Pharmacological and natural products diversity of the brown algae genus Sargassum

Sargassum (F. Sargassaceae) is an important seaweed excessively distributed in tropical and subtropical regions. Different species of Sargassum have folk applications in human nutrition and are considered a rich source of vitamins, carotenoids, proteins, and minerals. Many bioactive compounds chemically classified as terpenoids, sterols, sulfated polysaccharides, polyphenols, sargaquinoic acids, sargachromenol, and pheophytin were isolated from different Sargassum species. These isolated compounds and/or extracts exhibit diverse biological activities, including analgesic, anti-inflammatory, antioxidant, neuroprotective, anti-microbial, anti-tumor, fibrinolytic, immune-modulatory, anti-coagulant, hepatoprotective, and anti-viral activities. This review covers the literature from 1974 to 2020 on the genus Sargassum, and reveal the active components together with their biological activities according to their structure to create a base for additional studies on the clinical applications of Sargassum.


Introduction
Marine natural products have been characterized by their chemical structural diversity, along with different biological activities. The Red Sea is considered one of the most important marine hotspots comprising high biodiversity. Many marine algae are native to the Red Sea, which could be classied into brown algae (Phaeophyta), green algae (Chlorophyta), and red algae (Rhodophyta). Brown seaweeds are predominantly brown in color because of their contents of carotenoid fucoxanthin and polysaccharides, namely alginates, laminarins, fucans, and cellulose. Green seaweeds are characterized by their chlorophyll a and b content with ulvan being the major polysaccharide. While, in red seaweeds, the principal pigments are phycoerythrin, phycocyanin, and the primary polysaccharides are agars and carrageenans. 1 Also, marine algae are rich sources of structurally diverse bioactive compounds with various biological activities, although only a few species have been chemically examined in the last decades. 1 Sargassum (F. Sargassaceae), of the order Fucales, subclass Cyclosporeae, and class Phaeophyceae, is a genus of brown algae, communally known as gulfweed or sea holly, and is considered one of the most complex Phaeophyceae genera. 2 Sargassum was discovered by Agardh in 1820 and is reported to contain 537 species names in the algae database, of which 358 species have been accepted taxonomically. 2 It comprises many different species that are distributed worldwide, although primarily found in tropical and subtropical marine waters, and also generally growing on rocky reefs.
Sargassum thallus (10-200 cm) may be linear or bushy, with stipes 1-20 cm long arising from a discoid-conical holdfast, and do not penetrate the substratum. Its main axes are perennial, short, and cylindrical or attened in sections, and bear the scars of deciduous branches. The shape of the leaves can be simple, bid, or divided several times, round, spatulate, turbinate, lanceolate, ovoid, linear or of any intermediate form with air bladders (vesicles) normally present, subspherical to the ovoid, petiolate, mutic or apiculate, replacing the ramuli or axillary to the laterals. The basis of the leaves is rounded or attenuate, symmetrical or not. The pedicel may be variable in length, cylindrical, or attened in sections and smooth. The leaves margin may be simple or doubled at the apex, and may be smooth, undulated, nely serrated, deeply dentated, or any intermediate aspect. The midrib may be short and thick or thinner and reaching the apex or any intermediate length. The apex may be acute, rounded, or truncated, simple, or showing a cup-like shaped depression (Fig. 1). 2 A survey of folk uses of Sargassum spp. in the last 20 years period (1977)(1978)(1979)(1980)(1981)(1982)(1983)(1984)(1985)(1986)(1987)(1988)(1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996), showed that different regions in the tropical country use the brown seaweed differently. Commonly, Sargassum spp., is used as a cover or wrapper of sh to maintain their freshness. In the Ilocos Region in the Northern Philippines, Sargassum spp. is used as a vegetable; whereas in the Visayas and Northern Mindanao, natives utilize Sargassum spp. as a fertilizer, ower inducer, and insect repellant. The Boholano people also use the brown seaweed as animal feed. In certain parts of the island of Bohol, a Sargassum drink is made and is reported to have health benets. 1 For nearly 2000 years, Sargassum spp. has been also used in Traditional Chinese Medicine (TCM) to treat a variety of diseases, including thyroid. 1 Although Sargassum has not attracted the attention of most researchers, the therapeutic potentials of pure compounds isolated from Sargassum are promising for their antiviral, antimicrobial, cytotoxic, antipyretic, anti-inammatory, cardioprotective, hepatoprotective, and hypolipidemic properties. 3 Some metabolites, such as embelin, tanacetol A, and oxygenated fucosterols, have attracted great attention because of their uncommon structural complexity and interesting pharmacological properties. 1,3 Some species are economically important, especially in the food, textile, cosmetics, and pharmaceutical industries. This review covers the literature on the genus Sargassum along with its chemical and medicinal potential.

