successful antimicrobial activity [68–70]. The mechanism behind these molecules may be because they directly interact with enzyme and inhibit the action of enzymes or induce membrane permeability loss and protein leakage, where these have been exhibited by polysaccharides, polyphenols, and phlorotannins (Figure 2) [71, 72].Figure 2
Antibacterial activity of compounds of brown algae.


### 4.2. Anticancer Activity

The efficient approach for killing cancer cells is to provoke apoptosis over tumor cells. Tumor necrosis factor- (TNF-) related apoptosis-inducing ligand (TRAIL) is an integral membrane protein which can bind to membrane-bound death receptors [73]. TRAIL and its receptor binds together and transmit an apoptotic signal across their intracellular mortality zones. As a result of this, cancer cells undergoes apoptosis. On gastric cell line (AGS) of humans, the anticancer activity of ethanolic extract of Hyalogonium fusiforme (H. fusiforme) was investigated, and the findings showed that the extract (0 to 25 μg/mL) could induce apoptosis in tumor cells by upregulating the expression of TNF-α. In a recent research, it was discovered that the extracts were taken using ethyl alcohol of H. fusiforme towards the protein expression in human hepatoma cancer cells Hep3B and inhibits matrix metalloproteinase (MMP) activity and was also found to control metastasis-related and tumor invasive genes (TSP-1, claudins, IGF-1R, and E-cadherin) as well as activity-related genes of MMP (TIMP-1, TIMP-2, MMP-1, and MMP-2), which induce apoptosis in cancer cells [74]. 5-Hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone is found in the extracts of ethanol (80%) of H. fusiforme which also possesses potential anticancer activity in human's AGS and DR4 cancer cell lines [73, 75] where the compound isolated increased the apoptosis mediators connected to the death receptor like TRADD, Fas, FADD, and Fas L that were in a dose-dependent manner (Figure 3). Son et al. [76] claimed that extracts using ethanol from H. fusiforme may minimize the development of aberrant crypt foci regulated by azoxymethane in male rats. Prenoplastic damage to the colon, which result in colorectal cancers, has alluded as aberrant crypt foci [76]. Ethanol extract of H. fusiformecan also provoke apoptosis of human leukemia U937 cell lines. The outcomes of the findings stated that the apoptotic cell death in U937 cells was caused by Bcl-2 protein inhibition and downregulation in the form of IAP family members like XIAP, IAP1, and IAP2 [77, 78]. Remya et al. [79] studied the phytochemical composition and profiling of Turbinaria ornata and its antiproliferous effect against human retinoblastoma Y79 cells [79]. When compared to the existing chemotherapeutic agents, chemopreventive agents extracted from natural resources have gotten a lot of attention because of their potential to suppress cancer cell development with less or no side effects.Figure 3
Anticancer activity mechanism algal metabolites.Cytotoxic effect have been discovered in certain solvent extracts such as ethyl acetate, chloroform, and methanol from different brown algae species such asColpomenia sinuosa, Cystoseira myrica, and Sargassum swartzii, against NIH 3T3, HT-29, T47D, Caco-2, and MDA-MB468 cells [79–81]. On seven cancer cell lines, Dictyota dichotoma (D. dichotoma) extracts had strong dose-dependent cytotoxicity but were more selective on PC-3 and MCF-7. The fraction from chloroform extract of D. dichotoma had the greatest effect of cytotoxicity against CACO (IC502.71±0.53 μg/mL), PC3 (IC502.2±0.18), and MCF-7 (IC501.93±0.25), respectively. Apart from the extracts, certain bioactive components isolated from numerous brown algae showed good cytotoxic potential against cancer cell lines [82]. By increasing the ROS production, the fucoidan isolated from Sargassum cinereum brown seaweed exhibits potential apoptotic and anticancer effect on Caco-2 cells. The anticancer potential of the extracted Sargassum wightii polysaccharides have been assessed on breast cancer cell lines MDA-MB-231 and MCF7, and the polysaccharides were detected to substantially decrease the development of cancer cells [83]. At IC50 values of 11.6 and 32.0 μg/mL, a few fractional compounds and three additional linear diterpenes isolated from Bifurcaria bifurcate mildly prevented the development of the MDA-MB-231 cells [84].