Sargassum angustifolium
S. angustifolium, commonly known as narrow leaf Sargassum weed, is widely distributed around the Western Indian Ocean. 4 The n-hexane, dichloromethane, and n-butanol fractions isolated from S. angustifolium, collected from the Persian Gulf, were reported to have a cytotoxic effect against HeLa (cervical cancer) and MCF-7 (breast cancer) cells, where the cell survival was inversely proportional to the increase in the concentration of the different extracts, respectively, from 150 mg mL À1 to 900 mg mL À1 . The, n-hexane fraction was shown to have a median growth inhibitory concentration value (MIC) of 71 and 77 mg mL À1 , against HeLa and MCF-7, while the MIC of the dichloromethane fraction was 36 and 88 mg mL À1 , respectively. The n-butanol fraction showed an MIC of 25 mg mL À1 against MCF-7. 4 Sulfated polysaccharides isolated from S. angustifolium were reported to have potent immuno-stimulant activity, through inducing RAW264.7 macrophage cells to release nitric oxide, IL-1b, TNF-a, IL-6, IL-10, and IL-12 through activation of the NF-kB and MAPKs signaling pathways. 5 Also, the phosphate buffer extract of S. angustifolium had a low a-amylase inhibition activity with an IC 50 of 1.85 mg mL À1 . 6 3. Sargassum aquifolium GC-MS of a crude petroleum ether extract of S. aquifolium (Turner), collected from the Red Sea of Jazan (KSA), was reported containing phenol, 2,4-bis(1,1-dimethylethyl) 1, phenol, 2,2 0 -methylenebis[6-(1,1-dimethylethyl)-4-methyl 2, stigmasta-5,24(28)-dien-3-ol, (3á,24Z) 3, and stigmasterol 4 (Fig. 2). 7 The crystals of a petroleum ether extract of S. aquifolium dissolved in Millipore water were tested for antibacterial activity against S. aureus, S. pyogenes, B. subtilis, E. coli, P. aeruginosa, and K. pneumonia. The maximum antibacterial activity was exerted against E. coli, with an MIC of 100-150 mg mL À1 . 7 L-Fucose, Dgalactose, D-mannose, D-glucuronic acid, D-xylose, and sulfate were found to be the main constituents of fucoidan detected in S. aquifolium, collected from Vietnam, with anticoagulant,  cytotoxic, and antitumor activities, which increase with sulfation. 8

Sargassum cinereum
Fucoidan was detected in S. cinereum, collected from Tuticorin Lat. (India). Fucoidan was reported to contain 65.753% of Lfucose and 3.7% AE 1.54% of sulfate, respectively, with a monosaccharide composition, such as L-fucose, D-galactose, Dmannose, and D-xylose. The maximum 2,2 0 -diphenyl-1picrylhydrazyl (DPPH) scavenger activity for the fucoidan extract was found at the concentration of 100 mg, whereas the crude extract of S. cinereum showed 63.58% AE 0.56% scavenging activity. Fucoidan extract showed 50% cell death aer 24 h of incubation (75 AE 0.9037 mg mL À1 ) against the colon cancer cell line HCT-15. 17 The mechanism of fucoidan was a dosedependent inhibited growth of the colon cancer cell line Caco-2, (IC 50 ¼ 250 mg mL À1 ), the increased production of reactive oxygen species (ROS), and augmented mitochondrial membrane permeability. 18

Sargassum cristaefolium
Sodium alginate was detected in S. cristaefolium, collected from Poteran Island (Indonesia). This alginate had a molecular weight of 217.94 AE 7.14 kDa with a mannuronic acid to guluronic acid ratio (M/G) of 0.28, and the L-guluronic acid block was 0.78, which was higher than the D-mannuronic acid block. 20

Sargassum dentifolium
Polysaccharide extracts of S. dentifolium collected from the Red Sea (Egypt) had a protective effect against cyclophosphamide (CP)-induced genotoxicity in mice bone marrow cells (BMCs). 21 Also, the ethanol extract of S. dentifolium, reported as hepatoprotective in carbon tetrachloride (CCl 4 )-induced hepatitis in rats, had antioxidant activity. 22

Sargassum filipendula
Heterofucan extracted from S. lipendula was shown to have antiproliferative and apoptosis activities against human cervical cancer (HeLa) cells, at a concentration of 0.1 to 2.0 mg mL À1 . 24

Sargassum fluitans
The in vivo anti-brotic effect of a fucoidan extract of S. uitans (chemically composed of carbohydrates, sulfates, uronic acids, protein, and phenols), collected from Puerto Morelos (Mexico), was detected in a CCl 4 -induced liver damage model in rats. The daily oral administration of fucoidan extract (50 mg kg À1 ) showed a signicant reduction in liver enzymatic activity, liver inltration of inammatory cells, collagen ber deposition, and gene expression cytokines. 25

Sargassum fulvellum
Grasshopper ketone 32 was detected in an ethanol extract of S. fulvellum (SFEE) collected from Jindo (Korea). Grasshopper ketone 32 and SFEE were investigated on 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD)-like skin lesions in BALB/c mice. SFEE and grasshopper ketone 32 were found to have an inhibitory effect on AD by regulating immune mediators and cells and thus may be a potentially effective alternative therapy for AD. 26 Boiling water, ethanol, and dichloromethane extracts of S. fulvellum, collected from Wando aquaculture farm (Korea), were tested for anti-inammatory, antipyretic, and analgesic activities in mice. The dichloromethane extract (0.4 mg per ear) signicantly inhibited the inammatory symptoms of mouse ear edema by 79.1%. 27 Pheophytin A 33 was detected in S. fulvellum collected from the Japanese coastline. When PC12 cells were treated with a low concentration of pheophytin A 33 (3.9 mg mL À1 ) in the presence of a low level of nerve growth factor (10 ng mL À1 ), the compound produced neuritis outgrowth similar to that produced by a high level of nerve growth factor (50 ng mL À1 ). Pheophytin A 33 also enhanced signal transduction in the mitogen-activated protein kinase signaling pathway, which is also induced by nerve growth factor.

Sargassum fusiforme
The polysaccharide fraction detected in S. fusiforme collected from Qingdao (China) consisted of L-fucose, D-mannose, Lrhamnose, D-glucose, D-galactose, and D-glucuronic acid with different molar ratios. Regarding the hypoglycemic and hypolipidemic effects, the oral administration of these polysaccharide fractions prominently restrained the loss of body weight and increase of water intake, and also signicantly controlled the increase in the levels of fasting blood glucose of diabetic rats, as well as showed better effects in controlling fasting blood glucose, alanine aminotransferase (ALT), uric acid (UA) and urea nitrogen (BUN) levels. 31 The polysaccharide also showed a signicant protective effect against ultraviolet B (UVB) radiation in hairless Kun Ming (KM) mice. 32

Sargassum hemiphyllum
A hot-water extract of S. hemiphyllum collected from the coast of Penghu County (Taiwan) was found to have antioxidant activity and immune-stimulating activities when using HB4C5, and J774.1 cells. The antioxidant activity increased with a concentration <3.5 mg mL À1 . The HB4C5 cells showed the maximum relative activities of cell proliferation (174%) and IgM secretion (132%) with 120 mg mL À1 of the hot-water extract at 80 mg mL À1 , while J774.1 cells showed the maximum relative activities of cell proliferation (141%) and phagocytosis (147%). 35 The major polyphenols (17.35 AE 0.93-36.66 AE 2.01 mg g À1 ) were extracted using water, ethanol, and acetone (WES, EES, and AES, respectively) for S. hemiphyllum. The inhibition of a-amylase, aglucosidase, sucrose, and maltase activities and stimulation of insulin secretion were greater with AES than with WES or EES. Moreover, 250 mg mL À1 EES and AES signicantly increased insulin secretion in the presence of 25 mg mL À1 glibenclamide compared to with 50 mg mL À1 glibenclamide. 36 Sulfated polysaccharide extracted from S. hemiphyllum (SHSP) was detected on the mouse macrophage cell line (RAW 264.7) activated by lipopolysaccharide (LPS), which can used as a model system. The secretion proles of pro-inammatory cytokines, including IL-1b, IL-6, TNF-a, and NO, were found to be signicantly reduced in 1-5 mg mL À1 dose ranges of SHSP treatments, in which the anti-inammatory properties of SHSP may be attributed to the downregulation of NF-kB in the nucleus. 37