### 4.3. Antioxidant Activity

Crude extracts and compounds isolated from seaweeds have been used as defenders of health, in cosmetics, and food; and antioxidant activity have been studied. Brown algae have relatively higher levels and powerful antioxidants when compared with green and red algae [85]. Antioxidant property is based on its radical or oxygen scavenging ability; chelation of metal [86] and the free radical scavenging are vital in determining the antioxidant property [87]. Phenolic derivatives (phenolic -OH) have the ability to transfer a hydrogen atom to the free radicals and form a stable product; the longevity of maintaining the stability of the product determines the antioxidant properties of the constituent isolated [88, 89] (Figure 4).Figure 4
Antioxidant activity mechanism of algal metabolites.Phenolic acids have a phenolic ring with carboxyl group [90]. Occurrence of phenolic acids, including gallic acid, catechin, caffeic acid, coumaric acid, quercetin, rutin, and kaempferol, are indicated to be present in brown algae, and the antioxidant property of these molecules have been reported [91]. The aromatic benzene ring structure of the aforementioned phenolics with -OH (hydroxyl) moieties play a crucial function in H-donation and free scavenging properties [90, 91]. Benzene ring with -CH = CH-COOH moiety has been reported to increase hydrogen donation and increase antioxidant property [92]. Phlorotannins, a hydrophilic marine algal metabolite of size from 125 to 600 kDa, which are abundant in brown algae, are classified as fuhalols (extra hydroxyl group at third ring), phlorethols (ether linkage), fucols (phenyl linkage), fucophloroethols (ether and phenyl group), and eckols (dibenzodioxin linkage) [92, 93]. These extra functional groups enhances its antioxidant property. The antioxidant potency of brown algae, namely, Anthophycus longifolius, Sargassum plagiophyllum, and Sargassum myriocystum, was assessed using various in vitro antioxidant studies. The ethyl acetate extract from Anthophycus longifolius showed extensively higher radical scavenging ability of hydroxyl radicals and have been shown to be effective in stabilizing 2,2-azino-bis-3-ethyl-benzothiozoline-6-sulphonic acid (ABTS) and also 1,1-diphenyl-2-picryl-hydrazil (DPPH) radicals. There were no substantial differences observed in the scavenging properties of hydrogen peroxide and ferrous ion chelation properties of seaweed ethyl acetate extracts [94]. Ascophyllum nodosum, Laminaria japonica, Lessonia trabeculate, and Lessonia nigrecens have been examined for their antioxidant activities. Among all four species, Ascophyllum nodosum extracts have the strongest antioxidant activity [95]. In another study, ethanol and water binary solvent system were used to produce raw extracts of edible algae Ascophyllum nodosum (A. nodosum). The extract of A. nodosumwas optimized using the Box–Behnken design and also the response surface methodology to achieve extracts with high antioxidant activity or high effectiveness. In the two optimal conditions, the antioxidant property was found to be at 74.05±0.51mL/g with respect to the yield at 53.80±1.65mg. This explains the ability of both models to predict with precision and improve antioxidant extraction using A. nodosum [96]. Padina tetrastromatica comprises a significant quantity of polyphenols that have antioxidant properties [97]. Sodium alginates that were obtained at various seasons from brown seaweed, Cystoseira schiffneri, had been checked for antioxidant activity using DPPH and Fe2+ chelating potential assays where antioxidant property varied considerably depending on the season [98].


### 4.4. Anti-Inflammatory Activity

Reactive oxygen species (ROS), at normal condition, involve in signaling pathways as a part of metabolism; mostly, ROS are produced by mitochondria during respiration [99]. When these are produced in higher level than normal, it degrades the biological macromolecules, including lipids, DNA, and proteins, which lead to abnormal cellular function including inflammation [100]. Inflammation-inducing cells mostly mast cells and eosinophils generate chemical signals leading to the release ROS, where it kindles signal transduction and induces nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2), nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). This induction leads to higher inflammation and harms healthy cells which sometimes triggers cancer cells also [99, 100]. Decreasing the expression of these aforementioned genes or any signal transduction pathways or free radical scavenging reduces the inflammatory reaction. Apo-9′-fucoxanthinone, a norisoprenoid isolated from Sargassum muticum, is effective against nitric oxide (NO) and prostaglandin E2 (PGE2) synthesis in LPS-mediated inflammation against cell line RAW264.7 where it regulates the activation of NF-κB activation by suppressing IκB-α within macrophages (Figure 5). Ethanolic and DMSO extract of Cystoseira amentacea collected from the Ligurian Sea showed a strong anti-inflammatory effect against inflammatory cytokines [101]. The brown algae Padina commersonii fucoidan- (PCF-) based sulfated polysaccharide was examined for anti-inflammatory activities and was also tested against LPS-activated RAW 264.7 macrophages. The impact found that PCF is a promising component that inhibits LPS-induced inflammatory reactions by preventing transduction of LRT/MyD88/NF-κB signals [102]. Furthermore, the fucoidan extract of Turbinaria decurrens was tested for its anti-inflammatory properties. Fucoidan had an anti-inflammatory potential with upregulation of antioxidant levels through NF-κB, thus suppressing proinflammatory genes. [103].Figure 5
Anti-inflammatory activity mechanism of algal metabolites.The anti-inflammatory activity of brown seaweeds such asCystoseira crinita (AQ-C cri), Cystoseira sedoides (AQ-C sed), and Cystoseira compressa (AQ-C com) was assessed in vivo, with carrageenan generated rat paw edema test. The extracts AQ-C cri, AQ-C sed, and AQ-C com displayed an important anti-inflammatory effect depending on the dose correlated to the reference drugs [104]. Turbinaria conoides, collected in the Gulf of Mannar, extracted with three substituted 2H pyranoids, which were showing activity against 5-lipoxygenase and cyclooxygenase-2, are found to be more effective than nonsteroidal drugs on the market [105]. In particular, phlorotannin fractions of Cystoseira sedoides (PHT-SED) collected on the Tunisian coast have been tested for pharmacological potential with other algae. A substantial anti-inflammatory potency of the fractions was performed using in vivo models at the 100 mg/kg dose against the reference drug [101].