Sargassum kjellmanianum
(+)-Kjellmanianone 49 (Fig. 4), is a highly oxygenated cyclopentenone isolated from S. kjellmanianum collected from the Bay of Hiroshima (Japan), and was shown to have moderate antibacterial activity against E. coli and B. subtilis var. niger, Gram-positive microorganisms. 43 Sargassumlactam 50 ( Fig. 4) was also detected in S. kjellmanianum and was shown to have a moderate antibacterial effect against S. aureus and E. coli. 44 An aqueous extract of S. kjellmanianum collected from Hahakimoku (Japan) was effective in the in vivo growth inhibition of implanted Sarcoma-180 cells, but showed no effect against L-1210-bearing mice. Polysaccharide fractions containing Lfucose and ester sulfate in the amounts of 12.6%, and 15.4%, 23.5%, and 17.2%, respectively, were extracted from S. kjellmanianum. The sulfated polysaccharide was effective against L-1210 leukemia with an ILS value of 26%. 45 The in vitro immuneregulatory and anti-tumor activities of sulfated polysaccharides from a hot-water crude extract of S. kjellmanianum (SKP) were detected; the polysaccharides were composed of L-fucose, Dgalactose, D-xylose, and D-mannose. All three types of polysaccharides were sulfated, with the sulfate group accounting for 3.4%, 25.6%, and 29.9% of SKP1, SKP2, and SKP3, respectively. SKP2 and SKP3 signicantly enhanced the immune function of immunocytes, and SKP2 increased the proliferation rate of spleen lymphocytes and peritoneal macrophages by up to 53.56% and 51.41%. Cell culture showed that SKP1, SKP2, and SKP3 all inhibited the proliferation of HT-29 and HeLa cells. 46

Sargassum ilicifolium
The anticonvulsant activity of S. ilicifolium collected from Bhatkarwada (India) in maximal electroshock (MES)-and pentylenetetrazole (PTZ)-induced convulsion in mice was detected. Chloroform (600 mg kg À1 ) and ethanol extracts (400 mg kg À1 and 600 mg kg À1 ) of S. ilicifolium signicantly downregulated the duration of tonic hind limb extension in a maximal electroshock (MES) model and upregulated the latency to the onset of convulsions in a pentylenetetrazol (PTZ) model. These results were comparatively similar to the effects of phenytoin (25 mg kg À1 ) and phenobarbitone (20 mg kg À1 ). 47

Sargassum integerrimum
Heteropolysaccharides were detected in S. integerrimum, and were shown to have neuroprotective and antioxidant activities. 48

Sargassum linifolium
The carbohydrate moiety of sargassan involves a backbone chain of D-glucuronic acid and D-mannose residues, and side chains involving residues of D-galactose, D-xylose, and L-fucose with sulfate attached to some galactose and fucose residues were detected in S. linifolium collected from Alexandria (Egypt). 51

Sargassum macrocarpum
Sargafuran 54 (Fig. 4) was detected in a methanol extract of S. macrocarpum, collected from north to south along the Japanese coastline, and showed activity against Propionibacterium acnes, with an MIC of 15 mg mL À1 . 52 Sargachromenol 55, isolated from S. macrocarpum, had a marked nerve growth factor (NGF)dependent neurite outgrowth promoting activity to PC12D cells with a median effective dose (ED 50 ) of 9 mM, against PC12D cells in the presence of 10 ng mL À1 NGF. Sargachromenol 55 signicantly promoted the survival of neuronal PC12D cells at 0-50 ng mL À1 NGF in a serum-free medium. 53 Tuberatolide B 56 (Fig. 4) is a diastereomeric meroterpenoid detected in S. macrocarpum, and inhibits tumor growth in breast, lung, colon, prostate, and cervical cancer cells, and suppresses cancer progression by promoting the ROS-mediated inhibition of STAT3 signaling. 54 The anti-inammatory effects of an extract of S. macrocarpum (SME), collected from Jeju Island (Korea), in bone marrow-derived macrophages (BMDMs) and dendritic cells (BMDCs) were detected. Primary BMDMs and BMDCs were used for cytokine production and western blot analysis. SME (0-50 mg mL À1 ) pre-treatment led to a strong inhibitory effect against IL-12 p40, IL-6, and TNF-a, production in CpGstimulated BMDMs and BMDCs. SME pre-treatment caused a strong inhibitory effect against NF-kB activation. 55 29. Sargassum mangarevense S. mangarevense collected from Tahiti contained alginate (9.3% AE 1.7% dw, M/G ¼ 1.42 AE 0.24), mannitol (12.2% AE 2.1% dw), and phenolic contents (2.85% AE 1.12% dw). The aqueous and ethanol extracts of S. mangarevense showed antimicrobial activity against S. aureus with MICs of 9.5 and 12.5 mm, respectively. 56

Sargassum marginatum
The growth inhibition of human pro-myelocytic leukemia (HL-60) cells by lipid extracts of S. marginatum collected from Goa (west coast of India) was detected with special reference to the fatty acid composition. PL exhibited cytotoxic activity at concentrations <20 mg mL À1 . 57

Sargassum myriocystum
Sulfated polysaccharides extracted from S. myriocystum (SMP) were investigated for gentamicin-induced nephrotoxicity in adult zebrash. The SMP showed maximum carbohydrate, sulfate and L-fucose contents, which suppressed mRNA expression levels of KIM-1, NF-kB, TNF-a, and IL-6 in a dosedependent manner. 67

Sargassum natans
Sodium alginate was detected in S. natans collected from both Manzanilla and Mayaro Bays (Trinidad). 70

Sargassum patens
The anti-inammatory effect of an ethanol extract of S. patens (SPEE) collected from Busan (Korea) was detected. The production of NO was suppressed by SPEE to 28%, at 100 mg mL À1 , and the levels of IL-6, TNF-a, and IL-1b were dosedependently suppressed. In vivo, a croton oil-induced mouse ear edema was attenuated by SPEE and the inltration of mast cells into the tissue was suppressed. 74 A sulfated polysaccharide was detected in S. patens, and was reported to inhibit the replication of herpes simplex virus type 2 (HSV-2) in a dosedependent manner by 38.5-96.1%, of the control level, aer incubation with 0.78-12.5 mg mL À1 of the polysaccharide. The sulfated polysaccharide exhibited extracellular virucidal activity only in high concentrations ($12.5 mg mL À1 ), but suppressed the virus attachment to its host cells by 45.1%, at a concentration < 1 mg mL À1 . 75  (Fig. 6). 77

Sargassum polycystum
The total yield of fucoidan isolated from S. polycystum was 4.51 AE 0.24%, and contained 46.8% of L-fucose and 22.35% AE 0.23% of sulfate respectively. The cytotoxicity effect of fucoidan, showed a higher percentage (90.4% AE 0.25%) of inhibition against the MCF-7 cell line, at 150 mg mL À1 , with an IC 50 of 50 mg mL À1 . 78

Sargassum ringgoldianum
An extract of S. ringgoldianum collected from Jeju Island (Korea), showed the inhibition of a-glucosidase and a-amylase, and alleviated postprandial hyperglycemia in streptozotocininduced diabetic mice. The IC 50 values of S. ringgoldianum extract against a-glucosidase and a-amylase were 0.12, and 0.18 mg mL À1 , respectively. The blood glucose levels of the S. ringgoldianum extract in the administered group were signicantly lower in the streptozotocin-induced diabetic mice compared to in the control group. 79