### 4.5. Antidiabetic Activity

The antidiabetic potential of brown algae has has been studied extensively over the last few years due to the presence of several bioactive compounds. Enzymes such asα-amylase and α-glucosidase are essential in carbohydrate hydrolysis and it releases glucose; inhibiting these enzymes reduces postprandial hyperglycaemia; and inhibitors of these enzymes could be an antidiabetic drug [106]. Other enzymes including aldose reductase, protein tyrosine phosphatase, and protein tyrosine phosphatase 1B do play a major in the formation of glucose, thus its action to be blocked to prevent postprandial hyperglycaemia [105–107]. Phlorotannin has been reported to suppress the activity of α-amylase and α-glucosidase [108, 109]. The methanolic extract and fucoxanthin fraction obtained from Sargassum siliquosum and Sargassum polycystum showed inhibitory action against angiotensin converting enzymes such asα-amylase, and as well as α-glucosidase [110]. Phlorotannin eckol of Ecklonia maxima was found to be an effective α-glucosidase inhibitor [111] where pholotannins compounds like phloroeckol and dieckol from Eisenia bicyclis were inhibiting 87% acidity of α-amylase. Ascophyllum nodosum was found to be effective against both the above-mentioned enzymes [112]. Laminaria digitata's methanol extract and Undaria pinnatifida's acetone extract have shown to inhibit α-amylase with IC50 values at 0.74±0.02mg/mL and 0.81±0.03mg/mL, respectively. The 2,5-dihydroxybenzoic acid phenolic compound in both algae was an effective α-amylase inhibitor with IC50 value of 0.046±0.004mg/mL. The alginates and polysaccharides present in brown algae exhibit strong inhibitions against α-amylase with an IC50 range ranging from 0.075±0.010 to 0.103±0.017mg/mL. In general, the above results demonstrated that crude extracts, phenolic compounds, and brown edible algae alginates are strong inhibitors of α-amylase [113]. In addition, the extraction of phenolics isolated from four brown algae such as Ascophyllum nodosum, Laminaria japonica, Lessonia trabeculate, and Lessonia nigrecens have been studied for activities inhibiting pancreatic lipase and tyrosinase. Among the four algae, Lessonia trabeculate extract demonstrated strong activity towards α-amylase, α-glucosidase, pancreatic lipase, and tyrosinase inhibition activities [95]. A brown alga Padina tetrastromatica was used to isolate polyphenols and to study their antidiabetic properties. Polyphenols showed a strong α-amylase effect at IC50 value 47.2±2.9 μg and α-glucosidase at 28.8±2.3 μg of inhibitory activities [97].There are some metabolites which are active diabetes-induced models. Fucoxanthin obtained using seaweedIshige okamurae has been evaluated for oxidative stress due to high blood sugar against umbilical vein endothelial cells in vitro as well as in the zebrafish model in vivo. The two studies mentioned above has demonstrated that the isolated fucoxanthin is capable of providing protection against damage to organs and cells [114]. Antidiabetic effectiveness of oligosaccharides from brown algae named Sargassum confusum (SCO) has been evaluated in vivo with hamsters that are high in sucrose. Following the administration of SCO, the decreased levels of blood glucose levels were observed. The primary function of SCO in the antidiabetic effect was revealed by the 1/phosphatidylinositol 3-kinase and c-Jun N-terminal kinase routes of the insulin regulator receptor substrate. Thus, SCO has been used in people with obesity and diabetes for the regulation of intestinal microbiota [115]. Phlorotannins gained using Cystoseira compressawas checked for the antidiabetic effect. The results suggest that phlorotannins significantly reduced the activity of serum glucose, liver malondialdehyde, α-amylase, and glucosidase, and histopathological studies have shown that phlorotannins distinctly reduce and protect lesions in pancreatic β cells [116].


### 4.6. Antiparasitic Activity

Many terrestrial plants have been shown to have antiparasitic activity and clinically potent medicinl value, but the potential of the algae have been less explored. Thein vitro activities of Sargassum oligocystum gathered across Bushehr coast in south-west Iran against Leishmania species were estimated to be highly significant [117]. The prophylactic effect of few algal extracts from the southern coast of England were studied against parasites in the blood stage and liver stage of Plasmodium. Based on numerous extracts, Cystoseira tamariscifolia (CT) and Cystoseira baccata (CB) possessed the utmost antimalarial action of IC50 ranging in between 3.3 and 3.8 μg/mL [108]. A further study found that diterpene called eleganolone was obtained using the French algaenamed Bifurcaria bifurcate inhibiting Trypanosoma brucei and Plasmodium falciparum [109]. Similarly, the bioactivity of dichloromethane/methanol extract (DME) of Dictyota mertensii on Leishmania amazonensiswas also assessed. This indicated inhibition effect of IC50 at 71.60 μg/mL over growth of promastigote forms. DME showed toxic against the promastigote and amastigote forms that were revealed to be effective, indicating a potential agent in treatment of cutaneous leishmaniasis [118]. Brown macroalagae namelyCladostephus spongiosum, Cystoseira sedoides, Dictyota spiralis, Padina pavonica, and Halopteris scoparia were gathered in the coastal zone of Tabarka to investigate antiprotozoan activity against A. castellanii. All extracts showed parasitic inhibition with an IC50 of 3±1.8μg/mL for ethyl acetate and134,6±0.7μg/mL for hexane extracts. This could lead to the conclusion that it could be used as the best antiamoebic source [119]. Fucosterol isolated with Sargassum linearifolium from south-eastern India was investigated for antiplasmodic effect against Plasmodium falciparum (P. falciparum). IC50 values were observed at 7.48 μg/mL and 12.81 μg/mL based on the antiplasmodic effect of fucosterol against P. falciparum and chloroquine, respectively [120]. Fucoidan which is an existing polysaccharide present in Fucus vesiculosus was identified to have increased immunomodulatory activities against Schistosoma japonicum. The above results suggest the emergence of a new therapeutic mechanism initiated by a chronic parasitic infection for hepatic diseases with a higher response [121].


## 4.1. Antimicrobial Activity

The method of extraction and conditioning may affect the yield of bioactive compounds. The drying stage is crucial because high temperatures can cause the deficit of unsteady antimicrobials associated with fresh algae (terpenoid, hydrogen peroxide, bromo-ether compounds, and volatile fatty acids) [62, 63]. Improved cell membrane permeability was observed and discovered in high-temperature treated dried seaweed extracts which showed broader inhibition zones against Listeria innocua, Pseudomonas aeruginosa, Salmonella enteritidis, and Staphylococcus aureus. It was found that dried Chondrus crispus crude ethanolic extracts had a lower MIC than extracts from fresh seaweed against the growth of phytoplankton and bacterial species [64]. Similarly, during drying and hydrothermal processing, a decline was discovered in the antioxidants and the total phenolic content against H. elongate. The phytochemical content was increased, and enhanced inhibitory potential was observed by drying followed by boiling. Storage and cell wall polysaccharides attained in red, brown, and green algae, such as laminarin, alginates, carrageenans, fucans, and ulvans, can activate plant resistance pathogen control mechanisms [65]. Oligosaccharides produced by depolymerization of algal polysaccharides protect plants from bacterial, fungal, and viral infections, resulting in the accumulation of antimicrobial compounds and proteins. Cytotoxicity study against the murine cell line of macrophages RAW264.7 as well as acute toxicity test on mice indicated that the moderate doses of radioactive E. cava derivatives can be used safely by humans [66, 67]. Evidence of significant antimicrobial activity was observed in various algal species. In one study, the effect of Spatoglossum asperum brown algal solvent extracts on dermatophytes and nondermatophytes was assessed. The maximum potential of chloroform extract against the nondermatophytic fungus Aspergillus flavus was determined. The methanolic extract showed significant antifungal activity against the dermatophyte fungi Candida albicans and Candida tropicalis in relation to other solvent extracts [68]. In another study, the brown algal extracts from Laminaria digitata and Undaria pinnatifida showed the strongest antifungal activity against Botrytis cinerea on strawberries and Monilinia laxa on peaches, followed by Penicillium digitatum on lemons [69]. The different solvent extracts from algae were tested against some of the pathogenic human fungi Candida albicans, Candida parapsilosis, Fusarium sp., Aspergillus flavus, and Aspergillus fumigatus. Hexane, chloroform, and ethanolic extracts were found to be highly inhibitory against Candida albicans and Candida parapsilosis [70]. Some compounds isolated from brown seaweeds also possess certain antimicrobial activities. The phlorotannin isolated from brown seaweeds has been reported to have antifungal activity against dermal and plant fungi [71]. In the Chnoospora bicanaliculata, Sargassum wightii, Padina tetrastromatica, and Stocheospermum marginatum extracts derived from India’s southwestern shore provide credible information that brown seaweeds sustain successful antimicrobial activity [68–70]. The mechanism behind these molecules may be because they directly interact with enzyme and inhibit the action of enzymes or induce membrane permeability loss and protein leakage, where these have been exhibited by polysaccharides, polyphenols, and phlorotannins (Figure 2) [71, 72].Figure 2
Antibacterial activity of compounds of brown algae.