Sargassum serratifolium
An ethanol extract of S. serratifolium collected from Busan (Korea) ameliorated paw swelling, reduced the arthritis score, decreased the secretion of pro-inammatory cytokines in the serum and joint tissue, and suppressed the collagen-induced rheumatoid arthritis of mice. The ethanol extract showed a downregulated This journal is © The Royal Society of Chemistry 2020 RSC Adv., 2020, 10, 24951-24972 | 24959 NF-kB signaling pathway by suppressing the phosphorylation of protein kinase B, c-Jun N-terminal kinase, and p38 mitogenactivated protein kinases. 86 An ethanol extract of S. serratifolium exhibited potential antimicrobial activity against pathogenic commensal bacteria related to acne vulgaris (P. acnes, S. epidermidis, S. aureus, and P. aeruginosa), and C. albicans, which causes cutaneous candidiasis. Among the solvent-soluble fractions from the ethanol extract, the n-hexane fraction showed the strongest antimicrobial activity against all the tested human skin pathogens (MIC from 32 to 512 mg mL À1 ). 87 An ethanol extract of S. serratifolium, collected from Tongyoung (Korea), which mainly contained sargachromenol 55 and sargaquinoic acid 57, efficiently suppressed adipocyte differentiation and lipid accumulation in 3T3-L1 cells by downregulating the proteins involved in cell cycle progression and adipogenesis, and also downregulated the key transcription factors, such as C/EBPb, C/EBPa, PPARg, RXRa, SREBP1c, and STAT3, which were responsible for the observed suppression of lipid accumulation upon treatment with an ethanol extract of S. serratifolium. 88

Sargassum siliquosum
Methanol extracts of S. siliquosum (ME) and a fucoxanthin-rich fraction (FRF) showed antioxidant activity, with IC 50 values of 0.2, and 0.04 mg mL À1 , respectively. Also, the IC 50 values for the angiotensin-converting enzyme (ACE) inhibitory activity of ME (IC 50 ¼ 0.03-0.42 mg mL À1 ) was lower than that of FRF (0.94-1.53 mg mL À1 ). CE and FRF also showed a-glucosidase inhibitory activity, with IC 50 values of 0.57, and 0.50 mg mL À1 , respectively. 95

Sargassum vachellianum
Fucoidan-rich polysaccharide extract (SPS) and polyphenol-rich extract (SPP) from S. vachellianum, collected from Nan'ao Island (China), showed a protective effect on the skin from UV damage. SPP showed good free radical scavenging ability, antimicrobial activity against E. coli and S. aureus, and effectively absorbed UVB and UVA rays. Whereas SPS hardly absorbs UVA and UVB rays and showed weak free radical scavenging ability and no antimicrobial activity. SPS showed considerable inhibition of tyrosinase (51.21%) and had better moisture absorption (52.1%) and retention (63.24%) abilities than SPP. 113 (4Z,9Z)-4-Methyl- Fig. 9 Chemical structures of compounds 142-162.