## 4.2. Anticancer Activity

The efficient approach for killing cancer cells is to provoke apoptosis over tumor cells. Tumor necrosis factor- (TNF-) related apoptosis-inducing ligand (TRAIL) is an integral membrane protein which can bind to membrane-bound death receptors [73]. TRAIL and its receptor binds together and transmit an apoptotic signal across their intracellular mortality zones. As a result of this, cancer cells undergoes apoptosis. On gastric cell line (AGS) of humans, the anticancer activity of ethanolic extract of Hyalogonium fusiforme (H. fusiforme) was investigated, and the findings showed that the extract (0 to 25 μg/mL) could induce apoptosis in tumor cells by upregulating the expression of TNF-α. In a recent research, it was discovered that the extracts were taken using ethyl alcohol of H. fusiforme towards the protein expression in human hepatoma cancer cells Hep3B and inhibits matrix metalloproteinase (MMP) activity and was also found to control metastasis-related and tumor invasive genes (TSP-1, claudins, IGF-1R, and E-cadherin) as well as activity-related genes of MMP (TIMP-1, TIMP-2, MMP-1, and MMP-2), which induce apoptosis in cancer cells [74]. 5-Hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone is found in the extracts of ethanol (80%) of H. fusiforme which also possesses potential anticancer activity in human's AGS and DR4 cancer cell lines [73, 75] where the compound isolated increased the apoptosis mediators connected to the death receptor like TRADD, Fas, FADD, and Fas L that were in a dose-dependent manner (Figure 3). Son et al. [76] claimed that extracts using ethanol from H. fusiforme may minimize the development of aberrant crypt foci regulated by azoxymethane in male rats. Prenoplastic damage to the colon, which result in colorectal cancers, has alluded as aberrant crypt foci [76]. Ethanol extract of H. fusiformecan also provoke apoptosis of human leukemia U937 cell lines. The outcomes of the findings stated that the apoptotic cell death in U937 cells was caused by Bcl-2 protein inhibition and downregulation in the form of IAP family members like XIAP, IAP1, and IAP2 [77, 78]. Remya et al. [79] studied the phytochemical composition and profiling of Turbinaria ornata and its antiproliferous effect against human retinoblastoma Y79 cells [79]. When compared to the existing chemotherapeutic agents, chemopreventive agents extracted from natural resources have gotten a lot of attention because of their potential to suppress cancer cell development with less or no side effects.Figure 3
Anticancer activity mechanism algal metabolites.Cytotoxic effect have been discovered in certain solvent extracts such as ethyl acetate, chloroform, and methanol from different brown algae species such asColpomenia sinuosa, Cystoseira myrica, and Sargassum swartzii, against NIH 3T3, HT-29, T47D, Caco-2, and MDA-MB468 cells [79–81]. On seven cancer cell lines, Dictyota dichotoma (D. dichotoma) extracts had strong dose-dependent cytotoxicity but were more selective on PC-3 and MCF-7. The fraction from chloroform extract of D. dichotoma had the greatest effect of cytotoxicity against CACO (IC502.71±0.53 μg/mL), PC3 (IC502.2±0.18), and MCF-7 (IC501.93±0.25), respectively. Apart from the extracts, certain bioactive components isolated from numerous brown algae showed good cytotoxic potential against cancer cell lines [82]. By increasing the ROS production, the fucoidan isolated from Sargassum cinereum brown seaweed exhibits potential apoptotic and anticancer effect on Caco-2 cells. The anticancer potential of the extracted Sargassum wightii polysaccharides have been assessed on breast cancer cell lines MDA-MB-231 and MCF7, and the polysaccharides were detected to substantially decrease the development of cancer cells [83]. At IC50 values of 11.6 and 32.0 μg/mL, a few fractional compounds and three additional linear diterpenes isolated from Bifurcaria bifurcate mildly prevented the development of the MDA-MB-231 cells [84].


## 4.3. Antioxidant Activity

Crude extracts and compounds isolated from seaweeds have been used as defenders of health, in cosmetics, and food; and antioxidant activity have been studied. Brown algae have relatively higher levels and powerful antioxidants when compared with green and red algae [85]. Antioxidant property is based on its radical or oxygen scavenging ability; chelation of metal [86] and the free radical scavenging are vital in determining the antioxidant property [87]. Phenolic derivatives (phenolic -OH) have the ability to transfer a hydrogen atom to the free radicals and form a stable product; the longevity of maintaining the stability of the product determines the antioxidant properties of the constituent isolated [88, 89] (Figure 4).Figure 4
Antioxidant activity mechanism of algal metabolites.Phenolic acids have a phenolic ring with carboxyl group [90]. Occurrence of phenolic acids, including gallic acid, catechin, caffeic acid, coumaric acid, quercetin, rutin, and kaempferol, are indicated to be present in brown algae, and the antioxidant property of these molecules have been reported [91]. The aromatic benzene ring structure of the aforementioned phenolics with -OH (hydroxyl) moieties play a crucial function in H-donation and free scavenging properties [90, 91]. Benzene ring with -CH = CH-COOH moiety has been reported to increase hydrogen donation and increase antioxidant property [92]. Phlorotannins, a hydrophilic marine algal metabolite of size from 125 to 600 kDa, which are abundant in brown algae, are classified as fuhalols (extra hydroxyl group at third ring), phlorethols (ether linkage), fucols (phenyl linkage), fucophloroethols (ether and phenyl group), and eckols (dibenzodioxin linkage) [92, 93]. These extra functional groups enhances its antioxidant property. The antioxidant potency of brown algae, namely, Anthophycus longifolius, Sargassum plagiophyllum, and Sargassum myriocystum, was assessed using various in vitro antioxidant studies. The ethyl acetate extract from Anthophycus longifolius showed extensively higher radical scavenging ability of hydroxyl radicals and have been shown to be effective in stabilizing 2,2-azino-bis-3-ethyl-benzothiozoline-6-sulphonic acid (ABTS) and also 1,1-diphenyl-2-picryl-hydrazil (DPPH) radicals. There were no substantial differences observed in the scavenging properties of hydrogen peroxide and ferrous ion chelation properties of seaweed ethyl acetate extracts [94]. Ascophyllum nodosum, Laminaria japonica, Lessonia trabeculate, and Lessonia nigrecens have been examined for their antioxidant activities. Among all four species, Ascophyllum nodosum extracts have the strongest antioxidant activity [95]. In another study, ethanol and water binary solvent system were used to produce raw extracts of edible algae Ascophyllum nodosum (A. nodosum). The extract of A. nodosumwas optimized using the Box–Behnken design and also the response surface methodology to achieve extracts with high antioxidant activity or high effectiveness. In the two optimal conditions, the antioxidant property was found to be at 74.05±0.51mL/g with respect to the yield at 53.80±1.65mg. This explains the ability of both models to predict with precision and improve antioxidant extraction using A. nodosum [96]. Padina tetrastromatica comprises a significant quantity of polyphenols that have antioxidant properties [97]. Sodium alginates that were obtained at various seasons from brown seaweed, Cystoseira schiffneri, had been checked for antioxidant activity using DPPH and Fe2+ chelating potential assays where antioxidant property varied considerably depending on the season [98].