Conclusion
Sargassum is an important seaweed that is widely and excessively distributed in tropical and subtropical regions and has been reported to contain 537 species, with 358 of them accepted taxonomically. Sargassum species are used in many folk applications in human nutrition and are considered a rich source of vitamins, carotenoids, proteins, and minerals. Signicant progress has been detected in the publication rates of studies mentioning the genus Sargassum over the past ve years (Fig. 11), with many bioactive compounds reported with diverse chemical structures, from oxygenated cyclopentene, farnesylacetone, glycerol derivatives, plastoquinones, hydrocarbons, fatty acids, amino acids, to meroditerpenoids, meroterpenoids, sterols, polyphenolic, and sulfated polysaccharides (Fig. 2-10).
According to the reported data concerning the phytochemical metabolites identied in the different Sargassum spp., the sulfated polysaccharides and polyphenolic compounds represent 27% and 20% of the major isolates, followed by meroterpenoids, sterols 9%, meroditerpenoids 8%, and amino acids 6%, reecting their history as a nutrient in folk use (Fig. 11). These isolated compounds and/or extracts exhibit diverse biological activities; such as skin protection for the polysaccharide rich extract of S. vachellianum, and S. fusiforme, whereas the polysaccharide hardly absorbs UVA, UVB rays, and has shown considerable inhibition on tyrosinase (51.21%), as well as better moisture absorption (52.1%) and retention (63.24%) abilities. Also, Sargassum spp. contains mainly sulfated polysaccharides, and polyphenolic compounds (Fig. 11) and 24x-hydroperoxy-24vinylcholesterol 24 were reported to have cytotoxic activities against HL-60, with IC 50 values of 7.8 and 8.5 mg mL À1 , respectively. While, fucosterol 5 and 24-ethylcholesta-4,24(28)dien-3,6-dione 23 showed potent cytotoxic activities against P-388, with IC 50 values of 0.7 and 0.8 mg mL À1 , respectively. Sargachromanol R 126 had potent cytotoxic activity against AGS, HT-29, and HT-1080 cell lines, with IC 50 values of 6.5, 3.4, and 13.9 mg mL À1 , respectively, compared with paclitaxel and This journal is © The Royal Society of Chemistry 2020 RSC Adv., 2020, 10, 24951-24972 | 24965 doxorubicin. Also, fucoidan extracted from S. glaucescens, S. siliquosum, S. swartzii, S. tenerrimum, and S. pallidum exhibited antioxidant activities in a dose-dependent manner against DPPH. A hot-water extract of S. hemiphyllum collected from the coast of Penghu County (Taiwan) had antioxidant activity and an immune-stimulating one. The antioxidant activity was showed to be increased related to a concentration <3.5 mg mL À1 . Heteropolysaccharides extracted from S. integerrimum were shown to have neuroprotective and antioxidant activities. Sargachromanol A-P 109-124, isolated from S. siliquastrum, exhibited signicant antioxidant activity in the DPPH assay. Sargachrominol 55, sargaquinoic acid 57, sargahydroquinoic acid 94, and sargathunbergol A 143 were detected in S. thunbergii, and showed antioxidant activities (EC 50 values of 32, 27, 20, and 38 mg mL À1 respectively), compared to BHT (EC 50 ¼ 42 mg mL À1 ) and a-tocopherol (EC 50 ¼ 23 mg mL À1 ). Also, thunbergol A 144, and thunbergol B 145, isolated from S. thunbergii, were showed to scavenge DPPH radicals, with EC 50 values of 30 and 31 mg mL À1 , respectively. Additionally, an extract of S. fulvellum (SFEE) and grasshopper ketone 32 was shown to have an inhibitory effect on atopic dermatitis (AD)-like skin lesions in BALB/c mice by regulating immune mediators and cells and may be a potentially effective alternative therapy for AD. The sulfated polysaccharides from a hot-water crude extract of S. kjellmanianum showed an immune-regulatory effect, through the enhanced immune function of immunocytes and increased the proliferation rate of spleen lymphocytes and peritoneal macrophages up to 53.56% and 51.41%. Sargassum spp., isolated compounds and/or extracts, also exhibited anti-diabetic, brinolytic, anti-coagulant, hepatoprotective, and anti-viral activities. Despite the wide diversity in the reported biological activates for Sargassum spp., only 54/537 species, representing about 10.05% from the species accepted taxonomically, were detected as having chemically and pharmacologically relevant activities. Consequently, further studies on the remaining species, their constituents, and biological activities are needed to exploit their maximum therapeutic potential in the eld of medicinal and pharmaceutical sciences for novel and fruitful applications.
In 2007, the genus Sargassum extracts were the focus of a patent as a cosmetic product (KR1020090064079A) for their activities in lowering photo-induced cytotoxicity, whitening effect, inhibiting MMP-1 biosynthesis in human broblasts, and promoting the synthesis of biosynthesis type 1 procollagen, thereby improving skin elasticity and ne wrinkles, and effectively inhibiting the photo-aging phenomenon promoted by ultraviolet rays, etc. 120 Specially Sargassum horneri (KR1020120065631A), which has a deep relation to the photoaging inhibitory effect on skin cells using the chromenes compound derived from it, increased the expression of collagen synthesis markers, such as procollagen and type I collagen in UV-A treated broblasts, and also enhanced elastin by modulating elastase activity, and thus could be used as a material and cosmetic for improving skin wrinkles and preventing wrinkles by UV. 121 Also, Sargassum natans was part of a patent for removing gold ions from aqueous solution or suspension using a biomass-derived from it, and this process can be utilized to remove gold from industrial or natural waters.