## 4.4. Anti-Inflammatory Activity

Reactive oxygen species (ROS), at normal condition, involve in signaling pathways as a part of metabolism; mostly, ROS are produced by mitochondria during respiration [99]. When these are produced in higher level than normal, it degrades the biological macromolecules, including lipids, DNA, and proteins, which lead to abnormal cellular function including inflammation [100]. Inflammation-inducing cells mostly mast cells and eosinophils generate chemical signals leading to the release ROS, where it kindles signal transduction and induces nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2), nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). This induction leads to higher inflammation and harms healthy cells which sometimes triggers cancer cells also [99, 100]. Decreasing the expression of these aforementioned genes or any signal transduction pathways or free radical scavenging reduces the inflammatory reaction. Apo-9′-fucoxanthinone, a norisoprenoid isolated from Sargassum muticum, is effective against nitric oxide (NO) and prostaglandin E2 (PGE2) synthesis in LPS-mediated inflammation against cell line RAW264.7 where it regulates the activation of NF-κB activation by suppressing IκB-α within macrophages (Figure 5). Ethanolic and DMSO extract of Cystoseira amentacea collected from the Ligurian Sea showed a strong anti-inflammatory effect against inflammatory cytokines [101]. The brown algae Padina commersonii fucoidan- (PCF-) based sulfated polysaccharide was examined for anti-inflammatory activities and was also tested against LPS-activated RAW 264.7 macrophages. The impact found that PCF is a promising component that inhibits LPS-induced inflammatory reactions by preventing transduction of LRT/MyD88/NF-κB signals [102]. Furthermore, the fucoidan extract of Turbinaria decurrens was tested for its anti-inflammatory properties. Fucoidan had an anti-inflammatory potential with upregulation of antioxidant levels through NF-κB, thus suppressing proinflammatory genes. [103].Figure 5
Anti-inflammatory activity mechanism of algal metabolites.The anti-inflammatory activity of brown seaweeds such asCystoseira crinita (AQ-C cri), Cystoseira sedoides (AQ-C sed), and Cystoseira compressa (AQ-C com) was assessed in vivo, with carrageenan generated rat paw edema test. The extracts AQ-C cri, AQ-C sed, and AQ-C com displayed an important anti-inflammatory effect depending on the dose correlated to the reference drugs [104]. Turbinaria conoides, collected in the Gulf of Mannar, extracted with three substituted 2H pyranoids, which were showing activity against 5-lipoxygenase and cyclooxygenase-2, are found to be more effective than nonsteroidal drugs on the market [105]. In particular, phlorotannin fractions of Cystoseira sedoides (PHT-SED) collected on the Tunisian coast have been tested for pharmacological potential with other algae. A substantial anti-inflammatory potency of the fractions was performed using in vivo models at the 100 mg/kg dose against the reference drug [101].


## 4.5. Antidiabetic Activity

The antidiabetic potential of brown algae has has been studied extensively over the last few years due to the presence of several bioactive compounds. Enzymes such asα-amylase and α-glucosidase are essential in carbohydrate hydrolysis and it releases glucose; inhibiting these enzymes reduces postprandial hyperglycaemia; and inhibitors of these enzymes could be an antidiabetic drug [106]. Other enzymes including aldose reductase, protein tyrosine phosphatase, and protein tyrosine phosphatase 1B do play a major in the formation of glucose, thus its action to be blocked to prevent postprandial hyperglycaemia [105–107]. Phlorotannin has been reported to suppress the activity of α-amylase and α-glucosidase [108, 109]. The methanolic extract and fucoxanthin fraction obtained from Sargassum siliquosum and Sargassum polycystum showed inhibitory action against angiotensin converting enzymes such asα-amylase, and as well as α-glucosidase [110]. Phlorotannin eckol of Ecklonia maxima was found to be an effective α-glucosidase inhibitor [111] where pholotannins compounds like phloroeckol and dieckol from Eisenia bicyclis were inhibiting 87% acidity of α-amylase. Ascophyllum nodosum was found to be effective against both the above-mentioned enzymes [112]. Laminaria digitata's methanol extract and Undaria pinnatifida's acetone extract have shown to inhibit α-amylase with IC50 values at 0.74±0.02mg/mL and 0.81±0.03mg/mL, respectively. The 2,5-dihydroxybenzoic acid phenolic compound in both algae was an effective α-amylase inhibitor with IC50 value of 0.046±0.004mg/mL. The alginates and polysaccharides present in brown algae exhibit strong inhibitions against α-amylase with an IC50 range ranging from 0.075±0.010 to 0.103±0.017mg/mL. In general, the above results demonstrated that crude extracts, phenolic compounds, and brown edible algae alginates are strong inhibitors of α-amylase [113]. In addition, the extraction of phenolics isolated from four brown algae such as Ascophyllum nodosum, Laminaria japonica, Lessonia trabeculate, and Lessonia nigrecens have been studied for activities inhibiting pancreatic lipase and tyrosinase. Among the four algae, Lessonia trabeculate extract demonstrated strong activity towards α-amylase, α-glucosidase, pancreatic lipase, and tyrosinase inhibition activities [95]. A brown alga Padina tetrastromatica was used to isolate polyphenols and to study their antidiabetic properties. Polyphenols showed a strong α-amylase effect at IC50 value 47.2±2.9 μg and α-glucosidase at 28.8±2.3 μg of inhibitory activities [97].There are some metabolites which are active diabetes-induced models. Fucoxanthin obtained using seaweedIshige okamurae has been evaluated for oxidative stress due to high blood sugar against umbilical vein endothelial cells in vitro as well as in the zebrafish model in vivo. The two studies mentioned above has demonstrated that the isolated fucoxanthin is capable of providing protection against damage to organs and cells [114]. Antidiabetic effectiveness of oligosaccharides from brown algae named Sargassum confusum (SCO) has been evaluated in vivo with hamsters that are high in sucrose. Following the administration of SCO, the decreased levels of blood glucose levels were observed. The primary function of SCO in the antidiabetic effect was revealed by the 1/phosphatidylinositol 3-kinase and c-Jun N-terminal kinase routes of the insulin regulator receptor substrate. Thus, SCO has been used in people with obesity and diabetes for the regulation of intestinal microbiota [115]. Phlorotannins gained using Cystoseira compressawas checked for the antidiabetic effect. The results suggest that phlorotannins significantly reduced the activity of serum glucose, liver malondialdehyde, α-amylase, and glucosidase, and histopathological studies have shown that phlorotannins distinctly reduce and protect lesions in pancreatic β cells [116].


## 4.6. Antiparasitic Activity

Many terrestrial plants have been shown to have antiparasitic activity and clinically potent medicinl value, but the potential of the algae have been less explored. Thein vitro activities of Sargassum oligocystum gathered across Bushehr coast in south-west Iran against Leishmania species were estimated to be highly significant [117]. The prophylactic effect of few algal extracts from the southern coast of England were studied against parasites in the blood stage and liver stage of Plasmodium. Based on numerous extracts, Cystoseira tamariscifolia (CT) and Cystoseira baccata (CB) possessed the utmost antimalarial action of IC50 ranging in between 3.3 and 3.8 μg/mL [108]. A further study found that diterpene called eleganolone was obtained using the French algaenamed Bifurcaria bifurcate inhibiting Trypanosoma brucei and Plasmodium falciparum [109]. Similarly, the bioactivity of dichloromethane/methanol extract (DME) of Dictyota mertensii on Leishmania amazonensiswas also assessed. This indicated inhibition effect of IC50 at 71.60 μg/mL over growth of promastigote forms. DME showed toxic against the promastigote and amastigote forms that were revealed to be effective, indicating a potential agent in treatment of cutaneous leishmaniasis [118]. Brown macroalagae namelyCladostephus spongiosum, Cystoseira sedoides, Dictyota spiralis, Padina pavonica, and Halopteris scoparia were gathered in the coastal zone of Tabarka to investigate antiprotozoan activity against A. castellanii. All extracts showed parasitic inhibition with an IC50 of 3±1.8μg/mL for ethyl acetate and134,6±0.7μg/mL for hexane extracts. This could lead to the conclusion that it could be used as the best antiamoebic source [119]. Fucosterol isolated with Sargassum linearifolium from south-eastern India was investigated for antiplasmodic effect against Plasmodium falciparum (P. falciparum). IC50 values were observed at 7.48 μg/mL and 12.81 μg/mL based on the antiplasmodic effect of fucosterol against P. falciparum and chloroquine, respectively [120]. Fucoidan which is an existing polysaccharide present in Fucus vesiculosus was identified to have increased immunomodulatory activities against Schistosoma japonicum. The above results suggest the emergence of a new therapeutic mechanism initiated by a chronic parasitic infection for hepatic diseases with a higher response [121].


## 5. Conclusion

Due to the rise in interest in natural products, especially those extracted from marine species, marine seaweeds have become the subject of intense research because of the proven capacity of brown algae to synthesize a vast array of secondary metabolites. The marine ecosystem, which includes a diversified spectrum of algal species, may be a better means of exploring new therapeutics. Establishing modern and innovative brown algae cultivation methods to increase the variety of cultivable isolates and shorten the cultivation time might be fruitful in obtaining significant amounts of cells for greater efficiencies and improved target molecular production. The key breakthroughs in isolating, extracting, and characterizing new metabolites and their structure may assist in effectively evaluating their therapeutic potential and biological activities. Furthermore, macroalgae are expected as an essential raw material in the manufacturing of vitamins, amino acids, or other pharmaceuticals. Therefore, macroalgae cultivation can offer comprehensive insights into their biotechnological implications and practical uses, which may aid in the production of the compounds with therapeutic potential. The insight into the brown algae phytoconstituents shows that this vast community of marine algae is not only used for the production of food and fodder, but also as a huge source of secondary metabolites. The present review completely focused on the biologically active metabolites of brown seaweeds, which have far more functional characteristics than green and red seaweeds since Phaeophyta community is the key representative of fucoidans and polysaccharides that are accountable for their influential biological processes. It was observed that the varieties and concentrations of secondary metabolites altered by species are influenced by environmental conditions. Multiple mechanisms of action stimulate the production of biologically active secondary metabolites utilizing brown algae that precisely enhance the bioactivity and thus promote the development of drug production by pharmaceutical industries. As a result, efficient research on this population of brown seaweeds will aid in the development of novel drug molecules that can be used to treat numerous lethal human diseases.



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*Source: 9104835-2022-05-06.xml*